Filling the Pipeline
The founders of both SGX and Syrrx have the credentials to back their claims. Colleagues credit SGX scientific co-founders, Columbia University biophysicists Barry Honig and Wayne Hendrickson, with coining the term “structural genomics.” Hendrickson is a celebrated crystallographer who invented an ingenious method for tackling otherwise unsolvable proteins. Honig, who has written widely used computer programs for analyzing and predicting protein structures, knew that more solved structures would make his job much easier. “These [prediction] methods depend on data,” he points out.
There’s no single breakthrough technology that’s made structural genomics feasible. Rather, a combination of more DNA sequence data, powerful X-ray “beamlines” and high-speed computers have sped up the entire process and made it more reliable. By the late 1990s, says Honig, he and Hendrickson had concluded “the time was ripe” for a concerted assault on the protein universe.
The idea of industrializing crystallography also fired the imagination of Ray Stevens, a chemist who invented a novel “micro-crystallization” system for making protein crystals from droplets up to a hundred times smaller than usual-a key element in Syrrx’s system. Working feverishly within the walls of the Novartis Institute, Stevens and a team of engineers have already built a prototype system for fully automating X-ray crystallography. Machines sporting intricate mazes of glass flasks, rubber tubing, test tubes and electrical harnesses include a crystallization robot that can perform 139,000 experiments a day and process a million time-lapse photo images of crystal growth. “If you do this one protein at a time, there is no way in the world you can reach those numbers,” Stevens says. “Everything is set up in parallel.”
That doesn’t mean everything will work. “We’re going to have a high failure rate at first,” Stevens readily admits. In 2002, Syrrx’s first year of full-scale production, fewer than two percent of its proteins are expected to yield three-dimensional structures. But since the company plans to test 60,000 proteins, that still means nearly 1,000 successful structures coming out the end of the pipe.
A thousand novel structures a year would, in Ned David’s words, “make drug discovery move at a genomics pace.” While SGX is compiling a database of structures to sell to pharmaceutical companies, Syrrx will go a step further by developing lead drug compounds using computer-based rational design techniques. To do this, it will model virtual libraries of chemicals for proper fit to protein structures. “We’ll be able to dock 200,000 compounds [to a protein] in under a day,” says David. “The value here is making drugs, and making them fast.”
That’s the promise. In the near term, however, both startup firms will simply be racing to generate as much structure data as possible. That’s because, as on the Internet, commercial success may go to whoever gets there first with the most. “We have momentum, and we have first-mover advantage,” says Harris, whose company has found about a dozen structures in its first six months of operation. “Believe me, we are going to exploit that, ruthlessly. I like that word, because I mean it.”