Search This Blog

Tuesday, May 23, 2006

Marketing Skills

Let's go all the way back to the very first post on this blog. I talked about Koreas number one scientist, Dr. Hwang. He became number one because of his skills in the ways of cloning stem cells. It turned out that he had, in fact, not cloned one single stem cell. No big deal, no one has succeeded at this little task. The big deal is that he was hell bent on telling everyone he had. Why did he want to do this? Most likely it was about ego or an exterior pressure to succeed. Whatever it was Dr. Hwang knew he had to overcome his inability to clone stem cells. Science tells us that it should be possible to do so. Technology is now the hard part. Instead of working on the hard part Dr. Hwang decided to use his marketing skills to sell his story to a major science journal.

How could a journal that calls itself Science have been sold this story? The name Science would indicate that they come to their conclusions based upon experimentation and observation. A journal is in a tough spot here because they can't take a paper such as Dr. Hwangs and simply repeat his work. They can't take a clone from him and seqeunce the DNA to verify the clone status. They have no choice but to rely upon what he has said. Of course arogance plays a part in the inability of the reviewers and the editors to admit their limitations. They will have us believe that most of what you are reading is solid science and it makes damned good sense. But how do they know? They were wrong about Dr. Hwang. He fooled them with his marketing skills. How can the editors and the reviewers tell the difference between real science and a marketing campaign? How can they tell the difference between shit and shinola?

The Cargo Cults of the world will never bring the planes from the skies using their current methods. If however you moved them to an area of the world where there is an airport, they would have much more success with their methods. The planes would come. You are now working in the wolrd of marketing. You want the world to believe that your rituals brings airplanes from the skies. All you have to do is perform the rituals with an airport behind you. Ritual plus airplanes equals success! You don't know a damned thing about how those airplanes end up coming from the sky to the field behind you. You know that they come however and you have put yourself in the right position to "prove" your skills.

Now look at Dr. Hwang. Rather than use science he published a ficticious paper in a magazine called Science. If it's in Science then it's science.

A very similar scenario took place in a publication that covers a softer science, Sociology. The journal was called Social Text. The paper was called Transgressing the Boundaries: Toward a Transformative Hermeneutics of Quantum Gravity. The author, Dr. Sokal, had a different motive than Dr. Hwang but let's not let our biases get in the way of comparing these two cases. They both had a motive to publish a paper that depicts complete rubbish. They both knew what they had to do to get published. It had to do with marketing. Dr. Sokal was thinking like a marketer.

"Would a leading North American journal of cultural studies... publish an article liberally salted with nonsense if (a) it sounded good and (b) it flattered the editors' ideological preconceptions?"

In other words, would they buy a bogus paper. (a) and (b) refer to the marketing skills.

Cloning a stem cell had the groundwork laid out for it to be marketed. Cloning stem cells sounds good. It would also verify the theory that this could be done. After the cloning techniques are worked out the skies the limit on what can be done. You could cure diabetes. No further treatments would be needed. You could clone a human being! We've cloned a sheep so this should be possible. It is exciting. It is the power of applying science to create life! This excitement is also a bias. The bias (a) sounded good and (b) flattered the editors' ideological preconceptions."

As I said earlier, the journals are in a tough spot if they are to publish articles based on their ability to see past marketing skills. They cannot reproduce the experiments that are written about. A real science journal would however. The CounterCargoCulture publication would handle the problem of marketing by reproducing experiments. It would demand DNA samples and cell cultures and whatever else is used to make a claim. This science journal would really look at the experiment and worry less about the marketing of it. If you've ever seen what PhD students study and what goes on with a disertation you know that marketing is what it is all about. They are preparing to go out and be published so they can live the life of their professor/mentor, publish or parish. A real science journal would acknowledge this bias and demand real proof behind the mere conclusions written up in a paper. The number of papers would be reduced to one per publication. Every little piece of evidence will be discussed philisophically and empirically. In the end the conclusions of a group of reviewers will be published. Each reviewer will not be allowed to discuss their conclusions with the other reviewers until after publication. Again, this is to reduce the bias imposed on you by others. In general a real science journal would take every measure possible to remove bias. Marketers exploit our biases in ways we have never even thought about. A real science journal must think like a marketer and stop them from contaminating the scientific discourse among critical thinking human beings.

Saturday, May 20, 2006


Get it? Counter-culture? The counter to the cargo cult? Like a beatnik or a hippy, there have to be scientists out there who would love to get away from the culture of modern day science. Where are the radical scientists who believe in the aneuploidy-cancer hypothesis? Where are the scientists who pursue ideas that are untested. One norm in biotech science these days involves looking for antibodies against known targets and patenting your antibody as a drug against the known disease. Another norm involves using siRNA in the same manner, to eliminate a known target protein. That just doesn't rise to the level of science. It's more like baking cookies. Someone may have a good recipe but it doesn't involve too much clever thinking. Intellectually there have got to be people starving to death due to a lack of interesting projects to think about. Where are the goddamned scientists who can think up their own projects? Chances are, those types of people are horrible at getting funding. Going out and getting government grants or venture capital money is not an interesting thing to roll around your brain unless you are more interested in money than in the natural world.

There has always been a counter culture. Early caveman drawings were probably countered by young people with cheap materials smeared on cave walls where only young cave people gathered. Perhaps this is an important part of the evolution of ideas. Good ideas start but are quickly taken over by the powers that be. Only the young and older, off-center, people venture to make changes to the status quo. If you have a stake in maintaining the status quo, such as having a hefty mortgage, you'll do what the group is doing in order to keep your house. If you don't feel included in the group or you don't want to be a part of it, you'll work against the tide. Maybe you'll protest the war, you'll write a book without first obtaining a PhD in english, you'll quit eating meat, you'll take up Buddhism in a Christian society, you'll take up Christianity in a Buddhist society, you'll be a scientist in a religious society...

Here is a simple example of changing the thinking surrounding the norm. I've mentioned siRNA research before. Has anyone ever thought about the consequences of the proposed mechanism of action? The second law of thermodynamics suggests that if order is created in one part of the universe then a greater amount of disorder is created somewhere else. In siRNA then, what happens if you knock down the activity of a protein? The popular concept is that the only possible outcome is that a person becomes healthier. What is the most lethal siRNA? Is it a 20 nucleotide sequence that will kill C-elagans? Is it a double stranded piece of RNA with a hairpin loop that will prevent ears of corn from growing out of a stalk? Most of the status quo research in this field involves known targets, siRNA selected by internet based tools, and low paid technicians. Who would have the guts to make a grant proposal where you claim you are going to seek out deadly siRNA. Maybe you want to create a cancer by stopping a cell cycle regulator. Maybe you just don't know exactly where you're going but you are going to start with stem cells and some gene mutation tools.

Radical science, like radical youth movements, is going to be discouraged by those who have established the norm or at least by those who benifit from the norm. Imagine living in Alabama in 1964, your hair is trimmed nicely, your glasses the latest fashion, your clothes sharp like everyone else around you. Then one day Ken Kesey and the Merry Pranksters drive through your town. They are traveling in an old school bus painted in a hundred bright colors. They are dressed as jesters and fairies throwing flowers and blowing bubbles. They don't have jobs to go to. Yet they are living life in America. They are seeing your town where you will probably never see theirs. You have to ask yourself, is their way of living meaningful? Chances are, having grown up in a small Alabama town, you prefer your ways. You like having a job and a family that you support. You are clean and safe. You travel a couple times a year but you get to come home to a stable world that you like. Who are these hippies to come around here being different, jumping around as if they are here to show us a better way of living? Your kids however might see it as a new and exciting prospect. They are secure in their world so they can come back if they don't like the new way. There is an alternative lifestyle that they can try. There is no harm in trying new things.

Now imagine an old scientist. He works at the University, he writes grant proposals, teaches classes and does a little research. He submits papers, reviews papers, serves on PhD committees and all of the other stuff. Along comes a kid whose parents left him a billion dollars. He skips college and starts his own lab where he does research to prove HIV doesn't cause AIDS. He brings in Peter Duesburg and supports his work on the aneuploidy-cancer hypothesis. He starts his own journal because no one else will publish him. He starts a philosophy organisation that discusses how things like N-rays or anything that Robert Gallo ever did could happen. All of the grad students can be found reading the journal in spite of your efforts to put it down. One day something useful comes out of the lab and the journal. Big deal you think, anyone can get lucky. Your young grad students might be tempted to go off on the new path but if they know what's best they'll stay with you. Maybe they'll be gone for awhile but they'll be back. You offer the safety just like the family man with a good job in Alabama. The counter culture is reckless.

The system is currently set up such that it really would take a rich kid with a billion dollars and an interest in science to overcome the obstacles in the way of a radical science movement. Most rich kids these days however are not science kids. Their positions in society lead them to other pursuits. They may become philanthropists but they will only support the status quo. They may become capitalists but they too only support the status quo. The status quo dictates that lots of money must be spent to do science and it must lead to the generation of more money. I've mentioned how biotech has taken 100 billion and reduced it to 60 billion so far. As in any Cargo Cult, the lack of success does not deter the followers and those in charge. The counter cult would simply seek out advances in understanding of living organisms. They would work to accurately measure what is going on inside the body. There would be no need for profit, just pure joy in discovering new things. Of course in the end there would be much that could be commercialized but the hippy scientist would not be interested. He's got a billion dollar padding that prevents him from commercial influence. He's got a disdain for suits and ties making shit up so they can sell drugs.

The radical science would not require as much money. I just threw a billion dollars out there to make us all feel safe. Ideas are more powerful than money if they are based on fact. Radical science would become the target of criticism by some of our best critics. Yet imagine a movement where an explanation for the 40 billion dollars loss in biotech could be analyzed. Imagine aneuploidy research explaining a very basic concept in cancer. Imagine a bunch of young people sitting around reducing the status quo science down to easy to understand concepts that have flaws. Imagine young people getting excited about science because there is a counter culture that has the ability to chop down the tall trees in a forest of arrogant old ideas.

Imagine old Bob Gallo, picking lint from his pin striped suit as he tells everyone how he was the most cited scientist of his day. Along comes a young kid in jeans and a T-shirt who points out that Bob was wrong and that he lead a lot of people to the wrong conclusions. The young kid has cured AIDS and has shown that the emperor (Bob) has no clothes. AIDS, cancer, malaria, alzheimers, baldness, and the list goes on. These are things that science doesn't have a clue about. They are on a path that involves simple concepts wrapped in hard to understand terminology that arrogant men and women love to use. A counter culture is needed to bring life back into the world of science. Excitement is needed. Currently it is dying. Money is the goal and failure is the result. We need that billion dollar kid willing to support this cause. Think of that billion dollar investment as Ken Keseys bus. The billion dollar radical science movement might just fizzle out but for young people it could symbolize the freedom to think again. You take that education they give you and get rid of the things you think are bullshit. Think your own thoughts and nevermind what the elders say.

Monday, May 15, 2006

A Well Funded Cult

Working with the scientific method can be tough. Nature has a way of frustrating us human beings. To get around our ignorance we have created religions and we have created science. In between these two extremes there are varying degrees of getting the world to do what we want it to do. Say for example, you have cancer and you want it to go away. You could pray and it might go away. If it does you attribute the disappearance of the cancer to the praying. Likewise you could take a drug that is on the market. Again, if the cancer goes away, it's because of the drug. The problem is that we are only guessing. It could have gotten worse. What then becomes of our beliefs on prayer or the drug industry?

When drug companies run clinical trials they have many options for obtaining the best possible results. Like religion, they can work around evidence that detracts from their hypothesis. What can we do as consumers to varify if the drug companies are operating in a less than honest manner? We can use the scientific method.

TUESDAY, May 16 (HealthDay News) -- In a revealing look at the impact of funding on medical research, a new study found that clinical trials funded by drug companies and other for-profit entities were more likely to report positive findings than similar trials funded by nonprofit groups. ...according to background information in this article, surveys of randomized trials conducted in the 1990s found that for-profit trials were more likely to report positive findings. Those surveys raised questions about the design and conduct of industry-funded clinical trials. A study published earlier this year found that industry is paying for more and more medical research, with a full half of studies now funded solely by the private sector.

In this paper published in JAMA, May 17 2006, they looked at the data from 324 consecutive superiority trials of cardiovascular medicine published between January 1, 2000, and July 30, 2005, in JAMA, The Lancet, and the New England Journal of Medicine. The question was whether or not the trend of for-profit funded trials providing favorable results continued from 2000 to 2005. Since it is known that industry is paying for more and more research, we might want to take a closer look at the studies that are being conducted. If the drug companies are going to pay for the studies, we have to study the studies. We have to question the questions they are asking.

It's difficult to take a random sampling and come up with an exact description of what you've got. Say you you want to measure handfuls of dirt. You hire people all over the world to pick up a handful of dirt and analyse what they get. In China people have smaller hands than people in France. The French might report that their dirt weighs more than Chinese dirt. In Palm Springs where dirt is very dry they say that their dirt weighs less than the dirt in Nebraska. So already we've got problems in measuring the weight of a handful of dirt. How do we account for factors such as hand size and moisture content?

One way to analyse the results that get published is to look at who is doing the study. Do they want the dirt to weigh more or less? Maybe the French have already reported on the correlation of the weight of dirt and the annual production of crops. Lets say that an increase in the weight of dirt corralates with an increase in crop production. Palm Springs has a desire to introduce farming into their economy. The French make a pitch to sell them their dirt as do the Nebraskans. The Palm Spring folk see that the dirt from each group is roughly the same based on their studies. The Nebraskans protest with a study that they funded indicating that the French cheated by only using data from dirt picked up by men. Men have larger hands than women. The French tout a study that they conducted where the dirt in Nebraksa was picked up by Chinese women. Of course they don't mention that part of the study. The Nebraskans go after the scientific integrity of the French. Who do you believe? All this science is just so confusing.

As you can see, this can get out of control. The real issue that we've forgotten is whether or not the weight of dirt has anything to do with growing a crop. What is the crop anyway? Cactus? In order to get to the bottom of an issue in nature it is important to know what you are looking for. It is critical that the questions asked are non-biased.

In the same issue of JAMA there is a study on the cancer risks in taking HUMIRA and Remicade, both monoclonal antibodies against TNF alpha. The drugs are prescribed for treating rheumatoid arthritis. One of the authors, Eric L. Matteson, MD, MPH, is getting paid by the makers of another TNF alpha inhibitor (Enbrel) to do a similar analysis on Enbrel alone. The reason Enbrel was left out of the trial was because Enbrel differs at the molecular level. HUMRIA and Remicade are antibodies whereas Enbrel is a modified TNF alpha receptor. Should that really matter? Was this study fair? Before the article begins perhaps factors such as Dr. Mattesons relationship with the makers of a competitors drug should be divulged.

Dr. Matteson may or may not publish a similar article on Enbrel. The effects of this corporate study will be people switching from HUMIRA and Remicade to Enbrel. That's just a guess. To be fair however Enbrel needs to be put up to the same rigors of the HUMIRA/Remicade study. Ultimately we might find out the effects of TNF alpha levels. It is complicated but drug company motives are not. Study the studies. Look at what they are doing and make decisions based on their own research. Use their data to draw conclusions that they never intended you to draw. The more we learn about corporate science the better we'll be able to gauge their conclusions.

The Investment in People

Seattle Washington
Pacific Northwest Research Institute
Job Posting:

Assist in basic cancer research: cell culture; purification of proteins, lipids, nd other membrane components; molecular biology work (including RT-PCR, gene cloning); and other biochemical and biological assays. Position requires a B.S., basic lab skills in biochemistry, cell biology, molecular biology; and a familiarity with MS Word and Excel.

And what does it pay you ask?

23000 dollars per year!!!

Median price of a house in Seattle?


NIH budget?

28 billion 7 hundred and 40 million dollars

What percentage of the budget will go to that new graduate with the entry level job?


So put on that white lab coat and work til late in the night. You're doing it for nobility. Maybe you'll do it because you know someone who died from cancer and you want to help. Your next hurdle will be getting over a researcher who puts that value on the people wearing the white lab coats in his/her lab.

Friday, May 12, 2006

Faith Healers

In a previous post I quoted Leigh Turner of McGill University Quebec as saying, "Biotech, in a similar manner to many religious movements, has its charismatic prophets, enthusiastic evangelists and enrapt audiences. Like religions, it offers a comforting message of salvation. Instead of imagining a day of rapture when the dead rise from their graves to begin eternal life, biotech enthusiasts imagine the era when medical technologies provide a renewable, largely imperishable body. … Biotech is not just an assemblage of research programs and techniques. In a scientific and technological era, biotech also offers a surrogate religious framework for many individuals."

I'd like to discuss two examples of this. The first one religious, and the second Biotech.

Benny Hinn is a faith healer. He makes a whole lot of money off of people who are desperate for Gods intervention into their problems. He recently had a gig over in Denmark where a young girl with a serious spinal condition attended.

From the James Randi webpage:

Unfortunately, the little girl with a damaged back did not regain her health – she had to drive home with her parents, disappointed. She did, however, have a more pronounced desire to stand up and walk than she had before. Somehow, I think her parents hoped more than she did. She never looked as if she believed anything would happen anyway. Which, in the Land of Faith Healing, means that she is to blame for Benny Hinn's failure. If you are cured, it is the work of God (through the faith healer). If you are not cured, it is because you haven't believed enough.
But desperation breeds hope, hope springs eternal, and hope will make people pay. The collection of money (cash, checks or plastic) in white buckets to fund these "crusades," while songs of the promise of upcoming miracles churned out from the stage, made it very clear: "Prosperity Teaching" means that you can be healed, but only if you pay up.

I believe that Benny Hinn is a bad guy. He's been exposed by James Randi. 20/20 ran a piece on him that showed just how much luxory he has wrapped himself in with the faithfuls money. He profits because he knows what people need to hear. He does not stop for any proof, he tells the masses what they want to hear and it sounds good to them.

Now! Biotech.

NeoRx has been around since 1984. This is a company that made the promise of curing cancer. Year after year they went to their investors (their faithful) and assured them that they were on the verge of something big. Hundreds of millions of dollars later, NeoRx is gone. The leaders however, have found a way to preserve the funding of their efforts. Since they did such a good job they will now be installing themselves into a Cargo Cult control room called Poinard Pharmaceuticals. The drug will be Picoplatin. As it is with all drug companies, the drug may or may not work. What matters is that the new companies big plan.

"NeoRx Corporation will formally change its corporate name to Poniard Pharmaceuticals, Inc. to reflect its strategic repositioning as a global specialty pharmaceutical company focused on the discovery, development and commercialization of innovative products to impact the lives of people with cancer."

That's important stuff. People with cancer need their lives impacted by innovative products. In addition to Picoplatin they are working to build a diverse portfolio of oncology product candidates. Did I mention that they've been in business since 1984?

Faith healers can make any promise that people want to hear. Want a cure for cancer? You got it. Spinal cord not working? It'll be fixed. There is no limit to what they can promise to do. They can promise that all sorts of airplanes will be coming to their Cargo Cult Airport but so far none have come. Benny Hinn and NeoRx have been around since at least 1984. Before that they were developing their strategy to become successful. They have been out there in front the faithful preaching the good news and they are still alive. They have succeeded. Whether the money was stuffed into a white bucket or transferred from a TD Waterhouse account, the money went to where the faith healers wanted it. It went into their livelihoods. Nice hotels, luxory cars, new clothes and ever increasing bank accounts have all been their rewards. If you don't have any faith in them it doesn't matter. They survive on the resources of their believers.

Thursday, May 11, 2006

The Flu In Big Trouble

Don't worry about the avian flu everybody. It messed with the wrong group this time. Them dumb birds aint got no scientists among them to fight back. But we do! So go ahead flu, come and get us humans. We got scientists!

There is biotech company that is working on a way of dealing with this pending pandemic. Our old friend siRNA is going to prevent the flu from replicating once it gets inside our bodies. The pandemic will work this way: the virus becomes infectious, hospitals begin to report cases to the public, panic will set in among the masses, the siRNA drug will be dispersed, the virus will dissapear and that little biotech company will become filthy rich! Now why didn't anyone else think of matching siRNA technology with the biggest health scare in recent history?

"In vitro and in vivo results were presented for siRNAs that are specifically designed to target conserved regions of the influenza viral genome."

Conserved regions are stretches of a DNA sequence that are the same among a variety of DNA genomes. In the case of the flu, conserved regions are conserved as the various strains arise from season to season. In other words, strains of the virus arise as the result of mutations. Conserved regions have not been subjected to mutations for many many seasons.

"We believe that targeting the conserved regions could enable a siRNA therapeutic to be effective against both current and future strains of the influenza virus, which is essential in stockpiling a treatment for rapid mobilization during an influenza pandemic."

We're not just going to fight the avian flu virus, we're going to fight them all. Each year they come at us, we're going to knock them out. Avian flu? You want some of this? What about the Spanish flu of the 1918 pandemic? Come on back! Thanks to conserved regions of DNA, we've got them all by the balls. Think of conserved regions as the Achilles heal of the virus world. The only weapon against that heal is siRNA.

The company that will be putting an end to the influenza problem is not very big. We'll call them Company A to avoid any lawsuits. How big is Company A? Pfizer, who lists itself as the worlds largest pharmaceutical company, employs over 115,000 people. The slayers of influenza have about 100 people. Of those 100, less than half work in the science end of the business. Of that half less than ten work directly on the avian flu project. Of that group of less than ten, most sit in on meetings and listen to the results of experiments and try to put together a story to tell their superiors regarding the progress of the work.

How did it all begin? Company A needed to find a new siRNA project. The drug target TNF alpha (for cancer and inflammation) has several drugs on the market already. By using the siRNA, Company A assumed they had a way around the patents against TNF alpha. They soon found out that they would not be going far with this project. They spent a lot of time on the issues of delivery and assay development. When they finally ran a mouse experiment with 300 mice, they knew their goose was cooked. They tried again. Same results, nothing. They changed the dose, the delivery reagents, the mice, the RNA sequence and on and on until they just couldn't face the future. They needed a smoke screen. It had to be an siRNA smoke screen so they could claim to be continuing on with their "siRNA program". That's a lot easier than saying that you are ending the damned thing. Enter siRNA against the avian flu virus.

Company A did not have the time to go back and use their research methods against a conserved region of the influenza virus. They found a "company" that had already been on the case. A research scientist from MIT had begun the "company" after his academic lab had made some findings that allowed him to sell the technology. He received funding and a "company" was formed. We'll call that Company B. Company B obtained enough preliminary data to sell the license to Company A. Company A announce the acquisition of company B on 2-23-06. On 3-16-06 presentated results demonstrating the effectiveness of the Company's small interfering RNA (siRNA) therapeutics to broadly target and inhibit influenza viral production. With a little bit of money and some clever talent scouting, Company A turned their siRNA research around in one month.

Now... will it put up a good fight against the influenza virus? I'm going to stop writing about it now but I will come back to you later with some results that can answer that question. Unlike the scientists who are fighting the influenza virus with siRNA, I am an observer. I have no money to be gained or lost. This is science. I admit my bias. I don't think it will work. I believe that millions will be spent and many a PhD will work long days on the project. In the end it will fade away. Stay tuned.

P.S. Job Posting 5-8-06

Company A is seeking a highly skilled virologist with a good understanding of drug discovery and development to join our team. This position requires an experienced bench virologist with a comprehensive knowledge of influenza and other respiratory viruses including viral research in an industrial setting; broad knowledge of viral assay methods, screening and characterizing anti-viral drug compounds, drug delivery methods, pulmonary delivery, and in vitro and in vivo studies to determine efficacy of anti-viral compounds. For the exceptional individual this position has significant growth and leadership potential. In this role, you will lead virology projects involving RNAi research with a focus on the therapeutic development of siRNAs. Successful candidate will, supervise one or more research associates, provide scientific leadership and guidance for virology research programs, and collaborate with other team members in the identification and optimization of new siRNA anti-viral candidate therapeutics.Qualified candidates will have a Ph.D. in virology or related field with 3-5 years experience; industrial experience preferred. We are looking for a hands-on bench scientist with good analytical skills and management abilities. Must be an independent and critical thinker, experienced in leading project teams, perform well under heavy work loads, and possess excellent oral and written communication skills. Experience in RNAi research preferred.

Wednesday, May 10, 2006


There are trends in science. RNAi (short for RNA interference) is one of the latest trends. The story is that DNA makes RNA which makes proteins which make us. Since we have a hard time following a protein around and seeing what it's doing, we try to stop the protein from doing anything. In the past we have created "knock-out" mice, which lack the gene that codes for a protein. We have made antibodies go proteins so that they'll bind to and block the protein. We have thus been able to look at the world without the protein. What happens when a protein is taken out of the picture? Does the organism need it? Is it compensated for by the upregulation of another protein? RNAi is the latest tool in asking these types of questions. It is also much faster than making antidodies or knock-out mice.

There once was a Biotechnology company called Ribozyme Pharmaceuticals Inc. They failed. RNAi came along and they reinvented the company, "at the forefront of the effort to create RNAi-based therapies." They describe the technology as follows:

RNAi is a natural, selective process for turning off genes. RNAi is triggered by short interfering RNA (siRNA). An intermediate in the RNAi process in which the long double-stranded RNA has been cut up into short (~21 nucleotides) double-stranded RNA. The siRNA stimulates the cellular machinery to cut up other single-stranded RNA having the same sequence as the siRNA. molecules that engage a group of cellular proteins called RISC RISCRNA-Induced silencing complex, a protein siRNA complex that can recognize and destroy target mRNAs. (RNA induced silencing complex). The RISC guides the siRNA to its target messenger that is copied from a gene with the intention of being translated by ribosomes into a protein molecule. (mRNA mRNAmessenger RNA– the messenger between DNA DNADeoxyribonucleic acid. The primary genetic material of the cell, consisting of two long chains of nucleotides twisted together into a double helix. The sequence of the nucleotides (A, G, C, and T) in the DNA defines the genetic code for the organism; the sequence is copied and maintained through the complementary pairing of nucleotides (A with T, and G with C) across the strands of the double helix.and proteins) to destroy the mRNA. The process is extremely specific and enables siRNA to break up the mRNA associated with a disease-causing gene geneThe basic unit of genetic information, which is coded in the characteristic string of nucleotide bases (coded as A, C, T and G), in a specific sequence that provides the information usually for making a specific protein.or virus.

Okay so siRNA is a short piece of RNA that attaches itself to a RISC complex and directs the nucleic acid destroying enzyme to mRNA. The mRNA is chopped up and the protein doesn't get made. There are many questions regarding the actual mechanism of action. Does siRNA have to be double or single stranded? Is there any logic behind what fragment of the mRNA must be homologous with the siRNA? Does one piece of siRNA lead to many other pieces (after the mRNA is chopped up) which leads to more mRNA destruction? How does it end?

It is known that the effect is quite often short lived. The siRNA must be delivered into a cell which has lead to every researcher in the field testing various transfection reagents. The papers on delivery have yet to establish a coherent explanation of how this will work as a drug. Some targets are knocked down to a greater degree than others. The effect lasts longer in some targets than others. The RISC complex is made up of proteins. What happens if you try to knock out one of those proteins?

The entire field began back in 1989 when researchers were trying to make a purple petunia more purple by adding RNA that codes for purple. What they got was a white petunia. The color was eliminated and thus, they concluded that they knocked out the gene. Anti-sense had also been shown to knock out plant colors. The mechanism there is different. The entire anti-sense strand of an mRNA is attached to the mRNA molecule thus blocking it from being translated. (why wouldn't siRNA do this?) Later siRNA was shown to knock out genes in mammalian cells and the biotech world was off to the races. Money came in and careers and companies (like Ribozyme Pharmaceuticals) were revived. Papers on how RNAi works have chimed in on what the rules are for developing a good siRNA. The papers go into details of molecular modifications that make siRNA molecules more effective. Companies like
Qiagen, Invitrogen, Dharmacon and Sigma have all cashed in on the Biotech appetite for expensive little pieces of RNA and the assays needed to do the research.

Years later, there is no drug on the market. There is no definitive experiement that explains the mechanism. siRNA is going the way of gene therapry and anti-sense technology. Once again we've been fooled! Was it the marketing departments of Qiagen, Invitrogen, Dharmacon and Sigma? Were companies like Ribozyme Pharmaceuticals desparate for a new approach to RNA therapy? It seems as if we do not really know enough about the basics of nucliec acids inside a cell to really describe what is happening. We know that protein production is regulated. How, for example, is a protein downregulated? How does the cell know if it has enough protein? By the mRNA levels? Could this be effected by short pieces of the mRNA? What have we learned about the measurements of proteins and mRNA? Can we use RT PCR to acurately measure mRNA levels? The answer is no. Why not? Shouldn't RT PCR be corralated to protein levels? If not, what does that tell us about our understanding of the quantitation of nucleic acids and protein production?

There are so many questions left open for the scientific mind. Something is happening but what. Biotech companies are very simple in their approach to research. Whether they've chosen antibody technology, siRNA or some other small molecule approach, all they do is select a target and throw the technology at it. The details are left up to junior personel who don't stand a chance. It's too simple. The real science can only be done by those who don't care about the effects, but rather the measurements. Are they real and can they fit some mathematical model? The research could at least answer questions on the outside, such as how can we measure protein production? Tartrate resistant alkaline phosphatase for example is upregulated as osteoclast precursors fuse into an osteoclast. Prior to witnessing with your own eyes the final formation of the osteoclasts, the TRAP production stops. Can we find a way of predicting exactly when the production goes down. Do the enzyme activity measurements corrolate with enzyme production? How is the activity stopped? How is production shut down? So many questions and all basic and all fascinating if you think that the world inside of a cell is the great unknown.

Inside a cell there are little pockets of highly acidic solutions. There are scaffolds where RNA conducts the production of proteins. There are shuttles that take the proteins where they need to go. There is DNA twisting around making more DNA and RNA. There is a time when the whole production needs to focus on making another cell just like itself. To simply call up Invitrogen and order some siRNA against a target and have some kid mix it all up and run an assay and give you a PowerPoint slide show with some Excel charts does not constistute science. So far siRNA has given us jack squat and I predict that we will never see any real results from this latest trend. We may see a drug on the market but that doesn't count. Until we start studying our methods of measuring what happens inside a cell, we can't know what siRNA, or anti-sense is really doing. Even antibodies against proteins are a mystery. A recent paper on anti-TNF alpha showed that the antibody lead to an increase in protein production. Was the measurement accurate? Did the antibody cause more protein to be made because the protein interacting with the antibody was tied up? So many questions. They may be naive questions but those are usually the best ones. The big brained scientists sometimes get too fancy. The big funded scientists have gotten way to simple. The questions we attempt to answer should be simple. The answers may or may not be simple. That's the fun of trying to find things out. You never know how it will play out. What goes on in a cell? We just don't know yet.

Monday, May 08, 2006

What We Know but Cannot Prove is So

It's an interesting question. We know things deep in our hearts yet they are things we cannot prove. Many people believe in Gods. Their scoiety backs them up and eliminates the need for hard core proof. Others around them can choose not to believe but society will make the non-believer the outcast. There is no way of knowing how to prove the existance or non-existance of god. All one can do is use their beliefs to make sense of the world.

I believe something that I cannot prove. I believe that there are people among us who, given the opportunity, could be brilliant scientists. These people work as carpenters, bakers, ditch diggers, and all sorts of, what we believe, are lower forms of contributions to society. Given the chance they could figure out how life began on earth. They could help ease world poverty, hunger, war, and all of the other real problems that confound mankind.

One example is Kary Mullis, the man who dreamed up Polymerase Chain Reaction. This technology is used to amplify DNA. He won the Nobel prize for this work. He was considered a slacker by his superiors, even after they sold the technology for over 300 million dollars. Kary was given a ten thousand dollar bonus. Prior to this job, where he outlined how PCR would work, where his company made hundred of millions for this scientific idea, where the Nobel prize was earned, Kary worked as a baker. He baked bread and muffins and cakes.

Imagine, this mind working away in a bakery. The smell of fresh bread wafting through the air. Customers are picking up orders as casual is exchanged over the display cabinets. Somewhere else there is a biotechnology company starting up. They put together their business plan, seek out funding, write up the corporate policies and so on. At some point they probably picked up something from the bakery for an early morning meeting. One day the need for a supervisor is discussed at the biotech company. "We need someone who will supervise the DNA amplification group." In the old days DNA was amplified by growing it in viruses. Kary decides he needs more money so he leaves and joins the new biotech company. A few years later, after all the meetings and the original research plans have been forgotten, the company cashes in on the one idea from the ex-baker.

Somewhere out there, right now, a group of attractive and well dressed individuals are sitting in a board room overlooking New York City. Among this group are lawyers, MBAs, PhDs from the finest schools. They are making a plans that will make them rich. Somewhere else there is a young girl, gutting fish in a factory off the shores of the Mississippi. Given the chance she has the kind of brain that could turn water into fuel. She'll never figure out how to earn a decent living however.

I use this belief to make sense of the world. If our leaders were truly the best at what they do then we'd live in a perfect world. Most likely, the truth is that our leaders are the best at getting themselves promoted. Our leaders know what society believes and treat the beliefs as if they were truths. If you want to be president in America, you have to go to church. You must believe in God. Likewise, if you want to be a successful scientist you must believe in the current dogma of the establishment. If you want to be involved in discovery, you have to know what the current trends in popular thought are, and you have to start tearing them down. Piece by piece you have to get to the heart of the matter and see if "the truth" really is the truth.

There are probably only a handful of individuals who have the ability to get at the truth. There are certainly far more individuals who can learn something in a book and pass that information on as if they understand it. The young lady working at the fish factory in Mississippi might read something in a book that is short on logic and thus she appears confused. Teachers will misconstrue this as not understanding. The truth is that the teacher doesn't understand that what was written was not acceptable to the type of person who has the ability to get at the truth.

Galaleo once told the church that the world revolved around the sun. They threw him in jail. He didn't understand that the world revolved around us because God made us and we were the center of the universe. Galaleo looked up at the stars and asked them what they thought. Real learning is not done in a book. It is done by looking at the world around you and trying to come up with explanations for the way things are. Why do fish live in water and humans on land? I can imagine the young lady in Mississippi thinking these thoughts as she's gutting fish on the second shift. The sun is slanting through the dirty windows of the factory in the late Mississippi evening. The shift boss and the other workers are focused on their gutting techniques or maybe what they are going to do at midnight when they are off. The young lady has her thoughts and never thinks about what to do with them. She was never taught self promotion and it never occured to her. She can think about the natural world but the human world is too hard.

I can't prove that she exists. I think she does and she knows why fish survive in water.

Thursday, May 04, 2006

Brother Can You Spare a Dime

Medical bioethicist Leigh Turner of McGill University, Quebec

"Biotech, in a similar manner to many religious movements, has its charismatic prophets, enthusiastic evangelists and enrapt audiences. Like religions, it offers a comforting message of salvation. Instead of imagining a day of rapture when the dead rise from their graves to begin eternal life, biotech enthusiasts imagine the era when medical technologies provide a renewable, largely imperishable body. … Biotech is not just an assemblage of research programs and techniques. In a scientific and technological era, biotech also offers a surrogate religious framework for many individuals."

Biotechnology research is mostly cargo cult science. The actual research is performed by some of the lowest paid individuals in a company. The data is hand selected for presentation so as to not offend the corporate ideology. It is then filtered through executives to the investing community. The purpose of this process is to extract money from investors who are easily swayed by the charismatic prophets.

After attending the BIO 2004 conference reporter David Ewing wrote in the San Francisco Chronicle, "As of yet, most of what I’m looking for here is in the ‘promise’ category - and has been each year I have come to this ever-larger industry fete."

"Last year, this industry lost $5.4 billion, and has lost a staggering $57.7 billion since BIO last held its annual conference in San Francisco in 1994, according to an Ernst and Young study. Only a few companies have been consistently profitable in the 30 years since biotech was born - a few, such as Amgen and Genentech, fantastically so. Remove them, and the losses and numbers are far worse for the rest of the industry."

Biotechnology simply has not succeeded in applying real science to develop products. It has succeeded only in selling stocks. According to Burrill & Co., US biotech firms raised almost $4 billion by selling new stock to investors in 2004. US biotechs posted almost that much in losses the same year. That is not the power of science. That is the power of greed over common sense. How can the recent discoveries in basic molecular biology and 100 billion dollars lead to jack squat?

Let us go back to Richard Feynmans Cargo Cult Science.

"I began to think, what else is there that we believe? (And I thought then about the witch doctors, and how easy it would have been to check on them by noticing that nothing really worked.) So I found things that even more people believe, such as that we have some knowledge of how to educate. There are big schools of reading methods and mathematics methods, and so forth, but if you notice, you'll see the reading scores keep going down--or hardly going up--in spite of the fact that we continually use these same people to improve the methods. There's a witch doctor remedy that doesn't work. It ought to be looked into; how do they know that their method should work? Another example is how to treat criminals. We obviously have made no progress--lots of theory, but no progress--in decreasing the amount of crime by the method that we use to handle criminals.

Yet these things are said to be scientific. We study them. And I think ordinary people with commonsense ideas are intimidated by this pseudoscience. A teacher who has some good idea of how to teach her children to read is forced by the school system to do it some other way--or is even fooled by the school system into thinking that her method is not necessarily a good one. Or a parent of bad boys, after disciplining them in one way or another, feels guilty for the rest of her life because she didn't do "the right thing," according to the experts.

So we really ought to look into theories that don't work, and science that isn't science."

Why don't we look into the biotech theories that don't work? How's that genome project working out for us? What about the promise of gene therapy and now siRNA therapy? There are so many examples of Cargo Cult Science in the history and present day biotechnology that it could become a field all its own. At least it could become an important part of the philosophy of science. There are things to be learned in failed experiements. As such, there is a whole lot to be learned from Biotechnology. Mostly we could learn about human nature. What makes a large group of well funded, well educated men and women sit around and try to sell the world a drug like Vioxx? Why do people take monoclonal antibodies against TNF alpha when it has been shown to not only have little effect, but it has also been shown to increase levels of TNF alpha! An entire book needs to be devoted to the story of statins and cholesterol levels.

No one can say what is missing better than Feynman.

"But there is one feature I notice that is generally missing in cargo cult science. That is the idea that we all hope you have learned in studying science in school--we never say explicitly what this is, but just hope that you catch on by all the examples of scientific investigation. It is interesting, therefore, to bring it out now and speak of it explicitly. It's a kind of scientific integrity, a principle of scientific thought that corresponds to a kind of utter honesty--a kind of leaning over backwards. For example, if you're doing an experiment, you should report everything that you think might make it invalid--not only what you think is right about it: other causes that could possibly explain your results; and things you thought of that you've eliminated by some other experiment, and how they worked--to make sure the other fellow can tell they have been eliminated. "

Investors quite often do not have the scientific background to make good decisions when dealing with the charismatic prophets of biotechnology. It's nothing to be embarrassed about. Every venture capital group needs to fund a small laboratory. The scientific staff of that laboratory needs to reproduce key experiments and read the scientific literature very carefully. They must bend over backwards to prove it wrong. If they can't, then it might just be a good investment.

Tuesday, May 02, 2006

What Happened Here?

Drug makers are in a tough business. Here are a few companies and their failures.

DOV Pharmaceutical: ...DOV Pharmaceutical, Inc. (NASDAQ: DOVP) announced today high-level results recently developed from the first Phase III placebo-controlled clinical trial – study 020 – of its novel analgesic bicifadine in patients with chronic low back pain (CLBP). Bicifadine did not achieve a statistically significant effect relative to placebo on the primary endpoint of the study at any of the doses tested:

Nastech Pharmaceutical: ...Merck & Co. ended its collaboration with Nastech Pharmaceutical Co. on a spray treatment for obesity because the product wasn't effective in early studies.

CancerVax: ...Another round of disappointing clinical trial data has led CancerVax and Serono to abandon research on a treatment for malignant melanoma

Cell Therapeutics: ...said a late-stage clinical trial of its Xyotax treatment for non-small cell lung cancer didn't go well, falling short of its primary goal of showing that Xyotax works better than standard chemotherapy.

Targeted Genetics: ...said its experimental cystic fibrosis treatment failed to significantly improve lung function in clinical-trial patients over those who received placebo

NeoRx: ...The Skeletal Targeted Radiotherapy program has a long history of ups and downs, and the company has burned through millions of dollars in its development. The FDA suspended clinical trials of the therapy in October 2000 after several patients developed serious delayed side effects.

You get the point...

But what about this one?

TeGenero: ...six test subjects were hospitalized for several weeks after severe reactions to injections of the TeGenero medicine at a Parexel facility in north London on March 13. Five of the volunteers have since been released. The sixth may have to stay in the hospital for as long as six months, and is certain to lose the tips of three fingers

The first set of failures showed a lack of efficacy. The latter was highy effective but in a negative way. The latter drug was an antibody. There are currently 18 antibody drugs on the market. The one thing you can say about the antibody drugs is that they have an effect. I have personally used Rituxan in tumor studies using mice and that drug completely eliminated tumors in mice. I have no comments on their effects in human beings. The point is that some "drugs" make you well, some make you ill, and the ones that most pharmaceutical companies sell you don't do anything at all.

The Cargo Cult scenario: Many rituals were performed but no airplanes came. Someone found a radio and a book on the Japanese language. They put together some very offensive words and spoke them into the radio. They also gave their location. Planes came but they dropped bombs instead of cargo. What the cargo needs to do here is to find out how to apologize in Japanese and ask politely for cargo. At least with the hostile reaction, the cargo cult got something. When nothing happens they continue down the same path that leads to nothing.