Bio Diversity

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Gruber, Grier and company have long since replaced the plastic with a liquid-crystal device, which they build into a small, box-shaped machine that you could call a cell catcher. Arryx has dubbed it CellRyx. Where BioRyx is useful "for anyone with a need to have hands in the microscopic world," notes Grier, CellRyx is specifically for sorting cells. A blood-equipment company, Gruber says, will soon purchase a CellRyx that will remove platelets from donated blood. The platelets, which induce clotting, would then be given to hemophiliacs. The same blood machine could remove bacterial cells, or could extract red cells to give to anemics. The CellRyx box operates faster and captures much smaller particles than the centrifuges and filters that medical laboratories use today, says Gruber.

Harren Jhoti, too, made a discovery that had eluded better-funded corporate researchers. In October 2002, Jhoti and his colleagues at Astex discovered in their Cambridge lab a chemical that bound to a protein called beta-secretase (Bace), which researchers had identified as a possible cause of Alzheimer's disease. The chemical was just a fragment of what could eventually become an Alzheimer's-conquering drug. But it represented a big step in the quest for a Bace-targeting substance, which drug giant AstraZeneca had been seeking for years; the firm enlisted Astex's help. "AstraZeneca worked on it for four years. We delivered an early drug candidate within a year of signing with them,'' says Jhoti, who is Astex's founder and chief scientist.

How did they do it? By deploying a process called X-ray crystallography. First, they grew a Bace crystal. Then they exposed it to an array of X-rays. A protein is too small to be "seen" by a normal X-ray, but if run through a series of rays, it will produce a recognizable pattern of small dots — it's a bit like seeing the bear in the pattern of stars that make up Ursa Major. The crystallography technique was once used by legendary dna discoverers James Watson and Francis Crick. As Jhoti notes, "it took Watson and Crick over a decade just to image one dna molecule." Astex has sped up the process with a series of computer algorithms and hardware processes.

Astex calls its drug discovery method "fragment-based,'' because rather than throwing an entire proposed drug molecule at the target protein, they throw just pieces at a time. Jhoti claims this yields a much higher success rate than trying out whole molecules, an approach favored by large drug companies like the one he left in 1999, Glaxo Wellcome (now GSK).

Astex has also developed a general anticancer chemical that Jhoti says has the potential to stop all cancers at a very early stage by thwarting the initial cell- division process. He hopes to win regulatory approval to begin testing the drug on humans in the first half of 2005.

A different approach to Alzheimer's is being pursued at Memory Pharmaceuticals. Drawing on Nobel-prizewinning research by co-founder Eric Kandel, the company hopes to develop drugs that reverse dementia, memory loss, depression and schizophrenia. Chief executive Tony Scullion says it has already developed a drug that fights Alzheimer's by restoring the process by which short-term memories are logged in for long-term recall. Swiss drug firm Roche is now testing it on humans, with clinical results expected in the near future.

Another disease-fighting Pioneer is Jennie Mather of Raven Biotechnologies in South San Francisco. Like Jhoti, Mather is out to fight cancer, but her approach is radically different. She postulated that what really counts in a target protein — that is, a protein that causes a disease and that a drug would aim to disable — is the protein's surface. Since a body's natural antibodies never enter a diseased cell but do their work entirely on the cell's exterior, she reasoned, drugs should work the same way. Such thinking was heresy to her former employer Genentech, which analyzes a target's entire genetic structure. "They were just interested in genomics,'' she says. "There are 500 to 1,000 genes in a disease — the problem is, it takes a long time to understand what 1,000 genes do.'' Genomic drug development can typically take four to five years. Mather figures she can cut times down to an average of about six to nine months.

But to test her theory in a lab dish, she needed to get around the problem that human cells die outside the body. She created a patent-pending process to keep them alive, and her efforts paid off. Mather hopes that the Food and Drug Administration in the U.S. will soon approve one of her drugs for human testing. The drug, called raag 12, is a protein that in the dish destroys another protein found in 90% of all gastrointestinal cancers and in 50% of of all breast, lung and prostate cancers. It works by crippling the cancer cell's surface, she says.

A few hundred miles south at Xencor in Monrovia, California, Dahiyat is also experimenting with proteins that he hopes will become disease-fighting drugs. If all goes as planned at his Caltech spin-off, in about a year Xencor will start human trials of a protein that combats multiple sclerosis, rheumatoid arthritis and other diseases.

His drug targets a protein called Tumor Necrosis Factor (TNK). TNK can help immune systems fight infections and tumors, but an excess of it causes inflammatory diseases. Xencor's protein binds with the excess TNK and shuts it down. The company believes this is a superior approach to existing treatments, which simply seek to lower TNK levels. Xencor's approach derives from a process Dahiyat invented in 1997 while a graduate student at Caltech. Instead of using time-consuming methods like trial and error, he asked a computer to figure out what mix of amino acids would make a protein of a particular shape. (Shape is important because a protein's structure determines its function. Just like a flathead screwdriver is appropriate for some jobs and a Philips for others, proteins' different shapes help them effectively attack different disease cells.) The desired shape is easy to figure out; finding the single protein in a world populated by trillions of them is the hard part.

In 1997, Dahiyat wanted to show that he could make a V-shaped protein with a coil falling off the top of one arm. His Caltech colleagues laughed, but off he went to the supercomputer at Caltech's famed Jet Propulsion Laboratory. "I said, here's the shape I want to make, tell us the sequence,'' he recalls. By the end of the day, the computer gave him billions of possible amino acid combinations and recommended the best one. Dahiyat threw that sequence into a small, tunnel-like device called an NMR spectrometer. About a minute later, Dahiyat noticed that the V-shaped protein was indeed falling into place. "I could see it wasn't spaghetti. I said, 'Oh my God, we've got structure!'" Thus was born a protein-creation process that Dahiyat calls Protein Design Automation (PDA) and that became the foundation of Xencor. PDA no longer requires supercomputing power but can run on a mere PC. Dahiyat's team is now applying their techniques to other therapeutic drugs that they hope will boost the human immune system.

Most of the Pioneers are a long way from marketing their drugs. Clinical trials can typically last for four or five years before regulators approve or reject their general use. But if in a few years their efforts are aiding those with crippling diseases like Alzheimer's and cancer, it will be testament to a well-known scientific theorem: sometimes you've gotta quit the day job.