The First Combinatorial Library

Mario Geysen's combinatorial library, circa 1984.

Courtesy of Terry Sharrer

In the early 1980s, Mario Geysen, working for Australia's Commonwealth Serum Laboratories, hoped to mimic an antigenic epitope for foot and mouth virus that could become the basis for a vaccine.ﾠWithout knowing the natural epitope's chemical composition, however, he had to consider a very large number of possible peptide combinations.ﾠHis method for creating a "library" of those combinations involved a series of 96-well microtiter trays holding amino acids - some wells with individual amino acids, others mixed. With an aligning plate of plastic pins that provided the solid supports, he cycled through a progression to create an array of 1.28 billion peptides, which was more compounds than had been synthesized in all earlier history. Seen here are some of the pin grids and well plates, representing the first combinatorial library, which Geysen used at the Serum Laboratories in April 1984.

Geysen.

Courtesy of Terry Sharrer

The first combinatorial library did not result in a "mimotope" for foot and mouth virus.ﾠIt did, however, demonstrate a new discovery approach: It begins with a problem in an appropriate search space that is pursued through robotic handling and generating large numbers of candidate solutions. Each outcome is assayed, and positive and negative data are analyzed for insights toward an ultimate answer.ﾠThis became a mantra not only for drug discovery, but also for array approaches in genomics and proteomics. For more, see H. Geysen et al., "Use of peptide synthesis to probe viral antigens for epitopes to a resolution of a single amino acid,"ﾠProc Natl Acad Sci, 81:3998-4002, 1984.