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Sunday, January 24, 2016

C Glen Begley Demonstrates the Perils of a Biopharma Career

C Glen Begley, author of The Amgen Study, is out of work again.

After the company terminates the 19 employees it plans to, TetraLogic will be left with 10 employees, the Journal said. Among those terminated are G. Glenn Begley, the company’s chief scientific officer, and Lesley Russell, the company’s chief operating officer. Their termination will occur on April 19, the Journal reported.

When Begley and Ellis wrote their paper on the difficulties of using bad science as a foundation for ones research they were acknowledging that there was a problem. Not everything we read in the journals is true. Some say most of it is not true. If you work in the biopharma industry you know that job of yours is contingent upon the success of the molecule on which you are working. If it does not perform according to the narrative of the company, you might be tossed out the door along with the project. Even if your job is to simply clone, grow, purify, define biochemically the molecule, you will be packing up your belongings from your cubicle if the molecule does not succeed in the clinical trials.

TetraLogic had a plan. Birinapant was to be a treatment for high-risk patients with myelodysplastic syndromes. However, phase II trial results showed birinapant did not demonstrate any clinical benefit over placebo. The study has been terminated, and C Glen Begleys job has been terminated. So has 18 other individuals including the COO/CMO! Was that a part of their plan? Were the leaders upfront about the connection between everyones job and the outcome of the phase II trials of birinapant?

Of course the CSO and CO/MO are a part of the leadership. They make the decisions and serve as spokesmen/women for the narratives of the company. Scientifically they had to have reason to believe that birinipant would succeed but I doubt they were betting their jobs on it.

Birinapant is designed to mimic the activity of an endogenous protein, the Second Mitochondrial Activator of Caspases, or SMAC, which is involved in the regulation of the apoptotic process within cells. Avoidance of apoptosis is a critical step in cancer tumor development and certain infectious diseases. Birinapant reactivates one of the common apoptotic pathways, thus restoring the natural balance in our bodies. This is a completely novel approach to treating these diseases and may provide new treatment options for patients suffering from cancer or serious infectious disease. The company is reviewing its strategic alternatives in light of the birinapant clinical trial results announced on January 6, 2016.

To add a little more detail to the scientific knowledge of SMAC for us laymen:

Myelodysplastic syndromes are a group of cancers in which immature blood cells in the bone marrow do not mature or become healthy blood cells. In patients diagnosed with myelodysplastic syndrome, the “blood stem cells (immature cells) do not become mature red blood cells, white blood cells, or platelets in the bone marrow. These immature blood cells, called blasts, do not work the way they should and either die in the bone marrow or soon after they go into the blood. This leaves less room for healthy white blood cells, red blood cells, and platelets to form in the bone marrow. When there are fewer healthy blood cells, infection, anemia, or easy bleeding may occur,” according to a report on

So birinapant was suppose to fine tune apoptosis of blasts which would make proper room for healthy white/red blood cells and platelets to form in the bone marrow. That was the narrative. Once the fine tuning was accomplished by birinapant the disease state would no longer bedevil the patient. It worked as well as, but no better than a placebo.

The cynefin method of thinking would have helped the people who lost their jobs.

All biopharma research projects have a narrative that states molecule X will cure or treat disease Y. Biotechnology works. It operates in the known knowns area after the known unknowns are dealt with. Does birinapant properly mimic SMAC. That was a science/technology project that succeeded and that is the job of the scientific staff at TetraLogic. Then came the unknown unknown. Will birinapant go into the body, find its way to where SMAC was lacking and properly restore the function of the endogenous protein? When the narrative went from known unknown (SMAC is lacking and birinapant will fix the problem) to unknown unknown (will birinapant solve the problem?) and then to known unknown (birinipant will not fix the problem of SMAC deficiency) the project was deemed a failure and jobs were shed.

That is how it works. Even an honest man such as C Glen Begley is not immune to this dilemma. Everyone working in science must admit that they are not going to get it right every time. The most perilous place to be is on the scientific frontline when the results come in.

Sunday, January 03, 2016

Hillary Clinton Cures Alzheimers

Hillary Clinton has announced a nine year plan to cure Alzheimers. Not a bad idea. What about the plan of action? I want to examine her plan from the perspective of Design of experiment . You won't get the perfect method using the statistical method of design of experiment. You will get the best possible method within the time and materials set forth.

Experimental design involves not only the selection of suitable predictors and outcomes, but planning the delivery of the experiment under statistically optimal conditions given the constraints of available resources. -Wikipedia

According to the Alzheimer’s Association "nearly all we know about Alzheimer’s, we have learned within the last 15 years, due in large part to significant federal investments in research". $2 billion per year for the next nine years will finish what was started. Why that amount? The research advisory council to the congressionally backed National Plan to Address Alzheimer's Disease have said $2 billion a year could make a cure possible by 2025.

The bullet points of the plan:

1) Commit to preventing, effectively treating and making a cure possible for Alzheimer’s by 2025.
2) Dedicate a historic decade-long investment of $2 billion per year for Alzheimer’s research and related disorders.
3) Ensure a reliable stream of funding between now and 2025.
4) Establish a plan of action with NIH, leading researchers, and other stakeholders to see the 2025 goal through.

Who are the players in this plan? If we look into the details of the bullet points we get:

Top researchers have noted that this is achievable if we make the commitment, marshal the resources, and provide the needed leadership.

$2 billion annually, the level leading researchers have determined is needed to prevent and effectively treat Alzheimer’s and make a cure possible by 2025.

Clinton will appoint a top-flight team to oversee this initiative and consult regularly with researchers to ensure progress toward achieving the treatment target.

These top researchers providing leadership will guide the spending of $2 billion per year. Ultimately Hillary Clinton is the leader but her top flight team will oversee this initiative.

The 2014 National Plan to Address Alzheimers Disease omits "making a cure possible" by 2025. The goal they had set forth was only to prevent and effectively treat Alzheimers Disease by 2025. Hillary, being the master politician said I will get you the money but we will add the wording, "making a cure possible".

One can assume that a cure is already possible because the disease exists. The question is the probability of finding a cure. Does this plan increase the probability to the point of certainty by 2025? The wording here is very cargo cult. Will the cure by delivered from the belly of the big metal birds that come from the sky? Will the belly open up and spill out large boxes filled with syringes of medicine that stop the elderly from losing their minds? According to our leaders, nine years and $18 billion down the road... sure it's possible to get that cargo.

Something is missing. Feynman said:

This long history of learning how not to fool ourselves — of having utter scientific integrity — is, I’m sorry to say, something that we haven’t specifically included in any particular course that I know of. We just hope you’ve caught on by osmosis.

That same "something we haven't specifically included in any particular course" is also missing from Hillarys' plan. The most troubling aspect of the plan however involves the end of the Cargo Cult speach.

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.

You cannot have that freedom when you have to answer to Hillary and/or her "top flight team". When you have nine years to cure Alzheimers so Hillary can check that off of her legacy list, you will have to spend considerable energy maintaining your position in her organization. If you fail to convince the politicians of progress your funding will go to the golden child down the road.

To pinpoint that thing that is not specifically included in Caltech science courses let us turn to the classic "Betrayers of the Truth" by William Broad and Nicholas Wade.

Chapter 7, The Myth of Logic - Science is the distinctive enterprise of Western civilization in the twentieth century, and yet it is perhaps the least well understood. A major reason for this gap is that the philosophers of science, who have influenced the general conception of how science works, describe it as a purely logical process.

There is indeed a logical structure to the body of scientific knowledge, but the logic is often easier to see in retrospect, after the knowledge has been gathered. The way in which scientific knowledge is produced and disseminated is a wholly different matter. It is an activity in which nonrational elements such as creativity or personal ambition play conspicuous roles. Logical thought is of course a vital element in scientific discovery, maybe even more so than it is in poetry, art, or any other high exercise of intellect. But it is not the only element.

Certainly, Hillarys' plan has the ambition. But it also assumes that the research of the past 15 years has put us on a nine year path to curing Alzheimers. I can just hear the argument now, "We never said we would have a cure! We said we'd make a cure possible. That's different! In the year 2015 will we see the logic in retrospect the same as we see the logic in todays plan? What in the plan provides for learning how scientists and politicians can work together to cure disease? If Hillary and her top flight team can cure Alzheimer's then we need them to create the Design of Experiment method for all future scientist/politician teams. For they will not only have solved a problem that has plagued humanity since the dawn of time, they will have found a method of solving problems.

In closing I will conclude that this is bad for science. What is needed is experienced scientists. We need the kind of people who will not attract the likes of Hillary Clinton. We need the people who will shoot down the popular sexy ideas that make headlines but lead us astray. We need scientists who understand that we can only follow the path. We can't decide where it is leading based on what we want. We only have the method of following one truth to the next truth. False claims can take years to correct. If we want to cure any disease we must find ourselves where we are free to maintain our integrity. Where we don't feel forced by a need to maintain our position in the organization, or financial support. The nine years plan to cure Alzheimers does not understand what is needed to properly conduct science.