cargo cult scientist

Our New Business Models

2012-02-14T14:27:00.000-08:00

While scientists toil away in their offices directing the bachelor degreed underlings to run western blots and ELISAs in their laboratories, the businessmen have been trying to solve even bigger problems. How to make money from the directing and toiling.

A few business model concepts were discussed on Xconomy this week. Stewart Lyman and Connie Wong both had interesting articles.

My own take on what is going on these days comes from the lessons learned from Amgen. The book, "800 Million Dollar Pill" begins with a discussion of how Amgen began. It tells the story of the discovery of erythropoietin, or EPO by Eugen Goldwassser. After pitching his product to numerous companies, Applied Molecular Genetics finally bought in, which they advanced by cloning the first cell line that produced recombinant EPO. Prior to the Amgen deal in 1983, Goldwasser spent 25 looking for and researching EPO. The discovery was the result of a government-funded research that began as a Cold War experiment to cure radiation sickness. According to Goldwasser,

Private companies rarely support that kind of research. It takes too long, and the odds of success are even longer.

How did Amgen and Goldwasser come to the conclusion that this product could be used for anemia? GoozNews.com (Merril Goozner, author of 800 Million Dollar Pill) posted a brief history of Goldwasser upon his death in 2010. One commenter, Phil Peckham, pointed out the work of two other scientists whom advanced Goldwassers research into the realm of a marketable drug candidate.

In the basement of the first outpatient kidney center in Seattle, Joseph Eschbach and John Adamson do experiments on sheep. As I understand it they exsanguinated one set of sheep thereby inducing amemia. They then collected the EPO rich plasma from the sheep with induced anemia and infused it into a a sheep (I believe named Dolly) that they had induced anemia by removing the kidneys and then sustained via dialysis.

The EPO rich plasma reversed the anemia in Dolly.

Sheeps urine plays a role too but I am not exactly sure – one reason I’d love to read the order of events after an actual journalist looked into it – but this was all happening in ’70s. I suspect that their experiments with sheep, if nothing else, gave the green light to Goldwasser to use his precious sample.

One thing to note is that Eschbach had a large practice during the day. He was the Medical Director of the first home hemodialysis program at Northwest Kidney Centers and followed many patients through his practice at Minor and James a large Seattle medical practice. Imagine your doctor working nights to solve a problem that plagues you and everyone else on dialysis. And then succeeding.

I would love to see an authoritative version of the story. In 2007 Kirin Amgen (I think they initially funded Amgen) established the Joseph W. Eschbach Endowed Chair in Kidney Research at the University of Washington.

The story is one of science that dates all the way back to 1906, if one wanted to write this story.

Amgens success was the result of so many factors it is hard to imagine reproducing that success story. Remove one the many pieces of the puzzle and maybe you don't get the success. It would be like removing a piece of the puzzle from a Sherlock Holmes novel. There are many logical errors found in Sherlock Holmes novels that are elementary logical fallacies. Which brings us back to biotechnology business models.

In Stewart Lymans piece he talks about our ecosystem. One of the members of our ecosystem are the businessmen, who get to make the big decisions. The story of Goldwasser highlights how several groups of businessmen (companies) passed on this opportunity. In my opinion businessmen are businessmen. They excel at talking in meetings and advancing their own careers. Scientists, another part of the ecosystem are different than the businessmen, or at least they used to be. Many of the businessmen today are PhD'd and/or M.D.d individuals. They get to make the big decisions because they have studied how to use the big words that come out of science. But not scientifically. In our ecosystem, the businessmen should listen to the scientists, not tell them what to do.

In Connie Wongs piece she talks about sharing "the words" that come from scientists. The Amgen story is about people, dating back to 1906, who ran experiments and came to the conclusions needed to make Amgen a drug. The science decisions were not business decisions. Part of the Amgen success story is science. There are many branches on this family tree, most of which lead to nowhere. But through the persistence of the scientific process, EPO emerged. Through technology, a recombinant form of the protein emerged that could be manufactured and administered by doctors into patients, two more members of our ecosystem. The businessmen, yet another piece of our ecosystem, made some pretty shrewd, although underhanded, deals with the government that led to the most successful biotech company in our history. All of the branches of the tree succeed by building off of the information of others.

When we look at the work put into making Amgen who they are today, we see that many people are involved. Luck is involved. Randomness, as always, rules our lives. Business models are best described by the ideas put for in "A Drunkards Walk". Perhaps we need to abandon business and once again get back to researching the cell and the human body, without dreaming of fortune and fame. One group studies function, the next studies an application, the next manufacturing, the next clinical and so on. The businessmen are merely one piece of the puzzle. They have a long history of making more bad decisions than good. One of the decisions has been to create a minefield in the career paths of those who conduct the scientific research that leads to products like EPO.

To use another analogy stemming from the biotech ecosystem, I think of the industry like a field of soybeans. The soybeans cannot grow without trees that prevent soil erosion and cleanse the air. Only the soybeans can be sold on the market however. After the harvest the farmer drives his soybeans into town and sells them. He sits at the bar counting his annual pay. It's never enough. He decides to remove the trees to make room for more soybeans.

Marina Biotech, RNAi's 2nd Hit of 2012

2012-02-14T11:31:00.000-08:00

Marina Biotech, formerly MDRNA, formerly Nastech, a world leader in RNAi drug development, formerly a world leader in nasal sprays, has announced the closing of their Cambridge facility. The Cambridge facility was formerly known as Cequent.

The closing of the Cambridge site is consistent with our continued efforts to reduce our cash utilization. The individuals affected by this decision were all part of the former Cequent team who then, and certainly over the past several years, were instrumental to the development of CEQ508 and the successful execution of the START-FAP trial. I want to thank them for their efforts and wish them all well in their future endeavors."

Translation: This failure is consistent with our failing management and wasteful spending of other peoples money. We're sacking the Cequent staff as planned. Thanks for CEQ508 and starting the clinical trial. We'll take it from here and fuck it up. So long suckers!

But of course this is RNAi. In an industry that pigeon holes employees, puts them in silos, this is a blow. There are no RNAi jobs out there. RNAi is a passing fad, one that sucked billions out of biotechnology and made a small handful of Cargo Cult leaders very wealthy. There will never be a useful RNAi drug on the market. The RNAi job market can be best described as a falling knife. If you have a notion to enter this field, think again. If you have a chance to get out, do so. The Cequent folk can now move along, but where? It is tough out there. Good luck indeed.

Micheal French and his cult are following the lead of John Maraganore at Alnylam. Sack the scientists to save money for clinical trials. It is the Hail Mary for RNAi. The scientists have all been sent home. The remaining RNAi money will be spent on clinical trials.

M. French, April Fools Day, 2010

We are very excited to bring to MDRNA the unparalleled expertise and commitment of the Cequent team."

M. French, Valentines Day 2012

I want to thank them for their efforts and wish them all well in their future endeavors."

Formatechs Yard Sale

2012-02-13T10:40:00.000-08:00

According to the Formatech website:

We seek to Make a Difference in the lives of our clients, their patients and our employees by helping make new drugs happen at the speed of science.

According to a few former employees:

If they (the FDA) dig deep enough they will find that the services they provided over the years were laced with incompetence, and extreme mediocrity.

It is a sweat shop. Horrible working conditions

I know a few people that have worked there in the past and not a single one of them have anything good to say about Formatech.

According to the FDA warning letter:

investigators from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211.

But there is a positive side to this story if you work in science. According to Equipnet.com:

Complete Liquidation of a Formatech Facility: Featuring Lab Equipment, Sterile Processing Equipment, Facility Equipment, Office Furniture & Much, Much More!

What happened? Cellceutix had a contract with Formatech. Surely they were honest people. Why then did someone make this claim:

Take a good look at Cellceutix, they are having their "drug" Kevetrin, formulated by these guys. Cellceutix has claimed to have noted chemist SD on their SAB, yet SD doesn't even know them.

Kevetrin is nothing more than a simple S-alkylthiourea, they claimed it was a novel selective kinase inhibitor, with only millimolar activity! Anyone knowledgeable in this field knows that a kinase inhibitor must have low nanomolar activity to be considered in this regard.

Cellceutix has been reported to the office of criminal investigation at the FDA with regards to their IND submission for this compound.

Oh the seven degrees of separation. In this case biotechnology bullshitters lead from one bad apple to another. One degree of separation. Of course I don't know if any of this news about Cellceutix is true. Professional liars certainly pad the resume of their companies. They flock to biotech. They do things like put down on their resume that they were Rhodes Scholar. Where there is smoke there is fire. What else could be uncovered if one were to look?

Anil Potti

2012-02-13T06:32:00.000-08:00

When a professional baseball player gets caught gambling on baseball, he is out of the game. Pete Rose agreed to permanent ineligibility from baseball amidst accusations that he gambled on baseball games while playing for and managing the Reds. He denies ever betting on his own team. The Baseball Hall of Fame formally voted to ban those on the "permanently ineligible" list from induction in 1989. Before 1989 excluding players on the list was done by informal agreement among voters.

Anil Potti was caught cheating in science. Anil Potti still has a job in his chosen field. According to the Coastal Cancer Center website:

In addition to patient care, Dr. Potti is passionate about teaching and research. Over the past ten years including his time at Duke University, he has received several recognitions for mentoring, teaching and research efforts,

True, he received a lot of attention for his research efforts. Still does.

Professional sports takes cheating seriously. Breaking the rules of gambling is not allowed. Getting caught, as Pete Rose was caught, leads to a lifetime ban on playing and/or coaching. Pete Rose should be in the hall of fame. But the leadership of the sport takes cheating seriously.

Science and medicine?

A Curious Deception

2012-02-11T12:17:00.001-08:00

Just a quick post about something that has been bugging me lately. It is the human resource "skill" of briefly removing a job posting then re-posting to hide the length at which a job has been lingering. In Seattle they post biotech jobs on the WBBA website. This job was vacated in June of 2011, 8 months ago. It was removed last week and has now resurfaced. I had been meaning to catch the latest remove/re-post moment.

I understand that human resource department do not want to advertise their inability to fill positions at their firm. I have a low opinion of HR. That is my bias. What is their bias that leads to the little white lie here?

Filling positions, especially in science, is not a skill HR possess. What do they do then? Most paperwork functions are outsourced. Is this a part of their job, to project an image?

Machiavellian Leadership

2012-02-09T07:18:00.000-08:00

The reason we lose so many jobs and so much money in biotechnology and pharmaceuticals is because we do not fully understand the diseases we set out to make drugs against. Without the ability to follow through on our promises, we need a special kind of leadership.

"Because how one ought to live is so far removed from how one lives that he who lets go of what is done for that which one ought to do sooner learns ruin than his own preservation: because a man who might want to make a show of goodness in all things necessarily comes to ruin among so many who are not good. Because of this it is necessary for a prince, wanting to maintain himself, to learn how to be able to be not good and to use this and not use it according to necessity."

I once read, in "The Scientist, Magazine of the Life Sciences" that science is what scientists do. To take that logic out further, leading is what leaders do. Scientific leaders thus lead science. Here at the CCS we believe that they neither lead nor understand science. Without having read Machiavelli's "The Prince" they have come to the same conclusions:

"...a prince must not have any objective nor any thought, nor take up any art, other than the art of war and its ordering and discipline; because it is the only art that pertains to him who commands. And it is of such virtue that not only does it maintain those who were born princes, but many times makes men rise to that rank from private station; and conversely one sees that when princes have thought more of delicacies than of arms, they have lost their state."

The leaders will fight to keep their status. The battle between Baltimore/Imanish Kari against a lowly post-doc and a minor laboratory issue, demonstrates this fact. Why not retract the paper? The scientific community would not be served well to allow for the bad science that Baltimore and Imanishi Kari had published and became very well aware of. That wasn't their concern however. They needed Margot O'Toole to keep her mouth shut. She wouldn't. The three of them engaged in the art of war. A book was written about the war. No book was written about the paper and the reason it caused a war. The scientific research was, as Machiavelli was say, "a delicacy".

For a more recent example of biotech leadership, check this one out! A leader in biotechnology could be any leader. They all want the same thing. The spoils of war.

Anil Potti, Bharat Aggarwal, Silvia Bulfone-Paus, Dipak Das, to name a few famous "scientists" of late, have had setbacks in the Machiavellian leadership game. They know that this is part of the game however. Samuel D. Waksal (PhD, Immunobiology, Ohio State U.) of Imclone was caught cheating at a couple of endeavors. He was arrested in 2002 on insider trading charges. He pleaded guilty to charges of securities fraud, bank fraud, obstruction of justice, and perjury. In 2003 he pleaded guilty to charges of conspiracy and wire fraud for avoiding $1.2 million in sales taxes on $15 million in artwork. Waksal was sentenced to seven years and three months in prison and ordered to pay more than $4 million in fines and back taxes, all the maximum punishments allowable under law. He was released from custody in 2009.

He is currently the chairman and CEO of Kadmon Pharmaceuticals in New York City.

The Squeaky Floor In the Rat Maze

2012-02-05T06:38:00.000-08:00

There have been over 12,000 layoffs announced so far this year at Tekeda, Novartis, Alnylam, and Astra Zeneca so far. Genzyme is letting go an undisclosed amount of their R&D staff in Massachusetts. The exact tracking of layoffs and the consequences is difficult. An outsider, if they had the real stats on our field, may wonder why biotech and pharma drug researchers have such a high rate of layoffs. The best explanation I have heard is from a comment on "In The Pipeline" blog regarding the AstraZeneca layoffs:

If new effective drugs were being discovered all the time there would be no layoffs. The reason they are not being discovered, is that drugs are agents trying to alter a system that is only dimly understood (the cell and its interactions with other cells).

In Feynmans Cargo Cult speech he speaks of a rat maze that was studied by a researcher. The rat maze is a system used to extract an understanding of how rats think. Upon closer scrutiny, the rat maze was dimly understood. The researcher published his findings but it was not well received:

I looked into the subsequent history of this research. The next
experiment, and the one after that, never referred to Mr. Young.
They never used any of his criteria of putting the corridor on
sand, or being very careful. They just went right on running rats
in the same old way, and paid no attention to the great discoveries
of Mr. Young, and his papers are not referred to, because he didn't
discover anything about the rats. In fact, he discovered all the
things you have to do to discover something about rats. But not
paying attention to experiments like that is a characteristic of
cargo cult science. - R. Feynman

The discovery was about research, not rats. You would think we would make research a field of research. But we assume we already understand that system too.

Ignoring things we don't think will get us noticed, things that aren't sexy enough to advance our careers has led us to the continued high rate of layoffs. Those of us who work at the bench level should know when we are working in a cargo cult. When your leaders ignore the murky research methods and they push you along with projects that support a narrative they have prepared, you work in a cargo cult.

The big picture narrative for biotechnology and big pharma is that we fully understand what is happening inside of cells. To prove that, we will be curing and treating diseases. The truth is that we have a dim understanding of the system we are studying. We even have a dim understanding of the tools we use to conduct our research. Human beings have figured out how make a large chunk of metal fly from one side of the ocean to the other. The human body is a far more complex system than that airplane, yet the science is softer.

The amount of layoffs is an indication that we do not know enough about our proverbial rat maze. The scientist who does not know or who has ignored information about the squeaky floor will send forth his staff to obtain information that supports his/her narrative. But in the end the staff will go away, having learned very little. Those who noticed the squeaky floor and failed to make the leadership stand up and take notice will become disgruntled. They may question their ability to apply good science in the world they work in. A trillion dollars can be lost. Several hundred thousand jobs will be created and lost in the process. A lab will sit empty until another sexy narrative is created by a charismatic young wiz kid. The lights will come back on in the lab and the old rat maze will be brought out again.

Catch Us If You Can

2012-02-04T07:29:00.000-08:00

This image struck me as very interesting. I pulled it from the Abnormal Science blog. I've blogged about my own experience with the same assay. The concept is simple. You culture RAW 264.7 cells in the presence of RANK-L. In about 5 days this group of cells will fuse together resulting in a group of ugly multinucleated osteoclasts. By adding an antibody against the RANK-L or it's receptor, you can retard or prevent osteoclastogenesis. You could also try RNAi against a critical protein in the pathway kicked off by the RANK-L. Either way, that office bound scientist needs the picture we see above.

My experience with this assay was with RNAi. The very first time I used RNAi I obtained the results that we hoped for. I could not however, repeat those results. I still don't know what happened. I used RNAi against IL-2 which was accused of being in the pathway by a bio-informatics program we were selling. This evidence showed that we were geniuses. In spite of the 9 times this assay did not work, we had photographic evidence that it did. No one was going to ask us how many times we tried this and what was the outcome.

It is not at all difficult to imagine what your P.I. wants when he designs an experiment. Especially if your P.I. is in the business of churning out publications. If he/she says, "provide evidence of osteoclastogenesis and the inhibition of it with my awesome idea", then that is what will be accepted. If you can't do it, someone else will. Do you want to be important and successful like the P.I. or do you want to argue with him/her. P.I.s don't like dissention.

In my example, I obtained the desired outcome right out of the gate. After a few more failed attempts the assay was passed on to another person who gave a presentation of his work on the assay. It was 'sort of working", he claimed. The TRAP assay, which measures tartate resistant alkalyne phophatase, can be done but on a separate petri dish of cells. So for each condition two groups of cells are treated in order to obtain visual and enzyme assay evidence of osteoclastogenesis. If you want to test a treatment more than once, as good science would require, you would need two groups of cells for each replication. What the new lab researcher did was to run the TRAP assay on the same group of cells being photographed at day 5. TRAP accumulates on days 3 and 4. It is the same at days 1,2, and 5. There is a flaw in experimental design. But the P.I. is looking for good images for a powerpoint presentation. He isn't receiving a presentation on experimental design.

Areas on the petri dish where the cells were not fusing were captured in the knock-out treatment. Areas where the cells were fusing in the RANK-L only control were captured. Without using photoshop, the desired images were obtained. The P.I. was happy but the images were not as good as my originals. The researcher had to keep trying.

The new researcher could not hide the fact that the enzyme assay quantified the enzyme being produced for the entire plate of cells. He could not cut out a small section of the plate as he did with his camera, and measure TRAP. What does one do? When showing data on a powerpoint you have a biogolical science tool that has been used over and over. Run the assay over and over. Find the measurements, both within a margin of error, where the measurements differ the most in the direction required by your P.I. Make a bar graph from the data and stretch that graph out to make the height of the bars tell the story you are working on.

When I saw the obvious re-use of the image of the Zerumbone treated cells at days zero and 3, I thought perhaps they could be two different pictures of the same plate. I would have no way of knowing what day they were taken. The darkened circular outline on the right side of the image gave it away. The filter inside the imager created that outline. With a little more effort they could have slid the filter out of the way and photographed a different section of the dish. Dishonest yes but at least not an insulting lack of effort. The re-use of the same picture shows how easy it is to use photography to deceive. You do not even need to use photoshop.

In the concept I put forth in the last post, a Consumer Report for Science Consumers, a small group of image experts would offer non-biased opinions on the images used in each publication being analyzed. The area of expertise would not be in osteoclastogenesis.

Making Money from Honesty, Consumer Reports for Scientific Consumers

2012-01-20T09:56:00.000-08:00

What if you didn't have to make anyone happy with your research? What if you ran a small laboratory with about 10 really smart scientists who conduct research according to a well defined philosophy of science? That means no long winded narratives about your awesome pipeline. You are developing a biotechnology company that sells a service. Research! I am not talking about a CRO here. I am talking about a company that has no bias other than to tell the truth. Who needs such a company?

Those who are embarrassed by the scandals taking place at their organization.
Those who have to retract papers when their chosen peers are led astray.
Those who want to invest in a company but are only getting the input of the people trying to get their money.

How do you make money from a company trying to sell unbiased evaluations? Sell your service. Finance auditing services make money. Why couldn't a science auditing company make money? If it is true that one trillion dollars, (274 million dollars a day) was lost in the past decade on research then we have a business model. One of our original American entrepreneurs, Ben Franklin, told us that a penny saved is a penny earned. We could have earned a whole lot of pennies from that past decade. Of course that money wasn't really lost. It was earned by people who would love to see us continue down the path we are on. David Sinclair is an example. What about those who lost money, such as Roche did with Sinclair? Would they do anything different if they could?

Unlike computer science, engineering or physics, the life sciences do not always have clearly defined tests that lead to predictable outcomes. Medical science is at best soft. At its worst it is a bunch of misleading sciency nonsense that looks for the suckers who are born every minute. The old logic is that the nonsense is snuffed out by wise investors or a team of high powered scientists and lawyers working on the due diligence for a new partnership. That hasn't worked. The product/service of our business model must focus here. Why can't those who are suppose to catch the nonsense do so? How can we succeed where they fail? We will replace faith based methods such as peer review and return to empiricism. The scientific method will be a guiding light.

No matter how good you are in businessman, you can't be an honest success selling broken mouse traps. You can be a dishonest success but those are the guys who profited from the $Trillion dollar loss of others peoples money in the past decade. We are working against them. They have been winning. As of late however we are starting to see new weapons against the Cargo Cults of research. Original online creations like Retraction Watch are pulling the curtain back on the secretive world of research Wizards of Oz. There is a changing attitude towards science. It is fallible. However there is a possibility that Retraction Watch will run it's course and become boring without a greater cause. Abnormal Science blog will start to appear as repetitive because science will always have a dishonest population. The good must also be pointed out as well as the bad, just as it is in the automobile consumer reports. Pointing out that the Honda Accord has bad breaks, for example, is considered useful among car buyers. That doesn't mean that the Honda Accord isn't a nice car, it is. The same may go for a particular field of research or a drug candidate. There may be a highly effective antibody drug available for partnership but it comes with manufacturing issues such as low expression. These are issues that management, investors and future scientists and engineers of the project should know about prior to joining the effort.

Instead of forming an antibody company or an RNAi company, start a research company. Before putting anything on the market, develop the product/service. Like any biotech company, that means spending time establishing the company structure, mission, and financials. Methods must be put in place so that evidence or data isn't accepted without sound basis. Personal relationships must be healthy. Checks and balances can trump supervisors and annual reviews. Ultimately, there must be tests. That means a separate group will offer up several cases each year that should come up as nonsense (a negative control). A positive control will also be required. Each group must specialize in the ways of Cargo Cults.

Human beings have been trying to distinguish shit from shinola. since the dawn of time. We are all consumers of science whether we know it or not. We need better stewards of the information that is out there. Can those stewards be a for-profit organization?

Risperdal and Tamiflu Hidden Data

2012-01-18T08:37:00.000-08:00

Tamiflu: A new review of the influenza drug oseltamivir (Tamiflu) has raised questions about both the efficacy of the medication and the commitment of its maker to supply enough data for claims about the drug to be evaluated by independent experts.

We looked into our own thoughts on Tamiflu. We talked about it here on our very second post on the CCS.

Risperdal: Johnson & Johnson officials hid three studies showing some patients using Risperdal developed diabetes while claiming the antipsychotic drug didn’t cause the disease, a witness testified.

I'm starting to think there may be some systemic dishonesty in the Cargo Cults.

Type I error and Type II error are precise technical terms used in statistics to describe particular flaws in a testing process, where a null hypothesis that should have been accepted was rejected (Type I error) or where that hypothesis should have been rejected, but was accepted (Type II error).

Clearly Roche and J&J did not make an error. The came to the right conclusions and decided that no one should be allowed to come to the same conclusions. Johnson and Johnson was hit with a $158 million fine this week. Tamiflu and Roche seem to be getting away with their sins against science.

They made billions, for those who don't follow this Cargo Cults. They did not make an error. In the Cargo Cults, Risperdal and Tamiflu are success stories. And they created a lot of jobs in their legal departments.

Western Blot / The Tool of Scoundrels

2012-01-14T05:52:00.000-08:00

The Nobel Prize in Physics 2009 was divided, one half awarded to Charles Kuen Kao "for groundbreaking achievements concerning the transmission of light in fibers for optical communication", the other half jointly to Willard S. Boyle and George E. Smith "for the invention of an imaging semiconductor circuit – the CCD sensor".

The image from a CCD is black and white, but by placing a red, green or blue colored filter over the top of each pixel, color information can be read directly from each pixel — but only for one primary color per pixel. Subsequently, software can also extrapolate the color of adjacent pixels based on their brightness, so that each pixel winds up with its own red, green and blue values. A RAW file is the “raw” color data from the chip before any of the post-processing extrapolation has been done. Cameras usually do all of this processing for you and spit out the result as a JPEG. With the RAW file you actually have all the original sensor data, which is much more information-rich.

So far so good. Here we pack up the Allied forces airport and the Cargo Cult takes over. Next we introduce the western blot. Somewhere between running the western and generating the image of that western we enter the cult.

Post-processing extrapolation was my job for five years. I was a photographer. The original data that I used was a roll of film. I learned how to expose film using f-stops and shutter speed. I learned how to process and print black and white, color and slide film. Interesting things to know but digital technology now takes care of all the things I was doing manually. Post-processing image quality issues like color, contrast, and density are now automatic.

My first few years running western blots were done on film. Then one day we received our first AlphaImager. It is a box with a light table that fold down so you can take pictures of SDS PAGE gels. Fold the light table up and there is a UV light box for DNA gels. Shut off all light and you can take pictures of chemiluminescent western blots. A a RAW file is generated, with all the original sensor data, which is much more information-rich than a processed image.

The western blot has seen some method advancement. There are E-gels and I-blots which speed up the time to transfer the proteins onto the membranes. There are more sensitive reagents for developing the westerns so lower amounts of protein can be detected. Each change challenges the Cargo Cult tribesmen. If a transfer is sped up, they claim, you will get less protein transferring. "How do you know?", I would ask.
Using film, I was told, was superior to digital images when it came time to expose for weak signals. "Can I see the evidence?" I was respond. I wasn't getting a satisfactory answer. I developed a test. I loaded a gel with high to low amounts of protein. The low end concentrations dropped below the level of detection even at maximum exposure time (chemiluminescent probes lose their energy after about one hour). I prepare two identical westerns. One western was visualized by exposing it to film for one hour and the other was visualized using an AlphaImager CCD camera.

Test number one: Hold film in hand and use eyes to compare with digital image on computer screen. Oh the varying opinions! Based on ones bias, a subjective argument would break out. "The film is more sensitive!"

Test number two: Use ImageQuant software from GE Healthcare to quantitate sensitivity. The bias was still there but the data was irrefutable.

Science and technology wins the day.

Next I ran the same western blot and probed it with a fluorescent dye conjugated antibody. I used the CCD camera to capture the image. I also captured the image of the very same western on a lazer scanner. The fluorescent probe provided greater sensitivity measured by the signal from the lowest detectable amount of protein. The scanner produced cleaner data as measured by the correlation coefficient of the linear curve generated by the protein signals. I laid the western in a drawer and let it dry out. Every month for six months I scanned the western. The results did not change.

So I had determined empirically the best way to run one particular western blot. I'm not done yet however. If I am to get reproducible results from my western I must also account for the protein sample I am loading. Purity and stability, for example, must be known. In a proper research organization all of this is known by the QC group. The people who develop the methods take these factors into account. The people who then run the western blots must adhere to the standard operating procedure. They are tracked electronically so that deviations can be accounted for. For example, if a standard curve appears to be lacking in linearity or range, the protein standards can be identified to see if they were used beyond their stability window.

This all leads to the quality control of a cargo cult. I consider a peer reviewed journal to be part of the cult. The tracking of source material, equipment, and technician is not something that a journal editor asks for. It is even rare for immediate supervisors to read over a laboratory notebook, especially when the results turn out in their favor. The cargo cults do not have quality control mechanisms. They rely on their intuition and intelligence. As a result, any questioning of the finalized data is frowned upon. Lower ranking members of the organization are then held accountable for any transgressions, since the scientist above them has such a high standard for their honesty.

If the JPEG or TIFF files were made available we wouldn't have to use our eyes to try and discover fraud. Variances in density, for example, could indicate cutting and pasting. That clear line that gets erased with density adjustment remains on the pre-processed image file. The pre-processed data is what we need, not the post-processed product offered up for publication. The post processing is where the scoundrel plies his/her understanding of imaging and ways of fooling the older generation of leaders. Fortunately, post-processing is tracked by the software. If post-processing takes place, that image must be saved as a new file. The family tree of an image is stored automatically. It all leads back to the pre-processed image.

This is a critical point in the Cargo Cults use of imagery in their ceremonies. The real wealth of the imaging systems comes from the pre-processed data. Office dwelling scientists don't publish relevant information on image enhancements. They offer up aesthetically pleasing images that support their narrative. Orthogonal methods should be required to back up the western analysis, such as the ForteBio.

Hanging From a Tree in a Forest In Belgrade

2012-01-04T11:12:00.000-08:00

You hear about pharmaceutical companies bribing doctors, promoting off-label use of their drugs, cherry picking clinical trial data, ghost writing scientific papers, and all sorts of bad behavior. You rarely hear about the people who do this work for a living. When they get caught the Corporation steps up to the plate and takes the hit. The corporation loses lots of money. The public furls its brow and says, "Bad corporation!". Who are the people who do these bad things? Do they go on to more prosperous positions? Are they ultimately rewarded for their dedication to profits? Or do they succumb to ridicule and ostracism from an honest industry such as biotech/big pharma?

One such person, Nenad Borojevic, a former director of the Serbian Institute of Oncology and Radiology, was found hanging from a tree in a forest in Belgrade. He was charged with supplying drugmakers with information on the amount of cytostatic drugs needed and on public procurement plans. Nenad Borojevic and representatives from several pharmaceutical companies, including AstraZeneca and Roche, were indited on suspicion of accepting and giving bribes totaling about $1.4 million.

Who were the employees at AstraZeneca and Roche who worked with Nedad? According to reports, police also arrested the director of Roche pharmaceuticals office in Belgrade, Vojislav Petrović. Other suspects detained include Director of PharmaSwiss Oncology Sector Andrej Soretić and Predrag Marinković of AstraZeneca bio-pharmaceutical company. Who were their superiors?

How does this relate to a Cargo Cult? The drugs are already approved thus the cargo arrived. I tend to believe however that the drugs are of little interest scientifically to a certain sector of the industry. The drugs are merely widgets that generate profit. With a little help, those profits can go up considerably. The execs with the right credentials, who talk pretty are tasked with making the most money possible from the pills. They have to convince the world of medicine that they need to prescribe the pills. They have to educate. In the process they tend to stretch the truth. And the truth is what we are all about here.

The truth about the pills, in this case, was stretched to the point of criminal activity. One of these leaders was found hanging from a tree in a forest in Belgrade. How can an industry that relies on science employ leaders who have cumulatively created such a corrupt corporate culture? How can such leaders understand how scientific research is conducted? It is fairly easy to deceive ourselves and our fellow human beings. To do so purposely seems to be the skill that the leaders have in spades. Such leaders thrive in Cargo Cults. Sometimes they get caught.

Allozyne Layoffs and Sacrificial Lambs

2012-01-04T05:22:00.001-08:00

The last post was about the fallout of a merger that went sour. The CEO and four board members from company A resigned. Company B has possibly laid a few of its 20 employees off but their CEO denies the claim. The details of the merger and the subsequent fallout would be good reading for those of us interested in the business of science. It is not however, what we want to do here on the CCS. What we do here is philosophy. An interesting technology came out of Caltech that enabled one to add a non-natural amino acid to a recombinant protein. That non-natural amino acid would allow for conjugation to other proteins or PEG chains that could add some pharmacokenetic advantages to a protein. Fantastic. What happens next is of interest to the CCS.

What happens next is a business plan is written up and submitted to a venture capital group, a biotech incubator, an angel investor, a rich relative, or whoever has the money that the inventors lack. In a classic "you've got the money, I've got the brains" situation, a relationship is formed. Trust and money is given to the inventors by the investors. A meeting takes place. Where are we going to set up shop? What should we pay for rent. Who do we need to hire? Who can we put on the board and advisory committees to attract other players in the industry? In all of this shuffle it would be easy to lose sight of the original excitement of being able to stick a couple antibodies together and see what happens.

This is of interest to the CCS because what usually happens ends in failure. We ask ourselves how so much interesting science and so much money result in failure? We believe that this is no ordinary business failure. We have recently given a number to the failures of drug research ventures. A trillion US dollars has been lost! That is veritable petri dish teaming with life for a philosopher such as the CCS. I want to put that petri dish under a microscope and watch the interactions and understand what is happening. In one petri dish I have a thousand little companies. 999 of those companies die but one lives. If I look real hard through the microscope I can see a little sign and it says Amgen! What did Amgen do to survive?

What happened at Allozyne is a microcosm of the Trillion Dollar Failure that is drug research. The inventors left the business up to the Cargo Cult Leaders of Seattle and went back to Caltech. One outsider, the CEO, came from the business side of Novartis. The rest of the crew, including the chief scientific officer were selected from the usual suspects of the Seattle Cargo Cult. The CEO and the board are now in charge of turning legitimate science into a profitable business model. They need those Powerpoint slides to tell a story. The story was told to Wall Street but Wall Street didn't bite. Allozyne and Poniard leaders failed. Poniard leadership accepted responsibility and fell on their knives. Allozyne sacked a couple low level techs and offered up soundbites like, "“The syndicate is extremely excited that we are on a Phase III trajectory in 2012” and that their pitch to Wall Street was, "very well received" and that “No one here is in fact at all disappointed. We are very much looking forward to 2012. We are invigorated about the challenge ahead.”

Allozyne began with an initial investment from the Accelerator Corporation. Accelerator usually ponies up around 1 to 2 million dollars. From there Allozyne received 50 million dollars and moved into some rather swanky digs a block away from the Accelerator building. As of June 2011 they were down to 1.4 million cash on hand, leaving 49.6 million to contribute to the lost trillion dollars. I've mentioned that Allozyne is a part of a microcosm. I've mentioned that the microcosm could be thought of as a petri dish teaming with life. 1000 entities begin life in that petri dish. Rather than studying that one Amgen life form that strives, we are looking at one life form that looks sickly. We know that we must add a certain concentration of money into our petri media to keep all of the companies in there alive for a few years. We don't have a good idea what is needed to make the Amgens emerge. In fact, if Amgen were put into a modern biotech microcosm petri dish... it wouldn't survive either. Is Allozyne like an early Amgen? Are they misunderstood yet poised to one day make their detractors very sorry? Or are they dying because the management team is Cargo Cult?

It is hard to study what is happening in our biotech petri dish. Allozyne is a secretive group. One or more people were laid off but according to management it was of no consequence. It was merely a ceremonial sacrifice. Part of the cult rituals is to seek out the members who wear white lab coats and give them pink slips and watch them march out the front door with a box of their meager belongings. These sacrifices take place towards the end of the process. It is believed that the laboratory workers are causing the airplanes to not land. By removing them the investors breathe easier which relieves stress among the managers. The white lab coat clad members of the cult are like lambs. They have no power over the direction of the research they conduct on behalf of their leaders. They do what they are told and they disappear without explanation. It does not however signal the end of another dot in our petri dish. It only signals trouble.

We would like to see a research class that emerges one day with the power to fight. A small biotech is not where that power will come from. It will come from outside of the lab. Slowly people will begin to speak up about the common mistakes that we make in trying to manage science as if it were a business. Firing lab workers is like firing an automobile assembly worker for making a Yugo or an Edsel. The real culpability lies in the minds of those who design the car. The reason the airplanes do not land in our airport is not because the man in the tower is doing his job improperly. It is because Cargo Cults are missing something. That something is unknown or is purposely being ignored by the management class. One thing the are missing is the knowledge that sacrificial lambs make for a dull and timid research staff.

Journalism

2012-01-03T13:40:00.000-08:00

The Cargo: Allozyne

Biologic therapeutics represent the vanguard of innovation. By 2006 they had captured a $30 billion dollar market with forecasted growth to $60 billion by the end of 2010. Although the creation and adoption of biologics has been rapid, the markets that they serve are still burgeoning with unmet medical need. We, a privately held and clinical stage biopharmaceutical company, have rapidly developed a number of protein therapeutics product candidates through its next generation protein engineering technology in order to serve unmet medical need in various autoimmune diseases and cancer.

Ka-Ching!

The Xconomy Headlines:

* Allozyne, Developer of Multiple Sclerosis Drug in Fewer Shots, Poised to Enter Clinical Trials 10/16/08

* Allozyne’s Next Drug, Made to Kill Two Birds With One Stone, Being Prepped for Clinic 11/16/10

* Allozyne Passes First Clinical Trial, Dreams Big About a Once-Monthly Multiple Sclerosis Drug 1/10/11

* Allozyne Acquires Poniard Pharmaceuticals, Finds Backdoor Route to NASDAQ 6/22/11

* Allozyne Looks to Rustle Up Interest on Wall Street With Backdoor IPO 7/13/11

* Allozyne, Poniard Scrap Plan to Merge Amid Investor Apathy 12/22/11

* Allozyne Raises More VC Cash, Looks to FDA Meeting After Poniard Deal Fizzles 12/23/11

One final headline by the Wall Street Journal: Poniard CEO, 4 Board Members Resign In Wake Of Merger Collapse

Xconomy missed that story.

The unfettered enthusiasm remains a mystery. The journalistic approach to the story is non-existent. A balance comes in the comment section of a few articles. A reader who goes by the moniker Nanostring added a few points on the Poniard deal that the article does not mention:

1. Based on today’s price of PARD, the merger values Allozyne @ ~$20 M ($11M*65/35).
http://finance.yahoo.com/q?s=PARD&ql=1
That is: they took valuable technology from Caltech + $43M in investor money and ended up with $20M in value. You do the math.

2. Even that $20M may be too rich, considering that PARD got immediately hit by two lawsuits for agreeing to the terms of the merger.
http://yhoo.it/qbHfKv
http://yhoo.it/mOWjQe

3. As of now PARD shareholders have twice rejected the reverse stock-split, which is a prerequisite to the merger:
http://biz.yahoo.com/e/110725/pard8-k.html (second graph)

Nanostring sounds like an interested party with ties closer to the money than the science. He was correct about the market value falling short. He is no fan of the Xconomy cheerleading.

Will this FAIL be covered at Xconomy? What happens next? Will we hear again from OVP’s Carl on how proud he is with Allozyne, now that PARD shareholders have flipped a middle finger to this merger? Why are comments disabled on the other Xconomy article?

Unfortunately, (as I have complained to Luke and Buderi on numerous occasions), Xconomy again wants to be more of a PR shop for the local VCs rather than a real news-reporting blog with journalistic integrity…

Keeping the positive spin on the disastrous management of Allozyne is worthy of journalistic coverage all by itself. Meena Chhabra is very attractive. Yet she was unable to attract the kind of attention needed among the geniuses of Wall Street. While she continues to go unscathed in Xconomy and among her local peers, her counterparts at Poniard suffered a different fate.

Will Allozyne survive? With plans to skip phase II trials and sign up only 700 people in a phase III, funded by Allozyne alone, all carried out by a management team that orchestrated the Poniard fiasco... we think this plane won't land. And all of this for the hope of a longer lasting form of a drug already on the market.

Will Xconomy cheer leading continue, leaving in the good and leaving out the bad? Unfortunately we think they will. They are a part of this Cargo Cult.

Friend or Foe

2012-01-01T08:26:00.000-08:00

Retraction Watch estimates close to 400 papers were retracted in 2011. A couple comments came up with retraction numbers below 100 for the year:

Thanks so much for providing this valuable service. Of interest, a PubMed search for “Retracted Publication” or “Retraction of Publication” for 2011 yields only 35 papers. So if you and your colleagues weren’t on the job, we’d be missing out on ~1 in 12 of these papers!

Pat French

“Retraction notice” gives 63 hits. Still, the problem is exactly that it is not clear how to retrieve all the retractions, which may well be in the PubMed database. There should be a standard tag!

Jon Beckmann

We think that retractions are important pieces of scientific information. Unlike a Friday night bar conversation where you make the claim that the Buffalo Bills won the Superbowl back in 1995, the accuracy of claims made in science matters. When the folks at Nature faced the prevalence of chicanery taking place in big science labs and big science journals they concluded:

these days image detection software and the vigilance of media outlets such as Retraction Watch can catch irregularities—be they due to innocent error or misconduct—much sooner. The ability to track these changes provides benefits to biomedicine, as experiments in the scientific literature lay the foundation for future experiments.

The peer review process employed by science journals is the opposite of the scientific method. Peer reviewers don't repeat any experiments thus their judgments are not empirical. Peers have a bias that is not eliminated by the process. The authors and their organizations carry with them a cache that brings with it bias that is also not eliminated. The science isn't the only thing being evaluated. In a perfect world a journal would publish articles and offer only minimal interference into what the authors intend to say. Once published the true peers can evaluate the paper and agree or disagree with it. Scientists after all, are the peers.

The question that peer reviewed journals have to wrestle with is whether or not Retraction Watch is their friend or enemy. With over 1.5 million hits online Retraction Watch is clearly popular among scientists. Who else would read about retractions? It appears that the demand is there for more information. Transparency is our friend.

The Arrivals

2011-12-21T16:12:00.001-08:00

If you've made up your mind
to test a theory, or you want to explain some idea, you should
always decide to publish it whichever way it comes out. If we only
publish results of a certain kind, we can make the argument look
good. We must publish both kinds of results. -RF

If we could make one change that could turn the cargo cults into real airports it would be to create a place where the results of all experiments are published. In Cargo Cult Airplane terms, what cargo planes were scheduled to land and did they report on the landing? If you are looking for a big deal struck between big pharma and biotechnology (the departure) you will have no problem finding the publicity. If you are looking for the results of a big pharma/biotech deal you will have to begin conducting research.

Let's look at a deal between Pfizer and Scripps back in 2006.

Under the terms of the agreement, Pfizer will pay Scripps Research $100 million over a five-year period, during which time scientists from Pfizer and Scripps Research will work together to identify and perform specific projects of mutual interest.
Pfizer will pay Scripps Research milestones and royalties on therapeutic compounds created through the collaboration. In addition, Pfizer will have the first right to license many discoveries made at Scripps Research during the agreement.

This particular deal was given journalistic coverage by the San Diego Union Tribune. (Beware the trade PR publications such as Fiercetech and Xconomy)

Pfizer would pay Scripps $20 million a year for five years, he said. Scripps would have full control over how the money is spent.

In return, Scripps would give Pfizer the right to review all of the institute's discoveries, plus the right to license up to 47 percent of them. Pfizer would be able to make such actions only during the five-year funding period.

In order to evaluate the results of this collaboration it is important to know that Pfizer was given access to all of Scripps publicly funded research, not just the work initiated and researched during the five year $100 million deal. It makes the 2011 arrival time even more interesting.

The Pfizer deal replaced Scripps' controversial 10-year alliance with Novartis. The institute came under scrutiny in the early 1990s after the NIH questioned aspects of its initial deal with Sandoz Pharmaceuticals Corp., who later became Novartis. According to the Union Tribune:

During a congressional inquiry, federal officials said the agreement gave Sandoz too much control over Scripps' research priorities, stifled academic freedom and prevented smaller biotechnology companies from competing for access to Scripps' scientific discoveries. The partnership allowed Sandoz to license nearly all of the institute's inventions.

Some legislators suggested that the Scripps-Sandoz deal made the federal government, through its grants to Scripps, a patron of a foreign corporation.

We certainly don't want that to happen. We want pills that make people better when they get sick. After the Scripps-Sandoz partnership, the NIH established policies to clarify how institutions that receive its funds should enter into licensing agreements with for-profit companies.

The institutions' responsibilities include:

Preserving the academic freedom of its scientists.

Ensuring that findings based on taxpayer-funded research are disclosed in a timely manner.

Not entering into agreements that permit a corporate partner to acquire exclusive licensing rights to a discovery without plans to actively develop and commercialize it.

Promoting the manufacturing of its products in the United States.

That is a positive outcome, although not the one intended. A cargo plane landed here, bringing with it a new set of rules. If you are a drug exec or a politician in charge of funding massive organizations like the NIH, this is cargo. This set of rules effects how you do your job. It effects how scientists do their jobs.

What did we get from this deal? What did Pfizer get? One benefit was offered up from the citizens of Palm Beach County Florida. They ponied up $310 million to get Scripps to set up shop in Florida and bring with them high paying jobs. A quick Google search finds a story of hope via the Pfizer deal and an unrelated spin-off from Scripps, Xcovery. On their website Xcovery lists one job. Scripps Florida lists 3 jobs. 4 jobs currently available after $410 million. Are both investments drying up or was there a surge in hiring and thus scientific progress is ? We can't say.

Another potentially related story, "Scripps Research/Pfizer Team Produces a Potential New Painkiller". The team reports on the promising new compound in the April 24, 2009 issue of the journal Chemistry & Biology. The Cravatt group began collaborating with Pfizer in 2003 however to pursue, among other goals, development of fatty acid amide hydrolase (FAAH) inhibitors. This collaboration (began in 2003) led to the discovery of a promising class of inhibitors known as piperidine ureas. This potential painkiller appears to have been sold off as a research tool and can be purchased at various chemical companies. Although not a blockbuster, this is scientific progress. This is a cargo plane that landed with an alternative cargo. It all began in 2003 however.

What really became of this deal? The extensive Pfizer pipeline may contain candidates from this collaboration. Novartis may have picked over the carcass leaving little behind after their ten year manipulation of scientific activity at Scripps. For the Cargo Cult Scientist, this is where research begins. If you want to know what the leaders have been up to you start with a press release. You wait the advertised amount of time and you draw a conclusion on what happened. It really is no different than a laboratory experiment. But who is conducting this research? The NIH and Pfizer executives are the foxes guarding the coup. Quite often a failing project begins to lose favor and piece by piece it begins to disappear. Which brings us back to Feynmans rule of reporting results regardless of outcome. By simply trying to evaluate the outcome of a $100 million dollar deal, we begin to see the complexity of such a human undertaking. Yet we know it is being done everyday by some group of people. They are who we are studying in this research project. What did they do with the money and how are they reporting the value of the investment?

If in fact the drug industry has lost over a trillion dollars in the past decade, this $100 million deal is small potatoes. It tells a story however. Each deal tells a story that is fascinating and worthy of research. There is the psychology of the major players. The structure of scientific research organizations can be studied. Did the Pfizer/Scripps deal solve the productivity issues facing big pharma/biotech R&D?

Greatest Loss of 2011

2011-12-21T08:41:00.000-08:00

Daily Hitchens: UK Channel 4 Tribute

Imagine an articulate curmudgeon who would dedicate his career to fighting the abuses of scientific authority. Who is the Christopher Hitchens of the scientific community?

While Hitchens was no scientist, he was a brave man who derived his courage from the truth. When you believe you are on the side of the truth, regardless of the accuracy of your assumption, you are empowered to speak up. Hitchens relished a good argument and made a living out of speaking up. I don't believe he engaged in any Cargo Cult intellectualism.

We could use a man like him in our ranks. It would be amusing, as we look to the sky for our Cargo planes, to hear a lone voice, slightly inebriated with a British accent... "They're not coming you God-damned fools!"

"Beware the irrational, however seductive. Shun the 'transcendent' and all who invite you to subordinate or annihilate yourself. Distrust compassion; prefer dignity for yourself and others. Don't be afraid to be thought arrogant or selfish. Picture all experts as if they were mammals. Never be a spectator of unfairness or stupidity. Seek out argument and disputation for their own sake; the grave will supply plenty of time for silence. Suspect your own motives, and all excuses. Do not live for others any more than you would expect others to live for you.” ― Christopher Hitchens

Most Signficant Fire Burning Out in 2011

2011-12-18T07:30:00.000-08:00

In January of 2010 Alan Sachs of Merck was interviewed about SIRNA, a subsidiary of Merck who specialized in RNA interference. SIRNA was purchased for 1.1 billion dollars. Before the end was announced they had burned through 1.5 billion dollars. Alan Sachs was their leaders and well aware of the hype:

My background in molecular profiling was around when the Human Genome Project sequence came out in 2000 and 2001, and living through that bubble. What you realize is that the essence of the excitement is correct, and the reduction to practice may make it less-than-anticipated, but it’s still real. The same thing will be true of the RNA therapeutics space. There is a lot of expectation and anticipation. The reality will be somewhere between that and zero. We’d like to think because of the experience we have in our company that we have a clear line of sight on what’s practical within a certain time frame.

This will settle down. The acquisition of Sirna by Merck really set this thing off. We’re three years past that. I think in two more years, you’ll see this settle down, much like in the genomics space. In genomics, many of the opportunities consolidated into a few big players. The same thing will happen here. But the big companies like Merck, Roche, Novartis and Pfizer, that have committed to do this, ultimately will be there. Because of the long-term potential of the modality, not the immediate potential, but the long-term potential. It’s huge.

All of the companies mentioned have ended their RNAi programs, including Alan Sachs' Merck. Alan was correct, It was a huge promise. A huge investment followed and a huge fall from grace has finally been completed. Among the Cargo Cults, Merck had the biggest RNAi airport.

Some investors still believe there is a pot of gold at the end of this rainbow. Here is why the CCS places the science into question.

The talking point among RNAi sympathizers is that monoclonal antibodies had likewise been left for dead back in the 90s. The difference however is that RNAi is a nucleic acid therapy like gene therapy. It is different than protein therapy. The diagrams and animations that depict the mechanism of action (MOA) of RNAi failed to depict the delivery of the small RNA pieces to the gene expressing cell targets. It offered a crisp clean MOA that had the same end result of monoclonal antibody therapy, a reduction in the amount of a specific protein. Without changing the highly simplified approach to biotech research, office bound PhDs ordered their white lab coat staff to run the same ELISAs and western blots to demonstrate knock-down. As a white lab coat staff member, I worked through a microcosm of what was to come back in 2002. My first blog post on RNAi was on May 10, 2006. After four years of thinking about RNAi, working with RNAi, watching others work with RNAi, and most importantly, watching the Cargo Cult leaders deal with the lack of efficacy in RNAi, I had come to the conclusion that this stuff is snake oil. That was several months before Merck bought SIRNA.

Since RNAi didn't work very well in the laboratory, it seemed preposterous that it would work in the clinic. The pharmaceutical industry relies heavily on pharmacy and much less on pharmacology. The two main areas of pharmacology are pharmacodynamics and pharmacokinetics. The former studies the effects of the drugs on biological systems, and the latter the effects of biological systems on the drugs. In broad terms, pharmacodynamics discusses the interactions of chemicals with biological receptors, and pharmacokinetics discusses the absorption, distribution, metabolism, and excretion of chemicals from the biological systems. In contrast, pharmaceutical research is primarily concerned with preparation, dispensing, dosage, and the safe and effective use of medicines. Biotech and Big Pharma leaders put up the money to put RNAi through the latter forms of research. The lack of efficacy left RNAi companies scrambling to explain why RNAi wasn't panning out as a drug. Delivery of the little pieces of RNA to a cell that was actively translating the drug target became a hot topic. In other words, they needed to get a handle on the pharmacology. Delivery of the little pieces of RNA was the reason the leaders decision making had hit a snag.

Currently, delivery of little RNA pieces remains the missing link to the promise. It keeps the promise alive. If the pharmacology techniques were in place we could check on the likes of Alnylam and Tekmira. We should not take their word for the promise of SNALPs, Stable-Nucleic-Acid-Lipid-Particles. We should have a separate organization that works for the FDA and the NIH. This group of scientists would development methods ahead of time to test the claims of for profit organizations who can both profit and cause harm. Other possibilities with RNAi is that they can do no good or they can help what ails us. The important thing for scientists to work on is in the development of a science that will help evaluate claims.

In July of this year Merck ended their RNAi efforts after 5 years and $1.5 billion. They claimed that this was a difficult decision based not on science but on financial needs for the Merck corporation. As usual a learning opportunity was lost. As Feynman said;

In summary, the idea is to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgement in one particular direction or another.

It is our biased opinion here at the CCS that 2011 witnessed a most significant ending to biotechnology's biggest promise of the past decade. I didn't present any data that might have suggested that RNAi works. I left that up to the experts who still claim that RNAi works. As far as putting ones money where ones mouth is, the verdict is in. RNAi is not moving forward in the world of BigPharma.

Here at the CCS we began in 2006 with a strong opinion and we end in 2011 with the same opinion, backed by a huge failure of RNAi in biotechnology and BigPharma. Alan Sachs was right, the promise was huge. That is why the failure is also huge. Huge shifts in thinking are fun places to be in science. Not just in the beginning, like those who jumped on the RNAi bandwagon, but in the end like those who kept the story of N-Rays and cold fusion alive. We have much to learn in the psychology of Cargo Cults. It remains and area in the philosophy of science that is itself a mystery. How do these things happen and why are so many people successful leading failures? What RNAi has taught us is that, in fact, science corrects itself. How do we stray from the truth and how much work goes into correcting ourselves?

Don't believe in the hype of a trendy science story. Believe in the truth. As Alan Sachs would say, there is power in the long term potential of the modality.

RNAi Strikes Again

2011-12-13T06:30:00.000-08:00

It appears that the only thing RNA interference has accomplished thus far is a whole lot of disappointment. After my first RNAi experiment worked I was on board. We knocked out IL2 which led to an inhibition of osteoclast formation. Of course that was early on in the research. I later came to the conclusion that the inhibition of osteoclast formation was a fluke. Did I forget to add RANK-L? Would another day of observation have resulted in a full bloom of osteoclasts? As is normal in unreported science, the result was unclear. The probability of what we were hoping for (RNA interference) seemed to diminish with each new attempt at repeating the IL2 knockout.

The company I was working for soon ran out of cash and shut down having never repeated that experiment. Many laboratory workers tried but none could reproduce the results of that simple experiment. The way this type of science works is to have a desired result or even better, a one time observation, and force it to be the truth. The Beer and Pizza diet began. What concentration of RANK-L was used? Where did you buy the cells? Different technicians were brought in to overcome the incompetence of the last. All the while our successful experiment was presented to the investment world in 3 perfectly understandable slides. Just add RNA and away goes osteoclastogenesis.

The reason we went after IL2 was because we were a Bioinformatics company. We alone made the connection of IL2 to the RANK pathway using Bioinformatics. For that brief moment of success, we had added laboratory evidence. It brought out the worst in everyone. We needed this to be true. Our company was hurting and eventually filed for Chapter 7 bankruptcy. If IL 2 had become a drug target for Osteoporosis it would have changed everything.

RNA interference and IL 2 research continue however, with expected outcomes. AVI Biopharma (self proclaimed global leader in RNA based therapeutics) is axing 28% of its staff after missing out on a potentially huge federal contract to make an RNA-based treatment against pandemic flu. RNAi is also used by Dr. Steven Elledge.

Using the power of small interfering RNAs (siRNAs) to silence gene expression, we are now undertaking loss-of-function screens in mammalian cells.

Why is such a powerful research tool involved in such a curious story as the one coming from Dr. Elledge's laboratory?

IL 2 is in the news lately with a new retraction from the Bulfone Paus saga.

RNAi and IL2 research could one day lead to important information that will advance the life sciences. What I do is merely research. We find pieces of evidence and we try to figure out what is really going on. The complexity of a pathway is not simply understood by knocking out one of the many proteins involved. Nor is the complexity of RNAi understood by witnessing the many cases of gel manipulation in major publications from Harvard professors. It is odd but not direct evidence that RNAi does not work. IL2 is involved in a few sketchy cases of misconduct as well. It proves nothing.

All we have here is job loss and possible scientific misconduct associated with a couple areas of popular research being conducted by highly successful scientists. Are they Cargo Cult leaders? No comment. Is science correcting itself? Yes.

A Trillion

2011-12-09T08:49:00.000-08:00

One of the interesting 2011 reports on the drug industry came from Burrill and Company. They made the claim that Big Pharma hasn't been doing very well.

During the past decade large pharmaceutical companies have pursued an aggressive strategy of mergers and acquisition in an effort to grow their businesses. But an analysis from Burrill & Company suggests the approach has been a failure as these companies have seen the loss of $1 trillion in value during the past decade.

We lost a trillion bucks in a decade? Those of us who enjoy math will stop and reflect on that number. For example, a million seconds lasts about 11 days. A billion seconds lasts about 31.5 years. To be exact, a trillion lasts 31688 years, 269 days, 1 hour, 46 minutes, 40 seconds.

In order to have lost a trillion dollars in ten years we would have to lose $100 billion each year or about $274 million a day.

What does it mean to lose that much money? In that decade I received some of that money in the form of an income. I also spent that money buying reagents and equipment. We paid Retrogen to sequence our DNA and Alphalyse for protein sequencing. While that money was being "lost", others were finding it. Some companies, like Retrogen and Alphalyse, were smart businessmen and women and they positioned themselves to be in line for some of the biopharma largesse.

My car has aged and is now worth less. The value was in fact lost. During the course of the devaluation I enjoyed the usage of my car. It had value and still does, just not as much. Likewise, BioPharma has aged and decreased in value. Unlike my highly reliable Honda Accord however, this baby was a lemon. One of the experts you would trust to make sure you don't pick a lemon is Cargo Cult leader biotech visionary G. Steven Burrill. As the industry was busy losing a trillion dollars G. Steven Burrill was succeeding.

During the course of the trillion dollar loss G. Steven Burrill must have given a warning. Leaders know that losing a trillion dollars is not the goal of any investment. We couldn't actually find any warnings that a trillion dollars was going to be lost. Did G. Steven Burrill succeed in spite of the loss or as a result of the loss? Was the industry loss his gain? How do the Cargo Cults select their leaders when the planes never land?

Prior to the loss of a trillion dollars there were warnings.

Biotech losses 94 to 04

biotech losses 90 to 93

Then came the new millennium.

biotech job losses 00 to 11

To G. Steven Burrill I offer up a different kind of award. The first ever Lifetime Achievement Cargo Cult Leader Award.

A leader is a dealer in hope.
Napoleon Bonaparte

The first ever Annual Cargo Cult Scientist Awards are coming! Silvia... you're getting one. The rest of you will have to wait and see.

Don Polderman

2011-12-01T05:41:00.000-08:00

One of the things I do from time to time is check the stats on my blog. Most recently I've been getting a lot of hits from people typing Don Polderman into their search engine. There are people who want information. What has Don been up to lately? Has he found a new job, issued some statement regarding his dismissal, published a new paper, invented a new drug, started a biotech company... But a curious thing is happening. If you type Don Polderman into Google, the Cargo Cult Scientist is third on the list!

Are people concerned about the impact of a scientist who published over 500 articles and was fired for scientific misconduct? Are they willing to talk about it? Why hasn't this incident generated a public discussion?

My answer to that question would be cynical. I would cast dispersions on the world of science. I will join the rest of the scientific community who type his name into Google and stumble across this crazy blog. I will skip a detailed research project into the impact of Dons Sins Against Science.

This blog is really about the scientific method. The method can be applied to finding out whether or not your kid is lying to you about brushing their teeth. It can be used to find out if a drug can be manufactured at a 50,000 liter scale or if that drug is useful in treating human disease. The method can be used to find out how much BS Don Polderman has put into the scientific discourse. But professional scientists talk like Don. Judging by the amount of publications, Don was very good at talking. Now we have more information on Don however. Somewhere between the proper application of the scientific method and the kind of scientific misconduct Don Polderman is accused of lies the truth. Was he an outright fraud? Did he really make unintentional mistakes? Is it worth finding out? What about those 500 papers. If they were worth publishing in the first place, is it worth revisiting them? Why, at this point in Dons career, are we abandoning the scientific method? In our opinion now is the most important part of a scientists career to be analyzed using the scientific method. Instead we will brush this one under the rug.

Don Polderman will fade away. But here at the Cargo Cult Scientist, we will hold him in high regard as one of our leaders. Our airports do not bring in cargo. Our airport is a place where people who have no idea how airplanes operate (or even where airplanes come from) become experts in airports and airplanes. The tribesmen are suppose to be obedient and not talk about embarrassing moments experienced by our leaeders, best described in The Emperors New Clothes. We don't know where airplanes come from. But some of us know that our leaders don't either.

A Tale of Two Janets

2011-11-30T06:31:00.000-08:00

Janet had an important job. Unfortunately, just as she was about to wrap up the show, her boob fell out. The exposure was an embarrassment to those who placed their confidence in her. The exposure of that one boob led to a Congressional investigation!

Of course I'm talking about Janet Jackson, not Janet Allen the director of research at the Biotechnology and Biological Sciences Research Council. Janet Allen had an important job as well, director of research for the Biotechnology and Biological Sciences Research Council. She finished her career there with a boob exposed in the form of a former PhD student and world class Cargo Cult Scientist Alirio Melendez. There was no federal government investigation into her culpability in this boob incident however. She let this boob out into society. This boob should have turned her face red and sent her scrambling to find a solution to reversing the damage that was done. Instead:

Douglas Kell, chief executive of the BBSRC, publicly thanked Professor Allen for her work at the research council. He said her "leadership and personal drive" had led to "noteworthy" contributions to the delivery of every aspect of the organisation's strategic plan, including multipartner programmes and the move to longer, larger grants.

Contrast this praise with the fallout from Janet Jackson boob falling out. The NFL Commissioner Paul Tagliabue was apologetic before Congress! How much control would he have over such an incident? How much warning did he have that this boob would be exposed? Perhaps we need science commissioners to apologize and help make sense of our own boobs.

What Janet Allen did was have a successful career. She did increase her organizations grants and their duration. Who could ask for more? Well... I could. Did the planes land? What was the outcome of those longer more expensive grants? Who benefited most? I would have to say that it was the brass at the BBSRC.

Those of us who watched Janet Jacksons boob falling out at halftime of the superbowl on national tv had something to talk about the next day. It was funny to me and I knew there would be outrage amongst our conservative branch of society. Yet in science, we are not seeing that branch who are outraged by people who direct bogus research. We don't think they have any responsibility controlling rogue scientists who blatantly manipulate data and spin yarns in scientific journals.

And so we continue on with another saga in the Cargo Cults of Biotechnology. A director of scientific misconduct offers no apology. Janet Allen stepped down as director citing personal and private reasons. Her relationship to Melendez and the research they did together is not something she wants to revisit. Another unsatisfactory ending to a possible learning experience. I'm guessing we will see many more cases of scientific misconduct before we see another female breast on mainstream TV.

Geron Research

2011-11-24T08:40:00.000-08:00

What is research? Wiki says, "Research can be defined as the scientific search for knowledge, or as any systematic investigation, to establish novel facts, solve new or existing problems, prove new ideas, or develop new theories, usually using a scientific method."

Geron conducted research into the use of human stem cells for use in spinal cord injuries. What we at the CCS would like to spend our days doing is conducting research into research. Measuring the measurements. We would love to learn everything we could about stem cell research. That is to say, we want to research the research. A prime target of our research would be the Roslin Institue and Geron.

The curiosity of Keith Campbells departure prior to the Roslin Institute selling their cloning technology to Geron followed by the failure of Geron to reproduce the work needs to be understood. Why couldn't Geron scientists do what Campbell could do? Campbell left the Roslin Institue in 1997. In 1998 Campbell in collaboration with PPL (Pharmaceutical Proteins Limited) created another sheep named 'Polly'. She was made from genetically altered skin cells containing a human gene. In 2000, after joining PPL Ltd, Campbell and his PPL team (based in North America) were successful in producing the world's first piglets by somatic cell nuclear transfer (SCNT), the cloning technique. The PPL teams based in Roslin, Scotland and Blacksburg (USA) also used the technique to produce the first gene targeted domestic animals as well as a range of animals producing human therapeutic proteins in their milk.

Geron finally called it quits last month. What went wrong? That is the research question is ask. What were there success stories and how did it all lead to nothing? My hypothesis is that scientists and businessmen do not think the same way. Both groups of thinkers wish to hold the title of scientist. The former adopt the title to help others identify their chosen profession. The latter want to make others think they are like the former.

Ultimately I am trying to get at the understanding of the thinking that separates a scientist from the rest of the human race. An example of scientific thinking comes from a comment given on the link to Gerons decision to hang up the stem cell research.

This company would not walk away from this trial in the absence of an unexpected complication or safety concern, if there was any evidence that it was working," said Dr. Daniel Salomon, associate professor in the department of molecular and experimental medicine at the Scripps Research Institute in San Diego. "The assumption has to be that they designed a study with a purposeful plan to complete it to a certain benchmark of efficacy and that they had the funds for that effort in hand.

Then comes a concept straight out of the Cargo Cult Science speech.

Without seeing the data, one cannot be certain that there was not a clinical reason for stopping the trial," said Dr. Robertson Parkman, professor of pediatrics at the University of Southern California.

Indeed in the research of the research, the data must be seen. We must present all of the data, not just the stuff we want people to see. How could a researcher of research gain access to the data? Who would pay such a person to conduct such research?

The data is piled high but in that pile is Dr. Campbell and his successes. Geron scientists couldn't pull out what was necessary to reproduce the work. The executives steered the research into a profit driven R&D project that failed. The connection between cloning an animal and using stem cells for regenerating human tissue, organs and whole beings is there. That is a separate research project. What I am interested in is how we miss that connection and veer off into the cargo cults.

Like Poldermans 500 papers, the quantity of research is great. The quality is suspect. Stem cell research was and is overhyped. "Embryonic stem cells are not ready for 'prime-time,'" said Dr. Bryon Petersen, professor in the Institute for Regenerative Medicine at Wake Forest Baptist Medical Center. "There are too many variables about these cells that we just don't know about." How do we get to "know about" the variables? Certainly not by starting a biotech company and hoping to make drugs out of the cells. Science conducted honestly will eventually spit out a useful medical application. Pursuing a useful (profitable) medical application will most often not produce anything resembling science.

Avastin Oh Avastin

2011-11-20T06:35:00.000-08:00

"Sometimes, despite the hopes of investigators, patients, industry and even the FDA itself, the results of rigorous testing can be disappointing." FDA Commissioner Margaret A. Hamburg

Hamburg said the choice was difficult because so many women and their doctors have put their faith in the drug and lobbied hard on its behalf.

"It does not improve survival," said Dr. Joanne Mortimer, director of the Women's Cancers Program at City of Hope in Duarte, who served on two of the three FDA advisory panels that debated Avastin's use for breast cancer. "Yes, it keeps your cancer under control longer. But … the risks are pretty huge."

They claim that Avastin will keep your cancer under control but you will have a higher risk of death from stroke or heart attack. The medication raised blood pressure and increased the risk of congestive heart failure. The risk of serious bleeding was five times higher among users of Avastin than it was for those on chemotherapy only. What about survival?

Hopes that Avastin could prolong life for patients with advanced breast cancer rested on a 2007 study in the New England Journal of Medicine. Researchers found that patients who took the drug in combination with the chemotherapy agent paclitaxel experienced an 11.8-month window, on average, during which their cancer was not growing. That compared with an average of 5.9 months of progression-free survival in patients receiving standard chemotherapy alone.

But even in that study, patients on Avastin did not live longer, said Dr. Kerin Adelson, a medical oncologist at Mount Sinai School of Medicine in New York.

A later study confirmed Avastin's failure to extend survival, and brought the drug's risks into better focus, Adelson said. (One of her own breast cancer patients who took Avastin had a massive stroke, she said.)

"Many drugs will improve the amount of time it takes for a cancer to grow but don't improve the amount of time a patient lives," she said.

Alas you would think that an interesting cancer research project would be born. Using tumor growth as an end point to a cancer drug development program is flawed. What could be a better approach? Avastin generated about $3.5 billion in sales in the United States in 2010. Sales have dropped since the FDA made it known that they were concerned about the risks and the lack of efficacy on survival.

That plane did not land. People still want to take it. At $5oK per year, that cargo plane should land and bring with it plenty of health and happiness for those running short due to breast cancer. Since it doesn't, we have to say good by. The choice should not be difficult for the FDA boss. Ah but how reluctantly the mind consents to reality!

500 Papers

2011-11-18T06:19:00.000-08:00

Retraction Watch posted the story yesterday of Dr. Don Polderman who was fired from Erasmus University in Rotterdam for scientific misconduct. He studied the risk of complications during cardio-vascular surgery. According to the DutchNews website, "In particular, he failed to obtain patient consent for carrying out research and recorded results ‘which cannot be resolved to patient information."

Having a forum like Retraction Watch allows for a conversation that doesn't always take place among people interested in science. We know people cheat. We know all of us are prone to fooling ourselves. What a forum such as Retraction Watch does is provide a journalistic approach to the fallout of being wrong. You might be purposely wrong or accidentally wrong. Being wrong however is nothing to be ashamed of. In fact finding out that you were wrong is how some of us learn. The greater our concern over right and wrong, the greater our desire is to understand why something is true or false. Retraction Watch opens up room for a conversation on the way in which scientists communicate (publish their work) and how flawed the system can be.

Our analogy of the Cargo Cults provides another way of looking at modern science. We like the philosophy of right and wrong and how subjective the two can be among mere mortals. Let's take two of the four comments currently up on Retraction Watch's story on Dr. Polderman.

Polderman has “some 500 publications to his name”; does that number, 500, alone incite incredulity? A vast undertaking would be to review all of those publications to determine just how unique and how reliable was each study. Conrad Seitz M.D.

It’s a culture in clinical medicine to just look at the quantity, not the quality. You need to get more than 15 publication/year in order to reach 500 in a 30 year career span and this is a theoretically impossible task if you’re doing real science. Jey

These two concerned scientific people seem to be at odds in their philosophy. Dr. Seitz suggests that the quantity of publications is not important. He suggests reviewing each paper. Jey suggests that 500 papers in 30 years is too good to be true. Looking at the quantity of publications versus the quality of them seems to be a part of the culture of success in clinical medicine.

When I was a boy in Boy Scouts we had a contest of who could hold their breath the longest. The winner went about 4 minutes. Of course the winner and everyone who made it past the first minute were cheating. We didn't really need to follow each boy scout to see when they took in a fresh lung full of air. We didn't need to hold a mirror under every kids nose to see if they were breathing. We knew that the max of holding ones breath lasts about a minute. Jey is very astute in his observation regarding the number of papers Dr. Polderman has his name on. Jey goes on to say "Only possibility I can think of is that everyone in the building have been putting his name as a co-author. It’s even difficult to make up over 15 papers/year".

It is very difficult to take a single paper and reproduce the entire set of experiments and come to the same conclusion as the lead author. The list of authors on a paper haven't even taken the time to verify (in the lab) what is being reported. Therefore Dr. Seitz has proposed a far more difficult way of resolving this situation. Rather it would be of some value to assess the main thrust of what Dr. Polderman has put forth for the medical profession and to first look into the papers that support those ideas. Along the way perhaps a pattern will emerge that will lead us to pull out other papers that may contain false information.

The fact of the matter remains, a successful doctor/scientist has been caught cheating once again. As Jey pointed out, one would have to publish 15 papers a year. In 2001 Jan Hendrik Schon of the infamous Schon Scandal was listed as an author on an average of one newly published research paper every eight days. A pattern is thus already apparent for scientists. The quantity of ones publications may be inversely correlated to the quality.

I have my name, as an author, on a paper that was "published" in the Journal of Biological Chemistry. In fact, that paper is listed as a paid advertisement.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Other than that paragraph, the paper looks like a normal peer reviewed article. It is listed on the authors resumes. I did the work, my supervisor wrote the paper, our CSO signed off on it and a couple others got their names on it as well. And of course it is part of the art of deception.

Those who work inside the laboratories are usually too young, scared and otherwise unfit to take on the likes of a powerful doctor such as Dr. Polderman. It takes a lot to correct someone who has captured the attention of the scientific community. My thanks go out to Retraction Watch for the valuable service they are providing to help shine a light on the dark side of science. We, who have worked or currently work inside the laboratories know all about the pressure to obtain publishable results. It is the Cargo Cult Culture. It is not important whether or not the planes land. Our careers present a conflict of interest in the pursuit of the truth.

The Art of Journalism

2011-10-23T07:45:00.000-07:00

Bill Moyers recently quoted a mentor of his: "News is what people want to keep hidden; everything else is publicity."

Does science truly have a journalistic style publication? Does anyone report on the ebb and flow of information being put forth by scientists? Xconomy sponsors the "Biotech is Back" conference. The WBBA organization holds an annual meeting. "This intense program will be a celebration of our successes, and a discussion of the industry’s current challenges and coming opportunities locally, nationally and globally." One of the speakers is the CEO of Eli Lilly who took control of Washington's largest biotechnology and fired the vast majority of its employees in 2007.

This is of course an example of publicity. The public relations groups include WBBA, Xconomy and the governor. They are the leaders. Who could report on their activity? Objective journalism should come from somewhere but who could gain access into these leaders and tell the story of what they do? This is science and the leaders have set up a system that excludes the sharing of information.

It would go something like this: WBBA hosts annual meeting. Guest speakers include governor Gregiore and the CEO of Eli Lilly. In 2007 Eli Lilly gained complete ownership of Cialis, and promptly shut down Icos operations and laid off Icos personnel, except for 127 employees working at the biologics facility. Icos was the largest biotechnology company in the state of Washington at the time of the acquisition, and employed around 700 people. In December 2007, CMC Biopharmaceuticals A/S, a Copenhagen-based provider of contract biomanufacturing services, bought the Bothell biologics facility and retained the existing 127 employees.

In addition to the layoff of Icos employees, other aspects of the acquisition were equally controversial, such as assertions that Icos was being sold too cheaply and that conflicts of interest existed. The latter related to Icos senior executives, who – despite poor stock performance, in part from failed clinical development programs and an inability to successfully license drugs over the preceding years – were to be massively compensated upon a successful acquisition.

Senior executives at Icos received cash payments worth a combined $67.8 million for selling the company to Eli Lilly. Icos chairman, chief executive, and president Paul Clark received "a 'golden parachute' worth $23.2 million in severance pay, cashed-out stock options, restricted stock awards and other bonuses for retention and closing the deal." Nine senior Icos executives received similar packages, each worth more than $1 million.

Pharmaplasia and Us

2011-10-19T07:14:00.000-07:00

What ails the pharmaceutical industry? There are many perspectives. The one from the leaders of Seattle is that nothing ails us. We're doing fine. Then there are the others.

I've just started reading Pharmaplasia by Mike Wokasch. He is coming from the executive level in business and marketing. He has worked as a pharmacist, a pharmaceutical sales representative, marketing manager for blockbuster products, and he has held corporate officer positions at large and small companies. He is passionate about the need for expertise and professionalism in any career choice or job function.

Having yet to read the book, I am skeptical about the marketing side of pharmaceuticals. In Cargo Cult terms, his job is to make people believe that the planes are coming. He does not need to have any idea how a real airport works. After all of the business and marketing meetings are over, you still know absolutely nothing about the natural world or how the human body lives and dies. Yet M. Wakasch has taken an important step. He has admitted that there is a problem. In Cargo Cult terms, he acknowledges that the planes aren't going to be landing as advertised.

There is a distinction that has to be made however. A laboratory scientist is not considered a professional. We do not have the same kind of career paths as executives or marketing professionals. We do not make as much money. We are not expected to grow as laboratory professionals. The layoffs, such as Amgens announcement today, make laboratory workers who serve the R&D side of the industry less than professionals. We learn a skill such as running an ELISA and that becomes our "profession". We serve a piece of the puzzle being assembled by higher ranking PhD scientists who work out of offices. When they fail, we fail. A true professional must have some control over their livelihood. The laboratory professional lives each day in fear of the layoffs that result from not curing cancer. The marketing professional at least has some control over how a product sells, whether is works or not.

The current system is based on the assumption that leaders are the creative types who innovate. Pharmaplasia at least takes on the notion that we have not done well as of late. Here at the Cargo Cult Scientist, we believe that human beings have always had a problem with new and powerful ideas. New and powerful ideas upset the status quo. They elevate true innovators above those who sit comfortably in powerful positions. There is resistance. Imagine sacking the staff who makes the decisions and leaving behind the professionals who can take direction and quickly test the ideas of any leadership. Imagine a research staff held accountable only for executing the experiments set forth by them by the leaders. The outcomes of the experiments must be dealt with intelligently and scientifically by the leadership. When they fail, they shouldn't be allowed to wash it all away by laying off the laboratory staff.

As I read on in Pharmaplasia, I am certain I will find new things to write about. As a former "professional" who was placed into various silos and pigeon holes, I am certain I will be receiving an education as to how those who put me there think. My own inability to effectively communicate with the leaders of my cults is of little concern to me. I see the fallout everyday when I read about "massive layoffs, slowing revenue growth, a major blockbuster “patent cliff”, disappointing R & D productivity, never-ending product liability lawsuits, allegations of illegal marketing and sales activities that lead to billion dollar fines and settlements, and the list goes on" (as stated on the Pharmaplasia website) I know I wasn't exactly wrong about my predictions. I feel we in the industry are average people convinced that we are Einsteins. Certain things prevent us from succeeding but those things can be overcome. You do not hire a group of recent college grads and tell them to go make an airplane. You need experience and not just any experience. You need professionals. Those professionals must then produce new professionals. The most important thing is that the airport works.

I no longer work in the industry. I've moved far from the hubs of biotechnology. Yet I still care. The complexity of the human body makes R&D the most perilous profession out there. Research and development remains an area where human beings will always attempt to employ the scientific method. It is that method and the Cargo Cult Science approach that keeps my interest. I long for the day when we begin to face our failures and learn from them. You can layoff the laboratory staff but you are left with a poorly educated (and I'm not talking about the University education) group of professionals who do the bidding of those who never seem to suffer the consequences of bad science. Good luck to the Amgen R&D folk who have lost their jobs. You are tribesmen. Learn from your experience. Speak out. Tell us what you think went wrong. Read Pharmaplasia. Read. Write. Think. Talk.

Why Quit Now?

2011-10-17T07:23:00.000-07:00

I've reached my new location. I'm in a secret hiding place where I have decided to keep taking shots at the Cargo Cults of Science.

First news item. Bristol Myers Squibbs drug, Yervoy, has been rejected by the UK Health Cost Agency.

About 30 percent of patients treated with the drug would have improved survival, with 10 percent potentially experiencing long-term benefits, the National Institute for Health and Clinical Excellence said in a statement today, citing clinical specialists.

The drug costs about 80,000 pounds ($125,600) per patient, said the agency, known as NICE, which advises the National Health Service on whether drugs provide value for money. Yervoy is the first medicine proven to extend the lives of patients with advanced melanoma, the most deadly form of skin cancer.

Has Dendreon tried to get approval in the UK? Would it prove to be cost effective? Should the U.S. form a Cost Efficacy Agency within the FDA? Step A, approve or reject a drug. Step B, decide if the government is going to pay for it. If not, let the drug maker sell the approved drug on the free market. As BMSs mission statement goes, "Bristol-Myers Squibb is a global BioPharma company firmly focused on its Mission to discover, develop and deliver innovative medicines that help patients prevail over serious diseases." It is their job to deliver $100K+ drugs to people without government or insurance assistance.

News item number 2: Cargo Cult Scientst #1, Hwang Woo Suk has cloned a coyote.

What did we learn from his stem cell scandal? The disgust we may have for him is merely a personal feeling. It is not what motivates science. Yet we are now faced with a profound skepticism that will bring about the scientific method. Did he clone or not? How do we find out? At least we know that a peer review process isn't enough.

Time to grow. Biotech/Pharma drugs are getting too expensive. They are asking the sick and dying to assist them in extracting undue amounts of money from our government and insurance agencies. Hwang Woo Suk is claiming to have cloned again. They have cloned a dog and it is said that this was verified. It is time to see him hired by Geron. Assemble the same people who gave him the stamp of approval for his stem cell work and let them try again.

A Cargo Cult Tribesman No More

2011-09-21T05:02:00.000-07:00

After 18 years in Cargo Cult research (how to get the planes to come), I'm calling it quits. The planes never came. As we looked to the skies, fires lit along the runway, man in tower with coconut headset, the clouds floated by gracefully with no signs of even a distant jet stream. We stared upwards for hours, months, years, but they never came. We rearranged our airports, made new tiki torches to illuminate our ceremonies, changed radio ladies so our leaders could talk to the gods more clearly. It seemed like we couldn't fail. We had so much hope.

As I prepare to leave the Cargo Cults of Seattle, I must draw some final conclusions on what this has all been about. The blog, the work, the career must all come to an end. The traveling from town to town was Woodie Guthrie without a soul. This past summer I had an epiphany about what biotech/pharma is all about. On a dreary gray day early in summer, I made my way to an old theater in the University district that showed mostly documentaries and Indie films. The film was called Forks Over Knives. The two doctors featured in the film came from farms. They grew up eating food that they grew and/or killed themselves. They studied other cultures and learned that what we eat has a major factor on how we feel and how we die. I realized that I work in a field that treats the side effects of the American diet/exercise/stress lifestyle. We have pills for stress, insomnia, obesity, diabetes, stiff joints, restless legs, diarrhea, head-aches, cancer and AIDS. In the case of the last two illnesses, I'm convinced that some of the treatments make the situation worse. Because we have a hopeless population, we've gotten away with it. We don't want people to get better. We want them to die taking our $100K+ pill regime.

The real treatment for what ails us is diet and exercise. In the film, Forks Over Knives, patients given two year death sentences by their doctors were still alive after five years. Diabetes patients were no longer in need of the pills, much to the chagrin of their doctors. An old Chinese gentleman diagnosed with cancer talked about how his sex drive returned as a side effect of treating cancer with proper diet and exercise. It worked better than Viagra! The side effects of treating one target with pills are usually things like diarrhea and vomiting. The side effects of proper diet and exercise treatments are erectile functioning!

In Forks Over Knives I saw the real Cargo planes landing. On the other side of the island where we weren't allowed to go was an airport with Allied forces still operating. They demonstrated that the real way to treat what ails us is to ingest proper food. They taught me how to get "wealth into the system". I learned how to get the Cargo planes to land. I saw the cancer patients remain alive and well. I saw the diabetic who no longer needed his pills. The pills come after the sugar chains and processed boxed cereals, mashed potatoes and macaroni and cheese powder. The pills are the greasy eggs and sausage used to treat a hangover. When I see my older relatives, obese, suffering from heart disease and diabetes, I know I can help them. But they live on the Cargo Cult side of the island. They want the pills. Pills are hope. Pills are Cargo.

I've been angry about many things. I'm not the good obedient worker that George Carlin depicts in American Dream. I wanted to avoid the cubicle and the endless meetings. In the lab I found a place where being clever was a measurable quantity. If I clone a gene, grow it up, purify the protein, and run a binding test, I can watch my progress. I've seen people do that much work in two weeks. I've seen others flail away at such a project for years. I've seen the good and the bad and I know that they are aware of each other. The Allied forces airport workers know that the natives are on the other side of the island trying to emulate their airport. The contract manufacturing organization who requested that our director not attend the process development meetings was such a situation. Our small biotech company was not aware of the terms upstream and downstream process development so we labeled our director, "Scientist". Later it became director of target biology. He was the proverbial old lady with the wire wrapped around her (Cargo Cult radio) so our chief (CSO) could speak to the gods. When he met with what our cult thought were his real airport counterparts, they cut him out of the process. Happily he went back to the cult to prepare the next ceremony. He dealt with natives, not allied forces. He made me angry, as did the followers who adored him. The five people who left the part of the cult, including me, left shaking our heads. We represented nearly fifty percent of the Cargo Cult process development group. The first to leave came directly from the Allied side of the island. He left a note one day that read only, "Beam me up Scottie, no signs of intelligent life".

I don't know where to go now. It's hard to explain a career of working in this Nobel Prize winning lab, two failed teeny tiny southern California biotechs, one failed Seattle biotech and a final biotech hasn't failed yet, but is the most bizarre of them all. The Prusiner lab taught me that even a Nobel Laureate has a hard time interpreting a simple western blot. The antibody company in East LA sold themselves to a bigger company that failed clinical trials (phase III) in 2005 and called it quits after 20 years and half a billion dollars. The bio-informatics company folded up shop 9 months after I started after losing a battle with Rosetta to become a subsidiary of Merck. Rosetta was shut down last year. The nasal spray company fired the staff and replaced the CEO and CSO with RNAi successes from SIRNA. SIRNA was shut down a couple months ago. The RNAi company fired the CSO but kept the CEO. They are now on life support. And the most bizarre company of all have not made any news lately. Such an uncomfortable silence from a company that sells promises is usually a sign that they are ready to give up the scam and take their profits. What I know is that they have not taken a serious run at a second drug development candidate. The first candidate in the pipeline was successfully partnered up but it will never become a viable product due to a profound manufacturing incompetence. The other two candidates announced just last year will never be partnered up because they were announced to break the silence of a four year lack of productivity. The leaders of this Cargo Cult led a previous group of 90 that was shut down for their... lack of productivity.

For those who are not angry, you're not paying attention. I'm a concerned scientist who sees an industry ran by greed and other forces that destroy scientific integrity. The failure of so many projects and companies, compared to the success of Forks Over Knives, has led me to my belated decision to move along. My final experiment will be to continue on the Forks Over Knives path and live to be 100.

So I have just one wish for you--the good luck to be somewhere
where you are free to maintain the kind of integrity I have
described, and where you do not feel forced by a need to maintain
your position in the organization, or financial support, or so on,
to lose your integrity. May you have that freedom.

Multiple Intelligence

2011-09-15T09:02:00.000-07:00

Every day in life we experience education. You learn something new every day. There are several concepts here that I think need to be explored in order to understand yourself and those around you.

If you were an A student, the chances are you have what Howard Gardner calls law professor intelligence. You have linguistic and logical intelligence. Think Naom Chomsky. If you are heavy on logic and weak on personal intelligence you are more like Ted Kazinski. Both obtained PhDs and found employment in highly regarded universities. Both went on to international fame. Both might be considered misanthropic with regards to some segment of our society. What was the intelligence that prevented Naom from falling into the same hole as Kazinski? As Naom pointed out on the video I posted last week, he put up with stupidity in order to reach the next level. Naom Chomsky believed the end justified the means. Kazinsky believed the means ruined the end. He saw the means as a filter that separated the good from the bad and the bad was what was left at the end.

Education is a filter. We have "weeding out" courses in science. Freshman chemistry can be a tough course for some and many will drop out. The first day of class there are 400 students. By the final exam you are at less than 100. Simply by looking at the percentage of drop-outs in a weed out class, we can get an idea who excels in logical intelligence. Where do the drop-outs go and do they then excel at their new class? Maybe they switch to English and get an A. They are word smart. How would Oscar Wilde have succeeded as a chemist?

We have many examples of extraordinary genius in logical intelligence. Autistic humans have an uncanny ability to do math, to see numbers as colors and shapes that comes together quickly for a logical conclusion. They may also be able to play Beethovens Moonlight Sonata after hearing it only one time. These are forms of intelligence we try to teach students. I think of it as intelligence chromatography. We have a resin that captures certain kinds of intelligence. We pass through the entire student body. Those that pass through we give Bs, Cs, Ds, and Fs. Those who get As stick to the resin. We can then pass them on to other resins. The linguistic and personal intelligence resin shows that our logical intelligent autistic A student is not fit for society. They move on to all Fs.

Who succeeds as A students in all forms of intelligence? The law professor! Lucky for the law professor we don't require that they get an A in gym. It is our society that puts together the list of intelligence to which one must demonstrate a stickiness. As we pass through the education system we must go through numerous intelligence chromatography columns. After education comes employment. Now is where biotechnology comes in.

Most biotechnology workers are of average intelligence. The average laboratory worker is content to remain in the lab cloning, purifying and running the assays. They would have been successful farmers or mill workers in an alternate era. They passed through the intelligence filters with a smattering of As Bs and Cs. The leadership excel in linguistic but not business logic. Their intelligence filters come from PhD programs in science. They lack the ability to translate good science into scientifically developed products. They would have been snake oil salesmen in an alternate era. The support industries, companies like GE Healthcare or Stratos Product Development, provide equipment that automate things like DNA sequencing, cell culture, and protein purification. They would have worked for GE in an alternate era.

I often wonder what would happen if you could get a small child from a modern day cult. How would they succeed in our society. Could they become biotech professionals? As they say, it's not how smart you are, it's how are you smart? I think they would do well. Show them the ritual to purifying DNA. Let them know when the ritual is to begin. They wouldn't aspire for more. They would look too the leaders and hope they get to share in some of the cargo. When it never comes they just keep performing their part of the ceremony meant to bring the cargo. When sent from the tribe they go and find another. They hope the ritual performance is equal to that of their would-be new tribe. The tribe, suspicious of other tribes probes them on their understanding of the cargo rituals. If they possess the proper intelligence they will be allowed in to perform their understanding of the ceremony.

Rice Fields

2011-09-14T12:46:00.000-07:00

Once again Malcolm Gladwell has stopped me dead in my tracks and forced me to rush back to this ridiculous blog. The topic is rice fields. In Outliers Malcolm discusses Chinese peasants who meticulously set up their rice paddies. They have a clay bottom with mud and fertilizer base for the seeds. They are then flooded with water and tended to every day. There is a balance that is maintained by hand, not automation. What the peasants know is hard work and an exact science.

Conversely there are the peasants in Russia. They plant their seeds and hope for rain. Their form of farming relies on luck. The Russians believe that God will provide.

So what is the culture of biotechnology? On October 24, a meeting with the "leaders" in the field of sequencing genomes will convene. They believe that this is the future for medicine. Why? If you step back and take a different angle, you will see sequencing a genome as a research tool. One probability is that the future will be same as Retrogen or Qiagen. The people excited about it should have already done the kind of thinking that would make this tool desirable and not just another sequencing service for researchers. It is a tool. What to do with it?

Think of it this way. A prion is a mis-folded form of the PrP protein. The theory goes that the mis-folded protein causes the formation of plaques in the brain and eventually a horrific death. We now have a few end points to look for if we could just find a way of preventing the proteins from becoming mis-folded. We need a tool. That tool could be an antibody that only recognizes the mis-folded protein, not the normal PrP protein. The antibody will bind to the mis-folded protein and prevent its theoretical action of causing other PrP proteins to become mis-folded and joining hands to become a plaque. To be honest, I worked on such a project. Such an antibody is hard to find. We never found it nor has anyone else.

From the above paragraph the average sophmore should be able to create a list of projects one could embark on if they were magically handed the prion antibody. For example, coat 2 ELISA plates with 95 normal brain samples and 1 scrapie infected hamster. Test one plate with the anti-PrP antibody and the other with the new tool antibody. One plate will light up in all wells. The other plate will have only one well light up. Eureka! Next you move on to in vivo studies. You create analytical methods.

This type of research in fact takes place every day. We select targets, make antibodies and run them through our tests. Going back to the genome sequencing, we don't have a plan. Both situations are similar to the concept of planting seeds and hoping the Gods will provide. The board and the executives plant the seed and they leave the field work to the peasants. If the seed is strong and there is plenty of sunlight and rain, success will be certain.

Now back to the Chinese rice farmers. They do not take chances. They are extremely poor and failure is not an option. This is akin to what engineers do. If you make a car, everything must work. If the brakes go out or even if they squeak, you will have to go back to the drawing board. Therefore, each new version of car is built upon the history of making cars. Engineers develop the cars. Engineers develop the way in which a car is assembled. Engineers develop the assembly line!

Biotechnology executives however, have to hold public chat sessions where they discuss what can be done with the latest tool. They have given the problem some thought and are now ready to talk about it in public. In public speaking is what they are good at. Knowing what to do with new tools is not what they are good at. They are not like rice farmers or engineers. They are like Russian farmers who have planted a seed. A dust-bowl season will ruin the crop. That season is akin to a small handful of genetic researchers being the main customers of the $1000 human genome sequencing companies. The ideas that come from the stage of the upcoming meeting must inspire. They must convince the world that science is going to be turned upside down by this technology.

But we've heard this before. The human genome project created so many patents they had to end the practice of patenting genes. Where were the guys who knew what they were going to do with the genome sequence? Where are they now? The executives of the old companies got rich but what did we learn about our genome? Is it a useful tool? The new companies are like the old. They are hoping for someone, something to take a hold of their seeds and nurture them into a rich harvest for themselves. Whoever solves that problem won't be the ones up on the stage next October.

I've spoken about practical intelligence. A clever fellow with a high I.Q. can solve difficult math problems but he cannot necessarily become a successful human being. The rice farmers are peasants who live with little money. We on the other hand are successful humans with lots of money and comfortable lives. We rarely succeed. But facing the future of the human genome, who will solve the problem of "what to do with it?" It won't be the executives on the stage. It will be that guy with below average practical intelligence but above average problem solving skills. If biotechnology really wants to figure out what to do now, they have to put an end to the cheer leading, the mitigated speech and the low opinion of the peasants.

They'll Know It When They See It

2011-09-13T07:43:00.000-07:00

Stewart Lyman from Xconomy gives a nice summary of how a drug can act within the body.

Drugs can directly stimulate (e.g. morphine) or block (HIV protease inhibitors) enzymes. They can bind to and sequester molecules (TNF blockers for rheumatoid arthritis). Drugs can replace missing molecules (insulin, hemophilia) and alter the rate of movement of molecules into or out of cells (anti-arrhythmics like sodium channel blockers). Some drugs stimulate the immune system (Provenge, Yervoy), change the pH balance in the body (sodium bicarbonate for acidosis), or interfere with the assembly or function of intracellular structures (anti-cancer drugs like taxanes). Drugs can stimulate the release of stored molecules (epinephrine), or interfere with DNA synthesis (sulfa antibiotics). Drugs can perturb cell membranes (anesthetics), and effect the modification of proteins, thereby altering their function (histone deacetylase inhibitors). In gene therapy, the drug is often a replacement gene; anti-sense drugs block the formation of proteins by binding up specific mRNAs.

Once you imagine a drug development project, what is the process? The target, where the action takes place, needs to be reached by the drug. Delivery becomes a new research project. How do you make the drug? Process development becomes a new project. The list goes on. What part of the puzzle is the role of a small biotechnology company? What is the responsibility of Big Pharma who is looking for a partnership to beef up their pipeline? What about the CROs, CMOs and the clinical trial branches of the process?

We assume that everyone knows their role. It begins with education. We set up a hierarchy. Responsibility of innovation falls upon the highest ranking members. The lower ranks must bring the innovation to fruition.

A better way to view the field of biotechnology drug development is to draw a straight line. On the X axis is time. On the Y axis is money. Assume ten years and 1 billion dollars. Where along that line are you searching for investment money? Where are you spending the most on clinical trials? Where along that line are you making the critical decision on the drug candidate?

Currently there is no graduate degree where you go through the entire process, without the spending of 1 billion dollars and ten years. We just hope the leaders will react to each situation in the proper way. A graduate degree would speed up the process by building a base of understanding what is coming down the pike. Base the courses on real life situations, such as the pricing mistakes of Dendreon. Maybe throw in a course on the history of financing so the students can have that trajectory in the back of their minds while they think about staying in business.

Undergraduate degrees can become more focused. Biochemistry, microbiology, molecular biology are all degrees that have become nothing more than vocational degrees for low level biotech lab jobs. Instead, focus all of the relevant information into the various areas of early stage research, process development, analytical development and so on. The graduate degree holders will know how to structure a company and thus they will know who to hire based on the education.

Overall, we need an end to the "we'll know it when we see it" process in biotechnology business strategy. You won't know it. It is not an ad hoc process to be ruled over individuals who feel they possess a special understanding of science. At this point it is fair to say that they are not very good at "knowing it when they see it". The weakest point along our line from 0 to ten years ($0 to $1 billion) comes in the early stages. What to do and what to select as the drug candidate is a very "know it when you see it" moment, and thus the weakest moment. It will make or break everything that happens along the line of progress. The rest of the work however is where we can focus education. You should not stumble in process development. It is not a "know it when you'll see it" process. It is not ad hoc. You take on the work, make a plan and you finish the job. The same goes for a clinical trial. Make a plan, execute and analyze. Need money? You have experts in that area.

Currently, Big Pharma is leaving that critical early stage "know it when we see it" up to small biotech. Big Pharma is setting themselves up for even greater failure than we are already experiencing. As Warren Buffet says, you don't ask the barber if you need a haircut. The education we require will not come from the current experts. They are experts in a failed experiment. In the process of getting smarter the cost of that drug development will go down. The time line will be reduced. Imagine a gant chart instead of the single line. Each line, each function along the way to approval becomes separate and can thus be analyzed and improved. Step one is to step back and look at where we are. Look at what we do. The real skill that is missing is not "knowing IT when we see IT". The skill is knowing how to get to "IT".

Mitigated Speech

2011-09-11T10:43:00.000-07:00

Every case of scientific misconduct involves a powerful scientist and dishonest or disgruntled underlings. In the case of Silvia Bulfone-Paus, two rogue post docs were assigned the blame for fraud. In the Baltimore Case a disgruntled post doc outed her P.I. Speaking truth to power is never easy, even when the powerful are scientists. They expect certain outcomes. If the truth differs from the expected outcome, you have a choice. Do you stick with the truth or do you tell the leader what they want to hear?

Telling the truth will require mitigated speech. You have to decide how to tell the powerful scientist something they don't want to hear. In a recent post I talked about a situation where the CEO of a biotechnology company would tell the white lab coat scientists what they were suppose to do in order to find drug delivering molecules. Point A, (do this) did not lead to point B (and you will have a drug delivering molecule). What was doable was point A. We could make a peptide library. Point B was scientific analysis of point A. To this date, no one has said to the leaders of the biotech company, "this isn't going to work".

The first question that really needed to be addressed was the logic behind the drug delivering holy grail research. The leadership had decided how the holy grail would be found. A peptide or protein would bind to certain cellular proteins and the binding would lead to all sorts of wonderful effects. But how did they know? We hadn't found the molecules that bind yet. Do you ask questions or do you do what you can and hope that things will work out? How do you deal with the research when you find a molecule that binds to it's intended target but the desired effect does not happen?

The term 'mitigated speech' was recently popularized by Malcolm Gladwell in his book, Outliers. He defines mitigated speech as "any attempt to downplay or sugarcoat the meaning of what is being said". He continues with reference to Fischer and Orasanu, to describe 6 degrees of mitigation with which we make suggestions to authority:

1. Command – “Strategy X is going to be implemented”

2. Team Obligation Statement – “We need to try strategy X”

3. Team Suggestion – “Why don’t we try strategy X?”

4. Query – “Do you think strategy X would help us in this situation?”

5. Preference – “Perhaps we should take a look at one of these Y alternatives”

6. Hint – “I wonder if we could run into any roadblocks on our current course”

Gladwell brings up the concept in the context of how crews relate to each other in the cockpit of a commercial airliner, graphically illustrating the degree to which mitigated speech can be detrimental in high risk situations which require clear communication. Gladwell also talks about different cultures and how they use mitigated speech.

What then can we make of the culture of science? It has been shown to be, at times, the art of deception. It is self correcting, but those who possess power work against the self correcting, as exhibited in the Baltimore Case. It pits the P.I. against the underlings, the office versus the lab. There is no way to correct a superior when they are wrong, other than to hope they are open to such a discussion. When a paper needs to be retracted everyone, scientists and journal editors, are embarrassed. They mitigate the need for the retraction or worse, they brush it under the rug.

A new way of communicating science is needed, Does mitigated speech stifle innovation?

Practical Intelligence and Success

2011-09-05T07:03:00.000-07:00

The biotechnology and pharmaceutical industry continues to try and figure out new ways to encourage innovation. As patents expire and streams of revenue dry up, they need the next big thing. It's not that they didn't plan on this contingency. They knew these days would come and they shelled out the money to get people working in the laboratory. What happened?

The lack of innovation can be linked to what is ailing all of science. In a recent discussion on scientific journal retractions from "OnTheMedia" I found two comments from people who have interesting and similar concepts.

Paul Charles Leddy

Science is social, and if a bunch of morons decide to do science, they'll create a world of moronic truths. Those of us who don't want to live in a world filled with these "truths" have to be careful not to let the morons say what is truth. I think the past 10 years have shown this over and over. Same goes for journalism, btw.
Sep. 06 2011 12:43 AM

The key point here is that science is conducted by human beings and we tend to form groups of like-minded cohorts. We create the truth. Those with practical intelligence who want to be a success will gear their work towards the truth of the group, not the truth of nature.

p.f.henshaw from way uptown

Brook and Jonah,
You seem to be seeing only the manageable tip of the problem of finding and correcting errors in science. The cases where right and wrong are simple to identify are not the problem. Science never had, and can't have, a way to "purify" its archives, other than the same way nature purifies her complex systems to remove useless branches, by experiment and evolution.

The deep problem of modern science is that "useless branches" of thinking become the basis of social structures and clung to relentlessly. You see it in how the different "silos" of reasoning form around different socially preferred ways to ask the same questions. One dominant paradigm of that kind is "science as computers" with the dazzling display of results conveying the image of powerful insight, but if tested against the subject addressed often represents no insight at all.

Theorists tend not to study nature at all, just data, their theoretical models, and their social status. The naturalists who actually study the complex naturally behaving subjects of such a study are unable to contribute to the process, at all... don't even get brought in for discussion, for the simple reason that nature does NOT behave at all like a computer (!!) and the questions a naturalist would ask upset the social status of someone representing their theory as nature! ;-) See the problem?

So the core of the problem is the social basis of the questions that each science and sub-science organizes itself around, not just our present self-defeating obsession with computers. As a battle between social cells science becomes as much as if some endless TEA Party argument. Your radio piece seemed to assume that scientists were engaged in scientific debate, but you can't do that when people all standing on different platforms.

I love the imagery of useless branches being the basis of social structures being clung to relentlessly. This takes place inside each company but also among all of science such as the case of RNAi. Where was the hint that Merck bailed out on RNAi because after an exhaustive study they came to the conclusion that it will not be useful as a drug? They bailed but they did not send out any dissenting opinion that would upset the social group who still cling to RNAi.

In order to be successful you have to know what the group wants to believe. That is the easy part. The hard part is maneuvering around empirical evidence to the contrary of the groups "truth". For that reason the most successful members of science do not work in laboratories. Those who do lack the practical intelligence that keeps one out of harms way.

What To Do With It

2011-08-29T11:32:00.000-07:00

It was not a beautiful paper.

Next came the patents. The news that came out today is that the U.S. Patent and Trademark Office (USPTO) has issued a Notice of Allowance for our patent application.

A primary advantage of this patented peptide library is the ability to rapidly screen and identify novel peptides that exhibit cell specific targeting characteristics for directed delivery of nucleic acid therapeutics," said the Chief Scientific Officer. "Delivery remains a significant challenge in the nucleic acid therapeutic space, and peptides with high affinity and specificity are expected to be a fundamental component to developing delivery approaches to a wide spectrum of tissues and cell types. In addition, the library may also be exploited to screen for peptides that function as specific antagonists, agonists or generally exhibit drug like properties.

The only problem is that the library has no ability to do the things described above. It was a dud. The obedient workers did everything they could but they couldn't get the results that validate the statements of the Chief Scientific Officer quoted here.

The CSO didn't mention that the team who developed and tested the library were sacked. They needed to go out and find someone who could figure out what to do with that library.

There are very few people with the expertise and resources to perform this kind of science.

"What to do with it?" was always the question. There was no conversation about "what to do with it" other than use it to target this cell or that cell. But how? That was the scientific "wealth into the system" that Feynman speaks of. Everything else was what Kurt Vonnegut referred to as "Kit Science" in Cat's Cradle. We had molecular biology kits, phage display kits, and we did some cell culture work. We got our patents and paper. But what should we have done with the library?

A lot of scientists I've worked with believe that there is some clever thing we didn't think of. When we got the orders to test the library against specific cells there was no discussion about the possibility that it wouldn't work. We tested the random thoughts of the leaders, various methods of treating the cells, different buffers and so on. When about 100 random thoughts had been tested they told us to go home. It was a relief.

But it doesn't work. No airplanes land. So
I call these things cargo cult science, because they follow all the
apparent precepts and forms of scientific investigation, but
they're missing something essential, because the planes don't land.

Now it behooves me, of course, to tell you what they're missing.
But it would be just about as difficult to explain to the South Sea
Islanders how they have to arrange things so that they get some
wealth in their system. It is not something simple like telling
them how to improve the shapes of the earphones. But there is one
feature I notice that is generally missing in cargo cult science.
That is the idea that we all hope you have learned in studying
science in school--we never explicitly say what this is, but just
hope that you catch on by all the examples of scientific
investigation.

The CSO makes the claim that "peptides with high affinity and specificity are expected to be a fundamental component to developing delivery approaches to a wide spectrum of tissues and cell types". Why are they expected to contribute to this Holy Grail of RNAi technology? How will it work? Feynman also said:

You can know the name of a bird in all the languages of the world, but when you're finished, you'll know absolutely nothing whatever about the bird... So let's look at the bird and see what it's doing -- that's what counts.

I think of the peptide in this library as the name of a bird. They are looking for that name spelled out in amino acid letters. But even if they find it they will still know nothing about the peptide. They have to see what it's doing. How will they do that? Once again, "what to do with it?". Who will ask the question?

There is nothing wrong with not knowing something. That is why we do research. The problem comes when we want to believe something so much that we accept false answers. This library is just a library. It was not conceived of by someone who had any idea what to do with it. That person, and all of the others are gone now. The CSO quoted above inherited the library and he doesn't know what to do with it. Somehow he's figured out that it will be fundamental to solving the RNAi delivery problem. How will he know when they've found the magic RNAi delivery peptide? I guess they'll know it when they see it.

What Is Really Stifling Innovation

2011-08-29T09:57:00.000-07:00

Profit

2011-08-26T15:03:00.000-07:00

The Art of Deception

2011-08-22T14:10:00.000-07:00

Magic is the only honest profession. The pricing of Seattle Genetics new drug is an example of dishonesty in the biotechnology industry. Clay Siegall, their CEO, is good at the art of deception. He holds a PhD and a large number of patents and publications. You might be lead to believe that he is a scientist. He is actually a businessman. He tells you his company is dedicated to unmet medical needs. That is the diversion. While we are patting them on the back for doing something to help mankind, they are plotting to charge us over 100K to have access to their drug.

The trick is not hard to do. The Invisible Gorilla is an example. In the invisible gorilla experiment there are people in white t-shirts and black t-shirts passing a basketball around. You are told to count the number of times the people in white t-shirts pass the ball to each other. While you are counting passes, someone in a gorilla suit walks through the scene. Most people seem to not see the gorilla because their attention has been diverted by the direction to count passes. You are tricked into not seeing something that is quite obvious once you know it is there.

This is how biotechnology operates, and much of the scientific community as well. Biotech CEOs and principal investigators do not wear white lab coats. They do not work in laboratories. They get noticed. They work very hard to gain a reputation that can be cashed in for money. Once the research grant or investment is in the bank, they go out and hire low paid obedient bachelor degreed servants to do the work. The only requirement is that the results must further the career of the leader.

We at the CCS are always looking for that gorilla walking past the screen. Go to the Seattle Genetics website and count white lab coats.

Did you see the businessmen deciding on the price of the drugs and the size of their bonuses?

Magic is the only honest profession.

Ideas Not Preached from the Pews

2011-08-15T19:01:00.000-07:00

The discussion of ideas is necessary for them to catch on. Watching TV or reading a book can be enjoyable but the best shows and books lead to further discussions. You get to participate in the seed that was planted. Watching NOVA or reading a Malcolm Gladwell book may enhance your ability to hold an intelligent conversation. It's up to you to surround yourself with people who also enjoy discussing new ideas. If you enjoy science, you should have friends who have something to share about the latest findings in Science or Nature or any of the other journals. Beyond the mandatory presentations and seminars, you should discuss the latest ideas.

I've had an epiphany on this very subject. I have no friends who enjoy exploring the absurdity of science as it is currently practiced. No one I know has anything negative to say about the profession of science. It seems impolite to be so negative about something that has a positive effect on our society such as science. I believe that only a small percentage of the ideas put forth by scientists ever amount to any greater understanding of our world. And that small percentage is very powerful. The other 95% of our ideas are not going to be useful. They may even be harmful. That 95% of BS deserves greater discussion.

For example, there is a paper out in Nature this week entitled "Broad neutralization coverage of HIV by multiple highly potent antibodies". The title itself seems unscientific. Using words like "highly potent" should be qualified in the conclusions of your paper. But that is the conversation I can't have.

Upon hearing about the HIV paper in Nature, I asked a friend if it would be a good idea to test the authors ability to identify their antibodies by coding each one (A, B, C... Q). Using the techniques reported in Nature, could they retake those measurements to identify each antibody. My friend was shocked that I was nothing but excited about how far science has advanced in HIV research. I said that I would be very excited if I could believe it were true. I was told I was just a skeptic. We did not discuss the paper, just the benefits of believing versus non-belief.

Every Sunday you will find churches full of people listening to a person discuss some aspect of the bible. That one book is discussed in a one way conversation by the preacher to the congregation. Later that conversation is carried on amongst the congregation. The better the sermon the more it will be discussed. Where do scientists gather on a weekly basis to discuss the latest findings? Usually, in the U.S., we gather in rooms where the lowest ranking "scientists" present their data to the highest ranking scientists. The direction of the conversation is taught in graduate school where the wannabe PhD "defends" his/her work to their committee. The preaching among scientists, in other words, is done from the pews, not the pulpit. Subsequent conversations are usually held by disgruntled grad students back at the laboratory, well out of the hearing range of a college professor. It is here where the real scientific conversations take place. Ideas are put forth to squash the dumb ideas. All of the proper controls are thought up. But rarely will those ideas be taken seriously unless they support the ideas of the preacher from the pew.

The mainstream idea to improve our world through science is to increase funding. The idea that I have today is to increase the discussion of scientific work. How to do it? If you read the Huffington Post, you will see that certain articles illicit more comments than others. What if there were a Huffington Post-like science blog where people could discuss work such as the latest HIV/AIDS paper in Nature? As we do with the work of social/economic engineers (our elected leaders) we can discuss the ideas and the merits of the scientific community leaders. Thought leaders such as Andrew Fire and Craig Mello can offer up their thoughts on why RNAi has been such a bust. Throw in a some comments from RNAi biotech CEOs and CSOs and see what the rest of us who are very interested in the subject have to say. We'll get into arguments and have an old fashioned debate, rather than the usual Lead Zepplins found in the journals. Break a paper down to pieces such as the IC50 measurements used in the HIV/AIDS Nature paper. Try and illicit a discussion on the measurements, the use of statistics, and the conclusions that can realistically be drawn. Highlight vested interests and how they effect certain outcomes. Talk about the "sexiness" of the research and how it enhances careers but increases the amount of BS being put forth. Highlight seemingly boring observations and how they can make a big difference.

The preachers from the pews do not seem to inspire. They conspire to keep bad information in the published journals so as to not hurt their careers. They have created a situation where laboratory work is looked down upon. Their greatest sin however, is that they are boring. They do not want the lower ranking members of science to discuss their work. They want us to read about how successful they were and thank them. If we don't believe them or we question them we are nattering nabobs. It flies in the face of what science is all about. If we want to know what really happened in the laboratory, we are going to have to let the people who actually do the work have a say. Let the people who read the papers and try to use them have a say. By increasing the level of talk surrounding science we'll increase the honesty.

The Complexity Issue/Type III IV Errors

2011-08-09T12:17:00.000-07:00

An idealist is one who, on noticing that a rose smells better than a cabbage, concludes that it will also make better soup.

H. L. Mencken

Thought experiment: Executive Bill believes that siRNA can be used to knock out TNF alpha and reduce swelling in joints in rats and thus it will do the same in human beings.

Think of Executive Bill as a Martian who has come to the conclusion that humans will prefer rose soup over cabbage soup. He sends his little Martians out to prove him right.

By setting up such a complex hypothesis Bill has failed to acknowledge that the siRNA may not even be the proper molecule that mimics a naturally occurring small piece of RNA that will reduce gene expression. Smell alone may not predict food preference.We fool ourselves all through the hypothesis testing and reach the end point (where Executive Bill demands a full report in his office) with the false assumption that a human being should see a reduction in joint swelling. Executive Bill wants to know one thing, did the human see a reduction in joint swelling? Did the humans prefer rose soup?If the human sees an improvement, Executive Bill is vindicated. If there is no improvement, Executive Bill sends the scientists back into the lab to tweak the system.

In colloquial usage type I error might be called "failing to believe the truth". In biotechnology this is a common error when desired results do not match actual outcomes. Executive Bill will reject the truth (siRNA against TNA alpha has no effect on joint swelling) and send the scientists back to the lab to get the desired results. The Martian leader will send the little Martians back to earth to get them to prefer Rose Soup.

Type II error is "believing the falsehood". This would be the case if the data showed a reduction in joint swelling from the siRNA treatment when the siRNA had nothing to do with the reduction. Executive Bill would eagerly accept this type of error.

The Martian leader would eagerly accept any data that showed humans preferring Rose Soup. Let's say that the problem came from a mislabeling of the soups or fraud was committed by an ambitious little Martian. The desired results were obtained. They were false. They were accepted. Executive Bill and the Martian leader accept what they are being told.

In these two examples, siRNA and Rose Soup, we (the Cargo Cult Scientist) are saying that the non-erroneous outcome would be that siRNA has no effect on TNF alpha or anything in the human body, and that human beings will not eat Rose Soup. Our antagonists, Executive Bill and the Martian leaders' desired outcomes should be proven false. No matter what the outcome, they will only be accepting validation of their hypothesis. The easiest path to success, as defined by Bill and the Martian, is a type II error. Type I errors will be made until a type II can be arranged.

Now let's enter a superior being I will refer to as God. It is the Cargo Cult God and he needs to keep his subjects ignorant for amusement purposes. He delights in the folly of the minds who keep themselves fooled at all times. The Cargo Cult God wants to explain how Executive Bill and the Martian leader reach their status in their respective groups and how they maintain their positions. First, they are bullshitters and thus would use the truth if they could get to it. But getting to the truth would be a random act since they do not know how to conduct research. They begin from ignorance, either type I or type II errors or they are randomly yet unknowingly correct. They then select a desired outcome and draw a line from A) type I or II error or random correct assumption, to B) desired outcome. The desired outcome however cannot be attributed to the path of reasoning that is depicted by the line from A to B.

In 1974, Ian Mitroff and Tom Featheringham argued that "one of the most important determinants of a problem's solution is how that problem has been represented or formulated in the first place".

They defined type III errors as either the error of having solved the wrong problem when one should have solved the right problem or the error of choosing the wrong problem representation when one should have chosen the right problem representation.

In other words, Executive Bill set out to solve the problem of how to make siRNA into an anti-RA drug where he should have tried to solve the problem of determining the possibility of using siRNA as a drug in the first place. Maybe siRNA cannot survive in the human body.

Likewise, the Martian leader wanted to prove that Rose Soup would be preferable to Cabbage Soup. He should have conducted research on the relationship between the human senses of smell and taste.

In 2009, 'Dirty Rotten Strategies' by Ian I. Mitroff and Abraham Silvers was published regarding type III and type IV errors providing many examples of both developing good answers to the wrong questions (III) and deliberately selecting the wrong questions for intensive and skilled investigation (IV). Most of the examples have nothing to do with statistics, many being problems of public policy or business decisions.

The human body is complex. Biotechnology has yet to accept this fact. The study of type III and IV errors has been handed a gift in the form of medical research. How did we get to the point where we are today? 90% inaccuracy in our scientific journals? Publication retractions on the rise for unknown reasons.

The desired (i.e., non-erroneous) outcomes of a test are called true positive meaning "rejecting null hypothesis, when it is false" and true negative meaning "not rejecting null hypothesis, when it is true". What is the case when the desired outcome is not defined as non-erroneous?

Typing on Blue Paper

2011-08-07T10:18:00.000-07:00

If you type 100 words a minute with ten years experience typing TPS forms on blue paper for ACME Products, what is your skill?

Typing

If you are the finance officer of a biotechnology company, what is your skill?

Finance

If you conduct research in a life science laboratory, what is your skill?

Research

The question however, is whether or not anyone conducts research in a biotechnology laboratory. Research is not about any particular piece of equipment or assay. An individual who can obtain a degree in science should have the ability to learn how to operate the various pieces of equipment. But biotechnology companies do not conduct research. The board will select the drug target and the antibody/siRNA or whatever is in fashion will be developed to address the target. Most often, they do not match target to technology and they one day will have to close up shop. What is missing is an understanding of research.

Research is an evolution. We begin with ignorance and evolve to understanding. Ignorance has an unpleasant connotation however, one that PhDs do not want associated with their work. Thus, they begin with an ignorance of their own ignorance. How many biotech PhDs have tried to make an antibody against amyloid beta? How many have used phage display to bind to amyloid beta? The concept is that they begin with the knowledge that something that binds to amyloid beta should prevent it from forming plaques in the brain and thus cure Alzheimer's patients. Research did not create that evolution of understanding. This stepwise cure for Alzheimer's has cost billions but has not panned out. There is something we don't know. We are still ignorant about the beginning of our research. Why are the plaques there?

As a result of the inability to admit our own ignorance, we have established a new paradigm for conducting research. We draw out mechanisms, such as we did with RNAi being used as a drug. The siRNA will enter the blood stream, go to its target and begin to reduce the translation of mRNA. Nothing else will happen and the target knock-out will cure or slow down the condition. Early on, it seemed that siRNA was knocking out targets. There was a leap of faith that this could be a drug. Since then we have a large body of evidence (both known and hidden from the light of day) that would lead us to think more about where this research emerged from. Did we begin from ignorance and evolve to understanding? It seems we began from a vague understanding and evolved to ignorance.

What does any of this have to do with identifying a persons skill? Does the secretary type 100 words per minute or does she specialize in typing on blue paper? A researcher in biotechnology is not a person who usually obtains 20 to 30 years of experience conducting research. Rather, they will begin their career as someone who is given the task of knocking out a target to effect a specific condition. The conditions are well documented so we assume the only way forward is to tackle the unknown of dealing with them. You will need molecular biology specialists, cell culture specialists, protein purification specialists, analytical machine operators, and so on. All of the people working in the laboratory are usually non-PhD research associates. Their careers begin with one of the above specialties and they advance their careers only in terms of years of experience. Typing is not enough. They must type on blue paper. For example, I've seen technicians with five years of experience running a Waters HPLC. The laboratory they apply to has Agilent HPLCs. They are out of the running. The skill is required by the researcher. It is not a skill that they must understand, thus they can make the mistake of not identifying what matters most. Do they want someone to effectively use the HPLC for its intended use or do they have an Agilent in their lab that no one knows how to turn on?

The researcher then, should be the person working to put all of the skilled technicians together to move from ignorance to understanding. The most in-demand researchers however are those who have the most patents and publications. The assumption here is that they have reached the level of understanding more often than those with less patents and publications. Science however is a superior way of thinking that takes great pains to distinguish between quantity and quality. Biotechnology is not science, it is a business. It needs experienced obedient workers to turn on the machines and do the paperwork. Research is handled by those who can most often get published and get patents. As a result the amount of useless patents and inaccurate publications have sky rocketed. The companies have had to return time and again to the point of ignorance, the point where research begins. It's not a bad place if you are a scientist. It is a place that fascinates and brings on the evolution of understanding. If you just spent $1.1 billion, such as Merck did on Sirna, it is a bad place to be. You just hired a bunch of people who all had experience typing on blue paper. Typing however, was not their specialty. Research was not their specialty. RNAi was.

Biotechnology has been reduced to mostly monoclonal antibody companies. They sometimes try to break up the molecule or make it more stable but these are bells and whistles that don't work very well. The business model remains, select target, make antibody, start clinical trials, partner or be acquired by big pharma. It's all just typing on blue paper specialists. Basic research, starting from a known ignorance, is the only way innovation will take place. Who has the courage to admit that they know how to type but they don't have any experience typing on blue paper?

Dendreons Four Extra Months

2011-08-04T16:43:00.000-07:00

My wealth is all at your command
If you will move your icy hand

Dendreon heard the plea and they made a deal with death. But death is a son of a bitch. Now Dendreon is not going to be the next billion dollar biotech in the Northwest. The projection of $350 to $400 million in earnings for 2011 was a little off. It now looks like the number will be below $200 million.

What the leaders didn't count on was a lack of interest in what they were offering. Dendreon diagnosed their situation and found that the problem is primarily happening with small community-based physicians. As leaders of the biggest Cargo Cult in the Northwest, they had only been associating with "top academic centers that have been familiar with the product for years in clinical trials." They are having a hard time getting the dumb hick doctors on board. David Miller, an analyst with Biotech Stock Research in Seattle said, “Docs are not prescribing Provenge until they are certain they are going to be reimbursed.”

One reader of Xconomy had a slightly different version of the predicament Dendreon is in:

As an oncology practice administrator other than the high cost another issue is the data itself- patients may be hesitant to use a drug with 4 month survival when there are other options available. And if medicare remibursement decreases to ASP + 4 next year, these very expensive drugs could be difficult to justify administering in the community setting

Mitch Gold, the CEO of Dendreon said that the company needs to educate physicians about how the reimbursement process has been streamlined. The education in this case goes in the opposite direction. The market has educated Mitch Gold and the investors.
In their arrogance, they forgot that the patient has a say in their health care. It's not just a paycheck for Dendreon, it's an end of life decision with options.

For the investors, the education came from the earnings call this week. For Mitch Gold and the insiders of Dendreon, the education took place on a daily basis. They just didn'tshare it with the investors. Someone asked the question back in March, "Why is Mitch selling his shares?" We have an answer.

When a company is dying, you don't pump more money into saving it. Clearly, the insiders at Dendreon knew they were in trouble.

Research Department

2011-08-02T14:05:00.000-07:00

My mom called with an idea. Her neighbors son was working down at the local university in the "Research Department". Why don't I apply and move closer to home?

The Research Department?

What Feynman was talking about in Cargo Cult Science, was research. He did not condemn all of psychology for flawed research methods. He spoke specifically to a problem in their experimental design. Not all people can spot experimental flaws, but it can be taught. For some this course would be easier than it is for others. Take for example, a recent Huffington Post article looking at the divorce rate for childless vs. couples with kids. It was mentioned that in 1950:

For couples without children, the divorce rate in 1948 was 15.3 per 1,000. Where one child was present, the estimate rate was 11.6 per 1,000. The figure thus continues to decrease, and in families with four or more children, it was 4.6. Altogether, the rate for couples with children was 8.8 per 1,000. In other words, the rate for childless couples was almost double the rate for families with children.

Over 2,000 comments turned up with people chiming in with their views on kids and marraige. One person however called attention to the notion that only 11 to 15 people per 1,000 were getting divorced. The divorce rate is currently around 50%.

The bias here got everyone talking about marriage and family. The "Research Department" guy picked up on a research issue.

Why don't they teach courses on how research is conducted. We can teach chemistry, biology psychology, and we assume that they understand where all of that information came from. Why don't we specifically get at the issue of research? In another HuffPo article a Gender Studies professor asked the question of whether or not men are what they used to be. She mentioned a study where men and women were asked questions about family and marriage. Once again, the comments section found people focusing on what makes a man a man. There were however those who brought up the fact that no such questionnaire was given to people in a previous era.

By all means, every University needs to establish a research department. Before a grad student begins conducting research for his/her professor, they need to do research without the bias they will encounter. Give students the tools they will need when facing a Bulfone-Paus or David Baltimore.

Talent vs Experience

2011-07-31T22:56:00.000-07:00

I believe it is more important to hire for talent than it is for experience.

Bill Biggs, President of Li Cor

Talent: A special natural ability or aptitude

Experience: A particular instance of personally encountering or undergoing something

What are the lessons from the rise and fall of SIRNA? J. Michael French, former Sr. V.P. of Corporate Development at SIRNA, is currently the CEO of Marina Biotech, another RNAi company. Barry Poliski, former Chief Scientific Officer of SIRNA, is now the Chief Scientific Officer of Marina Biotech. One might think that Marina Biotech is in for a slow painful death. Can these executives make their RNAi company a success? They made Sirna a success story in 2006. Sirna made that success questionable.

How do you separate talent from experience from the pool of RNAi people? In an environment such as biotech R&D, obedient workers are highly desirable. I know a researcher who once worked for Marina when it was called Nastech. This PhD scientist was to use RNAi to knock out one of biotechs favorite targets, TNF alpha. In a one-off experiment, RNAi appeared to reduce joint swelling in a set of three mice (pos control, neg control, RNAi). In the next experiment 300 mice were put to the test. At the end of the treatment each mouse was euthanized and put into a jar with formaldehyde. Without any actual measurements it was clear that the experiment did not reproduce the original results. No measurements were taken. The experiment at this point ended. 300 jars, each containing a dead mouse sat under an unused bench space for a year. The PhD who ran the experiment was a smart person who knew the honest approach would be to take the measurements. But he was also a new father and he needed to keep the job. Contributing to a massive pile of failed RNAi experiments would be detrimental to his career. Whatever scientific talent he had (the ability to bend over backwards to prove yourself wrong, to report all results...) had to be put aside.

Any person who has worked with RNAi can tell stories like this. It is the classic beer and pizza diet research project. The obedient worker is told to go into the lab, put small pieces of RNA in a plate of cells or a mouse and come back with results that indicate the knock out effects of RNAi. Long before the delivery issue was adopted, researchers were pointing fingers at whoever last touched the RNA. After trying to beat that square peg through a round hole, they finally decided to use a chemistry approach to getting the RNA to behave. Nucleic acid analogues, changes in formulation, injection techniques and many more ideas have come and gone. What remains is the decision that it is the delivery of the RNA that is preventing the desired action. At this point in the career of an obedient experienced RNAi lab worker, you should be questioning the talent of the decision makers.

Yet when you hear the talk, it can be some of the finest you've heard. Complex systems are eloquently spelled out with limitations being overcome by clever ideas. The talent is in the discussion. Experienced scientists are accumulating more and more data that is being processed by a talented scientific advisory board that will lead to the successful completion of a RNAi drug development program. We still have Alnylam, Marina and many more smaller players trying to make this work. They have plenty of experience in RNAi research. Do they have the special natural ability/aptitude to translate what they've experienced into a successful drug development project?

Is It Me or Is the Emperor Naked?

2011-07-29T06:56:00.000-07:00

It's time to take another look at the Cargo Cult of RNAi research.

Merck bought Sirna back in 2006 for 1.1 billion U.S. dollars. They announced last week that the company will be eliminating 13,000 jobs, 12 percent to 13 percent of jobs by 2015. Merck also announced an end to its Sirna unit.

I first started blogging about siRNA research back in June of 2006. I mentioned the Merck deal in March of 2006. It is now July 30, 2011. Roche has given up. Pfizer gave up. Now Merck, while not yet admitting that the Emperor has no clothes, is making significant cuts and shutting the doors of its main RNAi investment research facility.

It's easy to be the Cargo Cult Scientist and use my considerable skills to predict the future. A pessimist is more often correct than the optimist but that is not my secret. I've done the research. I have spoken directly with the leaders and I have studied their ways. Why was RNAi selected by the leaders to be the next big thing?

The leaders of the Cults need to tackle problems that they can handle. Curing disease and helping people is tough. Making drugs is a bit easier. They begin with a Drunk Under the Streetlight approach. RNAi is an easy choice for this approach.

How do they direct the lab people to do actual laboratory research in RNAi? Beer and Pizza diet!

At some point some naive little person is going to point out that the Emperor has no clothes. How are they going to handle that?

An Emperor who cares for nothing but his appearance and attire hires two tailors who promise him the finest suit of clothes from a fabric invisible to anyone who is unfit for his position or "just hopelessly stupid". The Emperor cannot see the cloth himself, but pretends that he can for fear of appearing unfit for his position; his ministers do the same. When the swindlers report that the suit is finished, they mime dressing him and the Emperor then marches in procession before his subjects, who play along with the pretense. Suddenly, a child in the crowd, too young to understand the desirability of keeping up the pretense, blurts out that the Emperor is wearing nothing at all and the cry is taken up by others. The Emperor cringes, suspecting the assertion is true, but holds himself up proudly and continues the procession.

The Emperors of the RNAi cult are cringing more than ever. But they hold themselves up proudly and continue the procession.

Still, McConnell said Merck continues to invest significantly in RNAi technology. The decision to close the facility was based on other factors, including ongoing efforts to manage fixed costs. The technology Merck acquired in its acquisition of Sirna has been integrated across the company’s R&D organization, he said.

I succeed at predicting the future because I have looked into the eyes of the leaders and I know how Cargo Cults operate. I know that a scholarly scientific look into the research of RNAi will not appear because it fails to promise the coming of the cargo, only reasons as to why it did not come. We continue to look to the skies.

Cetero Response to Form 483

2011-07-27T21:13:00.000-07:00

A spokesperson for Cetero Research sent Science Business the following statement:

Cetero Research, the leading provider of early phase research services, remains fully committed to maintaining the quality and integrity of the data collected in each of its facilities, including the Houston, TX, bioanalytical laboratory. It is this commitment that makes the broad action announced publicly by FDA on July 26, 2011, even more difficult to understand.

Cetero initiated its own internal investigation of its Houston bioanalytical laboratory over two years ago when it discovered the recording of inaccurate day/time data by a small number of research chemists in its Houston facility. Cetero proactively contacted the FDA to self-report its preliminary findings, as well as seek agency feedback on its comprehensive investigation plan.

At that time, Cetero clients were also contacted to make them aware of the situation. The Untitled Letter does not accept the results of our rigorous scientific analysis and discredits the Company’s 1,200 dedicated and experienced employees. The research conducted on behalf of our pharmaceutical sponsors can be, and has been, properly validated.

The FDA said in its public announcement: “It is unlikely that these concerns relating to data integrity affect the overall safety and efficacy of drugs already on the market and, at this time, there is no evidence of problems with the safety, quality, purity or potency of drugs already approved.” Thus, the FDA has not questioned the safety or efficacy of drugs already approved, marketed, and based on data generated from Cetero’s Houston bioanalytical laboratory.

We are pleased that we will now have the opportunity for the first time since our voluntary disclosure was filed in June 2009 to meet with FDA decision-makers to seek to resolve this matter in an appropriate manner. Cetero will continue to cooperate fully with FDA and with our clients and support them through this confusing process.

The little guys are going under the bus! If the FDA had any scientific proclivity they would immediately and randomly audit another group working in the sample group of "the Company’s 1,200 dedicated and experienced employees". As for the narrow window Cetero speaks of in this response, the FDA is looking into a five year period between April 2005 and June 2010.

As noted in a letter FDA sent to the company, Cetero also failed to conduct an adequate internal investigation to determine the extent and impact of the violations and failed to take sufficient measures to assure data integrity within the 5 year time frame.

FDAs Form 483 for Cetero

2011-07-27T09:20:00.000-07:00

Just an image. Poor quality I know but I wanted to post this rare recognition of a Cargo Cult Organisation. I don't think Cetero is unusual in its dishonesty but it is unusual that they were caught.

Cetero

2011-07-27T07:25:00.000-07:00

Oh my!

The Food and Drug Administration said on Tuesday two 2010 inspections, an internal company investigation and a third-party audit uncovered "significant instances of misconduct and violations" at a Cetero facility in Houston.

The Cary, North Carolina-based firm does early-phase clinical research and bioanalytics for a number of drugmakers. The pharmaceutical companies can then use those studies as supporting evidence in drug approval applications to the FDA.

What if this type of inspection became routine for all of science? Randomly pick a NIH grant recipient, a biotech company, or a pharmaceutical company and ask them how they came to their conclusions.

“When someone says, ‘Science teaches such and such,’ he is using the word incorrectly. Science doesn’t teach anything; experience teaches it. If they say to you, ‘Science has shown such and such,’ you should ask, ‘How does science show it? How did the scientists find out? How? What? Where?’ It should not be ‘science has shown.’ And you have as much right as anyone else, upon hearing about the experiments (but be patient and listen to all the evidence) to judge whether a sensible conclusion has been arrived at.

What we have is a pandemic of scientific misconduct. Cetero, Cargo Cult Contract Research Organisation!

Malcolm Gladwell

2011-07-26T14:14:00.000-07:00

"You don't start at the top if you want to find the story. You start in the middle, because it's the people in the middle who do the actual work in the world," writes Malcolm Gladwell in the preface to WHAT THE DOG SAW.

"How do we know whether someone is bad, or smart, or capable of doing something really well?" he asks in his book 'Blink'. In this book he looks into how educators evaluate young teachers, how the FBI profiles criminals, how job interviewers form snap judgments.

In 'Outliers' he tries to figure out why some people are successful. He comes to the conclusion that we've focused too much on the individual and failed to consider the other factors around successful people. We fail to see the forest for the trees.

Interestingly he gives an example of successful people. Jewish men who grew up during the depression whose fathers worked in the garment district apparently have done quite well as corporate lawyers in New York City. Our hero R. Feynmen also fits this category.

'The Tipping Point' explores meaningful changes and what really brings them about.

I've struggled all my life to understand this world. I got into the science business to seek refuge from a demon haunted world. Things were no different. There is of course the beauty of real science that occasionally works its way into the mess that professional scientists have created. But the world seemed even more bizarre watching people with PhDs use science in the manner that they do. Professional scientists are people who want to be known as smart. They want to be experts. Actual scientific people would never devise a thing such as the peer reviewed journal. RNAi does not come from scientific minds. Biotechnology hasn't failed for no reason.

This blog wonders how a group of highly educated individuals with billions of dollars create the system of scientific research that now passes for "discovery"? We are still standing on the shoulders of giants, but we seem to be looking in the wrong direction.

Along my journey I have extracted ideas from people and things I've read and observed. These ideas tend to follow what is considered to be the scientific method. That doesn't mean the ideas have always come from scientists. Malcolm Gladwell for example is a journalist. People who are good at what they do have the ability to see what matters. Gladwell applies new questions to old problems. Why are some people, of equal ability, more successful than others? When do good ideas (and bad) become accepted? To those of us who are dissatisfied with current explanations, this is a breath of fresh air. The books serve two purposes. First to see new explanations to old problems and, more importantly, to take the journey of how they were obtained.

Malcolm G. is not without his own flaws however. In the future I hope that he re-visits the following ideas posted on his website:

Journalism is not like the business world, where the mechanics of decisions and procedures take place behind closed doors. It is, rather, like science, where the fruits of all endeavor are put on public display. In the world of science, that transparency allows the profession to be self-policing. It is very hard to commit scientific fraud because all significant findings are published, scrutinized by other members of the scientific community, and—if they are sufficiently controversial—independently tested.

No one's perfect.

Tumor Size

2011-07-14T08:43:00.000-07:00

A tumor, as described by Wikipedia, is commonly used as a synonym for a neoplasm (a solid or fluid-filled (cystic) lesion that may or may not be formed by an abnormal growth of neoplastic cells) that appears enlarged in size. Tumor is not synonymous with cancer. While cancer is by definition malignant, a tumor can be benign, pre-malignant, or malignant, or can represent a lesion with no cancerous potential whatsoever.

What does the size of a tumor have to do with cancer and health? It is possible that we often develop tumors. Without a doctor around to tell us what they are, our body deals with them and we are none the wiser. Some tumors however grow and make people quite uncomfortable, such as the picture on Wikipedia. Besides discomfort, a tumor can be a threat to your health.

In 1971 Dr. Juhah Folkman formulated the idea of tumors being dependent on blood vessel formation. Researchers eventually warmed up to the idea and started looking for angiogenic factors that could be target by drugs. VEGF, Vascular endothelial growth factor became a target and it worked, some of the time. In cancers deliberately developed on the backs of mice, for example, blocking VEGF prevents tumors from growing. Clinical trials on human beings showed that it adds time to a cancer patients life when used in conjunction with chemotherapy on colon and non-small cell lung cancer. However, it did not add time to a patients if they had breast cancer. But science isn't always straight forward.

The FDA approved Bevacizumab in 2008 for use in breast cancer. A panel of outside advisers voted 5 to 4 against approval, but their recommendations were overruled. The panel expressed concern that data from the open label clinical trial did not show any increase in quality of life or prolonging of life. The trial did show that Bevacizumab reduced tumor volumes and showed an increase in progression free survival time. Based on this data the FDA chose to overrule the recommendation of the panel of advisers.

Two subsequent double blind studies showed little efficacy and some serious side effects. The first rule in medicine is to do no harm. It is a rule that is being ignored by scientists and doctors at Roche and Genentech. Careerism has them continuing to tout the drug in spite of the trial data. It may help some people just as it might result in the many side effects. Prescribing the drug by doctors (which they can still do) would be a random act. If the patient gets better... Eureka! If they get the side effects or they die on schedule, it was an act of compassion. None if it could be considered science. At $90,000 a year, Avastin is a money maker. It is the number one selling cancer drug in the world bringing in around 6 billion dollars a year. Removing the breast cancer indication will cut profits by a billion dollars.

Tumor size is biotech endpoint. Shrinking tumors means making money. The real question is whether or not it helps cancer patients feel better and live longer.

The Value of Blogging

2011-07-11T22:13:00.001-07:00

While reading David H. Freedmans book, "Wrong", I knew he was preaching to the choir. But what would someone like my mother, a non-skeptic, think about the book? She needs to believe that our chosen experts are reliable. When something happens such as the Casey Anthony verdict she becomes a skeptic of the legal system. When the damned liberals take control of the white house she becomes a skeptic. More on that line of thought later. In general however, the non-skeptic does not like books like 'Wrong'.

Being accepted as an expert takes time. You have to build up credentials like college degrees, years of experience, and you have to be well spoken. The credentials quite often trump real expertise. Take for example the GETRAPL story. Using the 'drunk under the streetlight' approach the experts found GETRAPL. They are wrong. But who will take the word of a blogger who has never given any credentials and who seems to be an angry person?

My non-skeptical mother doesn't like angry people. Not many people do. She prefers the well spoken, soft spoken, expert who affirms her own beliefs. The same could be said about myself and the author of 'Wrong'. But I differ in that I don't care what the credentials of D.H. Freedman are. I like the ideas he presents. As a skeptic, I would like to think that I could tell the difference between right and wrong based on my experience, not the background of the person to whom I'm listening.

To what extent then do I, the Cargo Cult Scientist, expect to be taken seriously as a contributor to what is right and what is wrong? I don't. I want the words I write to be considered but I don't want to be an expert. I am not willing to go on camera and give away my identity. I have not spoken kindly and without anger about my chosen profession. The notoriety I could achieve would certainly focus on my anger, and weak credentials. I would be labeled a fool. As pointed out in 'Wrong':

It has long been established that when people are part of a crowd in which they're anonymous, they tend to behave less conscientiously than when they're identifiable.

Blogging about the how wrong other people are is cowardly. Yet the track record of the industry is hard to dismiss. Many people have sang the same song, Biotech is a failure. Working with the people has left me dazed and confused about what science is suppose to accomplish.

On the surface, a brave approach to the discussing the biotech business would be to start a website and actually talk to the leaders of the industry. Xconomy is such a website. Just yesterday an article was posted regarding the troubles facing Biotechs inability to attract the kind of financing it did back in its glory days. A lack of guts seems to be an issue. The author of the article, Luke Timmerman, is a well respected member of the biotech business. Luke didn't start a blog. He started an online website dedicated high tech news that is meant to make money. Telling investors they are lacking guts, takes guts. Luke also posted an article telling college students to pursue computer science instead of biotechnology. That takes guts. Luke finds himself in front of the crowd, conscientiously discussing their work. He must be smart and not come across as I do.

What then is the value in this blog? The value of the Cargo Cult Scientist has been mostly therapeutic. The daily struggle of listening to people with all the right credentials and millions of dollars is difficult. They are in the right place. But are the right? According to the ideas of Cargo Cult Science and numerous books such as 'Wrong' they are not. Being right is often the wrong thing to cling to but in science, it is the only thing that matters. I blog because I think science is a beautiful abstract concept, just like Feynman laid out for us in CCS. It makes me feel better.

The Same People

2011-07-07T11:49:00.000-07:00

When you invest in biotechnology, you are investing in people. The Cargo Cult you invest in is a group individuals who will be spending your money.

H. Stewart Parker is a 55 year old seasoned veteran of the cargo cults of Seattle. She's a pioneer. She was the first employee at Immunex right around the beginning of biotechnology. She went on to be the CEO of Targeted Genetics, a spinoff of Immunex. Before her reign ended, Targeted had ran up a deficit of $310 million. She left her cocoon in 2008 to become a consultant, as most execs do after their companies tank. She moved on to WBBA, the local biotech promoting organization of the Northwest. Today she announces an end to that moonlighting job so she can work full time as the CEO of the Infectious Disease Research Institute.

Let's break down her place in the Seattle field of leaders. The nonprofit she'll head up was founded by immunologist Steve Reed in 1993. Steve Reed is the Executive VP of Immune Design, and co-founder of Corixa. Bruce Carter, former CEO of Zymogenetics, is the Chairman of the Board for Immune Design. Other Corixa co-founders include Ken Grabstein of IL-15 fame and CSO of local Allozyne and Steven Gillis, co-founder of Immunex. Steven Gillis hired Ms. Parker straight out of college (UW). The names of the companies may change but the people (who spend your money) remain the same. They are all still here, running companies and enjoying the excess of the massive funding that comes and goes in the cargo cults.

This group has done well for themselves but have done little in terms of creating a career path for scientists. The business people have the job of telling the story that is intended to be told from the inception of the company. That is the career path that Seattle biotech cargo cults nurtures and structures. The career of the scientists is to come in as needed and fill in a piece of the puzzle and then go away. If a scientist can't tell the story, they can easily be replaced.

How can we find success in biotechnology when the leadership seems to be making it all up as they go along? Ms. Parker has had an experience. Since the beginning of biotechnology she has worked as a leader. She remains a leader. She has experience. But unlike a winning Superbowl coach, her experience will not land her a book deal on managing a winning team. But it will get her another CEO job in Seattle.

The IL 15 Cargo

2011-06-01T11:39:00.000-07:00

Science is an abstract concept. In describing the cargo cults Feynman pointed out the difficulty of defining what science is.

But there is one feature I notice that is generally missing in cargo cult science. That is the idea that we all hope you have learned in studying science in school--we never say explicitly what this is, but just hope that you catch on by all the examples of scientific investigation. It is interesting, therefore, to bring it out now and speak of it explicitly. It's a kind of scientific integrity, a principle of scientific thought that corresponds to a kind of utter honesty

How has the scientific community dealt with the IL-15 story?

if you're doing an experiment, you should report everything that you think might make it invalid--not only what you think is right about it: other causes that could possibly explain your results; and things you thought of that you've eliminated by some other experiment, and how they worked--to make sure the other fellow can tell they have been eliminated.

One thing that casts doubt over the IL-15 story is that people seem to have a hard time finding it. N-Rays were hard to find so we looked into it. There are those who have created a convincing narrative to describe the life and times of IL-15. The problem is that recently there have been an inordinate amount of retractions of papers that created the narrative. Silvia Bulfone-Paus has had 12 papers retracted. The reason was fabricated data obtained by two rogue laboratory people. Problem solved? Not quite. Six more papers are under investigation at a second University where the Silvia Bulfone-Paus also works. The rogue white lab coat wearing scoundrels, Elena Bulanova and Vadim Budagian, weren't around during this research!

Why so much controversy? There appears to be a discrepancy between the IL-15 narrative and its ability to predict what will happen in the laboratory. Rather than presenting the puzzling data, they altered the results to fit the narrative. They were caught. Twelve papers and counting have been taken out.

Is IL 15 real? You can buy the protein from R&D Systems. There are antibodies against it. It was cloned in 1995. But a real scientific approach to understanding this protein would start by going into the laboratory to reproduce some critical work. Start by cloning the protein again. Does the DNA sequence match? Do the antibodies available bind to the newly cloned IL 15? Does the purified protein mimic IL-2–induced T-cell proliferation? The basics would be a simple place to start, accumulate IL 15 and begin to examine the role of this protein.

Another way to examine the role of IL 15 is to look into the careers of the researchers. We know there are a couple researchers who wish they had never met IL 15. The lead author of the first paper describing IL 15, Kenneth Grabstein, is now the CSO at Seattle based Allozyne, an Accelerator company that recently bought Poiniard indicating their dedication to business as opposed to science. This company is a tiny little place one block away from Accelerator that has a singular mission to merge and make money for its investors. When did Dr. Grabstein move on from IL 15? In the world of Cargo Cults Seattle, Dr. Grabstein has done quite well for himself. However, he has left path of abandoned research for others to sort out while cashing in on companies such as Immunex and Corixa. Immunex made its fortune from TNF alpha. Corixa was acquired by GSK. IL 15 provided Dr. Grabstein some early publications but later in his career he lost interest in helping the world understand this protein.

You would think that the laboratory approach to clearing up some of the mystery would be employed by someone. Make a list of things that were fabricated, such as the many western blot images. Simply redo them and publish your results. Your conclusions would be simple, "We do (or do not) see a band on this western blot. Keep the narrative out of it. Make a list of repeated experiments and provide your results. Don't interpret them, just provide the results. While the office-bound professors and early-pioneers-now-turned-businessmen hope it will all blow away, lets hope it doesn't.

Teaching the Dog and Pony Show

2011-05-31T14:40:00.000-07:00

From the website of the Biotechnology Institute:

Biotechnology has a wide variety of career opportunities ranging from sales and marketing, to research and development, to manufacturing and quality control and assurance.

Are these really the primary high paying jobs in biotechnology? This is where science goes awry. The Cargo Cult leadership needs people in these positions and they need to start training them how to think as soon a possible.

In the cargo cult science speech, Feynman spoke of a man who ran the Institute of Parapsychology.

This man also speaks about a new institution, in a talk in which
he was resigning as Director of the Institute of Parapsychology.
And, in telling people what to do next, he says that one of the
things they have to do is be sure they only train students who have
shown their ability to get PSI results to an acceptable extent--
not to waste their time on those ambitious and interested students
who get only chance results. It is very dangerous to have such a
policy in teaching--to teach students only how to get certain
results, rather than how to do an experiment with scientific
integrity.

You can teach quantitative analysis, organic chemistry, physics and biology but you can't teach biotechnology. At least not in the manner described by the institute of biotech. You can teach the history of biotechnology. You could try and find a coherent pattern in the organization of tasks that start from idea and end with a product that is sold for money. You could spend years trying to explain how the financing of the business used to work and what the future challenges are. You cannot teach biotechnology as if it were a learnable subject, being taught by those who have already learned how it works. The field is far too complex.

James Randi spoke of a young girl who developed a test for psychic energy readers. She made a barrier between her and the reader. There were two holes where the psychic put his/her hands through. The little girl would then place one of her hands under the right or left hand of the psychic. The psychic had to select which hand based on its readable "energy". Twenty readings were done to rule out random guessing.

Did this little girl have to learn about psychic ability? Did she have to study at the Institute of Parapsychology to conduct research in the area of psychic energy? No, she was conducting a study on whether or not a random pattern could be discovered in what appears to be non-random event. A randomness test could have also been done by tossing a coin in the air. She also did not have to attend a course on how the U.S. Mint makes coins! The real science was in identifying a random set of information that appears to be otherwise and to use statistics to highlight the randomness. The dog and pony show was in identifying a random set of information that will catch the judges eye.

Our mission is to engage, excite, and educate as many people as possible, particularly young people, about biotechnology and its immense potential to heal the sick, feed the hungry, restore the environment, and fuel the economy.

The mission is admirable but we are getting close to teaching kids what to think, not how to think. Biotechnology has been a failure. The adults have not yet figured out how to accomplish the goals listed yet they purport to teach the next generation. We are not "there" yet. There is no "there" there. Let the kids do science projects and let them meet the president. But before we start an institute for biotechnology, let us step back and figure out what biotechnology is. We have to separate the science from the dog and pony shows. The dog and pony show is what they are teaching at the institute.

Lessons From a More Advanced Field

2011-05-27T08:43:00.000-07:00

Long ago I worked as a photographer. I learned all about setting the F-stop so as to not over or under expose the film. I learned how to process black and white, color, and slide film. I printed photographs in black and white and color. I shot portraits, crime scenes, ceremonies, and just about anything that required a professional quality image. For five years I honed my skills. I left it all behind one day and went to college to study biochemistry. Most of the skills that I learned are no longer required. Exposures on digital cameras are well balanced. Digital pictures can be corrected for using computer software. Prints come out color balanced. The exposure and contrast is taken care of via the software as well. Everything that I did subjectively is now done by objective physical qualities in the camera and by image software.

In a period of roughly 20 years the field of photography changed dramatically. It's easier now but a new set of skills are required. What brought about the change was science and engineering. What about the laboratory skills I now have in the field of biotechnology?

The science that I speak of is not medical science. In order to bring about the proper changes needed for biotechnology a new science must be elucidated. If you put a small strand of RNA into a living organism what happens to the RNA? Never mind what happens to the living organism. Focusing on the outcome of the cell culture, mouse, or the human being is ignoring the interaction of the drug and its host. The human body is also dealing with the disease. What is the fate of a foreign molecule that we design and introduce to a living organism? What happens when we change the living organism? If I have the same CDR regions in a Fab, Fab2, and a full length antibody, what is the fate of the three molecules that are the same only in the CDR region? The CDR region is what interacts with the drug target. The rest has to deal with the living organism. Perhaps they will all block the target in the cell culture but only the full length antibody will find the target inside the human body.

Here is a real time example of the kinds of questions that are too often not asked. Roche this week announced a new antibody;

an antibody with two arms. One arm was the anti-BACE1 drug; the other docked with a receptor called transferrin that carries iron to brain cells, providing a ferry across the barrier.

The system allowed the researchers to deliver anti-BACE1 to the brains of mice, blunting the impact of the BACE1 enzyme and cutting in half the amount of amyloid in the brains of mice 48 hours after injection

I am assuming that the molecule has one CDR region that binds to the transferrin receptor, and the other binds to BACE-1. How does the antibody dissociate from the receptor on the other side of the blood-brain barrier? What percentage of the drug load goes through the barrier? How does the drug reach the barrier in the first place?

Other issues are of course the amyloid beta story. The amyloid beta protein could run into a rotten bunch of brain cells that are kicking out amyloid beta denaturing agents (low pH, enzymes...) that will make the long journey of the anti-BACE molecule futile. Rather than relying on the endpoint that Roche and friends have set forth, someone should look at the entire picture from a scientific standpoint. Roche and friends wanted to tell the story that they've told. What does science have to say about it? What do we know about the measurements they took? The story they have told is more of a narrative rather than a factual description of their molecules journey into the brain and into the cascade of events involving amyloid beta. The solution here is an electronic notebook that researchers at higher levels must keep. The narrative approach to science of higher ranking scientists is an issue that software engineers can overcome. But don't ask the Bioscience PhDs to help design the software. They are not good at that type of thinking and they stand to lose a lot of BS room that they need to continue their careers. But it is their careers that have been a hindrance on advancing the field.

Photography was not advanced by photographers. Scientists and engineers were asked to answer a specific set of questions that lead to an improved system. Likewise, biotechnology research will not be advanced by anyone with a PhD in Microbiology, Immunology or Pharmacology. The sciences that rely heavily on math must get involved. Design of experiment is an example of statistics being used to help Bioscience people understand what has been missing in their research. For 30 years the big words of medicine have been used to bring in the big bucks. Now is the time for the big concepts of science to be used instead.

A Biotech Incubators Success Record

2011-05-25T14:56:00.000-07:00

Accelerator puts up 1 to 2 million dollars, lab space and some admin support to start promising new biotech companies in the Seattle "build it and they will come" Lake Union area. They have been around since 2003 so it is interesting to see how things have gone since then. They've started up twelve companies.

VieVax 2004
VLST 2004
Theraclone 2004
Homestead 2005
Allozyne 2005
Seridigm 2006
Recodagen 2008
GPC-RX 2008
Mirina 2008
Xori 2009
Acylin 2010
Oncofactor 2011

So what happened? If you click on the link above you will see early success in series B financing and a long dry spell since then. Did financing dry up in late 2007 or did Accelerator start making bad decisions around this time?

The latest company to come out of Accelerator may be an indication of what is happening inside the offices. The company will be ran by Sarah Warren a 29 year old, newly minted PhD immunologist. Warren will develop experimental antibody drugs against biological targets selected by Carl Weisman, the Accelerator CEO. Weissman came up with his idea about 18 months ago.

“If you can stop cancer from blunting the immune system, then you can free up the immune system’s ability to clear the cancer cells,” says Weissman.

Accelerator seems to have left their old business model behind.

The evaluation of potential Accelerator companies is very rigorous and the process is extremely selective... Accelerator has seen and reviewed more than 500+ proposals, executive summaries, and business plans.

Why then are they now starting a company based on Weismans simplistic, select target/make antibody, idea? Why have they chosen a 29 year old with no experience in the real world? Is she really going to run the company?

Ms. Warren will report to the Accelerator scientific advisory board that includes Pat Gray, (Accelerator’s chief scientific director), David McElligott (lead scientist at Mirina, Accelerator) Ken Grabstein, (chief scientific officer of Allozyne, Accelerator) Mike Deeley, a former senior director at Icos, Steve Gillis, a managing director at Arch Venture Partners; Larry Tjolker, (a scientist at Xori, Accelerator) and Charlotte Hubbert, (a Kauffman Fellow at Accelerator).

A little heavy handed with the Accelerator upper echelon. With four employees, including Ms. Warren, Oncofactcor looks more like a post doc and three lab techs doing the bidding of the old white guys. Perhaps Accelerator has grown tired of the failures. They've dipped into their emergency funds to keep up the image of a thriving incubator of biotechnology companies. They've put someone in place whom they can shove around. Was this the vision of the early days of Accelerator?

Worst of all, they are using RNAi to validate their drug targets. The targets are selected with bioinformatics. Both RNAi and bioinformatics have been a disappointment to say the least. They don't have the ability to make the antibodies that are suppose to become their drugs. Instead they will spend their days struggling through the aweful lab experience of trying to get RNAi to work for that brief fleeting moment. From this they will instruct a CRO to make their antibodies. Failure is almost guaranteed. They would be better off waiting for the CRO to send antibodies and use them to validate targets. But then how would a 29 year old bioinformatics immunologist know that?

Will Accelerator one day close its doors? We think it will. It is a Cargo Cult Airport Incubator.

Harry Perry

2011-05-25T12:36:00.000-07:00

I want to take a break from trying to figure out the Cargo Cult world and think about something that has worked. This is Harry. He began playing guitar and singing songs for people down on Venice Beach back in 1973. Some people think of him as strange. But if you were to look at his life on paper you would find a stable successful American businessman. He's had the same job since 1973, he leads a healthy lifestyle and he shows up to work everyday. He has no boss, just the hassles of everyday busking on the beach.

As a philosopher, I don't pass judgment on whether or not Harry is an odd fellow. Personally, I like to think about Harry happily blading up and down the boardwalk while I suffer through days of bad science and endless meaningless meetings at multimillion dollar mistakes with sciency names. I do judge cargo cults. Harry is not participating in a cargo cult. He plays you a song and asks you to buy a CD, a shirt or both. Twenty bucks for both. While he plays you can take as many pictures as you like. He has branded himself. He brings his product right to you and you can take it or leave it.

As a biotech employee I have never actually worked at a company that has sold a product. We've brought in millions of dollars but we've never turned that money into a profitable company or product. The only remaining company that I've worked for that hasn't folded is one that makes the claim (among many odd claims) of growing their drug in a more efficient way than the rest of the industry. The claim is false. In fact I don't know of a group of people who know less about the actual manufacturing of such a drug. It seems to me that they took the truth and simply said the opposite. If my experience has taught me anything however, this company will fail. You can only BS for so long.

As I contemplate the future, mine and the cargo cult airports, I can't help but think of Harry. He's outlived 100 billion dollars in biotech waste and hundreds of companies staffed and ran by the brightest minds of our life science scholars. His music isn't the best. He just rolls up to people and plays them a song and asks them to buy a T-shirt. At night he goes for a jog up the coast of that beautiful beach as the sun sets over the hills of Malibu to the north. His future will be to keep on doing his thing til old age takes him out of the game. Our industry will try to get him to hand over some life savings for the pills we make for old people with two months to live, our primary target. But I think Harry will die quick with only a little pain and no regrets.

Everything Is Obvious

2011-05-18T06:00:00.000-07:00

If I were to put together a college course on Cargo Cults it would be based on five books:

1) Innumeracy (John Allen Paulos)
2) A Drunkards Walk (Leonard Mlodinow)
3) How to Lie With Statistics (Darrel Huff)
4) Surely You're Joking Mr. Feynman (Richard Feynman
5) Everything Is Obvious, Once You Know the Answer (Duncan J. Watts)

All of the books describe a lot of what Feynman hopes we all get through the course of our educations:

There is one feature I notice that is generally missing in cargo cult science. That is the idea that we all hope you have learned in studying science in school--we never explicitly say what this is, but just hope that you catch on by all the examples of scientific investigation.

Book one asks us to evaluate our relationship to math. Book two is a hilarious view into our random lives. Book three is a classic on how statistics are used to tell any story imaginable. Book four is Feynman telling funny stories from the point of view rarely seen. Book five is new so I'll elaborate on why it's on the list.

The author has an education in physics and engineering. As a profession however, he chose Sociology. Although the field has done a poor job of applying the scientific method, the author believes things are turning around. In his book, Watts explores what we think we know (not just sciency subjects) and he asks us to question that reality. We use common sense to decide what to wear to work versus what to wear to the beach. We use common sense to tell us what to do and we don't really question why. In science we are suppose to ask why.

What this course will do is important. Many in the class will be in the process of preparing for the corporate world. Many of those people will pursue science degrees in their quest to start a biotech company or to climb the ladder at Pfizer. They are bullshitters. Science is going to help them sound sciency. The others in the class however will be nice normal people who just want to learn a little and go into the world where they can contribute, go home and live their lives. They all need to know what the tricks are so that the bullshitters are less confident in bullshitting. It may even put a few bullshitters on the straight and narrow path.

After the course, students may a new framework in which to think. In questioning pharmaceutical executives for example, they might find their thinking more in line with common sense. RNAi is a good example. A Nobel Prize was awarded for describing a process that common sense tells us would be the next big drug platform. Drugs interact with molecules that cause disorders. Eliminating those molecules will prevent the molecules from causing the disorder. It's sciency but it's not science. Science is proving the common sense notion of RNAi to be wrong.

In the field of economics we have common sense notions such as giving the wealthy more tax breaks will lead to more jobs. How is that working out for us? The common sense comment I've heard is, "I never got a job from a poor person." True, but by the same logic, we could make that poor person rich and then he would give you a job. The truth lies somewhere else most likely. Jobs are created... how? We don't know. As a leader in the field you must appeal to the majorities common sense to make them think you do have an answer. Tax breaks for the rich is the answer. It's a common sense solution and it hasn't solved the problem.

The term sciency, by the way, is used in the field of Bullshit. Sciency refers to things that seem scientific by virtue of what scientist is speaking and how scientific they appear to be. Bullshit doesn't rely on lies nor the truth. Bullshit relies on whatever needs to be said or done to achieve the goal. Common sense is the foundation of the process. It's just common sense to listen to scientists when they speak of science. If you don't know what you are talking about you can bullshit your way around by sounding sciency.

The Cargo Cult Science course would also go against the grain of common sense knowledge. The five books are about uncommon, yet learnable knowledge. It would be a science course that isn't very sciency. There would be math but it would come in the form of Innumeracy questions like, "how fast does hair grow in miles per hour?" There would be expert guest speakers. The tests would be to distinguish which ones were bullshitters and which ones were actually who they said they were. Unlike science courses, the CCS course would be fun and accessible to all students interested in looking at the world more objectively. It would prepare you for no occupation but it would help everyone do their job better. When the students leave class and go to the next one, maybe they'll raise their hands and ask more questions.

The Proverbial N-Ray Prism

2011-05-12T09:55:00.001-07:00

In a story related to my last, comes the story of the mutated prion that wasn't. We all make mistakes. It is how science deals with them that the keeps us from the truth.

There was a young post-doc who began his career in a laboratory of a prominent scientist. The scientist, not the post-doc, had an idea that needed to be verified. The idea was that a single amino acid substitution could prevent the conformational change of a protein that allegedly led to a brain disorder. There was cloning to be done, assay development, and the usual gels and western blots. Not rocket science but the conclusion, if things worked as expected, would put the world on notice. This was to be a major stepping stone.

At the end of a year the data was in and it all looked kosher. It was time to write up the paper and get the news out. There was only one problem. No one had sequenced the DNA of the clone being used in the study. Prior to submitting their paper the clone was sequenced. The mutation in the amino acid sequence wasn't there. The research was done on a protein that was the same as the controls. A new question arose. How did the data fit the preconceived notion?

How did they see their N-Rays without the prism?

The young post-doc failed in his task. It wasn't his idea but he understood what was expected of him. If he was to make it in the business the results needed to come out a certain way. Like a Sherlock Holmes novel, the final outcome smooths out the leaps of faith and unwarranted assumptions. Science is about genius. At least that is what we think the world expects of us.

Imagine a P.I. testing his post docs by giving them a bias in the form of a protein that is suppose to do something. An assay is provided to give an output signal that will vary from run to run. The protein and its control are in fact the same protein. Will the post-doc point out the precision issues of the assay or will he run the assays until the desired story has been told? In other words, create an N-Ray story. Short, sweet, elegant and false. Provide the measuring tools and bias the outcome. Who uses science to tell the truth? Who uses the bias to tell the story they know will get them them ahead in life?

If you've ever been in a bad job and you needed to get out, you knew better than to tell the next potential employer you want out of a bad situation. You tell the employer that you are looking to advance your career or something along those lines. The truth is not well tolerated in many human endeavors. It is not tolerated in professional science. It is not tolerated in finance or government. We want certain things to be true. Whether or not the prism is there, we want to see N-Rays.

The Drunk Under the Streetlight

2011-05-12T09:55:00.000-07:00

A policeman came across a drunk on a dark road scrounging around on the ground under a streetlight.

"What are you doing?"
"Looking for my wallet, I lost it in that ditch over there."
"Why are you looking for it here?"
"The lighting is better."

I'd like to go back to a phage display project because it encompasses the fundamental flaw of science as it is conducted in the biology, medical world. Unlike other sciences, we have a low standard. W are wrong most of the time. The unofficial measurement, wrong 90% of the time, did not raise much protest.

Dr. Nicklin is one of the scientists who worked on the GETRAPL project. The paper is titled:

Development of efficient viral vectors selective for vascular smooth muscle cells.

And it's findings are false. Here is why.

Nicklin et. al. performed phage display as instructed by the kit purchased from New England Biolabs and they came up with a list of peptide sequences. It was decided that a peptide of 7 amino acids would bind to and deliver their DNA to a specific cells type. Once the peptide was discovered it could be used to deliver the viral vector to the cell where the vector will then enter the cell and increase gene therapy activity.

Many assumptions have been made but we will focus on one thing, phage display. The following is the list of peptides the turned up when using the phage display kit.

Peptide Frequency Peptide Frequency Peptide Frequency
AAPMQVT 1 KVTTTRV 1 TARQDSI 1
AKPSPFP 1 LAKHPDS 1 TGHHIFY 1
ALQBKPI 1 LERGPYG 1 THLSRTP 1
AMPYAPR 1 LVPPSGT 1 TLSNYSQ 1
ANMSLLT 1 MGPPSTP 1 TNGLRTA 1
ANSKLSP 1 MPPGYPH 1 TPPQSTG 1
APATSIG 1 NALKFSA 1 TPTIHKT 1
APQPWLM 1 NPFYSLR 1 TPVQQVA 1
ASTQQPT 1 QLTMFPS 1 TQEYRSA 1
DLRIAAS 1 QPNNHAH 1 TQMRQPP 1
EGLPANP 1 QQQHPFK 1 TQPPIRT 1
EYHHYNK 2 SAPERFS 1 TSPIPPK 1
EYTHTPY 1 SFGENSI 1 TTPRFIL 1
FPGKQTT 1 SGSPPSV 1 TTTLRPS 1
GETRAPL 5 SLPDPIH 1 TYATDRR 1
GHSHSHS 1 SLRPSID 1 TYSQSMT 1
GPGPNIS 1 SMPKLIN 1 VKPBTGA 1
GPNQVEW 1 SNAQSMR 1 VLPRASY 1
GSTQPPW 1 SNMAQHR 1 VNPVNTH 1
HLHTIGR 1 SPIRHVH 1 VSAQTRQ 1
HPFILKP 1 SPQLPQL 1 WAPPPAG 1
HPPBVSS 1 SQSPFFP 1 WNLQPPQ 1
HSFPHAP 1 SSHGSLS 1 WPNTYRL 1
HVLWTPP 1 SSQYAHL 1 YHPMSSL 1
IRPPSII 1 SWLPHNA 1 YLKPPGP 1
KLVASNP 1 SYMYKPQ 1

The two peptides of interest recur twice (EYY) and five times (GET). Had the New England Biolabs provided a database of sequences from other panning experiments, Nicklin would have known these sequences are contaminants from the NEB library. The observance of these sequences is to be expected. They are an annoyance and not the holy grail of DNA delivery for gene therapy. What we have here is a limited data set, kit science, and a hope that something shows up. The kits cost $300 dollars each and thus they provide the streetlight that can be used to search for the wallet in the ditch.

The peptide sequences that were "discovered" in this project are the proverbial prism in this modern day N-Ray story.

Once you have "something" the leadership can get to work. You now have a solution and the corrective measure that can be organized and managed. Leadership knows how to organize and manage. They hire team leaders and project managers and directors and even a few white lab coat kids to run the assays in the lab. And they are kids. They will take that useless phage contaminant and make the assays tell the predetermined story. The only question they ever had was how far the bars on their charts would be separated.

Management has found a nice comfortable streetlight. But the wallet is over in the ditch, under water behind a patch of thick weeds 3 feet high. It is hidden in a big way. 20 yards away the leadership stands with their hands in their pockets directing low paid grunts to look harder. Failure in this system is a guarantee. In order to not face failure, hope is put in its place. Hope keeps the project lumbering on and costing countless wasted man-hours and plenty of money.

A recent comment on the state of medical research from Roy Mankovitz.

I have a background, and publications, in the field of rocket science, having designed control systems for planetary landers and deep space probes. As most folks know, we have had a phenomenal record of getting it mostly right.

Well, with respect to science, research is research, but when I finally starting poking around in the area of medical research, spending decades reading and analyzing thousands of studies, I was horrified. It seems they get it mostly wrong.

We do and this is one example. I worked in a different part of the world but I did the same project. The NEB libraries were the same, the cell target was different, the peptide sequences were the same (we found EYHHYNK)and we made the same charts. We used the streetlight approach because it was within our understanding (so we thought) and we found what we wanted. We found the same peptides Nicklin did. Our bosses were satisfied for the time being and kept our project aimlessly moving forward. We too eventually gave up and found new jobs.

Never Confuse Movement With Action

2011-05-11T14:27:00.000-07:00

In the book 'Science Business' Gary Pisano begins with the premise that biotechnology has not lived up to its promise. He has ideas and research and conclusions.

I argue that the performance of a science based business, like biotechnology, hinges on how well the sector is organized and managed to deal with the fundamental business problems created by science.

I argue that organizing and managing a cargo cult airport differently results in another cargo cult airport. The science hasn't produced enough drugs so they must shift the science work to someone else. It appears that science is a word that everyone thinks has one meaning. Medical "science", physical "science" cargo cult "science". It's the equivalent of assuming that "God" is understood by all and thus you start a church in Jerusalem with a Catholic priest. It's a good business model. It's a very religious town. You should make a lot of money in the old collection plate over there.

Gary Pisano does a little scientific research himself in his book. Academia and industry claim that industry scientists are the problem. The solution is to sack the staff and shift funding to university and biotech scientists. Gary points out however, that big pharma was no less successful at R&D than small biotech firms or academia.

Universities clearly began to see their science as a buiness. They aggressively patented and sought licensing deals, collaborated with venture capitalists to launch firms, and even began to mve downstream into drug development. Both private enterprises and universities were in the business of science.

So academia has been in the business for quite some time. If industry and academia were to conduct research into finding the successful formula for drug development, they would find that success is random. But then, they need an excuse and a corrective action. Randomness is not an option. Not succeeding is. In fact, it's the most likely outcome, but it is an unsatisfactory answer. No one is going to get at the big pharma money if they tell the leadership that there is no formula for success.

The current theme in industry and academia is to blame the structure of the old ways. Think, cargo cult airport structures such as the man in the watch tower with coconuts over his ears.

A businessman sitting in a room full of other businessmen makes the claim that the in-house science project aren't working. (The cargo planes aren't landing) He claims that this is a cancer and it must be cut out. The anatomy of this real life scenario can be followed by clicking here, then here. The scientists didn't have the freedom to pursue ideas like those in academia do!

A professor at a University sits in a room full of his peers and makes the claim that he is good at science projects that work. Regis Kelly director of the California Institute for Quantitative Biological Research

Academics like myself are great at discovery but are frequently embarrassingly ignorant of the useful applications of our discoveries.

Ahh, arrogance tempered with a dose of humility. He's a genius, but no one knows what to do about it. This is the premise of the alliance. Adacemia = genius Industry = know how. It's a winning formula. The plan is not random. The old ways were flawed, the problem has been identified, and the solution is in place.

Prof. Mark Pepys at the Royal Free and University College Medical School in London, commenting on an alliance with Gilead

We all agree that big pharma is useless at discovering new drugs and has to get its ideas from somewhere else.

Ahh, arrogance tempered with presumptuousness.

So where are we now? Industry believes that there might be some creative restrictions in the corporate world that have hindered "scientists" from innovation. The academia scientists believe that they are good at innovation but they require industries money and "know-how" to translate their genius into drugs. And they are doing it for the good of mankind. Again, Regis Kelly

Alliances with Pharma can bring the knowledge of society needs that we lack. ...it was NOT about the money.

The businessmen are busy forming alliances with old white bearded professors. A call to action or just movement?

The American/Scientists Dream

2011-05-06T14:42:00.000-07:00

What is the American Dream? This is what George Carlin has to say about it.

George Carlin and The American Dream

The owners want obedient workers who are just smart enough to run the machines and do the paperwork... It's a big club, and you aint in it!

Let's replace "American" with "Scientists" dream. The concept of obedient workers in science seems to fit. I'm only going to focus on the fate of early stage researchers here because they do the grunt work to create the foundation of the cargo cults.

The leadership will identify what drug targets can be pursued. Each decision is the starting point to a possible billion dollar bet. Ten years might pass between this decision and FDA approval. Think of it as a linear time line, Point A; zero dollars, day one. Point B; one billion dollars, year ten. During this time many things will occur that are classified as work. If you could create a chart of the work and how it is all related you would see how complex it really is. For example, deciding how much drug will be needed for a phase one clinical trial is related to expression level measurements from early stage R&D. This is real work. Somewhere in the chart however, is cargo cult science. This is the area where the billion dollar bet is most vulnerable.

Rather than admit the pitfalls of cargo cult science in the path to a successful drug development, the industry has switched the location of cargo cult work and the financing of this work. Big pharma is getting rid of their in house workers and farming out the early stage work that tells the higher ranking leaders what billion dollar bets they should make. Smaller biotech firms and academia will be taking over that role. Gilead and Yale, for example have a research alliance that will bring corporate sums of profit to the school. The workers now are state university employees or low paid entry level college graduates working at small biotech firms. Big pharma still requires the same obedience and science that conforms to their ten year plan, only it will cost them less. Our scientific dream is now regulated by for-profit pharmaceutical companies.

The employees of the airport must remain obedient workers just smart enough to run the machines do the paperwork. The science that goes into target selection is done by lower ranking people. Final decisions on the billion dollar bet are made by higher ranking people who must also consider making their investors a profit. Once the bet is made, lower ranking people must make the data fit in spite of the rigors of the scientific method. Avenues may open up that could shut a project down. This will effect whether or not you will continue having a job. Cargo cult leaders do not wish to be embarrassed by experiments that point out the foolish premise of their billion dollar bets. Scientists working before and after the billion dollar bet is placed must practice their expertise with diplomacy.

The cargo cults are changing their ways. The scientific dream remains as allusive as the American dream. The man in the watch tower with coconuts over his ears has been moved to the local campus. Universities officials will now look to their natural science colleges as a revenue generating machine on par with the football team. Superstars will arise and move on to high paying jobs in the industry. Both industry and academia run cargo cults so it won't matter much where the superstars take their desk job. It is the lower ranking tribesmen and women who will find it harder and harder to earn a living. The biggest casualty however will be the science that makes some people dream of exciting careers. There will be a lazer like focus on your research. The new science must identify drugable targets and pathways that, when disrupted, lead to the cargo planes landing on the airport owned by your corporate sponsor. Cargo cults dream of the cargo first. They still haven't figured out a way to get it. They've just came up with ways of reducing the cost of running their airports.

Biotech is Back Revisisted

2011-05-05T10:12:00.000-07:00

Last year I posted a few times about the 'Biotech is Back' forum here in Seattle.

Seattle’s life sciences industry has been on life support for a few years, but now, for the first time in a long time, biotech has started to show some legit signs of rebirth.

The organizer of this event, Luke Timmerman, posted a very interesting article this week. The title:

Considering a Career in Biotech? How About Trying Computer Science Instead

The comments were also interesting. In them, we get to hear from some of the employees in the field.

As someone who is currently in the biotech industry and have been doing lab work for 10 years, I would not recommend anyone going into biology or life science period. The risk and reward is not worth it and yes, the ladder of success is extremely tough. I agree with this article, change major if you are still in school.

Given the training required and average payout for skills achieved, life sciences / bioengineering is a long, long row to hoe. It is slow, it is expensive, it is glass ceilinged to anyone without a PhD (this includes nearest neighbor industries where PhD’s have fled their serfdom), and it is dominated by a relatively older generation of scientists who do not provide a healthy work structure for young employees. Life Science is an extremely dangerous career path for bright young people, and I encourage them to avoid the field and it’s ever-thirsty vampires.

...be mindful of tailoring your experience to be too protocol specific, in this field having immunohistochemistry experience will only help you get a job doing more immunohistochemistry.

Ironically, on the same webpage, there is a piece by Ken Stuart entitled, "An Investment Opportunity: Training in Biosciences". One reader commented:

I thought it should be noted that the people in positions of leadership in biotech, ala Ken Stuart, can seem detached from the economic reality of what’s happening on the ground. I have to question the sanity of a pushing an training continuum that currently lasts over 12 years, fails to achieve an average pay above 50k at any point, and whose target field is experiencing large funding cuts. That isn’t even taking into account the trainwreck/vacuum of PhD management. In light of the problems already facing life science, Mr. Stuart’s suggestion of starting even earlier seems ludicrous.

We focus on the cargo cult science of biotechnology and hold it accountable for the woes of the field. The leadership can have meetings all day long on how to make more money so they can provide a life long career for young aspiring scientists. Until they understand the concepts explored in CCS and start to weed it out, they will not be successful.

Funny Stories

2011-05-02T06:27:00.000-07:00

Lately, the Xconomy folk have been having a hard time coming up with stories to write about the local biotech scene here in Seattle. Since I'm not making a living at it I'd like to share a few stories I've encountered over the years that I think may have something to do with our troubles

There once was a lady who had just receiveed her PhD. During the course of her education she had worked in a lab but she had never dialyzed a protein. We showed her the cassettes and the flotation sponges. The next day we showed up and to our amazement, she had managed to balance the cassettes on top of the sponge, exposed only to the air. The dialysis cassette had not touched the buffer.

Our fermentation scientist (not a PhD) had six 3 liter fermentors. Every two weeks she would set up six runs, usually testing six different methods. When we asked her why she didn't do anything in duplicate she said that it was because she could get more tests done that way. "Ya, but how do you know if the data is reproducible?" "Trust me, it is," she barked at us as she stomped off. Then one day she needed to test only 3 pHs during a particular step. DO EACH ONE TWICE! we begged of her. She did. pH 4 gave very different results, pH 5 both died, and one of the pH 6s gave the best expression. The other pH 6 run died. Conclusion; pH 6 is the best condition but pH 4 could be used in a pinch. pH 5 is lethal.

PS: The six reactors were named after six of the seven dwarfs. Actual conversation: "Which pH 6 run died?" "I think it was Sleepy."

Related story: We had six fifteen liter fermentors. The original process development scientist on the larger fermentors was perusing the fermentation scientists "pH 6" method. The fermentation scientist entered the lab. "What are you doing?" "We're going to try this method at the 15 liter scale." The fermentation scientist snatched the method out of the hands of the process development scientist and stomped out of the room. The process development scientist had to get the method from someone else.

PS: The six 15 liter reactors were named 1, 2... 6.
PSS: The process development scientist was later fired and replaced with an even more experienced scientist. The fermentation scientist was to be a member of his staff. Within the first week of his arrival the he wanted to fire the fermenation scientist. It wasn't allowed. He later left a note reading "Beam me up Scotty, no signs of intelligent life." We never saw him again.

In a Nobel Prize winning lab, they decided to generate antibodies against infectious prions (and not the normal confirmation protein) by denaturing the protein with guanidinium and using phage display technology. As a result of the denaturation, it was impossible to fish out antibodies that adhered to our hopes and dreams. The phage display was done at the Scripps Institute in San Diego. Without testing they sent up numerous samples for western blot analysis. After 3 months it was determined that I (the cargo cult scientist) was incapable of running a proper western blot. In spite of my examples of almost daily western blots using proper antibodies, the job was turned over to another person. They retested my most recent lot. Same result. After a long meeting, my replacement returned to the lab. "How'd it go?" I asked. "You know the step where you boil your sample for 5 minutes prior to running the gel? Well I only boiled for 4 minutes." I responded that I had done that many times and it doesn't really matter. My replacement repeated the work with the 5 minute sample boiling and still obtained the same results. The supervisor was none to happy. She gave us both a dirty look when she saw the same results for the third time.

The ForteBio is a machine that will measure your binding affinity between two proteins. Our ForteBio people tested ten antibodies, 3 times each. In their presentation they listed the 30 results from strongest to weakest binding. A couple of us asked why they had not made a bar chart with the average of each antibody binding affinity and an error bar to show us the deviation of the measurement. The director then took a different tack. On the spot he created an excel spreadsheet and they began using the excel functions to list the 30 antibodies in as many ways as they could think of. Never an average with a deviation measurement. From the strongest to weakest list they selected the one with the first, fifth and 12th strongest binding affinity. It was the best.

AstraZeneca Destroys Their Airports

2011-04-28T19:04:00.000-07:00

AstraZeneca has lost faith in R&D. The rituals have not brought them the cargo they hoped for. The airports are being destroyed.

R&D does not lead to profit. Scientists do not add value to Pharmaceutical companies and they won't be invited back!

Crime on the other hand...

The investment by AstraZeneca in scientists and their laboratories did not pay off. The whole point of this blog is to make the claim that what has taken place throughout the entire industry has largely been a cargo cult science. The scientists and their laboratories have been employing real science, such as the cloning of genes, expressing of proteins, and demonstrating various qualities of the products. But careerism takes over and the science quickly turns cargo cult. As Feynman would say:

they follow all the apparent precepts and forms of scientific investigation, but they're missing something essential. Now it behooves me, of course, to tell you what they're missing. But it would be just about as difficult to explain to the South Sea Islanders how they have to arrange things so that they get some
wealth in their system.

How do you arrange the good science and technology to get some wealth into the system? AstraZeneca is not giving up on science, just their scientists. Someone else can now do the early stage research and AstraZeneca will take over at a later stage. Their businessmen will make the decisions as to what is good science and they will invest accordingly. The gamble now is whether or not the businessmen will make the right decisions. On the surface it seems reasonable. The expensive laboratories will cease to exist and the entire world of science becomes an open field to explore. Small biotech companies can present their work to the AstraZeneca businessmen and those who are at the proper stage of development will be partnered up. The businessmen know how to arrange partnerships. They know how to attend meetings. Do they know how to spot a scientific endeavor that has wealth built into the system?

Science vs. Scientists

2011-04-26T09:43:00.000-07:00

Imagine I am the Csar of Science and I am tired of the culture that places scientists on a pedestal but ignores science. I, as a high ranking government official, have the ability to conduct experiments with 100 NIH funded scientists. There is no hidden agenda here. They are told that it is their ability to uncover the truth that is being studied.

I express a protein in CHO cells. It will be a human antibody against TNF alpha, one of the most popular biotech drug projects. It will be purified to 99% purity and be in PBS. All I tell the labs is that it is a pure protein in PBS. The information that they send back is entirely up to them. What I am looking for is clarity, simplicity, and accuracy. Science shouldn't be any harder than it needs to be. I am looking for a response that identifies human IgG.

This will be stage one. Hopefully they will pay a CRO 500 bucks to perform amino acid sequencing and do a BLAST search. Expense is also a factor in my experiment. Who is the most efficient in simple tasks?

Next I reveal what the protein is. I tell the first 50 to provide physical details such as molecular weight, glycosylation, binding constant... I tell the other 50 to do the same but I throw in that we (the government) want to market the antibody to compete with the others. Once again, I do not tell the scientists exactly what to do. Even the format of the report is up to them.

How does the added information (compete against marketed drugs) affect that reporting on physical properties of the antibody?

Why do I consider this a good science experiment? To begin with, I do not have a bias towards any particular outcome. Next, I have not formatted the scientists thoughts on how to report their findings. We are all blinded as to what the information will be. I am testing the scientists, not the science. I know that the science and technology is available to get the right answers. The known unknown is the antibody. We know what it is. Can the scientists make it a known known? Next is the unknown unknown. I don't know what the group of scientists will do. Will 100% pass step 1 and name that protein? Finally, what affect will the added information (compete against marketed drugs) have on the analysis? Higher binding affinities? Will the government antibody successfully compete against marketed drugs as opposed to simply being fairly compared to them?

My experiment is about bias and science. Are there ways that leaders can prevent bias from affecting science or do the leaders want to bias research? Are there ways of measuring the affects of bias? Here at the CCS we naturally assume that any group of humans will be lead by those most adamant to obtain the desired outcomes. It is science, not scientists, that has no such bias.

Blind Clinical Trials

2011-04-20T10:47:00.000-07:00

Last week the Seattle Genetics manager of clinical programming accused of insider trading committed suicide.

One can't help thinking about the leadership of the cults once again. They all seem to know how their trials are going. They design their trials in a manner that allows them to manipulate the data. Dr. Aubrey Blumsohn had this to say about working with a drug company in the analysis of clinical trial data:

It’s hard to encourage anyone to speak out about poor practice in the current environment. This case sums up what has gone wrong with systems set in place to ensure safety and integrity in scientific medicine. It would help if regulators put as much effort into responding to serious critics and whistleblowers as they do producing glossy brochures and yet more guidance.

Dr. Fan committed the crime of using inside information to turn a nice profit for himself and his family. Sam Waksal did the same thing. Aubrey Blumsohn did something a little different. He didn't focus on helping the biotech company tell their story. He tried to tell the story that science would dictate.

What does it mean to have a blinded clinical trial? Who can we trust? Are we blinding the trials to ensure integrity?

When to Retract

2011-04-14T16:39:00.000-07:00

Retraction Watch posted a piece on why people/groups retract papers. The reasons people give all point in the direction that what was stated may not be true. What about the papers that are not retracted? Where is the line scientists cross that leads them to correct their mistakes officially?

Previously I've written about the peptide sequence GETRAPL. GETRAPL is the peptide sequence despayed on a contaminating bacteria phage that is found in New England Biolabs phage display kits. If you don't believe me, and you care, you have a few options. A) you can search and search for information on the sequence. B) you can call New England Biolabs and ask them if this is so. C) you can purchase a kit and use it until you start seeing white plaques in the presence of beta galactasidase. You will find GETRAPL!

That is the curious thing about modern science and our near religious faith regarding peer reviewed papers. Rather than going into a lab and reporting your results, people would prefer to find information from others. This is not uncommon. We went to war on faulty CIA information regarding weapons of mass destruction. We didn't retract Colin Powells speech at the U.N. We were wrong, but the war was just. Right? This is akin to the retraction of a paper. We can be wrong but that is not what gets a paper retracted. If you are a scientist who has spent the last 10 years studying the amazing effects of GETRAPL you are not about to retract all of your papers. You would rather just let the subject fade away while you find a way of burying the inaccurate information.

PubMed published an article on a peptide database that came across the GETRAPL confusion.

We suggest that one of the utilities for PepBank is to search the peptide sequences of interest to the user with BLAST or Smith-Waterman algorithms to find any important similarities to the known peptides collected in our database. In this example, the search can be used to remove a relatively nonspecific binder GETRAPL.

Even the last sentence is misleading. The reason GETRAPL ends up on your radar is because the phage displaying the peptide grows faster than the other phage. It has nothing to do with specificity. The sequence has been published and patented and beaten to death by cargo cult scientists. They needed to find something and they did.

So the question is simple: Do they have to retract? The Cargo Cult Scientist studies the ways in which errors occur in the minds of individuals highly educated in the ways of science. Where do they go wrong? Do their peers really get a chance to investigate and add to the story?

GETRAPL is a minor, insignificant story in terms of its impact on curing AIDS or targeting specific cells. It is however a modern day N-Ray story to the Cargo Cult Scientist. After all of the papers about GETRAPL, I have only one conclusion when I see the sequence. The authors used New England Biolabs phage display 7mer kits. That's all I can be sure of. Back in 2009, two years after the PepBank exposed GETRAPL we still have papers like the following:

Recognition of Patterned Molecular Ink with Phage Displayed Peptides
Yue Cui, Anupama Pattabiraman, Bozhena Lisko, Samantha C. Collins, and Michael C. McAlpine*
Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, New Jersey 08544
Received October 2, 2009; E-mail: mcm@princeton.edu
Published on Web 01/06/2010

An aliquot of phage display library
(New England BioLabs, Ph.D. 7) (Figure 1a) was incubated with
a C8-functionalized Si surface (Figure 1b) and then eluted from
this surface to collect the bound phage (Figure 1c).First, ﬂuorescent characterization for the binding of this phage to
C8 and Si substrates was investigated. This was accomplished by
exposing the substrates sequentially to (1) ampliﬁed single-colony

Eureka! I've done it! I've proved that New England Biolab libraries contain GETRAPL.

Education cannot teach people to Google GETRAPL. It is not considered science. Yet it is information. Education cannot teach people to design experiments. It will always be a subjective pursuit. Should Cui et. al. retract "Recognition of Patterned Molecular Ink with Phage Displayed Peptides"? They are wrong. They may have higher degrees in Aeronautical Engineering and work at an Ivy League school, but they have made a mathematical mistake. The data set was too small. The information from other scientists was ignored. They failed to consider alternative explanations. They are wrong. The research, even if correct, wouldn't be all that important. It is the fact that they erroneously attached such significance to their honest mistake that makes it a Cargo Cult Science paper.

Living Up to Our Promise

2011-04-13T08:28:00.000-07:00

I've come across a book that acknowledges the lack of productivity from biotechnology. It's called 'Science Business', written by Harvard business professor Gary Pisano.

Why has the biotechnology industry fallen so short of expectations - despite its grand promise?

At the Cargo Cult Scientist world headquarters here in Seattle, we are very excited to hear someone come right out and say this. Earlier this year the leaders of the Seattle Cargo Cults held a conference called, "Biotech is Back". The title was a clear indication that the biotechnology industry does not employ scientific reasoning. The industry continues to suffer from business as usual.

According to Pisano, the problem is the relationship between business and science. Science deals with unknowns. When something becomes known (scientific advancement) we attempt to use it (technological advancement). The scientists know how hard science can be so they chose to become businessmen. They work in offices and adopt business logic. This is where Feynman hopes we do not end up.

So I have just one wish for you--the good luck to be somewhere
where you are free to maintain the kind of integrity I have
described, and where you do not feel forced by a need to maintain
your position in the organization, or financial support, or so on,
to lose your integrity. May you have that freedom.

It's clear that not everyone gets into science because they feel the same passion as Feynman. A degree in BioPhysics will earn you more money than a degree in Theology. When the money started pouring into biotechnology, the wrong people started showing up. They created places where the Feynman version of integrity was not welcome... biotech places.

The book, Science Business, analyzes the industry and its performance over the past 25 years. One of the current assumptions about biotechnology is that smaller biotech firms are better at innovation. Big pharma is tied down with bureaucracy and corporate BS. What they found out in the course of their research was that there was no discernable difference in the R&D productivity of biotech and big pharma. The notion that there is a difference is one that biotechnology is using as a selling point. Executives at big pharma buy into this idea as well, hoping to partner up their next big drug rather than making harder decisions on in house development projects. In the book the author has done the research that those in the industry have ignored. The question was asked, "Who is best at R&D?" The data showed that no one wins.

The book 'Science Business' is on my reading list and I'm sure will generate more posts. We seek to find out why something so promising can turn out like it has. The hypothesis we have is that biotechnology is not doing well. We are not alone.

Retraction Watch, Omeros, and Confounding Factors

2011-04-04T14:50:00.001-07:00

Retraction Watch is a scientific gift. Those who value the truth now have a source to help them through the minefield of scientific publications.

Our own blog here, The CCS, follows the retraction of scientific ideas. The ideas manifest themselves as biotech companies. We think of each company as a torch that illuminates a cargo cult airport. The airport I speak of most often is Seattle Biotech since I live here. Our cargo is a drug approval.

Today we report on Omeros. The torch has grown dim.

Omeros (NASDAQ: OMER) said today that its most advanced program in clinical trials, a combination of generic drugs designed to reduce pain and swelling in patients undergoing arthroscopic knee surgery, has failed. There was nothing to sugarcoat here—the drug, OMS103HP, failed to meet its goals in the third and final stage of clinical trials.

Of course we don't just sit back and judge a company based on whether or not they succeed. That is what investors do. We want to know why they failed. Due to the secrecy of modern day science, we don't get the full story. But we do get some hints as to what they think may have gone wrong.

Omeros blamed confounding factors in the studies, which means that if patients improved, it could have been caused by some other reason than the Omeros drug.

Sounds like they made their mistakes before the trials began way back in 2004. Statistics was the problem? How can this be?

The confounding factors in the Omeros clinical trials are what we want to know all about. Omeros is the victim of the confounding factors, and now their investors are as well. We believe that real science can prevent these things from happening. Like Retraction Watch, we believe there is value in negative results. The team at Omeros and their investors are hurting. They took a gamble and lost. Now they are going to put all of the negative behind them and forge ahead. Now is the time however for those in the negative sciences to start their research. If allowed, what would a couple of cub reporters for the Science of Negative Results turn up? The secrecy behind the trial data alone would merit a book. Imagine a series of scientific and business avenues all interlocked that led to the demise of the Omeros lead candidate. Which ones hurt the most? Who made the decisions. Did the molecule really act on its target as advertised? Did the statistical set up of the trials make sense? Many questions could be asked. The answers would serve the industry. Will they be asked? Should they be asked?

400 Million Dollars

2011-03-22T08:18:00.000-07:00

I wanted to go with a more positive note today. Then I saw a report on a 400 million dollar planning experiment. In 1997 the Washington Department of Transportation set out to replace the 520 bridge that connects Seattle to the opposite side of Lake Washington. The old bridge remains in place. I couldn't go on with a positive attitude. A few gems from the research into the spending showed projections of starting construction in 2002 and 2004. Tolls were set and never put in place. Starting later this year (???) a toll system will be put in place with scanners and varying tolls based on the time of day. Out of towners will be billed (unbeknownst to them) by taking a photo of their license plate and sending them their bill for 5 dollars in the mail. I couldn't believe how badly local officials can do their job and get away with it. We are shutting schools down out here to save sums of money far less than 400 million dollars.

This is what a Cargo Cult does. They plan, they design, they talk and the use up resources with almost no regard to the actual goal. The cargo in this case is a bigger bridge that will ease congestion during peak travel times.

Allow me to digress and mention the "positive" story I was going to write about. It is related to the 400 million dollar bridge plan. I recently went to New England Biolabs (NEB) in Ipswich MA. NEB sells restriction enzymes for cloning DNA. They are a rare biotech company because they make money. They also use a portion of the money on environmental causes. For example, when planning to build their headquarters, they ran into the obstacle of three 200 year old Birch trees. They could have easily chopped them down. They spent over a million dollars extra to save the trees. The company is owned by one man, who at the age of 80 goes to work everyday in his own lab. The running of the company has been turned over to the younger generation. The old man conducts science in hopes of finding new ways of extracting energy from things like lobster shells.

The old man must have had a plan. He did not cash in and sell the company. As a result, the old man did not have to argue with investors over whether or not he could shell out the million plus to save three old trees. The employees could relax and do their jobs without fear of shutting down. Research tools were developed to help users use the products, free of charge. The plan was to make NEB synonymous with molecular biology while respecting employees/customers and our world.

What then can we say about the 400 million dollar bridge plan? There is a lot that can be learned from the investment. The problem however, is that the lessons are considered negative. We want to be positive. We want a bigger bridge. We don't want to sit around bickering about who wasted what and why we didn't stop them. Yet that is important to know.

It is the study of the Cargo Cult. The cargo in this case is a bigger bridge. After 13 years and 400 million dollars, we still have the same old bridge. But that is not all we have. We have 13 years of plans. You can research this. Surely something went wrong. It is not negative to want to find out why. The bridge planning leadership will accuse the Cargo Cult Scientists of seeking to judge and blame, but a science merely seeks the truth.

So I am left wondering two things: 1) Why did New England Biolabs succeed? 2) Why did WSDOT fail? There are concrete logical practices that could explain both.

BMS and California

2011-03-20T09:59:00.000-07:00

Corporations don't commit crimes, their people do.

Bristol Meyer Squibb is full of criminals. They paid $515 million in 2007 to settle allegations by the federal government and other states that it used a kickback scheme to defraud the Medicare and Medicaid insurance programs. Now the state of California is going after them. Apparently it is illegal to bribe doctors to get them to prescribe your pills. The article makes the claim that BMS had paid out of 15,000 bribes in a six year period.

Let us not leave out the blame to be placed directly on the medical profession. Doctors don't want to sit down with their patients and explain the relationship between diet and exercise. They deal with the relationship between sickness and pills.

Cargo Cult Journals

2011-03-14T20:36:00.000-07:00

I've come across a most interesting contributor to the idea that science is simply the pursuit of the truth. Bruce G. Charlton is a Professor of Theoretical Medicine, University of Buckingham, and was formerly the editor of the journal Medical Hypothesis. He was fired from his position after the journal was taken over by Elsevier and Dr. Charlton had decided to publish a paper from Peter Duesburg.

In their actions towards Medical Hypotheses, the publishers (Reed-Elsevier - who publish about 20 percent of the world scholarly journals, and a higher proportion of those journals with high impact in their fields) decided what went into the scholarly literature and what did not.

One of the great threats to science (the truth) comes from the demands of a large group of human beings. Many will engage in the competition to be in charge of the group. Elsevier executives must know what the corporate identity is and what they can do to preserve it. Mentioning Peter Duesburg is taboo within Elsevier so they had to remove Dr. Charlton from his position as editor. The next generation of scientists are also effected. They rely on being published by Elsevier journals. They too mustn't upset the non-living entity known as Elsevier. Their livelihoods depend upon understanding what is acceptable. The most successful will pursue what is not just acceptable, but what is favorable.

I'm going to explore some of the ideas (as I interpret them) presented by Dr. Charlton in greater detail later. The moral of todays post is that we are facing a monopoly in science. Executives at a large corporation are making decisions that should be left up to the talent. Elsevier took control of a journal and control of editorial decision making. Warren Buffet doesn't even operate this way. Buffet researches companies and buys the good ones. He leaves the management in place and lets them do their job. Science needs to learn this lesson. Smaller groups of humans means more groups of leadership. More groups of leadership assures a diversity of ideas. Since scientists are good at convincing people of both good and bad ideas, diversity is needed to get at the truth. When leadership is consolidated into one group we have lost a battle.

We here at the CCS dream of a journal of negative results. By asking scientists to write about things that did not work, we can get a fresh perspective on things like RNAi.

Another Dendreon Exec Departs

2011-03-12T15:22:00.000-08:00

What is going on at Dendreon? Last year Dendreon lost a high ranking executive with no explanation. Varun Nanda, the Senior Vice President of Global Commercial Operations was said to be an arrogant egotistical a-hole but when did that ever work against an exec? Now they are losing the Chief Scientific Officer and co-founder of the company, David Urdal.

Anyone who has talked to me for more than two minutes knows that I have become bewitched, bewildered and bedazzled with the arrival of our first grandchild last April. The same month that the FDA brought us into a new era of cancer treatment with the approval of Provenge, my daughter brought the Urdal family into the next generation with the birth of my granddaughter – Ava. I look forward to seeing the world through her eyes and the eyes of the grandson we expect to see in June.”

“I am now in my sixteenth year with Dendreon and what an extraordinary journey it has been – the first autologous cellular immunotherapy approved by the FDA! What an achievement and what a pleasure it is to be a member of such a truly extraordinary team – the Dendreon team – as we won the high achievement of Provenge approval. We are just getting started.

Why would a high ranking member of Dendreon leave when they are just getting started? Because he wants to hang out with his grandkids? Do these types of people even take off work to watch their own kids grow up?

Something is wrong at Dendreon. They have a drug that has marginal efficacy. A lot of work has to go into bullshitting your way through life. Maybe he has grown tired of it and wants to take a rest.

Improving Early Stage Research

2011-03-09T08:19:00.000-08:00

The NIH has a new one billion dollar plan to help the cargo cults get more airplanes to land on their runways. It seems that about 1 out of every 10,000 molecules selected to become drugs ever make it. And the biopharmaceutical research sector invested an estimated $65.3 billion to discover and develop new medicines in 2009. How does all of that money and brilliant science result in such failure?

The National Center for Advancing Translational Sciences has been created to fix the problem. According to NIH director Francis Collins, the goal is to develop old discarded drug development programs far enough to interest industry in finishing the job. The government is going to help the pharmaceutical industry get more drugs into the market. I guess they have some data that shows a correlation between the number of drug approvals with an improvement in the health of the American people.

To be fair, they are claiming to take on disease indications that are not profitable to big pharma. When the NIH scientists get to a certain stage, big pharma will take over. There will be a smooth tech transfer and drugs will be made available to help people.

It seems like the government is working for the drug companies. The new center will be in the same position as a small biotech company, offering up possible drug programs for pharmaceutical companies. How will this effect the claim of one molecule in ten thousand becoming a drug? Will government scientists improve early stage research or will they take the financial hit for some of the failures?

Me Talk Pretty One Day

2011-03-07T11:58:00.000-08:00

After listening to a few panel discussions from this years WBBA Life Science Innovation Northwest, it became painfully obvious that an interest in science is of little use in the business of biotech. Ironically, neither is there much discussion on how to make investors money. The individuals speaking at the meetings were already making good livings off of other peoples money. Investors can make money in a number of ways, including betting against a public company. But the business of biotechnology has many different kinds of companies and business models. Innovation Northwest was a group of Cargo Cult leaders talking about ways in which to keep the gravy train rolling regardless of scientific progress.

Imagine if you will, the very first Innovation Northwest meeting 11 years ago. The individuals speaking at those meetings were all leaders of the field. They spoke of how to pursue an IPO, how to get initial funding, and all of the money ideas of the time. This years meeting was no different, only the ways of getting money have changed. It is much more difficult to get money because whatever they were talking about 11 years ago didn't go very well. One thing that the CCS takes great interest is in the ways people talk about things that aren't so. The tones of certainty that were used 11 years ago were probably the same as those used this year. It is a tone of certainty that makes you believe that what you are hearing is about progress. But is it?

James Randi spent his early career as a magician, tricking people into believing things that didn't seem to be real. He called it magic. If he were to be honest with the people he would take away the magic. For example, he would lay a pencil on a table and make it move with his mind. In reality he blew on the pencil to make it move. There was a misdirection involved where he appeared to be focusing really hard and thus causing he audience to focus on the pencil as well. While they started at the pencil his lips were free to pucker up and blow.

The tone of certainty is one such misdirection. While you sit and listen to the biotech leaders you get the sense of a pending success story. The same tone was in effect 11 years ago but we know something was amiss. People lost a great amount of money. However, had they listened closely 11 years ago, and this year as well, they would have heard the real story. The people speaking were speaking about making a company money, without making a product. They spoke of making partnerships. They spoke of being acquired. They did not speak of the tricks they intend to use to get the money. Making a product takes too long and costs too much. Seattle folk don't have the time, money nor expertise to do what is needed. They are selling something else. The question, is it real or is it bullshit?

The best way to sum up the concept of certainty, bullshit, and biotechnology is to take on the case of Sam Waksal. He wasn't an honest man. He didn't invent or discover Erbitux. He ran a biotech business. He got rich and went to jail long before Erbitux made its first sale. People lost money but Sammy made sure he and his friends and family weren't in that group. A few of them did some time and that is very sad. But what remains is Sams influence on the business. Sam does talk pretty and you have to when there is a book on your shameful career, yet you go on to found another biotech company.

How many speakers on the Innovation Northwest stage would shun the likes of Waksal. He speaks as they do. He knows the industry. People give him millions of dollars in spite of his history. Perhaps it is all about being a good magician. Get people writing checks and keep them from looking at the past. It's not a Cargo Cult, it's a shiny new biotech company and the future is looking bright. Trust us.

An Old Idea

2011-03-07T08:24:00.000-08:00

The company is called NeuroPhage. The idea is one that I have personally worked on at several different companies. Bind something to amyloid beta (antibody, phage, peptide) and amyloid plaques will not form. The population of potential customers and their end of life spiral makes this disease indication enormously popular among biotechnology companies. You might call this one the holy grail of biotech.

The concept makes several assumptions. It is assumed that binding to amyloid beta in the laboratory will scale to binding amyloid beta inside the human brain. Scaling from a cell line in a petri dish, to an animal model, to a human being, is not something that bio-scientists can rely on.

It is assumed that preventing the formation of amyloid plaques will result a significant reduction in the symptoms of Alzheimers Disease.

It is assumed that phage will be more efficacious than using antibodies or small molecule approaches.

Having done this research I take great interest in the amyloid beta story. I watched others attempt to cure or treat this disease in Cargo Cult amazement. At the highest levels the amount of thought that seemed to go into the "research" was to hire people to find the binder. The executive view (and their investors) was to name the molecule and send in the lower ranking people to finish up the details... of curing Alzheimer's!

On NeuroPhages' website they offer up some evidence. They begin with the perfect world graphic arts version of the disease and how the drug will work. They then show two pictures. In one you see the plaques in a "vehicle control", which appears to be a brain slice. In the other picture there appears to be far less plaques. That is the drug working.

This is a red flag. Science is not done by selective photography. I've seen this trick used in many fields, especially RNAi. You show a knock-down by simply finding the highs and lows of a non-homogeneous system. In this case the system is a brain slice. As far as we know the pictures offered up could be from the same brain slice. We are left to trust the authors that they are not interested in pulling the wool over our eyes.

We're off to a bad start. Now comes the worst part. How do they propose the drug get into a humans brain? How do you measure phage floating around in a brain, breaking up plaques. The Alzheimer's patient is not officially diagnosed with the disease until after an autopsy. Where is the graphic art depiction of drug administration and finding of the target? There is an entire field of science that is not being addressed by the Cargo Cult here. It's called ADME. Tracking the phage on its journey into the body, to the plaques, breaking up the plaques and being cleared is not something that can be done. That frees up management to worry about other things like financing and perhaps adding information to one of the sparsest websites in the biz.

It won't work. I've seen it not work over and over. It's an idea that is taken to the point of, "what do we do next?" and left off to lower paid worker bees. In real science, this is the starting point. Did this really work? How did it work? Does it work every time? Will it work in a human being? The questions are instead left up to the white lab coat people who have only one option in reporting their findings, tell management it works and don't bother with the details that weren't ask for. Keep the story just as it is on the website. There is no turning back now. Look to the skies and wait for the delivery of the Cargo Airplane that carries the cure for Alzheimer's. Once it lands get your sales people together and get ready to make some money.

Delivering RNAi

2011-03-05T15:12:00.000-08:00

I would be remiss if I were to not revisit the Cargo Cult of RNAi.

Last week we had a conference on the Cargo Cults of Seattle. RNAi was represented by PhaseRx. Since their inception they have had very little to report besides their 19 million dollar series A financing. They do however make very bold claims on their website.

RNAi therapeutics, also referred to as short interfering RNA or siRNA, have demonstrated broad applicability to many therapeutic areas, including cancer, inflammatory and autoimmune diseases, infectious disease and metabolic disorders.

These promising therapeutics are being held largely in check today by the lack of broadly applicable delivery technology. RNAi therapeutics generally cannot, on their own, penetrate the cell membrane and gain access to the cytoplasm where they can reach the drug targets.

The PhaseRx polymer system overcomes the central stumbling block in the field of RNAi therapeutics by delivering RNAi molecules into the cytoplasm where they can reach and inhibit the desired target of interest.

How do they have evidence of efficacy for the diseases if they've been held in check by delivery. Does their delivery include a ride straight to the cells of interest, avoiding a depletion of drug by being absorbed by other cells?

The problem is scalability. If you work as an engineer in a biopharmaceutical manufacturing facility you start small and scale up. There are certain relationships involved in scaling up that have been addressed by the industry, resulting in predictable outcomes. But with RNAi, they have predicted the outcomes without doing the research. The outcomes exist mostly on company websites. What do they now know that makes everything work where it failed in the past? As predicted by the CCS, the RNAi industry is not evolving.

Inside Information

2011-02-27T13:36:00.000-08:00

When you think of disgruntled employees you think of crazy people. The kinds who come back to work with guns and mow down their old colleagues. But there are other kinds. Some people are good and the company management is lacking.

Here is what a high ranking former employee at a small biotech had to say about the management:

I thought they had some good technology..., however, the leaders had no clue how to develop ethical pharmaceuticals and they weren't folks that I could respect. It was really unfortunate as they hired good people but really didn't allow themselves success due to incompetence at the top.

Will those four clowns at the top every get rich like they want?

For the record, the leaders went on to make a rather lucrative deal with Big Pharma. The Big Pharma company wanted a large amount of the drug to start their own research. Little Biotech company had about 2% of what the Big Pharma company asked for. What they did have did not pass the bioburden test. So how did they get the positive data that attracted Big Pharma?

Overseas, third world country testing! Unethical? Yes. Could the leaders "develop" pharmaceuticals? No. They haven't made one molecule that could be used in the US or Europe. Did they get rich? Yes. The "clowns" at the top have multiple houses and new cars and all of the things a greedy person would cherish.

Could we blow the whistle on this company? I don't think so. Overseas testing is legal. Incompetence in medical research is subjective. Unethical conduct can be argued against by claiming ignorance to the rules. They could claim that they had to go outside the US and Europe because they are small and can't afford the rigorous process in the modern world. Once again medical science has designed in flaws that select for the bad guys.

But this is the kicker today. Our history is rotten to the core. Human beings can't be trusted. Testing dangerous drugs on human subjects is decidedly bad. Now we know better. Right?

The new test subjects have to take "medicine" that would not pass muster in the US or Europe. Once again, we've lowered our standards and found people whom we have less fear of. They are not protected as Americans and Europeans. The prisoners and mentally ill were not protected either. How far have we come in our humanitarian ways?

The "clowns" at the top of this little biotech are not evil. They are greedy and they want to be powerful players in the business. They are a small and dangerously desperate company.

Biotech Inc.

2011-02-17T12:25:00.000-08:00

I took my latest lab tour after a 2 hour interview for a 5 week temp job. It was a small space with all of the usual things. Hoods, gel apparatus's, incubators, shakers, PCR machines... It was merely a satellite branch of Biotech Inc. Sometimes I think biotech is all one big secret corporation (Biotech Inc.) whose mission is to collect money from gamblers (biotech investors). Each branch has a twist to the usual story. They cure disease with big brain ideas that no one really understands. The idea needs money to work. In reality, Biotech Inc. needs money. Invitrogen, GE Healthcare, BioRad, Pall, Millipore and companies like these have made a fortune off selling to Biotech Inc. As a result each lab looks the same. The tour I took yesterday was short. I'd seen it all before.

Rumor has it that this particular company is looking to sell itself off for a quick profit for investors. I was interviewing for a 5 week job at the bottom, once again. I was informed of the temporary status of the job half way through the interview. During the lab tour I knew I was looking at an entire group of temps. They had more benefits and longer contracts than an admitted temp, but they didn't have long to go. The company is looking to be sold. If they can't pull it off they will shut it down. Either way, the laboratory staff had short futures with a small company.

Big Pharma has tired of wasting their time and energy trying to develop drugs. Big Pharma has made the claim that the small biotechs will become their feeding ground. They will let the innovation take place on someone elses dime and snatch up the winners. The Biotech Inc. lab space that previously had taken up real estate in Pfizer and Merck is fading away. The Biotech Inc. space moved to small dangerously desperate companies. Like a dishonest post-doc who needs data to fall in his/her favor in order to advance his/her career, the desperate small biotech gets the kind of results that go over well in a meeting. Easily understandable stories that put dollar signs in wealthy peoples eyes are what people want.

A fair amount of money had to be spent on the company work space. Besides the Biotech Inc. lab, there was a nice reception/office/cubicle space. All of the colors matched on the carpet, walls and tile. It was a nice theme. The management comes from The University. They have higher degrees in science than the lab staff so they get to spend some time developing color schemes and picking out carpet. This job could not be done by people earning the same as the lab staff. The difference in salary is an indication in importance of daily work. Although The University tends to teach things that would be most useful in the lab, the money from the investment pool can be used to hire the best biotech architects and interior design experts. In the end it looks as though the high ranking members of Biotech Inc. have really done a good job. You can look at the end result.

The end result of the laboratory work is a different story. The laboratory looks the same before and after major accomplishments. Each worker has the same white lab coat supplied by the same white lab coat company. Their Invitrogen DNA preparation kits look the same stacked up in their Thermo 4 degree refrigerator. Their Eppendorf pipettes look the same. The chemical cabinet, the hood, the tips, the gel boxes all look the same. But these tools of the trade are powerful when used properly. The laboratory staff can create molecules. They can alter a molecules shape, size and chemistry. But ultimately, it is the decisions of those who pick out the carpet and wall colors who decide what to do with the products created in the laboratory.

Biotech Inc. is not just a collection of Cargo Cults. There are many useful people in the corporation. You have to break it down to components and people are the indivisible component that separates the Cults from the companies.

The People

2011-02-13T17:42:00.000-08:00

In 2001 I was working at a little biotech company in East Los Angeles. The founders were two professors at the USC Med School. The company had a pipeline of 4 antibodies against "denatured" collagen. The idea behind them was that they would prevent blood vessels from forming around tumors and thus kill them. The company was funded by an angel investor. The goal was for us to obtain some data that could be used to sell the company off and make our investor some money.

The experiment consisted of three groups of bald mice. Each group had 10 mice. There was a positive control group, treated with Rituxan. Rituxan is a monoclonal antibody that binds to VEGF. There was a negative control group, treated with PBS. There was an unknown group, treated with one of our antibodies. Day one we injected cancer cells subcutaneously on the backs of the mice. Each day the mice were injected with a large dose of the drug or PBS shot into their belly. In a couple days tumors began to grow, which we measured with a caliper.

It was extremely inhumane because no one had a painless way of doing this. The mice were horrified when the lights came on. I tagged along to write down the readings. I watched as each mouse was held upside down and a large needle was injected into a non-distinct region of their underbelly.

The experiments were done over and over. That is because we had to get the set of data that our superiors wanted. The investor had decided that the antibodies were a great idea and he sank millions into making a profit from them. The lab people needed to get the results. The problem was that we our antibodies didn't work. The Rituxan worked great. No tumors. The other two groups were statistically the same. But this would not do. We were sent back to have a graduate student from one of the founders lab show us how to "properly" use the caliper to make the measurements. She spoke as she measured, instructing us. As she instructed she was clearly favoring the hoped for measurements. Using a caliper is not a skill. When she had finished getting the data to look "better" and she ended her lesson on measuring tumors.

I had just one question. I handed her a mouse that she had already measured. She asked, "what is this?".

Me: It's a mouse with a tumor. Can you measure this one?

Her: Didn't we measure it?

Me: Yes, if you are measuring accurately you should get the same tumor size.

She measured again and was off by 30%. This number of course was not written down. It was for my own assessment. That was my N-Rays moment. I knew in my heart that they had been playing these games. The new measurement didn't count. I knew I was in a Cargo Cult.

The graduate student and the boss needed to show a reduction in tumor size. Somehow by measuring the mice again, they did not feel that they were simply fabricating data. After all, they had performed the measurements. To me, this was fraud. To the boss and the grad student, this was survival. They needed the data as much as anyone else.

My entire biotech career is littered with this ilk. They are good people until the data doesn't go their way. They convince themselves that these things are simply little white lies. They don't matter. In the big picture they know their drugs work and they'll be vindicated later. The little experiments where data is cherry picked is no big deal. It's one or two slides in a presentation that tells a much more interesting story. And the story is what sells. Investors open their pocket books and bigger companies start listening.

Oh Pfizer Again

2011-02-10T08:28:00.001-08:00

Good thing they have lots of money. Pfizer is once again shelling out hundreds of millions to pay for covering up the danger of their drugs.

I posted last week about Pfizer being sued for 142 million for promoting their drug off label knowing it was potentially dangerous.

Paying out money is a lot better than going to jail. But actual human beings made these bad decisions. They are allowed to hide behind the corporate logo?

Who Likes Bad Science?

2011-02-05T12:44:00.000-08:00

I used to joke with my friends in the physics community that if you want to cleanse your discipline of the worst scientists in it, every three or four years, you should have someone publish a bogus paper claiming to make some remarkable new discovery — infinite free energy or ESP, or something suitably cosmic like that. Then you have it published in a legitimate journal ; it shows up on the front page of the New York Times, and within two months, every bad scientist in the field will be working on it.

Gary Taubes

The quote brings self doubt into the mind of the CCS. Are the people in the laboratories attracted to bad science? Is it just easier to get a degree in a bio science than a harder science such as chemistry or physics? Would it behoove the Biotechnology industry to insist on stronger math skills?

Let's look at a couple jobs and their requirements for the industry:

Entry level research associate: Education; A B.S. or B.A. in Molecular Biology, Biochemistry or Chemistry or an Associate’s Degree in Biotechnology.

A bachelors degree in Chemistry = an associates degree in Biotechnology?

A protein science temp job: QUALIFICATIONS; Ph.D. or equivalent industry experience.

A PhD? A PhD in what?

And these come from Craigslist. Would an executive recruiting company use craigslist? Why are biotech scientists subjected to a craigslist ad?

Bad businessmen and bad scientists are attracted to bad science. They hire their scientists from Craigslist ads. Critical positions that can cost the company millions in delays getting a drug through the approval process are left up to temps. The businessmen and those applying for the jobs don't know or they don't care. They are in it for the short term.

In The Big Short there was a Cargo Cult Science taking place in the financial industry. A handful of people became aware of it and they bet that the sh*t was going to hit the fan. They found the way to make money off of it. The biotech professionals who have bet their careers can do the same. Be aware of bad science and stay away. There are places to go where the science is real. Seek out good science. It won't be as easy as you think. If you find yourself in the pool of bad scientists who Gary Taubes described above, get out. Leave that RNAi company. Don't apply to that PhD temp job. Work harder and get where you need to be. The Cargo Cult Airports are very tempting. They pay the same and they look the same. But they are not long term winners. Career professionals need to work for the longterm. A resume of short term bets will not be very satisfying.

And so I don't think that working in biotechnology is just a bunch of bad scientists who are attracted to bad science. There are good places, even inside bad companies. Seek them out. Look for long term options that make sense.

So I have just one wish for you--the good luck to be somewhere
where you are free to maintain the kind of integrity I have
described, and where you do not feel forced by a need to maintain
your position in the organization, or financial support, or so on,
to lose your integrity. May you have that freedom.

Feynman

Huge Airport Shutting Down

2011-02-03T12:59:00.000-08:00

This isn't like shutting down that quaint little coffee shop you thought would be a good idea to buy so you quit your job and sank your life savings into and ended up staying up late at night counting up your daily losses until finally you had to file for bankruptcy... Whew! I'm just saying... that would be a bad idea.

Pfizer and Merck won't be facing an end to their dominance in the drug pushing business. But they have different ways of facing their future. Pfizer sees their massive R&D campus as a Cargo Cult Airport and they are tired of not getting the cargo.
Merck maintains their faith in their airport.

Since we at the CCS believe that most drug success stories are random events it will be interesting to see how these two companies fare. Does it matter if a major drug company shuts down a major scientific research center?

Oh Pfizer

2011-01-30T08:03:00.000-08:00

I've spoke of the truth spectrum. On one end you can miss the truth by making an honest mistake. On the other end you have committed a fraud that you hope to benefit from. In between you can be in a place where you don't care what the truth is as long as it supports your story. That is called BS. Many professional scientists have been exposed as BS artists and gone on to have successful careers. It takes a corporation to be able to get caught at the far end of the spectrum and still survive. It takes money and power to get past violating federal racketeering laws.

Pfizer was ordered to pay $142.1 million to Kaiser Foundation Health Plan and Kaiser Foundation Hospitals for illegally promoting Neurontin for unapproved uses.

Before I go on I must comment on Kaisers responsibility when handing out drugs. Corporate for profit medicine is not a bunch of doctors who get together to discuss what works and what doesn't. They seem to assess symptoms, google them in their brain or some big pharma database and prescribe the magic pill. Problem solved. It reminds one of a scene from Anchorman with Will Ferrell. The main character, Ron Burgandy would read whatever was on the teleprompter. He did not think before he spoke. As a joke someone wrote something for him to say at the end of a broadcast. "I'm Ron Burgandy, that's the news, go fuck yourself San Diego". And that is how the broadcast ended. It wasn't Rons fault. Right?

Kaiser officials alleged they were duped into believing that migraines and bipolar disorder could be treated effectively with Neurontin, approved in 1993 by the U.S. Food and Drug Administration for epilepsy.

They were duped. There is a lot of duping in Cargo Cults. They don't think before they prescribe. It's not their fault.

There are over 300 lawsuits over off label prescribing of Neurontin. It is a dangerous thing according to the lawyers. The scientists and marketing department at Pfizer allegedly knew Neurontin was dangerous also. Where on the truth spectrum does this case really fall. How dangerous is this little pill and what group of people are most vulnerable? Did the scientists, clinical trials professionals, or doctors know that the marketing department was trying to sell the drug to the vulnerable people just for a profit? Did the marketing department really not care about the people they were hurting?

Sinning Against Science

2011-01-28T08:42:00.000-08:00

The Sins of Science : A small compilation of people who know how to succeed in the Cargo Cult Airports. It's not as if anyone is ever going to go into the laboratory and check on their results. Right?

The article about scientific scams that you will not find is the one about a team of hard working laboratory professionals who can spot BS and quickly disprove it with empirical data. It is merely assumed that the review process weeds out the liars and cheaters. Why? Because at the highest level they are too sharp to be fooled. This is mandatory for a Cargo Cult. Leadership cannot be questioned. But what do they know of empirical data if they do not venture into the laboratories they rule over?

The word empirical denotes information gained by means of observation, experience, or experiment.[1] Empirical data is data that is produced by an experiment or observation.

A central concept in modern science and the scientific method is that all evidence must be empirical, or empirically based, that is, dependent on evidence or consequences that are observable by the senses. It is usually differentiated from the philosophic usage of empiricism by the use of the adjective empirical or the adverb empirically. The term refers to the use of working hypotheses that are testable using observation or experiment. In this sense of the word, scientific statements are subject to and derived from our experiences or observations.

Those who are charged with deciding if Silvia Bulfone-Paus engaged in scientific misconduct are not the ones who called attention to the BS in her publications. The judge and jury are like her. They left the laboratory long ago and never looked back. Laboratories are for prestige. You raise money for them and put little people in them to obtain results that prove you were correct. But what obligations does the PI have in verifying the results? What do you call second hand empirical data?

The story of N-Rays once again helps us describe modern day science. Long ago, scientists had a way of verifying puzzling results.

Nature magazine was skeptical of Blondlot's claims because laboratories in England and Germany had not been able to replicate the Frenchman's results. Nature sent American physicist Robert W. Wood of Johns Hopkins University to investigate Blondlot's discovery. Wood suspected that N-rays were a delusion. To demonstrate such, he removed the prism from the N-ray detection device, unbeknownst to Blondlot or his assistant. Without the prism, the machine couldn't work. Yet, when Blondlot's assistant conducted the next experiment he found N-rays. Wood then tried to surreptitiously replace the prism but the assistant saw him and thought he was removing the prism. The next time he tried the experiment, the assistant swore he could not see any N-rays. But he should have, since the equipment was in full working order.

What can one say about N-Rays and the multitude of scientists who publish papers on things they've never seen first hand? Self deception is one explanation. On the other end of the BS spectrum you find Dr. William Summerlin who coloured in the black patches of fur on white mice with permanent markers to prove his skin graft technique was a success. Bulfone-Paus' people coloured protein bands on western blots. Either way, they got what they wanted. By separating yourself from the collection of empirical evidence you will have an easier time climbing the ladder of successful scientists in todays world. By not entering that lab you will not have to fabricate data. You hire people to do that for you.

Questioning Favorable Results

2011-01-24T18:43:00.000-08:00

Baltimore, Bulfone-Paus, and Daniel Klessig all had the wool pulled over their eyes by people telling them what they wanted to hear. It is not only easy to do this to some scientists, it seems to be the only way to get ahead in their world.

It's not always black and white. Baltimore wanted the data from Imanishi-Kari. Imanishi-Kari got the data from her lab staff. The data that was wanted was published. The data that contradicted the desired results was the cause of a whole lot of trouble.

Bulfone-Paus wanted the data from subordinates who worked in her laboratory. She got it and published. When did she decide that there was a problem?

Daniel Klessig wanted the data and he published. Trouble!

How does the Cult deal with the trouble?

Highest level:

A BTI investigation concluded there "was no conclusive evidence that Dr Chandok achieved the results reported" but also found "no conclusive evidence" that misconduct had occurred.

Publishing data that no conclusive evidence supports isn't scientific misconduct?

Principle Scientist Leadership level:

This was considered a significant discovery in the field of plant biology. Dr. Klessig and Dr. Chandok began work on a paper to publish the results. Dr. Klessig requested that Prof. Brian Crane, a researcher of animal NOS activity who was familiar to Dr. Klessig, attempt to confirm.

And it was confirmed! How?

Prof. Crane assigned the work to Mr. Pant, a doctoral student who was already performing similar work. Dr. Chandok worked with Mr. Pant to reproduce the results, which was reported as a success. At that time, Dr. Klessig seemed satisfied with this verification, and the paper he and Dr. Chandok completed was submitted to Cell for publication. The paper was published in the Spring of 2003.

Remember the degrees of separation? The fact that PHd scientists do not work in laboratories to confirm data? Dr. Klessig needed to keep building on this foundation of quick sand. He needed more proof. To the lab?

In 2003, Dr. Kim was hired and assigned to verify Dr. Chandok's work.

Were they not convinced yet? What was wrong? Whatever it was, Dr. Chandok wasn't about to go back into that damned laboratory to validate her work. Dr. Kim was not getting the same results as she did. She sued over the retractions of the papers.

Was it scientific misconduct? Bad science? Fraud? Error?

It was a Cargo Cult Science!

The Culture of the Cult

2011-01-19T07:15:00.000-08:00

Western blot and ELISA are simple things. They are also what got David Baltimore and Silvia Bulfone-Paus into trouble. Both tests can give varying and ambiguous results. When you are on the margin of detecting a signal that proves your theory, you should bend over backwards to prove you did or didn't detect it. This, however, is a part of the culture of the cult.

As a cargo cult leader, you must set up what you perceive to be the truth. The bamboo antennas for example, may be reshaped time and time again. Each time you must have a reason for reshaping the antennas and a reason for the new shape. Therefore, there must be some truth that makes the old shape wrong and the new shape correct. That truth is the heart of the matter. If the makers of the antennas screw up, you can maintain, as a leader, that you are still the keeper of the truth. You are in charge and the others need to do their job better. In general, you must keep several degrees of separation between your "heart of the matter" and the incompetence of the others. They keep the planes from landing in spite of your brilliance.

How does this translate in the real world of science? You may think that scientists work in laboratories and maintain careful records of all they do. This is false. I once worked for a Nobel Prize winning scientist. He came into the lab once to have his picture taken for the award ceremony. He was loaned a white lab coat. He posed next to a hood where inside we had lit a bunson burner for a special "sciency" effect. Later that photograph was hung up inside the laboratory. The caption underneath the picture read, "this isn't like my piano at home". Rest assured, this would have made the Nobel Prize winning scientist very angry. There was little chance of him ever seeing it however. It was inside the lab.

It is not just Nobel Prize winning scientists who stay away from the plebeian confines of the laboratory. Almost all PHds stay away. The laboratory worker is the lowest member of any scientific project. Ironic? There are scientists, project managers, department heads and many more individuals, all of whom help create the degrees of separation. This is why Dr. Silvia Bulfone-Paus had the wool pulled over her eyes by her scientific misconductors. 12 papers now have to be retracted which will effect the other non-laboratory scientists. Their lab staff may have already tried to replicate the results that were a part of the misconduct. At this point it becomes a toss up between who is right, your lab tech or the published (un-retracted) paper. It's hard to use laboratory data to refute published data. Non-laboratory scientists prefer published data.

The quest for fame and funding create this culture. That is what this Cargo Cult Scientist believes. Toiling away in the lab for days only to find out your protein was misfolded or your reagents were at the wrong pH in step 27 is tough. It's also boring. You end up in an office with the non-laboratory scientists explaining what happened. If it is what they wanted to happen you will have an easy time. If it's not the mood turns dark and the relationship becomes more adversarial. But reality is best observed in the laboratory. That is where we need to go back to. Considering how much money has been lost in the industry, can we afford to keep the degrees of separation in place?

WikiScienceLeaks?

2011-01-18T10:40:00.000-08:00

Once again we see an old pattern. A scientist wants the world to work the way they think it does. They've done all the right things and they are in a position to help write/rewrite the texts books used in Universities throughout the world. They must be scientists! So it is time to get to work and publish everything you can that supports your career. There may not be time to follow Feynmans recommendation:

if
you're doing an experiment, you should report everything that you
think might make it invalid--not only what you think is right about
it: other causes that could possibly explain your results; and
things you thought of that you've eliminated by some other
experiment, and how they worked--to make sure the other fellow can
tell they have been eliminated.

The journal Nature seems to be against this idea.

An unknown agitator using the presumed pseudonym Marco Berns is engaged in an e-mail and Internet offensive against two biomedical researchers whom he accuses of scientific fraud.

It seems as though they (Nature) are against "blinding". This agitators greatest crime is his/her anonymity. What do we know about the people who wrote this article in Nature? They represent authority just like Silvia Bulfone-Paus in her role as a principle investigator. What really matters? Are we religiously placing faith in Nature editors and tenured professors? Perhaps anonymity is a scientific imperative. There needs to be a "blinding" of the judges and those presenting the case. Then take a different angle at looking at the problem. That is what we do in clinical trials. That is what we do in the laboratory with our "controls". The content of the claims is what needs to be analyzed. Rather than addressing the issues, Nature has chosen to attack an unknown person for going about things the wrong way. But what are the chances of getting Nature or the Research Center Borstel to explain to the rest of us how they came to their conclusions? Is it not a pattern for these organizations to protect the scientists and attack their detractors through anonymous reasoning? Just trust them because they are in charge?

What you don't hear about in many articles about the Silvia Bulfone-Paus story is what exactly her "agitator" is saying. It is interesting stuff. This is the stuff you want to know if you are honestly doing what Feynman suggests. I'm not talking about IL15 and the papers that need to be retracted. I'm talking about whether or not Silvia was not at fault. The data that was fabricated supported her story. She didn't look into it nor did anyone else try to repeat a simple western blot. The false data fit her story and she stuck with it. It's a crime against the good name of science.

Why Sequence Your Genome?

2011-01-12T10:22:00.000-08:00

As one reporter puts it, "it’s worth remembering that it took $3 billion and about 13 years just to sequence one genome, and as of a couple years ago, it was so expensive and time-consuming, only about a dozen or so complete genomes were sequenced. Today, a company tells the world it will sequence 615 complete genomes for a single customer, and Wall Street gives it a paltry 5 percent stock lift".

The problem with sequencing your genome is this. You can take your car apart and lay out each part in a line. Maybe photograph each part and catalog it in a book. What does it mean? You still don't know how your car operated. Now imagine a new company trying to sell you a technology that makes the dismantling and cataloging of the parts 10 times faster. So what?

They need to put some wealth into their system.

I had a professor tell the class that most of the DNA in our genome is junk. It didn't do anything. He was referring to the fact that genes make proteins and that is doing something. The rest is doing nothing. Arrogance! When certain environmental changes occur a stem cell will decide to become a specific kind of cell. How does the linear sequence of nucleotides change? Perhaps not at all but certain genes will cease to "do something" while others will begin to "do something".

Of course there are many many scientists who are working to explain what DNA does. Geospiza for example, is a company that makes software for biologists to analyze genomic data. Biologists are taught to know what DNA is. They know about the nucleotides and the phosphate backbone and so on. But what do they know about translating a DNA sequence into an explanation of life? I guess that's what the software is suppose to help them do. That is the most interesting aspect of genome sequencing. If only there was a translator to accompany the sequencer! I don't believe one exists. Indeed, the field of Genetics is full of cargo cult scientists.

So where is the profit in the new superfast DNA sequencers? Those with the money and an almost religious faith in "science" will have their genomes sequenced and rely on their doctors to tell them if they are at risk for certain diseases. For example, the ApoE-ε4 gene isoform is tied to an increased vulnerability to Alzheimer's. There is nothing you can do about it but some people want to know what to expect. Probably not enough however to turn a profit. One would think that the rapid sequencer companies would have a genetics branch in R&D to explain what your sequence means. Imagine your future is written in book form in Spanish. Wouldn't you hope for at least a translator to tell you what the book says? The sequencer companies have a business model for half a product. They are too blinded by how neat the first half is.

What if the Genetics scientists were the real customers for the sequencing machines? Sequence one persons DNA every month for his/her life. How does it change? What do the changes mean? What if you had identical twins and one smoked and the other did not? What happens to the linear sequence of nucleotides on a genome then?

We have to build wealth into this system. It can be done. It is very interesting for reasons no one is talking about. It's not sexy and it's not going to result in a Nobel Prize for a young scientist anytime soon. Rather this kind of research should be done by a group who toils for the lifetime of the subjects being tested. After we all die the next group of scientists will still have to try and make sense of the variations. The telomeres fade away. We see anuploidy in cancer cells. Point mutations, silent mutations, hairpin loops and on and on. How does any of this happen and what does it mean?

What Works

2011-01-08T09:28:00.000-08:00

Biogen Idec runs in the black. It generated $4.37 billion in revenue in 2009, and has a workforce with 4,275 employees at last count. The R&D budget was about $1.3 billion in 2009.

Despite all that, Biogen hasn’t been able to deliver a new FDA approved product since natalizumab (Tysabri) in 2004. The lack of R&D output has prompted blistering critiques from billionaire investor Carl Icahn, who accused the company in 2009 of suffering from “failed leadership.”

Last year was the first time in a decade that Pfizer Inc., the world’s largest drugmaker, as well as Merck, Eli Lilly & Co. and Bristol-Myers Squibb Co., each failed to win regulatory backing for a new molecular compound.

The airplanes did not come!

Leadership? Finance experts telling scientists how to do their job? Businessmen who run companies have all the answers as to why scientists in their organizations aren't producing. But what about this?

Brain plaques, long considered the chief killer of brain cells and the cause of Alzheimer's disease, may actually play a protective role under a new theory that is changing the way researchers think about the disease.

Imagine that. Scientists have been trying to treat a disease by possibly attacking a protective response by the body.

Scientists in biotech succeed all the time. For example, if you have an protein drug, scientists successfully identify cleavage products that are considered impurities. Next the scientists successfully remove those impurities. Science, when properly applied, gets the job done.

What have drug companies mentioned above been missing? Perhaps they could hire a team of scientists to look into what targets are taking them down the wrong road. The "experts" have lead the drug manufacturers into the state they are currently in. Perhaps a new biotechnology could one day arise that sells unbiased assessments of the path they are currently on. No Yes Men!

Merck Logic

2011-01-07T10:17:00.000-08:00

Merck has a plan. The new Chief Executive Officer Kenneth Frazier said the company will make “tough” research spending decisions while developing innovative products.

Merck hosts regular symposia where its finance experts teach scientists how to seek better return on invested capital, Frazier said. The three-year return is now tied to researchers’ compensation, he said.

Finance experts? Teaching scientists? We at the CCS are of the belief that no one who works in finance holds half the expertise in their field as the average mechanic holds in theirs. We clearly do not believe that a scientist can be taught anything. Their arrogance prohibits them from being on the learning side of the any educational scenario.

I guess we all want to be the expert/teacher. Those running Cargo Cult Airports teach their underlings how to run the Cult. The underlings (middle management) hire the people who run the airport. Upper management then lives and dies on the Cargo. How far gone must Merck be to have finance employees telling scientists how to get the most out of their R&D budgets?

Why is this story not scorned by the entire world, let alone some lone voice that can be heard? My voice is not heard. No one is going to say, "the CCS makes a valid point, Merck has tied finance to science and that just doesn't make any sense". But if you are like me, you get in your time machine and you go back and listen to all of the intelligent talk about how Merck and Pfizer and all the rest were going to turn things around and start getting drugs approved. Then you come back to the present and you see how they did.

I leave you now to hop into that time machine. I will travel three years down the road to see the how this plan worked out.

Writing About Work

2011-01-02T07:51:00.000-08:00

In order to build "wealth into our system" we have to learn how to write. In school we are taught how the English language is to be used properly. Grammatical errors in any course your take may just lower your score. You could use a double negative on an essay question in history class and you lose points. Proper English is always important. What is just as important in science is knowing what needs to be documented.

That may just show my own bias towards certain people I've worked with. The worst of the worst rarely put anything in writing. When they do you almost always have to ask for clarification. The best of the best always try to get what matters written down. Yet even in college the laboratory notebook is taken for granted. It's another thing that is graded. Mistakes are quantitated. The more you make the worse your grade. However, the biggest mistake is to not say anything about something that people are going to want to know. Most often you are going be that person.

The FDA, your scientific misconduct investigators, your PI, your boss are also groups of people who are going to want to know what you do in the laboratory. Most likely you're going to be in trouble if these guys come snooping into your notebook. They are going to grade your notebook. The Baltimore Case gives us keen insight into how this works. A postdoctoral fellow in Imanishi-Kari's laboratory, Margot O'Toole, could not reproduce the results from an experiment that was discussed in a paper published in Cell. Once an office bound scientist publishes something, they protect their claims in a most unscientific way. They did not compare notes taken by two different people who performed the work in the lab. They took what suited their story best and stuck with it using their authority to silence the confounding evidence. But Margot had her data. She used it to make her case. A personal conflict between the two scientists developed. Margot O'Toole bravely went forth with her laboratory notebook to back up her story. What happened next was non-science and Imanishi-Kari and Baltimore got away with their misconduct. Margot O'Toole spent the next few years working out of science as a result.

This would appear to indicate that Margot O'Toole did not have compelling evidence written in her notebooks. It was however alleged that Imanishi-Kari was the one who had not been adept at keeping notes on her work.

"I was supposedly wasting materials by doing the experiment and coming up with the wrong answers." Shortly thereafter she was demoted to breeding lab mice. Then, in the course of researching the heredity of one particular mouse, O'Toole consulted lab notebooks used by Imanishi-Kari and made an astonishing discovery: The data recorded there didn't support Imanishi-Kari's conclusions either. "I knew [the conclusions] had been fudged," says O'Toole. "Finally the world made sense again to me."

Writing down what you do is a skill. You don't always realize something is important when it is happening. Imanishi-Kari didn't realize that there was evidence left behind that what happened with O'Toole was the expected outcome. The laboratory notebook had the real story. The journal Cell, was lied to. This leads to a very important piece to what Feynman was talking about when he spoke of building wealth into a system of discovery. The things you observe and take note of can lead to the truth. Even if you write down that you looked up at the moon last week and it wasn't there, you have useful information. The moon was there but we had an eclipse. You just didn't know about the eclipse. Not seeing the moon (okay I know you can still see it) doesn't mean the moon failed to exist. So just be honest and you will be rewarded. Do what Baltimore and Imanishi-Kari do and you will probably get published more often, but you will not get the rewards that scientific people care about.

Celebrex is an example of how the Pharmaceutical industry doesn't get this. Pfizer had clinical trial data that showed how the use of this pill increased the likelihood of heart attack and stroke. The FDA doesn't require the drug companies to disclose information on every trial so they do not actually have the ability to protect us. They hear what the drug companies chose to tell them.

In summary, the idea is to try to give all of the information to
help others to judge the value of your contribution; not just the
information that leads to judgment in one particular direction or
another.

Keep good records, even when you don't know what they mean. It will come to you later when you have more information.

AstraZeneca vs the CCS

2010-12-29T09:48:00.000-08:00

In a drunkards walk there was an example of decisions based on improper data sets. A movie producer was hailed as a success after a string of money making films. Then there was a string of less successful films and she was fired. If the data set was taken as one set, the leadership would have realized that the producer was par for the course over of her tenure.

AstraZeneca is going down the same path. The CEO believes in R&D.

Brennan’s commitment to research has its origins at Merck & Co., when the U.S. drugmaker dominated global drug discovery and blockbusters were easier to find. He joined Whitehouse Station, New Jersey-based Merck as a 21-year-old salesman in 1975, and was there when the company’s labs pioneered new ways to treat hypertension and cholesterol.

“This is what David saw happening,” says P. Roy Vagelos, who ran Merck’s R&D and later, when he became CEO, promoted Brennan to run its collaboration with Swedish drugmaker Astra AB, a predecessor to AstraZeneca.

David, the CEO, saw something happening at Merck while working as a salesman. Now he is a CEO and he is going to save the science culture at AstraZeneca. He finds others who have succeeded, so he thinks. Let us refer to the Cargo Cult Science speach once again. The natives observed the Allied forces building and operating their airport. They took notes and replicated the work. How is David saving R&D? By hiring people he thinks have succeeded.

Menelas Pangalos helped build an industry-leading pipeline of experimental drugs at Wyeth, helping persuade Pfizer Inc. to buy the company in 2009 for $68 billion. He was lauded by New York-based Pfizer’s then-CEO Jeffrey Kindler for his “incomparable” expertise.

At 43 Panalos has not had a history of scientific success. He was in the right place at the right time when some "experimental drugs" were put into a pipeline. Where are those drugs now? What exactly did Panalos do?

Like the movie producer, people in positions such as Panalos live and die on the decisions of others. Statistics tell us that someone has to emerge in the position Panalos was in that so impressed David. Together they have gone over the highly unsuccessful R&D branch (the airport) and they have honed it into what they think will work. It sounds as though they've sat in an office and worked out a plan to change the shape of the Cargo Cult Airport Controllers' "two wooden headphones and bars of bamboo sticking out like antennas".

But wait, they brought in a scientist. Martin Mackay is president of R&D. Now we are going to get closer to the problem. In a recent setback the U.K. drugmaker failed to win U.S. approval for a new blood thinner, Brilanta, to rival Plavix, the world’s second-best selling drug. Regulators didn’t ask for new clinical trials for the drug. and “Our highest priority is to provide the requested Plato analyses to the FDA,” Martin Mackay, AstraZeneca’s president of research and development, said in the company’s statement.

So Martins job is to articulate what the company is doing scientifically. The people he communicates with are indeed part of the problem. The FDA, the board of directors... All of these people are convinced that they are the judge and jury of scienticif merit and progress. As we have seen, even their success stories lead to death and/or a lower quality of life. The formula AstraZeneca has come up with puts new symbols into a formula that never calculated anything. It is the logic that is missing.

I would suggest taking one project at AstraZeneca and subject it to the CCS Manual For Discovery. What seems trivial to the big picture guys is actually the core of scientific discovery. Building a solid foundation for a project is non-negotiable. What was once considered trivial must now be written about by the highest members of the R&D staff. It must be clear to the laboratory workers what the leadership thinks is happening. Then give the laboratory staff the opportunity to "bend over backwards to prove them wrong". Most importantly, document everything. In general, I suggest flipping the project upside down for a change. Let the guys in the lab judge the words of the executives. After all, they have scientific backgrounds and laboratories to help them make their points. People in offices have their words and their arrogance. That is the old formula. Nothing has changed at AstraZeneca. The new leadership is focused on dealing with issues left behind by the old leadership. The laboratory scientists are left in their labs to figure out the new structure of discovery while those who created it try to get the FDA to approve Brilinta.

The Next Step

2010-12-28T09:52:00.000-08:00

Version one of your companies manual has been written. There are various chapters describing all of the groups, their roles and the roles of their members. There are details about communication and who has what responsibility. Now lets focus on what matter most to the company, the product or service. In the case of our fictional company, the product is a service where we help biotech companies stray from the status quo and start making real discoveries by following a path. This path quickly discards things that do not work. The path has the ability to identify things that are working and will work in the real life scenario.

The status quo tells us that PHds are the leaders and those who fell short of the PHd is the followers. However, our company employs purists. Our University system is not a group of vocational schools. If in fact the world were fair, leadership roles would employ the best leaders. If the University system selected for the best of the best, their PHds would compete for and win most of the leadership roles in a biotech company. As it is, a PHd is required for leadership positions. This precludes any chance of a newly minted PHd earning a leadership role in an environment very different from the one they previously succeeded in (college). The PHd is simply given a leadership role instead of being given a chance at earning it.

Let's consider a PHd who is hired to run a protein purification group. Developing methods and using cutting edge systems and leading others are not things taught in graduate school. Quite frankly, most University laboratories can't afford the same technology as industry. What is needed is a specialist. The medical field has long had specialized doctors who require a very different education from other MDs. A cardiac surgeon differs from a Gynecologist. The protein purification group requires a leader who also has a specialized education. There is little chance that a PHd will come out of the university properly educated to perform the tasks required by industry. Therefore the PHd must be taught. The manual will provide a path the new leader must take. He/she must learn how to develop, how the equipment and the operators work, and how to lead.

True leadership will not hire and hand over responsibility. The leaders will hire someone to fill the purification leadership role. They will then provide the education that is needed.

Finally, leadership requires something that most people just assume PHds do well. We assume PHds know how to communicate. We assume they speak and write in full sentences. Give this a test. Secretly record a conversation you have with a friend. Type out the words that are spoken and see how many proper sentences are spoken. The chances are there will be a correlation between education level and percentage of full sentences. But there will be many outliers who must be dealt with. The non-PHd who communicates well and understands methods must be promoted. The PHd who is the opposite must be demoted. This is a business model, not a PHd club.

To conclude todays topic, the University system is not a vocational system. Don't assume the answer to scientific discovery is the PHd. It's what the PHd does that leads to success not what they did in the past. You must provide them with the platform on which they will work. It's your company, not theirs. A biotech company shouldn't be started and left to succeed or fail by people who did not participate in the founding ideology of the company. They are just looking for a job like everyone else. It is the job of leaders to define the job and give the workers every chance at succeeding.

A Manual for Discovery

2010-12-26T22:29:00.000-08:00

How arrogant must I be to propose that I could help anyone discover the truth about anything? But of course, this is just a thought experiment. I'm doing it on a blog that I assume no one reads. So I can do it. I can invent a biotechnology company that does succeed.

We are talking about business, of which I know nothing. But since biotechs are run by people who know nothing of science then I will put together a business plan. I will assume the executive and administrative are simple. I will search for people with the proper qualifications and looks. There will be no board since this company is run on my own vast fortune. Therefore, the executive staff will answer to me. They will all be paid a cut below the scientific staff. A new paradigm for sure. Our mission will be to create a company that has a platform of discovery that can be sold to others. That is our product, a platform for discovery.

Scientific progress is not done by hiring smart people to figure out that which you do not know. You are the ones who start your business. You must hire smart people to follow your plan. If your plan is to tell other people to discover a cure for cancer and the only thing you give them to go on is RNAi technology or monoclonal antibody technology, you are going to fail. If my company is hired, we will run a scenario, start to finish, of your plan. How do you go from a basic concept of using technology X to cure disease Y?

But we are here to help. You will be writing a manual for The Company with our help. Like any act of writing, you can't just start with a pencil and a piece of paper. We'll give you a template. When any employee in the corporate world is told to evaluate themselves, they are given a template. What were your goals? Did you acheive all of your goals? What could you have done better? So our template would help you evaluate your company discovery platform. Fill in your introduction and mission statement. Lay out your justifications and methods. Explain the kind of people who you need and what the scope of their work will be. Timelines? Fill in the data where we have provided the space in our template. All you will need will be the answers to the questions.

It's easier for the board and the execs and all of the potential partners to not have such a template. But the high rate of failure has provided a good reason to rethink the old business model. So step one is to acknowledge that you need a platform of discovery. It needs to be put into writing in a specific way.

Epiphanies of 2010

2010-12-23T03:26:00.000-08:00

I was sitting in the break room when I came across a publication called Pharmaceutical Manufacturing. It was volume 9, issue 1. The article was 'Tech Transfer: Do It Right'. Sounds boring I know but the following excerpt explained the latest debacle of my career. My latest job was abysmal.

There are two groups in biopharma today: those who "get" tech transfer and those who don't. For those in the first group, technology transfer is a mature discipline that follows a structured approach, with predictable outcomes. For those in the other, tech transfer is a perennially new frontier with surprises at every turn.

There seems to be a pattern in biotechnology of people who don't "get it". We all study science but we don't all see the structures that lead to real progress. Most work is begun at the top levels. The executives present the board with ideas for research projects. Drug targets like TNF alpha and Amyloid beta are popular due to the massive profits that can be made off of people growing old and falling apart. TNF alpha is a molecule targeted by several products already on the market. It can be prescribed for aches and pains as well as for cancer. Amyloid beta is the protein found in plaques that form in alzheimer's patients. Executives and board members keep thinking that a molecule can be found that will bind to a certain region of the protein and prevent the plaques from forming. A simple minded approach to a complex problem. Once the executives have made their decisions it's handed off to the next level down, the scientists.

The scientists read up on the literature and go off into the perennially new frontier with surprises at every turn. Junior personnel without PHds generally do the laboratory work and end up taking the brunt of the criticism for ideas that don't pan out. This leads me to the second epiphany I had in 2010.

The Handbook of Process Chromatography is a manual that describes ways in which to develop purification methods. It depicts methods for developing methods. It occurred to me that there is no such book for conducting scientific research. As Feynman said, we assume that we are teaching people how to arrange things so that they get some
wealth in their system. The Handbook does just that. It teaches people how to arrange their process development efforts so that they can get work done as quickly as possible. Each company should have a handbook that describes their process for developing drugs. But there isn't one. They call it creative minds at work. But that is where process chromatography was 40 years ago. They showed up and winged it. Somewhere along the way a small percentage of forward thinkers make progress and set up systems. We have yet to articulate the system of translating ideas from the boardroom to the market.

Non Religious Women Have Better Sex Lives

2010-12-22T16:46:00.000-08:00

This post is not about religion or sex. I thought of a "research study" that I thought would get peoples attention. Religion and sex are attention grabbing topics. Why not put them together and add in my own bias towards a blissful non-religious world? If I could fund the research, I could find people to do the work, let them know what my expected outcome is, only accept outcomes that fit the title and this headline would make the news.

It takes on the notion that women who are atheists are rewarded with better sexual satisfaction. Religion and sex may have nothing to do with each other however. In statistics we have the example that home break-ins increase in the summer months. Thus one can make the case that as ice cream consumption increases, so does home invasion. We haven't actually said that eating ice cream makes people want to break into a house. The truth is that the weather leads to an increase in ice cream consumption, home invasions and other things like days spent on the beach. Correlation is not causation.

The title does not state that atheism causes a better sex life. It states a possible correlation. It simply says that, as a population, atheist women may enjoy sex more than their religious counterparts. If you put this up on the Huffington Post you will get a spate of responses that have little to do with defending the science behind the study. People will respond to the title of the study. Religious folk who are open minded about sex will shout it down by sharing their own sexual outlook. Religious folk who are not open minded about sex may condemn the study as being biased. Atheists will say that they knew it all along. The scientist however, will respond to what they feel the data is depicting. Maybe the study was flawed and the religious group of women were all catholic nuns and the atheist women came from the local strip club.

If Dr. Ioannidis is correct and roughly 90% of the medical research that doctors rely on is misleading, exaggerated, or flat-out-wrong, then the question is why. Why do we as scientists select for research that is interesting as opposed to being true? We know that what is true should trump what is more interesting. It should be just as interesting to the scientific community to find out that there is no correlation between religion and sex.

Feynman touches on this with the example of the scientist who tested the maze used in mouse studies. The scientist tested the test (the maze) and found that there was an alternative explanation why mice do what they do inside a maze. The sound or texture of the floor below them led them to the door where food was previously found. The science is in telling the mouse testing world that they have to control for extraneous signals that will confound their research. That should be of interest to scientists.

Getting someone to listen to you is what anyone who desires to move up the ranks of their field needs to do. The trick in science is to get people interested in simple truths. If a study is interesting enough to get funding, it's interesting enough to be published. Imagine a science journal that publishes experimental design then later publishes the outcome. Reviewers of the work have their reviews published along with study. Review the proposed study. Review the work. Review the conclusions. Then review the reviews. Give researchers attention before during and after their work and they'll go back to pursuing what is true versus what will produce most eye catching headlines.

Five Years In the News

2010-12-06T14:33:00.000-08:00

2010 Nice review
2009 BOOM
2008 ZING SON OF A...
2007 BLA-ZAMM
2006 OUCH
2005 POW

Okay, I'll stop at five years gone by. You get the idea.

A new decade is soon upon us. What will come? In the last decade we had a net loss of about 3500 jobs and an approximate 60% drop in market cap valuation. How shall we measure success from 2011 to 2020?

Biotech is Back Tonight

2010-11-29T17:32:00.000-08:00

I've been typing away on this ridiculous forum of a blog since 2006. I'd left my latest job in biotech and I was at a loss to explain my life. Were these people honestly conducting what they thought science was or were they running a scam? I couldn't tell. So I started writing as a form of therapy. Why not, it was free.

It's 2010. The company I left back in 2006 is gone. They set a record on Wall Street for the rate of decreasing market capitalization. Impressive indeed. I moved onto another company that hasn't crashed yet, but in many ways could be more of a Cargo Cult than the previous company. I used the metaphor of fires along a cargo cult airport to track the comings and goings of the biotech companies. The fires have been burning out left and right since I began. Big ones like Zymogenetics, gone. Small ones like Homestead from Accelerator Corp. whom you never hear about. They just burn up a couple million bucks and they go away.

Tonight we have the Biotech Is Back forum taking place at the Path headquarters downtown. If you haven't seen this place let me set the stage. Paul Allen decided to "build it and they will come". He started building lab space, high rise apartments and high end commercial space to accommodate the well paid science community. In his "corridor" you will find a plethora of brand new spaces. As a fan of all things urban I am impressed and saddened that it is wasted on biotech. But there is a well funded high rise that houses the headquarters of PATH. Bill and Melinda Gates fund PATH, a non-profit organization that helps poor folk in third world places, including those in the good old USA. That doesn't mean the employees don't profit. They are living large. The ergonomic chairs in their cubicles are worth more than two years of the average salary of the people they are setting out to help in Africa. Tonight PATH will be hosting a forum where 4 of the few remaining biotech CEOs are going to try and make the case that biotech in Seattle is going to come roaring back.

I do not fault the sponsors. They are trying to make money. That's what good Americans do. I wish Biotechnology was into making money honestly for the sake of myself, our vendors and the people who need useful biotech products. But the forum, I fault! It's about bullshit. Biotech in Seattle is not back. It's the same people with the same tools trying to solve every problem in the same old ways.

In my next post I will compile a list of the companies that were here in the last ten years. You will see what happened and you can decide if biotech is back or not.