Sunday, January 09, 2005


ALNY, Science, Technology


It's a stock symbol for a company named Alnylam Pharmaceuticals Inc. They describe themselves as an early-stage, biopharmaceutical company. They seek to develop and commercialize therapeutics based on a biological pathway called RNA interference (RNAi).

Direct RNAi therapeutics will be applied directly to the site of disease. These therapies will probably be developed before systemic RNAi therapeutics, which move through the bloodstream to sites of disease. The direct RNAi therapies are focused on treating age-related macular degeneration and Parkinson's disease.

You may have heard of Parkinson's disease more often since the disease afflicts Michael J. Fox, who started a foundation to find a cure. Parkinson's is a disease mentioned often in the debate over whether or not to use fetal stem cells in research programs, as Parkinson's might be stopped or reversed by cell replacement therapy. Embryonic stem cells demonstrate qualities that some researchers feel makes them excellent candidates for cell replacement therapy.

The interface between science and society is one of historic forces. Like tectonic plates, these forces can work togehter, work against each other, work orthogonally, or lie dormant, layered and silent. There is hardly anyone on the planet that is not affected, driven, or impassioned by the human need to figure out how things work. The heart of science is the how. The heart of religion is the why. Although these two mostly mental disciplines answer different questions, their answers in practice can and do create conflict on the ground. Where and how to spend money, what and when and where to do something, and whether or not the negative repercussions can be contained. The application of science is called technology. The application of technology is often, in capitalism, commercialized. Commercialization creates democratization of products. The democratization of products allows for the dissemation of power. Redistributon of power creates new questions, which science and religion (or philosophy, or ethics, or spiritualism) seek to answer.

In Thomas Kuhn's Structure of Scientific Revolution, better instrumentation (often through commercialization of a technology, such as the spyglass in Galileo's era) reveals things that were not seen before (like craters or Jovian moons). These new things must be explained, and new theories that may augment, contradict, or supplant the old are proposed. Through a rapid period of Great Strides Forward, competing scientific ideas are allowed to compete in the "marketplace" of peer review under (mostly) objective conditions. Once the dust settles from this "step up", the plateau of "normal science" kicks in. This is where scientists and engineers spend most of their time, to be honest. Ideas are refined. Things are explained. Better methodologies, processes, tools, and products are created and refined.

When enough people, for example, have mobile phones with cameras in them, that can seamlessly connect to the internet and provide not only still images, but video and audio, there is a subtle shift in the balance of power. We saw something similar to this change in the balance of power (and were not surprised) when blogging "helped bring down Dan Rather." Many people, working together, analyzed the documents that CBS claimed were legitimate, and found they were not. Several hundred "instant experts", with libraries and resources a click away, with intellectual curiousity and a desire to figure things out, circumvented the authority of the traditional media to tell us what the truth was. That story - the story of the distributed analytical blogger brain - was the story of the year, hands down.

It's hard to beat the distributed process. It's hard to beat a large community, working together in brownian motion. The mechanics can be found in books such as The Wisdom of Crowds. People, even when they don't know they're working together, can accomplish a staggerly large amount of work when focused on certain types of work, and certain types of questions. Some would say that collaborative effort trumps all individual effort, but some problems are not solved by adding more people, as The Myth of the Man Month points out so well.

So many of these things can be appreciated when you study a company like Alnylam.

Their market cap is only 150 million. Ken thinks it could be a ten-bagger. He followed the genesis of the RNAi concept and wrote a bit about it recently.

"you know that their technique for RNA interference gene silencing was discovered in flower research? I told you this story right? they were trying to make a blue petunia. fascinating how a nagging oddity that they observed in the botanical field blossomed (pun heh) into this area of genomics and medicine possibilities. I think I follow the biosciences enough to recognize this really has some merit. last time I felt this was was with Angiogenesis and Judah Folkman's remember me getting buzzed on that - stopping cancer by stopping capillary construction in tumors. other thing that fascinates me in the area is prions and stanley prusiner's work there to show the causative agent in mad cow. Amgen and Genetech both are commercializing the anti-angiogenesis drugs. been mixed bag so far. cancer so hard to nail - working in human-gene mice doesnt always translate into success on human trials
but this RNAi really has a lot of potential in many many diseases - hopefully ALNY has some fundamental core IP on it - from what I can tell they do
startups just burn thru cash takes years to get a product out. reason i'm into this one is seems they have some IP that will extend beyond any one drug."

IP stands for intellectual property. ALNY has staked a claim on the particular sequence of events that must happen in order to make RNAi work. For companies working in biotech, having defensible intellectual property is very important. The power of the idea becomes science becomes technology becomes product becomes therapy, which allows life to continue on longer and better than before, which allows more ideas to be considered.

Science cannot be planned. Petunias have next to nothing to do with Parkinson's. Yet research on making something blue that doesn't have the genetic capacity to be blue (like the continuing search for a true Blue Rose) ended up having everything to do with something that might break the back of an awful disease. The decline of pure research, whether real or imaginary, has powerful consequences.

CEO John Maraganore provides a good overview in their industry presentations.

Their IP position outlined on page 35. Exciting stuff.

Webcast link:

others may pop up at:

This is a really thorough writeup of the company, its technology, patent position, and prospects

Seems to have been written in early 2003 - lot has changed since and many things the report predicted have in fact come to pass since them.

A major, if not the main, issue for developing RNAI therapies is figuring out how to deliver RNAI systemically. The report above looked at a number of options, some pretty wild - such as using viruses or elevated blood pressure to force the RNAI across cell barriers. The Nov Nature article showed their innovative approach of attach the RNAI snippet to a cholesterol molecule and using that to piggy back into the cell worked - huge breakthrough but not clear (at least to me) if this can scale to humans - lot more work needed there. Their first targets don't need systemic delivery.
They just announced an effort with the cystic fibrosis foundation - that sounds like a good one - delivery might be able to use an inhaler or something along those lines.

Been reading and other big issue seems to be certain RNAI sequences the cell interferon response - this is a system wide defense mechanism where a cell recognizes foreign RNA and self-destructs to stop viral replication. The needs of the many out weigh the needs of the few ... or the one! So far they have been generally able to avoid the interferon response by limiting their snippets to very short lengths (21 bases). But it seems a subset of possible codewords can still provoke an interferon response which would be very bad. Hopefully they can master a technique to side step the response (and license/patent it!).

RNAI seems like magic - a short snippet can knock out expression of a large chunk of genetic material. Drug discovery really becomes more a question of tailoring and confirming no side effects. They also have to make sure the snippet doesn't cause an interferon response, and it has enough specificity so that it doesn't affect other unrelated cell functions. I wonder how they will screen against genes with a lot of variation among the population, its one thing to look at the genome snapshot we have and say yep this is it but then to account for the all the possible variations in the sequences is another
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