400 Million Dollars

I wanted to go with a more positive note today. Then I saw a report on a 400 million dollar planning experiment. In 1997 the Washington Department of Transportation set out to replace the 520 bridge that connects Seattle to the opposite side of Lake Washington. The old bridge remains in place. I couldn't go on with a positive attitude. A few gems from the research into the spending showed projections of starting construction in 2002 and 2004. Tolls were set and never put in place. Starting later this year (???) a toll system will be put in place with scanners and varying tolls based on the time of day. Out of towners will be billed (unbeknownst to them) by taking a photo of their license plate and sending them their bill for 5 dollars in the mail. I couldn't believe how badly local officials can do their job and get away with it. We are shutting schools down out here to save sums of money far less than 400 million dollars.

This is what a Cargo Cult does. They plan, they design, they talk and the use up resources with almost no regard to the actual goal. The cargo in this case is a bigger bridge that will ease congestion during peak travel times.

Allow me to digress and mention the "positive" story I was going to write about. It is related to the 400 million dollar bridge plan. I recently went to New England Biolabs (NEB) in Ipswich MA. NEB sells restriction enzymes for cloning DNA. They are a rare biotech company because they make money. They also use a portion of the money on environmental causes. For example, when planning to build their headquarters, they ran into the obstacle of three 200 year old Birch trees. They could have easily chopped them down. They spent over a million dollars extra to save the trees. The company is owned by one man, who at the age of 80 goes to work everyday in his own lab. The running of the company has been turned over to the younger generation. The old man conducts science in hopes of finding new ways of extracting energy from things like lobster shells.

The old man must have had a plan. He did not cash in and sell the company. As a result, the old man did not have to argue with investors over whether or not he could shell out the million plus to save three old trees. The employees could relax and do their jobs without fear of shutting down. Research tools were developed to help users use the products, free of charge. The plan was to make NEB synonymous with molecular biology while respecting employees/customers and our world.

What then can we say about the 400 million dollar bridge plan? There is a lot that can be learned from the investment. The problem however, is that the lessons are considered negative. We want to be positive. We want a bigger bridge. We don't want to sit around bickering about who wasted what and why we didn't stop them. Yet that is important to know.

It is the study of the Cargo Cult. The cargo in this case is a bigger bridge. After 13 years and 400 million dollars, we still have the same old bridge. But that is not all we have. We have 13 years of plans. You can research this. Surely something went wrong. It is not negative to want to find out why. The bridge planning leadership will accuse the Cargo Cult Scientists of seeking to judge and blame, but a science merely seeks the truth.

So I am left wondering two things: 1) Why did New England Biolabs succeed? 2) Why did WSDOT fail? There are concrete logical practices that could explain both.

BMS and California

Corporations don't commit crimes, their people do.

Bristol Meyer Squibb is full of criminals. They paid $515 million in 2007 to settle allegations by the federal government and other states that it used a kickback scheme to defraud the Medicare and Medicaid insurance programs. Now the state of California is going after them. Apparently it is illegal to bribe doctors to get them to prescribe your pills. The article makes the claim that BMS had paid out of 15,000 bribes in a six year period.

Let us not leave out the blame to be placed directly on the medical profession. Doctors don't want to sit down with their patients and explain the relationship between diet and exercise. They deal with the relationship between sickness and pills.

Cargo Cult Journals

I've come across a most interesting contributor to the idea that science is simply the pursuit of the truth. Bruce G. Charlton is a Professor of Theoretical Medicine, University of Buckingham, and was formerly the editor of the journal Medical Hypothesis. He was fired from his position after the journal was taken over by Elsevier and Dr. Charlton had decided to publish a paper from Peter Duesburg.

In their actions towards Medical Hypotheses, the publishers (Reed-Elsevier - who publish about 20 percent of the world scholarly journals, and a higher proportion of those journals with high impact in their fields) decided what went into the scholarly literature and what did not.

One of the great threats to science (the truth) comes from the demands of a large group of human beings. Many will engage in the competition to be in charge of the group. Elsevier executives must know what the corporate identity is and what they can do to preserve it. Mentioning Peter Duesburg is taboo within Elsevier so they had to remove Dr. Charlton from his position as editor. The next generation of scientists are also effected. They rely on being published by Elsevier journals. They too mustn't upset the non-living entity known as Elsevier. Their livelihoods depend upon understanding what is acceptable. The most successful will pursue what is not just acceptable, but what is favorable.

I'm going to explore some of the ideas (as I interpret them) presented by Dr. Charlton in greater detail later. The moral of todays post is that we are facing a monopoly in science. Executives at a large corporation are making decisions that should be left up to the talent. Elsevier took control of a journal and control of editorial decision making. Warren Buffet doesn't even operate this way. Buffet researches companies and buys the good ones. He leaves the management in place and lets them do their job. Science needs to learn this lesson. Smaller groups of humans means more groups of leadership. More groups of leadership assures a diversity of ideas. Since scientists are good at convincing people of both good and bad ideas, diversity is needed to get at the truth. When leadership is consolidated into one group we have lost a battle.

We here at the CCS dream of a journal of negative results. By asking scientists to write about things that did not work, we can get a fresh perspective on things like RNAi.

Another Dendreon Exec Departs

What is going on at Dendreon? Last year Dendreon lost a high ranking executive with no explanation. Varun Nanda, the Senior Vice President of Global Commercial Operations was said to be an arrogant egotistical a-hole but when did that ever work against an exec? Now they are losing the Chief Scientific Officer and co-founder of the company, David Urdal.

Anyone who has talked to me for more than two minutes knows that I have become bewitched, bewildered and bedazzled with the arrival of our first grandchild last April. The same month that the FDA brought us into a new era of cancer treatment with the approval of Provenge, my daughter brought the Urdal family into the next generation with the birth of my granddaughter – Ava. I look forward to seeing the world through her eyes and the eyes of the grandson we expect to see in June.”

“I am now in my sixteenth year with Dendreon and what an extraordinary journey it has been – the first autologous cellular immunotherapy approved by the FDA! What an achievement and what a pleasure it is to be a member of such a truly extraordinary team – the Dendreon team – as we won the high achievement of Provenge approval. We are just getting started.

Why would a high ranking member of Dendreon leave when they are just getting started? Because he wants to hang out with his grandkids? Do these types of people even take off work to watch their own kids grow up?

Something is wrong at Dendreon. They have a drug that has marginal efficacy. A lot of work has to go into bullshitting your way through life. Maybe he has grown tired of it and wants to take a rest.

Improving Early Stage Research

The NIH has a new one billion dollar plan to help the cargo cults get more airplanes to land on their runways. It seems that about 1 out of every 10,000 molecules selected to become drugs ever make it. And the biopharmaceutical research sector invested an estimated $65.3 billion to discover and develop new medicines in 2009. How does all of that money and brilliant science result in such failure?

The National Center for Advancing Translational Sciences has been created to fix the problem. According to NIH director Francis Collins, the goal is to develop old discarded drug development programs far enough to interest industry in finishing the job. The government is going to help the pharmaceutical industry get more drugs into the market. I guess they have some data that shows a correlation between the number of drug approvals with an improvement in the health of the American people.

To be fair, they are claiming to take on disease indications that are not profitable to big pharma. When the NIH scientists get to a certain stage, big pharma will take over. There will be a smooth tech transfer and drugs will be made available to help people.

It seems like the government is working for the drug companies. The new center will be in the same position as a small biotech company, offering up possible drug programs for pharmaceutical companies. How will this effect the claim of one molecule in ten thousand becoming a drug? Will government scientists improve early stage research or will they take the financial hit for some of the failures?

Me Talk Pretty One Day

After listening to a few panel discussions from this years WBBA Life Science Innovation Northwest, it became painfully obvious that an interest in science is of little use in the business of biotech. Ironically, neither is there much discussion on how to make investors money. The individuals speaking at the meetings were already making good livings off of other peoples money. Investors can make money in a number of ways, including betting against a public company. But the business of biotechnology has many different kinds of companies and business models. Innovation Northwest was a group of Cargo Cult leaders talking about ways in which to keep the gravy train rolling regardless of scientific progress.

Imagine if you will, the very first Innovation Northwest meeting 11 years ago. The individuals speaking at those meetings were all leaders of the field. They spoke of how to pursue an IPO, how to get initial funding, and all of the money ideas of the time. This years meeting was no different, only the ways of getting money have changed. It is much more difficult to get money because whatever they were talking about 11 years ago didn't go very well. One thing that the CCS takes great interest is in the ways people talk about things that aren't so. The tones of certainty that were used 11 years ago were probably the same as those used this year. It is a tone of certainty that makes you believe that what you are hearing is about progress. But is it?

James Randi spent his early career as a magician, tricking people into believing things that didn't seem to be real. He called it magic. If he were to be honest with the people he would take away the magic. For example, he would lay a pencil on a table and make it move with his mind. In reality he blew on the pencil to make it move. There was a misdirection involved where he appeared to be focusing really hard and thus causing he audience to focus on the pencil as well. While they started at the pencil his lips were free to pucker up and blow.

The tone of certainty is one such misdirection. While you sit and listen to the biotech leaders you get the sense of a pending success story. The same tone was in effect 11 years ago but we know something was amiss. People lost a great amount of money. However, had they listened closely 11 years ago, and this year as well, they would have heard the real story. The people speaking were speaking about making a company money, without making a product. They spoke of making partnerships. They spoke of being acquired. They did not speak of the tricks they intend to use to get the money. Making a product takes too long and costs too much. Seattle folk don't have the time, money nor expertise to do what is needed. They are selling something else. The question, is it real or is it bullshit?

The best way to sum up the concept of certainty, bullshit, and biotechnology is to take on the case of Sam Waksal. He wasn't an honest man. He didn't invent or discover Erbitux. He ran a biotech business. He got rich and went to jail long before Erbitux made its first sale. People lost money but Sammy made sure he and his friends and family weren't in that group. A few of them did some time and that is very sad. But what remains is Sams influence on the business. Sam does talk pretty and you have to when there is a book on your shameful career, yet you go on to found another biotech company.

How many speakers on the Innovation Northwest stage would shun the likes of Waksal. He speaks as they do. He knows the industry. People give him millions of dollars in spite of his history. Perhaps it is all about being a good magician. Get people writing checks and keep them from looking at the past. It's not a Cargo Cult, it's a shiny new biotech company and the future is looking bright. Trust us.

An Old Idea

The company is called NeuroPhage. The idea is one that I have personally worked on at several different companies. Bind something to amyloid beta (antibody, phage, peptide) and amyloid plaques will not form. The population of potential customers and their end of life spiral makes this disease indication enormously popular among biotechnology companies. You might call this one the holy grail of biotech.

The concept makes several assumptions. It is assumed that binding to amyloid beta in the laboratory will scale to binding amyloid beta inside the human brain. Scaling from a cell line in a petri dish, to an animal model, to a human being, is not something that bio-scientists can rely on.

It is assumed that preventing the formation of amyloid plaques will result a significant reduction in the symptoms of Alzheimers Disease.

It is assumed that phage will be more efficacious than using antibodies or small molecule approaches.

Having done this research I take great interest in the amyloid beta story. I watched others attempt to cure or treat this disease in Cargo Cult amazement. At the highest levels the amount of thought that seemed to go into the "research" was to hire people to find the binder. The executive view (and their investors) was to name the molecule and send in the lower ranking people to finish up the details... of curing Alzheimer's!

On NeuroPhages' website they offer up some evidence. They begin with the perfect world graphic arts version of the disease and how the drug will work. They then show two pictures. In one you see the plaques in a "vehicle control", which appears to be a brain slice. In the other picture there appears to be far less plaques. That is the drug working.

This is a red flag. Science is not done by selective photography. I've seen this trick used in many fields, especially RNAi. You show a knock-down by simply finding the highs and lows of a non-homogeneous system. In this case the system is a brain slice. As far as we know the pictures offered up could be from the same brain slice. We are left to trust the authors that they are not interested in pulling the wool over our eyes.

We're off to a bad start. Now comes the worst part. How do they propose the drug get into a humans brain? How do you measure phage floating around in a brain, breaking up plaques. The Alzheimer's patient is not officially diagnosed with the disease until after an autopsy. Where is the graphic art depiction of drug administration and finding of the target? There is an entire field of science that is not being addressed by the Cargo Cult here. It's called ADME. Tracking the phage on its journey into the body, to the plaques, breaking up the plaques and being cleared is not something that can be done. That frees up management to worry about other things like financing and perhaps adding information to one of the sparsest websites in the biz.

It won't work. I've seen it not work over and over. It's an idea that is taken to the point of, "what do we do next?" and left off to lower paid worker bees. In real science, this is the starting point. Did this really work? How did it work? Does it work every time? Will it work in a human being? The questions are instead left up to the white lab coat people who have only one option in reporting their findings, tell management it works and don't bother with the details that weren't ask for. Keep the story just as it is on the website. There is no turning back now. Look to the skies and wait for the delivery of the Cargo Airplane that carries the cure for Alzheimer's. Once it lands get your sales people together and get ready to make some money.

Delivering RNAi

I would be remiss if I were to not revisit the Cargo Cult of RNAi.

Last week we had a conference on the Cargo Cults of Seattle. RNAi was represented by PhaseRx. Since their inception they have had very little to report besides their 19 million dollar series A financing. They do however make very bold claims on their website.

RNAi therapeutics, also referred to as short interfering RNA or siRNA, have demonstrated broad applicability to many therapeutic areas, including cancer, inflammatory and autoimmune diseases, infectious disease and metabolic disorders.

These promising therapeutics are being held largely in check today by the lack of broadly applicable delivery technology. RNAi therapeutics generally cannot, on their own, penetrate the cell membrane and gain access to the cytoplasm where they can reach the drug targets.

The PhaseRx polymer system overcomes the central stumbling block in the field of RNAi therapeutics by delivering RNAi molecules into the cytoplasm where they can reach and inhibit the desired target of interest.

How do they have evidence of efficacy for the diseases if they've been held in check by delivery. Does their delivery include a ride straight to the cells of interest, avoiding a depletion of drug by being absorbed by other cells?

The problem is scalability. If you work as an engineer in a biopharmaceutical manufacturing facility you start small and scale up. There are certain relationships involved in scaling up that have been addressed by the industry, resulting in predictable outcomes. But with RNAi, they have predicted the outcomes without doing the research. The outcomes exist mostly on company websites. What do they now know that makes everything work where it failed in the past? As predicted by the CCS, the RNAi industry is not evolving.

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.

Five Years In the News

2010 Nice review
2009 BOOM
2008 ZING SON OF A...
2007 BLA-ZAMM
2006 OUCH
2005 POW

Okay, I'll stop at five years gone by. You get the idea.

A new decade is soon upon us. What will come? In the last decade we had a net loss of about 3500 jobs and an approximate 60% drop in market cap valuation. How shall we measure success from 2011 to 2020?

Biotech is Back Tonight

I've been typing away on this ridiculous forum of a blog since 2006. I'd left my latest job in biotech and I was at a loss to explain my life. Were these people honestly conducting what they thought science was or were they running a scam? I couldn't tell. So I started writing as a form of therapy. Why not, it was free.

It's 2010. The company I left back in 2006 is gone. They set a record on Wall Street for the rate of decreasing market capitalization. Impressive indeed. I moved onto another company that hasn't crashed yet, but in many ways could be more of a Cargo Cult than the previous company. I used the metaphor of fires along a cargo cult airport to track the comings and goings of the biotech companies. The fires have been burning out left and right since I began. Big ones like Zymogenetics, gone. Small ones like Homestead from Accelerator Corp. whom you never hear about. They just burn up a couple million bucks and they go away.

Tonight we have the Biotech Is Back forum taking place at the Path headquarters downtown. If you haven't seen this place let me set the stage. Paul Allen decided to "build it and they will come". He started building lab space, high rise apartments and high end commercial space to accommodate the well paid science community. In his "corridor" you will find a plethora of brand new spaces. As a fan of all things urban I am impressed and saddened that it is wasted on biotech. But there is a well funded high rise that houses the headquarters of PATH. Bill and Melinda Gates fund PATH, a non-profit organization that helps poor folk in third world places, including those in the good old USA. That doesn't mean the employees don't profit. They are living large. The ergonomic chairs in their cubicles are worth more than two years of the average salary of the people they are setting out to help in Africa. Tonight PATH will be hosting a forum where 4 of the few remaining biotech CEOs are going to try and make the case that biotech in Seattle is going to come roaring back.

I do not fault the sponsors. They are trying to make money. That's what good Americans do. I wish Biotechnology was into making money honestly for the sake of myself, our vendors and the people who need useful biotech products. But the forum, I fault! It's about bullshit. Biotech in Seattle is not back. It's the same people with the same tools trying to solve every problem in the same old ways.

In my next post I will compile a list of the companies that were here in the last ten years. You will see what happened and you can decide if biotech is back or not.

Daily dose of drug cuts risk of HIV for gay men: study

A total of 2,499 men at high risk of HIV infection participated in the study, which was conducted at 11 sites in Brazil, Ecuador, Peru, South Africa, Thailand and the United States. Half of study participants received the PrEP pill, while the other half were given the placebo.

In all, 64 HIV infections were recorded among the 1,248 study participants chosen at random to receive the dummy pill, while 36 HIV infections were recorded among the 1,251 participants who got the drug.

These are the last two paragraphs from an article from CTV News, the Canadian Press.

I've also cut and pasted their headline and used it as my own. The headline indicates that there is a risk of HIV and the drug "cuts" that risk for gay men. What the last paragraph shows is that less gay men in the drug group of the trial contracted HIV than in the placebo group. The "risk" in the headline is about the risk of being infected by the virus. This shouldn't be confused with the risk of dying of AIDS because you are HIV positive.

A true test would be unethical. 2500 HIV negative people are split in two groups just as they were in this trial (placebo vs drug). They are allowed only to have sex with men from a group of HIV positive men. The sexual encounters must be done without condoms.

The truth about the trial however is that the men were allowed to randomly have sex as they saw fit. Condom use was not measured. This issue appears to have been dealt with by providing both groups with safe sex education. The measurement of whether or not each participant took his daily pill was done on the honor system. Daily use was not true to the design of experiment but dealt with after the fact to the advantage of the pharmaceutical company paying for the trial.

And I could go on. What was the diet between groups. What were their incomes. Where did they go for sex? Then you take just the ones who contracted HIV. The list of variables is beyond our comprehension. Yet a fair trial would be unethical. Science is up against a whole lot when it comes to this kind of research. In the end all you have are two groups. In one, 5% get HIV. In the next, 3% get HIV. Surprising?

Game Changer!

RNAi and Roche

The RNAi world took a big hit this week. Had they listened to the lowly CCS they could have saved over 800 million dollars! Why am I not a high paid adviser in this industry.

I know of a couple people who swear that gene therapy works. I know of no one who says that RNAi works. Keep in mind, the people I know wear white lab coats at work and speak of results that they have seen first hand. The people I mostly poke fun at wear Friday business casual and work in offices. They conduct science in board rooms with white boards and powerpoint presentations as their only tool. They need a certain story to be told and they direct people to go and get certain results.

We still have a couple RNAi fires lighting our runway up here in the Northwest. Marina, formerly MDRNA, has been raising money in dribs and drabs for the past several years. Why did they take the RNA out of their name? Next is AVI Biopharma who work with RNA anti-sense, which is different than RNAi, but equally is certain to fail. Why get nit-picky with BS?

The problem I've always had with RNAi is that it is too easy. A PHd need only select a drug target then pretend that it has been knocked out. Hitherto you had to create a knock-out mouse which is hard to do and expensive. This bailed out a whole generation of lazy scientists. It reinvented old gene therapy farts who were at end of their wasted careers. It said to the world, we have a new tool box for fighting disease. You open that tool box and their is one hammer in there that they whack every problem with. Where are we now?

Finally, a major player has closed its books on this foolish pursuit. Others will have to come to the same conclusion, but this is still biotech. They will fight for their professional lives until the money dries up. But remember, you can trust the CCS. The RNAi cargo planes will never come.

Dendreon Stats Revisted

Provenge has traveled a rocky road. In 2007 it was recommended for FDA approval but not approved. Controversy surrounded the FDA decision. In 2010 it was approved.

On Wednesday the Centers for Medicare and Medicaid Services, or CMS, are going to review the drug.

Just last week a government health agency that studied Provenge on Medicare's behalf found only "moderate" evidence that it works. In the clinical trial that led to FDA approval, statistics on 512 patients demonstrated a median survival of a little more than two years, or four months longer than patients in the control group.

The question for Medicare is not about the cost of the drug. Their job is to assess the efficacy and safety of Provenge. In the background is the projected sales peak of nearly $2.3 billion in 2016. If Medicare gives Provenge a thumbs up, the stock price could increase 60% in 12 months. Based on the history of the reception of the data touting Provenge, I would say Medicare approval is a toss up. Add in the money to be made and the lobbying efforts of Dendreon, I would buy up as much of this stock as you can afford.

Biotech's Back Bullshit

Are Cargo Cult leaders honest, liars or bullshitters?

What is the motivation behind the "Biotech's Back in Seattle" forum.

In order for a Cargo Cult to survive you must convince people that the airplanes will arrive. The tribesmen are easy to convince. In the case of Seattle there are plenty of people around with the proper credentials to don a white lab coat and convince investors that there is a company engaged in research. You can find them working at Starbucks or the grocery store or even at the few remaining biotech firms up here. The investors are the real problem.

I want to point out the difference between what a tribesman thinks is in the Cargo planes and what an investor thinks. The tribesmen think that it will be great science that leads to lifelong prosperity making useful drugs. Investors think it's cash.

What does it take to get investor money? It takes bullshit. Investors in biotech have been notoriously susceptible to bullshit. That is because they are bullshitters too. They know bullshit when they see it. And when they think it's being done to the proper standards, they invest. Just check out the portfolio of the FrontPoint hedgefund.

Imagine the potential losses you could incur by running an investment firm with nothing but Seattle Biotechnology companies. I know what you're going to say, "you have to diversify". The point of this horrific financial scenario is to put yourself in the shoes of the target audience at Biotechs Back in Seattle. How much of what they are going to say will be bullshit and how much will be an honest assessment of the state of Seattle Biotech? Just look at the title of the forum! It's bullshit!

On Bullshit

Harry G. Frankfurt

Liquidity

It's really about money. Without money we can't live our lives. We could work in science but it would just be a hobby, like monks who contribute to scientific ideas such as genetic order or new math formulas.

As we eagerly await the Biotech is Back summit here in Seattle, we get the news that Ikaria has pulled the plug on their IPO.

We're coming back with the ferocity of a small African Gazelle.

Keep Flames Alive

Hilarious title

Are they reading my blog?

MBA Students Cheat?

One of the most interesting interviews from the report on the Central Florida University cheating scandal is at the end of this GMA report. where the student doesn't see why it's a big deal. More interesting than getting caught is A) the percentage of the class cheating and B) the attitude of the interviewee. It's not important. Everyone does it. He even claims that 100% have cheated on a test at one point or another.

I've said before what a waste it is to spend so many years of your life learning natural science only to end up a businessperson. To think the PHd in Biochemistry ends up in a group like these students is a shame. So I propose a new degree. Lying Cheating Bastard, LCB. My name is John Smith, LCB.

The degree is about bullshitting. Liars tell lies. Bullshitters don't care if they are telling the truth or not. They say what needs to be said, just like the students who found a way to pass a course at CFU. The LCB candidate must take courses all throughout the University system and at least pass them. Failure is not an option. After the course is completed the LCB graduate student must write a report on how he/she did it. Studying hard and learning the material is an option but more points are given for working around such a system. Of course, the LCB will be Big Pharma management material.

200 out of 600 students were caught cheating, thanks to the powers of statistical analysis. Ha! I've told the story about the car dealership where 11 out of 20 salesmen tried to steal money from a mentally retarded man who came in bragging about large sums of cash he kept at home. The percentage of dishonest people, all willing to act on the first opportunity to cheat, was astonishing. 33% of MBA candidates acted upon this opportunity to cheat. Could this number have been higher? How many of the other tests given to this population were cheated on? What do these students do once they enter the corporate world? Do they seek ways to continue tipping the scale in their favor? Statistically you would have to believe so.

The LCB idea might not take off. Let's just think of 1/3rd of MBAs as LCBs. The other 2/3rds probably won't make it in business.

The Logic of Picking the Perfect Ice Cream

This is my favorite analogy of the mindset that has plagued my biotech life.

How do you know what the truth is?

Location Location Location

Bio Nebraska: Inspire, Invent, Innovate... inNebraska

This is not a criticism, like the usual post. I like the idea of people in a place like Nebraska thinking about science and technology. Most people think they are all farmers. The CCS thinks that farmers are quite often smarter and much more honest than the average PHd. They have a lifestyle that allows for this. The PHd has pressure to publish and has way too much competition to maintain employment. The farmer wakes up each day and does what he has always done. It's a sustainable lifestyle versus publish or perish.

Why do biotechnology companies have to reside in San Diego, Boston or North Carolina? Inspiration and innovation occurs in the mind. You have in the United States a plethora of resources from educational institutions to wealthy locals to invest in ideas in all 50 states.

The creative mind of the corporate world however is such that success occurs only specific geographical locations. Yet Warren Buffet set up shop in Omaha, not Wall Street. What if he had chosen Wall Street? Berkshire Hathaway makes money by investing in organizations that make money, regardless of their location. Why is Biotech different? Why does the CEO of Dendreon worry that he won't be able to attract top talent if the location of Washington state scares them away due to its tax structure? Is the talent he seeks that superficial?

Where do ideas come from? How do you apply them to real world needs? The Cargo Cult Airports that I speak of are in the minds of individuals. They believe their degrees and those of their colleagues lead the way to innovation. The Cargo Cult Airports are people in boardrooms talking about what is needed but not specifically how to get it. They know where, who, why, when but not how.

Clinical Trial Fraud

MannKind's former senior director for regulatory affairs John Arditi is alleging that the company hid "scientific misconduct" from regulators. In a lawsuit filed Sept. 16, Arditi said he uncovered irregularities at Russian and Bulgarian trial sites, noting that patients at the Russian site were recorded as having the same blood pressure at several visits--something that is highly unlikely. In Bulgaria, patients were said to have been treated with the drug despite the fact that Afrezza packing slips indicate the drug had not yet been delivered to the site. Both issues points to the possibility of fake patients. The former exec further alleges that he was fired after bringing the issue to the company's attention.

Read more Clinical trial fraud accusations rock MannKind .

Mannkind is in for a fight Biotech companies never want to get into. Standard practice is to prepare a severance for the departing Cargo Cult Scientist with a clause that prevents him/her from exposing the Cargo Cult secrets. This one should be fun to watch.

Like Aubrey Blumnsohn, people with integrity and inside clinical trial information can be a real pain in the arse. The two cases differ in the kind of information that is meant to be hidden but they are the same in the struggle to tell the truth. You begin to question yourself, "does this matter"? Your superiors are saying that it does not and perhaps you are not smart enough to understand. You dig deep and try to prove yourself wrong. Your career is at stake. Does it matter? You can't prove yourself wrong. Not only do you think your concerns matter, but you think most rational people would agree.

In a sane world clinical trials be completely transparent. In the Cargo Cult you can still have fake patients. Once discovered you can't bring it to the attention of upper management without negative effects on your career. No one ever said leaving the Cargo Cult would be easy.

Herb and Dorothy Vogel

There is a very interesting documentary about two people who are the polar opposites of me. Herb and Dorothy were two art collectors living in NYC. Dorothy was a librarian and Herb worked at the post office. They used her salary to pay the bills and his to buy art. Their collection is now kept at the National Gallery of Art.

I enjoy art and visiting museums. I've even created a few paintings myself. But I don't understand how anyone can assess art. It seems to me that these types of judgements are too subjective. Yet Herbs lifetime postal salary was spent on art that he and his wife deemed to be important. In the end others agreed with them. Many of the artists who they supported early in life went on to become famous. Did they know something special or were they two eccentrics who got lucky?

I say I'm the polar opposite because I want to focus on things that can be quantitated. Paintings are simply good or bad. You can look at them, learn about them and enjoy them. A professional career deciding where a modern art painting falls on the genius to crap continuum would be almost purely nonsensical. By using science one can understand the world and even predict certain outcomes.

So how did Herb and Dorothy become famous? I think their NYC location was a part of it. They met artists you just don't meet in Cleveland or Omaha. Devoting an entire blue collar salary for investment increased their odds. In the end, they had their own special brand that lead people to believe in them.

I think of the Vogels like I think of a venture capitalist who focused on Biotechnology. Most of these types failed miserably. A few made it big. Who do we remember?