Tuesday, January 20, 2009

Ah, them gold rush days!

Derek Lowe had a nice piece yesterday looking back on the genomics bubble. I might quibble with his benchmarking of the end of the insanity -- the stock market bubble would not peak until just before the 2000 elections, but it's a fine piece & pretty accurate.

I should know -- I was there. I was more than just there, I was a significant part of it. No, I didn't think it up & I won't try to exaggerate my importance, but for what is perhaps the poster child of genomics excess (and if not that, certainly in the Pantheon of genomanic deities).

When I got to Millennium they were still largely focused on the positional cloning of disease genes. But, they had started throwing sequencing capacity at ESTs, small bits of genetic message which serve as toeholds to larger ones. The catch was that the sequencing analysis software had been designed for positional cloning work & not ESTs, and it's a very different ballgame. When sequencing genomic DNA seeing anything which looked like a gene was interesting. But when sequencing stuff that is almost nothing but genes, the challenge was to sort the wheat from the chaff. Lots of scientists spent mind-numbing hours scanning BLAST reports for things of interest, and often found things. But this is a lousy technique -- not only might eyes glaze over (or neurons croak) from monotony, but a really interesting match might not be obvious -- what if the top hit was "Uncharacterized protein X" but the 3rd match down was "TotalPharmaceuticalGold"? Or worse, that BLAST couldn't even find a useable match? Plus, was that a match or an identity -- did you find something new or just rediscover a lousy fragment of the old? More mind numbing staring.

Enter a cocky recent Ph.D. After building up some expertise and some more refined tools (which in their embryonic form nailed me the one gene patent of mine perhaps worth something), I had built a system which churned through all the ESTs and crudely organized them by what made things interesting (and tried to ignore all the boring stuff). Ion channels -- look on this web page. GPCRs -- that's over here. Possible secreted proteins, look at this analysis. Furthermore, it also attempted to amalgamate all the different ESTs into a view which was higher quality, longer and more compact -- and tell you which things were already described as proteins and which might be novel. Plus, more sensitive algorithms than BLAST were used to pull things into families.

Now in all honesty, it wasn't nearly perfect. Some of the mind-numbing review had shifted to me -- the early versions in particular had every homology approved (and named!) by me. The semi-automatically generated names were ugly. Various EST artifacts could join webs of unrelated genes into a horrible tangle. But, now there could be reviews of consolidated, pre-analyzed data (though also in fairness nobody ever totally trusted it, so the manual sequence-by-sequence reviews often continued).

Of course, if you have a mountain of loot you probably want to protect it. Enter the lawyers. Millennium had always filed on their discoveries; now they had lots of discoveries to protect. But protect from what? Well, the paranoia was a loss of "Freedom to Operate", usually known as FTO. Nobody knew what would stand up as a patent -- but there were instructive examples from the early biotech era of business plans sunk by a loss of FTO -- and expensive lawsuits that clearly marked that loss. So the patenting engine took off -- an expensive insurance policy against an unpredictable future.

Of course, what the lawyers wanted for the filing was as much info as possible -- and the automated analyses provided lots for them. But, they had been designed to be viewed in a web browser individually, not printed out en masse. Worse yet, by this time Informatics & Legal were in separate buildings -- one of my least pleasant Millennium memories was trying to script the printing a raft of analyses on a printer located in the other building. Plus, if there were inventions then somebody had to have invented them -- such as the person who wrote the code to find them & then reviewed the initial output. And so, I started having dates with the paralegals, an hour of hand-cramping signing of document after document. At one point, there were somewhere between 120-140 patent applications where I was sole or co-inventor.

This was the late 90's and the hype was getting thick -- we were guilty but so were others. Millennium wasn't a big pusher of high gene counts -- at least in the terms of the day (but that's another whole story), but certainly we started selling all those genes we had & the ones we extrapolated were still out there. A key part of the business model was to sell the genes many times -- if we could sell the same gene to Lilly for cardiovascular & Roche for metabolic and AstraZeneca for inflammation, all the better. Not that anything underhanded went on; we'd present the case to each company & most of the deals had exclusivity only within a therapeutic area.

How much did we believe our own Kool Aid? It varied. There was one day where I got in a blue mood because I convinced myself that once MLNM found all the genes we'd put ourselves out of work! But that was an extreme ( and what I hope is the height of my own personal stupidity); most of the time we thought we might be right or we might be overestimating a bunch -- but that our partners were intelligent adults who could make the same calculations. Never did I see an attitude that we were fleecing the suckers.

In particular, I remember one of my colleagues making a comment when the Bayer deal was about to be signed. A premise of that deal is that Millennium would identify proteins which could be easily screened, associate them by multiple means with a plausible role in disease, configure an HTS assay for them -- and then Bayer would quickly get hits from their libraries. Those hits in turn would be used to finish determining whether the protein of interest really played a role in disease. MLNM's (over)confidence in genomics matched by Bayer's (over)confidence in chemistry. My colleague said it was one thing to think up such an idea -- and another to 'go over the cliff' -- and he was nervously surprised that someone else was joining us. He was one of the most sober minded fellows around & wasn't making allusions to
Bayer being foolhardy -- just that we were both taking the leap together. Alas, I didn't think to laugh & reply "The fall will kill you".

The genomics rush, alas, did not end with a huge rush of new drug candidates. We thought we'd get a huge leap in biology -- and we did, but not as big as we thought. Traditional drug development & biology had cleaned out the easy stuff; there weren't tons of hidden gems. The chemical biology concept pretty much disappeared from the Bayer collaboration -- turned out it was long-and-painful to configure all those assays (though we did get them done).

BUT, I will admit to being only a partially reformed genomics fan. We got oversold, and it hurt. Much effort was wasted, and just think of the savings if the patent office had declared that you had to have actual causal function to patent a gene! But, much of what we proposed doing still is worth doing -- or has been done. In some sense the genomics companies were just too early for their own good (though the late entrants such as DeCode haven't fared much better). There are no genomics companies -- yet genomics is everywhere. Basic biology fueled by the genome or the technologies pushed by genomics permeate the drug industry (based on the 2 large pharmas I interviewed at in the year MLNM laid me off & what I can read; constructive dissent on this point is welcomed). Probably no novel small molecule drug development history will be directly pinned back to a 1990's genomics effort -- but also virtually no drugs going forward will have their development unaffected by the knowledge of the genome. Everything is tangled up & confused & merged.

The genomics gold rush was insane & wasteful -- but they were fun times!


Unknown said...

I remember that there was a real competition to claim the greatest number of secret genes in your proprietary database- HGS claimed they had 55,000 that nobody else knew about, and Incyte claimed they had 60,000.

After the smaller numbers came out, Incyte claimed that they were talking about alternative forms, but the head of HGS insisted that theirs were all real, distinct genes.

Someday some janitor will find all the missing genes stashed in a closet somewhere and get really rich off of them...

Anonymous said...

Interesting history. I spent a lot of time in biotech as well, not quite the same modus operandus but along similar lines. Rather than looking back, let's review where we are now. There are roughly 3000 or so classically druggable genes in the genome. Many of these have known physiological functions, some even have good human or mouse genetics. There are perhaps two dozen or so major commercial diseases. Do the math, there are only so many patents possible - those with blockbuster potential. A large fraction of these probably already exist in various stages of pushing through patent review. At some point almost everyone will be paralyzed. The only feasible solution I see is to operate in ignorance and cross-license when a viable compound actually comes along. It's a poor business model, ripe for lawyers scaring the pants off everyone (and ensuring their own job security of course). I could wish that gene patents for therapeutic development were simply ruled out by the patent offices, not based on any particular precedent or technical definitions, but simply so everyone can get on with the job.


InformaticsMD said...

In some sense the genomics companies were just too early for their own good (though the late entrants such as DeCode haven't fared much better)...everything is tangled up & confused & merged. The genomics gold rush was insane & wasteful -- but they were fun times!

Well, at least the expenditures were enjoyed.

Perhaps there's a "missing link", though, that might help resolve the confusion. Collaboration between the molecular and clinical informatics cousins comes to mind.

See my provocative post "Has Bioinformatics Hit A Hard Wall of Stagnation?" here.