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Thursday, March 29, 2012

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?

Wednesday, March 28, 2012

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. 

Tuesday, March 27, 2012

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. 

Monday, March 26, 2012

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 philosophyad hoc means the addition of extraneous hypotheses to a theory to save it from being falsifiedAd 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. 

Saturday, March 24, 2012

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?

Thursday, March 15, 2012

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!

Wednesday, March 14, 2012

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.

Tuesday, March 13, 2012

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.