Historical Fine-Mapping

When phage biologist and historian of science Gunther Stent reviewed Jonathan Weiner's book on Seymour Benzer, Time, Love, Memory: A Great Biologist and His Quest for the Origins of Behavior (1999), he praised the book yet complained that "the work that should secure for Benzer a place in the pantheon of biology—his bridging the experimental gap between formal genetics and DNA structure—occupies only a dozen or so of the book's 300 pages" (Stent 1999). As his final piece of scholarship, Frederic L. Holmes produced the book that Stent felt should be written: a careful history of Benzer's virtuosic fine-mapping of the rII region of the phage T4 genome. Benzer demonstrated that the gene was not an indivisible unit—that recombination could happen within a single gene. His results showed that the recombination and complementation maps of this genetic region of phage were in agreement, and strongly suggested that both mirrored the linear structure of DNA. By the late 1950s, his high-resolution maps helped geneticists accommodate the perspective of molecular biologists, who regarded genes as specific sequences of nucleotides.

Reconceiving the Gene is only part of the book Frederic Holmes set out to write before he was diagnosed with a terminal illness. It was, in the end, a heroic achievement that Holmes completed this book at all. Ironically, this succinct account of the Benzer's early experiments may have a greater impact than the more comprehensive book Holmes originally had planned. Alongside Investigative Pathways, a book of historiographical reflections that he also wrote during the last two years of his life, this may well be his most readable monograph. I knew Holmes personally and was in conversation with him about this project while he was writing it; I also read his draft chapters and offered my own comments and suggestions. I will not pretend to be a completely impartial reviewer. But this review provides me an opportunity to offer a critical appreciation of Holmes's technique and contributions as reflected in this capstone of his scholarly career.

Holmes remains best known for his meticulous, fine-grained reconstructions of experimental science, which include, in addition to many essays, books on Antoine Lavoisier (two), Claude Bernard, Hans Krebs (two volumes), and on the collaboration of Matthew Meselsohn and Frank Stahl. His writings range across scientific fields, from chemistry to biochemistry to physiology to genetics, and also span two centuries and four countries. On the one hand, Holmes approaches scientific investigation in these diverse contexts the same way, as if there is a constant essence to the enterprise. He tends to treat experimentation as a quintessential form of human creativity, and at times I have questioned his presumption of science's universal, even transhistorical, character. On the other hand, Holmes's studies focus on specific cases where the detail matters to the argument—and this is an aspect of his work that even the most particularistic historian can appreciate.

Here Holmes applies his method to a key experimental achievement of molecular biology. The first two chapters of Reconceiving the Gene provide an insightful overview of the prehistory of Benzer's work, sweeping through early developments in genetics and recounting his protagonist's foray from physics into biology. In the late 1940s and early 1950s, Benzer spent several years investigating the response of phage to irradiation, a radiological approach to genetics that originated with "target theory" and attracted the energies of many biophysicists, though it never did shed as much light on the nature of the gene as its practitioners hoped. At the time, the concerns of classical geneticists and the ambitions of phage biologists were strikingly divergent, despite a professed mutual interest the nature of the gene. In 1952, Guido Pontecorvo observed that one could define the gene as a unit of recombination, a unit of mutation, or a unit of physiological activity (Pontecorvo 1952). Each was valid, but in certain cases discrepancies arose, and the inconsistencies were most...