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Sunday, February 26, 2017

One of My Heroes

Gary Taubes has a new book out. I love what he does. Here is an early piece he wrote on one of my old bosses.

Prusiner's proposition has been controversial from the get-go. The researcher who did Prusiner's lab work at the University of California at San Francisco quit over the publication of Prusiner's very first prion paper in 1982, arguing that Prusiner was overinterpreting the available data to push the prion hypothesis.

After three years in Prusiners lab I came to same conclusions as Gary and the above researcher. Prusiner and his minions were hammering a square peg through the round hole of the prion narrative. Only information supporting their narrative was offered up to the public. It was during my time at this laboratory I first read Feynmans Cargo Cult Science speech and it hit me like a ton of bricks.

Quick story: To grow cells that express proteins, we sometimes use spinner flasks. The flasks hold media with growing cells. In the flask is a magnetic rod. The flasks sit on a spinner plate that spins the rod thus stirring the growing cell culture. One day the plate stopped spinning. I took it to the repair shop and had it fixed. When I brought it back the ladies using the plate complained that their cells were no longer growing as well. I suggested they adjust the speed at which the cells were spinning. My supervisor informed me that the plate was perfect before I put my hands on it. "Take it back and get it fixed right!" When I explained that the speed is adjustable and that it is up to us to set the proper speed, she doubled down. "Take it back!" I unplugged the plate and walked on down the hall with it. Down in the basement repair shop I told the guy what I was up against. He volunteered to explain the mechanics to the boss lady. I said no. I was defeated by then. I brought it back up, set the speed to where I knew it would work. I let her think we had fixed the problem in the repair shop. She has since been promoted to laboratory manager at Dr. Prusiners Institute for Neurodegenerative Diseases. 

Gary Taubes pointed out in his opening remarks at the Seattle Town Hall (see video below), he was obsessed at how hard it is to do science right. How do we do it right? How do we know if the science we have been given is right? Experimentation? Reproducible results? Is that how professional scientists operate? That has not been my experience.

Gary Taubes went on to the most important work of his life, correcting the bad science behind nutrition. We have been handed a load of crap from nutrition science in the western world. Our diet is the leading cause of our poor health. Our health care professionals and their prescriptions are not the solution.

People believe what they want to believe however. What sets Gary Taubes apart is that he has let his research guide him to his beliefs. You can disagree with his message but not his method. The research leads, the scientist follows.

Sunday, February 12, 2017

I Bought Amgen

I bought Amgen just before they won their lawsuit against Regeneron/Sanofi. I didn't know about the pending PCSK9 lawsuit though. I was betting on a comeback. They were down 10% from last year and they are winning the CGRP race (migraine headache medicine). That could be a big thing. So far it looks like I got lucky. I got in around 147 and today AMGN is around 167.

I had three close calls with working for Amgen. I had interviews and phone conversations. I was flown to Thousand Oaks. I interviewed in Seattle for what turned out to be an RNAi group. That was humorous because they didn't tell me that upfront. I went on a rant about how I wouldn't work with RNAi. I could see in their eyes that they were planning on using RNAi to achieve their goals. Long story short, I did not succeed at securing employment at Amgen. Had I done so there would be little chance I would still be there today. It would have been a bad investment of ones career. Amgen has more ex-employees than most biotech.

The way I see the world of work these days is in terms of value investment.  I would not want to work at Amgen nor any biotechnology company because they do not provide career value. The main reason is because they are in the biotechnology industry. I can go to my LinkedIn account and search through the ruined careers of many a smart charismatic scientist with fancy degrees, publications and patents. Where are they today? I don't know because when you lose your biotech career it is not wise to put your new job at Starbucks on your LinkedIn account. The value of those degrees, patents, publications, years building new skills, and associations with big players like Amgen, can all add up to a job at Starbucks.

Back to my stock portfolio.

My next pick was going to be General Electric. I want a solid dividend payer. In my research however I came across the fact that they are planning to add more women for the sake of diversity.

Today, GE announced its goal of having 20,000 women in STEM roles at the company by 2020, resulting in an impressive 50:50 gender balance in technical entry-level positions. Right now, GE has 14,700 women in engineering, manufacturing, IT, and product management positions. 
The value of a company that depends on science and engineering comes from the scientists and engineers. What makes for a good scientist or engineer? Apparently GE thinks that preference for those with vaginas will aid in their search. If they had a preference for those with penises I would also have a problem. You hire scientists and engineers based on their skill and knowledge.  A college degree from a good school is one indication that a person has what it takes. MIT, CalTech... Next I would seek value in candidates based on their work history. I would look for publications. I would speak with them about their work to find out how interested they are in what they do.

When it comes to a company like GE, the engineers matter. They, unlike biotech, make things that have to work. If my refrigerator conks out it's going back. Biotech on the other hand does not make products that work. They don't have to. See my post on Serepta. They only need to convince the FDA and the doctors that their statistics indicate some efficacy. I value Amgen, not for their science and technology prowess, but for how they will make investors feel.

The ruined careers of chemists, biochemists, biologists, molecular biologists are something that doesn't get media attention. The job losses that have occurred since the big recession of 2007 have not been given proper journalistic attention. Who lost their jobs/careers? Amgen, for example came to Seattle, started a huge campus, started a Masters Degree in Biotechnology at UW, embarked on a decade of research and then the left town. Expedia took over the campus. What did their ho hum hirelings go on to do? Do they have anything of value to share with the rest of us? Has their LinkedIn account stopped marking their progress?

I want to end this post with an example of finding value in things complicated versus complex. Mark Zuckerberg has done quite well with hiring strong scientists. Here is what he values in employees.



Then he gets a little full of himself and decides he can do anything. He is now going to cure all disease. Very noble but disease is not like a computer website. Zuckerberg may have spotted a place where computer science can add value to our lives. He may have found ways of making a ridiculous profit from that work. But now he is venturing into the world of the cargo cults. This stuff is not easy and the scientists are not as smart as the ones he currently employs. I won't be investing in this.

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.

Juno!

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.
and
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
and
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.
and
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.