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The Cutting Edge: COMPUTING / TECHNOLOGY / INNOVATION : 'Grind and Find' : Robots, VDTs May Be the Rx for New Pharmaceuticals


SEATTLE — Ever since Scottish biologist Alexander Fleming stumbled on penicillin in 1929, drug development has been more serendipity than science. Researchers at large pharmaceutical companies screen thousands of compounds in trial-and-error "grind and find" tests before finally hitting on a promising drug--typically spending $400 million and 12 years in the process.

Biotechnology was supposed to change all that with breakthrough techniques such as genetic engineering. But while a few early pioneers such as Genentech and Amgen have struck it rich by "picking the low cherries on the tree," in the words of one scientist, broader progress has been slow: Though there are about 520 biotech companies in the United States, only 26 biotech drugs are in commercial use.

Now many researchers and biotech industry watchers are pinning their hopes on a new set of drug development techniques that exploit cutting-edge computer methods and advanced robotics technology. By combining the ability of computers to analyze and model reams of data with robots' precision handling and cutting abilities, these methods could radically reduce the amount of time and money it takes to develop new drugs--to the benefit of the sick and biotech investors alike.

"You can often make breakthroughs by marrying two separate technologies," says Ken Lee, national director of the life sciences practice at accounting firm Ernst & Young and co-author of an annual report on biotechnology. "That's what's happening with high-powered computing and biotech. Something great is going to happen."

There are no guarantees, of course: None of these technology-savvy companies have approved drugs to validate their approach, and some analysts say they lack the broad expertise in pharmaceuticals needed to produce effective drugs.

But the techno-drug companies have been producing an impressive number of drug candidates for human clinical trials, often in record time. The Johns Hopkins Oncology Center will soon begin the trial of an anti-cancer drug that BioNumerik Pharmaceutical of San Antonio developed in just 18 months using supercomputers. Agouron, a San Diego drug company, is now testing two anti-cancer drugs and a possible treatment for AIDS. Arris Pharmaceuticals, a South San Francisco-based company, is testing a drug for asthma.

And even if the current purveyors of the new approach to drug making don't survive, few question that the technology they are developing will become part of the mainstream, accelerating drug development in companies large and small and transforming a stream of new discoveries about man's genetic makeup into useful drugs.


"A hundred years in the future, everybody will be 'genotyped' and you will design drugs on demand fitted to that person's target protein," says David Galas, vice president for research at Darwin Molecular Sciences, a start-up company backed by Microsoft Corp. Chairman Bill Gates. The firm plans to combine advanced robotics with high-speed computers to sequence genes and find new ways to tackle such treatment-resistant diseases as cancer, AIDS and multiple sclerosis.

While there are many different approaches to computer-driven drug development, the broad goal is typically the same. First, the objective is to find a protein, or "receptor," that plays a key role in a disease. Once a receptor is found, the task is then to find a compound that will attach itself to the receptor and either disable the receptor if it has harmful functions or activate it if it has a positive role. Think of the receptor as the lock that must be opened or closed for treatment and the drug as the key that must be found.

But though their goals are similar, the various companies are tackling the problem in radically different ways.

Agouron's method, called rational drug design, is to create new compounds "atom by atom." When Agouron set out to find a compound to disable the HIV protease, a piece of the AIDS virus that's involved in replication, it began by cloning the protein and turning it into a crystal structure.

By bombarding the crystal with X-rays and recording the way in which the rays are deflected--a process called protein X-ray crystallography--company researchers created a three-dimensional image of the HIV protease. The image was then used to design on computer a new compound that would fit neatly into the protein, like a plug into a socket.

"We designed a molecule you couldn't come upon in any other way," says Peter Johnson, Agouron's chief executive officer. "These are things that don't occur in nature."

A frequent criticism of rational drug design is its failure to recognize that compounds and their targets change shape under different conditions, which means the computer model sometimes bears little resemblance to reality. And X-ray crystallography doesn't work on the many proteins that cannot easily be converted to a crystal structure.


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