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Wednesday, September 21, 2011

A Cargo Cult Tribesman No More

After 18 years in Cargo Cult research (how to get the planes to come), I'm calling it quits. The planes never came. As we looked to the skies, fires lit along the runway, man in tower with coconut headset, the clouds floated by gracefully with no signs of even a distant jet stream. We stared upwards for hours, months, years, but they never came. We rearranged our airports, made new tiki torches to illuminate our ceremonies, changed radio ladies so our leaders could talk to the gods more clearly. It seemed like we couldn't fail. We had so much hope.

As I prepare to leave the Cargo Cults of Seattle, I must draw some final conclusions on what this has all been about. The blog, the work, the career must all come to an end. The traveling from town to town was Woodie Guthrie without a soul. This past summer I had an epiphany about what biotech/pharma is all about. On a dreary gray day early in summer, I made my way to an old theater in the University district that showed mostly documentaries and Indie films. The film was called Forks Over Knives. The two doctors featured in the film came from farms. They grew up eating food that they grew and/or killed themselves. They studied other cultures and learned that what we eat has a major factor on how we feel and how we die. I realized that I work in a field that treats the side effects of the American diet/exercise/stress lifestyle. We have pills for stress, insomnia, obesity, diabetes, stiff joints, restless legs, diarrhea, head-aches, cancer and AIDS. In the case of the last two illnesses, I'm convinced that some of the treatments make the situation worse. Because we have a hopeless population, we've gotten away with it. We don't want people to get better. We want them to die taking our $100K+ pill regime.

The real treatment for what ails us is diet and exercise. In the film, Forks Over Knives, patients given two year death sentences by their doctors were still alive after five years. Diabetes patients were no longer in need of the pills, much to the chagrin of their doctors. An old Chinese gentleman diagnosed with cancer talked about how his sex drive returned as a side effect of treating cancer with proper diet and exercise. It worked better than Viagra! The side effects of treating one target with pills are usually things like diarrhea and vomiting. The side effects of proper diet and exercise treatments are erectile functioning!

In Forks Over Knives I saw the real Cargo planes landing. On the other side of the island where we weren't allowed to go was an airport with Allied forces still operating. They demonstrated that the real way to treat what ails us is to ingest proper food. They taught me how to get "wealth into the system". I learned how to get the Cargo planes to land. I saw the cancer patients remain alive and well. I saw the diabetic who no longer needed his pills. The pills come after the sugar chains and processed boxed cereals, mashed potatoes and macaroni and cheese powder. The pills are the greasy eggs and sausage used to treat a hangover. When I see my older relatives, obese, suffering from heart disease and diabetes, I know I can help them. But they live on the Cargo Cult side of the island. They want the pills. Pills are hope. Pills are Cargo.

I've been angry about many things. I'm not the good obedient worker that George Carlin depicts in American Dream. I wanted to avoid the cubicle and the endless meetings. In the lab I found a place where being clever was a measurable quantity. If I clone a gene, grow it up, purify the protein, and run a binding test, I can watch my progress. I've seen people do that much work in two weeks. I've seen others flail away at such a project for years. I've seen the good and the bad and I know that they are aware of each other. The Allied forces airport workers know that the natives are on the other side of the island trying to emulate their airport. The contract manufacturing organization who requested that our director not attend the process development meetings was such a situation. Our small biotech company was not aware of the terms upstream and downstream process development so we labeled our director, "Scientist". Later it became director of target biology. He was the proverbial old lady with the wire wrapped around her (Cargo Cult radio) so our chief (CSO) could speak to the gods. When he met with what our cult thought were his real airport counterparts, they cut him out of the process. Happily he went back to the cult to prepare the next ceremony. He dealt with natives, not allied forces. He made me angry, as did the followers who adored him. The five people who left the part of the cult, including me, left shaking our heads. We represented nearly fifty percent of the Cargo Cult process development group. The first to leave came directly from the Allied side of the island. He left a note one day that read only, "Beam me up Scottie, no signs of intelligent life".

I don't know where to go now. It's hard to explain a career of working in this Nobel Prize winning lab, two failed teeny tiny southern California biotechs, one failed Seattle biotech and a final biotech hasn't failed yet, but is the most bizarre of them all. The Prusiner lab taught me that even a Nobel Laureate has a hard time interpreting a simple western blot. The antibody company in East LA sold themselves to a bigger company that failed clinical trials (phase III) in 2005 and called it quits after 20 years and half a billion dollars. The bio-informatics company folded up shop 9 months after I started after losing a battle with Rosetta to become a subsidiary of Merck. Rosetta was shut down last year. The nasal spray company fired the staff and replaced the CEO and CSO with RNAi successes from SIRNA. SIRNA was shut down a couple months ago. The RNAi company fired the CSO but kept the CEO. They are now on life support. And the most bizarre company of all have not made any news lately. Such an uncomfortable silence from a company that sells promises is usually a sign that they are ready to give up the scam and take their profits. What I know is that they have not taken a serious run at a second drug development candidate. The first candidate in the pipeline was successfully partnered up but it will never become a viable product due to a profound manufacturing incompetence. The other two candidates announced just last year will never be partnered up because they were announced to break the silence of a four year lack of productivity. The leaders of this Cargo Cult led a previous group of 90 that was shut down for their... lack of productivity.

For those who are not angry, you're not paying attention. I'm a concerned scientist who sees an industry ran by greed and other forces that destroy scientific integrity. The failure of so many projects and companies, compared to the success of Forks Over Knives, has led me to my belated decision to move along. My final experiment will be to continue on the Forks Over Knives path and live to be 100.
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.

Thursday, September 15, 2011

Multiple Intelligence

Every day in life we experience education. You learn something new every day. There are several concepts here that I think need to be explored in order to understand yourself and those around you.

If you were an A student, the chances are you have what Howard Gardner calls law professor intelligence. You have linguistic and logical intelligence. Think Naom Chomsky. If you are heavy on logic and weak on personal intelligence you are more like Ted Kazinski. Both obtained PhDs and found employment in highly regarded universities. Both went on to international fame. Both might be considered misanthropic with regards to some segment of our society. What was the intelligence that prevented Naom from falling into the same hole as Kazinski? As Naom pointed out on the video I posted last week, he put up with stupidity in order to reach the next level. Naom Chomsky believed the end justified the means. Kazinsky believed the means ruined the end. He saw the means as a filter that separated the good from the bad and the bad was what was left at the end.

Education is a filter. We have "weeding out" courses in science. Freshman chemistry can be a tough course for some and many will drop out. The first day of class there are 400 students. By the final exam you are at less than 100. Simply by looking at the percentage of drop-outs in a weed out class, we can get an idea who excels in logical intelligence. Where do the drop-outs go and do they then excel at their new class? Maybe they switch to English and get an A. They are word smart. How would Oscar Wilde have succeeded as a chemist?

We have many examples of extraordinary genius in logical intelligence. Autistic humans have an uncanny ability to do math, to see numbers as colors and shapes that comes together quickly for a logical conclusion. They may also be able to play Beethovens Moonlight Sonata after hearing it only one time. These are forms of intelligence we try to teach students. I think of it as intelligence chromatography. We have a resin that captures certain kinds of intelligence. We pass through the entire student body. Those that pass through we give Bs, Cs, Ds, and Fs. Those who get As stick to the resin. We can then pass them on to other resins. The linguistic and personal intelligence resin shows that our logical intelligent autistic A student is not fit for society. They move on to all Fs.

Who succeeds as A students in all forms of intelligence? The law professor! Lucky for the law professor we don't require that they get an A in gym. It is our society that puts together the list of intelligence to which one must demonstrate a stickiness. As we pass through the education system we must go through numerous intelligence chromatography columns. After education comes employment. Now is where biotechnology comes in.

Most biotechnology workers are of average intelligence. The average laboratory worker is content to remain in the lab cloning, purifying and running the assays. They would have been successful farmers or mill workers in an alternate era. They passed through the intelligence filters with a smattering of As Bs and Cs. The leadership excel in linguistic but not business logic. Their intelligence filters come from PhD programs in science. They lack the ability to translate good science into scientifically developed products. They would have been snake oil salesmen in an alternate era. The support industries, companies like GE Healthcare or Stratos Product Development, provide equipment that automate things like DNA sequencing, cell culture, and protein purification. They would have worked for GE in an alternate era.

I often wonder what would happen if you could get a small child from a modern day cult. How would they succeed in our society. Could they become biotech professionals? As they say, it's not how smart you are, it's how are you smart? I think they would do well. Show them the ritual to purifying DNA. Let them know when the ritual is to begin. They wouldn't aspire for more. They would look too the leaders and hope they get to share in some of the cargo. When it never comes they just keep performing their part of the ceremony meant to bring the cargo. When sent from the tribe they go and find another. They hope the ritual performance is equal to that of their would-be new tribe. The tribe, suspicious of other tribes probes them on their understanding of the cargo rituals. If they possess the proper intelligence they will be allowed in to perform their understanding of the ceremony.

Wednesday, September 14, 2011

Rice Fields

Once again Malcolm Gladwell has stopped me dead in my tracks and forced me to rush back to this ridiculous blog. The topic is rice fields. In Outliers Malcolm discusses Chinese peasants who meticulously set up their rice paddies. They have a clay bottom with mud and fertilizer base for the seeds. They are then flooded with water and tended to every day. There is a balance that is maintained by hand, not automation. What the peasants know is hard work and an exact science.

Conversely there are the peasants in Russia. They plant their seeds and hope for rain. Their form of farming relies on luck. The Russians believe that God will provide.

So what is the culture of biotechnology? On October 24, a meeting with the "leaders" in the field of sequencing genomes will convene. They believe that this is the future for medicine. Why? If you step back and take a different angle, you will see sequencing a genome as a research tool. One probability is that the future will be same as Retrogen or Qiagen. The people excited about it should have already done the kind of thinking that would make this tool desirable and not just another sequencing service for researchers. It is a tool. What to do with it?

Think of it this way. A prion is a mis-folded form of the PrP protein. The theory goes that the mis-folded protein causes the formation of plaques in the brain and eventually a horrific death. We now have a few end points to look for if we could just find a way of preventing the proteins from becoming mis-folded. We need a tool. That tool could be an antibody that only recognizes the mis-folded protein, not the normal PrP protein. The antibody will bind to the mis-folded protein and prevent its theoretical action of causing other PrP proteins to become mis-folded and joining hands to become a plaque. To be honest, I worked on such a project. Such an antibody is hard to find. We never found it nor has anyone else.

From the above paragraph the average sophmore should be able to create a list of projects one could embark on if they were magically handed the prion antibody. For example, coat 2 ELISA plates with 95 normal brain samples and 1 scrapie infected hamster. Test one plate with the anti-PrP antibody and the other with the new tool antibody. One plate will light up in all wells. The other plate will have only one well light up. Eureka! Next you move on to in vivo studies. You create analytical methods.

This type of research in fact takes place every day. We select targets, make antibodies and run them through our tests. Going back to the genome sequencing, we don't have a plan. Both situations are similar to the concept of planting seeds and hoping the Gods will provide. The board and the executives plant the seed and they leave the field work to the peasants. If the seed is strong and there is plenty of sunlight and rain, success will be certain.

Now back to the Chinese rice farmers. They do not take chances. They are extremely poor and failure is not an option. This is akin to what engineers do. If you make a car, everything must work. If the brakes go out or even if they squeak, you will have to go back to the drawing board. Therefore, each new version of car is built upon the history of making cars. Engineers develop the cars. Engineers develop the way in which a car is assembled. Engineers develop the assembly line!

Biotechnology executives however, have to hold public chat sessions where they discuss what can be done with the latest tool. They have given the problem some thought and are now ready to talk about it in public. In public speaking is what they are good at. Knowing what to do with new tools is not what they are good at. They are not like rice farmers or engineers. They are like Russian farmers who have planted a seed. A dust-bowl season will ruin the crop. That season is akin to a small handful of genetic researchers being the main customers of the $1000 human genome sequencing companies. The ideas that come from the stage of the upcoming meeting must inspire. They must convince the world that science is going to be turned upside down by this technology.

But we've heard this before. The human genome project created so many patents they had to end the practice of patenting genes. Where were the guys who knew what they were going to do with the genome sequence? Where are they now? The executives of the old companies got rich but what did we learn about our genome? Is it a useful tool? The new companies are like the old. They are hoping for someone, something to take a hold of their seeds and nurture them into a rich harvest for themselves. Whoever solves that problem won't be the ones up on the stage next October.

I've spoken about practical intelligence. A clever fellow with a high I.Q. can solve difficult math problems but he cannot necessarily become a successful human being. The rice farmers are peasants who live with little money. We on the other hand are successful humans with lots of money and comfortable lives. We rarely succeed. But facing the future of the human genome, who will solve the problem of "what to do with it?" It won't be the executives on the stage. It will be that guy with below average practical intelligence but above average problem solving skills. If biotechnology really wants to figure out what to do now, they have to put an end to the cheer leading, the mitigated speech and the low opinion of the peasants.

Tuesday, September 13, 2011

They'll Know It When They See It

Stewart Lyman from Xconomy gives a nice summary of how a drug can act within the body.

Drugs can directly stimulate (e.g. morphine) or block (HIV protease inhibitors) enzymes. They can bind to and sequester molecules (TNF blockers for rheumatoid arthritis). Drugs can replace missing molecules (insulin, hemophilia) and alter the rate of movement of molecules into or out of cells (anti-arrhythmics like sodium channel blockers). Some drugs stimulate the immune system (Provenge, Yervoy), change the pH balance in the body (sodium bicarbonate for acidosis), or interfere with the assembly or function of intracellular structures (anti-cancer drugs like taxanes). Drugs can stimulate the release of stored molecules (epinephrine), or interfere with DNA synthesis (sulfa antibiotics). Drugs can perturb cell membranes (anesthetics), and effect the modification of proteins, thereby altering their function (histone deacetylase inhibitors). In gene therapy, the drug is often a replacement gene; anti-sense drugs block the formation of proteins by binding up specific mRNAs.

Once you imagine a drug development project, what is the process? The target, where the action takes place, needs to be reached by the drug. Delivery becomes a new research project. How do you make the drug? Process development becomes a new project. The list goes on. What part of the puzzle is the role of a small biotechnology company? What is the responsibility of Big Pharma who is looking for a partnership to beef up their pipeline? What about the CROs, CMOs and the clinical trial branches of the process?

We assume that everyone knows their role. It begins with education. We set up a hierarchy. Responsibility of innovation falls upon the highest ranking members. The lower ranks must bring the innovation to fruition.

A better way to view the field of biotechnology drug development is to draw a straight line. On the X axis is time. On the Y axis is money. Assume ten years and 1 billion dollars. Where along that line are you searching for investment money? Where are you spending the most on clinical trials? Where along that line are you making the critical decision on the drug candidate?

Currently there is no graduate degree where you go through the entire process, without the spending of 1 billion dollars and ten years. We just hope the leaders will react to each situation in the proper way. A graduate degree would speed up the process by building a base of understanding what is coming down the pike. Base the courses on real life situations, such as the pricing mistakes of Dendreon. Maybe throw in a course on the history of financing so the students can have that trajectory in the back of their minds while they think about staying in business.

Undergraduate degrees can become more focused. Biochemistry, microbiology, molecular biology are all degrees that have become nothing more than vocational degrees for low level biotech lab jobs. Instead, focus all of the relevant information into the various areas of early stage research, process development, analytical development and so on. The graduate degree holders will know how to structure a company and thus they will know who to hire based on the education.

Overall, we need an end to the "we'll know it when we see it" process in biotechnology business strategy. You won't know it. It is not an ad hoc process to be ruled over individuals who feel they possess a special understanding of science. At this point it is fair to say that they are not very good at "knowing it when they see it". The weakest point along our line from 0 to ten years ($0 to $1 billion) comes in the early stages. What to do and what to select as the drug candidate is a very "know it when you see it" moment, and thus the weakest moment. It will make or break everything that happens along the line of progress. The rest of the work however is where we can focus education. You should not stumble in process development. It is not a "know it when you'll see it" process. It is not ad hoc. You take on the work, make a plan and you finish the job. The same goes for a clinical trial. Make a plan, execute and analyze. Need money? You have experts in that area.

Currently, Big Pharma is leaving that critical early stage "know it when we see it" up to small biotech. Big Pharma is setting themselves up for even greater failure than we are already experiencing. As Warren Buffet says, you don't ask the barber if you need a haircut. The education we require will not come from the current experts. They are experts in a failed experiment. In the process of getting smarter the cost of that drug development will go down. The time line will be reduced. Imagine a gant chart instead of the single line. Each line, each function along the way to approval becomes separate and can thus be analyzed and improved. Step one is to step back and look at where we are. Look at what we do. The real skill that is missing is not "knowing IT when we see IT". The skill is knowing how to get to "IT".

Sunday, September 11, 2011

Mitigated Speech

Every case of scientific misconduct involves a powerful scientist and dishonest or disgruntled underlings. In the case of Silvia Bulfone-Paus, two rogue post docs were assigned the blame for fraud. In the Baltimore Case a disgruntled post doc outed her P.I. Speaking truth to power is never easy, even when the powerful are scientists. They expect certain outcomes. If the truth differs from the expected outcome, you have a choice. Do you stick with the truth or do you tell the leader what they want to hear?

Telling the truth will require mitigated speech. You have to decide how to tell the powerful scientist something they don't want to hear. In a recent post I talked about a situation where the CEO of a biotechnology company would tell the white lab coat scientists what they were suppose to do in order to find drug delivering molecules. Point A, (do this) did not lead to point B (and you will have a drug delivering molecule). What was doable was point A. We could make a peptide library. Point B was scientific analysis of point A. To this date, no one has said to the leaders of the biotech company, "this isn't going to work".

The first question that really needed to be addressed was the logic behind the drug delivering holy grail research. The leadership had decided how the holy grail would be found. A peptide or protein would bind to certain cellular proteins and the binding would lead to all sorts of wonderful effects. But how did they know? We hadn't found the molecules that bind yet. Do you ask questions or do you do what you can and hope that things will work out? How do you deal with the research when you find a molecule that binds to it's intended target but the desired effect does not happen?

The term 'mitigated speech' was recently popularized by Malcolm Gladwell in his book, Outliers. He defines mitigated speech as "any attempt to downplay or sugarcoat the meaning of what is being said". He continues with reference to Fischer and Orasanu, to describe 6 degrees of mitigation with which we make suggestions to authority:

1. Command – “Strategy X is going to be implemented”

2. Team Obligation Statement – “We need to try strategy X”

3. Team Suggestion – “Why don’t we try strategy X?”

4. Query – “Do you think strategy X would help us in this situation?”

5. Preference – “Perhaps we should take a look at one of these Y alternatives”

6. Hint – “I wonder if we could run into any roadblocks on our current course”

Gladwell brings up the concept in the context of how crews relate to each other in the cockpit of a commercial airliner, graphically illustrating the degree to which mitigated speech can be detrimental in high risk situations which require clear communication. Gladwell also talks about different cultures and how they use mitigated speech.

What then can we make of the culture of science? It has been shown to be, at times, the art of deception. It is self correcting, but those who possess power work against the self correcting, as exhibited in the Baltimore Case. It pits the P.I. against the underlings, the office versus the lab. There is no way to correct a superior when they are wrong, other than to hope they are open to such a discussion. When a paper needs to be retracted everyone, scientists and journal editors, are embarrassed. They mitigate the need for the retraction or worse, they brush it under the rug.

A new way of communicating science is needed, Does mitigated speech stifle innovation?

Monday, September 05, 2011

Practical Intelligence and Success

The biotechnology and pharmaceutical industry continues to try and figure out new ways to encourage innovation. As patents expire and streams of revenue dry up, they need the next big thing. It's not that they didn't plan on this contingency. They knew these days would come and they shelled out the money to get people working in the laboratory. What happened?

The lack of innovation can be linked to what is ailing all of science. In a recent discussion on scientific journal retractions from "OnTheMedia" I found two comments from people who have interesting and similar concepts.

Paul Charles Leddy

Science is social, and if a bunch of morons decide to do science, they'll create a world of moronic truths. Those of us who don't want to live in a world filled with these "truths" have to be careful not to let the morons say what is truth. I think the past 10 years have shown this over and over. Same goes for journalism, btw.
Sep. 06 2011 12:43 AM

The key point here is that science is conducted by human beings and we tend to form groups of like-minded cohorts. We create the truth. Those with practical intelligence who want to be a success will gear their work towards the truth of the group, not the truth of nature.

p.f.henshaw from way uptown

Brook and Jonah,
You seem to be seeing only the manageable tip of the problem of finding and correcting errors in science. The cases where right and wrong are simple to identify are not the problem. Science never had, and can't have, a way to "purify" its archives, other than the same way nature purifies her complex systems to remove useless branches, by experiment and evolution.

The deep problem of modern science is that "useless branches" of thinking become the basis of social structures and clung to relentlessly. You see it in how the different "silos" of reasoning form around different socially preferred ways to ask the same questions. One dominant paradigm of that kind is "science as computers" with the dazzling display of results conveying the image of powerful insight, but if tested against the subject addressed often represents no insight at all.

Theorists tend not to study nature at all, just data, their theoretical models, and their social status. The naturalists who actually study the complex naturally behaving subjects of such a study are unable to contribute to the process, at all... don't even get brought in for discussion, for the simple reason that nature does NOT behave at all like a computer (!!) and the questions a naturalist would ask upset the social status of someone representing their theory as nature! ;-) See the problem?

So the core of the problem is the social basis of the questions that each science and sub-science organizes itself around, not just our present self-defeating obsession with computers. As a battle between social cells science becomes as much as if some endless TEA Party argument. Your radio piece seemed to assume that scientists were engaged in scientific debate, but you can't do that when people all standing on different platforms.

I love the imagery of useless branches being the basis of social structures being clung to relentlessly. This takes place inside each company but also among all of science such as the case of RNAi. Where was the hint that Merck bailed out on RNAi because after an exhaustive study they came to the conclusion that it will not be useful as a drug? They bailed but they did not send out any dissenting opinion that would upset the social group who still cling to RNAi.

In order to be successful you have to know what the group wants to believe. That is the easy part. The hard part is maneuvering around empirical evidence to the contrary of the groups "truth". For that reason the most successful members of science do not work in laboratories. Those who do lack the practical intelligence that keeps one out of harms way.