Dendreons Four Extra Months

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

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

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?

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

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

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

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

"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

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

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

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

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

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

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

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.

1. VieVax 2004
2. VLST 2004
3. Theraclone 2004
4. Homestead 2005
5. Allozyne 2005
6. Seridigm 2006
7. Recodagen 2008
8. GPC-RX 2008
9. Mirina 2008
10. Xori 2009
11. Acylin 2010
12. 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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?