A Pilgrim's Progress through Mutation Research

PERSPECTIVES IN BIOLOGY AND MEDICINE Volume 21 ¦ Number 3 ¦ Spring 1978 A PILGRIM'S PROGRESS THROUGH MUTATION RESEARCH C. AUERBACH* Mutations are sudden hereditary changes, as when a streptomycinresistant bacterium arises in a strain of sensitive ones and gives rise to a whole population of resistant bacteria, or when a yellow pup turns up in a kennel of black spaniels and becomes the ancestor of a line of yellow dogs. Mutation research inquires into the nature and causes of naturally occurring (spontaneous) mutations and into the means for producing mutations artificially. Mutations were objects of interest from the beginning of genetics in 1900 and had been so even earlier when they turned up as "sports" in animal or plant breeding. Mutation research as a scientific discipline was inaugurated by H. J. Müller, who, in the early 1920s, demoted mutation from its position as an unpredictable act of God to that of a chemical process that occurs rarely but at measurable rates, similar to other stochastic processes like the disintegration ofradioactive substances. The result ofa mutation is a gene with altered property and with the ability to reproduce itself. My own pilgrimage along the path of mutation "research started shortly before the Second World War when Müllerjoined our institute in Edinburgh for about a year. I had recently finished my Ph.D. thesis on a developmental problem in the fruit-fly Drosophila and was occupied with analyzing the effects ofcertain mutant genes on the development of the flies. I well remember the day when Müller came to the laboratory in which I worked, sat down beside me, and asked me what general purpose I was pursuing with my research. I answered that I wanted to find out something about the way genes act. He replied that the morphologi- *Address: Institute of Animal Genetics, University of Edinburgh, West Mains Road, Edinburgh EH9 3JN, Scotland.© 1978 by The University of Chicago. 0031-5982/78/2103-0030$01.00 Perspectives in Biology and Medicine ¦ Spring 1978 | 319 cal and histological effects of mutant genes which I was studying were still far removed from the primary action of the gene and that the best way to find out something about the gene itself was to see by which means it could be made to mutate. His enthusiasm for mutation research was infectious, and from that day on I switched to mutation research. I have never regretted it. The Basic Problem ofMutation Very early on Müller had pinpointed the fundamental mystery of mutation: the ability of a gene not only to change its properties but also to replicate at once in the changed, mutated form and to do so for hundreds of thousands or millions of times as faithfully as it had done previously in its original form [I]. In the extremely stimulating discussions which our little group around Müller had during his stay with us, the problem occupied a central place. All kinds of explanations were suggested, mainly based on analogies with physical resonance phenomena or with immunological processes. Long after Müller had gone back to the United States, the problem was solved finally and unequivocally by the Watson-Crick model ofthe gene [2]. In my experience it is rare to get a complete and final answer to a biological problem; when it does happen it is extremely satisfactory, and fortunately Müller lived to see it and to follow many of the important developments of mutation research that flowed out of it. "Molecular" geneticists often seem to think that there cannot have been any scientific study of mutation before the Watson-Crick model and that our discussions can only have been a floundering in the murky waters of speculation. They also think—and this opinion is shared by very eminent ones among them—that with this great discovery mutation research has come to an end—at least as regards its fundamental problems . Both ideas are quite wrong, as I hope to show in this article. It is true that our old discussions about the nature of self-replicating changes in the gene did not and—as I now see—could not lead to any definite conclusions without a...