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Sunday, December 16, 2012

Humdrum Hirelings and Dumb Followers

If you want to speak out against Cargo Cultism within science you should probably start by being someone like Richard Feynman, not a biotech laboratory worker. The leaders of biotech Cults may not fancy themselves as Cargo Cult leaders, rather real scientists like Feynman. Fools like me have a problem. Whereas the Cargo Cult leaders seem to lack that thing that makes science work, the common tribesman lacks that thing that influences others. Compare the following comments. The first comes from Douglas Fairbanks' book, "Laugh and Live":
Our natural aim is to make for ourselves a true personality that does not know defeat... How immeasurably inferior to such a spirit is the fellow who whines and moanes at every  evil twist of fortune. He has no confidence in himself an nothing else to do except confide his woes to all who will listen to his cowardly story of defeat. Such men are least useful in the important work of this world. They are the humdrum hirelings-the dumb followers. 
Next my friend from Allozyne:
Your posts are emblematic of someone who spends a lot of time complaining and little time actually working to try and make a positive impact a.k.a fighting the good fight. You couch yourself as a "leader" and yet your myopic POV is stark evidence that you have never sat at the "big boy" table nor been an influencer in any strategic decision... 

These two people, decades apart, separate vocations, never having met, would seem to put me and my philosophy in a nattering nabob category. A loser category. 

I was in fact a mere hireling. In my defence I am certain that I was hired to be a dumb follower. My attempts to alter that reality was met with great opposition. I turned to a simple blog to cleanse the mind. I've never thought of influencing anyone through this medium. To me this has been fun. Writing about the little things is enjoyable. Why does something like biotech, and scientific research in general, fail so often? It's fun to think that you might have a few thoughts on the subject. You are not just a humdrum hireling/dumb follower. In "Laugh and Live" Douglas Fairbanks offers up all kinds of advice on how to become the kind of fellow that was popular back in the early 1900's. In the Cargo Cult Scientist I offer up thoughts on a different kind of thinking. As Steve Jobs said, "Think differently". 

I came across an example of scientific/mathematic thinking that I think is important to this blog. Daniel Kahneman gives this simple puzzle to point out the battle between fast and slow thinking. "A bat and a ball cost $1.10. The bat costs one dollar more than the ball. How much does the ball cost?" The fast thinking mind comes up with the answer; ten cents. The correct answer is 5 cents. Think about it. I've come across this same mathematical error quite often among the tribesmen of biotech. For example, a one percent solution prepared by adding ten grams of solute to one a liter volume (not brought up to a 1 liter volume). It is a fast thinking error that is common. Does it matter? Is it complaining to suggest that fast (lazy) thinking is common in the life sciences.

In the above puzzle a common mistake is used to illustrate a bigger issue. An entire book from a Nobel prize winning scientist is dedicated to the subject. "Thinking Fast and Slow" should be required reading for anyone conducting research. You may think you don't make simple errors that arise from thinking too fast. Chances are you occasionally do. I'm not being a nattering nabob on this issue. I make simple errors and I don't think it is negative. The ambitious person may cover up their mistakes. Every time I catch errors I feel I get better at preventing them in the future. I even offer the scenarios up for others to contemplate, much like the common "ball and bat" math mistake described above. Not only do I point out my own mistakes, without guilt of having made them, I tend to point out the errors of others. I don't see the downside, perhaps because I have an un-diagnosed case of Asbergers. It is not the specific error or who made the error that attracts my attention, but the type of error that is made. If it is common we can train ourselves to be on the lookout. 

My response to Douglas Fairbanks and my Alloyzne friend would be that science requires a different kind of person. It requires people who prefer to think slowly and carefully. People who think slow are valuable people in the world of science. People who think fast are great in movie audiences or investor meetings. In science however we run the risk of promoting the "humdrum hirelings/dumb followers" because they are best at thinking fast and being a good follower. They don't know defeat... but they should. They may be too dumb to know they've failed. In science we know defeat. It is a small child dying of cancer or the grandmother/mother/sister/wife with Alzheimers. We have never tasted the success of a Douglas Fairbanks and his rise to Hollywood elite. We've never sat at the big boy table at Allozyne. We just don't care about those kinds of things. We want to succeed at something else.

My Allozyne detractor is someone I'd like to hear from again. I've taken his comments to heart. I've had the very same ideas leveled against me by a silent movie actor who died in 1939. I hear what they are saying. Am I a loser? That's rhetorical. In many ways the answer is yes. I am a bad fast thinker and a very slow thinker in general. It takes me a while to grasp the meaning of things.


James Randi once created a fake guru to fool the people of Australia. He trained a young man to get on stage and talk to dead people and bend spoons and so on. At the end of the experiment they told the people that the young man was scamming them. The people didn't care. Many still believed in the young man. They wanted to believe the young man. Randi failed to demonstrate to his audience that they were easily fooled. He failed! I think of my failures in the same way. Perhaps I am right about this cargo cult thing. Maybe I am too harsh and there are degrees of CCS to this business. But this is not what people want to hear. The truth, even in the scientific community, is not as influential as more pleasant explanations.

Whether or not I could explain that the correct answer to the "Thinking Fast and Slow" example above to someone who doesn't think it matters, the fact remains that the answer is five cents. I may fail to convince others but I have a way of getting to the truth. That is what I consider success. 

Wednesday, December 12, 2012

Data Analysis for Researchers? Who Us?

Recently I was looking at the requirements for a data analysis certificate at the local university. Biotechnology takes data analysis too lightly. Certification in anything other than HR is unheard of. The qualifications of a researcher or someone who designs experiments vary greatly. One company may require very little of a person working in their labs. The next company may require a PhD to run their western blots. Who is analyzing the data coming from the lab? Is the data handed off to a specialist for analysis?
The requirements for the data analysis certificate are the following:
Select 10 or 11 credits from the courses below to complete the certificate program.

Required courses
STAT 511 – Design and Data Analysis for Researchers I (4 cr.)

STAT 512 – Design and Data Analysis for Researchers II (4 cr.)


Select a minimum of two credits from the following courses.
STAA 565 – Quantitative Reasoning (1 cr.)

STAA 566 – Computational and Graphical Statistics (1 cr.)

STAT 547 – Statistics for Environmental Monitoring (3 cr.)

Admission to the University is not required to earn the Certificate of Completion in Data Analysis. You can register for any course in the certificate program as long as you meet the course prerequisites.
Data analysis for researchers? What kind of research? The prerequisite math requirements alone are beyond what most universities require for bio or life science degrees. The degrees most prevalent in biotechnology do not have the same standards as those required to obtain the data analysis certificate.

I took a look at a few jobs in the local area to see if they required the same rigorous standards as the university certification. The Allen Institute for Brain Science is hiring a Scientist I. This individual will be required to "Work with experimentalists to understand their data and to suggest new experiments." What would the difference be between "understanding the data" as it is arbitrarily shared with you by the experimentalists (as AIBS requires) versus packaging the data and subjecting it to the analytical tools taught for this certification program?

Of the jobs available on the WBBA website, none require any data analysis certification. To obtain this certification would be very expensive. The upside is the wonderful knowledge you will gain. The downside is having a useless degree with regards to working in biotechnology. It would be like having a PhD in Aeronautical Engineering in the Cargo Cults.

Stinking thinking? No. This is an area ready for profit. If the Reproducibility Initiative were to one day mature into a world class tester of the tests, analyzer of the analysis, it would need an entire department of nerds with data analysis certification. Job requirement: Certification.

Tuesday, December 04, 2012

Xconomy Is Running Out of Cargo Cults

I've always felt that the role of Xconomy in the biotechnology industry has been to cheerlead. They are to biotechnology what FOX News is to the right wingers. Xconomy was organized with the idea that biotechnology and money were a match made in heaven. They have tried and tried but they just can't make this Cargo Cult look like a real airport however. Each biotech company Xconomy hoped to befriend was a fire along the Cargo Cult Airport. The fires burned out one by one until only a tiny handful remains. Tribes like Seattle have almost completely disappeared. What is left is nostalgia.

When the Cargo Cult Scientist began back in 2006, I was well into a career in an industry that involved routine mass layoffs. The layoffs were meant to halt the negative direction in which a company was headed. Flash forward to todays headlines from Biospace. Six of eight stories are about laying off staff.

  1. Pfizer Inc. and the Incredible Shrinking Sales Force
  2. Sandoz Inc. Closes Med Plant
  3. AMRI to Close US Site and Shift Work to NY and Singapore
  4. NeurogesX Inc. to Cut Jobs
  5. Spherix Announces Restructuring 
  6. Cumberland Pharma Lays Off One Third of Sales Force

Some things never change. The leaders have been changing direction since we began. Rarely do we revisit the certainty the leaders had when they began doing the thing that they later had to change. Rarely does anyone at Xconomy use our history in understanding our present. Why did those companies hire all of those people? What were those people suppose to have done? Where is the Cargo now?

Xconomy does admit that there could be a problem. In the article linked above, a former Icos (of Cialis fame) employee spoke of what she like about her current biotech job.
This person pointed out that the company was appealing in part because it had a decent amount of cash, which meant it could operate for at least a couple years.
This "this person" has a job. She is not going to change the industry. She does not question her leaders. She does her job and stays the course. She is just glad to think that the layoffs won't be coming for at least another couple years.

What does this "this person" do? Xconomy has never been interested science, just the business of science. The people down below who work for the security of "at least a couple years", aren't interviewed on Xconomy stories. Xconomy was formed to facilitate the conversation between the money and the takers. The people whom Xconomy is written for do not work in the lab. Like a Cargo Cult, none of the people in charge know how things actually work. They know money. The leaders read Xconomy because it offers a positive spin on the one aspect of the business that they care about, the money. The money is the cargo in this cult. Drugs and drug development is of little interest.

The money seems to have dried up. To what extent has this industry faced a reduction in funding, jobs, productivity... Xconomy has been "reporting" on this industry for quite some time now. They seem to have missed the real story. While the industry was steaming headlong into its own personal depression long before the rest of the economy went south, Xconomy was telling feel good stories about people getting rich and making awesome drugs like Provenge. Now they are left wondering where that old "can do" spirit has gone. Never mind that, what happened to journalism? 


Sunday, December 02, 2012


If one were to study the origens of story telling, they might begin with cavemen and their paintings on cave walls. We are probably missing millions of years worth of information. No matter what we try and wrap our brains around we seem to only see the tip of the iceberg. I recently purchased a set of videos on the history of Hollywood. If you think it all began around the time of Edison you would be wrong. For a long time people had been gathering in darkened theaters to watch images of light flash by on a screen while music or some narrative played. When Edison et. al. came along they began with the simple fascinating images of people in movement. Not long after this novelty wore off they began telling stories. Science has turned out to be very much like Hollywood. Fictional stories are far more lucrative than documentaries that make you think. Peole prefer Batman.

Our history is like this history of Hollywood. Both began long before the era on which people choose to focus. All of the real science that went into creating both industries was exciting. The book "Silent Lives" describes the times of people in the early days of the motion picture industry. The book "Double Helix" describes the lives of two men in the early days of biotechnology. The early days were full of desperation and hope. We now know that success was obtained so we feel comfortable. The movies at first were short examples of pictures creating the illusion of motion. Nickelodeons offered very brief scences of a person jumping up and down or someone taking a walk. The Watson and Crick DNA structure paper was also short, one page long. The early days of both industries started with just the basics. We can show people in motion. We know the structure of DNA. Where do we go from here. We've come a long way.

An interesting side of the movie business is the throngs of young people who flock to Hollywood eager to make a living in the business. You hear about the success of Brad Pitt. He dropped out of college in his last semester. He worked as the El Pollo Loco chicken for a brief while and got a big break on Thelma and Luise. Who you don't hear about is Kathryn Carner. She is a lovely young lady with lots of talent. She never made it however. She is still out there being a creative person but she didn't make it like Pitt. When we think of Hollywood we think Pitt, not Carner. The truth is that Hollywood is both of them.

Now, likewise, when we think of biotech we think of Amgen. We think of Leroy Hood. Some people make it. Most people flounder. Just like Hollywood we have more talent than we can support. There must be some way of sorting out the ones who will make it. Who makes it and who doesn't? What science makes it? What does it take?

As we've often talked about here on the CCS, the narrative is something that all serious scientists take into consideration. The lesser men and women get their PhDs and go desperately searching for a job, any job. They may end up in Seattle or San Francisco. They may have a PhD in Microbiology and end up running a protein purification group at a small start-up. It is the serious scientist that forges his/her own path. David Sinclair, for example, knew that a Resveratrol career would get him tenure and a $720 million dollar biotech deal. Not many protein purification supervisors think big like that. It is that kind of dreaming that made Hollywood and biotechnology. Unfortunately for us, science is not all narrative. Where we part ways in comparisons is in the origens of our stories. In biotech it must be real. In Hollywood it just has to be interesting. In the Cargo Cults we prefer the Hollywood system.

Wednesday, November 28, 2012

Pills for Fat People

It's been a while since the leaders have offered up an anti-obesity pill. The FDA caught a little flack for the Fen Phen fiasco. The latest prescription diet pill, Vivus' Qsymia, came out recently but has seen slow sales. Maybe the diet and exercise secret has been let out. The real reason for this post however is something I came across while looking into the Vivus pill. I thought maybe Qsymia was PYY. Who would be so foolish as to try and make PYY into a diet pill and would the FDA approve such a thing. It turns out that leaders at the Novo Nordisk Cargo Cult put together a PYY program in 2011.

We first brought up the PYY story in 2006 when the now defunct Nastech crashed and burned in their attempt to make a drug out of the hormone PYY. In this post I pointed out the absurdity of this biotech company attempting to hammer this square peg through a round hole. Merck entered into a collaboration with Nastech but found no reason to continue pumping money into the project.

Novo Nordisk is of course an important and useful company, not a simple Cargo Cult. They have the experience and expertise to provide useful insulin products. They have plenty to teach us here in the Cargo Cults. At some point however, all companies run into a Cargo Cult area. They have to do research and someone will make the decision that will set newly employed scientific team on a path of no return. These new scientists will have only one choice, make PYY a drug or find a new job.

The question for the Cargo Cult Scientist is whether or not PYY is involved in satiety. Many scientist don't believe the research. As I pointed out long ago, not only does PYY fail to impress in the nasal spray form, it might just be another N-Ray in the life sciences.
Science 9 July 2004:Vol. 305. no. 5681, pp. 158 - 159DOI: 10.1126/science.305.5681.158

OBESITY RESEARCH:Labs Fail to Reproduce Protein's Appetite-Suppressing Effects

by Trisha Gura

"In an unusual joint letter in Nature this week, more than 40 scientists announced that they cannot reproduce the central findings of a 2002 Nature paper that showed that a molecule called peptide YY3-36, when injected into rodents, dampens appetite for 12 hours or more."
Once again we have a candidate for the Reproducibility Initiave! What would they do differently than Nastech, Merck, Novo, Dr. Bloom or any of the 40 scientists in the Nature letter lised above? Who could help resolve this issue? Let Novo take a stab at this molecule. But what about basic research? Is PYY what we think it is? Can anyone help us place bets on Novos chances?

Saturday, November 17, 2012

Alnylam and Tekmira RNAi Cargo Delivery

Tekmira and Alnylam made the news this week after settling their legal dispute over the use of Tekmiras RNAi delivery technology. According to Xconomy they have:
agreed to resolve all their ongoing litigation, and that the companies have restructured and clarified their relationship, so that Alnylam still has a license to Tekmira’s lipid-nanoparticle delivery technology.
For $65 million dollars Alnylam gets out of the manufacturing contract and they have restructured the licensing agreement for the use of the Tekmira delivery technology.  In 2007 the two companies formed their alliance and further added to it in 2009 with a manufacturing agreement. Then came the accusations from Tekmira that Alnylam was abusing the relationship by using Tekmiras intellectual property to create their own delivery system and sharing information with a third party. One has to wonder why Alnylam would feel the need to improve such an expensive technology that they had researched and selected over the many other options. 

The way forward for these companies? Alnylam is going to take over the manufacturing and Tekmira is going to develop drugs. Xconomy, ever the biotech cheerleaders with a special fondness for Alnylam describes the latest fiasco:

But now each company is on its own, and can’t count on the other side for help. Instead of relying on Tekmira as a contract manufacturer, Alnylam plans to focus on doing in-house manufacturing of the lipid-nanoparticles that it needs to deliver RNAi drugs into cells. The company has been building up that capability for a year, he says, and it has enough capacity to make batches of its lead drug candidate ALN-TTR02 for clinical trials, and into “early commercialization” of the product, Maraganore says. Alnylam also has been focusing on building up internal R&D strength for RNAi delivery. Alnylam’s in-house delivery group developed some new technology that is enabling it to start the first clinical trials later this year with an RNAi drug can be given through a subcutaneous injection—which goes just beneath the skin and is generally more convenient than intravenous delivery.
They have built up manufacturing AND delivery R&D? After laying off a third of their work force in 2010 they turned around and laid off a third of the remaining tribe in 2012. According to Julie M. Donnely at the Boston Business Journal: 
The layoffs include high-level positions including senior director of biotherapeutics, a senior director of business development, a senior director of pharma operations and a senior director of information technology. Nine senior scientists and 14 research associates positions will also be eliminated.
When did Alnylam make this commitment to improving their manufacturing capabilities? What did they do? How much did they invest? Who did they snag from what CMO? What about the delivery system they have developed? What was wrong with Tekmiras? They aren't getting rid of the technology. They've only restructured the agreement. Now they have yet another delivery technology? What is going on with the delivery of RNAi at Alnylam?

Of course we don't really know anything about actual data at Alnylam or Tekmira. Tekmiras claim to become a drug development company is equally as bizarre as the continued existence of Alnylam. They deserved each other. With no clear path, each company will continue to zig zag their way to oblivion. RNAi continues to be our number one Cargo Cult.

Tuesday, November 13, 2012

Tamiflu You

We know that Cargo Cults do not actually succeed at obtaining cargo from airplanes that they summon to land upon the runways. Likewise the leaders of pharma cargo cults know that they won't make it rich curing or even effectively treating disease. Not that they wouldn't want to have effective drugs. It is actaully very difficult to put together a group of humans and ask them to participate in a group think experiment in which the outcome would be to cure some disease. Endpoints become the goal. Convincing the FDA to approve a drug by paving your own path then taking the FDA on a walk down the path is a skill. A little insider help can't hurt.

The real issue we have always had with Tamiflu is the basic concept that such a vaccine would be worth so much. Annual flu vaccines are merely random guesses that make people lots of money. All you need is a group of leaders to give their stamp of approval on the vaccine. Why Tamiflu?

The latest in this saga is an example of how the leaders operate and to whom they must answer. No one!
Last year, Tamiflu was included in a list of 'essential medicines' by the World Health Organization, a list that often prompts governments or donor agencies to buy the drug.
Our leaders have the clout to get governments to buy drugs but they lack to ability to get evidence that they work. In a democracy such as ours we don't get to vote on things like this.

Some might think this is switching gears too fast but stay with me. RNAi has long been my own personal Tamiflu. It doesn't work. It's useless. The latest bit of evidence here demonstrates that large profits can be made by useless things. And it all takes place on the Cargo Cults of biotech/pharma.

Our Cargo Cult leaders create huge promises and ask for huge profits. When they lose they go easy on us and only ask for less millions. They stop selling us the crap and keep the profits they already made. The cargo never comes.

Sunday, November 11, 2012

Harry Makopolis

We need a guy like this:

We each have a story to tell. It leads to one of the biggest sins against science of our time. It's not just Silvia Bulfone-Paus or David Baltimore and their bullying leadership. Cumulatively we have a story that leads to a scam that has cost society hundreds of times more than Madoff. What we report in the journals is too good to be true. We aren't all that scientific. We aren't making investors money. We aren't having healthy careers. Something is a amiss. But our leaders are doing quite well. Where could we go to tell our stories and confess our sins against science? Would anyone listen?

Sinatra Was A Tough Guy

When you live a life like Frank Sinatra you leave behind plenty of film footage. There is one piece that I've seen on two separate documentaries. In the first documentary you see Sinatra surrounded by a bunch of burly men. They are rehearsing a scene for a movie while Frank is recording music at Capital Records. The thesis of this scene in the documentary is that Frank is a workaholic. In the next documentary you have the same film footage. It starts just when the rehearsing begins. The scene Frank and friends are going over is one where Frank is playing a tough guy. He calls one of the other men out while the rest stand back in deference to the boss. In this documentary they leave out the fact that the men are only acting. The thesis is that Frank really is the tough guy he is playing. 

The point here of course, is that context matters. Bullshitting, as I've mentioned, does not care about the truth. Bullshitting can take something that really happened, such as this Sinatra scene, and tell a number of stories. In everyday life we fall prey to such deceptions but they don't really harm people who take an active interest. In time, any Sinatra fan will come across the actual scene that took place in the first documentary. They will learn the truth. Frank is still a tough guy but he's not that big of a bully. 

What about stories that come from the lab of a published group of scientists? The stories that come out in the journals allegedly depict something that took place in a laboratory. The scientists who dictate the thesis behind the published work are not the guys who work in the lab. They are more like the producers of the latter Sinatra documentary. They begin with a thesis, they look for data/information that supports the thesis, and they present what they find. Some editing is required. The data/information that is left out often times will tell a different story. One in opposition to the original thesis. What then are the safeguards employed by journal editors and peer reviewers to avoid believing the wrong story?

I have written up a few of my experiences. Here is a cancer study using an antibody against denatured collagen. Here is a phage library that contains the holy grail peptide of RNAi drug delivery. Here is a computer program that pulls out drug targets from published information. Here is the origen of Prusiners prion theory. In each case I sat watching as a laboratory worker highly interested in the big picture science. What role does collagen play in tumor growth? How do we follow a drug molecule after it enters the body? Can we use published data, do we have enough information in the books, to begin to mine for molecules in a disease pathway. On each occasion I watched from my laboratory seat. I saw the whole scene, then read the version of the story that was published. Like Sinatra surrounded by his cronies, we had a scene. We had only to manipulate that scene, edit out the stuff that would hurt the narrative, and offer it up to the journals. Eventually some journal would accept the bullshit, and we could put the publication down on our resumes. After the publications, and maybe a patent or two, we would flounder with what we had put forth. We had to employ the political skill of saving face and distancing ourselves from what we said. If we couldn't use our science to advance our project goals, what were the chances of others succeeding? That was none of our business.

The cases I've listed are all MIA, missing in action. I can't track down the outcome of the work in which I took part. Long ago I had a role but I was removed through company buy-outs, lay-offs, temporary suspensions of projects and me just up and leaving. There is only one project that remains. It is the biggest scam of all. It is the 50,000 liter manufacturing claim from a company that expresses antibodies in yeast. The claim is bullshit. The bullshit claim was accepted by one of the major pharmaceutical companies. They shelled out over $100 million so far because the antibody may have a chance in demonstrating efficacy in comparison to the already approved drug. The question then becomes, can we make the drug in a cost effective manner to steal away sales from the competition? Like Sinatra and the tough guy scene, does the bullshit deception damn the project? Will that claim lead to another MIA biotech product? Would a full disclosure of the problems with manufacturing have prevented the potential loss of capital towards yet another biotech product? 

The potential loss in faith is something that is affecting everyone in biotech/pharma. Job losses have been massive. The promise of the science has not been realized by the scientists. We have to take some of the blame ourselves for not standing up and pointing out that truth. If we were in the room when Sinatra was rehearsing and someone is telling the story as if it were Sinatra being himself, someone should state the truth. Who will listen? Like the MIA projects from my own past, one has to wonder if anyone cares? Hundreds of millions of dollars of other peoples money is also MIA. I know where a lot of that money went. Cars, houses, and plenty of nice things by the people who were in the proverbial room when Sinatra was rehearsing. We all knew it was acting and we helped our leaders tell the world it was real. We get in our new cars and drive to our nice homes and hope we never get caught. 

Wednesday, November 07, 2012

Cutting Edge World Class Science Leader Wanted

I was watching the election coverage last night. Billions of dollars per candidate were spent and we are pretty much back to the same old people running the show. One of the talking heads lamented, "What could we have done by putting that money into medical research?" As if money equals progress.

Here is a prime example of how it does not. Intellectual ventures is a patent troll company that has made plenty of money from nonsensical science patents. They've decided to get into the biotech biz. Step one: Find someone who knows what this biotech BS is all about. They may have had to hire a consultant to write up this job description since the world leading research team needs to be set up by the guy they hire. I've added a few notes in red:

Job Description

Intellectual Ventures Laboratory (IVL) discovers, invents & develops advanced technology solutions in a wide variety of fields. With broadly interdisciplinary teams of physicists, engineers, chemists, biologists, and physicians, we attack pressing technical problems in energy, medicine, communications, and global health.

Purpose of the Position:

The purpose of this position is to set up and lead a cutting edge and world class biotechnology laboratory to support new technology development projects in fields as diverse as medicine, food science, energy, and renewable chemicals.

They have figured out how to become cutting edge and world class. HIRE SOMEONE ELSE TO GET THE JOB DONE!!!  I hope the guy they hires doesn't realize that his genius could be spent on his own cutting edge world class laboratory.


•Position is for a project leader who will be expected to develop clearly defined projects, lead small groups of scientists and engineers to complete the projects, and clearly communicate expectations and results to project stakeholders.

This scientist must cleary define the projects that Intellectual Venture Labs envisions as being fan-fucking-tastic. Beyond that IVL does not really know what their new genius has in mind. They do know that it will involve small groups of scientists and engineers. 

•Must demonstrate a broad knowledge base in the field of applied molecular biology and experience using project management tools to complete important projects in the field

They need a molecular biologist to lead engineers?
•Position is primarily a project leader role which requires frequent and clear communication with multiple internal and external customers and stakeholders.

•Limited travel required

•Must be able to lead biotechnology projects that broadly require manipulation of DNA, proteins, microorganism, and possibly plant and animal cells to solve diverse science and technology problems.

I'm getting the idea that they want someone to lead projects. Is the science getting a little broad here? The scientist must be an expert in molecular biology. This kind of scientist will manipulate DNA, proteins, microogranisms, and maybe... just maybe, plant and animal cells. These are the tools that will solve science and technology problems.  The "how?" is up to the new hire.

•Must help specify, purchase, set up, operate, and maintain molecular biology equipment and instrumentation as needed.

Ever seen a PI set up, operate and maintain lab equipment? What they have not specified yet is that they want a principal investigator with job functions at the RA level. 

•Must have experience leading teams which routinely perform several of the following kinds of tasks in the laboratory to solve problems:

•DNA manipulations including primer and gene design, routine PCR, vector construction, high throughput library construction. Pretty advanced buzz words in the mol bio biz! 

•Optimization of heterologous expression of wild type and modified proteins in various types of host organisms

•Engineering host cells via gene integration and gene knock-outs.

•Use of fermenters to grow and use wild type and engineered microorganisms

•Use of analytical instruments such HPLC and UV-vis to characterize proteins and engineered cells. We need a PI who knows UV-vis! 

•Must work with other technical teams (chemistry, physics, engineering) and customers to identify biotechnology needs and design projects to efficiently solve problems. It sounds like they've already started designing a project. 

•Must develop, plan, staff, and complete independent research projects in applied molecular biology

•Must safely work with biological agents, chemicals and compressed gases and coach others to do the same

•Must keep detailed documentation for all work and communicate results in clearly composed reports and presentations. A PI with a lab book.

•Must assist with the organization of data and other literature for reports and other communications and in files on the company’s server.


Qualifications and Skills:

•Master’s or Ph.D. in a Biological or Chemical/Chemical Engineering science. Excellent attention to detail skills. Chemical/Chemical Engineer indeed! 
What does a chemical engineer know about molecular biology?

•Degree and research experience in field which required extensive use of molecular biology techniques.
Didn't they just specifiy what your degree had to be? 

•Education and work experience that demonstrates fundamental knowledge of biochemical and molecular biology concepts and use of diverse array of equipment and instrumentation to do lab work in these areas.
So... molecular biology is required?

•At least 5 years of industrial project management experience in an active applied molecular biology laboratory and demonstrated success at defining and then completing those projects on time and on budget.

•Excellent verbal, written, and interactive communication skills are required.

•Being comfortable with freedom to explore is required

I am sure I come across snarky. I can't help it. If the leaders judge us, why not judge them? This is their best effort in searching for the man or woman who will lead their cutting edge world class laboratory. The first thing the new scientist must do is make their small team cutting edge and world class. IVL has already started advertising their greatness. They designed their cargo cult airport. They just need a manager. It's up to the new guy to bring the cargo.  

Sunday, November 04, 2012

The Brain Drain

Long ago, the Allied forces built and ran the airports that the cargo cults still to this day try to emulate. The aeronautics, logistics, geography and so on were put together in a system that escaped the observations of the natives. They recreated only what their eyes saw from behind the palm trees.

Likewise, the scientists of long ago created bodies of knowledge in a manner that is not practiced by the Cargo Cults of modern science. The first thing they held dear was reproducibility. Usefullness beyond ones career. As Newton pointed out in Principia Mathematica:
Rule I. We are to admit no more causes of natural things than such as are both true and sufficient to explain their appearances.
Rule II. Therefore to the same natural effects we must, as far as possible, assign the same causes.
First, these scientists of yore had to apply the scientific method to conduct their research, form explanations and causes. After years of honing explanations and causes they organized and wrote down their thoughts in the form of a text. They all felt that their understanding of mathematics or the natural world was worthy of passing on to future generations. Newton was so impressed with himself that he wrote Principia Mathematica in latin to discourage the wrong people from bastardizing his work. The great scientists of yore knew they were right and they had great confidence that what they had to say was reproducible and extremely useful. Lacking computers, the large collections of paper with hand written information were organized and kept until they day they brought them to the publisher. Therefore the information was in a very precarious position. What if a fire broke out? The information had to sit inside their heads until it was put down on that highly flammable paper. Lucky for us it has survived.
What then can we say about the body of knowledge that has been formed through biotechnology? Thanks to computers, it can be kept safe, if only someone were to take the time to write about our science. Occasionally we get ancillary texts. Lars Hagel, has written the seminal work on downstream process development. It's not a philosophical piece on how biotechnology research works. It's about one technology that is required in the business. He has published two editions of "Handbook of Process Chromatography". This is an example of good science. Anyone who has a job in downstream process development needs to read this book. Lars Hagel put it all down for the industry and future generations. He is just one example of a modern scientist who has something to say, people willing to let him say it, and an audience willing to listen and learn.

What about an individual company? I've worked for five. All but one no longer exist. The one that does is among the worst offenders when it comes to creating a Cargo Cult culture. If they were to write a text book for the benefit of others what would it say? What is the path from nothing to a drug on the market? What is that drug, what does it do, and how did we figure that out? It is not a simple nor is it complex. It is complicated. Thus, we could write a text book that is understandable to most people with an interest in science. We're not talking about Principia Mathematica here. The reason this text will not be written however is because the "scientists", all of whom have PhDs from very good schools, are now businessmen. They do not have the same interests that scientists of yore had. Rather than a text book laying out a lifetime of science, they have a string of biotech companies and executive positions. They have money in the bank. Yet the world will not benefit from their lives.

Who will even bother to make an attempt to put down in writing the science of biotechnology 1980 to 2012? We have ancillary texts like Lars Hagels book but it's not biotechnology. It's chemistry. It's physics. It's math. Drug development biotechnology is science, business, FDA regulations, clinical trial enrollment, patents, human resources, milestone payments, contract organizations, alliance management, and on and on. Many of these things will not be relevant to future  generations. The FDA will change (it must). The laws will change. The investors and doctors will all have a different set of rules. So what can we write a text book about? How to clone a piece of DNA? There are ancillary text books on this subject as well. The complicated task of writing a text book for future generations on how to create a successful science/technology company should begin with a similar set of rules as Newton. By now we should know that there are limitations to what we can do. We should also know that reproducible work is essential.
The leaders of the actual Cargo Cults in the Pacific Islands could write a book on aeronautics. It would be fun to read. If each tribesman could write out a description of their daily duties we could begin to study the leaders. Therein is the beginning of our study of the Cargo Cults of biotechnology. The leaders have many things in common. Likewise the tribesmen have things in common, that distinguish them from the leaders. There are patterns to identify and write down. There are philosophies to follow such as the preference for sexy narratives over boring reproducible science. The study of  biotech Cargo Cults however is losing very important information. With every round of layoffs from Pfizer, Astra Zeneca and so on, we lose a handful of long term tribesmen (and some leaders) to their inability to carry on. They take with them a knowledge of a daily life that we can learn from. Some of us learn a great deal from our mistakes. Each tribesman can speak of the mistakes they've been involved in. They can speak about the culture of their tribe. They can give us job descriptions and their titles. Did each watchman wear the same coconut headset and what did they do with it?

Once the information is gathered we would have to sit down and sort it all out. What were the trends? Was there a common thread among the success stories that the failures were missing? In the real cargo cults we could point to the study of aeronautics being absent among the cults but present in the Allied forces. If we were martians looking at this world we would come to the conclusion that aeronautics was essential. Likewise, to take a case from my own experience, Lars Hagels knowledge in process chromatography is essential. The company I worked for did not believe so and they had to suffer great expense. It is still possible this aspect of the company will be their downfall. If so, we could have an essential element to write down in our text. It comes with a philosophy as well. Process chromatography is an area in which a drug development company must employ highly skilled people, just as an airplane manufacturer must hire aeronautical engineers.

Our story is ready to be written. If you've worked in the business and you think you have something to say, organize our thoughts. Offer them to PLOS ONE and the Reproducibility Initiative. Someday the cargo culture will begin to shift. Someday perhaps, when Susan Koman wants to invest their research dollars will skip the Cargo Cult minefield and invest in someone else. Imagine a multi-million dollar project that involves reproducing work and finding the most promising paths to walk down. Imagine having the first edition of a text that will help lead the way. We've spent the money. We have thousands of minds to tap into.

It's not fire that threatens our text. It is our own apathy.

Thursday, November 01, 2012

Who Wants It

I believe that future generations will look back on us as Feynman looked back to the middle ages:
During the Middle Ages there were all kinds of crazy ideas, such as that a piece of rhinoceros horn would increase potency. Then a method was discovered for separating the ideas--which was to try one to see if it worked, and if it didn't work, to eliminate it. This method became organized, of course, into science.
The idea of reproducing someone elses experiments is nothing new. What is new is the idea that such a project would create so much dissent. A piece of rhino horn used for erectile disfunction could be put to the test in a Viagra style study these days. It would be put to the test if some proponent of its use had the clout to get the research put in motion. Therein is the pickle we find ourselves in with reproducibility. The people with the clout are the ones whose work needs to be subjected to reproducibility studies.
Now when I talk about the actual Reproducibility Initiative I am using it as an example of one such effort to get the conversation started about what actaully takes place in the lives and careers of any modern day participant in the scientific world. I think any reproducible science, even boring science that doesn't rise to the sexy standards narrative science, is better than the cargo cult science. You can get rich, you can get published, but that is not the primary concern with this conversation. What I am thinking about is a Utopian world where the members of the cargo cult begin to be skeptics. They lose their jobs in the watch towers because, as their leaders informed them, they were not wearing the coconut antennas properly. They begin to question the antennas. They build confidence in their own ability to distinguish bullshit from the pile of clever sciencey narratives that their leaders pile on them. They discover a method for separating the ideas--to try one and see if it worked, and if it didn't work, to eliminate it.

Having started with this concept, that science began not so long ago with the idea of testing popular ideas, I'll address the comment from my last post. (Thanks for the comment btw)

As long as the incentives are not directed towards reproducibility, it won't be happen. The Amgen study was great but we didn't hear about until years after the original work and the authors had left the company and felt free to publish.
And of course we still don't know which studies or which labs were involved due to confidentiality agreements.
I'm not sure what is meant here. The incentives in reproducible science is that it leads to bigger and better things. We see so far because we stand on the shoulders of giants.

For academics funding is limiting and precious. If you tell an academic "here is $10,000 and you can spend it on reproducing your own work or you can spend it on a new project which will bring you more money and more publications", which will they choose?
Who would be so foolish as to give someone this choice? I've never worked with anyone who would volunteer for an outside reproducibility study of their own work. As I said at the end of my last post however, we have to be creative. Step out of the mindset of an academic scientist. Think in terms of a beaurocrat who decides on the NIH budget or an investor who wants to give biotech one more chance. You have a choice: Fund the same old guys who burned you back in the 90s and 2000s, or tap into a new paradigm. Only fund people who agree to have their work double checked. We're all only human. That is what the same old guys don't want you to know. Don't believe them. If they don't want the money, find someone else.
If you ask academics, all of them will insist to you that their work is reproducible so why would any of them consider trying to reproduce it?
Again, the academics are not the consumers (yet). They are the ones in whom we've lost faith. A Reproducibility Initiative must first do business with the consumers of good and bad science. The consumers can continue to lose money like they have in the past or they can try and see what certifiably reproducible work can do for them.

tldr: You don't get into Science and Nature by reproducing published research.
Again, no one is trying to get into Science and Nature here. They are trying to get Science and Nature to get into reproducible science.
Thanks to whomever this commenter was. You are absolutely correct with everything you said. The issues you bring up are the exact issues to attack. The question is how. Can we find a stunt like the Carnegie elephant crossing a steel bridge stunt? We have to be creative. The academic scientist is not the guy who wants a reproducibility group hanging over their research. In time however, the people with the money will come to find investments in reproducible science to be far more lucrative than the investments they made without this safety net. Soon scientists will have no choice, if they want funding, but to conduct the kind of work that will be subjected to reproducibility.

I know I'm only dreaming. But this is all just a thought experiment.

Tuesday, October 30, 2012

Beyond Science

One of the lesser arguments against certified reproducible results is that research will cost too much to reproduce. The past 30 years of biotechnology is a testament that this logic is flawed. Non-reproducible cargo cult science is expensive. Pharm research has wasted an estimated trillion dollars in the past decade. If you are into math and science, one trillion is an impressive number when we are talking dollar bills. Something must be done or the good that is in the life sciences will be put on a shelf until some other generation of people take a different path. Until then we will continue to lose our jobs while the bullshitters live out their reckless scientific careers.

What I mean by reckless scientific careers can be seen in the Amgen study. When 47 out of 51 oncology papers turn out to be non-reproducible you have a problem. People use this information. Scientists must rely on their peers but clearly they must do so only through the scientific method. Most scientists do not have the resources to try and reproduce 51 papers. They thus have to go on faith. Faith has failed. It's time to get science police on the job, armed with the scientific method, to go out and do the work that the average scientist cannot afford to do.

Andrew Carnegie made a few bucks in his day. He wanted the world to buy his steel because he felt that it was an amazing material that could be used in mass quantities as the world became more modern. Bridges, railroads, skyscrapers and the list goes on. He saw the power of steel as well as the financial power that was possible. In order to convince the people that steel was the latest greatest building material he put on a show. It was thought that elephants would instinctively not walk across a bridge that they felt would not support them. In a publicity stunt he had an elephant walk across a steel bridge. The bridge was of course strong enough to hold the elephant. People became believers with stunts like this and Canegie became the richest man on the planet.

Science is also powerful. It is used these days in the place of elephants. We can calculate what it takes to build long lasting bridges and tall buildings. But the kind of science we use in biotechnology and pharma R&D is not quite so strong. Currently that kind of science can be used to extract large sums of money from Cargo Cult Leaders and some of their followers, but it has not led to any revolutionary changes in health care. What could we do with the real power of science if it were forced to be strong, like the science behind the building of a bridge or a skyscraper?

Andrew Carnegie saw the potential in steel. Somewhere there must be a businessman/woman who sees the potential in keeping the life sciences alive with a reenforcing steel like force that keeps the companies and the papers from crumbling to the ground the moment someone tries to use them to advance our field. It will take vision and showmanship. Someone must begin to demonstrate the strength to fight against the nay-sayers. Who will our Carnegie be? Has he/she been born yet? There are many reasons why any reproducibility initiative will fail in the world of science. We need to start thinking about why it will succeed. I think that good reprocuble science will make us a whole lot more money the the Cargo Cult Science.

Saturday, October 27, 2012

The First Reason

The first reason the Reproducibility Initiative and other efforts by PLos will succeed is because science is king. The scientific method is the most powerful tool we have as humans to understand our world and how it actually works. Religion has not given us indoor lighting or airplanes. Politicians have not given us a sustainable government. Scientists on the other hand have provided us with a body of knowledge that not only helps us now, but will help those in our future. We have an obligation to get it right.

We have a built in Reproducibility Initiative in our science education. The Merck Index lists a number of physical constants that are... reproducible. The are constant. Water, for example, boils at 100 degrees. We send our students into the laboratory to test that constant. I have yet to hear of a University where students discovered that constant to be wishy washy bullshit. You couldn't write up a paper on the fact that water boils at 100 degrees. You can't convince a journal that this has new and interesting applications. But if you get yourself a STEM degree, you will be taught this little fact. Why? Because it is useful reproducible information.

As I've mentioned in the past, research is like a crossword puzzle. When we get something wrong, but think that it is right, we trip ourselves up in the method. That method, the scientific method, is a method of solving a far more complex puzzle. Their are no individuals who are going to solve a complex puzzle such as cancer. Science will solve that puzzle. Each scientist must offer up their small answers with absolute certainty that they have something of value.

Arrogance, careerism, greed, desperation are a few excuses for jotting down the wrong answers without regard for the subsequent consequences. The greater problem is allowing for these wrong answers, and admiring those who provide them for the rest of us, thus hindering the progress of science. Science is powerful. Scientists are only men and women. What we must admire more than the people, is the science they leave behind. Real science has always opened doors, for good or evil, that lead to a new world. Throwing money at a biotech company or a cancer charity is simply wishful thinking. Wishful thinking is not science. If we respect science, we must subject it to rigorous standards. The status quo of publication is wishful thinking. The status quo is a mockery of the scientific method. The old white haired men who rule over their journals, never testing for reproducibility, looking only for sexy new narratives will never do to science what the boring old "water boils at 100 degrees" concept of science has done. Science has to be reproducible. When that happens the power of science is unleashed. When our first concern is financial or any other issue, we are misunderstanding the role science has played in our lives. We must get it right, or we are no better than a religion or a politician. Science is where we leave our hopes and dreams behind to allow reality to direct us in our pursuit of understanding the world we live in. Our first concern must be scientific integrity.

Fame on fortune will follow. The Reproducibility Initiative (or any idea/effort along these lines) will make your personal hopes and dreams come true because science is that powerful. When you put anything before that thing that Feynman speaks of, the concept of science over cargo cults, you begin to lose what science really is. You lose what science can do for you. You end up with a biotechnology company or a pink ribbon bumper sticker. Those things we hope for can come true if we stay focused and believe in science. It may not seem possible now, to have a for profit initiative to clean up the mess left behind by some scientists, but the power of real science, reproducible science, will make it worth our investments. In the future, scientists will scratch their heads and wonder why humans could have been so foolish to have had a system that did not attempt to reproduce what the leaders were putting forth. The same as we look back scratching our heads at the Salem witch hunts or using leaches to cure disease. It is merely scientific progress. That is first reason any efforts to highlight reproducibility matters.

Thursday, October 25, 2012

Doing The Dishes

Paul Ryan's dish washing scandal has Inspired me to keep going. Any person who can stand in front of other people washing clean dishes is clearly a Cargo Cult Leader. Why? Because the purpose of washing dishes is to make dirty dishes clean! Paul Ryan washes dishes to create an illusion like we in science use big words and wear white lab coats.

I won't prattle on about it. It's funny. It's a man who would be be equally successful had he pursued a career in science. A leader knows the dishes needn't be be dirty when the objective is only to convince people you are cleaning them. Put on proper attire, look like you are working...

Thus I must return to this project. The Cargo Cult Scientist took a little break. No excuse. Nothing to report. The world is still ruled by men who wash clean dishes. I want to talk about the reproducibility initiative. Next post. Why do we need it?

While checking out at Safeway lately, I've been asked to donate a few cents by rounding up my purchase to the next even dollar. I refuse. Knowing what goes on in research I refuse to give. I would give to the International Peace Love and Harmony chairity if there was one and I thought they could achieve such a goal. The same goes for breast cancer (or any cancer) research. I would give them money if I thought they were fighting cancer. I do not. Not until they have checks and balances would I consider their work to be worth a penny. Cancer charities need accountability financially and scientifically. The reproducibility initiative is what I where I would donate my money. It would be indirect however. The initiative needs to establish its efficacy in sniffing out bullshit and the bullshitters. It needs to gain the respect that the life sciences have failed to achieve.

Imagine a huge fund raising event to raise money to test the efficacy of the Reproducibility Initiative. Those who feel it cannot succeed, here and here for example, are the same who think biotech companies can succeed. Cargo Cult leaders! I think this will work. If Ryan Paul can be a successful politician with ideas such as washing clean dishes, then science can succeed by creating the illusion (at least) that we care too. And we have got the scientific method on our side. Some of us really do care. We care more than we care about our own careers and our venture capitalists careers. It's science that is in trouble these days. The way it's practice. The way moneyed interests profit via Safeway fund raising events. The cancer we face is the lack of reproducibility from more successful cheaters and bullshitters. More successful people like Paul Ryan wash clean dishes and nobody needs that. Science has always had its fakers but lately they've cut into our credibility and there is a way to fight back. Test the tests. Research the researchers. More later.

Tuesday, September 25, 2012

The Big Boy Table

Dedicated to my anonymous reader from Allozyne:

Many years ago While as an undergrad I came across a most unusual man on public tv. He was a communist, pacifist and so on. He never cut his hair. Each week he would go on public tv and espouse his views, most likely because others around him had no interest in his interests. He needed to get his thoughts and ideas out and it was easy to secure a little time on local public tv. One particular criticism of him sparked my interest. A young student called in with no interests in the communists message. He wanted to know why the guy never cut his hair. It was meant to be an insult. To his surprise the host of the show had an answer. I won't go into it. The point of the story is that there was a person who was not like the people I grew up with. That is why I went to college. It was an experience unlike any I had ever had. This long haired old hippy with his own tv show was different. The young man with the "long hair" insult was what I was used to. The norm would have been to accept the insult and offer one in exchange. Instead the answer was legit. He really had a reason his hair was so long.

Flash forward to my crazy blog. I started writing little essays on the plight of a lab tech working in an environment that I cosidered hostile to science. I used Feynmans Cargo Cult Science commencement speech to address some of the problems I see in methodology. Like that old hippy on public tv, I throw out my ideas, ill concerned if they will ever be heard. Along comes a man representing the norm. This man, like the young man concerned about hair length norms, is appalled by my lack of adherence to our shared authoritarian system.

Rather than accept the insults I will address the sentiment behind my perceived lack of influence and career success. I am no longer working in this environment. I saw the influential is people most successful in groupthink.
Group members try to minimize conflict and reach a consensus decision without critical evaluation of alternative ideas or viewpoints. 
 To my anonymous friend from Allozyne, I want to say that the big boy table is a place I was never a place I wanted to be. It is a place of groupthinkers involved in something I call bullshit. The big boy table at most any biotechnology company that has ever existed represents the most successful people in the Cargo Cults of science. Like the big boy table at Mary Kay Cosmetics or DNKY, it is a table surrounded by people who do things in life that I don't care about. I care about the scientific method, fairness, piecing together a long history of research hits and misses that eventually solve an unknown that others will be able to use in the form of technology. 

I wish I could be more like the old communist hippy on my local public station. The problem is that I like new cars and a semblance of normalcy. I put up with the leaders of the Cargo Cults because I made more money. But at the end of the day I had to admit that I was wasting my education and my brief opportunity to contribute something. So I do have my little blog. It isn't meant to illicit insults but I understand. It's pretty insulting at times. That is life. Look at it from a viewpoint outside of the big boy table:

Thursday, August 30, 2012

Why We Do It

In my last post I discussed a paper that I thought was complete bullshit. It was a sciencey narrative that did not stand up to the rigors of further analysis. The logic of the project, on paper, showed a complete lack of appreciation for the complexity of protein folding. The methodology and explanation of the results showed a complete misunderstanding of molecular biology techniques. In the end the project became another failure to be tossed on the steaming heap of bad science.

How does a group of highly educated people get together and do this kind of work? Physical Chemistry scientists take work seriously. They look at a system and determine of work was done. Energy may have been exerted. Heat may have been given off. An exchange of kinetic energy may have taken place but the question remains, was any work done. To look at the above situation you have to look at the system. Many people spent many hours on a hypothesis made by one man. That mans underlings all grunted, "yes yes" and they began adding bells and whistles to a very simple premise. The highest ranking scientist had dreamed up a protein without the benefit of billions of years of evolution. It just  came to him and his subordinates had his back. They knew who was signing their paychecks. Fast forward several years. The premise that the molecule would be used to deliver drugs turned out to not be true. Science wins again. No work was done in this system.

So how many people did it take to do this non-work? Energy, money, time, meetings, and all sorts of life science bullshit took place day after day. Each individual involved in this project played a role in trying to validate the narrative set forth by the high ranking scientist. Is that the job of modern day scientists? The emperor was stark raving naked here and no one had the courage to point that out. They did what they do until the project was one day ended. The questions then are what did they do and why?

One of the functions of one of the individuals was to write the paper. Another individual read what was written and made changes. The paper was then sent off for peer review. Several individuals at the JBC then exerted energy and gave off heat in their role. But no work was done. Why did they all do what they did? In the final analysis they were all part of a project that did not pan out. Wouldn't science demand an explanation of the outcome, even though it wasn't the desired outcome? The final analysis by this Cargo Cult member is that the project was flawed from the beginning. The tribesmen who worked on the project were not in the place Feynman wished for us. The ultimate conclusions is that this type of work always fails and we should do something about it.

In Cargo Cults however, we answer to authority. Science is not the authority, it is the whims of the highest ranking scientist. The man/woman who signs the paychecks determine what and why we do what we do. We are not allowed to question that authority. When a paper is written we all put our name on it claiming that we all agree with the guy who wrote it. And the guy who wrote it agrees with the guy who told him to write it. And so on and so on.

Imagine if each individual listed as an author was simply allowed to disagree with any points made in the conclusion section. After the paper is written alternative explanations are allowed and the individuals who offer them are not punished for insubordination. Ah but that would not be an authoritarian system. Imagine the guy in the watch tower with coconuts over his ears saying to the boss, "I don't think I'm doing any good up here."

Tuesday, August 28, 2012

Barbeque Contests

While sitting around in the early morning I came across a Travel Network show on BBQ contests. The chefs are well known in BBQ circles. Many had won several competitions over and over. When the judges sit down to do their taste tests, they are blinded as to who prepared the food they are eating. Contrast that with the peer review system. Why do we bias our peers with our reputations? Don Polderman had over 500 publications. That is what the peer review system creates. The quantity of Dr. Ps work seemed to have some influence that the quality did not. The quality of work being done by the current group of human beings who are professional scientists in general, as judged by the lack of reproducibility of the work they publish, is not good. As judged by the peers it's the cream of the crop. Apologists and defenders would attack such a statement because science is... Fill in the the rest of that sentence yourself. Science is...

Science is blinding the judges at your BBQ contest to see if they can spot the best chef. Cargo Cult Science is authoritarian. The judges (peers) usually allow only one explanation. This prevents any further judging (unauthorized peer reviews) of the judges (the authoritarian peers). I would like to offer up an example of a Cargo Cult paper that I participated in, briefly why it's Cargo Cult and how the authoritarian system let this take place. It is in fact the norm in science and it is very hard for an Asberger Syndrome sufferer such as myself to understand.

You be the BBQ judge. I won't tell you my name or how I am associated with this paper. I will only offer up an alternative explanation to a few of the Cargo Cult points.

The paper is about the Trp cage and phage dispaly. The two real scientific discoveries were combined to create nonsense. Selecting what phage display library to use for your project is a random process. You select your library on conjecture and sometimes it works out for you. The excuse for its failure is usually that the library lacks the proper structure. Ironically, protein structures and folding are what make us who we are. Proteins are fascinating molecules that have so much complexity in what they can do its hard to imagine how the judges of this work did not question the oversimplification. Why did they think that the Trp cage would be in tact with the randomization of 7 of 20 amino acids? It is simply a sciencey narrative that was never scrutinized. Unlike the harder sciences that employ NMR and computer modeling to analyze the structure of this fascinating little protein, the life science biotechnology folk simply took the concept, drastically changed the amino acid sequence, and made the claim that it was still the Trp cage. Drawing the line from the Trp cage to a phage display scaffold and the finally to drug delivery molecules is a stretch of the imagination that boggles the mind. How did the judges not question the logic?

"Mutations were observed at a frequency dependent on display valency".  This is a classic Cargo Cult maneuver. A confusing sentence that looks sciencey but makes no sense. Cargo Cults like to emulate real airports. Cargo Cult Scientists do the same when the speak in hard to understand terms. In this case it's hard to understand that sentence because it is complete nonsense. The mutations were simply the result of having the DNA produced by human beings. Ten separate preparations of DNA were sent from Invitrogen. Only one or two was used to make the library. The rest of the preparations had too many "mutations". This is a detail that a judge/peer would not know to question. Anyone who has ever worked closely in molecular biology will have noticed that not all of their clones have the exact DNA sequences that they designed. You don't need them to because you have clones. You only need one good clone. Discard the rest. In phage display libraries however, you have to take the whole set. The authors came up with this explanation out of A) ignorance of bench level molecular biology and B) a need to be sciencey. The explanation is more sciencey than the more probable one, that is good as they could get it. Lacking the expertise of more skilled phage display teams, and lacking time, money and patience, led this group to banging out their first ever library and it was not perfect. But that lack of perfection was not "dependent of display valency".

The biggest Cargo Cultism about this paper is that somehow the combination of real science (the discovery of the Trp cage) and phage display technology will somehow lead to drug delivery technology. It's an idea. It's a thought. But that is all it is. Once tested it became clear that this was a half baked idea. It was dreamed up by higher ranking scientists who told lower ranking laboratory members to make it all come true. When you work in the industry of drug discovery however, you mustn't let people know that any of the ideas of the superiors are half baked. This paper is a prime example of how far people go to talk and talk and never let anyone look up into the sky to see if the airplanes are coming. Thought experiment: If a molecule binds to a target inside a human body, what will it do? In this case the molecules were suppose to be used as drug deliverers. Besides binding to a target, how would this work?

Those of us down below watching the wheels turn in the minds of our Cargo Cult leaders have little to say over the publications and the patents. We need them in fact to advance our careers. We put this stuff on our resumes and we tell everyone we're smart scientists. But I think I have Asbergers. I have a heightened sense of fairness and this paper is bullshit. Who can you tell? The judges are not blind. They do not like to entertain too many thoughts at once, especially if introduced by the wrong ilk.

Nothing came of the library. It was Cargo Cult. No one ever attempted to reproduce the salient points made in the paper. It was good for JBC because it appeared to be scientific. It was judged by peers impressed with the credentials of a couple of the authors. The journal had a new article that wouldn't cause any trouble. The authors have another publication to add to their total count. But it's bullshit. No one will ever use it again, like much of what gets published.

The paper itself is not important here at the CCS. It is what the paper represents. The authoritarian approach to right and wrong. The indifference of the leaders to what is right and wrong. It accomplished their goals but not the one that was suppose to have scientific merit, that the library had some special properties. The airplanes did not land. The company ultimately closed shop due to bigger Cargo Cult issues. One thing shut this company down however and it was the same thing that got this paper published. Bullshit. There are not blinded judges to weed out bullshit in the Cargo Cults. What the leaders say goes. Luckily for the fans of good BBQ, there is a way of judging right and wrong, good and bad. Someday science will catch up.

Wednesday, August 15, 2012

The Loss of Tribesmen

Roche announced the closing of its New Jersey R&D hub taking away 1000 jobs. Amgen is going to shut down their Longmont plant where Epogen was produced. They employ around 400 people. Dendreon is cutting around 600. These are just a few recent stories of the Cargo Cults shedding their tribesmen. I worked with a lot of truly science minded people in the industry. Mostly however, I worked with Cargo Cult thinkers. When you have a majority of the latter, you have a sick industry with little need to keep the people around.

Long ago I floated the concept of biotechnology companies being fires lit along the runway of a Cargo Cult Airport. Since I began this blog we've gone through massive layoffs and massive company failures. All but one of the companies that I worked for have called it quits. They all shut down because of bad science fueled by an absolute requirement for specific results. I left the airport a couple years ago but I continue to watch the fires burning out. I continue to have conversations with scientists still in the business and I continue to sense the Cargo Cult mentality. As the industry continues to toss out it's tribesmen and tribeswomen, one has to wonder if the cumulative loss in expertise will affect its future productivity. If we are dealing with a true Cargo Cult, we should expect no loss. The guy in the watch tower with the coconut shell head gear really isn't doing any good. He won't be missed. 

The tribesmen may very well be going through an accelerated rate of job loss. New jobs are not being created and old ones are disappearing. Our leaders are the tribe members who are the best politicians thus they know to shield the publics eyes from the real numbers. Even the tribesmen who lose their jobs know its best to not draw attention to the possibility that our industry has disproportional job losses compared to other career paths. The numbers would most likely paint a picture of an unsuccessful group of human beings. This group was given billions of dollars, a wealth of scientific knowledge and they failed.

Cargo Cult leaders have a way of measuring the success of their lives and it's not based on successfully getting the airplanes to land. The cargo they seek has always been money. They measure success on how much money they earn before their fire burns out. IPOs are allegedly making a comeback which was a major factor in our dismal history. Many of the people that I've met base their success on maintaining employment within their cargo cult. Machiavellian tactics trump the scientific method. How many of these people are now sitting on that pile of discarded 2012 biotech/pharma scientists? With accelerated job loss comes a smaller population of leaders.

The true measure success is the ability to maintain the kind of integrity described to us by Richard Feynman in Cargo Cult Science.

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.

A biotech company can still succeed when the measurement of success is an IPO or a few guys at the top getting rich. If we switch that measurement to reproducible work that is of some use, we will be doing science. We can still read the narratives and be impressed by the minds who dreamed up the possibilities. But then we have to get to work to find out if what they are saying is true. Some of the discarded scientists need to speak up and help us root out the Cargo Cultisms. The Reproducibility Initiative is a great idea and one that will be met with great opposition. If it survives we may have a new sheriff in town. Those who have lost their job, those who hate their current job and those who have tired of losing their investment money will have a new ally. I truly believe that opposition to this initiative is an example of Cargo Cult Science. Your science is suppose to work. It's suppose to be reproducible. Technology is the practical application of science. If your science is bullshit, your technology will not work. The planes will not come.

Thursday, July 26, 2012

A LinkedIn Conversation

Modern technology has provided us with the ability to offer up our opinions. If you want to get into an argument online just offer up your opinion and wait. If you are on LinkedIn however, you are engaged in a professional conversation, you are not anonymous and you don't want future potential employers to see you offer up an honest but surly opinion. You end up with a Cargo Cult-like conversation.

The topic is phage display ELISAs. The worker used up his protein target panning for binding phage. Now he wants to use suspension cells expressing his target as his target in the ELISA. The first question one has to ask is whether or not it would be easier to find more of the pure protein than to develop an ELISA with suspension cells as the target.

There are many suggestions that are at the level of solving the problem stated. Those who wish to be leaders will accept that problem. It allows them to make suggestions but still leave the final decision to the worker. The probability of failure is high, but the accountability is not on the leader. A true scientific leader however, is the one who asks the questions. The scientist asks the questions because the scientist best knows what the problem is.

I've stated often that our education system selects for the best question answerers. The question askers often come across as the students. They seem naive, in need of a teacher to answer them. A scientist is someone who has the intellectual confidence to ask questions that many might consider to already have an adequate answer, and that answer has been placed into the heads of the educated. As is the case in the above problem, the intelligent response on this public forum would be to answer the question. Be the teacher to the student. Yet I think there is another approach which would have a higher probability of getting to the heart of the matter. Ask why the question has been posed. Question the question. The worker is trying to verify binding of phage to target. Has he set up the best experiment to answer his question. 

Ultimately, this is not a phage display problem. It is an ELISA problem. There is no phage problem because we have a phage expert in our lab with all of the skills needed to do the job. He is missing a reagent and we need to get him a substitute. That is our job as leaders accountable for the successful completion of this task.

As leaders we must take into account time and resources. We must also ensure that we get the best answer to the question. The most  important part of developing any ELISA is knowing the difference between signal and noise. Phage ELISAs have less separation between signal and noise than ELISAs with purified proteins and antibodies. With this new twist of using suspension cells in place of purified protein, one has to wonder what the signal and noise will be once you fully saturate the surface of your ELISA plate with your cells. Will you be able to distinguish the difference between noise and signal with this system?

Verification of binding is the forest. Attaching these cells to a plate is the trees. Make a list of your ideas and the suggestions you get from colleagues, use design of experiment to most efficiently run a set or series of tests and knock it all out at once. If nothing works, quickly move on to trying to get more pure protein.

Tuesday, July 24, 2012

The Five Year Outlook

Outlook for the next 5 years in drug innovation

Roy Berggren, Martin Møller, Rachel Moss, Pawel Poda & Katarzyna Smietana
The decade-long crisis in the productivity of pharmaceutical research and development (R&D) has been widely discussed1, 2. Indeed, expectations of reduced returns on R&D investment have led large companies to scale back their R&D substantially in recent years, and there have also been shifts in R&D investment and activity in particular therapeutic areas by the industry overall.

Nature Reviews Drug Discovery 

Decade long crisis?

What is the value of any five year plan or outlook? No battle plan survives contact with the enemy. The intellectual firepower of this article, likewise, will have to do battle with the reality of an industry that operates randomly. Without control over the randomness of FDA approvals combined with the lack of systematic training and educations that create researchers and research leaders, there is no way to predict our future. Perhaps a better approach would be to look at the 90% false findings in published research and attempt to predict if that will change.

The original assumption in predicting where we will be in five years, is the assumption that we know where we are right now. The assumption that we are in the midst of a ten year crisis is conjecture. The assumption that we can predict the future is just silly. The most scientific thing we could do at this stage of the drug industry would be to define where we are, why we succeed and fail, and what we can do to weed out more of the Cargo Cult.