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Friday, June 09, 2006

siRNA Pathology

The Cargo Cult Airport has leaders. They send the people out with coconuts over their ears. They make sure the fires are lit along the side of the runway. If it's anything like the American corporate style of leadership, it is assumed that the leaders know more about why these things are done. The followers just follow. Leaders instruct because they are "in the know".

siRNA has been in existance a relatively short period of time. As soon as it began however, scientist began positioning themselves into the leadership role. There were rules set up for how to design siRNA. There were papers written on the best way to get the most out of your siRNA knock-out. Like a Cargo Cult Airport however, it wasn't known how siRNA really worked. The experts seemed have a disdain for research that involved a mechanism of action. One of "the rules" for example was that the siRNA had to consist of a certain percentage gaunisine and cytosine. What was the data used to come to that conclusion? Five siRNA KOs? Ten? Were they in mice or hamsters?

Eventually the scientists have to come up with a MOA, mechanism of action. It has been decided that the mechanism of action involves mRNA interacting with an enzyme called Dicer. One of the leading siRNA researchers, Dr. Kazunari Taira of the University of Tokyo describes it this way:

The mechanism responsible for dsRNA-induced gene silencing, which proceeds via a two-step mechanism, appears to have been strongly conserved during evolution. In the first step, long dsRNAs are recognized by a nuclease in the RNase III family known as Dicer, which cleaves the dsRNA into small interfering RNAs (siRNAs) of 21–23 nt. These siRNAs are incorporated into a multicomponent nuclease complex, known as RISC, that is then responsible for the destruction of cognate mRNAs.

Dr. Taira was a leader in siRNA research. More specifically he was ranked number 4 (most cited authors) out of the 25,000 researchers who have published papers on siRNA. He took on the toughest piece of the puzzle, the MOA and he got burned. A panel at the university where he worked said that he "likely fabricated papers on a potential medical breakthrough". As I've stated before, big time scientists do not work in laboratories. They work in offices. They communicate on the things that take place in labs but they rarely go inside their labs. One of the people who did work in the lab was Hiroaki Kawasaki. Dr. Kawasaki was most likely fabricating the data and Dr. Taira either couldn't figure that out or he was complicit in this scam.

The question now is how much this impacts the origins of the science. Does this leave a gap open where Dicers role is not known as a fact. Dr. Taira was saying that he could use recombinant Dicer to make siRNA that will work so that you don't have to experiment with different pieces to find the best one. This is one of his pre-conceived conclusions anyway. However, has anyone ever cloned dicer and shown it to chop up dsRNA? What type of dsRNA modifications are needed for Dicer to grab ahold of it and chop it up. Certainly Dicer isn't running amok inside a cell grabbing any dsRNA it finds and chopping it up. If it did we'd have a hard time making proteins. What regulates the balance between dsRNA breakdown and mRNA protein production? There are many enzymes that are very well understood. We use them for chopping up DNA for cloning genes. We know exactly where they cut the DNA. Where does Dicer cut the DNA? Is it based on size? If it is, then how does the siRNA shut down the genes so specifically. We know that synthisized RNA is a hit or miss gamble. Somehow one enzyme gets it right in many many different genes. How can this be.

This is science. How does siRNA work. What are the unanswered questions? What tiny little piece of the puzzle can we study? Dr. Taira is rightfully getting his work put under a spotlight. What about putting a spotlight on the research area he was working on. Why did they have to lie? Certainly it's important for these guys to publish but why didn't the area they were working on give them the kind of results they wanted? This is the Feynman Cargo Cult edict of bending over backwards to prove oneself wrong. They inadvertantly proved that they could not do what they thought they could do. They were ranked #4 in the siRNA business. In the end their theory did not provide them with the knowledge it would take to simply clone an enzyme and characterize it. Something is wrong here.

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