Tech Pioneers

By Mark Halper

Who??says??there's??no??such??thing??as??a??eureka??moment? Physicist David Grier sure had one. Grier and graduate student Eric Dufresne were trying to build a new kind of "optical trap"--a device that splits a laser beam and uses it to capture particles of a single substance. They knew that multiple traps, used in tandem, could let scientists play traffic cops on a molecular level, separating a substance into component parts--removing bacteria from blood, for example. For a year, Grier and Dufresne had been trying out fancy glass splitters, but nothing had done the trick. As a joke, Grier tried a $5 piece of plastic. "It should not have worked," he says. But it did: the "cheesy piece of plastic" split the laser beam into 16 parts, which gave the two scientists the potential to capture 16 separate substances. It was the breakthrough they had long been after. "We were stunned," Grier recalls.

That aha! has paid off. Soon afterward, in 2000, Grier co-founded Arryx, an optical-equipment company whose laser gear can grab, trap and move minute particles of just about anything. The firm expects to make a profit this year--impressive progress for a biotech start-up. Arryx is one of 29 "Technology Pioneers" chosen by the World Economic Forum, the Geneva-based nonprofit organization best known for its annual meeting in Davos, Switzerland, which opens this year on Jan. 26. Others on the pioneers list--including technologists in the fields of energy, biotech and information--have become entrepreneurs too. The biotech scientists have achieved some extraordinary breakthroughs, but to do that, many had to leave comfortable corporate or academic jobs in which they were confined by institutional thinking.

At the California Institute of Technology, for example, Bassil Dahiyat and his professor Stephen Mayo ran into resistance when they proposed a new approach to fighting disease. They argued that because protein shapes vary according to their functions, it should be possible to create new disease-fighting proteins by first imagining their shape. "You could hear the people at Caltech snicker," says Dahiyat.

Determined to prove the naysayers wrong, Dahiyat 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. About a minute later, he noticed that the protein was taking form. "I could see it wasn't spaghetti," he says. "I said, 'Oh, my God, we've got structure!'"

Dahiyat and his professor may have the last laugh. In 1997 they founded Xencor, with Dahiyat in charge, based on the protein-creation process called Protein Design Automation (PDA) that they had refined on the supercomputer. If all goes as planned, in about a year Xencor will start human trials of a protein that combats multiple sclerosis, rheumatoid arthritis and other diseases. Xencor has signed contracts with Genentech, Eli Lilly and other companies to develop additional drugs.

Jennie Mather left biotech company Genentech also out of frustration when, she says, her bosses wouldn't accept her approach to fighting cancer. She argued 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. Because a body's natural antibodies do their work entirely on the cell's exterior, she reasoned, drugs should work the same way. Such thinking was heresy to Genentech, whose scientists, she says, generally analyze 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."

Genentech says it pioneered the use of antibodies that target the surface protein of cancer, and its popular drugs work on that principle. Nevertheless, Mather saw a way to carve several years out of drug development and left to found Raven Biotechnologies, a drug-discovery company based in South San Francisco. She created a process to keep cells alive outside the body, so she could test her theory in the lab. Her efforts paid off. In December the U.S. Food and Drug Administration approved one of her drugs for human testing. The drug, called RAV 12, is a protein that in the dish destroys another protein found in 90% of all gastrointestinal cancers and in 50% of all breast, lung and prostate cancers.

Similarly, Harren Jhoti left pharmaceutical giant Glaxo Wellcome (now GSK) in 1999 when he realized that his unconventional idea of how to find new drugs to attack disease-causing proteins might never be realized unless he pursued it himself. He founded Astex, based in Cambridge, England, so he could develop his own flexible approach to molecular research. He calls it "fragment based," because rather than throwing an entire proposed drug molecule at the target protein, he throws just pieces at a time.

Jhoti and four of his scientists hit the pub when they had their eureka moment. In October 2002 their advanced X-ray and crystal technique revealed that a chemical was binding to a protein that is a possible cause of Alzheimer's disease. The chemical was a fragment of what could eventually become an Alzheimer's-conquering drug. "I first thought the team had played a trick on me," says Jhoti. Drug giant AstraZeneca, which had been searching for such a chemical for years, enlisted Astex's help. In 2003 the company signed a contract to pay Astex $40 million if Astex hits milestone breakthroughs and to make royalty payments once AstraZeneca sells drugs based on Astex's technology. "AstraZeneca worked on it for four years. We delivered an early candidate within a year of signing with them," says Jhoti. He also hopes to win regulatory approval to begin testing a general anticancer drug in the first half of 2005.

At Arryx, Grier and Dufresne's 16-trap breakthrough was so exciting that the University of Chicago, where they were based, showcased their work to Lewis Gruber, a biotech entrepreneur and patent lawyer. Within months, he had invested in the technology, and Arryx was born, with Gruber as chief executive. Grier, who is now a professor at New York University, is the company's chief scientific adviser. 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. The technology is used today for tasks that include analyzing blood and separating sperm cells in bull semen that produce bulls from those that make cows (which might not seem important unless you're a dairy farmer who needs a supply of milk-producing females).

In late October, blood-equipment maker Haemonetics Corp., of Braintree, Mass., invested $5 million in Arryx to help develop a machine that would remove a blood donor's platelets, used for clotting. Under the deal, Haemonetics has agreed to make payments of $7.3 million and $5 million when Arryx hits predetermined development breakthroughs.

As entrepreneurial as some of these tech pioneers are, and as brilliant as their breakthroughs are, the R.-and-D.-reliant business of biotech is still very difficult. While the companies are developing processes and drugs, they survive on venture financing and funding from larger partners, often provided when they hit milestones. Payments from AstraZeneca and other partners have boosted Astex's revenues 170% annually since 2000, and Astex has raised $100 million in venture financing. Raven has raised $66 million and hopes to land another $35 million soon. It also receives milestone payments from Abbott Laboratories and others.

The big payout doesn't kick in until regulators approve the drugs for commercial use and the developers start receiving royalties, which can take years. "There are a lot easier ways to [make money] than to put your life into a high-risk adventure," says Dahiyat. Fortunately, the occasional chance to shout "Eureka!"--or at least, "We've got structure!"--also keeps their innovators going.