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Saturday, February 23, 2013

From a Molecule to A Cure

Just to be fair, I want to talk about someone who worked on single target - single drug treatments. This person did her work in a manner that had some "wealth in the system". This was not my experience but I can appreciate that it can be done. I went to a speech given by Gertrude Belle Elion a few years before she died. She won the Nobel Prize in Medicine in 1988. Of all the seminars I attended, this one has stuck with me. At the end of her talk she was asked by one of our professors if she would have benefitted from the modern tools of biotechnology. I can't remember her exact response but her answer was NO! She made it clear that research was something that requires the human mind, not just applying a few technologies. She showed a map of discovery. It went from chemistry to microbiology to biochemistry with stops through physics and math. The process she described was similar to Feynmans view of science. The stuff our professors hoped we had picked up during our education under their watch.

12 December 2008 , published , doi: 10.1098/rsbm.2007.0051 54 2008 Biogr. Mems Fell. R. Soc. 

After receiving her bachelor’s degree in chemistry from 
Hunter College in 1937, Trudy realized that neither she nor her family had enough money for 
her to attend graduate school. She began to look for a job, and immediately ran into the prover- 
bial brick wall. ‘Nobody … took me seriously. They wondered why in the world I wanted to 
be a chemist when no women were doing that. The world was not waiting for me.’ Secretarial 
school followed, and then teaching at a hospital and a high school. She finally landed a posi- 
tion, albeit nonpaying, with a chemist, just to keep busy in her field; during this period she 
decided to pursue her master-of-science degree, which she received in 1941 from New York 
University. During her graduate studies, she started teaching high school chemistry and physics 
as a ‘permanent substitute’ for $7.50 a day. 
Her big break came when the United States entered World War II. Since there were few men 
around, women came to be seen as potential employees, and Trudy was hired as an analytical 
chemist; her job included the measurement of the acidity of pickles and the colour of mayon- 
naise. After a while she tired of those functions and a spell of testing the tensile strength of 
sutures, and sought more meaningful work. The most interesting opening was at Burroughs 
Wellcome, where biochemist George Hitchings (ForMemRS 1974) was trying to make antago- 
nists to nucleic acid derivatives. Hitchings, who would later become a member of the National 
Academy of Sciences, ‘talked about purines and pyrimidines, which I must confess I’d never 
even heard of up to that point, and it was really to attack a whole variety of diseases by interfer- 
ing with DNA synthesis. This sounded very exciting.’ She accepted the position of biochemist 
in 1944 and spent the next 39 years at Burroughs Wellcome, becoming head of the Department 
of Experimental Therapy in 1967. 
Let Trudy explain how she started out making compounds and ended up eventually with the 
first effective drug that induced remission in childhood leukaemia. 
At the beginning … it was my job to find out how to make (compounds). So I’d go to the library, 
look up the old literature to see if I could figure out how to do it. … I would just go ahead and 
make the compounds, and then the question was, well what do we do with these compounds? 
How do we find out if they really do anything?

She attracted many associates who became known as 
a research dream team, some of whom invented azidothymidine (AZT), a mainstay drug for 
treatment of HIV (human immunodeficiency virus) infection. 

Trudy was awarded the Nobel Prize in physiology or medicine in 1988 for her discovery 
of important principles for drug treatment. 

What were those principles for drug treatment? Gertrude and George Hitchens demonstrated differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria and virus. On the basis of these differences they developed drugs that blocked nucleic acid synthesis in cancer cells and noxious organisms without damaging the normal human cells.

How does the biotech/pharma industry hire people? How do they use the new buzz word search technology to sort through resumes and end up with someone like Gertrude? Someone who can use the literature to make the molecules AND "find out if they really do anything?"

The executives may be concerned about whether or not they can find these people in the future. Gertrude came from the secretarial pool. She was a substitute high school teacher. Would Gertrude Elion have succeeded, sans PhD as she was, at Pfizer or Merck? What did she have that so many are missing today? What did she and George Hitchens do that the drug developers are not doing today? With all of our modern technology we are missing something. 

Friday, February 22, 2013

Implications of Missing The Complex

The paradigm of the single causative agent - single receptor antagonist, is one possible reality in the quest for new drugs. If so, this is a complicated system. The journey from complicated to complex:
  • Complicated, in which the relationship between cause and effect requires analysis or some other form of investigation and/or the application of expert knowledge.
  • Complex, in which the relationship between cause and effect can only be perceived in retrospect, but not in advance.
In a clinical trial, we are studying the relationship between cause and effect in retrospect. However, we have blurred the lines between complicated and complex. We begin pharma research by creating a cause, linking protein X to disease state Y. We have reduced our research to a complicated project. We hire experts to conduct the analysis that validates our cause and effect assumption. Our scientists know that their career aspirations lie on providing evidence that the drug intervenes on the cause and alters the effect, the disease. 

Look at health in a different way. Look at it in a complex way. In many disease states, it has been shown that diet and exercise works much better than the pharmaceutical interventions. In the documentary "Forks Over Knives" several very sick people were restored to health. The intervention was not simply that protein X causes disease Y. Some combination of the wrong food at the wrong quantities was causing a disease state. Changing diet and exercise habits brought about real change. But what was the cause, on the molecular level? A single target protein that was attacked by a barrage of vegetables? 

Let's replace the Forks Over Knives success stories with the curse of baldness. Have we ever changed a diet and exercise routine to reverse baldness? If we had, men all over the world would make the change. They do it to sculpt their bodies. Why wouldn't they take the advice seriously to stop losing their hair? What is it then that prevents people and scientists from learning more about the complexity of the human body and the relationship to diet and exercise? Is is because it is too hard, too complex? The madness of Resveratrol comes to mind. Someone noticed that the French had longer life spans than the rest of Europe. They focused in on red wine. They wanted to find one single molecule that they could make into a pill. A few years later Resveratrol. N-Rays in a capsule. Once again, a single agent that provides a key to long life. But it didn't work. 

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

Sunday, February 17, 2013

Covx, The Cult of Barbas

The last posts title was, 150,000 Jobs Lost Since 2009. Add another 100 or so losses from the ranks of Pfizer. Covx is going away. Started in 2002, Covx used phage display to make peptide-antibodies. Improving on natures invention of the antibody, Covx selected peptides that bound to target proteins (like an antibody) then they attached the peptides to a stealth antibody. The antibody protein is there only to stabilize the peptide and increase its bioavailability.

No one will talk about the demise of Covx like the Cargo Cult Scientist. The question we have is, and always has been, regarding the sustainability of the single target - single drug paradigm. We humans have thrown billions and billions into the paradigm and we haven't come up with much. Humans can still get rich in our current health/sick care system investing in this drug development approach. But are we really making any progress in treating disease? Do we understand how one protein can make us sick? How does one protein spin out of control, unregulated by the controls built into our DNA over billions of years, then suddenly become properly regulated by a single molecule that humans design in a few years tested at a few dosages? It seems highly unlikely that this actually works.

The CCS once worked with the laboratory that spun out Covx. Their phage displayed antibodies were sent to us in vials of various consistencies of goop. Our job was to take the goop and run western blots to verify binding to our target. Down in San Diego that merely had their technicians select candidate based on an arbitrarily selected ELISA signal. Anything above X was sent up to us at UCSF. Every single ding blasted frigg'n candidate was selected due to high background. We learned that they were panning their phage against completely denatured proteins. No structure! The day they started using non-denatured proteins to pan against was the day they started getting actual target binding antibodies. Those of us running the western blots were put through a humiliating few months of heavy criticism on our western blot skills.

Covx however was no different than most. They begin with the single target - single drug molecule paradigm. They have a technology to obtain the single drug molecule. A technology is a practical application of a science. That technology was not theirs originally. Phage display was developed by Dr.
George P. Smith at the University of Missouri. The folks at Scripps got ahold of a sexy new technology and ran with it. They made the Herculean leap from phage display technology to medical science. My personal knowledge that comes from experience indicated to me that they were lacking wealth in their technology system. How might they fare in the upper realms of science?

How can a group like this go on to form a multi-million dollar partnership? Some say the founder was awarded a couple hundred million dollars from Pfizer. Well of course the founder and a few at the top were the winners. The laboratory people are the ones who are suppose to  add those pesky details like having an actual test for target interactions. The leaders offer up the sexy narrative that attracts the investments. In our case, we were attracted to them by the narrative of getting antibodies quickly and for less money. In the end, we received ordinary antibodies that anyone with phage display skills could have provided. Ordinary...

Was Covx an ordinary phage display group that had an influential leader, Carlos Barbas, who excelled at the narrative? According to Pfizer, upon the acquisition of Covx:

CovXs biotherapeutic platform is a technology that links therapeutic peptides to an antibodyscaffold. The peptide targets the disease while the antibody scaffold allows the peptide to remain in the body long enough to achieve therapeutic benefit. The technology thereby allows half-life extension and bioavailability to support optimal dosing regimens for peptide therapeutics.
As validation of this technology, CovX has generated three early- stage compounds, one diabetes and two oncology compounds, that are expected to further strengthen Pfizers biologic pipeline portfolio.
Is it fair to say then, that "as validation" that this technology is just phage display, smoke and mirrors, Pfizer is sacking the entire staff of Covx? 
"We are pleased to transition the CovX technology to Pfizer's Biotherapeutic and Bioinnovation group and are confident they have the vision and resources to scale the platform and realize the opportunity to make efficacious drugs which will make a difference in peoples' lives," stated Shehan Dissanayake, Chairman of CovX and CEO of Tavistock Life Sciences.
I talked about a former gambler who decided it would be best to sell his picks rather than bet on them. For a fee he would let the gambler in on who he thought would be covering the spread that day. In a sense this is what Jeff Kindler and Corey Goodman did back in 2007 when they acquired Covx:
The acquisition of CovX is a further step in Pfizers strategy to acquire and identify new product candidates that we can put into development, leveraging both Pfizers expertise and that of world-class scientists charged with discovering and bringing in new compounds, said Jeffrey Kindler, chairman and chief executive officer of Pfizer. With this deal, we are building on our recent announcement of a new Biotherapeutic and Bioinnovation Center based in California and led by Dr. Corey Goodman. We are looking for the best science wherever we can find it, with a special focus in our priority areas, such as biotherapeutics.
 The ceremonial beginnings of Cargo Cult projects are always followed up by the rather unceremonious  announcement of their demise. It is sad to see so many people out of work. But we have to wonder if they were actually doing work, or were they focusing on the narrative offered by their leadership.

My friends you are getting tired of hearing it from me, but the cargo didn't come. Covx did not fail because the guys with the white lab coats were no good at phage display. They failed because the narrative was cargo cult. Phage display is real. We can select peptides that bind to targets. We can't make the binding lead to the outcomes described in the narratives.

Farewell Covx. Good luck to those who invested years of their professional lives on the Covx promise.

Saturday, February 09, 2013

150,000 Jobs Lost Since 2009

According to PricewaterhouseCoopers, 51% of pharmaceutical execs are of the opinion that it's getting harder to find good help. As reported by Pharmalot:
...a slight majority of drugmakers complain that it has become increasingly difficult to find the right talent and most worry they will not have access to the people they need to hire.
If this abstract group of humans, the pharma executives, has such a good idea of who the right people are, why did they hire all of the wrong people in the last couple of decades?

Since we think that the Cargo Cult mentality is the hidden story behind this industry, we find the question of finding talent interesting for other reasons. The question we ponder is about the actual research conducted by PricewaterhouseCooper and the innumeracy that goes into considering the validity of their work.

Driving home this evening I heard an ad from a Las Vegas odds maker. If you want to gamble and win, you give him some money and he will let you in on a few sure bets. Of course, if you take his advice and lose, the money you bet plus the money you paid the expert is all gone. No refunds. Knowing the odds is what gambling is all about. Once you figure out how tough it is to make a living gambling you might just want to turn to a safer bet. Rather than laying down your own money on the Superbowl, have people give you money for your pick. Genius! Don't be the gambler.

That is what we have here with the PricewaterhouseCooper research team. They serve as the expert selling the unknown knowledge hidden to the common man. The bias we may all have, that massive layoffs lead to talent shortages is not even being quantitated. The experts in judging an industry merely asked the experts who run the industry for their opinion. Even if difficulty is encountered when hiring the talent, it could just be that the experts are not good at identifying talent. Simply because the executives feel uncomfortable is no indication that talent does not exist?  It's just a feeling, like our gambling friends feelings about the Lakers chances over the Bulls next week.

What was lost in the course of laying off 150,000 people since 2009. Only the executives know. They are like the seller of gambling secrets. They know something you don't. At least, that is what they are selling.

Did you know that the word gullible can't be found in the dictionary?

What are the odds that the pharma experts in this research know what they are doing? They have yet to come up with anything as powerful as a proper diet and daily exercise. They attack single targets with the usual suspects; small molecules, antibodies, RNAi... and they want us to believe that clinical data is solid. Just don't ask for the raw data. The industry has been propped up by the occasional useful product. Antibiotics, Insulin, the Polio vaccine are the kinds of breakthroughs we wish for. Drug products like Provenge are what we seem to get. It appears that the talent they seek is in finding people who are best at hammering square pegs through round holes. The status quo has a track record of not being able to predict the breakthroughs. Without predictable success in our pipelines, we select for corporate types who succeed where more honest types accept defeat. As a result, chances are we'll lose more jobs. Some of the jobs may just be currently held by someone who offered up their expert opinions to PWC.
51 percent of life science execs – which is the highest of 19 sectors examined – say that hiring is getting tough and only 28 percent are confident about finding the right candidates. This comes as roughly 60 percent of pharma execs plan to invest more heavily over the next three years to create a more skilled workforce and 72 percent intend to boost their R&D capacity over the next 12 months, PwC Health Research Institute reports.
The ex-gambler who now sells his knowledge is an expert. He knows the odds and the futility of placing the bets. He makes the picks, sells them, and lets the gamblers lose. Perhaps the biotech/pharma industry, after sacking 150,000 people, has become concentrated with similar experts. They know where the risks lie in a career path in the industry. In spite of all of the losses, they are still there selling their knowledge. Quantitating that knowledge is most likely not going to provide any insight on the future in the drug industry.

Saturday, February 02, 2013

A Great Rant

I tend to enjoy what some refer to as "rants". I think this spirited dialogue posted on the "In the Pipeline" blog yesterday was most enjoyable.
I’m leaving bioinformatics to go work at a software company with more technically ept people and for a lot more money. This seems like an opportune time to set forth my accumulated wisdom and thoughts on bioinformatics.
My attitude towards the subject after all my work in it can probably be best summarized thus: “Fuck you, bioinformatics. Eat shit and die.”
 One commenter had this to say:

When someone finds fault with the way a field conducts itself, I would implore them to constructively influence that field. You might be surprised how many are actually sympathetic to your concerns. 
I'm not dismissing this author's concerns: to do that would really require knowing the molecular biology field (which is more than sequencing, it turns out). I do neuroscience right now, and programming can be a problem for some. But a constructive suggestion to change can have much more impact than a long rant.

This "long rant" was chock full of interesting ideas. The human genome project was not a science project, for example. Good science require an understanding of the limitations of ones tools. That is good stuff. This was a rant, devoid of mitigated speech. Notice how quickly the lack of mitigated speech became the topic of discussion for the commenter. He did not dismiss the author's concerns, nor did he have anything constructive to say about those concerns. What was at issue for the commenter was the rant.

Here at the CCS we feel that the rant was fun. It was real, written with obvious passion, and spot on. We too spent a short period of time at a bioinformatics company called Protein Pathways. Garbage in, garbage out. Our competitor, Rosetta, beat us to a buy-out from Merck. Neither Rosetta nor Protein Pathways are in business today. The cargo never came.

If you were an investor, you could easily discard such rants, my entire blog included. To some, we are not offering constructive criticisms. But read with a critical eye, vitriol in italics, big picture idea underlined.
All the molecular biologists, devoid of skills beyond those of a laboratory technician, cried out for the mathematicians and programmers to magically extract science from their mountain of shitty results.
The big picture idea here is straight out of the Cargo Cult Science speech from Feynman:

Now it behooves me, of course, to tell you what they're missing. But it would be just about as difficult to explain to the South Sea Islanders how they have to arrange things so that they get some wealth in their system.

"extract science from their mountain of shitty results"

"get some wealth in their system"

This is what it is all about. This blog and the numerous rants all focus on this area. Sure we are angry. We want to explain, using our education and experience at your Cargo Cults, what you are missing. We want to point out why there is no wealth in your system, nor your investors bank accounts. But it is as difficult as explaining to the South Sea Islanders how to arrange things.

Good job Fred Ross. You are an official ex-tribesman of the Cargo Cults of Biotechnology.