Simple, Complicated, Complex and Chaotic

How does this apply to scientific research?

I had written a rant against oversimplifying issues and delegating complicated issues into the simple category. I had came across the idea of simple, complicated and complex issues while reading The Checklist Manifesto. In this book simple issues are like baking a cake. Most people can bake a cake. Next are complicated issues. Sending a rocket into outer space is an example. It can be done but it requires much more knowledge than baking a cake. Then complex issues. Raising a kid is the example. Try as we might, we still have no way of knowing how the kid will turn out.

Chaos, in this video, added one more category to my rant. When we push complicated issues into the simple category, we slip over the edge into chaos.

Does that not describe a Cargo Cult Airport? By attempting to change the shape of the coconut headphones we fail to identify the complicated system in which the headphones play a part. We begin toiling with something that will not accomplish our goals. The question becomes when will we stop wasting our time?

How might this explain the failure rate in published research? RNA interference? Resveratrol? Biotech business models? Successful men and women in unsuccessful industries?

In my own career, the Cynefin chart helps me pin down the issues I've failed to articulate up the chain of command. One project involved a peptide library that was suppose to contain a molecule that would deliver siRNA to cellular targets. It wasn't my idea. I wondered why the MD PhD who dreamed it up thought something so simple could accomplish something so complex. In the complicated category I could create the library and start screening it against specific cell lines. In the complex arena we had no way of knowing if this library even contained a delivery molecule. Our screening methods were not very complicated. We treated cells as if they were proteins. We oversimplified, went over the cliff into chaos, and lost our jobs. As the CCS, I wondered why it took so long to end this project. I didn't predict the job loss, but I wasn't opposed to leaving such a place.

What was the decision making process from our chaotic predicament? Get rid of the white lab coat workers and send the library off to more experienced scientists. Simple! This took place in 2006/2007. The CEO and CSO eventually lost their jobs as well due to poor management and the loss of two large big pharma deals. The library lived on however because there was a simple solution, give it to someone else and let them fish out the magic molecule. The project remains in a state of chaos. The question remains, when will it end?

The library was sent off to Helsinki Finland. In spite of the expertise assumed in the transfer no progress has been made. Since biotech science has no journalistic reporting on the outcome of projects like this, we rely on company press releases to tell us what happens. No news is generally bad news. This experience is akin to what many in drug discovery R&D are facing. They put themselves in an occupation that is suppose to be complicated. However, the degree to which it is complicated is not well defined. When you start a project you cannot guarantee that you will succeed. Your leaders will insist that you do. Quite often, before you cease to be employed, you will enter the realm of chaos.

With a burn rate of $274 million a day, fewer and fewer drugs being discovered, drug discovery R&D is in a state of chaos. Massive layoffs have always been a part of industry. Scientific misconduct is rampant in academia. Published papers predominantly report useless false information. The state of science is chaos. I'm not sure it was ever otherwise. What is the future? It's complex, we can't predict. Will we continue to lose money and nurture the careers of cheaters? It's complicated but he answer is yes. Will we keep funding research? Yes, it's simple. Will we put the money where it will be the most useful? Chaos.

Business Models Vs Science Models

Businessmen make the decisions. When a young bachelor degreed lab tech enters the lab it is at the direction of his/her managers. They get orders from the board. Cure small cell lung cancer. Treat Alzheimer's by making an antibody to a specific region of amyloid beta.

The combination of business decisions, based on market valuation of certain diseases, along with science decisions directed at accomplishing business decisions has led to many a failed drug development program. In the following clip John Cleese describes this problem (towards the end of the clip). Business folk are too dumb to know how dumb they are. But it's not that they are dumb in business. They lack the scientific understanding needed to discover new avenues that are needed now that we've picked all of the low hanging fruit.



And from now on, read everything I write with an English accent. It just sounds better.

Our New Business Models

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

"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!