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Monday, January 28, 2013

Research Degree

College degrees come in levels; BS, MS, PhD. A university may have a liberal arts college, natural science college, engineering and so on. In each degree program the university will require the students to have a certain amount of credits from other colleges, to ensure a well rounded education. This is very important. The ability to communicate both in written and oral presentations is important. It may have little to do with learning about how a protein is translated but communication is a part of any professional life. Beyond communication, a career in research should require more.

If you want to become a high school chemistry teacher you need to learn how to teach. You earn chemistry degree and you get a teaching certificate. If you want to conduct research for a biotechnology company or the pharmaceutical industry... you have chosen the path of least resistance. You get your degree; BS, MS, or PhD, and you start looking for work. Your college professors were most likely researchers. They are looking for cheap labor. Research grants bring in lots of money for our modern universities. As a result the natural selection of tenured professors has created an emphasis on research ability as opposed to teaching ability. That means that lessons in writing grant proposals are seen as more important than a course in logic over at the Philosophy department. Over time we have watered down the scientific skills needed to conduct research. Human constructs such as grants and publications become our biggest challenge. When it comes time to apply what we have learned, to take a job, many will simply become middle managers. What they have is an understanding of how to please a superior.

In science, nature should be our boss. That means that we need to learn how to conduct research. If you chose to become a middle manager, perhaps you need only a BS and a middle management certificate. If you chose to work in business development, you will need a different set of skills. The most difficult career path to actually succeed in however, is in research. Nature does not reveal its secrets without a fight. You must learn how to fight.

Under the current system, those who work on the front lines in the laboratories show up to the fight with just a BS. Perhaps here is where we insert a research certification. BS, MS, PhD indeed, but what is the certification? Are you on a chosen career path or has your lack of ambition got you stuck in the lab?

Sunday, January 27, 2013

Freakology, The Hidden Side of Life Science

What would turn up if we took a Freakonomics approach to uncover the hidden side of the life sciences?

Imagine having control over a small percentage of the NIH grant money. Wouldn't it be interesting to task a handful of scientists with a different sort of project. Take the approach that Freakonomics has taken in looking at "the hidden side of everything". They actually use the scientific method to examine that "hidden side". For example, they looked at Sumo wrestling in Japan. Observation: Using statistics they found that cheating was commonplace at the highest level. Each year the wrestlers must compete once a day for 15 days. If you win 8 matches you are advanced into the Sumo wrestling premiere league. If you lose 8 or more, you are not advanced. What they found through the powers of statistics this. A wrestler with a record of 8 and 6 would lose to his opponent 75% of the time when the opponent had a record of 7 and 7. Later, when the same two opponents met again, the 8 and 6 wrestler would win a majority of the matches. Hypothesis: The loss was a free pass into the premiere league for the would-be loser. The stronger wrestler now has a weaker field to face in the coming season.

Because Sumo wrestling is so revered in Japan, the mere idea of cheating was not to be entertained. Prediction of future observations: Freakonomincs authors Levitt and Dubner were convinced cheating was taking place. Over time people came forth and verified that cheating was a part of the Sumo culture at the highest level. In spite of the human habit of ignoring things for which we don't have an appetite, the truth had to be faced. Cheating was accepted as fact.

Let's take this notion into the world of professional scientists. Certainly there has been no appetite for an examination of the hidden side of their profession. We hold scientists above the common man with regards to honesty and self-policing their occupation. The creation of this "Freakology", funded by an NIH grant, would first have to face this obstacle.

The Freakology exploration into the hidden side of the life sciences would also have a similar purpose as Freakonomics, to entertain. Wouldn't it be a nice break to set aside the latest issue of Science or Nature for some light reading on the hidden side of your occupation? For those who do not believe it is appropriate, those who have similar brain function as religious folk or Sumo wrestling aficionados, we leave them to continue reading the latest study on RNAi knocking out protein X and curing disease Y. For those who see science as the only worth while use of our brains, let's see what this NIH funded Freakology has to say about us.

The first issue of Freakology. WHAT WILL GET YOU PUBLISHED! According to the journal Science:

Science's Mission: Science seeks to publish those papers that are most influential in their fields or across fields and that will significantly advance scientific understanding. Selected papers should present novel and broadly important data, syntheses, or concepts. They should merit the recognition by the scientific community and general public provided by publication in Science, beyond that provided by specialty journals.
There is a hidden side of science (not the journal Science) to be explored here. This description of a Science journal publication versus say that of a Biochemistry journal publication implies that Science editors somehow know what is "beyond" the specialty journals limitations. The proper application of the scientific method is not priority number one, although it is suppose to be assumed that everything they publish has gone through the rigors of our method and is thus reproducible. Beyond that trivial little issue of the scientific method, the editors of Science want sexy science. They want the stuff that will change the world in one paper. They don't want follow ups and detailed sharing of information. They want superior sounding papers. Papers that are "beyond" the rest.

The hidden side to publications in the more elite journals is that there is this built in bias towards more sensational analysis. In the case of Stan Prusiners first prion paper in Science in 1982, for example, the researcher who did the actual lab work at UCSF quit over the publication. He felt that Prusiner was overinterpreting the available data to push the prion hypothesis. No one is willing to admit that a scientist would overinterpret to advance their reputation. Yet in order to be published, Science requires your work to go beyond that of common researchers. This might in fact lead researchers to simply go beyond what the data is telling them. You are after all required to impress by going beyond. Once it reaches the journal, a truly non-scientific method begins. No one reproduces the work. No one is allowed to offer alternative explanations. It is the word of one man, and the who need the publication on their resume. The greater the "sexiness" requirement, the greater the risk for bad science.

By contrast, lets look at the life of Ignaz Semmelweis. While working at the Vienna  General Hospital in the mid 1800s he discovered that the doctors had 3 times the mortality rate as midwives. The doctors had been conducting autopsies in the basement then going straight upstairs to deliver babies. Ignaz proposed the rather un-sexy and , to some, insulting idea that the doctors needed to wash their hands. In one study the mortality rate of women giving birth at the hospital (10 to 35%) was reduced to under 1%. Ignaz was ignored. Later institutionalized where he died at the age of 47.

This is an old issue for some of us. To some however it would seem to be a hidden side. Long ago we did things that does not make sense to us now. In 100 years or so we will look at the publication model and laugh. With new technologies that can search for plagerism we can spot cheaters. We can conduct meta-analysis to find conflicting results. In time we will have more tools to replace the assumed superiority of the reviewers. For now we can only hope to shine a spotlight on the hidden side of our profession. The first step is to admit that there is a hidden side.

Thursday, January 24, 2013

Pink Ribbons Inc.

Breast cancer has become the poster child of corporate cause-related marketing campaigns. Countless women and men walk, bike, climb and shop for the cure. Each year, millions of dollars are raised in the name of breast cancer, but where does this money go and what does it actually achieve? Pink Ribbons, Inc. is a feature documentary that shows how the devastating reality of breast cancer, which marketing experts have labeled a "dream cause," becomes obfuscated by a shiny, pink story of success.
"Instead of saying what has come out of these investments, they tell you how much money they've put in." 
Pink Ribbons Inc.
The 2011 documentary Pink Ribbons Inc. highlights a microcosm of Cargo Cult Science. Right around 47 minutes into this video (per Netflix) they start to ask hard questions of the science being funded by the Pink Ribbons money makers. What has been done, with regards to understanding breast cancer, as a result of all of the money raised? We know that the Susan Koman walks and Avon pink ribbons have raised money, and made a lot of people happy. The real cargo however is the productivity of breast cancer research. The productivity cannot be measured by dollars raised.

Who are the scientists supported with money from the pink ribbon people? What are the scientists doing? Are they on to something intellecually? Scientifically? Are they busy raising money? Do they understand the disease? Why in the hell have they not taken notice of the Amgen paper its ultimate discovery of how much payed-for and publilshed cancer research is of any use?

The inability to reproduce the work of ourselves and others is our greatest enemy. As I've often said, honesty in research is akin to honesty in a crossword puzzle. Purposely publishing non-reproduced research means that you have little concern for overall outcome of the body of knowledge to which you are contributing. Yet in our current system, the consequences of being discovered as "non-reproducible" are easily brushed aside. Blame a tech, blame someone or something, but never admit that you jotted down the wrong word in our proverbial crossword, because it benefitted your career.

Susan Koman and the Pink Ribbon people are not bad people. They raise money and that is a good thing. Where they leave the righteous path of actually doing something about breast cancer (or any cancer) is directly at the point of handing that money over to a small group of scientists. At that point we leave it in their hands. We have no way of checking on the validity of their work. The money goes into the hands of a specialized class of people who have convinced the world that they have some god like understanding of what we need to figure out. This special class does not want anyone analyzing their work. They do not want an accounting of the work. Simply accept the final word, which always comes with the line, "more research will be needed". More money will be needed.

Thursday, January 17, 2013

Thoughts on Mackey and AstraZeneca

I talked about the biotech/pharma "South Sea Islanders" and how they arrange things but never seem to "get some wealth in their system".  Back in 2010 AstraZeneca (AZN) rearranged their cargo cult airport and hired Martin Mackey to be their new head of R&D. He has now been let go in yet another shake up of Cargo Cult research and development leadership. The new guys will come in with great expectations, just as Mackey did, and they will proceed to do whatever people at that level do. I don't know what they do. It's not science. It's a new arrangement in the Cargo Cult Airport of AZN meant to build wealth into their system. According to Fiercebiotech:
Now the global R&D operation will be divvied among three key players: Mene Pangalos, MedImmune's Bahija Jallal and Morrison Briggs. They will each be given one of three tasks: Head of discovery and early development of small molecules, running early-stage work on biologics (MedImmune's role), and late-stage development.
Pangalos has been an outspoken proponent of finding a more flexible, lower cost approach to drug research, championing the virtual strategy adopted for neurosciences work and shunning big investments in bricks and mortar in favor of a more open R&D environment. Jallal, meanwhile, has been pioneering new deals as well, recently inking a pact with a Chinese CRO aimed at shaving four to 6 years off the development time for one of her biologic programs. Morrison, meanwhile, is another survivor of the storm. He was brought in a year ago to head late-stage work after stints at Merck ($MRK) and Pfizer.
"This new senior executive team structure, that draws heavily from the leadership talent within the company, enables us to bring an even sharper management focus to key pipeline assets, key brands and key markets, and helps us further accelerate decision-making," said Soriot in a statement.     

I mentioned (in this post), that high ranking positions in any company are often judged in non-scientific, random ways. In "The Drunkards Walk" Leonard Mlodinow tells the story of, Sherry Lansing, the former CEO of Paramount.  She was the boss during a string of blockbusters like “Forrest Gump,” “Braveheart” and “Titanic.” She was hailed by the Hollywood press as a genius. After a series of box-office disasters however, she was replaced. After she was let go for her poor performance Paramount went on to have its best summer in a decade. Mlodinow pointed out that the new success of her replacement came from such like, “War of the Worlds” and “The Longest Yard,” that were in production when Lansing was still in charge. 

Martin Mackey certainly doesn't like what is happening to his career. He lived and died in a random system that he felt was not random. When he was on top it was a great system. Now? When Martin Mackey was given his turn it was not a good time. 

The Cargo Cult Airport has been rearranged. We look to the skies...

Sunday, January 06, 2013


Soviet agronomist Trofim Denisovich Lysenko was a Cargo Cult Scientist. He had a job to increase crop yields. He did not succeed. He succeeded, in spite of his scientific shortcomings, at being one of the most powerful scientists in the Soviet Union during his lifetime. He is now considered an embarrassment. What can we learn from this dark story in the history of science and popular opinion. Certainly, if the opinion holders are influential human beings, opinions can trump scientific facts. At least until facts can no longer be ignored.

What led to the influence of Lysenko on Soviet science? We in the biotechnology business have had a similar problem. The influencers set up a system of conducting research that has been a failure. The rest of us bought into the prospect of riches and fame, in spite of our average minds. Is it possible that the social phenomenon that lead to the rise of Lysenko is infecting modern scientific systems?

Lysenko and the scientific method parted ways at the corner of Nature and Nurture. Lysenko did not believe in Mendelian genetics. He felt that the environment was a more important factor in the long run. For example, in 1927 Lysenko described a new method to fertilize fields without the use of fertilizers or minerals. The method was called vernalization. Germinating seeds were exposed to low temperatures under specific conditions allowing for human control of the plant's flowering time. In the modern world we could easily test his theories. Using design of experiment (DOE) one could create the series of growth experiments. Determine the variable, temperatures, lighting, soil, water... Undoubtably, there will be a sweet spot in which to grow your seeds. Lysenko, in this fashion, was not unlike many scientists today. Take a system in which something must happen, randomly test combinations of variables, and claim that you have discovered something. It is a useful process, testing variables via DOE, but something was missing in Lysenkos work.

Vernalization is a proven biological phenomenon. Lysenko however, utilized the cargo cult scientific method: Design research to reach pre-ordained results, ignore any results which do not advance your theories, report only positive results, and guard your career with Machiavellian political skills.  Lysenko pre-ordained that the process of vernalization could be inherited in plants.  He reported successful experiments that yielded healthy, robust pea plants in the dead of winter. Amidst the poverty and frequently frozen Soviet Union, Lysenko was portrayed as a hero of the Soviet state by the state-owned media.

That sounds familiar. For example, in biotechnology we pre-ordained RNAi technology as the next big thing. The media jumped on it, investors handed over billions and "news" organizations such as the journals and the lesser scientific reviewers such as Xconomy touted the coming of a new era in scientific advances. Finding cures for Cancers and Alzheimers was just a matter of time. Ironically, much of the research that I witnessed, and participated in, was very much like the work of Lysenko. If an experiment with RNAi did not produce the pre-ordained results, we were sent back into the lab to tweak the environmental variables. The temperature or CO2 in the incubators must have been off. Try again! The cell media needed to be tweaked. The measurement techniques were sloppy. There was always something wrong in the lab when the pre-ordained results were not obtained. Imagine one small lab experiencing this cargo cult scientific method, then multiply the experience by however much cargo cult work was generated by billions and billions in investments.

Lysenko was a successful man. In his day he accomplished his goals. Like most important members of a society, he was eventually deposed. He worked at the highest level, identified as a scientist, from the late 1920s to 1964. He never repented. He labeled his detractors as nattering nabobs and humdrum hirelings. He had power. When he lost it he was already an old man and people would remember that he was once here. However, in spite of his own opinion on his worth on earth, his name has become synonymous with bad science. According to Wikipedia:
Lysenkoism is used metaphorically to describe the manipulation or distortion of the scientific process as a way to reach a predetermined conclusion as dictated by an ideological bias, often related to social or political objectives.
That is an excellent description of Cargo Cult Science. Lysenkoism is alive and well. I worked under these conditions for years. The bias is related to careers and financial gain. Under our current system, nothing has to reach the market. No product needs to be sold to a customer. We sell potential. The science must be sexy and the potential profits must be identified and described eloquently to our real customers, the investors. Before a drug in the pipeline reaches its final destination, its own death, a few can have successful careers, like Lysenko. Success is merely getting another round of financing. At the lower levels, that of the tribesmen who work in the labs, success is another year or two of work.  The promise of biotechnology, like the promises of Lysenkos science, has not produced. My experience made me a skeptic of the leaders. It lead me skepticism, a word not allowed in the Lysenko approach to science.

The massive layoffs repeated year after year, the useless "Provenge" style products, the wasted educations, the 90% false published findings, THE AMGEN STUDY!, and the arguments against the Reproducibility Initiave are all part of our biotech Lysenkoism. The modern world of humans who thrive now, and who would have thrived under the leadership of Lysenko, are making a mess of science. The successful scientist interviewed in the Amgen study:
"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."

We are, after all, mostly average minds, trying to do what Einstein and Newton once did. We allow the successful scientist to operate in a "best story" environmnet. The leadership, such as Lysenkos, defines what is the best story. Nature is too tough to figure out sometimes. Sometimes we just tell the best story. But it's not science. It's Lysenkoism. It's a Cargo Cult Science.