Emil Fischer experimented with making polypeptides--chains of at least three amino acids--during the opening years of the 20th century. Fischer received the Nobel Prize in 1902 for his work on the synthesis of sugars and purines. But he never reached his goal of concocting a complete protein. Nearly 90 years later chemists were not doing that much better. The only practical methods of producing synthetic polypeptides had reached about the 50¿amino acid mark, the size of the smallest proteins. But much of the attention had switched to recombinant-DNA methods that copied a gene and then inserted the clone into a cell that could pump out protein.

A few diehards, however, could still see the promise of synthetic chemistry. In 1989 biochemist Stephen B. H. Kent, along with colleagues from the California Institute of Technology used a synthetic process to make the HIV protease--the enzyme needed to make the virus fully functional. Then, along with collaborators from the National Cancer Institute, the team went on to determine the crystalline structure of the protein. "Some of us were too old-fashioned to stop making things by chemistry," Kent says. "We beat out people in the pharmaceutical industry who were trying to clone and express proteins."

This article was originally published with the title Making Proteins without DNA.

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