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Jay Knowles is enjoying himself. The biotech executive sits in his San Diego office, where he directs business operations for Structural GenomiX (SGX). SGX, a startup company, has raised nearly $40 million in venture capital since its founding a year ago and is now turning away investors. “Being the next wave of the genomics business, everyone’s flocking to give us as much money as they possibly can,” Knowles boasts. And, he adds, several large pharmaceutical firms are eager to buy SGX’s product: three-dimensional protein structures, those intricate models with loops and whorls that lend a touch of the fanciful to the pages of scientific journals like Science and Nature. “We have lots of deals on the table,” says Knowles.

Suddenly, Knowles’ boss, president Tim Harris, bursts into the room. “Vertex has just cut a structural genomics deal with Incyte,” he says. “Bastards. This is war.”

Knowles is stunned. Before coming to SGX, he was director of R&D planning for Vertex Pharmaceuticals, the visionary Cambridge, Mass., drug company that specializes in structure-based drug design-the construction of medicines atom by atom, fitting drugs like finely cut jewels into protein settings. Out of courtesy to his former employer, Knowles has avoided raiding Vertex for employees. But if Vertex, with the help of Palo Alto, Calif.’s high-flying Incyte Genomics, wants to compete head-to-head with SGX in the emerging field of “structural genomics” (the large-scale discovery of precious protein structures), the truce is history. “Anybody you want to pull out of that place, go ahead,” says Harris. “The gloves are off.”

A few frantic phone calls later, however, and it’s clear that it’s a false alarm. Vertex has merely bought access to Incyte’s stockpile of human genes. But Harris and Knowles remain on red alert, prepared to battle any company that threatens SGX’s early lead in a field that they claim will revolutionize drug discovery. “We’ll see other groups jump on the bandwagon,” says Harris. “You can bet your life.”

Molecules to Medicine

SGX’s ambitious goal is to automate the production of information about protein structures, and sell the results to large drug companies. It’s a business plan with obvious precedent. After all, it was the introduction of high-speed machines for DNA sequencing that allowed quick-moving and well-financed companies such as Incyte to amass private empires of genetic data. Using the same technology, the public-sector international Human Genome Project is expected to publish (sometime this year, ahead of schedule) a working draft of the complete human genetic makeup.

That’s where Knowles’ interrupted pitch picks up: Mass production of protein structure, he believes, is the natural successor to mass production of DNA sequence. After all, those 100,000 or so genes are merely blueprints for making proteins-the versatile molecules that perform nearly every vital function in our bodies. Yet the function of most proteins remains unknown. Thus, the urgent task is to figure out what proteins do and how they work, and there is no better starting point than their three-dimensional shape. Until now, however, “solving” these protein structures has been a notoriously difficult undertaking.

Automating could yield big gains, not only for basic science, but also for what Harris calls the “bloody hard” business of discovering new drugs. According to this 20-year industry veteran, a significant jump in the number of available protein structures could transform how drugs are created.

Today, the vast majority of drugs are still found by hit-and-miss methods, albeit on a massive scale. The world’s top pharmaceutical companies have sunk billions into automated systems that can synthesize and test hundreds of thousands of chemical compounds a week, hoping to turn up a few “hits” against a protein target. (Most drugs on pharmacy shelves work by attaching to proteins, activating or disabling them.)

Structural genomics proposes turning traditional drug discovery on its head, putting protein structures first and using them to design new drugs from the ground up, a process known as “rational drug design” or “structure-based drug design.” Instead of relying on luck, with a three-dimensional structure as a starting point chemists can use the details of its shape to create a chemical compound that fits precisely. Drugs that result should, in theory, be exquisitely specific, avoiding the side effects that often doom otherwise promising compounds to the pharmaceutical dustbin.


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