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Thursday, April 26, 2012


Wednesday, April 18, 2012

The Information Scapegoat

Wise Old Sage:  Why hasn't the cargo shown up? Where are those big metal birds that brought food and medicine to the white man?

CEO of Cargo Cult:  We have information that can bring the cargo but everyone is hoarding it. If we could simply share our information using the "computers" we would get the cargo.

Enter Sage Bionetworks.  The Sage is now going to help the gatherers of information. The similarities between this information sharing and the Genome Project:
But a lot of what comes next will depend partly on what Sage does to clear the way, and what people in the biomedical research community choose to do with its platform. “Our mission is to develop flexible approaches that can be championed by others,” Friend says.
Championed by others?

Friend is Stephen Friend, a former VP at Merck who started a nonprofit with a bold vision to speed up drug discovery. He plans on offering the scientific community a common place online where scientists could pool their data and brainpower to speed up the pace of discovery and drug development. According to S. Friend, "biology has become far too complex for any lone researcher or Big Pharma company to keep tackling problems in isolation." 

Biology has gotten more complex?

Flash back to the days when biology was not too complex. It was so simple, we could still make progress without computers! Rene Descartes was a scientist who made many important contributions to the scientific community. He had a set of information that he thought had value.

 Meditations is by far Descartes's most popular work—though this would not have been the case in Descartes's day. This work is important to today's scholar for many reasons, not the least of which is its including as an attached text written objections from some of the best minds living in Paris. Mersenne sent the Meditations to philosophers and theologians for criticism. The list of critics includes: Caterus, Hobbes, Arnauld, Gassendi, and Mersenne himself, with several other unnamed readers who raised their objections through Mersenne. A later edition would include an objection from Bordin. Descartes replied to each critic, and the result was an appended text referred to as “The Objections and Replies.” The second edition contains seven sets in all.
Descartes's letter to the “learned and distinguished men” of the Sorbonne, which is appended to the Meditations, suggests that he was trying to pitch the Meditations as a textbook for the university. Though the endorsement of the Learned Men would not have guaranteed that the Meditations would be accepted or used as a textbook, it could certainly be viewed as an important step to getting it accepted. Unlike today's notion of a textbook, in Descartes's day “textbooks” were intended mostly for teachers, not students. Typically, at the close of a teacher's career, his notes would be published for the benefit of those who would go on to teach such course material.

A text book for teachers who would go on to teach... What we have with Sage Bionetworks is a list of information. The difference is clear. Sage offers random information that the proprietors did not generate themselves. They hope to share the information with people who will turn it into technologies that make money. Cargo. Descartes had a set of information that he gathered himself. He offered it up to the teachers in a manner that would allow them to understand, in great detail, who, what, when, why and how this information came to be and what can be done with it. It wasn't a football to be handed off but a playbook on how to play the game.

Disassembled an old car. Lay the parts on the ground. Bring in an engineer and tell him to make the car run again. It won't work. Sage Bionetworks likewise, will not work.

One of the ways scientists used to get information was in the laboratory. The laboratory is where you ask nature a question. If you are clever and do so in the right way, nature will reveal itself to you. At the end of your career you might have a very interesting text book to write.

Friday, April 13, 2012

John Le Carre

At 9:37 of this video you hear a great description of what journalism should be. "Whatever we came upon, however offensive it was to those in power, we told it straight".

There is plenty to cull from this interview that pertains to our own predicament in science. I'm certain that what we experience when dealing with the elite has been dealt with by those in the past. The concept then of telling the truth, as Feynman described, comes with great opposition that has always existed. If the truth is something that benefits power then they will have you go back and make sure you are accurate. If it goes against their hopes and dreams it might just get squashed on the spot. You will end up marching your meager possessions out to your car in a cardboard box that day. This is true now, yesterday, in industry and in academia.

My work in a Nobel Prize winning laboratory seemed to have a strange relationship with the truth. I wasn't alone in my utter confusion at this my very first foray into big time science. My lowly supervisor however understood what it took to get her name on a Prusiner publication. She has spent her entire working life at this lab and by professional science standards, is successful. Yet if she were to be sent to any other lab, her work ethic and intelligence may not be sufficient to keep her around. She found her niche, and it required a special talent. It wasn't scientific.

David Cornwell, aka John Le Carre, spoke truth to power. Gary Taubes spoke truth to power. What we need more of are people like these. It is difficult however because we have no real science journalists. Science information is told to us by people who journalists should be writing about. When Taubes wrote about Prusiners very first Prion paper he mentioned something Prusiner left out.
The researcher who did Prusiner's lab work at the University of California at San Francisco quit over the publication of Prusiner's very first prion paper in 1982, arguing that Prusiner was overinterpreting the available data to push the prion hypothesis. 
Only a journalist would enter that information into the public domain. In discussing Prion research one might want to know who this man was and why, exactly, he quit. All we know is that he quit due to "overinterpreting the available data".

To some of us, science is not just the boring details offered to us by the authors of published papers. It's personalities, power, lies, cheats and the occasional flash of brilliance. The truth behind our daily lives conducting science and spending billions of dollars is a good story. Who is really telling that story. If you are lucky enough to work in this field, whatever we come upon, however offensive it is to those in power, tell it straight.

Thursday, April 12, 2012

The DNA of Identical Twins, A Novel

Bill Clinton said that the Genome Project was going to be one of the major scientific discoveries of the 20th  century. Was the Genome Project a discovery? It was a project in which we laid out a simple plan. Sequence the DNA of five people.

Any one of us can sequence our DNA today. The details on how to do it are no more or less a mystery to us than it was to Clinton or any of the bigwigs on the project. Let someone else worry about it, and we'll take to the podium when the work is done.

I've taken up my own genome project. I have an identical twin brother so there will be two people sequenced and there will be two sequences for sale. That's right, for sale. This is a biotech business. The product I'm selling is not just a DNA sequence, but a genome of two clones that will be sequenced over and over as we progress through life and die. The genome project pieced together their sequence from five strangers from different parts of the world. I will be offering two separate genome sequences from identical twins who are very different people.

Unlike the genome project I am starting my project with a check list. What are our similarities and  differences, nature versus nurture? The sequences will be overlayed to find the differences and the similarities. I will look for correlations but make no claims to consequences (causation). Perhaps my smoking habit led to some damage. Then I throw in a twist. After all of the comparisons have been made I shell out another five grand and get another sequence done. What are the differences between me and myself? Could there be some human misunderstanding of how we humans go about DNA sequencing of a genome? We're still new at this.

I've seen the way in which humans interpret simple DNA sequences. A single read runs about 1000 nucleotides. In the beginning stretch there is usually some noise that must be thrown out. I've found explaining this to scientists is not easy because they don't want to hear about it. In explaining the little anomalies that come up when allowing Vector NTI to spit out your sequence from a FASTA file I have encountered opposition. I've engaged in adversarial conversations about who's fault it is that we have these little problems. In my own project I will address these issues.

Since 3 billion nucleotides 3X is a lot of letters to put down on paper, the sequences will be available online. The details of interest will be broken into chapters of a book where I lay out my naive view of DNA. Perhaps that will be of interest to the world outside of science. We have questions for the genetics community. How do they know, for example, that every cell in the human body has the same sequence. Surely they do not. A B-cell coding for different antibodies have shifted their DNA around. I should probably make a side project out of sequencing B-cells.

This is getting expensive!

It is also getting exciting, at least for me. According to the genome project logic, my brother and I should die on the same day from the same disease. But DNA as a predictor of health and happiness is a myth for now. We need to learn more before we can start making wild claims about future humans living to 150 years old. For now we need two clones, twins. But I promise to have this project done in the next five years. When I am done I will publish in book form, "The DNA of Identical Twins". Publish or perish is not a problem on this project. Along with cheap DNA sequencing, we now have the ability to publish books on our own. It will simply be a few DNA genome projects, of twins and a couple sequences of me alone, different times different cells. Online perusing of the sequences will be for sale. The book will be for sale and I will put forward my own naive ideas on what our DNA is there for. I couldn't do much worse than the leaders of the genome project. I am a free citizen. I have nothing to lose here but a little money. I don't predict any huge impact on the future of human health. I simply want to open up a window and see what is on the other side. Unlike the genome project folks, the philosophy here comes from Sgt. Joe Friday from Dragnet, "Just the facts ma'am."

Do it, publish the results, make a side project out of my own thoughts on the subject, and walk away.

Tuesday, April 10, 2012

"We Re-Measured" Honesty

In my study of the Cargo Cults of Biotech I have seen first hand the curious deceptions that humans employ to get around the rigors of the scientific method. We had a drug to prevent angiogenesis, for example, that was to stop tumor cells from growing. In a study using mice, the Rituxan control group stopped tumor growth entirely. The PBS group all sprouted various sized tumors. Some mice, with smaller tumors, had to be euthanized sooner than those with bigger tumors. The group of mice receiving our drug were no different than the PBS control group. Without any trickery, Rituxan was an obviously efficacious treatment for mice being injected with cancer cells. Our drug was not working.

We were sent back to the lab with a grad student who showed us how to "properly" measure the tumors. She got the desired results by squeezing the caliper a little tighter around our drug group, and less so around the PBS control group. When I handed her a mouse that she had already tested, she wanted to know what her first measurement was. I refused to tell her even what group the mouse was in. Should she measure tight or loose with the caliper?

Why not simply take out a new data sheet and change the numbers? Because that would be misconduct. By re-measuring the tumors we were being, by Cargo Cult standards, more honest. The ceremony of re-measuring made us feel better about fudging the data. It somehow took us out of the realm of flat out fraud.

This experience shaped my view of early stage cancer research. The measurements are meaningless because cancer doesn't work in a manner that would make our research easier. Tumor size is an end point that the human beings conducting research can handle. The reality of explaining the "leaves blowing in the wind" chaos of cancer cells in the body would be too hard to follow. Using the "Drunk Under the Streetlight" logic we now have a place to look for efficacy. Using the "Beer and Pizza Diet" we then have a way of dealing with the nonsense we find.

Our anti-angiogenesis drug used in the cancer study described above, was picked up by a company called Cancervax. Their product was an attenuated cancer cell that expressed 26 antigens on its surface. It failed clinical trials in 2005 and the drug development ended. The anti-angiogenesis drug faded away, last heard from in 2007. While these two anti-cancer products were discontinued, the methodology remains much the same. Cargo Cults may have many iterations of their airports but the thing that is missing is always missing.

Two news items came up this week to exemplify the Cargo Cult science as usual approach. Presage Biosciences make the claim that they can separate the winning compounds from the losers early in development. According to Xconomy, Presage has partners who, "are hoping to improve the odds of success in clinical trials, where only about one out of every 10 cancer drugs that enters clinical trials ever makes it through the hoops necessary to become an FDA-approved product." The leaders are right ten percent of the time? Well anyway, Presage will help them increase their hit rate. "One of the operative words in cancer research today is “combinations,” which Olson (Presage founder) said people are buzzing about this week at the American Association for Cancer Research meeting in Chicago. Companies are becoming more interested in finding those instances in which a single drug doesn’t work on its own, but can show a potent effect when given synergistically with another compound that works in a different way." 

In 2012 folks at the AACR are buzzing about combinations? Perhaps science needs historians to keep the research in a scientific perspective. In addition to CancerVax's 26 antigens, I think  the Anil Potti story is germaine to this company. The Presage approach assumes that maybe we are only off by a few targets. Instead of grandma taking one or two pills for her cancer, she might need ten. Twenty? A thousand? No, that couldn't be because we can't make grandma take that many pills. The bloggosphere is buzzing too. Here is a comment on the AACR from In the Pipeline:
Take a look at the 6000+ abstracts from the 2012 AACR national meeting last week. Wishful thinking is a mild description for that carnival sideshow. Maybe 3% of the work was worthwhile. Four darts and a genome map would provide a better chance of hitting a cancer response biomarker.
I added that because it cleanses the palette after Jim Olsons gung-ho attitude towards the AACR meeting. And it's funny. 

The second news item this week comes from Oncothyreon.  They are marching forward with a Beer and Pizza Diet approach to their original stinker. According to Xconomy:
There are some very interesting scientific and business reasons why Oncothyreon wants to test the second-generation product, called ONT-10. It is attached to a more potent immune-boosting compound than the original, and the new drug is designed to stimulate a sort of two-pronged immune response, instead of just the T-cell reaction sparked by the original.
Why not start with the more potent immune booster? Why did they need to improve something on which they had already placed a huge bet. The company and their investors have us thinking that the clinical trials of their original product won't be much to talk about. But the new and improved product... now that's... well it's just going to be better... that first thing we did wasn't well thought out and... is it getting hot in here?

My message is that we are not really changing the way in which we approach cancer research. At the end of the sciencey meetings and the millions of dollars, a low paid BS Biology major, in her early 20s will be given a caliper and told to go measure the tumors on the backs of nude mice. Whatever the method, whoever makes the measurement, some things will remain the same. All of the promises will be backed up by the same "we-remeasured" honesty. We have not worked out a method to prevent it. It is a human issue involving psychology, not a laboratory issue, business model or funding issue.

Of course we hope that Presage and Oncothyreon are telling the truth. We want to believe them. We want them to be honest and not just "we re-measured" honest.

Thursday, April 05, 2012

The Quilt

At the "Reinventing Biotech's Business Model" meeting yesterday here in Seattle we saw an assembly of men and women who will lead us to prosperity. At least that was their purpose for getting together.
“When you’re building a team today, you need to have people with enough former company T-shirts to knit together a quilt in a nursing home,” quipped Bruce Montgomery, the founder and CEO of Seattle-based Cardeas Pharma. 
That’s one way of saying biotech startups now need teams of highly skilled, highly experienced people who can go a long way on a little bit of money. That was one of the main themes that came out yesterday at our big Xconomy event, “Reinventing Biotech’s Business Model.
It's also another way of saying that we have created a multi-billion dollar quilt pieced together by failed biotechnology companies.

Quip:  A witty or funny observation or response usually made on the spur of the moment.

The main theme seems to be that failure is no big deal. Make a quilt and move on using the same people. Perhaps to reinvent biotech we should replace certain people. If you have made a fortune in the process of losing a fortune... you need to be replaced. 

We should think about making another quilt in ten years. This quilt will be built from success. 

Wednesday, April 04, 2012

Avi Biopharmas Major Advance

Over at Dendreon they have a mechanism of action that can't be confirmed. Rather they go with the survival data as evidence that their MOA, as depicted in cartoon form on their website, is accurate. Avi Biopharm this week has shown a different approach. Their product did what the cartoon depiction advertised.
The study, which randomly assigned 12 boys to a couple different doses of the AVI drug or a placebo, showed the boys were able to produce about 22.5 percent of normal dystrophin levels after 24 weeks on the therapy, while there was no increase on the placebo. No serious adverse events were reported in patients on the experimental treatment, and no patients dropped out of the study, AVI said.
On the downside, their was no improvement with the higher dose and worst of all, the boost in dystrophin had no clinical benefit. Researchers saw no difference in patients’ walking ability in a standard 6-minute walk test.  
The study’s lead investigator hailed the finding as a “major advance”. 
Opposite of Dendreon, Avi has evidence that they can make the body do something very specific. Dendreon made the claim that they could elicit an immune response resulting in tumor cell death, yet they could not provide evidence of that MOA. Avi made the claim that they could make the body produce dystrophin and they provided information claiming that they did. Yet Dendreon provided a clinical benefit to their unsubstantiated MOA. Avi could not provide evidence of clinical benefit to their substantiated MOA.

From a scientific standpoint it is indeed interesting that a piece of RNA can accomplish this result. Eteplirsen is the therapeutic candidate for DMD and uses their core PMO chemistry applied as a splice switching oligomer (SSO). The drug is intended to skip exon 51 of the dystrophin gene. By skipping exon 51, eteplirsen may restore the gene’s ability to make a shorter – but still functional – form of dystrophin. From this point one would think that the scientific community would begin conducting research into skipping exons to restore or improve gene function. What we do in biotech is swing for a home run however. In this case I don't think we have much of a chance. Are we altering our DNA or are we throwing nucleic acids at the body and hoping the DNA will know what to do with it?  

The investor community gave the major advance a thumbs down. The stock went down as much as dystrophin went up, 25%. This could help investors understand such claims of 25% changes. If the stock were worth $100 they would have lost $25 per share. Instead, after a 25% loss, the stock was worth $1.16, a loss of 38 cents. In terms of what matters, the percentage of change is less important than the consequences of change.

When dealing with our DNA, we are dealing with evolution. Can we change millions of years of selection that has produced human beings destined to live short difficult lives? Of course we should be trying. But is this the best way? A for profit effort hell bent on surviving one month to the next? The desperation in the careers of the Avi scientific staff leads to certain outcomes that ignore the sad results of this trial. In a fair world the science would be handed over to an academic lab to learn more about what happened. The expense of moving on with more clinical trials, the suffering of the patients through this invasive research on their muscles is not warranted. It is time to get back to learning about our DNA and to move away from trying to make it stop doing something evolution has somehow allowed.  

Tuesday, April 03, 2012

The Provenge Trials

The comment left yesterday directed me to this website created by Marie Huber about the Provenge Trials. A one woman crusade against a Cargo Cult is too good to be true. She has alliances with prominent scientists, a website, evidence, and she is clearly passionate about this company and what they did to get their product on the market. Will we see her on 60 Minutes one day? It is modern day "Emperors New Clothes" story. Have we all played along because we have to believe the FDA and the multi-billion dollar biotech?

I will let her tell her story so please go to her website and read all about Provenge and Dendreon.


Monday, April 02, 2012

Immunity to a Cancer in Progress

As Science Tsar of the World, I hereby assign Group A to study the Dendreon science and their vaccine for prostrate cancer. What I want Group A to study is the concept of a cancer vaccine, what they did to prove the mechanism of action, and how they conducted the statistical analysis of the clinical data.

Why is a hedge fund analyst more skeptical than the scientific community? Who is Marie Huber and what is her motivation?

If I, the Science Tsar of the World, want to know more about the Dendreon story I will need to know more about the psychology of the players. I know Dendreons vaccine story and it is bizzarre.
Each dose of Provenge is custom-made. A nurse or technician withdraws white blood cells from a man's arm in a three-to-four hour procedure called leukapheresis.
The cells are shipped to a Dendreon manufacturing facility, where for two days they are incubated with a "fusion protein:" One protein that stimulates the cells' growth and maturation and another called PAP, or prostatic acid phosphatase. PAP is an antigen that studs prostate cancer cells like antennae, pieces of it sticking out of the cells' surfaces.
Dendreon says the patients' white blood cells take up the antigen and within hours their surfaces bristle with fragments of the telltale molecule. The cells are then shipped back to the physician and infused into the patient. A full treatment includes three such procedures, two weeks apart.
Back inside the body, Dendreon claims the modified cells trigger the immune system to produce T cells that kill any cell sporting the PAP antigen — namely, prostate cancer cells.
In principle, that should eliminate the cancer, but Provenge does not shrink either the primary tumor or metastases.
I set the scientists down with the piles of data to sort through. That becomes one piece of the puzzle. I now set my sights on Marie Huber.
She argues that the main reason Provenge seemed to extend survival - a crucial factor in the FDA's decision - was that older men in the study who did not receive Provenge died months sooner than similar patients in other studies.
She raises the possibility the "placebo" they received was actually harmful and made Provenge, known scientifically as sipuleucel-T, look better by comparison.
My scientists are working on the placebo logic / clinical trial design. But Marie... who are you?
In documents JNCI requires authors to sign, she declared no financial conflicts of interest. Neither she nor her former firm nor anyone else she is connected to stands to benefit financially from her analysis, she said. Instead, she says she is motivated to help "vulnerable and desperate patients" - so much so that she gave up her job, salary and health insurance. 
Why did she give up her job for this? Because she cares? How did she get so much traction to her side of the story? An unemployed hedge fund analyst takes on a former $5 billion dollar biotech and people listen? It could have something to do with the unforgiving logical nature of science:

"There is no efficacy in the younger patients, the primary group where you would expect it," said Huber.Since the immune system weakens with age, an immune-based therapy should work better in younger men. Some experts agree."If it was really a vaccine, you'd think younger men would show more response, since they are more immunocompetent," said NCI's Rosenberg.

Then there is the logic of Dendreon:
"We have a lot of data that supports the idea that the product works the way it was designed to," said Dr. Mark Frohlich, Dendreon's chief medical officer. "We're seeing evidence of immune-system activation. The only question is whether the T cells are killing the tumor."
There is support but no verification. Marie Huber has just as much fire power scientifically. Applying Occams Razor, a principle urging one to select among competing hypotheses that which makes the fewest assumptions and thereby offers the simplest explanation of the effect, who should we believe? Do we even need to know who Marie is and what her motivations are? Scientifically, no. Cargo Cult Scientifically we would love to know more about her and why she is so into this issue.