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Sunday, July 31, 2011

Talent vs Experience

I believe it is more important to hire for talent than it is for experience.

Bill Biggs, President of Li Cor

Talent: A special natural ability or aptitude

Experience: A particular instance of personally encountering or undergoing something

What are the lessons from the rise and fall of SIRNA? J. Michael French, former Sr. V.P. of Corporate Development at SIRNA, is currently the CEO of Marina Biotech, another RNAi company. Barry Poliski, former Chief Scientific Officer of SIRNA, is now the Chief Scientific Officer of Marina Biotech. One might think that Marina Biotech is in for a slow painful death. Can these executives make their RNAi company a success? They made Sirna a success story in 2006. Sirna made that success questionable.

How do you separate talent from experience from the pool of RNAi people? In an environment such as biotech R&D, obedient workers are highly desirable. I know a researcher who once worked for Marina when it was called Nastech. This PhD scientist was to use RNAi to knock out one of biotechs favorite targets, TNF alpha. In a one-off experiment, RNAi appeared to reduce joint swelling in a set of three mice (pos control, neg control, RNAi). In the next experiment 300 mice were put to the test. At the end of the treatment each mouse was euthanized and put into a jar with formaldehyde. Without any actual measurements it was clear that the experiment did not reproduce the original results. No measurements were taken. The experiment at this point ended. 300 jars, each containing a dead mouse sat under an unused bench space for a year. The PhD who ran the experiment was a smart person who knew the honest approach would be to take the measurements. But he was also a new father and he needed to keep the job. Contributing to a massive pile of failed RNAi experiments would be detrimental to his career. Whatever scientific talent he had (the ability to bend over backwards to prove yourself wrong, to report all results...) had to be put aside.

Any person who has worked with RNAi can tell stories like this. It is the classic beer and pizza diet research project. The obedient worker is told to go into the lab, put small pieces of RNA in a plate of cells or a mouse and come back with results that indicate the knock out effects of RNAi. Long before the delivery issue was adopted, researchers were pointing fingers at whoever last touched the RNA. After trying to beat that square peg through a round hole, they finally decided to use a chemistry approach to getting the RNA to behave. Nucleic acid analogues, changes in formulation, injection techniques and many more ideas have come and gone. What remains is the decision that it is the delivery of the RNA that is preventing the desired action. At this point in the career of an obedient experienced RNAi lab worker, you should be questioning the talent of the decision makers.

Yet when you hear the talk, it can be some of the finest you've heard. Complex systems are eloquently spelled out with limitations being overcome by clever ideas. The talent is in the discussion. Experienced scientists are accumulating more and more data that is being processed by a talented scientific advisory board that will lead to the successful completion of a RNAi drug development program. We still have Alnylam, Marina and many more smaller players trying to make this work. They have plenty of experience in RNAi research. Do they have the special natural ability/aptitude to translate what they've experienced into a successful drug development project?

Friday, July 29, 2011

Is It Me or Is the Emperor Naked?

It's time to take another look at the Cargo Cult of RNAi research.

Merck bought Sirna back in 2006 for 1.1 billion U.S. dollars. They announced last week that the company will be eliminating 13,000 jobs, 12 percent to 13 percent of jobs by 2015. Merck also announced an end to its Sirna unit.

I first started blogging about siRNA research back in June of 2006. I mentioned the Merck deal in March of 2006. It is now July 30, 2011. Roche has given up. Pfizer gave up. Now Merck, while not yet admitting that the Emperor has no clothes, is making significant cuts and shutting the doors of its main RNAi investment research facility.

It's easy to be the Cargo Cult Scientist and use my considerable skills to predict the future. A pessimist is more often correct than the optimist but that is not my secret. I've done the research. I have spoken directly with the leaders and I have studied their ways. Why was RNAi selected by the leaders to be the next big thing?

The leaders of the Cults need to tackle problems that they can handle. Curing disease and helping people is tough. Making drugs is a bit easier. They begin with a Drunk Under the Streetlight approach. RNAi is an easy choice for this approach.

How do they direct the lab people to do actual laboratory research in RNAi? Beer and Pizza diet!

At some point some naive little person is going to point out that the Emperor has no clothes. How are they going to handle that?

An Emperor who cares for nothing but his appearance and attire hires two tailors who promise him the finest suit of clothes from a fabric invisible to anyone who is unfit for his position or "just hopelessly stupid". The Emperor cannot see the cloth himself, but pretends that he can for fear of appearing unfit for his position; his ministers do the same. When the swindlers report that the suit is finished, they mime dressing him and the Emperor then marches in procession before his subjects, who play along with the pretense. Suddenly, a child in the crowd, too young to understand the desirability of keeping up the pretense, blurts out that the Emperor is wearing nothing at all and the cry is taken up by others. The Emperor cringes, suspecting the assertion is true, but holds himself up proudly and continues the procession.

The Emperors of the RNAi cult are cringing more than ever. But they hold themselves up proudly and continue the procession.

Still, McConnell said Merck continues to invest significantly in RNAi technology. The decision to close the facility was based on other factors, including ongoing efforts to manage fixed costs. The technology Merck acquired in its acquisition of Sirna has been integrated across the company’s R&D organization, he said.

I succeed at predicting the future because I have looked into the eyes of the leaders and I know how Cargo Cults operate. I know that a scholarly scientific look into the research of RNAi will not appear because it fails to promise the coming of the cargo, only reasons as to why it did not come. We continue to look to the skies.

Wednesday, July 27, 2011

Cetero Response to Form 483

A spokesperson for Cetero Research sent Science Business the following statement:

Cetero Research, the leading provider of early phase research services, remains fully committed to maintaining the quality and integrity of the data collected in each of its facilities, including the Houston, TX, bioanalytical laboratory. It is this commitment that makes the broad action announced publicly by FDA on July 26, 2011, even more difficult to understand.

Cetero initiated its own internal investigation of its Houston bioanalytical laboratory over two years ago when it discovered the recording of inaccurate day/time data by a small number of research chemists in its Houston facility. Cetero proactively contacted the FDA to self-report its preliminary findings, as well as seek agency feedback on its comprehensive investigation plan.

At that time, Cetero clients were also contacted to make them aware of the situation. The Untitled Letter does not accept the results of our rigorous scientific analysis and discredits the Company’s 1,200 dedicated and experienced employees. The research conducted on behalf of our pharmaceutical sponsors can be, and has been, properly validated.

The FDA said in its public announcement: “It is unlikely that these concerns relating to data integrity affect the overall safety and efficacy of drugs already on the market and, at this time, there is no evidence of problems with the safety, quality, purity or potency of drugs already approved.” Thus, the FDA has not questioned the safety or efficacy of drugs already approved, marketed, and based on data generated from Cetero’s Houston bioanalytical laboratory.

We are pleased that we will now have the opportunity for the first time since our voluntary disclosure was filed in June 2009 to meet with FDA decision-makers to seek to resolve this matter in an appropriate manner. Cetero will continue to cooperate fully with FDA and with our clients and support them through this confusing process.

The little guys are going under the bus! If the FDA had any scientific proclivity they would immediately and randomly audit another group working in the sample group of "the Company’s 1,200 dedicated and experienced employees". As for the narrow window Cetero speaks of in this response, the FDA is looking into a five year period between April 2005 and June 2010.

As noted in a letter FDA sent to the company, Cetero also failed to conduct an adequate internal investigation to determine the extent and impact of the violations and failed to take sufficient measures to assure data integrity within the 5 year time frame.

FDAs Form 483 for Cetero

Just an image. Poor quality I know but I wanted to post this rare recognition of a Cargo Cult Organisation. I don't think Cetero is unusual in its dishonesty but it is unusual that they were caught.


Oh my!

The Food and Drug Administration said on Tuesday two 2010 inspections, an internal company investigation and a third-party audit uncovered "significant instances of misconduct and violations" at a Cetero facility in Houston.

The Cary, North Carolina-based firm does early-phase clinical research and bioanalytics for a number of drugmakers. The pharmaceutical companies can then use those studies as supporting evidence in drug approval applications to the FDA.

What if this type of inspection became routine for all of science? Randomly pick a NIH grant recipient, a biotech company, or a pharmaceutical company and ask them how they came to their conclusions.

“When someone says, ‘Science teaches such and such,’ he is using the word incorrectly. Science doesn’t teach anything; experience teaches it. If they say to you, ‘Science has shown such and such,’ you should ask, ‘How does science show it? How did the scientists find out? How? What? Where?’ It should not be ‘science has shown.’ And you have as much right as anyone else, upon hearing about the experiments (but be patient and listen to all the evidence) to judge whether a sensible conclusion has been arrived at.

What we have is a pandemic of scientific misconduct. Cetero, Cargo Cult Contract Research Organisation!

Tuesday, July 26, 2011

Malcolm Gladwell

"You don't start at the top if you want to find the story. You start in the middle, because it's the people in the middle who do the actual work in the world," writes Malcolm Gladwell in the preface to WHAT THE DOG SAW.

"How do we know whether someone is bad, or smart, or capable of doing something really well?" he asks in his book 'Blink'. In this book he looks into how educators evaluate young teachers, how the FBI profiles criminals, how job interviewers form snap judgments.

In 'Outliers' he tries to figure out why some people are successful. He comes to the conclusion that we've focused too much on the individual and failed to consider the other factors around successful people. We fail to see the forest for the trees.

Interestingly he gives an example of successful people. Jewish men who grew up during the depression whose fathers worked in the garment district apparently have done quite well as corporate lawyers in New York City. Our hero R. Feynmen also fits this category.

'The Tipping Point' explores meaningful changes and what really brings them about.

I've struggled all my life to understand this world. I got into the science business to seek refuge from a demon haunted world. Things were no different. There is of course the beauty of real science that occasionally works its way into the mess that professional scientists have created. But the world seemed even more bizarre watching people with PhDs use science in the manner that they do. Professional scientists are people who want to be known as smart. They want to be experts. Actual scientific people would never devise a thing such as the peer reviewed journal. RNAi does not come from scientific minds. Biotechnology hasn't failed for no reason.

This blog wonders how a group of highly educated individuals with billions of dollars create the system of scientific research that now passes for "discovery"? We are still standing on the shoulders of giants, but we seem to be looking in the wrong direction.

Along my journey I have extracted ideas from people and things I've read and observed. These ideas tend to follow what is considered to be the scientific method. That doesn't mean the ideas have always come from scientists. Malcolm Gladwell for example is a journalist. People who are good at what they do have the ability to see what matters. Gladwell applies new questions to old problems. Why are some people, of equal ability, more successful than others? When do good ideas (and bad) become accepted? To those of us who are dissatisfied with current explanations, this is a breath of fresh air. The books serve two purposes. First to see new explanations to old problems and, more importantly, to take the journey of how they were obtained.

Malcolm G. is not without his own flaws however. In the future I hope that he re-visits the following ideas posted on his website:

Journalism is not like the business world, where the mechanics of decisions and procedures take place behind closed doors. It is, rather, like science, where the fruits of all endeavor are put on public display. In the world of science, that transparency allows the profession to be self-policing. It is very hard to commit scientific fraud because all significant findings are published, scrutinized by other members of the scientific community, and—if they are sufficiently controversial—independently tested.

No one's perfect.

Thursday, July 14, 2011

Tumor Size

A tumor, as described by Wikipedia, is commonly used as a synonym for a neoplasm (a solid or fluid-filled (cystic) lesion that may or may not be formed by an abnormal growth of neoplastic cells) that appears enlarged in size. Tumor is not synonymous with cancer. While cancer is by definition malignant, a tumor can be benign, pre-malignant, or malignant, or can represent a lesion with no cancerous potential whatsoever.

What does the size of a tumor have to do with cancer and health? It is possible that we often develop tumors. Without a doctor around to tell us what they are, our body deals with them and we are none the wiser. Some tumors however grow and make people quite uncomfortable, such as the picture on Wikipedia. Besides discomfort, a tumor can be a threat to your health.

In 1971 Dr. Juhah Folkman formulated the idea of tumors being dependent on blood vessel formation. Researchers eventually warmed up to the idea and started looking for angiogenic factors that could be target by drugs. VEGF, Vascular endothelial growth factor became a target and it worked, some of the time. In cancers deliberately developed on the backs of mice, for example, blocking VEGF prevents tumors from growing. Clinical trials on human beings showed that it adds time to a cancer patients life when used in conjunction with chemotherapy on colon and non-small cell lung cancer. However, it did not add time to a patients if they had breast cancer. But science isn't always straight forward.

The FDA approved Bevacizumab in 2008 for use in breast cancer. A panel of outside advisers voted 5 to 4 against approval, but their recommendations were overruled. The panel expressed concern that data from the open label clinical trial did not show any increase in quality of life or prolonging of life. The trial did show that Bevacizumab reduced tumor volumes and showed an increase in progression free survival time. Based on this data the FDA chose to overrule the recommendation of the panel of advisers.

Two subsequent double blind studies showed little efficacy and some serious side effects. The first rule in medicine is to do no harm. It is a rule that is being ignored by scientists and doctors at Roche and Genentech. Careerism has them continuing to tout the drug in spite of the trial data. It may help some people just as it might result in the many side effects. Prescribing the drug by doctors (which they can still do) would be a random act. If the patient gets better... Eureka! If they get the side effects or they die on schedule, it was an act of compassion. None if it could be considered science. At $90,000 a year, Avastin is a money maker. It is the number one selling cancer drug in the world bringing in around 6 billion dollars a year. Removing the breast cancer indication will cut profits by a billion dollars.

Tumor size is biotech endpoint. Shrinking tumors means making money. The real question is whether or not it helps cancer patients feel better and live longer.

Monday, July 11, 2011

The Value of Blogging

While reading David H. Freedmans book, "Wrong", I knew he was preaching to the choir. But what would someone like my mother, a non-skeptic, think about the book? She needs to believe that our chosen experts are reliable. When something happens such as the Casey Anthony verdict she becomes a skeptic of the legal system. When the damned liberals take control of the white house she becomes a skeptic. More on that line of thought later. In general however, the non-skeptic does not like books like 'Wrong'.

Being accepted as an expert takes time. You have to build up credentials like college degrees, years of experience, and you have to be well spoken. The credentials quite often trump real expertise. Take for example the GETRAPL story. Using the 'drunk under the streetlight' approach the experts found GETRAPL. They are wrong. But who will take the word of a blogger who has never given any credentials and who seems to be an angry person?

My non-skeptical mother doesn't like angry people. Not many people do. She prefers the well spoken, soft spoken, expert who affirms her own beliefs. The same could be said about myself and the author of 'Wrong'. But I differ in that I don't care what the credentials of D.H. Freedman are. I like the ideas he presents. As a skeptic, I would like to think that I could tell the difference between right and wrong based on my experience, not the background of the person to whom I'm listening.

To what extent then do I, the Cargo Cult Scientist, expect to be taken seriously as a contributor to what is right and what is wrong? I don't. I want the words I write to be considered but I don't want to be an expert. I am not willing to go on camera and give away my identity. I have not spoken kindly and without anger about my chosen profession. The notoriety I could achieve would certainly focus on my anger, and weak credentials. I would be labeled a fool. As pointed out in 'Wrong':

It has long been established that when people are part of a crowd in which they're anonymous, they tend to behave less conscientiously than when they're identifiable.

Blogging about the how wrong other people are is cowardly. Yet the track record of the industry is hard to dismiss. Many people have sang the same song, Biotech is a failure. Working with the people has left me dazed and confused about what science is suppose to accomplish.

On the surface, a brave approach to the discussing the biotech business would be to start a website and actually talk to the leaders of the industry. Xconomy is such a website. Just yesterday an article was posted regarding the troubles facing Biotechs inability to attract the kind of financing it did back in its glory days. A lack of guts seems to be an issue. The author of the article, Luke Timmerman, is a well respected member of the biotech business. Luke didn't start a blog. He started an online website dedicated high tech news that is meant to make money. Telling investors they are lacking guts, takes guts. Luke also posted an article telling college students to pursue computer science instead of biotechnology. That takes guts. Luke finds himself in front of the crowd, conscientiously discussing their work. He must be smart and not come across as I do.

What then is the value in this blog? The value of the Cargo Cult Scientist has been mostly therapeutic. The daily struggle of listening to people with all the right credentials and millions of dollars is difficult. They are in the right place. But are the right? According to the ideas of Cargo Cult Science and numerous books such as 'Wrong' they are not. Being right is often the wrong thing to cling to but in science, it is the only thing that matters. I blog because I think science is a beautiful abstract concept, just like Feynman laid out for us in CCS. It makes me feel better.

Thursday, July 07, 2011

The Same People

When you invest in biotechnology, you are investing in people. The Cargo Cult you invest in is a group individuals who will be spending your money.

H. Stewart Parker is a 55 year old seasoned veteran of the cargo cults of Seattle. She's a pioneer. She was the first employee at Immunex right around the beginning of biotechnology. She went on to be the CEO of Targeted Genetics, a spinoff of Immunex. Before her reign ended, Targeted had ran up a deficit of $310 million. She left her cocoon in 2008 to become a consultant, as most execs do after their companies tank. She moved on to WBBA, the local biotech promoting organization of the Northwest. Today she announces an end to that moonlighting job so she can work full time as the CEO of the Infectious Disease Research Institute.

Let's break down her place in the Seattle field of leaders. The nonprofit she'll head up was founded by immunologist Steve Reed in 1993. Steve Reed is the Executive VP of Immune Design, and co-founder of Corixa. Bruce Carter, former CEO of Zymogenetics, is the Chairman of the Board for Immune Design. Other Corixa co-founders include Ken Grabstein of IL-15 fame and CSO of local Allozyne and Steven Gillis, co-founder of Immunex. Steven Gillis hired Ms. Parker straight out of college (UW). The names of the companies may change but the people (who spend your money) remain the same. They are all still here, running companies and enjoying the excess of the massive funding that comes and goes in the cargo cults.

This group has done well for themselves but have done little in terms of creating a career path for scientists. The business people have the job of telling the story that is intended to be told from the inception of the company. That is the career path that Seattle biotech cargo cults nurtures and structures. The career of the scientists is to come in as needed and fill in a piece of the puzzle and then go away. If a scientist can't tell the story, they can easily be replaced.

How can we find success in biotechnology when the leadership seems to be making it all up as they go along? Ms. Parker has had an experience. Since the beginning of biotechnology she has worked as a leader. She remains a leader. She has experience. But unlike a winning Superbowl coach, her experience will not land her a book deal on managing a winning team. But it will get her another CEO job in Seattle.