Why Sequence Your Genome?

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

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

They need to put some wealth into their system.

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

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

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

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

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

What Works

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

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

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

The airplanes did not come!

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

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

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

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

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

Merck Logic

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

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

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

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

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

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

Writing About Work

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

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

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

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

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

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

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

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

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

AstraZeneca vs the CCS

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

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

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

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

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

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

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

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

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

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

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

The Next Step

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

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

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

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

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

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

A Manual for Discovery

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

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

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

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

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

Epiphanies of 2010

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

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

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

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

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

Non Religious Women Have Better Sex Lives

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

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

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

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

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

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

Five Years In the News

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

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

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

Biotech is Back Tonight

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

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

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

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

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

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

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

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

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

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

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

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

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

Game Changer!

RNAi and Roche

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

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

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

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

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

Dendreon Stats Revisted

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

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

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

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

Biotech's Back Bullshit

Are Cargo Cult leaders honest, liars or bullshitters?

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

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

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

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

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

On Bullshit

Harry G. Frankfurt

Liquidity

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

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

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

Keep Flames Alive

Hilarious title

Are they reading my blog?

MBA Students Cheat?

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

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

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

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

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

The Logic of Picking the Perfect Ice Cream

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

How do you know what the truth is?

Location Location Location

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

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

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

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

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

Clinical Trial Fraud

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

Read more Clinical trial fraud accusations rock MannKind .

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

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

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

Herb and Dorothy Vogel

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

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

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

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

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

Empty Buildings

So up to 90 percent of medical science reports could be B.S. One of the consequences is of course that your doctor could be following a cargo cult science when he/she tells you to take your pills. But we like to look at the airport as well.

Here in Seattle we had a push to start up a biotech hub. We wanted to compete with Boston and North Carolina and San Diego and the bay area. We built expensive buildings with lots of lab space to accommodate that science that is 90% false. How did it pay off?

Empty promises bring empty buildings. Contrast our biotechnology investment with the investment in politicians. 3.7 billion! Giving politicians money produces desired results. Maybe you want the government to add an earmark to a bill that will provide you with the money you need to create a Laurance Welk museum. It's been done. You can't pay a politician to cure cancer. Nor can you expect a biotech to do it. It hasn't been done.

Imagine taking a walk today through the empty spaces available for biotech. The smell of new construction, the lights turned off, no people around, and you keep walking for miles. What happened? 1100 Eastlake was completed in early 2009 — "just around the time the world fell apart," Blume said. The world didn't just fall apart in 2009. Biotech has been falling apart since it began. The success of a few companies fooled investors into thinking easy money was to be made. But the data of failed companies as a direct result of bad science has escaped the wealthy. Their starting to come around to the truth. It's a cargo cult airport!

Meta Analysis, Measuring Measurments

In the early chapters of Dr. Ben Goldacres "Bad Science" he begins to unfold the concept of meta analysis. In statistics, a meta-analysis combines the results of several studies that address a set of related research hypotheses. Simply follow this link, and type meta analysis into the search box. I know I'm being lazy but no one says it better than Bad Science.

Bad science can be done in a clinical trial ran by a homeopathy company or a big pharma company. Both groups can work around almost any set of data. They practice an advanced form a cherry picking statistical analysis that is hard to detect. Meta analysis however has a way of measuring the measurements of clinical trials. In essence, it is a clinical trial of the scientific reasoning behind a particular area of interest.

Bring in Dr. Ionnidis (YO NEE DEES). In the November issue of The Atlantic David H. Freedman has an article titled "Lies, Damned Lies, and Medical Science". The main character is Dr. Ionnidis. He is a meta-researcher and he's one of the world's foremost experts on the credibility of medical research. Alas the CCS is just a lowly blogger but this guy has introduced science into the equation.

Dr. Ionnidis: "There is an intellectual conflict of interest that pressures researchers to find whatever it is that is most likely to get them funded".

Indeed!

Dr. Ionnidis sees a pattern (the as does the CCS) and he has a method of testing his hypothesis. Of course this means that he has his own bias. As they point out in the article, it would not be very interesting if he did the analysis and found that most clinical trials are more or less correct. Dr. Ionnidis claims that roughly 90% of the medical research that doctors rely on is flawed. By merely pointing out the bias however, he has risen above the norm.

Making a Drug Follow-up

Biospace reports a few snafus in the manufacturing side of big pharma.

Sandoz Pharmaceuticals Initiates Voluntary Recall of Ceplene in the US

B. Braun Medical Ltd. Voluntarily Recalls Seven Lots of Heparin Manufactured in 2008 Due to Supplier-Initiated Recall of Heparin Active Pharmaceutical Ingredient (API)

Crucell N.V. (CRXL) Halts Vaccine Shipments to Investigate Plant

This is not a cargo cult issue. It is quite the opposite. The reason for reporting errors and removing drug product from the market could be due to a moral issue of not wanting to hurt anyone or a business decision that makes the potential downside too high of a risk to take. Either way, the best thing to do was to remove the product from the patient.

This adds to yesterdays post on drug discovery vs drug manufacturing. Discovery is riddled with Cargo Cult Science. Manufacturing however must be done in a manner where predictable outcomes are an absolute requirement. When you have a problem you cannot hide it. Discovery is a whole different world.

Drug Development vs Making a Drug

How does a small company move from drug discovery to drug development? The answer is in partnering with people who know what to do. A handful of PHds from MIT who start up a biotech company based on some clever cloning vector do not have the proper experience to begin developing upstream and downstream processes that can be scaled to a GMP facility. They must seek help. This is difficult for any PHd.

What is happening to biotechnology today is similar to what happened during the dot com era. Initially people were very excited and money was not hard to find. After too many empty promises the money has dried up. Investors are looking for more advanced programs. In biotech that means they want a drug in phase II or III. In order to get there you have to have a drug to put into people. How do you do that? Biotech start ups only know how to get to the drug discovery phase. After this they must either outsource or learn new skills. The former is more desirable.

Big Pharma wants the little guys technology. Like the zillions of little companies that went out of business in the last 20 years, big pharma has also had a tough time discovering new drugs. They must look outside of their organization. They look to people who most often have never actually made a drug, small biotechs. They don't know the rules and there are lots of them. Still, big pharma and biotech partner up and roll the dice.

One group that doesn't gamble in this process are the contract manufacturing organizations. They accept the job, develop the methods and produce the drug. No further research will be required.

Does biotech understand the bottleneck of manufacturing? Do they understand clinical trials? That is another story. Once again, we clump the companies into a population. Some are better than others. Some are great at science but horrible at engineering issues. But go to a biotech company website and seek out the information that touts their ability to perform necessary routine development work. It's just not sexy. Without that expertise however, they won't even know who to call to get help. If you want money, you have to get smarter. There is now a new question start ups must answer besides "do you have a drug"? "Can you make it"?

Wiki Leaks Didn't Write the Documents!

Those in power often times work in secret. Those outside of the chosen circle can't handle the truth.

But the truth is a powerful force for good. The story about WikiLeaks release of Afghanistan and Iraq war documents has angered those in power. The truth can get you in trouble. But the truth is the truth. In the long run, the truth is your friend.

"In our release of these 400,000 documents about the Iraq war," WikiLeaks Founder Julian Assange said, "the intimate detail of that war from the U.S. perspective, we hope to correct some of that attack on the truth that occurred before the war, during the war and which has continued on since the war officially concluded."

What the mainstream media is ignoring is the organizations use of the truth to fight the notion that war is necessary. Science uses the same tactic. The truth is what is missing in cargo cults. It is replaced with ceremonial practices. If Wiki Leaks is in fact jeopardizing our security, where is the evidence? Why do Hillary Clinton and all of the other powerful people in our Cargo Cult claim that this will hurt us?

The Cargo Cult Scientist believes that war is a ceremony performed by group leaders to establish superiority over each other. It achieves very little and it destroys too much. Yet it has been established as a way of dealing with difficult outsiders. Does it work? Is it worth the guaranteed destruction of life and property? By looking at the reality of a war we can ask those who order the ceremony to account for it. We the little people do the ceremony. We look to the sky. Did the airplanes come?

Financial Crisis Adjustments

Having to sell a house at this time has taught the CCS a painful lesson. Nothing is impossible. A house once worth 200K more than it was paid for (in 1.5 years) is now selling for 5K less than the original price. And it's not selling!

A few years ago the house would have sold faster and for much more. Same house, different time. In the Yahoo news today the story is that Dubia real estate woes have sent the rent in the worlds tallest building to approximately 60% of what they went for last year. So who is in charge of determining value?

If you are a real estate agent and you made 300K per year between 2003 and 2006 is your job not harder now that houses are harder to sell? Same person, more difficult job, lower pay. You were overpaid (over-valued) and this is an adjustment.

The upper echelon must learn that they are like overpriced real estate. The value they placed on themselves needs to be adjusted. In essence, they are like the top penthouse apartments. Their children, getting advanced degrees in the finer universities, are like new construction that will soon dilute the money pool of executive pay.

The goal is to make the adjustment without destroying as many people as did the real estate market. Place more value back on making a product or providing a service.

Biotech Logic and Initiative 1098

How hard is it to attract the right people to your cargo cult airport? Cargo cult airport technicians are people of great logic. Whether they work in the watch tower with coconuts over their ears with sticks for antennas, or whether they wrap a wire around their body and serve as a radio, they don't want to pay taxes.

So says the CEO of Dendreon.

Dendreon CEO Mitchell Gold says more is to come. "My goal is to build a fully integrated biotech company in Seattle," he says. The company envisions a campus of buildings that would include a pilot manufacturing plant.

This, to remind you, is for a drug treatment that costs 93K for one round. Mostly well to do cancer patients will be treated. Poor folks will mercifully die sooner.

Back to the article:

"And that requires the hiring of top talent from around the United States, says Rich Ranieri, the company's head of human resources. The need is for scientific talent and also commercial talent specific to biotechnology — a talent pool that has not existed in Seattle since the sale of Immunex in 2002. And that means recruiting men and women from the big biotech centers in Massachusetts, New Jersey and California.

Some people in those states jump at the chance to move to Seattle, but many do not. This is not the center of their universe. A recruiter needs enticements — and one of ours is no state income tax.

"Having no state income tax is an attractive tool for us," says Ranieri. "It matters."

For this city, biotech matters. It is part of our future. Let's not mess it up Initiative 1098."

The gist of the initiative is that people earning over 400K year will have to pay an income tax.

My favorite comment from the online responses:

"Dendreon hopes to make its money selling $93,000
treatments for doctors to prescribe to old rapidly dying men for a 4 month survival "benefit". Who will pay the $93000 to Dendreon? Mainly taxpayers paying into the Medicare system.
Who does the money go to? A CO. w/ management that wants its taxes lowered!
What a country!"

Priceless

Airport Authority Discussion

It's gonna turn this whole thing around.

Of course our airport is in trouble. The investors gave generously, the cargo cult workers did what they thought would bring the metal birds, nothing happened, big pharma gave up hope, investors got tired of losing money, workers were laid off, and now it's October of 2010.

But it was not a lost decade. When you practice a biotech kind of science you can expect 99% failure with a lucky win from time to time.

What if there was a forum with the losers? What about the workers who knew about the mistakes that were made? What if there was a poster session of the most comical scientific logic displayed by local biotech leaders? To put it all in proper perspective there should be a counter forum to "Biotechs Back in Seattle".

Someone should put together the stats of jobs lost and jobs gained in the past year. How much money was poured into the existing companies and how many jobs did it create. What kinds of jobs are now in demand? What is biotech and how is it back?

The panel are people who need to attract money to the area. Should we trust what they are saying?

Top Ten of 2010

President Obama has put together a top ten list. They call it the National Medal of Science Laureates.

Stan Prusiner, Nobel Prize winner 1997, made the list. But what has he done since winning the prize? What did he do before he won the prize?

The key to winning awards however is to silence your enemies. As a brilliant politician, Prusiner has earned many awards. But it is Taubes who has fought a brave fight against the arrogance of scientific authority. He didn't care who was right, but what was right.

Nonscience

"Interestingly, mutations were observed at a frequency dependent on display valency".

This is a quote from a paper that was published regarding some work that I performed. It is a confusing statement. A phage library was made with 7 random amino acids stuffed into a 20 amino acid peptide. Does the statement mean if there were 8 random amino acids that there would be more mutations?

Like Feynman said, we should report everything we do, not just the things we want people to believe. Phage libraries can be made from simple oligo sythesis samples from companies like Invitrogen. There were ten vials of DNA preparations that came from several oligo orders from Invitrogen. One of the oligo orders came in with all phenylalalines where random nucleotides were suppose to be. Not a mutation, but a mistake at Invitrogen. There was one oligo that gave the best results. It was used to make 5 DNA preps that were inserted into our phage vector. Only 2 of these preps gave the results we needed to get the library done. 90% of the library come from the first prep.

The other oligos should have been the same but we humans were doing work with them. The "mutations" that the paper mentioned disappeared when a new oligo was ordered. However, new "mutations" came with new DNA. It is a normal occurrence in cloning man made DNA into vectors. The fidelity of the DNA insert was pretty good actually. The only thing interesting is how ignorant the authors of the paper and the editors of the journal were to this fact.

Perhaps someone else should have tried to reproduce the work. That would serve everyone interested by demonstrating that the papers "mutations" claim was not only wrong, but a non-science claim.

Scientific Satus Quo

Bad times have a scientific value. These are occasions a good learner would not miss.
Ralph Waldo Emerson

The best experiments have built in controls to help you believe the results. If you want to quantitate a protein, for example, besides an unknown there should always be a known. It should incorporate numerous measurements so that statistical analysis can be applied. What might happen is that your known shows a lack of precision and/or accuracy. Then you have some information about the measurements of your unknown.

Since the CCS is a biotech worker, we have often seen a standard curve of 5 data points, each measured once, and an unknown measured once. Even worse, we have seen the standard curve imported from a previous day. The unknown is measure once and that is all. Now would this be important information? Scientifically, yes. Would the CSO of the company waste his important time on such trivial details? No. But isn't this the part of the business that matters most? Whoever has power within an organization doesn't have to focus on every detail. But they should serve as the judge over whether or not rigorous scientific experimentation is taking place. This is how junior personnel pull the wool over the eyes of people like Dr. Woo and Baltimore who want specific results and aren't paying attention to how they are obtained.

So I go back to the concept of the Misconduct Journal. Each act of misconduct is a gem that can be used as a learning experience for everyone who works in science. And each monthly issue will have a fresh new case to explore! There are no shortages of those who get caught. Imagine the actual number of cases that should be reported.

Again... Feynman: "One example of the principle is this: If you’ve made up your mind to test a theory, or you want to explain some idea, you should always decide to publish it whichever way it comes out. If we only publish results of a certain kind, we can make the argument look good. We must publish both kinds of results".

The entire scientific community seems to be focused on positive results by top notch scientists. What about top notch science by human beings. Anyone can do it. A scientific journal should be able to focus on science.

Woo Retractions

Gene Therapy is interesting. There is something to confusing a cell with extra DNA. We know we can insert DNA into a genome and it will express a protein of our desire. It may also splice that piece of DNA out of the genome.

But to simply throw DNA at a cell is not science. You randomly introduce DNA to a living organism, see what happens and create a story behind the results. So far there hasn't been the kind of explanation of gene therapy that leads to a predictable outcome. Throwing dice on the other hand has been studied for centuries and we know what will happen.

Which leads to the Woo story. Two of Woo’s post-doctoral fellows at Mount Sinai School of Medicine were dismissed for “research misconduct,” said Ian Michaels, a spokesman for the institution. According to Michaels:

"When Dr. Savio L C Woo came to suspect that two post-doctoral fellows in his laboratory may have engaged in research misconduct he notified the Mount Sinai Research Integrity Office. Mount Sinai immediately initiated institutional reviews that resulted in both post-doctoral fellows being dismissed for research misconduct. At no time were there allegations that Dr. Woo had engaged in research misconduct. As part of its review, the investigation committee looked into this possibility and confirmed that no research misconduct could be attributed to Dr. Woo, who voluntarily retracted the papers regarding the research in question. Mount Sinai reported the results of its investigations to the appropriate government agencies and continues to cooperate with them as part of its commitment to adhere to the highest standards for research integrity".

The papers, which appeared in the Proceedings of the National Academy of Sciences, the Journal of the National Cancer Institute and Human Gene Therapy, involve findings published between 2005 and 2009, address various aspect of gene therapy. Two of the articles boasted of potential breakthroughs, and even a possible cure, for diseases with extremely high rates of mortality.

No there was no misconduct on Dr. Woos' part. Just an eagerness to see what he wanted to see. And that is a Cargo Cult offense.

Mercks Big Bet Revisited

Long ago I just knew that Mercks acquisition of Rosetta (bioinformatics) and SIRNA (RNA silencing) was a match made in the imaginary heaven that exists in the hollowed heads of BigPharma/Biotech executives.

See Mercks Big Bet, 2006.

Since then I've updated the blog to point out the closing down of Rosetta. Merck has been pretty tight lipped about the progress they've made in the four years since so I've nothing new to report.

There remains Marina Biotech, Tekmira, and Avi Biopharma in our Seattle Cargo Cult Airport.

We are still following the RNAi story and there still is a story. That is astonishing to me, the CCS. Somewhere out there, grown up men and women are still convinced that RNAi is going to become a drug. Why do they think that?

When Credentials Outweigh Capabilities

Credentials
–noun
1.
Usually, credentials. evidence of authority, status, rights, entitlement to privileges, or the like, usually in written form: Only those with the proper credentials are admitted.
2.
anything that provides the basis for confidence, belief, credit, etc.

Capabilities
-noun
1.
Usually, capabilities. qualities, abilities, features, etc., that can be used or developed; potential: Though dilapidated, the house has great capabilities.

I was talking to a person in the human resources side of biotechnology. He tells me that pHDs are removing the pHD from their resumes. Has the industry started to sour on the title? It used to say, "I'm capable". What does it say now?

The waiting is the hardest part

Can You Blow the Whistle on Bullshit?

In the Baltimore Case, Margot O'Toole, found she was unable to reproduce some of the reported results in her own experimental mice. Her attempts to resolve the problem with her immediate boss, Dr. Thereza Imanishi-Kari, led O'Toole to suspect defects or errors in the original research. Her doubts seemed to be confirmed when inspection of laboratory notebooks revealed discrepancies with the published results. Apparently fobbed off by Imanishi-Kari, with whom there was obviously a major personality clash, O'Toole felt affronted that her superiors appeared to show so little commitment to the fearless pursuit of scientific truth to which they paid lip service. She made her suspicions public and turned whistle-blower.

If you are gay, over 40, female, of a minority race or in some other protected class, there are laws that prevent you from the harassment Margot O'Toole experienced. Margot O'Tool left the biological sciences for many years after blowing the whistle on Baltimore and Imanishi-Kari.

What if there was a court of law that would hear your case against scientific bullshit. By bullshit I mean anywhere from honestly mistaken to fraud. The only issue of the court would be the truth. Credentials would not be allowed. The protected class would be those who are speaking the truth.

The Buy-Out

Zymogenetics has operated in Seattle since 1981. They even made a few products along the way. Their fire along our runway however will soon be extinguished. One of Zymos eulogies discussed the health of the biotech industry in Seattle.

"Biotech advances flow from the well of scientific discovery. Individuals who haven’t worked in a biotech setting don’t always grasp the synergistic benefits of putting together a research team that recombines individual talents to innovate fantastic discoveries that lead to new drugs."

He goes on to point out, "A quick look at the WaBio website shows only about 33 job openings at local biotech companies, with about an equal number of jobs listed for academic and other institutions. Since 2002, when Amgen bought Immunex, there have been over 3,200 layoffs at local biotech companies (not including any upcoming layoffs at ZymoGenetics or Trubion), and I would wager that a lot of these folks were unable to find employment locally."

That is 3200 gone and 33 still available. The only piece missing here is how many jobs have opened up since 2002? That is the health of the industry and its ability to keep the college educated work force required for research teams.

I found a comment from another article regarding demise of Zymo: "I’ve been in pharma work since ‘93, and with Seattle-area biotechs since ‘97 and I’ve been through three layoffs, five mergers and and two company failings.

I had a co-worker coming to me in tears asking me whether she should get a divorce and go back to a job she had out east, or stay with an intransigent husband and child and accept unemployment. I watched a co-worker selling off his furniture to help cover Cobra payments to carry them through the birth of their child. Out of roughly 100 scientists that I’ve worked with (i.e. in my “group” or department) since ‘97 only a little over a third are still in the Seattle area. I’ve spent almost three out of the last thirteen years in this area between paychecks. I know skilled scientists that hung it up to become tour guides, salesman, stay-at-home parents and retail clerks."

There was a Tiki torch along our Cargo Cult airport that burned for many years. It was labeled Zymogenetics. This one was a little different. Why did it burn so long?

The common thread, is that it will soon be gone. It goes on to live as a piece of a mega drug company. Of the hundreds of unemployed people, who will become tour guides, salesmen, stay-at-home parents and retail clerks? My hope is that these people find happiness. Those who find replacement biotech jobs must realize that they work in a cargo cult airport. We take someone from the watch tower, remove the 'coconuts with sticks for antennas' from their ears and we strap a wire around their body and tell them they are now a radio. It pays well for awhile but the duration of that paycheck is random. Zymo was long lived but what will happen next is more likely to be 'three layoffs, five mergers and and two company failings'.

What Did You Do To Cause This Recession?

An economist is an expert who will know tomorrow why the things he predicted yesterday didn't happen today.
Laurence J. Peter

A friend tried to get an advertised 10% off her phone bill. After 2 hours and numerous contacts she finally got a phone number to call tomorrow to see if that group knows how to get the discount.

When the economy went into the tank we ended up with a vast amount of Americans unemployed. Which ones could have helped customers get that 10% discount? Did any of those unemployed people have a job where they made the discount harder to obtain? Not everyone contributes to a better business. In any sizable group of people, some are good, some are bad. Which ones are the leaders and which ones are the smartest?

In our world we have valued individuals based on college education, job title, responsibilities and experience. Currently younger college educated people are having a hard time finding work as are the 50+ white collar workers. Like a piece of real estate, those two groups of workers have lost their value.

Was the cost of employing so many people not paying off? Or did the economy take away the business that paid the salaries. Anyone who has worked with a bad boss or a bullying HR department knows that not everyone is doing work that directly earns money. A software engineer may work 16 hour days developing a product only to one day find his job has ended. But business decision makers can be like cargo cult leaders and they may one day remove all of the useful people and leave behind an office full of white collar folk who have meetings all day wondering what to do next.

It is of course very complicated. Without sound business decisions, the money will dry up. The value of employing business decision makers is thus based on the companies financial health. The value of the product developers is based on whether or not people want to buy their product over the competitors. If you like X Box better than Play Station 3, you give your money to Microsoft. The business people must employ the product developers and direct them to make the best product. The business people must then shift the cost of business from R&D to sales.

But I end this post on a positive note. I have stepped out of the product development side of my own Cargo Cult business. For sanity purposes I am going back to my old ways of thinking more, working less. And I will write more.

A Drunkards Walk

'A Drunkards Walk' was a fine read. The reason it has resonated so much with the CCS is due to the randomness of the biotech business model. In our science, desired outcomes make everyone happy. When outcomes are not favorable, the laboratory technician who ran the experiment, the statistician, clinical trial doctor..., is grilled to determine what he/she did wrong. Does the desirability of results bias the judgment on experimental outcome?

In a Drunkards Walk the relationship between randomness and our interpretations of life are explored. On one hand, we have got some serious scientific problems when it comes to biology level scientists trying to distinguish between random and non-random events. But the scientists don't really put a company on the map. Investors do, and we need them to be ignorant of the lessons taught in "A Drunkards Walk".

Check out this comment from a biotech company yahoo finance message board: "@#$%^&* will either hit a home run or will be made to look like an idiot. Either way, I am still invested. Lottery ticket, hopefully a payout. I have lost before."

Thank you for investing sir.

At the End of the Day

I've been interested in the financial meltdown lately and how it is related to CCS. I recently watched a DVD with the Economic Hitman, John Perkins. As I've mentioned, I work in biotech for the money. The money is the sole reason for waking up and going to work each day. In better times perhaps I would try harder to find meaningful work. As it stands, I'm a son-of-bitch. John used to be the same way. Only he made a lot more money.

In the DVD, Mr. Perkins mentioned that the people who worked in the "Economic Hitman" field were not necessarily bad people. In fact, they may have been very honest people who believe they are working in the best interest of others. Yet Mr. Perkins, who worked in the same field, now feels the need to carry on a crusade to educate the world about the ways in which the rich are getting richer. He's different. He feels what was done was dishonest and those who work in high places should know better.

Cargo Cults are run by people who have always desired to be the boss. These people have always existed and they always will. Some are preachers in local churches. Some are CEOs and politicians. They love the power but feel most insecure when it is time for the planes to come. Religious leaders have it the easiest. The planes don't come in our lifetime. The afterlife is the promise. CEOs on the other hand have a problem. If shareholders start losing money then the CEO musts go. Politicians must pray the CEOs and religious leaders are pacifying the people during times of strife.

The scientist however thinks thoughts in a world aside from CCS leadership. He knows the ways to make the planes land, whether or not he/she has access to what is needed. CCS leaders have the power to keep themselves and their friends employed at the top for as long as they can stand it. Just look at the US Treasury and the Wall Street relationship. In spite of their failure, they have survived and they got even richer in the process. But John Perkins knows a thing or two about them and how they do it. John doesn't have the power unfortunately. He has his thoughts and he sees the damage before it is done. When the damage IS done, and a handful of people prosper as a result, he is not surprised.

So at the end of the day, when I head home from a day of Biotech non-science, I hang my head and hope for the day when I can work away from CCS. Is there a place in the world for people like John Perkins who leave lucrative positions and try to point out negative things to a tribe of people who only want to hear stories about the cargo. The world needs people who send out warnings that repeatedly come true. Not everyone wants to be rich. Some have a deeper purpose.

Are We Different?

Over the course of a few years I've come to a conclusion about biotech people. They are no more scientific nor any less religious than any other group of people. Most believe in the christian diety. Most have never heard of Richard Feynman. The story of N-Rays seems pointless.

Long ago people began to look at the world and wonder if they could discover things that no one had yet explained. By taking measurements for example, they soon learned that water boiled at the same temperature (more or less). When they were convinced that they had a fact they told others and challenged them to prove them wrong. A certain kind of person would find the study to be... interesting. Another kind of person would be confused as to why the would-be scientist had bothered to pursue their research.

In a group of 100 Americans, how many would be in the latter sub-group?

In the Cargo Cults, everything is known. The rituals are well established. The only thing to do is wait for the Gods to deliver the goods.

So in our biotechnology laboratory we can make proteins and cell lines and send them forth into the blood streams of animals to establish the simple fact, that our drug is the real deal. Our drug is going to be that airplane in the sky. We see it clearly.

In a group of 100 Americans, how many would see it clearly? Let's say that those 100 people work at the biotech company who made the drug. Do we all believe?

Did You Learn How to Believe?

I have a bad attitude regarding Biotechnology. I believe the financial interests spoil any chance of science taking place. In its place we build Cargo Cult Airports and occasionally make a whole lot of money from fools who believe our stories. The biggest fools however, are the ones who toil in the laboratories. They stand duty in that wooden hut with two wooden pieces on their head like antennas and they soon start to believe that they are indeed the controller of the airport. They wait for the airplanes in spite of what they have learned. They are now believers.

Yet I work in one of the Cargo Cult Airports. Why?

Money.

Life Coaches for the Life Sciences

Why do we have a life coach at our biotech company? Our "scientists" do need guidance in the ways of managing other human beings. That can be an important aspect of the service. But managers are hired to manage. Why not hire a "science coach"? The managers are also hired to do science.

The coach shows up in a 1992 Honda Accord. His 6'4" frame towers over the little car as he emerges desperately dialing someone, anyone, to make sure he looks busy on his way to our door. He could be here to visit our clinical trial leadership. He could be here to visit the HR person to recommend a new book for the in house leadership book club. Or perhaps the director of R&D... CEO? All people he has consulted with.

Does he have another job? Night shift at Target? Does he have an office? Does he know what DNA is or an antibody? No matter. He has his skills. We're dying to know what they are. But that is not information that is shared with most. It is another secret. Because we have secrets. The coach is one. What could he be teaching a science based company?

What to Say?

Lately I've been mulling over several topics.

Eli Lilly has a couple of cargo cult irons in the fire. Yesterday http://www.biospace.com/news_story.aspx?NewsEntityId=167679

But we expect dishonesty from those who practice the cargo cult science. More interesting is their own angst over being burned by the same kind of silliness. http://online.wsj.com/article/SB20001424052748704247504574604503922019082.html

Warren Buffet is qouted, "You don't ask the barber if you need a haircut". Is big pharma starting to get this concept?

The economic meltdown is another topic. Think of the financial system as a CCS airport. The meltdown is merely the locals who have given up on the arrival of the planes and gone home. It's an abstract concept. Is monetary value real or imagined? Do we gamble on the imaginations of "geniuses" or do they really have a system?

Lastly, tonight, Shadow Elite. I've just purchased this book, and have yet to read it. However I am intrigued by the notion. Is it possible that we look at our own Cargo Cult Airport and eagerly await the scholarly words of the leaders, yet off in the distance, there are those who know that the planes aren't coming? If so, how do they succeed in this type of pursuit?

These Airplanes Are Fake!

Imagine the leaders of the Cargo Cult Airport leading a group of people around their airport. They bring the people close up to the airplanes but never close enough to actually touch one. They show them the workers but never allow a conversation. If they did they would see that the airplanes are merely wooden replicas and the workers have no clue what they are doing.

This is a biotech website. Those who chose to look will see the white lab coats.

But alas, not all who contribute to the biz are cargo cult scientists. For example, some are there to make the product that goes into the clinical trials. These people have experience and expensive equipment that make biological products. They cannot survive for the long term making wooden replicas. They make real biological products. It is up to the biotech company to use the products to create the dream that one day the airplanes will come.

Now we see someone who has a real concern about the quality of the airplanes/drugs. The airplane/drugs must have certain attributes that are not properly ascertained by looking from a distance.

Long story short, we (my biotech co.) are being discovered. A contract manufacturer is asking questions about how we produced and purified and packaged our drug, an antibody. Not just how, but why did we do what we did. Our answers we not sufficient. The CMO is now doing what it does with less and less help from the little biotech who is paying them to do their job.

The moral of this story is that not all biotech is Cargo Cult. Although it is embarrassing to be on the wrong side of right and wrong, I am pleased to see a contract manufacturing company asking the right questions and getting the wrong answers... and knowing that they are wrong. 

A River Runs Through It

I'm currently faced with a situation that would have pushed me over the edge in my younger days. We are working in "process development" in a small biotech company. We spent a few years getting by, purifying antibodies on a routine basis. All of our methods seemed to have come from a contract manufacturer who was hired years ago to produce a drug candidate for us. Our people knew nothing to begin with, and after watching the contract manufacturer do their work, they knew very little. What our people did was to find out what buffers were used. That is all they came away with. They did not know why the buffers were chosen but they knew that they worked.

What we have now is a clear "Cargo Cult Science". (CCS)

Our contract manufacturers succeed. They must or they will not continue as an entity. We on the other hand can carry on for years, because we do not have to produce anything other than charts and graphs that can be presented at meetings with affluential people. Contract manufacturers produce our drug and they must not only convince the world that the protein exists, but it is in the very vials that they send forth! And they do it very well. We don't know how.

But we, in this little company, take the proteins in the vials and we take them to the Cargo Cult Airport. We incorporate them into our rituals and invite our investors to sit with us and wait for the airplanes to arrive. So far nothing but a whole lot of money.

Pfizer Shuts Down Several Airports

As part of its integration of Wyeth, Pfizer said it will close a total of six research facilities and ultimately reduce the work occurring at 20 research facilities into five main research campuses and nine specialized units around the world.

What were they doing wrong? Here they are admitting that the planes were not landing. They've restructured. Will the planes land?

It all seems so random. To the investor or the executive they have a new path. But what was really wrong? Why couldn't the millions of dollars, pHDs up the arse, cutting edge technology and the latest advances in medical science produce promising candidates?

Something was missing...

Science, Sequences and God

I used the Henderson–Hasselbalch equation to calculate the amounts of acetic acid and sodium acetate needed for a certain buffer. When the pH of the solution was taken it was exactly what it should have been.  This is the kind of science that the CCS likes.  Now consider the human genome project.  

After a fortune was spent on the project, and more than a few "leaders" of the sequencing became famous, what do we really have? Has anyone ever truly used it logically? It's a bunch of As Ts Gs and Cs.  I originally thought there would be patterns that a computer could pull out that would help us to understand what a gene is.  Unfortunately, most people believe they already know what a gene is.  The genome project has only resulted in the kind of science the CCS dislikes.  You take a finite set and you select a piece of the set that best describes your pre-conceived notion.  In the case of the genome project, they selected five people and they began sequencing their DNA.  When they were done they said, "wallah, the human genome, now go and cure diseases.  But don't ask us how to use this tool."  The "how" is science.  The sequence is a whole bunch of sequencing machines working day and night.  

Another such science is RNAi where you select a set of sequences to knock out a gene.  You select the best one.  You can't lose.

In the Henderson–Hasselbalch example, you can lose.  You can screw up the math and get the wrong pH.  Biotech companies practice the genome project and RNAi type of science.  A company selects a drug or some service and hires "scientists" to prove that it works.  The leadership are university trained scientists who find work in laboratories to be unpleasant and better suited for the lesser intelligent university trained scientists.  

This brings me to the point of this post.  One of the scientists who gained some fame from the genome project has been promoted to NIH director.  

http://www.bloomberg.com/apps/news?pid=20601087&sid=atJa8QDGj8QU

Here is the craziest part of it.

http://biologos.org/

Randomly Fumbling Through the Day

Quite often in our business we move from one experiment to the next, never analyzing the previous set of data.  After a while people begin to believe that such a logical process is not possible in our special set of circumstances.  

Take for example the case of the gender assay from AcuGen Biolabs Inc.  They claim a 99.9% accuracy in guessing the sex of your baby as soon as 5 weeks after conception.  Due to patent issues, they claim, they are unable to share with anyone the data from where this accuracy was calculated.  Statistically, how many tests would have to be done to verify that they can significantly predict male, female or twins with a 99.9% accuracy?  Can't we test this biotech company to make sure they are not selling a bogus product.  

But kudos for their method of sidestepping the FDA.  Each day we in biotech attempt to create data that we think will satisfy the FDA.  They do not tell anyone ahead of time what to do so we fumble along looking for things we think will help our case.  The real skill then becomes how to avoid exposing bad data.  Randomness allows less than favorable data to be hidden.  Well thought our research leaves you wide open for failure.  And that is a bad business model.

Stats

My career in biotech has been maddening.  But it is not biotechnology that is the issue.  The issue is statistical analysis of data.  This became very clear last week when some of us sat through a course in a software product that analyzes data.  A lot of time was spent debating what a sample was versus what a population was.  We even had people arguing over the term bogus results versus "not validated".  The useful aspect of statistics was not of interest to our group.  

There was a simple illustration about a lady who could tell the difference between tea with milk added versus milk with tea added.  The design of the experiment to test this lady was rigorous.  The people testing the lady were highly skeptical about her claim.  The design of experiment however, left out the possibility of bias on either side of the question.  In the end they all agreed, the lady could tell the order in which her tea and milk were combined.

When Feynman said, "So we really ought to look into theories that don't work, and science that isn't science." he seemed to touching on the powers of statistics to analyze experimental design.  Psychics and people who speak to the dead are best exposed using statistics.  Biotechnology can also be analyzed this way.  The real trick for our future is to find ways to get Biotech and the pharmaceutical industry to allow outside groups to analyze their data and their analysis of their data.  The thought of a group of MDs locking themselves in a conference room to make a recommendation to the FDA regarding research seems absurd to me.  The Design of Experiments is the whole issue behind the Cargo Cult Scientist.