Hairy Business

In addition to the sea urchin genome papers, the new Science also contains an article describing the positional cloning of a mutant gene resulting in hair loss. The gene encodes an enzyme which is now presumed to play a critical role in the health of hair follicles.

The first round of genomics companies had two basic scientific strategies. Companies such as Incyte and Human Genome Sciences planned to sequence the expressed genes & some how sift out the good stuff. Another set of companies, such as Millennium, Sequana, Myriad and Mercator planned to find important genes through positional cloning. Positional cloning uses either carefully collected human family samples or carefully bred mice to identify regions of the genome that track with the trait of interest. By progressively refining the resolution of the genetic maps, the work could narrow down the region to something that could be sequenced. Further arduous screening of the genes in that region for mutations which tracked with the trait would eventually nail down the gene. Prior to the human genome sequence this was a long & difficult process, and sometimes in the end not all the ambiguity could be squeezed out. It is still serious work, but the full human genome sequence and tools such as gene mapping chips make things much cheaper & easier.

Instead, it seemed like every one of the positional cloning companies picked new indications -- obesity, diabetes, depression, schizophrenia, etc. -- and generally the same ones. This set up heated rivalries to collect families, find genes, submit patents & publish papers. Sequana & Millennium were locking horns frequently when I first showed up at the latter. If memory serves, on the hotly contested genes it was pretty much a draw -- each sometimes beating the other to the prize.

Eventually, all of the positional cloning companies discovered that while they could achieve scientific success, it wasn't easy to convert that science into medical reality. Most of the cloned genes turned out to be not easily recognizable in terms of their function, and certainly not members of the elite fraternity of proteins known as 'druggable targets' -- the types of proteins the pharmaceutical industry has had success at creating small molecules (e.g. pills) to target. A few of the genes found were candidates for protein replacement therapy -- the strategy which has made Genzyme very rich -- but these were rare. Off-hand, I can't think of a therapeutic arising from one of these corporate positional cloning efforts that even made it to trials (anyone know if this is correct?).

Before long, the positional cloning companies either moved into ESTs & beyond (as Millennium did) or disappeared through mergers or even just shutting down.

I'm reminded of all this by the Science paper because hair loss was one area that wasn't targeted by these companies -- although the grapevine said that every one of them considered it. The commercial success of Rogaine made it an attractive area commercially, and there was certainly a suggestion of a strong genetic component.

If a company had pursued the route that led to the Science paper, it probably would have been one more commercial disappointment. While the gene encodes an enzyme (druggable), the hairless version is a loss-of-function mutant -- and small molecules targeting enzymes reduce their function. The protein isn't an obvious candidate for replacement therapy either. So, no quick fix. The results will certainly lead to a better understanding of what makes hair grow, but only after lots of work tying this gene into a larger pathway.

As for me, I'm hoping I inherited my hair genes from my maternal grandfather, who had quite a bit on his head even into his 90's, rather than my father's side, where nature is not quite so generous. As for urchins, I learned to avoid them after a close encounter on my honeymoon. I was lucky the hotel had a staff doctor, but I discovered on my return to the States that we had missed one & perhaps I still carry a little product of the sea urchin genome around in my leg.