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Sunday, January 18, 2015

Anil Potti vs Bradford Perez

"One day everything will be well, that is our hope. Everything's fine today, that is our illusion" - Voltaire

The Anil Potti saga is not just an isolated case of scientific misconduct. It is a case that follows the known patterns of cargo cult science. The latest news from the Duke University Potti scandal adds a few more details.

Let's first review the patterns of cargo cult science.

Step one: A narrative capable of being published is formulated by a person with above average ambition.

Step two: A skeleton outline of experimental design is set on stone by the ambitious author of the narrative. The design must protect the narrative. Assign a subservient laboratory work force to conduct the experiments.

Step three: The misconduct occurs in the analysis of the data. The author of the narrative aligns the data to the narrative. Any egregious deviations are dealt with by "correcting" the work of the subservient laboratory staff.

Step four: The narrative is written up and submitted to the journals.

In the Anil Potti case:

Step One: Anil Potti, a Principal Investigator at a prominent University, formulates a narrative, popular among the cargo cults. Genetic markers can be identified to help western medical professionals treat disease. Everyone loves a winner, and Anil Potti knew how to convince others that he was a winner. Anil Potti was not the only person with above average ambition. His superiors and most of the people around him supported what he was doing because his narrative was so attractive.

Step Two: Bradford Perez, a third year med student, is assigned to carry out the work that supported Anil Pottis' narrative. He came to the realization that the methods being used to assign patients to clinical trials were not validated. I.E. the methods were more narrative than scientific method. Yet Bradford Perez was in no position to influence the direction of Anil Pottis research/career. As Arthur Caplan, director of the Division of Medical Ethics at the NYU Langone Med Center who is reviewing this case, said, "I have a feeling his lowly status made him someone that they would be able to hope would just go away. There was a little bit of don't-let-the-door-hit-you-on-the-way-out."

Step Three: Perez made several attempts to discuss the methodological issues with Potti. Things do not go well for Perez. He has to make a decision; speak truth to power or join the power in the continuation of the Potti narrative. Validation techniques from the Potti narrative amounted to, "erasing the samples that don't fit the cross validation from the figure and then reporting the cross validation as meaningful and justification for a good predictor".

Step Four: Rather than publishing another paper supporting the Potti narrative, Bradford Perez decides to pursue the courageous path. He writes a 3 page single spaced summary of his concerns with Pottis lab. "I have nothing to gain and much to lose", stated Perez in his letter to the University. He gave up the opportunity to be included as an author on at least 4 manuscripts, a Merit Award for poster proetnation at the ASCO meeting, and a year of med school. He had to put in another year to replace the dishonest research with something in which he could take pride.

The politics of this case are worth studying. Not on a simple blog but at the level of real leadership. As we can see from this case however, the leadership is a large part of the problem. Anil Potti is indeed a Cargo Cult Hall of Famer, but what about everyone else around him? Below and above, many people were spending their scientific careers standing next to the steaming pile of cargo cult science that Anil Potti was putting forth. Why was Bradford Perez the only insider speaking out? Why did his words go unheard by so many for so long?

The rest of us must operate, as Bradford Perez did, against this powerful non-scientific political force. The Cargo Cults are not simple fiefdoms rang by rogue PIs. Rather the Anil Potti story is one of bullying by a powerful person who has no reverence for the scientific method. Political prowess continues to butt heads with the truth. The truth will always win in the long run. But how long is that run and who do we encounter along the way?

Wednesday, December 17, 2014

How Can You Not?

This is a clear case of a Cargo Cult leadership. Quality control/assurance is not possible at the NIH? The elephant in the room is how so many researchers get the results they seek regardless of what cell lines the use.

Why I Write

Monday, September 01, 2014

Optimism Is Essential For Our Success?

“I have always believed that scientific research is another domain where a form of optimism is essential to success: I have yet to meet a successful scientist who lacks the ability to exaggerate the importance of what he or she is doing, and I believe that someone who lacks a delusional sense of significance will wilt in the face of repeated experiences of multiple small failures and rare successes, the fate of most researchers.” ― Daniel Kahneman, Thinking, Fast and Slow
This is probably the most profound quote from 'Thinking Fast and Slow', pertaining to the CCS. However much I disagree with the concept of optimism, a human emotion, being essential for success in science, the statement is true. The fate of most researchers is to wilt in the face of repeated experiences of multiple small failures and rare successes. We get beat down from our inability to impress with our research. Just ask the 660 Amgen employees in the Seattle area who are facing an unknown future. Our version of the scientific method does not seem to work as well as other scientists. In order to succeed in a science career, we have to appear optimistic. I, the CCS, am not an optimist. I believe in the power of the negative. If I put my hand on a red hot skillet, I accept the negative burst of pain that prompts me to relocate my hand to prevent permanent damage. Negative outcomes are merely perceptions of the viewer. Any outcome is a clue for the researcher. You can choose to accept what you see or you can try again hoping for a different outcome. Success occurs when you accurately explain an outcome.
That is the idea that we all hope you have learned in studying science in school--we never say explicitly 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.
The person who can do this and not suffer the consequences of seeming less than optimistic is having a successful science career. The scientist who feels pressure to exaggerate the importance of their work is not as successful as they let on. Lysenko, for example, was a highly successful scientist, if ones rank in the hierarchy in which you serve is the criteria for success. Dipak Das and Diederik Stapel are examples of college professors who have a history of successfully getting their work published. Yet history has to paint a picture of unsuccessful scientists. Their work is not useful. So what is success? Does it require optimism? Certainly Lysenko, Das, and Stapel knew well the politics of a success career. If they could have been better researchers, they would have used the truths they uncovered to accomplish the same success they achieved through deception. Any BS'er will tell you, the truth is a better weapon than a falsehood. The truth does not have to be guarded and kept behind the curtain of Oz. Any time an exaggeration is used, the scientist must be careful not to cross that line Das and Stapel crossed.
“A reliable way of making people believe in falsehoods is frequent repetition, because familiarity is not easily distinguished from truth.” ― Daniel Kahneman, Thinking, Fast and Slow
So sayeth Dr. Kahneman.
We've learned from experience that the truth will come out. Other experimenters will repeat your experiment and find out whether you were wrong or right. Nature's phenomena will agree or they'll disagree with your theory. And, although you may gain some temporary fame and excitement, you will not gain a good reputation as a scientist if you haven't tried to be very careful in this kind of work. And it's this type of integrity, this kind of care not to fool yourself, that is missing to a large extent in much of the research in cargo cult science.
So sayeth Dr. Feynman. A successful science is the product of many individuals who work under the title of "scientist". A "successful scientist" is one of many such individuals who may be contributing positive or negative things to the science. And the truth will come out. A truly successful scientist is one who gains a good reputation in the long run. Our ideas and theories are bigger than our careers, in the long run. What determines a successful scientist is the science behind the rhetoric.

Tuesday, August 05, 2014

Location Location Location

The constant job loss is a part of the cargo cults. They hire with little understanding of what is really needed. In time the lack of cargo leads them to the path of laying off unproductive members of the tribe. Those who make the decisions have to retain their own services because they have a different function. It is their job to keep the cult alive so new ceremonies can be attempted. What Amgen did with their layoffs is no different than all of the other layoffs. In New Jersey, Roche has left enough empty laboratory/biopharma space to fill every floor of the Empire State Building. Seattle has nothing on the state of New Jersey.
Five years ago, Roche acquired Genentech, moved its management to San Francisco and started to slowly withdraw from New Jersey. That's a pretty typical story for what's been happening in the state. In the past 20 years, New Jersey went from having more than 20 percent of U.S. pharma manufacturing jobs to less than 10 percent.
The state of Washington or New Jersey is not the state we need to dissect. The state biopharma is the problem. When it comes to our hopes and dreams about jobs and useful drugs it is going to take more than new surrounding and new money. The constant relocation of the jobs and the shuffling around of the workforce is not working. It contributes to a weaker and weaker workforce. It leads to Yes-men and desperate researchers willing to say what is needed to work another day. If we were to look carefully at the state of biopharma and their scientific method, we would find that it does not vary from one place to the next. Likewise nor do the layoffs.
"Essentially, every time there's a merger or one company acquires another company, there's a reduction in force, and there's been furious mergers and acquisitions in the pharma industry, particularly over the past 10 years," says James Hughes, dean of the school of public policy at Rutgers.
The furious mergers and acquisitions are work functions that keep the leadership away from the higher risk activities of conducting research. It is hoped that someone else will come up with something in the pause created by merging companies, laying off people and articulating the way forward. History has shown that this is not a very effective method.
Business professor Erik Gordon of the University of Michigan says cutting-edge research isn't being done on closed campuses in the suburbs anymore. "The new innovation in biotech, in genomics is happening elsewhere. It's happening in places where there are graduate educational institutions that have research faculty doing that, and New Jersey really doesn't have that," he says.
Again, we see this concept that cutting edge research is done only at certain locations. We've even been given an explanation for why that is. You need to be close to graduate education institutions that have research faculty doing new innovation in biotech and genomics! Take that Rutgers. Serepta had this concept long ago. They moved from Oregon to Bothell WA then to the Boston area. They hired and fired a new Chief Scientific Officer and the CEO and Chairman of the Board had a public spat. Those who think long and hard about what science is know that it is not something that only occurs at certain locations. The natural world can be observed anywhere. A laboratory in Seattle versus a lab in New Jersey or China, is no different. When we want to purify DNA will will all go to the internet to purchase a kit from Invitrogen or some other favorite kit provider. When we want to buy an HPLC we will hold meetings and decide upon our favorite HPLC provider. All HPLCs work the same. They also work the same in Seattle, New Jersey and China. This is the beauty of science. If you are thinking about it correctly, you are thinking about things that do not change from location to location. It can be done anywhere.
"What really sets this site apart is its location," says Tom Stanton of Jones Lang LaSalle, the real estate firm marketing the site. The site is so big that to show it off, Stanton needs a minibus. Looping through a parking lot with thousands of empty spaces, Stanton stresses how close the campus is to Manhattan, Newark's airport and public transit. "Hiring young, talented people is really important to these companies. And that population of upcoming talent is more into the city life," he says.

Sunday, August 03, 2014

Positively Sink'n Think'n About Amgen Seattle

An Amgen spokesman told Xconomy its Seattle R&D site and Bothell manufacturing sites employed 660 people combined, with 430 more in Colorado. The facilities will be closed by the end of 2015.
I've extracted this bit of news from an article on Xconomy. The rest of the article depicts the upside that remains in Seattle.
When asked for his reaction to the Amgen news, Washington Biotechnology & Biomedical Association president and CEO Chris Rivera said, “In a word, disappointing.” But Rivera adds he is optimistic that the employees who don’t relocate—Amgen said it would shift jobs to its Cambridge, MA, and San Francisco Bay Area locations—should be able to find jobs in Washington state if they want to.
The Seattle Times reported Riveras' thoughts on the matter this way:
Chris Rivera, president of the Washington Biotechnology and Biomedical Association, said that while the news was a letdown given Immunex-Amgen’s history in Seattle, he is “pretty confident” those employees who want to stay here will be able to find a job in the sector. “There are plenty of opportunities here,” with about 190 biotechnology and pharmaceutical companies in the area, he said.
Next we hear from Bob Nelsen of ARCH Venture Partners, a longtime investor in the Cargo Cults of Seattle: "Amgen’s departure is not good, but the area’s strength in various disciplines will make up for it in the long run.” Oh sure, Amgen in Seattle had 1600 employees in 2004. In 2015 they will have zero. The 750,000 square feet facility will now go on Craigslist perhaps. 'R&D space available. Nice view! DNA bridge included!' The unemployed will take their resumes, many of which will list a degree from UW and one narrowly defined job at Amgen, and go find those jobs that Rivera and Nelsen believe exist. The cargo cults are going to be just fine. The truth is that this is bad. Really bad. We haven't learned anything nor have we admitted that this failure is something worth a concerted effort to prevent in the future. We cannot look past this spectacular failure of the biggest deal in the history of Seattle biotech. The demise was not sudden. There were 1600 jobs in 2004 and only 610 left to eliminate in 2014. The demise was a long slow process. Only one decade after the most grandiose R&D cargo cult was finished and fully staffed, it goes to the Seattle Biotech graveyard. We have seen the loss of many companies large and small. From the tiny 3 people companies at Accelerator to the larger implosions of Zymogenetics and Icos, Seattle biotech workers have had to exist in a minefield. Those losing their jobs must share in the culpability of this minefield. They are cargo cult tribesmen who do not want to speak of that lack of cargo planes landing on their runway. The optimism is always there. The cargo? Now they must be moving on to man the watch tower at the next airport. Once again there will be no gathering of "talent" to put down on paper what was learned. The only writing that will take place comes in the form of CVs depicting only positive information. The leadership that survives will rest assured that they have made the prudent decision and that ten years from now, all will be better. This is the problem with positive thinking. Nothing is gained. As one soon-to-be ex-Amgen researcher said, "I understand from a business angle but I think it is shortsighted." Really? You understand cutting out R&D from a science based company where the kind of research you do can take decades to complete? They shut you down in ten years! Get mad! This is a raw deal. Those who conduct research surely have a thing or two to say about a ten year period where 1600 people lost their jobs. Something was not going well. What was the negative side of your work? Why do you think the executives did not see the value in what you did for their company? Times like these require everyone to face the facts, just as the leadership at Amgen has had to face facts. The value of R&D is just not there. Either it is not very scientific (as the Amgen Study reported) or the leadership is missing its point. Why not make a decision yourself then? Speak out about what you did. I once interviewed for an RNAi job at the Seattle Amgen facility. I learned that it was an RNAi job while on the interview. I told them I would not work with RNAi. We chatted politely but the interview was over for all intents and purposes. I shared what I experienced with RNAi and why I did not believe in the future of the technology. Since then I have witnessed one RNAi company fail after another. Serepta continues to crumble. I gave up biotech entirely in 2010 but I remain loyal to the cause. Not in a positive way like Rivera and Nelsen. I am one of the guys who would have lost his job had I got the RNA job at Amgen. I saw the same value then as Amgen executives see now. The people I interviewed with at some point between my interview and now have lost their jobs. The value of the work we were talking about that day has been decided. It is worth nothing. Now what can we do to find value in ourselves? How can we work towards a brighter future for the next generation or will it be up to them to improve upon what we've been begun? What will become of the unemployed in the next few years? There are many questions but no one is asking them. We don't want to seem negative.

Sunday, July 20, 2014

The Trouble With Positive Thinking/Falling From Grace

What is the difference between purposely deceiving an audience and accidentally deceiving yourself? My hero James Randi points out that a magician is the only honest professional, in that s/he sets out to deceive you, tells you that they are going to do it, then does. Contrast that with an advertising professional. They are like magicians except they do not want you to know they are trying to deceive you. A true skeptic however, knows the score. We set our minds to the task of finding the deception, just as Feynman did in the Cargo Cult speech when discussing the Wesson Oil ad campaign.
The easiest way to explain this idea is to contrast it, for example, with advertising. Last night I heard that Wesson oil doesn't soak through food. Well, that's true. It's not dishonest; but the thing I'm talking about is not just a matter of not being dishonest; it's a matter of scientific integrity, which is another level. The fact that should be added to that advertising statement is that no oils soak through food, if operated at a certain temperature. If operated at another temperature, they all will--including Wesson oil. So it's the implication which has been conveyed, not the fact, which is true, and the difference is what we have to deal with.
Imagine Feynman standing in front of the Wesson Oil section of your local grocery store. "Hey, that oil is no different than this one." The would-be purchasers of Wesson Oil would think he is a nut. Yet he speaks the truth. Those who choose to deceive, on the other hand, positively convince the consumer through tv commercials with attractive middle class people that Wesson Oil is a wise choice. The facts thus take a back seat in influencing decisions when more pleasant narratives are in place. Our irrational behavior is our achilles heal. To make matters worse, we have been conditioned to believe that we cannot be so easily fooled. To consider the notion would be to admit a naivete that we don't want to believe. The leaders of biotechnology/pharmaceuticals likewise do not entertain the idea that their selection process has ever been faulty. They have selected for the best and the brightest individuals. Please ignore our history of successes and failures. These individuals simply cannot entertain the notions that luck has anything to do with the fact that they are still employed. Yet lately, even the positive thinkers are starting to have doubts about their chosen profession. In this article we see that people are starting to feel as if we are falling from grace. Grace? Were these people being positive to avoid getting weeded out of our industry? I began this blog with the exact opposite notion about myself and my cohorts. I felt that we were merely watchtower employees of a cargo cult. The layoffs were a part of my industry before I began and after I left. Every time I lost a job I felt that, while I had learned something, the world had not gained much from our efforts. I did not get down on myself because I had learned something. I had grown and every time I found myself at the next cargo cult, I would one day read about the demise of the last one. I made no excuses for myself nor the cargo cult. I failed and they failed because we did not take science seriously. We favored our careers over the thing that made our careers possible. We were standing on the shoulders of giants waiting for them to take us to the land of milk and honey. They didn't budge! As I come back to this blog it is with the purpose to attack the positive thinking that has created four decades of nowhere careers, bad science and the loss of a few hundred billion dollars. In his book, "The Antidote, Happiness for People Who Can't Stand Positive Thinking" Oliver Burkeman describes a study where researchers at a molecular biology lab at UC Berkely were themselves studied. Each time they encountered a result that they had not expected, they first questioned themselves. What had they done wrong. The thought that what they were seeing was to be taken seriously and used to move forward was not entertained. They moved forward in pursuit of the positive result, the one they designed into the experiment. These scientists aspire lead their own labs or groups within biopharma. They want a job! It's not getting harder to have a job as the "Falling From Grace" article suggests. It remains hard to keep a biopharma job. What we are doing is not working. Yet we don't give up. We fight to keep our employment because that one project is your whole job. This is not sustainable. Fight to remain in research, not just the research project you are on. Admit defeat when you know it's time to move on. And move on! It is a cargo cult science out there and that is the problem. Bend over backwards to be honest and leave your hopes and dreams at the door. The scientific method will lead you in directions your positive thinking irrational mind can't imagine.

Friday, January 31, 2014

Biotech Royalty

David Blech earned the title "The King of Biotech". Armed with a Masters degree in Music Education, he became a member of the Forbes 400 investing in companies like Genetic Systems Corporation, Icos, and Celgene. In 1990 he founded D. Blech and Co., a registered broker-dealer involved in underwriting biotechnology issues. On September 22, 1994 the company was deep in debt and ceased operations due to net capital rule violations. The day is known as Blech Thursday.
The uniform net capital rule is a rule created by the U.S. Securities and Exchange Commission ("SEC") in 1975 to regulate directly the ability of broker-dealers to meet their financial obligations to customers and other creditors. Broker-dealers are companies that trade securities for customers (i.e., brokers) and for their own accounts (i.e., dealers).
Blech was given a five year probation sentence in 1998 for criminal fraud. In May 2012 he pleaded guilty to manipulating shares of biopharmaceutical companies Pluristem Therapeutics Inc and Intellect Neurosciences Inc in 2007 and 2008. 

The Cargo Cult message of the story is that success in biotech financial matters does not require a PhD from MIT. It does not require bend-over-backwards scientific honesty. It requires the mind of a gambler. Remember the successes, but not the failures. Remember random events around your successes and tout them as skillful tricks of the trade you are in. 

In Seattle there is a building with four numbers in front. 

Inside this building are people who have chosen the same career path as David Blech. Carl Weissman and Steven Quay have been at the helm of several costly biotech investment decisions. Neither has found themselves on the Forbes 400 but they have had lucrative careers in biotechnology. The investments they have attracted have not been lucrative. Weissman is now the former CEO of Accelerator and Quay is in charge of a sinking ship known as Atossa Genetics. 

I don't want to go into further details about these investment opportunities. I've written about them before. Each man is a leader, as defined by the terms of a CEO. You are investing in them and the decisions they make with your money. Like David Blech, they are not scientists, as defined by the terms of a CSO. They seek money and use it to build biotechnology companies. The science is none  of their  business. Their careers have seen hundreds of millions come and go. They want you to focus in their ability to make the money come, never mind how it goes away.

The takeaway from  Blech, Weissman and Quay is that leadership matters. What makes a good biotech leader? In 1992 David Blech would have been considered a great leader. In their rise, Weissman and Quay were considered worthy of stewardship over millions and millions and the careers of many very smart people. In the ruins of their management is the loss of that money and the ruined careers of too many scientists. True, Blech (the music education master) started companies that made money and continue to do so. But he did not do the work that made these companies long term successes. These three individuals are prime examples of the short term mentality. Start company, get out before the fall. They are prime examples of why we need standardization, certified laboratories with certified lab workers. We need to create an career path for scientists who have the power of science to help investors avoid the song and dance of these three men. One of these men is in prison, one is looking for work, and one is draining $600,000 per year (CEO and CSO salaries for he and his wife) until the latest round of financing is depleted. Be assured that all three will continue to fight for their livelihood and raise money to spend on short term money making biotechnology companies.  

There is a little bakery on the bottom floor is 1616 Eastlake called Grand Central Baking Company. They are the most profitable company that has ever done business out of 1616 Eastlake. They have outlasted all of the Accelerator companies. They have a passion for what they do. 
More than two decades after our founder Gwen Bassetti introduced the Como loaf in Seattle’s historic Pioneer Square, we are still locally owned, led by a unique mixture of family and friends, and dedicated to the craft of artisan baking.
Biotech royalty, like Bech, Weissman and Quay, have a passion for the deal. They love being the biggest boy at the big boy table. But this isn't the craft that makes biotech success stories. The craft of "the deal" has led to many a lawsuit, jail time, and high unemployment. What makes any technology company succeed is a dedication to the science and technology behind the product. For this, you need someone outside the royal families.