Taking a Clue from Nature
Though weinberg and his colleagues at Symyx are the first to try to commercially apply combinatorial techniques to materials research, they didn’t invent the process. In fact, they were beaten out by a few billion years by a very creative innovator: Evolution. Cells have the ability to create a wide variety of molecules based on a limited number of building blocks and then select the ones that function best. In this familiar evolutionary process, cells create an enormous variety of DNA and protein molecules by arranging common building blocks in a different order. Natural selection does the rest.
Beginning in the early 1980s, researchers began imitating nature’s example. They started creating collections of peptides-short proteins that can bind to cell receptors and thereby regulate cell function. Just how well this regulation takes place depends on how tightly a peptide binds to a receptor, which itself depends on getting just the right sequence of peptide building blocks, amino acids. Researchers invented several methods that made it possible to arrange amino acids in different combinations and track the products they made. They found that they could easily create thousands of peptides in nothing flat. By testing these compounds for activity in cells, researchers could quickly home in on the most chemically active peptide and work out its structure.
These early successes didn’t win many converts among those who design new therapeutic drugs for a living. “There was enormous resistance from medicinal chemists in the beginning,” says Joseph Hogan, founder and chief scientific officer of ArQule-a Medford, Mass.-based combinatorial startup. “They felt it was completely inelegant and ugly” compared with the traditional approach of rationally designing and then painstakingly synthesizing compounds.
The approach also faced practical limitations. Because enzymes in the stomach break down peptides, most researchers considered them poor drugs. But the idea was in the air, and before long, new research teams showed that the basic strategy could go beyond peptides and turn out small organic compounds similar to those that make up most drugs.
By the beginning of the 1990s the craze for high-speed chemistry was sweeping through the pharmaceutical industry. Startups sprang to life to commercialize combinatorial know-how. Flush with hundreds of millions of dollars from investors, these companies set about creating libraries of potential drugs with as many compounds as big pharmaceutical companies had hoarded on their stockroom shelves during the past 100 years. Not to be left out, Big Pharma companies, such as Glaxo Wellcome and Merck, leaped into the fray starting their own combinatorial research efforts and striking deals with combinatorial chemistry startups. “In the mid-1980s, traditionalists were laughing at the idea of the combinatorial synthesis of drugs,” says Weinberg. “But they’re not laughing now.”