The Amgen Study

Why were 47 out of 53 landmark oncology papers studied by Amgen scientists found to be non-reproducible?

Six of the papers, 11.3% were reproducible. The assumption we should all have at this point is that around 90% of published papers are not reproducible. The Amgen study should have expected these results. The recent AACR annual meeting should have contained 90% non-reproducible information.
Each new issue of Nature, Cell and Science should have 90% non-reproducible information. The ten percent that can be used to develop a technology or advance human understanding, is science. The 90% is cargo cult, fraud, bullshit, honest mistakes, accidental or some form of fooling ourselves.

This blog is about both sides, but mostly about studying the 90%. I chose the analogy of Cargo Cults because it requires a religious type of mind to participate in the 90%. I talk about bullshit, in a serious way (ala Harry G. Franfurt, philosophy professor at Princeton), because I believe that is what the leaders are up to. The whole blog boils down to understanding the way in which we participate in non-reproducible "scientific" research and why so many defend the practice.

We begin with a narrative. Ideas get kicked around. A certain percent of those ideas get put to the test in the laboratory. The scientists (creators of the narrative) do not go into the lab and verify the research they are building upon. They do not go into the lab at any point. They send in younger weaker minds to retrieve specific results. Once the data is in it is applied to the narrative and used for writing a paper. Once published the idea must be advanced, preferably by others, to validate the mind (and career) of the person who came up with the idea.

I'd like to recount the journey of one idea and how it landed in the 90% group. It's an old story that I've told in many ways on this blog but it haunts me.

My story is about a small biotech. The company was in existence to sell an antibody against denatured type IV collagen. The mechanism of action was based on an unproven theory, the idea.

A humanized, affinity-matured IgG1 and its parental murine IgM have been shown to specifically bind denatured collagens and thereby inhibit angiogenesis and tumor growth in various animal models. 

The, "and thereby" was the whole idea. As a tumor spreads it tears into the structural matrix of our bodies. Most of that matrix consists of collagen. Therefore, angiogenesis is working on or with the surface of that matrix and its collagen, right where the tumors are spreading. But that was just a nice narrative. They skipped past the science part of proving the theory, made an antibody and swung for a home run.

I participated in several mouse studies where it was proven to me that the antibody did not have an effect on tumor size or growth. When the mouse studies showed no effect on tumor size they simply re-measured. In their minds this was not dishonest. This is precisely the kind of research that the scientists at Amben would have been unable to reproduce. Our initial report to the scientists provided no reduction in tumor size, compared to the PBS group. A paper was later published with a 57% reduction. I'm not sure if they used the re-measured data but it was the same drug on the same mice and tumor cells.

The efficacy of this antibody was presented at AACR in 2006. Also in 2006 Micromet filed an IND.  There is no information on the fate of the antibody. It was last reported on in 2007. My own work on the drug took place in the early 2000s. It was a painful experience. We lost a few good men. Eventually we handed the whole kit and kaboodle over to a group of "scientists" who knew what the narrative needed from the lab.

The people who conducted this research were intelligent people. They knew how to make their presence known in a meeting. They had impressive resumes and advanced science degrees. Their papers were well thought out and they competed well for publication. All of the authors in the 53 landmark studies evaluated by Amgen were of the same breed. Back woods hillbillies wouldn't be able to do what these men and women do. There is a skill involved. There is a culture to fit into. The knowledge of antibody structure, humanization and so on are all complicated concepts that require a certain mental capacity. My bosses had it. The papers and the posters and all of the money are of little value now however. If the goal was ever to put a drug on the market and reduce the size of tumors in cancer patients, they did not have enough intelligence. That intelligence tells you that the truth is the only way to move forward without one day shutting down because you missed something. We were always missing something and we knew it. In the Amgen study, that something was discovered in 47 out of 53 papers. We were always publishing and telling people about things we knew were not reproducible. We were smart and we knew how to avoid having to go back over our work.

What then happened to the research papers from the Amgen study?

The Amgen scientists approached the papers' original authors to discuss findings and sometimes borrowed materials to repeat the experiments. In some cases, those authors required them to sign an agreement that they would not disclose their findings about specific papers. Begley and Ellis were therefore not free to identify the irreproducible papers — a fact that the Comment should have mentioned.

Nature, like most journals, requires authors of research papers to make their data available on request. In this less formal Comment, we chose not to enforce this requirement so that Begley and Ellis could abide by the legal agreements.

The scientists at Amgen could not have implemented their study had they reserved the right to reveal the outcome for individual papers. The Comment highlights important systemic problems in preclinical cancer research, which we felt appropriate to communicate to our readers, even though the authors could not disclose the studies in question.

Bullshit Man!

I'm reading the book "On Bullshit" by Harry G. Franfurt.

That is why she cannot be regarded as lying; for she does not presume that she knows the truth, and therefore she cannot be deliberately promulgating a proposition that she presumes to be false: Her statement is grounded neither in a belief that it is true nor, as a lie must be, in a belief that it is not true. It is just this lack of connection to a concern with truth - this indifference to how things really are - that I regard as of the essence of bullshit.

The business of science fails when they have that lack of connection to a concern with truth. What the many people whom I have highlighted on this blog have taught us is that the truth is not a necessary part of a successful scientific career in academia or industry. Life sciences are most successfully pursued by those with the best bullshitting skills. They do not start off on a journey to find the truth. At the same time they are not deliberately being dishonest. They see the success criteria for a Cargo Cult and they know it is within their skill set to reach the higher ranks.

In the Amgen paper regarding 53 landmark oncology papers we learned that one author published the results of one experiment that was tried 6 times. The author admitted that the reported results made for the best narrative. That was the reason he published his result. This is a lack of connection to a concern with truth.

We've hit some dark times but bullshit remains safely behind the wall of, "It's science".



Would BullshitMan help?

Biology Versus Chemistry

In a recent In The Pipeline post, Derek Lowe asked the question:

Have any of my chemistry colleagues out there noticed the difference in presentation detail between the two disciplines?

The difference between chemistry and biology is blurred in the pharmaceutical business. For example Derek goes on to say:

...most chemists don't (to me) seem to go to the level of detail that I often see from protein purification people...

Let's take a look at a few protein purification job descriptions and their education requirements.

1) BioForce Solutions:  Protein Purification Scientist - BS degree in Biochemisty, Biology, Chemistry, or Chemical Engineering.  
2) Astellas Pharma: Group Leader, Purification Process Development - Ph.D. in a scientific discipline (Biochemistry, Chemical Engineering, or Biochemical Engineering)
3) Sunrise Systems Inc: Research Associate - BS in Chemical Engineering preferred 
4) Laguna Source: Senior Scientist, Protein Purification - Ph.D. in Biochemical Engineering, Chemical Engineering or related Scientific/Engineering field.
5) R&D Partners: Scientist I II, Purification - BS/MS in Biochemistry, Biology or other relevant discipline 


Okay, we've grabbed five random protein purification job listings. They all involve the purification of proteins. Out of the five jobs how many required the following degrees?

Biology     Biochemistry     Chemistry     Chemical Engineering     Biochemical Engineering     Other
2           3                 1             4                       2                            3


In order to address the question that Derek asked we have to first define what a chemist is versus a biologist, in a biotech/pharma setting. According to Derek, chemists are not protein purification people. What the above information shows is that chemists can be protein purification people. 

Have any of my chemistry colleagues out there noticed the difference in presentation detail between the two disciplines?

What if a chemist gets a job as a protein purification method developer? Will he/she present his/her work with less detail than their biologist predecessor?

A trivial detail for sure. It's just a bloggers question to provoke thought. I agree that chemists give less method details but they use too many big words. Ultimately however, details matter. We should worry more about what is not being said.

The easiest way to explain this idea is to contrast it, for
example, with advertising. Last night I heard that Wesson oil
doesn't soak through food. Well, that's true. It's not dishonest;
but the thing I'm talking about is not just a matter of not being
dishonest, it's a matter of scientific integrity, which is another
level. The fact that should be added to that advertising statement
is that no oils soak through food, if operated at a certain
temperature. If operated at another temperature, they all will--
including Wesson oil. So it's the implication which has been
conveyed, not the fact, which is true, and the difference is what
we have to deal with.

Winning The Lottery

I once heard that your odds of winning the lottery are very close to your odds of finding a winning lottery ticket. Holy Shit.

Finder

Keeper

trustus

The Information Scapegoat

Wise Old Sage:  Why hasn't the cargo shown up? Where are those big metal birds that brought food and medicine to the white man?

CEO of Cargo Cult:  We have information that can bring the cargo but everyone is hoarding it. If we could simply share our information using the "computers" we would get the cargo.

Enter Sage Bionetworks.  The Sage is now going to help the gatherers of information. The similarities between this information sharing and the Genome Project:

But a lot of what comes next will depend partly on what Sage does to clear the way, and what people in the biomedical research community choose to do with its platform. “Our mission is to develop flexible approaches that can be championed by others,” Friend says.

Championed by others?

Friend is Stephen Friend, a former VP at Merck who started a nonprofit with a bold vision to speed up drug discovery. He plans on offering the scientific community a common place online where scientists could pool their data and brainpower to speed up the pace of discovery and drug development. According to S. Friend, "biology has become far too complex for any lone researcher or Big Pharma company to keep tackling problems in isolation." 


Biology has gotten more complex?

Flash back to the days when biology was not too complex. It was so simple, we could still make progress without computers! Rene Descartes was a scientist who made many important contributions to the scientific community. He had a set of information that he thought had value.

 Meditations is by far Descartes's most popular work—though this would not have been the case in Descartes's day. This work is important to today's scholar for many reasons, not the least of which is its including as an attached text written objections from some of the best minds living in Paris. Mersenne sent the Meditations to philosophers and theologians for criticism. The list of critics includes: Caterus, Hobbes, Arnauld, Gassendi, and Mersenne himself, with several other unnamed readers who raised their objections through Mersenne. A later edition would include an objection from Bordin. Descartes replied to each critic, and the result was an appended text referred to as “The Objections and Replies.” The second edition contains seven sets in all.

Descartes's letter to the “learned and distinguished men” of the Sorbonne, which is appended to the Meditations, suggests that he was trying to pitch the Meditations as a textbook for the university. Though the endorsement of the Learned Men would not have guaranteed that the Meditations would be accepted or used as a textbook, it could certainly be viewed as an important step to getting it accepted. Unlike today's notion of a textbook, in Descartes's day “textbooks” were intended mostly for teachers, not students. Typically, at the close of a teacher's career, his notes would be published for the benefit of those who would go on to teach such course material.

A text book for teachers who would go on to teach... What we have with Sage Bionetworks is a list of information. The difference is clear. Sage offers random information that the proprietors did not generate themselves. They hope to share the information with people who will turn it into technologies that make money. Cargo. Descartes had a set of information that he gathered himself. He offered it up to the teachers in a manner that would allow them to understand, in great detail, who, what, when, why and how this information came to be and what can be done with it. It wasn't a football to be handed off but a playbook on how to play the game.

Disassembled an old car. Lay the parts on the ground. Bring in an engineer and tell him to make the car run again. It won't work. Sage Bionetworks likewise, will not work.

One of the ways scientists used to get information was in the laboratory. The laboratory is where you ask nature a question. If you are clever and do so in the right way, nature will reveal itself to you. At the end of your career you might have a very interesting text book to write.

  

John Le Carre

At 9:37 of this video you hear a great description of what journalism should be. "Whatever we came upon, however offensive it was to those in power, we told it straight".



There is plenty to cull from this interview that pertains to our own predicament in science. I'm certain that what we experience when dealing with the elite has been dealt with by those in the past. The concept then of telling the truth, as Feynman described, comes with great opposition that has always existed. If the truth is something that benefits power then they will have you go back and make sure you are accurate. If it goes against their hopes and dreams it might just get squashed on the spot. You will end up marching your meager possessions out to your car in a cardboard box that day. This is true now, yesterday, in industry and in academia.

My work in a Nobel Prize winning laboratory seemed to have a strange relationship with the truth. I wasn't alone in my utter confusion at this my very first foray into big time science. My lowly supervisor however understood what it took to get her name on a Prusiner publication. She has spent her entire working life at this lab and by professional science standards, is successful. Yet if she were to be sent to any other lab, her work ethic and intelligence may not be sufficient to keep her around. She found her niche, and it required a special talent. It wasn't scientific.

David Cornwell, aka John Le Carre, spoke truth to power. Gary Taubes spoke truth to power. What we need more of are people like these. It is difficult however because we have no real science journalists. Science information is told to us by people who journalists should be writing about. When Taubes wrote about Prusiners very first Prion paper he mentioned something Prusiner left out.

The researcher who did Prusiner's lab work at the University of California at San Francisco quit over the publication of Prusiner's very first prion paper in 1982, arguing that Prusiner was overinterpreting the available data to push the prion hypothesis. 

Only a journalist would enter that information into the public domain. In discussing Prion research one might want to know who this man was and why, exactly, he quit. All we know is that he quit due to "overinterpreting the available data".

To some of us, science is not just the boring details offered to us by the authors of published papers. It's personalities, power, lies, cheats and the occasional flash of brilliance. The truth behind our daily lives conducting science and spending billions of dollars is a good story. Who is really telling that story. If you are lucky enough to work in this field, whatever we come upon, however offensive it is to those in power, tell it straight.

The DNA of Identical Twins, A Novel

Bill Clinton said that the Genome Project was going to be one of the major scientific discoveries of the 20th  century. Was the Genome Project a discovery? It was a project in which we laid out a simple plan. Sequence the DNA of five people.



Any one of us can sequence our DNA today. The details on how to do it are no more or less a mystery to us than it was to Clinton or any of the bigwigs on the project. Let someone else worry about it, and we'll take to the podium when the work is done.

I've taken up my own genome project. I have an identical twin brother so there will be two people sequenced and there will be two sequences for sale. That's right, for sale. This is a biotech business. The product I'm selling is not just a DNA sequence, but a genome of two clones that will be sequenced over and over as we progress through life and die. The genome project pieced together their sequence from five strangers from different parts of the world. I will be offering two separate genome sequences from identical twins who are very different people.

Unlike the genome project I am starting my project with a check list. What are our similarities and  differences, nature versus nurture? The sequences will be overlayed to find the differences and the similarities. I will look for correlations but make no claims to consequences (causation). Perhaps my smoking habit led to some damage. Then I throw in a twist. After all of the comparisons have been made I shell out another five grand and get another sequence done. What are the differences between me and myself? Could there be some human misunderstanding of how we humans go about DNA sequencing of a genome? We're still new at this.

I've seen the way in which humans interpret simple DNA sequences. A single read runs about 1000 nucleotides. In the beginning stretch there is usually some noise that must be thrown out. I've found explaining this to scientists is not easy because they don't want to hear about it. In explaining the little anomalies that come up when allowing Vector NTI to spit out your sequence from a FASTA file I have encountered opposition. I've engaged in adversarial conversations about who's fault it is that we have these little problems. In my own project I will address these issues.

Since 3 billion nucleotides 3X is a lot of letters to put down on paper, the sequences will be available online. The details of interest will be broken into chapters of a book where I lay out my naive view of DNA. Perhaps that will be of interest to the world outside of science. We have questions for the genetics community. How do they know, for example, that every cell in the human body has the same sequence. Surely they do not. A B-cell coding for different antibodies have shifted their DNA around. I should probably make a side project out of sequencing B-cells.

This is getting expensive!

It is also getting exciting, at least for me. According to the genome project logic, my brother and I should die on the same day from the same disease. But DNA as a predictor of health and happiness is a myth for now. We need to learn more before we can start making wild claims about future humans living to 150 years old. For now we need two clones, twins. But I promise to have this project done in the next five years. When I am done I will publish in book form, "The DNA of Identical Twins". Publish or perish is not a problem on this project. Along with cheap DNA sequencing, we now have the ability to publish books on our own. It will simply be a few DNA genome projects, of twins and a couple sequences of me alone, different times different cells. Online perusing of the sequences will be for sale. The book will be for sale and I will put forward my own naive ideas on what our DNA is there for. I couldn't do much worse than the leaders of the genome project. I am a free citizen. I have nothing to lose here but a little money. I don't predict any huge impact on the future of human health. I simply want to open up a window and see what is on the other side. Unlike the genome project folks, the philosophy here comes from Sgt. Joe Friday from Dragnet, "Just the facts ma'am."

Do it, publish the results, make a side project out of my own thoughts on the subject, and walk away.

"We Re-Measured" Honesty

In my study of the Cargo Cults of Biotech I have seen first hand the curious deceptions that humans employ to get around the rigors of the scientific method. We had a drug to prevent angiogenesis, for example, that was to stop tumor cells from growing. In a study using mice, the Rituxan control group stopped tumor growth entirely. The PBS group all sprouted various sized tumors. Some mice, with smaller tumors, had to be euthanized sooner than those with bigger tumors. The group of mice receiving our drug were no different than the PBS control group. Without any trickery, Rituxan was an obviously efficacious treatment for mice being injected with cancer cells. Our drug was not working.

We were sent back to the lab with a grad student who showed us how to "properly" measure the tumors. She got the desired results by squeezing the caliper a little tighter around our drug group, and less so around the PBS control group. When I handed her a mouse that she had already tested, she wanted to know what her first measurement was. I refused to tell her even what group the mouse was in. Should she measure tight or loose with the caliper?

Why not simply take out a new data sheet and change the numbers? Because that would be misconduct. By re-measuring the tumors we were being, by Cargo Cult standards, more honest. The ceremony of re-measuring made us feel better about fudging the data. It somehow took us out of the realm of flat out fraud.

This experience shaped my view of early stage cancer research. The measurements are meaningless because cancer doesn't work in a manner that would make our research easier. Tumor size is an end point that the human beings conducting research can handle. The reality of explaining the "leaves blowing in the wind" chaos of cancer cells in the body would be too hard to follow. Using the "Drunk Under the Streetlight" logic we now have a place to look for efficacy. Using the "Beer and Pizza Diet" we then have a way of dealing with the nonsense we find.

Our anti-angiogenesis drug used in the cancer study described above, was picked up by a company called Cancervax. Their product was an attenuated cancer cell that expressed 26 antigens on its surface. It failed clinical trials in 2005 and the drug development ended. The anti-angiogenesis drug faded away, last heard from in 2007. While these two anti-cancer products were discontinued, the methodology remains much the same. Cargo Cults may have many iterations of their airports but the thing that is missing is always missing.

Two news items came up this week to exemplify the Cargo Cult science as usual approach. Presage Biosciences make the claim that they can separate the winning compounds from the losers early in development. According to Xconomy, Presage has partners who, "are hoping to improve the odds of success in clinical trials, where only about one out of every 10 cancer drugs that enters clinical trials ever makes it through the hoops necessary to become an FDA-approved product." The leaders are right ten percent of the time? Well anyway, Presage will help them increase their hit rate. "One of the operative words in cancer research today is “combinations,” which Olson (Presage founder) said people are buzzing about this week at the American Association for Cancer Research meeting in Chicago. Companies are becoming more interested in finding those instances in which a single drug doesn’t work on its own, but can show a potent effect when given synergistically with another compound that works in a different way." 


In 2012 folks at the AACR are buzzing about combinations? Perhaps science needs historians to keep the research in a scientific perspective. In addition to CancerVax's 26 antigens, I think  the Anil Potti story is germaine to this company. The Presage approach assumes that maybe we are only off by a few targets. Instead of grandma taking one or two pills for her cancer, she might need ten. Twenty? A thousand? No, that couldn't be because we can't make grandma take that many pills. The bloggosphere is buzzing too. Here is a comment on the AACR from In the Pipeline:

Take a look at the 6000+ abstracts from the 2012 AACR national meeting last week. Wishful thinking is a mild description for that carnival sideshow. Maybe 3% of the work was worthwhile. Four darts and a genome map would provide a better chance of hitting a cancer response biomarker.

I added that because it cleanses the palette after Jim Olsons gung-ho attitude towards the AACR meeting. And it's funny. 

The second news item this week comes from Oncothyreon.  They are marching forward with a Beer and Pizza Diet approach to their original stinker. According to Xconomy:

There are some very interesting scientific and business reasons why Oncothyreon wants to test the second-generation product, called ONT-10. It is attached to a more potent immune-boosting compound than the original, and the new drug is designed to stimulate a sort of two-pronged immune response, instead of just the T-cell reaction sparked by the original.

Why not start with the more potent immune booster? Why did they need to improve something on which they had already placed a huge bet. The company and their investors have us thinking that the clinical trials of their original product won't be much to talk about. But the new and improved product... now that's... well it's just going to be better... that first thing we did wasn't well thought out and... is it getting hot in here?

My message is that we are not really changing the way in which we approach cancer research. At the end of the sciencey meetings and the millions of dollars, a low paid BS Biology major, in her early 20s will be given a caliper and told to go measure the tumors on the backs of nude mice. Whatever the method, whoever makes the measurement, some things will remain the same. All of the promises will be backed up by the same "we-remeasured" honesty. We have not worked out a method to prevent it. It is a human issue involving psychology, not a laboratory issue, business model or funding issue.

Of course we hope that Presage and Oncothyreon are telling the truth. We want to believe them. We want them to be honest and not just "we re-measured" honest.

The Quilt

At the "Reinventing Biotech's Business Model" meeting yesterday here in Seattle we saw an assembly of men and women who will lead us to prosperity. At least that was their purpose for getting together.

“When you’re building a team today, you need to have people with enough former company T-shirts to knit together a quilt in a nursing home,” quipped Bruce Montgomery, the founder and CEO of Seattle-based Cardeas Pharma. 

That’s one way of saying biotech startups now need teams of highly skilled, highly experienced people who can go a long way on a little bit of money. That was one of the main themes that came out yesterday at our big Xconomy event, “Reinventing Biotech’s Business Model.“

It's also another way of saying that we have created a multi-billion dollar quilt pieced together by failed biotechnology companies.

Quip:  A witty or funny observation or response usually made on the spur of the moment.


The main theme seems to be that failure is no big deal. Make a quilt and move on using the same people. Perhaps to reinvent biotech we should replace certain people. If you have made a fortune in the process of losing a fortune... you need to be replaced. 


We should think about making another quilt in ten years. This quilt will be built from success. 

Avi Biopharmas Major Advance

Over at Dendreon they have a mechanism of action that can't be confirmed. Rather they go with the survival data as evidence that their MOA, as depicted in cartoon form on their website, is accurate. Avi Biopharm this week has shown a different approach. Their product did what the cartoon depiction advertised.

The study, which randomly assigned 12 boys to a couple different doses of the AVI drug or a placebo, showed the boys were able to produce about 22.5 percent of normal dystrophin levels after 24 weeks on the therapy, while there was no increase on the placebo. No serious adverse events were reported in patients on the experimental treatment, and no patients dropped out of the study, AVI said.

On the downside, their was no improvement with the higher dose and worst of all, the boost in dystrophin had no clinical benefit. Researchers saw no difference in patients’ walking ability in a standard 6-minute walk test.  

The study’s lead investigator hailed the finding as a “major advance”. 

Opposite of Dendreon, Avi has evidence that they can make the body do something very specific. Dendreon made the claim that they could elicit an immune response resulting in tumor cell death, yet they could not provide evidence of that MOA. Avi made the claim that they could make the body produce dystrophin and they provided information claiming that they did. Yet Dendreon provided a clinical benefit to their unsubstantiated MOA. Avi could not provide evidence of clinical benefit to their substantiated MOA.

From a scientific standpoint it is indeed interesting that a piece of RNA can accomplish this result. Eteplirsen is the therapeutic candidate for DMD and uses their core PMO chemistry applied as a splice switching oligomer (SSO). The drug is intended to skip exon 51 of the dystrophin gene. By skipping exon 51, eteplirsen may restore the gene’s ability to make a shorter – but still functional – form of dystrophin. From this point one would think that the scientific community would begin conducting research into skipping exons to restore or improve gene function. What we do in biotech is swing for a home run however. In this case I don't think we have much of a chance. Are we altering our DNA or are we throwing nucleic acids at the body and hoping the DNA will know what to do with it?  


The investor community gave the major advance a thumbs down. The stock went down as much as dystrophin went up, 25%. This could help investors understand such claims of 25% changes. If the stock were worth $100 they would have lost $25 per share. Instead, after a 25% loss, the stock was worth $1.16, a loss of 38 cents. In terms of what matters, the percentage of change is less important than the consequences of change.


When dealing with our DNA, we are dealing with evolution. Can we change millions of years of selection that has produced human beings destined to live short difficult lives? Of course we should be trying. But is this the best way? A for profit effort hell bent on surviving one month to the next? The desperation in the careers of the Avi scientific staff leads to certain outcomes that ignore the sad results of this trial. In a fair world the science would be handed over to an academic lab to learn more about what happened. The expense of moving on with more clinical trials, the suffering of the patients through this invasive research on their muscles is not warranted. It is time to get back to learning about our DNA and to move away from trying to make it stop doing something evolution has somehow allowed.  

The Provenge Trials

The comment left yesterday directed me to this website created by Marie Huber about the Provenge Trials. A one woman crusade against a Cargo Cult is too good to be true. She has alliances with prominent scientists, a website, evidence, and she is clearly passionate about this company and what they did to get their product on the market. Will we see her on 60 Minutes one day? It is modern day "Emperors New Clothes" story. Have we all played along because we have to believe the FDA and the multi-billion dollar biotech?

I will let her tell her story so please go to her website and read all about Provenge and Dendreon.

   

Immunity to a Cancer in Progress

As Science Tsar of the World, I hereby assign Group A to study the Dendreon science and their vaccine for prostrate cancer. What I want Group A to study is the concept of a cancer vaccine, what they did to prove the mechanism of action, and how they conducted the statistical analysis of the clinical data.

Why is a hedge fund analyst more skeptical than the scientific community? Who is Marie Huber and what is her motivation?

If I, the Science Tsar of the World, want to know more about the Dendreon story I will need to know more about the psychology of the players. I know Dendreons vaccine story and it is bizzarre.

Each dose of Provenge is custom-made. A nurse or technician withdraws white blood cells from a man's arm in a three-to-four hour procedure called leukapheresis.

The cells are shipped to a Dendreon manufacturing facility, where for two days they are incubated with a "fusion protein:" One protein that stimulates the cells' growth and maturation and another called PAP, or prostatic acid phosphatase. PAP is an antigen that studs prostate cancer cells like antennae, pieces of it sticking out of the cells' surfaces.

Dendreon says the patients' white blood cells take up the antigen and within hours their surfaces bristle with fragments of the telltale molecule. The cells are then shipped back to the physician and infused into the patient. A full treatment includes three such procedures, two weeks apart.

Back inside the body, Dendreon claims the modified cells trigger the immune system to produce T cells that kill any cell sporting the PAP antigen — namely, prostate cancer cells.

In principle, that should eliminate the cancer, but Provenge does not shrink either the primary tumor or metastases.

I set the scientists down with the piles of data to sort through. That becomes one piece of the puzzle. I now set my sights on Marie Huber.

She argues that the main reason Provenge seemed to extend survival - a crucial factor in the FDA's decision - was that older men in the study who did not receive Provenge died months sooner than similar patients in other studies.

She raises the possibility the "placebo" they received was actually harmful and made Provenge, known scientifically as sipuleucel-T, look better by comparison.

My scientists are working on the placebo logic / clinical trial design. But Marie... who are you?

In documents JNCI requires authors to sign, she declared no financial conflicts of interest. Neither she nor her former firm nor anyone else she is connected to stands to benefit financially from her analysis, she said. Instead, she says she is motivated to help "vulnerable and desperate patients" - so much so that she gave up her job, salary and health insurance. 

Why did she give up her job for this? Because she cares? How did she get so much traction to her side of the story? An unemployed hedge fund analyst takes on a former $5 billion dollar biotech and people listen? It could have something to do with the unforgiving logical nature of science:

"There is no efficacy in the younger patients, the primary group where you would expect it," said Huber.Since the immune system weakens with age, an immune-based therapy should work better in younger men. Some experts agree."If it was really a vaccine, you'd think younger men would show more response, since they are more immunocompetent," said NCI's Rosenberg.

Then there is the logic of Dendreon:

"We have a lot of data that supports the idea that the product works the way it was designed to," said Dr. Mark Frohlich, Dendreon's chief medical officer. "We're seeing evidence of immune-system activation. The only question is whether the T cells are killing the tumor."

There is support but no verification. Marie Huber has just as much fire power scientifically. Applying Occams Razor, a principle urging one to select among competing hypotheses that which makes the fewest assumptions and thereby offers the simplest explanation of the effect, who should we believe? Do we even need to know who Marie is and what her motivations are? Scientifically, no. Cargo Cult Scientifically we would love to know more about her and why she is so into this issue. 

WHat what WHAT!!!

What what what

Finally, a scientist at Amgen has come up with something useful in the cancer research sciences.

In cancer science, many "discoveries" don't hold up.  (Reuters) - A former researcher at Amgen Inc has found that many basic studies on cancer -- a high proportion of them from university labs -- are unreliable, with grim consequences for producing new medicines in the future.

So we really ought to look into theories that don't work, and
science that isn't science.

Now that we have published information regarding the things that don't work, we really ought to look into the theories. Retraction Watch get ready! Someone needs to track this guy down. Name names and get an explanation for this:

Part way through his project to reproduce promising studies, Begley met for breakfast at a cancer conference with the lead scientist of one of the problematic studies. 

"We went through the paper line by line, figure by figure," said Begley. "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story. It's very disillusioning." 

It's a Cargo Cult Leader in action. It's rare that we get to see such a species in nature. I would have climbed over the table, strangled him to death, put his head on a plaque and mounted it in my office. 

Ken Kaitlin sums up the world inhabited by the Cargo Cult Leaders.

"If you can write it up and get it published you're not even thinking of reproducibility," said Ken Kaitin, director of the Tufts Center for the Study of Drug Development. "You make an observation and move on. There is no incentive to find out it was wrong."

No incentive? Working in science these days provides no incentive to finding out right from wrong. Hmm.

Predictive Powers

There has been a bump in page views of the Cargo Cult Scientist. For some reason people are Googling Allozyne Layoffs. Allozyne is a Cargo Cult with a beautiful CEO and a beautiful space on the shore of Lake Union with a beautiful view of the Seattle skyline. The science???

What is happening? Can a blog such as this be a canary in the mine? Why has "Allozyne Layoffs" suddenly come up? Allozyne is more or less finished in my opinion. They have been unable to sell the company and/or its technology to anyone outside of The Accelerator Corporation.

I predict news from Allozyne coming soon. Time to wait and see. Is their fire burning out?

The Virtual Lab

I used to sit in meetings listening to one non-PhD research associate after another randomly talk about the highlights of their last week or two. The PhD scientists would listen carefully and look as though they were deep in thought. When the young lab workers spoke they were nervous. They really did not have a point nor did they care much about what they were talking about. They were told to give a presentation so they reluctantly came up with their best effort. A typical presentation lasted only a few slides. They would show something simple such as a western blot. The PhD would ask questions as if it were somehow more complicated. "Can you see any host cell impurities?" The kids would respond, "I don't think so," always mitigating their answers.

As the company progressed the undergraduate degree was less and less important when hiring new lab staff. New employees were picked up from the facilities group and the dish washing room. The most desirable trait was knowing that you could work with someone. Personality trumped skills and education. After all, it was just a lab tech we needed.

These kinds of experiences have led me to create the Cargo Cult Scientist. The location of the laboratory would be no more consequential than the location of a Cargo Cult Airport. No drugs will ever reach the market. No planes will land. The problem then is in the offices where the leaders ply their trade.

The news from Cetero this week pulls the curtain back on the Wizard of Oz. Most biotech science is virtual. Of all the clients who were burned by Cetero, none of them uncovered the truth behind their CRO. The FDA, a government agency, provided the oversight. The leaders, as usual, saw what they wanted to see and had no further questions.

The filing for bankruptcy allows Cetero management to sell the business, leaving the new owners “free and clear” of any liability coming from lawsuits related to problems uncovered by the FDA. Last July, the Food and Drug Administration notified Cetero that it had uncovered “objectionable conditions” at a company lab in Houston, including “widespread falsification of dates and times,” manipulation of data and other deficiencies that raised questions about the reliability of test results. In my own Cargo Cult experience, falsification of dates and times, manipulation of data etc. was fairly common. The kind of honesty we need in order to make science productive was never present. PhD scientists retreated to the office for obvious reasons. In the lab, cells and proteins are the boss. By making other people work in that environment created a buffer. If you were concerned about host cell contaminants you could ask a nervous technician if they see any on their western blot. "I don't think so." Good enough. 


The virtual lab is subject to two different interests, the clients and the FDAs. The former needs data to sell their IP. The latter needs data to keep us honest. The most successful virtual companies of the future will be the ones who realize that they too have an interest in keeping their CROs honest. 

Who Can You Believe

Leroy Hoods P4 Medicine institute was co-founded in 2010 by the Institute for Systems Biology and Ohio State University to help catalyze the transformation of medicine from a reactive mode to a system that is Predictive, Preventive, Personalized and Participatory.


"Participatory" struck me as a misunderstanding of the human race. People get sick because of their participation in things that are bad for them. When they get sick they go to the doctor. To circumvent this reality Leroy Hood has designed his consumer. According to the P4 website:

The problem solving capabilities of today’s educated and internet-savvy consumers will be systemically tapped to improve system-wide solutions.

As a fan of the documentary "Forks Over Knives" I have seen people improve their disease state without the use of pills. I have used it to improve my own health. The results seen in that documentary, when people started eating healthy and exercising, are absolutely astonishing. But people don't want to eat just vegetables. People don't want to quit smoking or drinking. Those who do will get better. ISB and P4 can only fail if their patients don't follow orders and/or if their remedies cause problems. A change in diet and exercise will make the biggest difference. This fact will be masked by the PR machine at ISB and P4.

Leroy Hood is indeed convinced of his greatness. Closer to God than the rest of us, he is going to fix our bodies like a mechanic fixes our cars. The idea pushed by P4 and ISB is that we are merely a set of parts. The ISB will find the important parts. P4 will use ISB tests (looking for specific parts) and fix the person.

Enter the spoiler...


U.K. research knocks wind out of personalized medicine push

The finding, if it stands, could make the process of genetically profiling patients and their tumors, and then developing or matching a specialized treatment that addresses the mutation, more challenging than previously believed. Thus, personalized medicine for the masses becomes much harder to obtain.

Our parts are hard to disassemble into a systematic biology. In a Utopian world where research can be conducted without hierarchy or money constrictions, this is a question that needs to be addressed in the lab. What are they calling a mutation? What is ISB calling a bio-marker? What is the criteria each of the leaders have come up with and why have they come to such disparate views? Today’s educated and internet-savvy consumers need to know. 


Leroy Hood is a powerful man. He can get money and send people to work on what ever crosses his mind. ISB has been around over a decade, with an ad hoc addition called P4 Medicine. Along comes a group of scientists from the UK to give him and all of his people something to think about. Has Leroy anything to say about this research? I can't find any commentary. When something like this comes up, an outsider might think that scientists quickly get together to sort out the contradictions. They do not. They seek to silence the other guy. So far Leroy Hood is the silent one. It is now up to P4 Medicine to make their point. 

Careful Observation

One of the key elements in all of the cases of scientific misconduct that I have highlighted is a lack of actual observation by the principal investigators. Modern science has taken the scientist out of the laboratory and into the office. The end result of this arrangement is the replacement of careful observations with ad hoc theories.

In science and philosophy, ad hoc means the addition of extraneous hypotheses to a theory to save it from being falsified. Ad hochypotheses compensate for anomalies not anticipated by the theory in its unmodified form. Scientists are often skeptical of theories that rely on frequent, unsupported adjustments to sustain them. Ad hoc hypotheses are often characteristic of pseudoscientific subjects. 

According to management, I once created a molecule so powerful the cell could barely handle it. The power of managements design made my molecular biology work result in mutations. There were no mutations however, just normal cloning issues. Some of the clones had DNA sequences that deviated from the DNA I had typed into the Invitrogen order form. This always happens when cloning single proteins. You pick 10 clones and have them sequenced. If only one clone has the right sequence you are done. Grow it up and freeze it down. But this was different. This was a library. Every clone was taken literally as a designed peptide or a mutant.

The mutation story is what I would consider an ad hoc explanation. No one besides myself anticipated the less than perfect set of sequence data. When it came in an ad hoc theory was put in place that supported the notion that the molecule was potent.

Phage libraries displaying linear or disulfide-constrained 

peptides often yield weak binders, upon screening against a 

target, and must be optimized to improve affinity. The disad- 

vantages of libraries based on larger complex proteins, such 

as single chain antibodies, have stimulated interest in the devel- 

opment of smaller nonimmunoglobulin protein scaffolds. A 

promising candidate is the Trp cage motif, a 20-residue C-terminal sequence of exendin-4.

Exendin-4 is the active biological component of Byetta. I believe the managers came up with the idea while strategizing a way of competing with Byetta. In their minds the Trp Cage would remain the same structure in spite of changing up to 7 amino acids. We did no work to ascertain the structure of our peptides. We were not allowed to do research into the mutation story.

These are observations from a person who worked in the labs. My lab observations and my leadership observations have led me to this blog. As I've watched the biotechnology industry evolve I think of these little things. What does it really matter if my library was mutating or if it was a normal cloning outcome? It mattered enough to management that no experimentation was allowed to verify the mutation story. It mattered that the mutation story supported their idea of structure. Yet it was an unverified ad hoc theory.

From my point of view I saw a group of PhD scientists who wanted to be thought of as protein engineers, "Intelligent Designers". They did not want the world to think of them as people who simply combined a piece of Byetta into a phage display library assembly kit. To me they had dreamed up the idea in ten minutes then spent over a year applying ad hoc theories to what actually happened in the lab. The patents and publications that followed are a collection of those theories. Five years on, the library has failed to deliver on its promise.

This isn't a blog were I simply complain about old bosses. It is about finding the key elements that turn good science and good money into Cargo Cults. The Trp Cage story is analogous to what I see happening at every turn in biotech and in science. Desired outcomes are formulated by management. Laboratory work is thought up by office workers and handed over to the lab staff. They obediently do the work and present the data. Back in the offices ad hoc theories begin to fly. If a theory doesn't fit we occasionally veer off into the world of fraud and misconduct. Real science is often too simple to advance a modern day scientists career.

Careful observations are important in science. Eratosthenes calculated the circumference of the Earth from careful observations. That was roughly 1,800 years ago. Perhaps our ability to Google has stopped our imaginations from thinking up ways of knowing things. All of those little unexpected details that take place in the lab are unavailable to the modern day scientist. The careful observation is at war with the ad hoc theory. 

A Cancer Cells Walk, A Research Opportunity

Randomness rules our lives. It also rules cancer. This paper is a glimpse into that randomness. It looks at cells after they have gone to the dark side to became part of what we call cancer. Scientists found that a single tumor can contain a number of genetic differences. A single biopsy only paints one tiny part of a cancer's molecular picture.

Once again we have a scenario akin to the testing of the Cargo Cult Science speech rat maze. We begin with our test subject, a single target drug. We put it into our maze, the human body. We assign significance to certain outcomes such as the patient getting better, and we set a time limit for collecting data.  The question remains, how much do we know about our maze?

Seattle Genetics had their first product approved by the FDA last year. ADCETRIS is indicated for the treatment of:

• Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT)
• HL in patients who are not ASCT candidates after failure of at least 2 multi-agent chemotherapy regimens
• Systemic anaplastic large cell lymphoma (sALCL) after failure of at least 1 multiagent chemotherapy regimen

The indications for ADCETRIS are based on response rate. There are no data available demonstrating improvement in patient-reported outcomes or survival with ADCETRIS. There is certainly no data on the cells found throughout the tumors.

Seattle Genetics took advantage of a pattern.  CD30 is expressed in both HL and sALCL but has limited expression in healthy tissue. Bio-technicians then made an antibody against CD30 - ADCETRIS (brentuximab vedotin). The antibody binds to CD30 on the cell surface which somehow initiates internalization of the ADC-CD30 complex. Inside the cell, MMAE is released via proteolytic cleavage. Binding of released MMAE to tubulin disrupts the microtubule network, inducing apoptotic cell death.

That is a highly detailed description of how the drug works.

"CD30 is expressed in both HL and sALCL but has limited expression in healthy tissue."

Is this true? Tumor samples have been shown to have different cell populations across their diameter. In this study diploid cells were found throughout the tumor. However, some of the cells tested were not diploid. These were found at only one end of the sample, fading out gradually towards the middle. Two other varieties (near-tetraploid) were found at the other end. Almost all of the diploids were normal cells, and most of those were immunocytes that had infiltrated the tumor.

What is the composition of the cancers being treated by ADCETRIS? In a 2010 clinical trial produced their official data set: 34% of patients with refractory Hodgkin Lymphoma achieved complete remission and another 40% had partial remission. Tumor reductions were achieved in 94% of patients. In ALCL, 87% of patients had tumors shrink at least 50% and 97% of patients had some tumors shrinkage. What exactly can we take away from such descriptions of cancer and how we treat it? What do we know about the Seattle Genetics mechanism of action proposal and the end results?



In the case of Seattle Genetics, we have seen cargo. A plane landed. We don't really know much about the plane or how it got here. Retraction Watch reported on such a case just this week. In this case, a method of measuring antibody-antigen binding led to faulty data which, not surprisingly, supported the outcome that was hoped for. There was a plane on our runway but upon closer inspection it was not real. 


The information we now have on tumor cells and the widespread "mutations" makes us wonder about single target treatments for cancer. Our industry tells us they work, sometimes very well. We here at the CCS see that claim as a research project. Why do they work? The possible fact that they work, coupled with the possible fact that tumors are not a homogeneous group of cells, demands an explanation. All a leader has to do is set a group of scientists into the laboratory to try and reconcile this contradiction. Then set another group of people into the lab half way across the world to do the same thing. Then another group! It is an important question. Drug companies aren't simply making pills that make money. They impact our understanding of the human body and the diseases we get. They create knowledge. Is it true?

Compensation Committee at GSK

During 2011, we assessed the competitiveness of the remuneration of the Executive Directors and other CET members and were satisfied that in most instances their remuneration was appropriate. However, we did identify a significant competitiveness gap for our CEO," the annual report states.

Good catch. Many people who don't have executive compensation skills would not have caught this egregious oversight. The ability to keep executive compensation competitive is a key factor in the success of the drug industry.

60 Minutes assessed the integrity of GSK executives in 2011. They were not satisfied with what they found.



What is the personality differences between whistle blowers, 60 Minute reporters and corporate executives? What could make a group of people get together and pay themselves so much money while running a company that is so indifferent to the health of their customers?



Beware of the jealousy. Johnson and Johnsons compensation committee has created a monster!

BMS Up Sanofi Down

The CEO of Bristol Meyers Squibb has received a 27% raise for being the boss of a company that saw a bump in success. The success came from the FDA approval of a monoclonal antibody that began life in 1993. What if the CEO and his people back in 1993 decided to axe the Yervoy project?

In "The Drunkards Walk" we read about the Hollywood CEO who was fired after a bad year of movies. The movie mogul didn't make the decisions regarding movies that tanked. The year after she was fired, the movies she produced made a nice profit for her former company. This sounds remarkably similar to the BMS story. What exactly did the BMS CEO do above and beyond keeping the company running? It seems the profits were on the way when he took over in 2010.

What if he were the CEO of Sanofi? The closing of the manufacturing plant in Fawdon is blamed on the growing use of low-cost generic drugs and the European economic downturn. It all seems unfair but that is the randomness that runs our lives. In the Leonard Mlodinow video (link to The Drunkards Walk) he talks about the association between the perceived quality of wine and the actual quality. When the same wine is given to the same person, but the price and/or rating is altered, the actual enjoyment of the wine changes accordingly. Replace the quality of wine with the quality of a CEOs performance. We may judge the CEO of BMS as being superior to that of the CEO of Sanofi based on the information given here. Could the CEO of Sanofi have done a good job at BMS had he won that job over Lamberto? How well would Lamberto do if he were running the show over at Sanofi?

One thing for sure is that the 450 people at Sanofi will take with them some valuable knowledge on how drugs are manufactured. Where they will go with that knowledge is unclear. Having witnessed the talents of other European drug manufacturers and how they interacted with their under qualified biotech customers, I came away with a great respect for that side of the drug industry. Making drugs is complicated. American biotechnology companies, especially the smaller start-ups, do not have the expertise to even begin talking about manufacturing issues. The soon-to-be unemployed Sanofi workers do have that knowledge. Are there any young start-up biotech CEOs who know that they need the expertise that Sanofi is letting go?

As one man randomly succeeds 450 men and women randomly fail. The closing of the Sanofi plant had little to do with the ability of the workers to do their job. As stated it was due to generics and the economic downturn. Lamberto Andreotti may have done his job very well. I am assuming he has been rewarded for a random series of events over which he had little or no control. No one has yet to figure out the best way manage complex scientific medical research. Many have made the claims of a new way that will revolutionize the industry. Yet success in drug innovation remains random. The success of Lamberto Andreotti is not a sign that BMS has fixed the drug industry R&D management problem. We randomly stumble along.

A Box Labeled Success

At some point the notion developed among the Cargo Cult members that cargoes were being sent for them by their long dead ancestors but those cargoes were being intercepted by the Europeans. This idea was confirmed in the strongest possible way for one islander during World War II. His name was Bateri and he had learned to read and write some. One day he went into the office of military post and saw stacked up boxes labeled Batteries. Obviously those boxes were his!

The investors at BioNovo saw the box labeled "Success", they foolishly thought it was theirs. Instead it is another happy biotech ending. Not for the investor but for the people who spent their money.

March 12, 2012 Bionovo, Inc. today announced that it will need to obtain substantial additional funding to achieve its objectives of internally developing drugs. The Company reduced its workforce by over 90%. The remaining management of the Company will receive reduced cash compensation until either adequate financing can be obtained or the Company is sold. The Company can not make any assurances about either of these events. As previously announced, management and the board of directors are continuing to explore strategic options for the Company. Management is currently reviewing the status of the ongoing clinical trial for Menerba.

The Company does not currently have adequate internal liquidity to meet its cash needs. If sufficient additional funds are not received in the near term, the Company may not be able to execute its business plan and may need to further curtail or cease operations.

That is a shame.

Bionovo, Inc. is a pharmaceutical company focused on the discovery and development of safe and effective treatments for women's health and cancer; markets with significant unmet needs and billions in potential annual revenue. The Company applies its expertise in the biology of menopause and cancer to design new drugs derived from botanical sources which have novel mechanisms of action.

We could have used the safe and effective treatments to keep our mothers and grandmothers alive and the investors could have used some of the billions in potential annual revenue. So who are the ten percenters left at BioNovo? I think I know who one of them might be.

Bionovo, Inc., a pharmaceutical company focused on the discovery and development of safe and effective treatments for women's health and cancer, announced today that its President and Chief Medical Officer will be awarded as one of California's 14th Assembly District Women of the Year at an awards ceremony taking place on March 8, 2012. Dr. Tagliaferri is being honored for her notable accomplishments in empowering women within the biotechnology and medical fields as well as serving as a role model and leader to women within the district.

The newly unemployed women can thank her for the empowerment. Maybe she failed to deliver safe and effective treatments worth billions of dollars, but she is a success. BioNovo is not. But then the award did not go to BioNovo.

It is such an honor to be recognized by Assemblymember Skinner as well as those who have nominated me for this award," said Dr. Tagliaferri. "My close colleagues and I have devoted our careers and research efforts to discovering safe and effective drugs derived from botanical sources for the treatment of breast cancer and menopause. At Bionovo, we are aiming to provide the 40 million women transitioning through menopause with a safer alternative to hormone therapy with the advancement of Menerba, our late stage development drug for the treatment of menopausal symptoms.

Surely she knew at the time she made this statement that the Company did not currently have adequate internal liquidity to meet its cash needs. And that if sufficient additional funds are not received in the near term, the Company may not be able to execute its business plan and may need to further curtail or cease operations. There was a box in her office labeled, "Success". The investors and employees walking out the door needn't think that box is theirs anymore.

The Reinventors

The evolution of a fact is a human journey to scientifically understand our world. Individuals will fully grasp a fact before the general population. It is up individuals to articulate the fact. Gravity is a force that exists on our planet. It is accepted as a fact. Isaac Newton and others articulated what this force is, how it operates in our world and gave it a value, 9.81 m/s squared

Along the way to establishing the human understanding of gravity we had to deal with the facts that were wrong. The earth being flat, for example, was a misconception that hindered getting to the fact of gravity. The earth being the center of the universe hindered us from understanding gravity. What does the shape of the earth and its relationship to the rest of its solar system have to do with gravity? One person describes the shape of the earth. One person describes energy. The next guy points out the force that can be generated by spinning a top and so on. Through the evolution of ideas we come to closer to the big picture. The bigger the idea, the bigger the scientist.

What happens then when there is not enough evolution? What happens when you want to get to a fact such as gravity yet you insist on believing that the world is flat? You get Cargo Cult Airports. In general, you want something so bad you are willing to accept answers that are too simple. You build a non-functioning airport and hope someone else will come along and make it work. The obstacles standing in the way of our understanding of the truth are often the little things. Evolution is a slow process that involves the interactions of billions and billions of little things.

It is with this world view that I watch the same old business people re-inventing biotechnology. It is assumed that the reason we have failed is due to our business models. No one suspects the activities in the lab have anything to do with biotechnology success or failure. It is the business model. The Flat World Society of Biotechnology is re-inventing itself.

Reinventing a cargo cult airport is, of course, an act in futility. If we could go back and randomly look at a biotech company that failed, would we discover that the problem was the business model? What are the odds that the company failed after a drug trial indicated their drug was not efficacious? What seems to be happening with "The Reinventors" is that they are no longer extracting money from the investment community. That is why they are reinventing themselves. The Reinventors must find new ways of convincing the investment community that they can mitigate the fallout of a failed drug trial. They must find ways of assuring the investment community that the lack of cargo won't get in the way of profit. The business model will change.

It is a fact that biotechnology has been a failure for the investment community. There is no need to reinvent ourselves in 2012. That time has passed. Those who will be reinventing our industry are the same ones who invented the old ways. Spend, hold meetings, spend, fire the lab staff, hire newer weaker lab staff... We are now an industry of old fools and young sheep. We replaced the Allied Forces, who ran our airports and ensured the safe and efficient delivery of cargo, with the natives. The evolution of biotechnology has weeded out people who were not good enough to make it and people not foolish enough to keep trying. Along with good and bad people, we've weeded out investment capital. It's not clear what kind of reinvention is going to make a company succeed when their drugs do not. We still haven't figured out how to mitigate the utter neglect of the scientific method.