book reviews A night at the operon

The lac Operon: A Short History of a Genetic Paradigm by Benno Muller-Hill Walter de Gruyter:1996. Pp. 207. $35.95, DM54

This book opens with the lament that for young molecular biologists history does not exist, and that they have no interest in the long struggle that has made the subject what it is today. I hold the somewhat weaker view that history does exist for the young, but is divided into two epochs: the past two years, and everything that went before. That these have equal weight is a reflection of the expo­ nential growth of the subject, and the urgent need to possess the future and acquire it more rapidly than anybody else does not make for empathy with the past. Benno Muller-Hill says that "one has to grow old to understand the functioning of a The three winners: Fran~ois Jacob, Andre Lwoff and Jacques Monod receiving the 1965 Nobel Prize for science". He has written a history of the lac Physiology or Medicine for their research into the genetic control of enzyme activity. system of Escherichia coli. He warns us that it is not a definitive history, which comes as a discovery of operator-constitutive mutants, on which they were based, and to distinguish reliefbecause that kind ofhistorywould have which were cis dominant, affecting the regu­ prediction from retrodiction. been boring. What Muller-Hill has written is lation of both 13-galactosidase and lactose The move to research on eukaryotes partly historical, partly autobiographical, permease on the same chromosome. The began atthe end ofthe 1960s, and prokaryot­ and even partly philosophical. It is best realization that virulent mutants ofbacterio­ ic research started to decline. We argued for described as a collection of stories (with a few phage A were equivalent reinforced the con­ manyyears about whether the Jacob-Monod parables, too) disguised as a history ofwhat is clusion that they had to affect a site on the model would have anything to do with cell now a small and almost unoccupied corner DNA that interacted with the repressor and differentiation in higher organisms, and it is of molecular biology. controlled the expression of two different ironic that positive regulation is generally About 30 years ago the lac operon stood genes. Operator-zero mutants also acted in found, with many transcription factors act­ in the centre of the scientific stage, and pro­ cis, but these were later shown to be due ing to enhance gene expression. There was vided the experimental basis for discovering to nonsense mutants with strong polarity; disappointment at the general absence of the principles of the control of gene expres­ they had nothing to do with operators but operons and the resulting unitary control of sion. Parallel research on the lac operon and nevertheless required the idea of the operon, a group of genes by one operator. What has bacteriophage A formed the basis for the a unit of expression containing more than survived, though, is the central principle that operon theory of gene regulation put for­ one gene. regulation is mediated by specific recogni­ ward by Fran~ois Jacob and Jacques Monod Muller-Hill and Walter Gilbert succeed­ tion ofDNA sequences by proteins. in 1961. One central idea was that regulation ed in isolating the lac repressor in 1966. This When molecular biology finally comes to was negative, that is, if the genes were placed was quite an achievement, as the only assay an end, and a massive crash of the computer in a control vacuum they would be for this repressor was that it bound the system in the library at Alexandria corrupts unleashed and express as much as they could. inducer, IPTG, and calculations showed that most knowledge, I hope that historians of Their expression was held back by repres­ the value of the binding constant and the science will unearth a copy ofthis book. They sors, and they were turned on by the removal number of repressor molecules would not will surely debate whether all of the stories of repression, either by an inducer in the case allow detection by equilibrium dialysis. are true and whether they could have been of the lac genes, or by destruction of the Muller-Hill selected for a mutant that had written by the same person, and might even repressor in bacteriophage A. Repressors a higher affinity for the inducer than the suggest that Muller-Hill was atleast two peo­ were later found that required a small mole­ wild-type repressor and this tight-binding ple. What will certainly puzzle them is that it cule to make them active so they could turn mutant made the experiments feasible. is full of characters they have never encoun­ off their target genes. The contemporary student finds it hard tered before, and that even the famous ones So central was this idea of negative con­ to understand that this research always had are hard to recognize. The only thing they trol that it became established doctrine, and to be carried out by indirect means, and not will learn about Watson and Crick is that those few scientists who worked on positive by looking directly at genes as we do today. the former produced a naked lady for the regulation were dismissed and had to strug­ The design and interpretation of such exper­ latter's fiftieth birthday. Was this perhaps gle for a hearing. It was later found that cap iments was the core skill of molecular biolo­ part of some obscure symbolic ritual enacted factor acts positively on the lac operon, and gy, and critical experiments often resorted to each year to celebrate the birth of another that the A repressor exerts a positive effect on what Francis Crick once called "special model? D its own synthesis, so the dogma of negative genetic tricks", a primitive kind of genetic Sydney Brenner is at The Molecular Sciences control gradually disappeared. engineering. It was also important to ensure Institute, Inc., 9894 Genesee Avenue, La Jolla, Evidence for the theory came from the that theories did more than explain the facts California 92037, USA.

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