In the late 1970s, the advent of DNA recombination techniques set the stage for a revolution in pharmaceuticals: the birth of the biotechnology industry.

Unknown startups like Amgen, Genentech, Genzyme and Biogen scrambled to harness the natural machinery for weaving proteins within each living cell. With the support of "big pharma," the giant pharmaceutical companies of the past, these startups rolled out scores of blockbuster drugs that addressed diseases like hepatitis and cancer in entirely novel ways.

Today, a new generation of startups is taking advantage of a new revolution--the application of cheap computing power and rapid automation to the drug discovery process.

And like the discoveries that paved the way for the first wave of biotechnology entrepreneurs, today's new techniques of drug discovery represent a profound--and unavoidable--shift in the growth of the global pharmaceuticals industry.

Structurally Sound

Two Cambridge firms, Millennium Pharmaceuticals and Vertex Pharmaceuticals, have been at the forefront of the second technological revolution.

Vertex, founded by a Harvard graduate in 1989, is a pioneer in "structure-based drug design." In theory, the idea is plausible enough: if one knows the precise three-dimensional structure of an enzyme target, one can use a computer to design a perfectly complementary "small molecule drug" to jam into the enzyme and disable it, just as a locksmith can build a key from scratch to open a lock.

Vertex's first major research effort--designing a safe and reliable inhibitor for the HIV protease that assists with the replication of the HIV virus--started with generating a molecular map of the protease enzyme.

The techniques of choice for this sort of cartography are x-ray crystallography and protein nuclear magnetic resonance spectroscopy (NMR), which take a snapshot of a protein at a resolution of less than a billionth of a meter.

"X-ray crystallography allows us to map out the atom-by-atom three-dimensional structure of a drug target, [especially] the active site," says Brum. "The more precise information we can have about the active site helps us to develop a safer, more potent drug."

Vertex scientists solved the structure in 1992 (see picture below) and began to explore several potential sites for artificial blockage, using supercomputers to suggest possible "keys" for the HIV "lock." In practice, the computer's guess is often far from perfect, but computers can help bench-top scientists refine their search for the molecule with the perfect fit.

"We do a lot in the area of computational chemistry," explains Lynne H. Brum, Vertex's vice president of corporate communications. "It helps us understand which chemical compounds [will be successful] on the bench."

Vertex scientists attacked the HIV protease with different drug candidates, using combinatorial chemistry to produce thousands of subtle variations of the computer's best guess. Combinatorial chemistry, explains Harvard Professor of Chemistry Gregory L. Verdine, "is a technology that allows one to make thousands to millions of organic compounds of defined structures in a very rapid period of time."

without combinatorial chemistry, a chemist might spend years synthesizing a few thousand variants of a drug candidate. Using the technology, a single researcher can brew the same number of molecules in minutes.

When a molecule showed promise, it was plugged back into the computer for another round of computer guessing and filtering.

By 1993, says Brum, Vertex had identified a likely anti-AIDS drug candidate--code-named VX-478--and signed an $42 million agreement with Glaxo-Wellcome to market and develop the compound under the brand name Amprenavir. Clinical trials began in February, 1995, and approval from the Food and Drug Administration (FDA) is expected by the end of 1998.

Automation and Information

Three blocks away from Vertex, at 640 Memorial Drive, another new pharmaceutical company is developing tools and techniques that are redefining the way the industry searches for drugs.

Millennium Pharmaceuticals, which is less than five years old but already has, three other locations in Cambridge, began by focusing on genomics, the science of understanding not only the sequence of all of the genes in human chromosomes, but also the function of the protein each gene codes for and under what circumstances each gene is expressed.

Such Knowledge is critical for pharmaceutical companies, which must constantly seek out new drugs to interact with new targets to find new cures, and Millennium already has lucrative alliances with six members of "big pharma," including Monsanto and Eli Lilly.

"What we hope to achieve is working with the pharmaceuticals industry to provide them with novel targets, gene products, which we feel are ripe for the development of a novel therapeutic, whether it be a small molecule or a protein therapeutic," says Robert Tepper, chief scientific officer for pharmaceuticals at Millennium.

But like Vertex, Millennium itself aspires to become a full-fledged pharmaceutical company and has several proprietary drug discovery efforts underway.

"I think we've anticipated the impact that the efforts going on in the Human Genome Project will have on biomedical science, and we have built tools...to come to bear with dealing with this enormous amount of information," Tepper says.

"These technologies include very state-of-the-art information systems, which really are relatively new to biomedical research and came of age as part of sequencing the human genome," he says, noting that computational techniques and databases as large as the human genome are commonplace in the financial industry.

Tepper says he believes bioinformatics, as these technologies are collectively called, are paving the way for the future of biotechnology.

"While foreign to most biologists and perhaps chemists, and, in fact, not taught in normal biomedical education, these become the most important tools for the next wave of biomedical research," he says.

In addition to information systems, Millennium has been an avid proponent of automation, such as the techniques of combinatorial chemistry employed by Vertex.

Millennium, says Tepper, has taken combinatorial chemistry a step further to become an expert in testing the multitudinous products of combinatorial chemistry reactions with enzyme targets in a technique called 'high-throughput screening.'

"If you're dealing with 10 or 96 samples at a time, that's doable by one person with a pipettor," explains Tepper. "When you're dealing with sets of tens of thousands of chemical compounds, automation becomes quite necessary."

The result of automation, he claims is both a reduction in expenses and a boost in the efficiency of scientists. "When you free up individuals to be creative and do the work that can't be done by machines, you free up a lot of potential," he says.

Renee J. Raphael, Joshua L. Kwan, Eran K. Mukamel and Amita Mi. Shukla contributed to the reporting of this story.

"When you free up individuals to be creative... you free up a lot of potential."  Robert Tepper, M.D.