Inside Information

When you think of disgruntled employees you think of crazy people. The kinds who come back to work with guns and mow down their old colleagues. But there are other kinds. Some people are good and the company management is lacking.

Here is what a high ranking former employee at a small biotech had to say about the management:

I thought they had some good technology..., however, the leaders had no clue how to develop ethical pharmaceuticals and they weren't folks that I could respect. It was really unfortunate as they hired good people but really didn't allow themselves success due to incompetence at the top.

Will those four clowns at the top every get rich like they want?

For the record, the leaders went on to make a rather lucrative deal with Big Pharma. The Big Pharma company wanted a large amount of the drug to start their own research. Little Biotech company had about 2% of what the Big Pharma company asked for. What they did have did not pass the bioburden test. So how did they get the positive data that attracted Big Pharma?

Overseas, third world country testing! Unethical? Yes. Could the leaders "develop" pharmaceuticals? No. They haven't made one molecule that could be used in the US or Europe. Did they get rich? Yes. The "clowns" at the top have multiple houses and new cars and all of the things a greedy person would cherish.

Could we blow the whistle on this company? I don't think so. Overseas testing is legal. Incompetence in medical research is subjective. Unethical conduct can be argued against by claiming ignorance to the rules. They could claim that they had to go outside the US and Europe because they are small and can't afford the rigorous process in the modern world. Once again medical science has designed in flaws that select for the bad guys.

But this is the kicker today. Our history is rotten to the core. Human beings can't be trusted. Testing dangerous drugs on human subjects is decidedly bad. Now we know better. Right?

The new test subjects have to take "medicine" that would not pass muster in the US or Europe. Once again, we've lowered our standards and found people whom we have less fear of. They are not protected as Americans and Europeans. The prisoners and mentally ill were not protected either. How far have we come in our humanitarian ways?

The "clowns" at the top of this little biotech are not evil. They are greedy and they want to be powerful players in the business. They are a small and dangerously desperate company.

Biotech Inc.

I took my latest lab tour after a 2 hour interview for a 5 week temp job. It was a small space with all of the usual things. Hoods, gel apparatus's, incubators, shakers, PCR machines... It was merely a satellite branch of Biotech Inc. Sometimes I think biotech is all one big secret corporation (Biotech Inc.) whose mission is to collect money from gamblers (biotech investors). Each branch has a twist to the usual story. They cure disease with big brain ideas that no one really understands. The idea needs money to work. In reality, Biotech Inc. needs money. Invitrogen, GE Healthcare, BioRad, Pall, Millipore and companies like these have made a fortune off selling to Biotech Inc. As a result each lab looks the same. The tour I took yesterday was short. I'd seen it all before.

Rumor has it that this particular company is looking to sell itself off for a quick profit for investors. I was interviewing for a 5 week job at the bottom, once again. I was informed of the temporary status of the job half way through the interview. During the lab tour I knew I was looking at an entire group of temps. They had more benefits and longer contracts than an admitted temp, but they didn't have long to go. The company is looking to be sold. If they can't pull it off they will shut it down. Either way, the laboratory staff had short futures with a small company.

Big Pharma has tired of wasting their time and energy trying to develop drugs. Big Pharma has made the claim that the small biotechs will become their feeding ground. They will let the innovation take place on someone elses dime and snatch up the winners. The Biotech Inc. lab space that previously had taken up real estate in Pfizer and Merck is fading away. The Biotech Inc. space moved to small dangerously desperate companies. Like a dishonest post-doc who needs data to fall in his/her favor in order to advance his/her career, the desperate small biotech gets the kind of results that go over well in a meeting. Easily understandable stories that put dollar signs in wealthy peoples eyes are what people want.

A fair amount of money had to be spent on the company work space. Besides the Biotech Inc. lab, there was a nice reception/office/cubicle space. All of the colors matched on the carpet, walls and tile. It was a nice theme. The management comes from The University. They have higher degrees in science than the lab staff so they get to spend some time developing color schemes and picking out carpet. This job could not be done by people earning the same as the lab staff. The difference in salary is an indication in importance of daily work. Although The University tends to teach things that would be most useful in the lab, the money from the investment pool can be used to hire the best biotech architects and interior design experts. In the end it looks as though the high ranking members of Biotech Inc. have really done a good job. You can look at the end result.

The end result of the laboratory work is a different story. The laboratory looks the same before and after major accomplishments. Each worker has the same white lab coat supplied by the same white lab coat company. Their Invitrogen DNA preparation kits look the same stacked up in their Thermo 4 degree refrigerator. Their Eppendorf pipettes look the same. The chemical cabinet, the hood, the tips, the gel boxes all look the same. But these tools of the trade are powerful when used properly. The laboratory staff can create molecules. They can alter a molecules shape, size and chemistry. But ultimately, it is the decisions of those who pick out the carpet and wall colors who decide what to do with the products created in the laboratory.

Biotech Inc. is not just a collection of Cargo Cults. There are many useful people in the corporation. You have to break it down to components and people are the indivisible component that separates the Cults from the companies.

The People

In 2001 I was working at a little biotech company in East Los Angeles. The founders were two professors at the USC Med School. The company had a pipeline of 4 antibodies against "denatured" collagen. The idea behind them was that they would prevent blood vessels from forming around tumors and thus kill them. The company was funded by an angel investor. The goal was for us to obtain some data that could be used to sell the company off and make our investor some money.

The experiment consisted of three groups of bald mice. Each group had 10 mice. There was a positive control group, treated with Rituxan. Rituxan is a monoclonal antibody that binds to VEGF. There was a negative control group, treated with PBS. There was an unknown group, treated with one of our antibodies. Day one we injected cancer cells subcutaneously on the backs of the mice. Each day the mice were injected with a large dose of the drug or PBS shot into their belly. In a couple days tumors began to grow, which we measured with a caliper.

It was extremely inhumane because no one had a painless way of doing this. The mice were horrified when the lights came on. I tagged along to write down the readings. I watched as each mouse was held upside down and a large needle was injected into a non-distinct region of their underbelly.

The experiments were done over and over. That is because we had to get the set of data that our superiors wanted. The investor had decided that the antibodies were a great idea and he sank millions into making a profit from them. The lab people needed to get the results. The problem was that we our antibodies didn't work. The Rituxan worked great. No tumors. The other two groups were statistically the same. But this would not do. We were sent back to have a graduate student from one of the founders lab show us how to "properly" use the caliper to make the measurements. She spoke as she measured, instructing us. As she instructed she was clearly favoring the hoped for measurements. Using a caliper is not a skill. When she had finished getting the data to look "better" and she ended her lesson on measuring tumors.

I had just one question. I handed her a mouse that she had already measured. She asked, "what is this?".

Me: It's a mouse with a tumor. Can you measure this one?

Her: Didn't we measure it?

Me: Yes, if you are measuring accurately you should get the same tumor size.

She measured again and was off by 30%. This number of course was not written down. It was for my own assessment. That was my N-Rays moment. I knew in my heart that they had been playing these games. The new measurement didn't count. I knew I was in a Cargo Cult.

The graduate student and the boss needed to show a reduction in tumor size. Somehow by measuring the mice again, they did not feel that they were simply fabricating data. After all, they had performed the measurements. To me, this was fraud. To the boss and the grad student, this was survival. They needed the data as much as anyone else.

My entire biotech career is littered with this ilk. They are good people until the data doesn't go their way. They convince themselves that these things are simply little white lies. They don't matter. In the big picture they know their drugs work and they'll be vindicated later. The little experiments where data is cherry picked is no big deal. It's one or two slides in a presentation that tells a much more interesting story. And the story is what sells. Investors open their pocket books and bigger companies start listening.

Oh Pfizer Again

Good thing they have lots of money. Pfizer is once again shelling out hundreds of millions to pay for covering up the danger of their drugs.

I posted last week about Pfizer being sued for 142 million for promoting their drug off label knowing it was potentially dangerous.

Paying out money is a lot better than going to jail. But actual human beings made these bad decisions. They are allowed to hide behind the corporate logo?

Who Likes Bad Science?

I used to joke with my friends in the physics community that if you want to cleanse your discipline of the worst scientists in it, every three or four years, you should have someone publish a bogus paper claiming to make some remarkable new discovery — infinite free energy or ESP, or something suitably cosmic like that. Then you have it published in a legitimate journal ; it shows up on the front page of the New York Times, and within two months, every bad scientist in the field will be working on it.

Gary Taubes

The quote brings self doubt into the mind of the CCS. Are the people in the laboratories attracted to bad science? Is it just easier to get a degree in a bio science than a harder science such as chemistry or physics? Would it behoove the Biotechnology industry to insist on stronger math skills?

Let's look at a couple jobs and their requirements for the industry:

Entry level research associate: Education; A B.S. or B.A. in Molecular Biology, Biochemistry or Chemistry or an Associate’s Degree in Biotechnology.

A bachelors degree in Chemistry = an associates degree in Biotechnology?

A protein science temp job: QUALIFICATIONS; Ph.D. or equivalent industry experience.

A PhD? A PhD in what?

And these come from Craigslist. Would an executive recruiting company use craigslist? Why are biotech scientists subjected to a craigslist ad?

Bad businessmen and bad scientists are attracted to bad science. They hire their scientists from Craigslist ads. Critical positions that can cost the company millions in delays getting a drug through the approval process are left up to temps. The businessmen and those applying for the jobs don't know or they don't care. They are in it for the short term.

In The Big Short there was a Cargo Cult Science taking place in the financial industry. A handful of people became aware of it and they bet that the sh*t was going to hit the fan. They found the way to make money off of it. The biotech professionals who have bet their careers can do the same. Be aware of bad science and stay away. There are places to go where the science is real. Seek out good science. It won't be as easy as you think. If you find yourself in the pool of bad scientists who Gary Taubes described above, get out. Leave that RNAi company. Don't apply to that PhD temp job. Work harder and get where you need to be. The Cargo Cult Airports are very tempting. They pay the same and they look the same. But they are not long term winners. Career professionals need to work for the longterm. A resume of short term bets will not be very satisfying.

And so I don't think that working in biotechnology is just a bunch of bad scientists who are attracted to bad science. There are good places, even inside bad companies. Seek them out. Look for long term options that make sense.

So I 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.

Feynman

Huge Airport Shutting Down

This isn't like shutting down that quaint little coffee shop you thought would be a good idea to buy so you quit your job and sank your life savings into and ended up staying up late at night counting up your daily losses until finally you had to file for bankruptcy... Whew! I'm just saying... that would be a bad idea.

Pfizer and Merck won't be facing an end to their dominance in the drug pushing business. But they have different ways of facing their future. Pfizer sees their massive R&D campus as a Cargo Cult Airport and they are tired of not getting the cargo.
Merck maintains their faith in their airport.

Since we at the CCS believe that most drug success stories are random events it will be interesting to see how these two companies fare. Does it matter if a major drug company shuts down a major scientific research center?

Oh Pfizer

I've spoke of the truth spectrum. On one end you can miss the truth by making an honest mistake. On the other end you have committed a fraud that you hope to benefit from. In between you can be in a place where you don't care what the truth is as long as it supports your story. That is called BS. Many professional scientists have been exposed as BS artists and gone on to have successful careers. It takes a corporation to be able to get caught at the far end of the spectrum and still survive. It takes money and power to get past violating federal racketeering laws.

Pfizer was ordered to pay $142.1 million to Kaiser Foundation Health Plan and Kaiser Foundation Hospitals for illegally promoting Neurontin for unapproved uses.

Before I go on I must comment on Kaisers responsibility when handing out drugs. Corporate for profit medicine is not a bunch of doctors who get together to discuss what works and what doesn't. They seem to assess symptoms, google them in their brain or some big pharma database and prescribe the magic pill. Problem solved. It reminds one of a scene from Anchorman with Will Ferrell. The main character, Ron Burgandy would read whatever was on the teleprompter. He did not think before he spoke. As a joke someone wrote something for him to say at the end of a broadcast. "I'm Ron Burgandy, that's the news, go fuck yourself San Diego". And that is how the broadcast ended. It wasn't Rons fault. Right?

Kaiser officials alleged they were duped into believing that migraines and bipolar disorder could be treated effectively with Neurontin, approved in 1993 by the U.S. Food and Drug Administration for epilepsy.

They were duped. There is a lot of duping in Cargo Cults. They don't think before they prescribe. It's not their fault.

There are over 300 lawsuits over off label prescribing of Neurontin. It is a dangerous thing according to the lawyers. The scientists and marketing department at Pfizer allegedly knew Neurontin was dangerous also. Where on the truth spectrum does this case really fall. How dangerous is this little pill and what group of people are most vulnerable? Did the scientists, clinical trials professionals, or doctors know that the marketing department was trying to sell the drug to the vulnerable people just for a profit? Did the marketing department really not care about the people they were hurting?

Sinning Against Science

The Sins of Science : A small compilation of people who know how to succeed in the Cargo Cult Airports. It's not as if anyone is ever going to go into the laboratory and check on their results. Right?

The article about scientific scams that you will not find is the one about a team of hard working laboratory professionals who can spot BS and quickly disprove it with empirical data. It is merely assumed that the review process weeds out the liars and cheaters. Why? Because at the highest level they are too sharp to be fooled. This is mandatory for a Cargo Cult. Leadership cannot be questioned. But what do they know of empirical data if they do not venture into the laboratories they rule over?

The word empirical denotes information gained by means of observation, experience, or experiment.[1] Empirical data is data that is produced by an experiment or observation.

A central concept in modern science and the scientific method is that all evidence must be empirical, or empirically based, that is, dependent on evidence or consequences that are observable by the senses. It is usually differentiated from the philosophic usage of empiricism by the use of the adjective empirical or the adverb empirically. The term refers to the use of working hypotheses that are testable using observation or experiment. In this sense of the word, scientific statements are subject to and derived from our experiences or observations.

Those who are charged with deciding if Silvia Bulfone-Paus engaged in scientific misconduct are not the ones who called attention to the BS in her publications. The judge and jury are like her. They left the laboratory long ago and never looked back. Laboratories are for prestige. You raise money for them and put little people in them to obtain results that prove you were correct. But what obligations does the PI have in verifying the results? What do you call second hand empirical data?

The story of N-Rays once again helps us describe modern day science. Long ago, scientists had a way of verifying puzzling results.

Nature magazine was skeptical of Blondlot's claims because laboratories in England and Germany had not been able to replicate the Frenchman's results. Nature sent American physicist Robert W. Wood of Johns Hopkins University to investigate Blondlot's discovery. Wood suspected that N-rays were a delusion. To demonstrate such, he removed the prism from the N-ray detection device, unbeknownst to Blondlot or his assistant. Without the prism, the machine couldn't work. Yet, when Blondlot's assistant conducted the next experiment he found N-rays. Wood then tried to surreptitiously replace the prism but the assistant saw him and thought he was removing the prism. The next time he tried the experiment, the assistant swore he could not see any N-rays. But he should have, since the equipment was in full working order.

What can one say about N-Rays and the multitude of scientists who publish papers on things they've never seen first hand? Self deception is one explanation. On the other end of the BS spectrum you find Dr. William Summerlin who coloured in the black patches of fur on white mice with permanent markers to prove his skin graft technique was a success. Bulfone-Paus' people coloured protein bands on western blots. Either way, they got what they wanted. By separating yourself from the collection of empirical evidence you will have an easier time climbing the ladder of successful scientists in todays world. By not entering that lab you will not have to fabricate data. You hire people to do that for you.

Questioning Favorable Results

Baltimore, Bulfone-Paus, and Daniel Klessig all had the wool pulled over their eyes by people telling them what they wanted to hear. It is not only easy to do this to some scientists, it seems to be the only way to get ahead in their world.

It's not always black and white. Baltimore wanted the data from Imanishi-Kari. Imanishi-Kari got the data from her lab staff. The data that was wanted was published. The data that contradicted the desired results was the cause of a whole lot of trouble.

Bulfone-Paus wanted the data from subordinates who worked in her laboratory. She got it and published. When did she decide that there was a problem?

Daniel Klessig wanted the data and he published. Trouble!

How does the Cult deal with the trouble?

Highest level:

A BTI investigation concluded there "was no conclusive evidence that Dr Chandok achieved the results reported" but also found "no conclusive evidence" that misconduct had occurred.

Publishing data that no conclusive evidence supports isn't scientific misconduct?

Principle Scientist Leadership level:

This was considered a significant discovery in the field of plant biology. Dr. Klessig and Dr. Chandok began work on a paper to publish the results. Dr. Klessig requested that Prof. Brian Crane, a researcher of animal NOS activity who was familiar to Dr. Klessig, attempt to confirm.

And it was confirmed! How?

Prof. Crane assigned the work to Mr. Pant, a doctoral student who was already performing similar work. Dr. Chandok worked with Mr. Pant to reproduce the results, which was reported as a success. At that time, Dr. Klessig seemed satisfied with this verification, and the paper he and Dr. Chandok completed was submitted to Cell for publication. The paper was published in the Spring of 2003.

Remember the degrees of separation? The fact that PHd scientists do not work in laboratories to confirm data? Dr. Klessig needed to keep building on this foundation of quick sand. He needed more proof. To the lab?

In 2003, Dr. Kim was hired and assigned to verify Dr. Chandok's work.

Were they not convinced yet? What was wrong? Whatever it was, Dr. Chandok wasn't about to go back into that damned laboratory to validate her work. Dr. Kim was not getting the same results as she did. She sued over the retractions of the papers.

Was it scientific misconduct? Bad science? Fraud? Error?

It was a Cargo Cult Science!

The Culture of the Cult

Western blot and ELISA are simple things. They are also what got David Baltimore and Silvia Bulfone-Paus into trouble. Both tests can give varying and ambiguous results. When you are on the margin of detecting a signal that proves your theory, you should bend over backwards to prove you did or didn't detect it. This, however, is a part of the culture of the cult.

As a cargo cult leader, you must set up what you perceive to be the truth. The bamboo antennas for example, may be reshaped time and time again. Each time you must have a reason for reshaping the antennas and a reason for the new shape. Therefore, there must be some truth that makes the old shape wrong and the new shape correct. That truth is the heart of the matter. If the makers of the antennas screw up, you can maintain, as a leader, that you are still the keeper of the truth. You are in charge and the others need to do their job better. In general, you must keep several degrees of separation between your "heart of the matter" and the incompetence of the others. They keep the planes from landing in spite of your brilliance.

How does this translate in the real world of science? You may think that scientists work in laboratories and maintain careful records of all they do. This is false. I once worked for a Nobel Prize winning scientist. He came into the lab once to have his picture taken for the award ceremony. He was loaned a white lab coat. He posed next to a hood where inside we had lit a bunson burner for a special "sciency" effect. Later that photograph was hung up inside the laboratory. The caption underneath the picture read, "this isn't like my piano at home". Rest assured, this would have made the Nobel Prize winning scientist very angry. There was little chance of him ever seeing it however. It was inside the lab.

It is not just Nobel Prize winning scientists who stay away from the plebeian confines of the laboratory. Almost all PHds stay away. The laboratory worker is the lowest member of any scientific project. Ironic? There are scientists, project managers, department heads and many more individuals, all of whom help create the degrees of separation. This is why Dr. Silvia Bulfone-Paus had the wool pulled over her eyes by her scientific misconductors. 12 papers now have to be retracted which will effect the other non-laboratory scientists. Their lab staff may have already tried to replicate the results that were a part of the misconduct. At this point it becomes a toss up between who is right, your lab tech or the published (un-retracted) paper. It's hard to use laboratory data to refute published data. Non-laboratory scientists prefer published data.

The quest for fame and funding create this culture. That is what this Cargo Cult Scientist believes. Toiling away in the lab for days only to find out your protein was misfolded or your reagents were at the wrong pH in step 27 is tough. It's also boring. You end up in an office with the non-laboratory scientists explaining what happened. If it is what they wanted to happen you will have an easy time. If it's not the mood turns dark and the relationship becomes more adversarial. But reality is best observed in the laboratory. That is where we need to go back to. Considering how much money has been lost in the industry, can we afford to keep the degrees of separation in place?

WikiScienceLeaks?

Once again we see an old pattern. A scientist wants the world to work the way they think it does. They've done all the right things and they are in a position to help write/rewrite the texts books used in Universities throughout the world. They must be scientists! So it is time to get to work and publish everything you can that supports your career. There may not be time to follow Feynmans recommendation:

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 journal Nature seems to be against this idea.

An unknown agitator using the presumed pseudonym Marco Berns is engaged in an e-mail and Internet offensive against two biomedical researchers whom he accuses of scientific fraud.

It seems as though they (Nature) are against "blinding". This agitators greatest crime is his/her anonymity. What do we know about the people who wrote this article in Nature? They represent authority just like Silvia Bulfone-Paus in her role as a principle investigator. What really matters? Are we religiously placing faith in Nature editors and tenured professors? Perhaps anonymity is a scientific imperative. There needs to be a "blinding" of the judges and those presenting the case. Then take a different angle at looking at the problem. That is what we do in clinical trials. That is what we do in the laboratory with our "controls". The content of the claims is what needs to be analyzed. Rather than addressing the issues, Nature has chosen to attack an unknown person for going about things the wrong way. But what are the chances of getting Nature or the Research Center Borstel to explain to the rest of us how they came to their conclusions? Is it not a pattern for these organizations to protect the scientists and attack their detractors through anonymous reasoning? Just trust them because they are in charge?

What you don't hear about in many articles about the Silvia Bulfone-Paus story is what exactly her "agitator" is saying. It is interesting stuff. This is the stuff you want to know if you are honestly doing what Feynman suggests. I'm not talking about IL15 and the papers that need to be retracted. I'm talking about whether or not Silvia was not at fault. The data that was fabricated supported her story. She didn't look into it nor did anyone else try to repeat a simple western blot. The false data fit her story and she stuck with it. It's a crime against the good name of science.

Why Sequence Your Genome?

As one reporter puts it, "it’s worth remembering that it took $3 billion and about 13 years just to sequence one genome, and as of a couple years ago, it was so expensive and time-consuming, only about a dozen or so complete genomes were sequenced. Today, a company tells the world it will sequence 615 complete genomes for a single customer, and Wall Street gives it a paltry 5 percent stock lift".

The problem with sequencing your genome is this. You can take your car apart and lay out each part in a line. Maybe photograph each part and catalog it in a book. What does it mean? You still don't know how your car operated. Now imagine a new company trying to sell you a technology that makes the dismantling and cataloging of the parts 10 times faster. So what?

They need to put some wealth into their system.

I had a professor tell the class that most of the DNA in our genome is junk. It didn't do anything. He was referring to the fact that genes make proteins and that is doing something. The rest is doing nothing. Arrogance! When certain environmental changes occur a stem cell will decide to become a specific kind of cell. How does the linear sequence of nucleotides change? Perhaps not at all but certain genes will cease to "do something" while others will begin to "do something".

Of course there are many many scientists who are working to explain what DNA does. Geospiza for example, is a company that makes software for biologists to analyze genomic data. Biologists are taught to know what DNA is. They know about the nucleotides and the phosphate backbone and so on. But what do they know about translating a DNA sequence into an explanation of life? I guess that's what the software is suppose to help them do. That is the most interesting aspect of genome sequencing. If only there was a translator to accompany the sequencer! I don't believe one exists. Indeed, the field of Genetics is full of cargo cult scientists.

So where is the profit in the new superfast DNA sequencers? Those with the money and an almost religious faith in "science" will have their genomes sequenced and rely on their doctors to tell them if they are at risk for certain diseases. For example, the ApoE-ε4 gene isoform is tied to an increased vulnerability to Alzheimer's. There is nothing you can do about it but some people want to know what to expect. Probably not enough however to turn a profit. One would think that the rapid sequencer companies would have a genetics branch in R&D to explain what your sequence means. Imagine your future is written in book form in Spanish. Wouldn't you hope for at least a translator to tell you what the book says? The sequencer companies have a business model for half a product. They are too blinded by how neat the first half is.

What if the Genetics scientists were the real customers for the sequencing machines? Sequence one persons DNA every month for his/her life. How does it change? What do the changes mean? What if you had identical twins and one smoked and the other did not? What happens to the linear sequence of nucleotides on a genome then?

We have to build wealth into this system. It can be done. It is very interesting for reasons no one is talking about. It's not sexy and it's not going to result in a Nobel Prize for a young scientist anytime soon. Rather this kind of research should be done by a group who toils for the lifetime of the subjects being tested. After we all die the next group of scientists will still have to try and make sense of the variations. The telomeres fade away. We see anuploidy in cancer cells. Point mutations, silent mutations, hairpin loops and on and on. How does any of this happen and what does it mean?

What Works

Biogen Idec runs in the black. It generated $4.37 billion in revenue in 2009, and has a workforce with 4,275 employees at last count. The R&D budget was about $1.3 billion in 2009.

Despite all that, Biogen hasn’t been able to deliver a new FDA approved product since natalizumab (Tysabri) in 2004. The lack of R&D output has prompted blistering critiques from billionaire investor Carl Icahn, who accused the company in 2009 of suffering from “failed leadership.”

Last year was the first time in a decade that Pfizer Inc., the world’s largest drugmaker, as well as Merck, Eli Lilly & Co. and Bristol-Myers Squibb Co., each failed to win regulatory backing for a new molecular compound.

The airplanes did not come!

Leadership? Finance experts telling scientists how to do their job? Businessmen who run companies have all the answers as to why scientists in their organizations aren't producing. But what about this?

Brain plaques, long considered the chief killer of brain cells and the cause of Alzheimer's disease, may actually play a protective role under a new theory that is changing the way researchers think about the disease.

Imagine that. Scientists have been trying to treat a disease by possibly attacking a protective response by the body.

Scientists in biotech succeed all the time. For example, if you have an protein drug, scientists successfully identify cleavage products that are considered impurities. Next the scientists successfully remove those impurities. Science, when properly applied, gets the job done.

What have drug companies mentioned above been missing? Perhaps they could hire a team of scientists to look into what targets are taking them down the wrong road. The "experts" have lead the drug manufacturers into the state they are currently in. Perhaps a new biotechnology could one day arise that sells unbiased assessments of the path they are currently on. No Yes Men!

Merck Logic

Merck has a plan. The new Chief Executive Officer Kenneth Frazier said the company will make “tough” research spending decisions while developing innovative products.

Merck hosts regular symposia where its finance experts teach scientists how to seek better return on invested capital, Frazier said. The three-year return is now tied to researchers’ compensation, he said.

Finance experts? Teaching scientists? We at the CCS are of the belief that no one who works in finance holds half the expertise in their field as the average mechanic holds in theirs. We clearly do not believe that a scientist can be taught anything. Their arrogance prohibits them from being on the learning side of the any educational scenario.

I guess we all want to be the expert/teacher. Those running Cargo Cult Airports teach their underlings how to run the Cult. The underlings (middle management) hire the people who run the airport. Upper management then lives and dies on the Cargo. How far gone must Merck be to have finance employees telling scientists how to get the most out of their R&D budgets?

Why is this story not scorned by the entire world, let alone some lone voice that can be heard? My voice is not heard. No one is going to say, "the CCS makes a valid point, Merck has tied finance to science and that just doesn't make any sense". But if you are like me, you get in your time machine and you go back and listen to all of the intelligent talk about how Merck and Pfizer and all the rest were going to turn things around and start getting drugs approved. Then you come back to the present and you see how they did.

I leave you now to hop into that time machine. I will travel three years down the road to see the how this plan worked out.

Writing About Work

In order to build "wealth into our system" we have to learn how to write. In school we are taught how the English language is to be used properly. Grammatical errors in any course your take may just lower your score. You could use a double negative on an essay question in history class and you lose points. Proper English is always important. What is just as important in science is knowing what needs to be documented.

That may just show my own bias towards certain people I've worked with. The worst of the worst rarely put anything in writing. When they do you almost always have to ask for clarification. The best of the best always try to get what matters written down. Yet even in college the laboratory notebook is taken for granted. It's another thing that is graded. Mistakes are quantitated. The more you make the worse your grade. However, the biggest mistake is to not say anything about something that people are going to want to know. Most often you are going be that person.

The FDA, your scientific misconduct investigators, your PI, your boss are also groups of people who are going to want to know what you do in the laboratory. Most likely you're going to be in trouble if these guys come snooping into your notebook. They are going to grade your notebook. The Baltimore Case gives us keen insight into how this works. A postdoctoral fellow in Imanishi-Kari's laboratory, Margot O'Toole, could not reproduce the results from an experiment that was discussed in a paper published in Cell. Once an office bound scientist publishes something, they protect their claims in a most unscientific way. They did not compare notes taken by two different people who performed the work in the lab. They took what suited their story best and stuck with it using their authority to silence the confounding evidence. But Margot had her data. She used it to make her case. A personal conflict between the two scientists developed. Margot O'Toole bravely went forth with her laboratory notebook to back up her story. What happened next was non-science and Imanishi-Kari and Baltimore got away with their misconduct. Margot O'Toole spent the next few years working out of science as a result.

This would appear to indicate that Margot O'Toole did not have compelling evidence written in her notebooks. It was however alleged that Imanishi-Kari was the one who had not been adept at keeping notes on her work.

"I was supposedly wasting materials by doing the experiment and coming up with the wrong answers." Shortly thereafter she was demoted to breeding lab mice. Then, in the course of researching the heredity of one particular mouse, O'Toole consulted lab notebooks used by Imanishi-Kari and made an astonishing discovery: The data recorded there didn't support Imanishi-Kari's conclusions either. "I knew [the conclusions] had been fudged," says O'Toole. "Finally the world made sense again to me."

Writing down what you do is a skill. You don't always realize something is important when it is happening. Imanishi-Kari didn't realize that there was evidence left behind that what happened with O'Toole was the expected outcome. The laboratory notebook had the real story. The journal Cell, was lied to. This leads to a very important piece to what Feynman was talking about when he spoke of building wealth into a system of discovery. The things you observe and take note of can lead to the truth. Even if you write down that you looked up at the moon last week and it wasn't there, you have useful information. The moon was there but we had an eclipse. You just didn't know about the eclipse. Not seeing the moon (okay I know you can still see it) doesn't mean the moon failed to exist. So just be honest and you will be rewarded. Do what Baltimore and Imanishi-Kari do and you will probably get published more often, but you will not get the rewards that scientific people care about.

Celebrex is an example of how the Pharmaceutical industry doesn't get this. Pfizer had clinical trial data that showed how the use of this pill increased the likelihood of heart attack and stroke. The FDA doesn't require the drug companies to disclose information on every trial so they do not actually have the ability to protect us. They hear what the drug companies chose to tell them.

In summary, the idea is to try to give all of the information to
help others to judge the value of your contribution; not just the
information that leads to judgment in one particular direction or
another.

Keep good records, even when you don't know what they mean. It will come to you later when you have more information.

AstraZeneca vs the CCS

In a drunkards walk there was an example of decisions based on improper data sets. A movie producer was hailed as a success after a string of money making films. Then there was a string of less successful films and she was fired. If the data set was taken as one set, the leadership would have realized that the producer was par for the course over of her tenure.

AstraZeneca is going down the same path. The CEO believes in R&D.

Brennan’s commitment to research has its origins at Merck & Co., when the U.S. drugmaker dominated global drug discovery and blockbusters were easier to find. He joined Whitehouse Station, New Jersey-based Merck as a 21-year-old salesman in 1975, and was there when the company’s labs pioneered new ways to treat hypertension and cholesterol.

“This is what David saw happening,” says P. Roy Vagelos, who ran Merck’s R&D and later, when he became CEO, promoted Brennan to run its collaboration with Swedish drugmaker Astra AB, a predecessor to AstraZeneca.

David, the CEO, saw something happening at Merck while working as a salesman. Now he is a CEO and he is going to save the science culture at AstraZeneca. He finds others who have succeeded, so he thinks. Let us refer to the Cargo Cult Science speach once again. The natives observed the Allied forces building and operating their airport. They took notes and replicated the work. How is David saving R&D? By hiring people he thinks have succeeded.

Menelas Pangalos helped build an industry-leading pipeline of experimental drugs at Wyeth, helping persuade Pfizer Inc. to buy the company in 2009 for $68 billion. He was lauded by New York-based Pfizer’s then-CEO Jeffrey Kindler for his “incomparable” expertise.

At 43 Panalos has not had a history of scientific success. He was in the right place at the right time when some "experimental drugs" were put into a pipeline. Where are those drugs now? What exactly did Panalos do?

Like the movie producer, people in positions such as Panalos live and die on the decisions of others. Statistics tell us that someone has to emerge in the position Panalos was in that so impressed David. Together they have gone over the highly unsuccessful R&D branch (the airport) and they have honed it into what they think will work. It sounds as though they've sat in an office and worked out a plan to change the shape of the Cargo Cult Airport Controllers' "two wooden headphones and bars of bamboo sticking out like antennas".

But wait, they brought in a scientist. Martin Mackay is president of R&D. Now we are going to get closer to the problem. In a recent setback the U.K. drugmaker failed to win U.S. approval for a new blood thinner, Brilanta, to rival Plavix, the world’s second-best selling drug. Regulators didn’t ask for new clinical trials for the drug. and “Our highest priority is to provide the requested Plato analyses to the FDA,” Martin Mackay, AstraZeneca’s president of research and development, said in the company’s statement.

So Martins job is to articulate what the company is doing scientifically. The people he communicates with are indeed part of the problem. The FDA, the board of directors... All of these people are convinced that they are the judge and jury of scienticif merit and progress. As we have seen, even their success stories lead to death and/or a lower quality of life. The formula AstraZeneca has come up with puts new symbols into a formula that never calculated anything. It is the logic that is missing.

I would suggest taking one project at AstraZeneca and subject it to the CCS Manual For Discovery. What seems trivial to the big picture guys is actually the core of scientific discovery. Building a solid foundation for a project is non-negotiable. What was once considered trivial must now be written about by the highest members of the R&D staff. It must be clear to the laboratory workers what the leadership thinks is happening. Then give the laboratory staff the opportunity to "bend over backwards to prove them wrong". Most importantly, document everything. In general, I suggest flipping the project upside down for a change. Let the guys in the lab judge the words of the executives. After all, they have scientific backgrounds and laboratories to help them make their points. People in offices have their words and their arrogance. That is the old formula. Nothing has changed at AstraZeneca. The new leadership is focused on dealing with issues left behind by the old leadership. The laboratory scientists are left in their labs to figure out the new structure of discovery while those who created it try to get the FDA to approve Brilinta.

The Next Step

Version one of your companies manual has been written. There are various chapters describing all of the groups, their roles and the roles of their members. There are details about communication and who has what responsibility. Now lets focus on what matter most to the company, the product or service. In the case of our fictional company, the product is a service where we help biotech companies stray from the status quo and start making real discoveries by following a path. This path quickly discards things that do not work. The path has the ability to identify things that are working and will work in the real life scenario.

The status quo tells us that PHds are the leaders and those who fell short of the PHd is the followers. However, our company employs purists. Our University system is not a group of vocational schools. If in fact the world were fair, leadership roles would employ the best leaders. If the University system selected for the best of the best, their PHds would compete for and win most of the leadership roles in a biotech company. As it is, a PHd is required for leadership positions. This precludes any chance of a newly minted PHd earning a leadership role in an environment very different from the one they previously succeeded in (college). The PHd is simply given a leadership role instead of being given a chance at earning it.

Let's consider a PHd who is hired to run a protein purification group. Developing methods and using cutting edge systems and leading others are not things taught in graduate school. Quite frankly, most University laboratories can't afford the same technology as industry. What is needed is a specialist. The medical field has long had specialized doctors who require a very different education from other MDs. A cardiac surgeon differs from a Gynecologist. The protein purification group requires a leader who also has a specialized education. There is little chance that a PHd will come out of the university properly educated to perform the tasks required by industry. Therefore the PHd must be taught. The manual will provide a path the new leader must take. He/she must learn how to develop, how the equipment and the operators work, and how to lead.

True leadership will not hire and hand over responsibility. The leaders will hire someone to fill the purification leadership role. They will then provide the education that is needed.

Finally, leadership requires something that most people just assume PHds do well. We assume PHds know how to communicate. We assume they speak and write in full sentences. Give this a test. Secretly record a conversation you have with a friend. Type out the words that are spoken and see how many proper sentences are spoken. The chances are there will be a correlation between education level and percentage of full sentences. But there will be many outliers who must be dealt with. The non-PHd who communicates well and understands methods must be promoted. The PHd who is the opposite must be demoted. This is a business model, not a PHd club.

To conclude todays topic, the University system is not a vocational system. Don't assume the answer to scientific discovery is the PHd. It's what the PHd does that leads to success not what they did in the past. You must provide them with the platform on which they will work. It's your company, not theirs. A biotech company shouldn't be started and left to succeed or fail by people who did not participate in the founding ideology of the company. They are just looking for a job like everyone else. It is the job of leaders to define the job and give the workers every chance at succeeding.

A Manual for Discovery

How arrogant must I be to propose that I could help anyone discover the truth about anything? But of course, this is just a thought experiment. I'm doing it on a blog that I assume no one reads. So I can do it. I can invent a biotechnology company that does succeed.

We are talking about business, of which I know nothing. But since biotechs are run by people who know nothing of science then I will put together a business plan. I will assume the executive and administrative are simple. I will search for people with the proper qualifications and looks. There will be no board since this company is run on my own vast fortune. Therefore, the executive staff will answer to me. They will all be paid a cut below the scientific staff. A new paradigm for sure. Our mission will be to create a company that has a platform of discovery that can be sold to others. That is our product, a platform for discovery.

Scientific progress is not done by hiring smart people to figure out that which you do not know. You are the ones who start your business. You must hire smart people to follow your plan. If your plan is to tell other people to discover a cure for cancer and the only thing you give them to go on is RNAi technology or monoclonal antibody technology, you are going to fail. If my company is hired, we will run a scenario, start to finish, of your plan. How do you go from a basic concept of using technology X to cure disease Y?

But we are here to help. You will be writing a manual for The Company with our help. Like any act of writing, you can't just start with a pencil and a piece of paper. We'll give you a template. When any employee in the corporate world is told to evaluate themselves, they are given a template. What were your goals? Did you acheive all of your goals? What could you have done better? So our template would help you evaluate your company discovery platform. Fill in your introduction and mission statement. Lay out your justifications and methods. Explain the kind of people who you need and what the scope of their work will be. Timelines? Fill in the data where we have provided the space in our template. All you will need will be the answers to the questions.

It's easier for the board and the execs and all of the potential partners to not have such a template. But the high rate of failure has provided a good reason to rethink the old business model. So step one is to acknowledge that you need a platform of discovery. It needs to be put into writing in a specific way.

Epiphanies of 2010

I was sitting in the break room when I came across a publication called Pharmaceutical Manufacturing. It was volume 9, issue 1. The article was 'Tech Transfer: Do It Right'. Sounds boring I know but the following excerpt explained the latest debacle of my career. My latest job was abysmal.

There are two groups in biopharma today: those who "get" tech transfer and those who don't. For those in the first group, technology transfer is a mature discipline that follows a structured approach, with predictable outcomes. For those in the other, tech transfer is a perennially new frontier with surprises at every turn.

There seems to be a pattern in biotechnology of people who don't "get it". We all study science but we don't all see the structures that lead to real progress. Most work is begun at the top levels. The executives present the board with ideas for research projects. Drug targets like TNF alpha and Amyloid beta are popular due to the massive profits that can be made off of people growing old and falling apart. TNF alpha is a molecule targeted by several products already on the market. It can be prescribed for aches and pains as well as for cancer. Amyloid beta is the protein found in plaques that form in alzheimer's patients. Executives and board members keep thinking that a molecule can be found that will bind to a certain region of the protein and prevent the plaques from forming. A simple minded approach to a complex problem. Once the executives have made their decisions it's handed off to the next level down, the scientists.

The scientists read up on the literature and go off into the perennially new frontier with surprises at every turn. Junior personnel without PHds generally do the laboratory work and end up taking the brunt of the criticism for ideas that don't pan out. This leads me to the second epiphany I had in 2010.

The Handbook of Process Chromatography is a manual that describes ways in which to develop purification methods. It depicts methods for developing methods. It occurred to me that there is no such book for conducting scientific research. As Feynman said, we assume that we are teaching people how to arrange things so that they get some
wealth in their system. The Handbook does just that. It teaches people how to arrange their process development efforts so that they can get work done as quickly as possible. Each company should have a handbook that describes their process for developing drugs. But there isn't one. They call it creative minds at work. But that is where process chromatography was 40 years ago. They showed up and winged it. Somewhere along the way a small percentage of forward thinkers make progress and set up systems. We have yet to articulate the system of translating ideas from the boardroom to the market.

Non Religious Women Have Better Sex Lives

This post is not about religion or sex. I thought of a "research study" that I thought would get peoples attention. Religion and sex are attention grabbing topics. Why not put them together and add in my own bias towards a blissful non-religious world? If I could fund the research, I could find people to do the work, let them know what my expected outcome is, only accept outcomes that fit the title and this headline would make the news.

It takes on the notion that women who are atheists are rewarded with better sexual satisfaction. Religion and sex may have nothing to do with each other however. In statistics we have the example that home break-ins increase in the summer months. Thus one can make the case that as ice cream consumption increases, so does home invasion. We haven't actually said that eating ice cream makes people want to break into a house. The truth is that the weather leads to an increase in ice cream consumption, home invasions and other things like days spent on the beach. Correlation is not causation.

The title does not state that atheism causes a better sex life. It states a possible correlation. It simply says that, as a population, atheist women may enjoy sex more than their religious counterparts. If you put this up on the Huffington Post you will get a spate of responses that have little to do with defending the science behind the study. People will respond to the title of the study. Religious folk who are open minded about sex will shout it down by sharing their own sexual outlook. Religious folk who are not open minded about sex may condemn the study as being biased. Atheists will say that they knew it all along. The scientist however, will respond to what they feel the data is depicting. Maybe the study was flawed and the religious group of women were all catholic nuns and the atheist women came from the local strip club.

If Dr. Ioannidis is correct and roughly 90% of the medical research that doctors rely on is misleading, exaggerated, or flat-out-wrong, then the question is why. Why do we as scientists select for research that is interesting as opposed to being true? We know that what is true should trump what is more interesting. It should be just as interesting to the scientific community to find out that there is no correlation between religion and sex.

Feynman touches on this with the example of the scientist who tested the maze used in mouse studies. The scientist tested the test (the maze) and found that there was an alternative explanation why mice do what they do inside a maze. The sound or texture of the floor below them led them to the door where food was previously found. The science is in telling the mouse testing world that they have to control for extraneous signals that will confound their research. That should be of interest to scientists.

Getting someone to listen to you is what anyone who desires to move up the ranks of their field needs to do. The trick in science is to get people interested in simple truths. If a study is interesting enough to get funding, it's interesting enough to be published. Imagine a science journal that publishes experimental design then later publishes the outcome. Reviewers of the work have their reviews published along with study. Review the proposed study. Review the work. Review the conclusions. Then review the reviews. Give researchers attention before during and after their work and they'll go back to pursuing what is true versus what will produce most eye catching headlines.