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.

Truth in Advertising

When you are in the business of selling Widgets, you have a physical product. If they are broken you have to replace them. If the Widgets don't operate as advertised you may have a hard time making money. It behooves you to have a high quality Widget.

In Biotech you are often times selling intellectual property or the promises/claims contained in a patent. I have an example of false promises being sold to RBC Capital Market participants today. Is it a crime to tell people you can select drug candidates quickly and manufacture them in an economically superior manner when in fact neither claim is true? There are claims made on a press release that one particular biotech can have a drug candidate in 5 months which can be ready to manufacture easily scaling from 1 to 50,000 liters. Since this is in the press release, and this is being presented to investors, is this legal if the claims are false? Are biotech companies protected by due diligence laws?

I'm quite certain the claims on the website and the press release are not true. With no real money, the company quickly selected a drug candidate. Luck was on their side and the drug candidate turned out to generate promising data. They received series A financing, hired a CMO to make the drug and they obtained early clinical data that led to a partnership that put the company on stable ground. After the partnership was solidified the big pharma partner soon found out that the small biotech company did not actually have any usable drug.

The data obtained from the small biotechs only drug candidate came from third world clinical trials where the manufacturing details were not closely scrutinized. The small bioech did not have the expertise to make the drug, thus they had to rely on their CMO for process development. They forced their CMO to move fast, with no consideration of future manufacturing processes at a larger scale. The scale listed on their website is 50,000 liters. As a result of the hasty leadership decisions, they were ensuring that the scale up would be disastrous. Ultimately they scaled DOWN from 2,000 liters to 1,000 liters, 49,000 liters short of the scalability claim on the website. If the 50,000 liter scale is ever acheived it will be due to the expertise of the CMO. No one at the small biotech has ever worked in manufacturing.

The claims made at RBC today, by the small biotech, are false. I have not mentioned the other claim that the drug discovery process only takes five months. Also false. The small biotech spent 5 years in between the first and the second drug candidate. The second candidate was mentioned a few years ago without any partnerships lining up. There is in fact, no screening strategy other than the usual methods using ELISAs and FACS analysis looking for drug and target binding.

Why would anyone question the sincerity of the small biotech CEO? If an investor gets excited by the promises and decides to invest, it will be up to them to do their due diligence. The term "due diligence" first came into common use as a result of the United States' Securities Act of 1933. This Act included a defense, referred to as the "Due Diligence" defense, which could be used by broker-dealers when accused of inadequate disclosure to investors of material information with respect to the purchase of securities.

During the partnership between biotech and big pharma, due diligence reviews are undertaken to identify and assess the business risks. In this case, the big pharma company did not do a good job during their due diligence audits of the manufacturing processes. The long delay in providing material for clinical trials was costly, but entirely the fault of the big pharma company. The investors listening to the small biotech CEO today don't know any of this. They are watching people talk. As all investors consider themselves savvy, they are starting the due diligence process as they are listening.

The business model of biotech thus does not require honesty. It requires due diligence on behalf of those we can get to listen to us. The same must go for those looking for that place Feynman speaks of.

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.

I can neither confirm nor deny any affiliation with the small biotech I speak of here today. They are a Cargo Cult, experienced at promising cargo, with no expertise on how cargo gets delivered.

Simple, Complicated, Complex and Chaotic

How does this apply to scientific research?

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

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

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

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

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

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

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

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

Business Models Vs Science Models

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

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



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

Our New Business Models

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

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

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

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

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

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

The EPO rich plasma reversed the anemia in Dolly.

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

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

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

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

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

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

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

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

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

Marina Biotech, RNAi's 2nd Hit of 2012

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

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

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

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

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

M. French, April Fools Day, 2010

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

M. French, Valentines Day 2012

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

Formatechs Yard Sale

According to the Formatech website:

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

According to a few former employees:

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

It is a sweat shop. Horrible working conditions

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

According to the FDA warning letter:

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

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

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

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

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

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

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

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

Anil Potti

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

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

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

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

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

Science and medicine?

A Curious Deception

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

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

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

Machiavellian Leadership

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

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

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

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

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

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

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

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

The Squeaky Floor In the Rat Maze

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

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

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

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

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

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

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

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