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Saturday, December 31, 2016

2016 PCRI Dr Eugene Kwon Provenge

Saturday, December 03, 2016

History of the Narrative

Respect for the truth!

The narrative, as defined by Wikipedia, is "any report of connected events, real or imaginary, presented in a sequence of written or spoken words, and/or still or moving images." Bullshit is defined as, "is mostly a slang profanity term meaning "nonsense", especially as a rebuke in response to communication or actions viewed as deceptive, misleading, disingenuous, unfair or false." Communicating ones scientific research is a narrative. It becomes BS when the communicators are deceptive, misleading and so on. 

OK. Serepta offered up a narrative to the FDA. The FDA told the rest of us that Sereptas narrative was not BS and approved the drug. Some disagreed. We covered that in the last post and time will let us know if the Serepta narrative is BS or not. In fact it seems that Janet Woodcocks approach was to approve the drug to find out. It's not the best way forward and here is why.


I've talked the fateful airplane trip that introduced Lawrence Corey of the Fred Hutchinson Cancer Research Center with David Fallace of the Alaska Permanent Fund. These two got Juno off the ground leaving the details to be filled in by the cargo cult scientists of Seattle. The unemployed tribesmen were gathered and put back into the watch towers with their coconut and stick antenna headsets. Once again they fired up the ceremonies of another biotech pharmaceutical company. The end result is death and destruction. 

It is a very interesting scientific development. Unlike the DNA manipulation that is the narrative of Sereptas Exondys 5, something very powerful is happening with Junos JCAR015. In July of this year the clinical trial known as ROCKET was put on hold after two patients died from a cerebral edema. The deaths were attributed to a protocol change (cargo cult alert!) that added fludarabine (chemotherapy) to the treatment. Juno convinced the FDA that fludarabine caused the deaths and the FDA let them continue on. The cold hard reality cut into that narrative. Since restarting the ROCKET trial 12 patients have been tested. two more patients have died of the same issue, cerebral edema. Take away the emotion of judging the FDA and Juno. What is happening? What would the mechanism of action be with CAR-T therapy directed at CD19 in patients with B Cell Acute Lymphoblastic Leukemia (B-ALL)?

In a Utopian world we would set a team of scientist on the case. What is happening. In the cargo cults we tend to focus on getting the endpoints (the cargo) we want. When we don't get them we try other avenues without understanding the basic science. We pursue the narrative even when BS has presented itself. Brian Orelli of Motley Fool pointed out, "Fortunately, Juno has other CAR-T cancer treatments, JCAR014 and JCAR017, in particular, which appear to be safer, and JCAR015 might still be useful in patients with other blood cancers, such as non-Hodgkin lymphoma. While this issue may be specific to JCAR015 and late-stage ALL, investors in Bellicum Pharmaceuticals, Kite Pharma, and Bluebird should keep in mind that CAR-T is largely uncharted territory that could result in other unanticipated issues with their treatments."

So we keep on keeping on and wait to see who else dies. The patients are in bad condition coming into the trials. This is a part of the bigger problem of treating end of life conditions as diseases we can cure. This is a narrative and it is BS. People being turned into patients for biopharma greed is what we are witnessing. If Juno, Bellicum, Kite and Bluebird can statistically demonstrate longer life (quality of life is not an issue) they can make money. So far Juno has demonstrated the opposite. 

Wednesday, September 21, 2016

Sereptas Cargo Plane Has Landed

“there were serious methodological concerns identified by FDA,” according to the documents.

To measure the drug’s effect on muscle function, the company performed a six-minute walk test on the trial’s participants. The FDA reports there was “no nominally significant difference” between patients taking either the higher dose of eteplirsen, the lower dose or the placebo. The agency also griped about the fact that the company chose to compare the performance of the patients on the six-minute walk test against “historical controls,” or DMD patients who were in different trials in the past. - Forbes

You can read all about the "serious methodological concerns" here.

The simple description of Sereptas plan to demonstrate the efficacy of their product:

1) expression of an altered messenger RNA in muscle (pharmacodynamic)
2) production of dystrophin protein in muscle (pharmacodynamic)
3) improvement or preservation of muscle function (clinical).

Throughout the approval process, critics have expressed concerns with the small population — 12 patients — involved in clinical trials for the rare disease, along with flaws in how the clinical study was designed. These factors make “judgment on science difficult,” Califf (the FDA commissioner) said.

No it doesn't. More data points lead to better understanding of the accuracy of what is being measured. It is simple precision and accuracy. You may leave college with a poor grasp of the math behind statistics but you get the concept. The more data points the clearer the picture gets. Poor precision leads to greater doubts about accuracy. You aren't making a "judgment on science" that is "difficult". You are doing math.

Here is an example of data on the production of dystrophin protein in muscle.

Western blots and immunofluorescence were used to quantitate dystrophin.

Table 2: Applicant’s Quantification of Dystrophin by Western Blot and Immunofluorescence Analyses

Patient Western Blot % of normal Immunofluorescence % positive fibers
A 2.05 18.5
B 1.15 19.1
C 0.38 33.5
D 1.62 24.0
E 0.52 21.5
F 0.98 12.8
G 0 7.1
H 2.47 20.7
I 0.96 28.2
J 0 1.4
L 0.14 4.5

A quick glance at Figure 1: Correlation between Two Methods Used to Quantify Dystrophin in Skeletal Muscle: Patients from Study 201/202 tells you all you need to know. As the FDA put it, "Of note, the correlation between the two independent methods used to quantify dystrophin in muscle samples was weak." They also stated, "As discussed above, we believe that immunofluorescence analysis (percent positive fibers) is not a reliable method to quantify dystrophin content." What other criticisms of Sereptas methodology did the FDA panel mention?

Regarding the first pharmacodynamic goal, to demonstrate expression of an altered mRNA in muscle the FDA states;
Because even a minimal PCR signal is interpreted as “positive,” this biomarker provides little support of efficacy for eteplirsen; it does provide evidence that eteplirsen causes at least some degree of exon 51 skipping, as intended.

Regarding the second pharmacodynamic goal, the demonstrate production of dystrophin protein in muscle the FDA states;
FDA conducted an inspection of the facility where the data reported in the publication were generated. Significant methodological concerns were identified, which cast serious doubt on the reliability of assessments from the first three biopsies.
Thus, the review team does not consider “percent dystrophin‐positive fibers” to be a meaningful way to estimate dystrophin content, and we believe the results reported by the applicant on this measure do not establish that a significant increase in dystrophin occurred in response to eteplirsen treatment
In any case, the level of dystrophin was 0.9% of normal after 3.5 years, such that, in absolute terms, the increase from baseline would be, at most, 0.9%, assuming a “worst case” for untreated patients, i.e., zero dystrophin.

Regarding the clinical goal, improvement or preservation of muscle function, the FDA stated;
Two patients in the 30 mg/kg group became unable to ambulate soon after the study start. The applicant then pooled the six remaining eteplirsen patients and compared them to the four placebo patients, an unplanned post hoc analysis. No nominally significant difference between eteplirsen and placebo was identified in that post hoc analysis.
The applicant conducted a number of additional post hoc analyses, comparing the 6 patients who received eteplirsen in the 24‐week double‐blind phase of Study 201 and could still ambulate at the end of Study 201 (and continued on open‐label eteplirsen in Study 202) to those originally treated with placebo in the double‐blind phase of Study 201, and later switched to open‐label eteplirsen.
The applicant conducted a post hoc comparison of the patients in Study 201/202 to data from the “Italian DMD Registry” and the “Leuven Neuromuscular Reference Center” registry.
The problems of externally‐controlled studies are well recognized.

Dr. Ronald Farkas, who led the FDAs clinical team in the neurology products division, suddenly departed the agency just before the approval of Exondys 51. The arguments for the governments approval of Exondys 51 not come in a highly detailed document such as the one Dr. Farkas and his team presented.
Both FDA camps had “exercised reasonable scientific judgment,” Califf found, adding that it’s “exceedingly rare” to overrule a decision by the director of the Center for Drug Evaluation and Research. Without any additional technical expertise of his own, Califf said, he deferred to CDER Director Dr. Janet Woodcock.
An appeal to the authority of someone elses knowledge!

The jury is still out. Serepta still has to put up or shut up. The FDA has just bought them some time and money. How much money? $300,000 per year. Good grief. With BS artists like these, who needs scientists anymore?

Sunday, September 11, 2016

Risk of Cheating Barometer

Cheating in all areas of life is something that will always exist. We frown upon cheating. We throw people in jail if they cheat others out of their hard earned money. It is in general a bad thing for someone to get something through trickery or fraud. The problem is that we all cheat to some degree. We try to pay as little taxes as possible. We beef up our resumes. We tell little white lies when the need arises. That is why we have skepticism. We need a homeland-security-esque risk of cheating threat level system.

If Hillary Clinton debates Donald Trump, the threat level for cheating should be high for both candidates. They will cheat by exaggerating their accomplishments and lying about their failures. If you like Hillary you might think that Trump is the only one cheating up there on the stage, and vice versa. If you are a fact checker for the debate you operate under a different belief. Your job is to check what they say and compare that to the facts. That is the most honest person in the mix.

If you are a scientist and your job is to create new drugs, you are operating at a high level risk of cheating. The FDA will serve as the fact checker. Your boss is a different story. Your boss is also under a high level risk of cheating. He or she may have a lot of pressure to get the latest antibody drug to show the kind of data the CEO can show the board at the next meeting. Does this mean you are going to cheat? No. But you might end up on a path that will lead to the termination of your project/job. What does an honest person do under these circumstances?

The last post I put on the blog was about race. Black vs white in America is a high risk of cheating topic. "Hands up don't shoot" was the mantra after the Mike Brown incident in Ferguson MO. It is highly probable that that was an inaccurate description of what took place. Facts not supporting the narrative include a discharged weapon prior to the final lethal shots and the strong armed robbery committed by Brown prior to the incident. At his funeral a friend stated the Mr. Brown was out spreading the word of God prior to his death. That narrative would indeed make everyone skeptical about the police departments conclusion that the officer who shot Mike Brown, Darren Wilson, was defending his life. Who needs to shoot and kill a person out spreading the word of God? The problem is that the facts of the gunshot and robbery have been verified. The preaching has not.

Race is a topic where our Risk of Cheating threat level will be high. Was Mike Brown feeling invincible the day he died or was he out saving souls? That information is not proof positive of anything. It is information that only supports a narrative.

Back to BS - biotech science.

Our narrative is simple. We apply basic research as avenues to treating and/or curing disease. Science is the most honest and pure way of thinking. We set aside our biases and stick only to the facts. Narratives involving our motivations (money, fame, altruism...) are not factors in our scientific method. Those who have chosen to question underlying threats to our honesty are not understanding how science works. That is the big picture narrative behind the benevolence of BS - biotech science. We make drugs to help people because we have dedicated our lives to serve our fellow humans. Just don't bring up the history of that narrative.

Quick example: My favorite cargo cult of Seattle WA, Juno. August 31, 2016: Juno CEO Hans Bishop nets $1.28M from 42,673 shares of his stock. Sept. 8, 2016: Juno stock surges on positive clinical trial data.

The stock dives after four deaths in a trial of 129 patients are reported. It goes from $40-something per share to $20-something. The stock creeps back up to around $30 per share. The CEO socks away a cool million in spite of the narrative pointing to a bright future. Threat level HIGH!

Beware investors! Bullshit level high. Store your capital far from the shores of biotech.

Sunday, May 22, 2016

Should Science Be More Boring?

Price is what you pay. Value is what you get. -Warren Buffet

Try not to become a man of success, but rather try to become a man of value. -Albert Einstein

One of my favorite watchdogs of science is Retraction Watch. They have taken a far better path than I to point out the fly in the ointment of scientific research. In our common way of thinking, scientists are the most honest people in the world. Their discoveries have led to all of our modern comforts, including life saving medicines. As a result the general public has come to think of scientists much the same as they used to think of religious figures. If a scientist publishes a paper on his/her work in a scientific journal it must be Gods honest truth. How else could the scientist have gone through such rigorous judgements to get their work accepted? Retraction Watch is not saying how or why. They simply shine a light on the things that scientists and publishers got wrong. And that is a good thing!

Many people choose to criticize the whole concept of pointing out negatives in a positive world such as scientific work. For example, in the recent Tweet "Science Should Be More Boring" the following responses were posted:

True but in today's marketplace it is not very practical. -Elizabeth Leary

Who's gonna pay the bills with boring articles? -Sheila Shakoor

Agree but that will mean fewer science stories. Unsurprising research is less newsworthy. -Simon McGrath

As much as I agree with publishing negative results, the marketing here stinks. Will Dichtel

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.

Aerodynamics, to most people, would be considered boring. The thing is, it is pretty damned important in the wealth of our system versus the wealth of the cargo cult system. The fact that civilized societies have useful things like airplanes is due to boring science. It is not boring however to the people who tend to obsess over understanding how things fly. The real question that follows from the above four comments is what is boring and what kind of non-reproducible science is preferable?

If you send an underling into the laboratory to conduct an experiment on the basic science on the Zeka virus, do you allow for that person to bring you results that they feel will best suit their career ambitions? Or do you expect them to present to you a completely transparent and clearly articulated accounting of what took place in the lab? At what point do we allow the above ideas (on practicality, bill paying, newsworthiness and the marketing of science) take precedence?

To link this concept to a real life biotech situation I must bring up the price of Seattle biotech investment and the value that has been returned. It was the marketing that raised the money to pay the price of funding the companies. It was the value created that led to the vast graveyard of failed companies.

If Sheila Shakoor came to me with an idea for a biotech start-up I would have to wonder, does she have good science as a foundation for her new company or has she been focused on paying the bills? If Simon McGrath has 300 publications on his resume should I be concerned about his focus on newsworthy research? As for Elizabeth and Will, I would ask them to stay in their side of the office and leave the science of the company up to the scientists.

The best comment from this tween was from Stephano Tonzani, "My prof of math methods for physicist once said "for researchers, science is boring 364 days of the year."

I do not find any of this boring. What makes science... science? Reproducibility is one way of truly assessing the value of published work. This idea is also one that meets great resistance among career minded scientists. But if you scroll through the latest postings from Retraction Watch you will find this article from Andrew Gelman.
Whatever the vast majority of retractions are, they’re a tiny fraction of the number of papers that are just wrong — by which I mean they present no good empirical evidence for their claims.
As someone who had to use these papers on a daily basis to conduct "newsworthy" research in the field of biopharma, I am far from bored when I read these words. For thirteen years I struggled with non-reproducible research and an inflexible chain of command that insisted the outcomes be true. In order to put wealth into our system we must change the attitude that subjective valuations on boring versus practical is what matters. Boring science can also be non-reproducible useless information. What matters is not the success of getting published. What matters is the value of the published paper.

Sunday, April 10, 2016

Born Sick, Commanded to Be Well

A cargo cult is an example of how any religion gets started. People see the complexity of the world and they can't accept not knowing how it works. They need answers. Faced with their ignorance they quickly seek anything that they can understand. Gods have always fit the bill. They created the world in which we live. Don't ask any more questions, just worship.

The actual cargo cults want to believe that someday they will have big metal birds delivering their food and medicine. Rather than focus on obtaining these things via the scientific method they take an easier route. To rectify the situation would be simple, at least in the beginning. Talk to the westerners and ask them how they built the airports. Learn that building your own airport is possible, but it is going to take hard work. They have to move from the simple belief system of religion to the complicated understandings of science and technology and progress at understanding the complexity of life on earth.

This clip of Bill Burr letting go of religion demonstrates a couple elements of the biotech cargo cult science. We often hear from the leaders that they cannot find the right people. The people they have to choose from are the ones the industry has educated and trained. They created us and now they want us to have a different skill set! Once again let me pick on Juno Therapeutics.

Hans Bishop, chief executive officer of Juno, said the state (Washington) needs to provide incentives to biotech companies in order to spur growth from existing companies and to attract small and mid-sized biotech companies to the region. Bishop said the state’s talent pool needs to be built up, which will happen through fostering innovation. He said Juno has had to attract more than half of its 300 employees from out of state.

Juno Therapeutics began when Lawrence Corey met David Fallace on a flight from Boston to Seattle. Fallace was in charge of special opportunities for the Alaska Permanent Fund. Ironic that a fund that wishes to be permanent would invest in biotech start-ups. Larry Corey was running the Fred Hutchinson Cancer Research Center. The two formed a partnership that got Juno off the ground.

Larry Corey. He once worked with Gertrude Elion, whom we at the CCS love and admire. At a presentation I attended in Colorado she ended with a slide that had a picture of the path she took in research. It went from chemistry to microbiology to biochemistry to medicine and so on. She was asked by a biochem professor how that path would have been altered if she had had the new technologies that we currently have. She said that it would not have mattered. The real work was done by thinking of the scientific problems and not the human constructs of technology. I'm paraphrasing but I believe her point was that research is a journey that takes you places. If you begin with technology and force it to take you to the land of milk and honey you will never get there. Larry Corey, on the other hand, took what Gertrude Elion had begun and headed off to the cargo cults. His career is in leadership, power, and money. In 1987 Corey directed the AIDS Clinical Trials Group, or ACTG, which conducted pivotal clinical trials confirming the use of the antiretroviral drug AZT to reduce maternal-fetal transmission of HIV and the usefulness of highly active antiretroviral therapy (HAART). Horrible research done without a heart and soul. He has authored 12 books and more than 690 scientific publications. Quantity over quality is a cargo cult career skill. Larry Corey has had one hell of a successful career in the cargo cults.

The "permanent fund" that invested in Juno no longer has Fallace and Corey to develop their idea. They have both moved on to other things. One has to wonder why anyone would leave such a promising narrative? Leadership in the cargo cults however requires one to keep moving. You don't want to be around when the followers look up to the skies to see once again that the planes will not be coming. The new leaders of Juno have already laid the foundation for failure. The state of Washington is somehow obstructing their ability to attract the right talent. "Washington state's talent pool needs to be built up, which will happen through fostering innovation." Has Corey innovated? The problems he set out to solve are now being left to people who must emerge from a talent pool that has not yet been built by our leaders. They need government money first!

The talent pool that currently exists in Seattle consists of ex-employees of the cargo cult companies that have come and gone. Resumes of people in Seattle life sciences include the companies that leave many an investor with a bad taste. Bad science is not sustainable nor is a talent pool that comes from such companies. The people naturally change their ideas on how to maintain employment. Like Lawrence Corey, they seek to distance themselves from the situation that makes science fun. That moment you go into the lab in the morning to see how your experiment turned out. The anticipation that your work is leading to bigger and better things. The confidence of mastering skills that once took so much of your time. The talent pool that innovates does not exist in Seattle. But unlike Bill Burr letting his religion go, it is the cargo cults that let their people go. The narrative lives on even though there is no talent to validate.

The problems facing life in the life sciences is daunting. Those who wish to have a career discovering new biotechnologies and helping mankind will soon run up against the need for survival. The likes of Lawrence Corey will be your competition. He, along with the other leaders of Seattle life sciences, have created a talent pool that is not good enough for their latest narratives. My advice to the young scientists is to stay away from biopharma, medical science and the gurus who start companies who seek massive profit. Develop technology, not drugs. Let go of the religion of western medicine. Biotechnology does not have to be synonymous with pharmaceuticals.

Sunday, March 27, 2016

The Money - Shkreli to Juno

Forbes had an article in their February issue called "Solving Pharma's Shkreli Problem". The subtitle, "The most hated entrepreneur in America did a public service in some ways: he revealed a fundamentally flawed system that threatens an entire industry".

My investors expect me to maximize profits. Not to minimize them or go half or 70% but to go 100% of the profit curve. -Martin Shkreli

This is a logical statement for any C level executive in Biopharma. They are not put in place to make wise scientific decisions. That is the task of lower ranking members of a biopharma company. C level execs are put in place to turn a profit for the investors. On one hand this works. Without profit or the promise or illusion of profit, no one has a job. Gone are the days where we had people like George W. Merck.

We try never to forget that medicine is for the people. It is not for the profits. The profits follow, and if we have remembered that, they have never failed to appear. The better we have remembered it, the larger they have been.
— George W(ilhelm) Merck

How prevalent are the Shkreli types in biopharma? We know that he did not operate in a vacuum. He had a board of directors. He had investors communicating with him daily. He also had counterparts at Valeant. As the Forbes article points out;

Shkreli had learned about price hikes by watching his elders. In 2007 a mechanical engineer and former defense chief executive named Don Baily took over Questor Pharmaceuticals and raised the price of a drug used to treat seizures in infants, Acthar Gel, from $50 to $28,000 a vial, and then marked it for diseases like multiple sclerosis where there was limited evidence it worked. Quester was sold to Dublin-based Mallinchrodt for $5.6 billion in 2014.

So we really ought to look into theories that don't work, and science that isn't science... Who told Forbes that Acthar Gel had limited evidence that it worked in treating multiple sclerosis? Where is the scientific publication that takes on the scientific claims both positive and negative against a drugs efficacy? It doesn't specifically exist. We have science journals. We have people who work as scientists and communicate much better than the average person. But they do not outrank the likes of Shkreli and Baily. They live perilous lives searching for a livelihood within organizations like Valiant and Mallinchrodt. They cannot rock the boat. Medicine is for the profits.

From Forbes:

In 2005 a banker named Steven Harr pointed out that the only barriers to sky-high prices for cancer drugs were pharma "companies" goodwill and tolerance for adverse publicity" but warned his clients that they risked subjecting the industry to increased regulation and quite possibly price controls. (Harr is now the chief financial officer of Seattle biotech Juno Therapeutics.)

Steven Harrs career is typical of biopharma executives. He was educated in science but quickly turned towards the money. His bio on the Juno website states that he joined Juno in April 2014. Previously he was Managing Director and Head of Biotechnology Investment Banking at Morgan Stanley from May 2010 until he joined Juno. Prior to his investment banking role at Morgan Stanley, Dr. Harr was Morgan Stanley’s lead biotech research analyst and Co-Head of Global Healthcare Research. Dr. Harr received a B.A. in Economics from College of the Holy Cross and an M.D. from The Johns Hopkins University School of Medicine. Dr. Harr was a resident in internal medicine at the University of California, San Francisco.

Johns Hopkins! UCSF!!! Banker?

The likes of Steven Harr could have been a force for good. He could have been one of those looking after our interests in medicine. Instead he is now a top level executive at the Dendreon spinoff Juno. Not as their CSO or CMO but their CFO! Ironically the mistakes of Dendron have proven that Steven Harr was wrong about drug pricing. Dendreon priced their dubiously efficacious product/service way too high and they ended up filing for bankruptcy. While Dendreon lacked the public arrogance of Martin Shkreli, they share his philosophy on drug pricing. They know that the investors want them to go after 100% of the potential profits. Having stumbled badly with Dendreon and the high price of Provenge, they are now ready to take another shot at making money off of their biotechnology.

Monday, February 08, 2016

Threnanos Seeks Bullshit Artist

Innovate and conceptually solve problems through the power of excellent storytelling.
Integrate narratives utilizing film, books, television, retail and emerging web entertainment.
Collaborate with the creative team on most projects.
Bachelor's Degree from a top tier university with solid journalistic/creative/marketing credentials.
3+ years of experience as junior copywriter/screenwriter in a creative environment advertising agency, studio, freelance writer, graphic design firm, etc. with experience working on narrative driven projects, both professionally and personally.
Strong knowledge of Microsoft word.
Demonstrate a high level of initiative and ability to function superbly in both individual and team environments.
Handle stressful situations and deadline pressures well.
Team-oriented and collaborative idea building skills are a must.
Bold experimentation in different styles of writing and communications are a must.

The book I am writing is tentatively titled, "The History of the Narrative". When I thought about the biggest difficulties facing real science and the cargo cult mentality within biopharma, it always came down to "the best story". As former Amgen scientist C. Glen Begley discovered:

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."

Such selective publication is just one reason the scientific literature is peppered with incorrect results. -Sharon Begley, Reuters

The narrative of the cargo cults of biopharma always seeks the best story. Contrast this with real science being restricted to only telling true stories. This job description from Theranos is either an example of the cargo cult "best story" problem or just a poorly worded ad for a marketing specialist.

The danger to the rest of us is the fact that Theranos is selling itself as a tool of the healthcare industry. The narrative they are putting forth can be found in their mission statement, "Our mission is to make actionable information accessible to everyone at the time it matters. By making actionable information accessible to everyone in the world at the time it matters most, we are working to facilitate the early detection and prevention of disease, and empower people everywhere to live their best possible lives." If there is any creativity from a top tier University B.Sc. found in the actionable information concerning the detection and prevention of disease, then we have a problem. Hopefully the writer would only be used to help spin the story about Theranos and their many scandals.

A very simple test on the Theranos product was shown here. Such a random sampling is so simple. In this piece Jean-Louis Gassée, a former director of engineering at Apple who is "compulsively curious" compared the Theranos narrative to reality. Using an alternative blood testing service Jean-Louis came up with some data. He contacted Theranos with his findings and received no response.

For a $9+ billion company that has the federal government on its board of directors, the hiring of an undergrad as a spin doctor seems crazy. Where in the massive dung heap of BS does the new guy enter? How many "creative storytellers" within Theranos have been brought in before him/her? What did their job description look like?

Tuesday, February 02, 2016

Harlan Krumholz On Data Sharing

It is easy to envision how a community of scholars should be organized. Every idea would be taken on its merits, and every person judged on the worth of his ideas. The need for a social hierarchy would be strictly limited. Each member of the community would enjoy status that was determined by merit and that owed nothing to social standing or any other personal attribute. Elite group[s might appear temporarily but would never outlast the original reason for their existence. -Betrayers of the Truth, Chapter 8, Power of thew Elite -William Broad and Nicholas Wade

In a world where social hierarchy is strictly limited, why would a scientist withhold data? To gain notoriety a scientist must get his/her work published. That means communicating with the rest of the community. Communication is the purvey of the bullshit artist. Scientists write up their papers according to the structure required. Somehow the required structure of the scientific paper has evolved to excise meaningful data. One possible explanation is that those who are now in charge were once up and coming researchers. They knew the perils of data sharing to their careers. Now, as leaders, they have opened up the path to more creative narratives. Science took the hit and careerists had way around the old fashioned rigors of science.

But there is one feature I notice that is generally missing in Cargo Cult Science. That is the idea that we all hope you have learned in studying science in school—we never explicitly say what this is, but just hope that you catch on by all the examples of scientific investigation. It is interesting, therefore, to bring it out now and speak of it explicitly. It’s a kind of scientific integrity, a principle of scientific thought that corresponds to a kind of utter honesty—a kind of leaning over backwards. For example, if you’re doing an experiment, you should report everything that you think might make it invalid—not only what you think is right about it: other causes that could possibly explain your results; and things you thought of that you’ve eliminated by some other experiment, and how they worked—to make sure the other fellow can tell they have been eliminated.

Scientific integrity, the layman might assume, means operating in the ideal world described above. The world where ideas are judged on their merits and not by the pedigree of the originator. Scientific integrity, the layman might assume, means that the leaders of the scientific community require their underlings to report everything, good and bad. Yet the scientific paper has evolved to the point where the actual data that supports the conclusions is top secret. And the rest of us do not have the proper clearance.

AllTrials is an organization that sees the problem and seeks to do something about it. AllTrials has targeted the pharmaceutical industry and their clinical trial data. Another scientist pursuing data transparency is Harlan Krumholz. Please read his article and listen to the NPR interview.

Data sharing is knowledge sharing. It is the same concept of forming a university where we share knowledge with intelligent young people in hopes that they will further the knowledge. Dr. Krumholz says
Among the first things we learn in school are to share and to show our work. This lesson has been lost on medicine for many years. The medical editors are reminding us that we scientists have a principal responsibility to society and to those who agreed to participate in our studies.

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.