Beadle’s progeny: Innocence rewarded, innocence lost

Beadle’s progeny: Innocence rewarded, innocence lost Perspectives Beadle’s progeny: Innocence rewarded, innocence lost* R OWLAND H D AVIS Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA 92697-3900, USA (Email, rhdavis@uci.edu) Introduction In the history of various sciences, we ﬁ nd periods of static tradition punctuated by discoveries that ignite rapid reorientations and novel lines of investigation. The dinosaurs die off and the shrews take over, beady-eyed and ignorant of the past as they spread into new, habitable niches. So it was in the early 1940s when Beadle and Tatum (1941) announced the isolation of their ﬁ rst metabolic mutants of the fungus Neurospora, followed by papers that elaborately bore out the promise of the “one gene, one enzyme” hypothesis. The promise of ﬁ nding the actual role of genes in the structure of proteins and enzymes, and how mutations might be used to dissect metabolic and other complex sequences was clear. Neurospora workers, small in numbers, sensed that a new day had come, a day in which the undiscovered country between the molecule and the cell surface might soon be revealed. When we were young, things were simple, and for some time thereafter, we retained our innocence. Creative innocence Two paths lie before a new graduate student. One is to discover something new; the other is to reﬁ ne doggedly what is known, usually on someone else’s grant money. I was forced to do the former, inasmuch as grant funds were not the way my mentor, Paul Levine, supported his students. Moreover, my fascination with Neurospora would contribute nothing whatever to his studies of Drosophila population genetics or his later work on recombination in Chlamydomonas. I had discovered early on that a student without purpose could acquire one simply by relaxing and waiting for mutations to appear. Such accidents, as Pasteur had said, favour the prepared mind, even if the mind was Keywords. prepared only with a need to discover something, however trivial. I entered graduate school in 1954, a year after Watson and Crick’s discovery of DNA structure (1953) condensed the gene’s abstract properties into a molecular model. It took some years for me to appreciate its signiﬁ cance, because my interests favoured the use of microorganisms to illuminate the genetics of haploid organisms and the workings of simple cells. But work on DNA developed in parallel with microbial and biochemical genetics, the three areas probing the fundamental structures and activities of living cells. Genetics would give us the means to dismantle the cell and to teach us, like Vesalius, to ignore the ancient texts. My graduate work had begun with a mutation affecting heterokaryons in Neurospora. My innocent delight in demonstrating its 1:1 segregation in a cross with wild-type conﬁ rmed my faith in genetics. After all, Beadle and Tatum had done this with somewhat more interesting mutations in 1941 and published it to wide acclaim. In 1958 I went to Caltech as a postdoctoral fellow, knowing that I must have a passing acquaintance with biochemistry, of which I was then wholly ignorant. My motives were base: I wanted to do biochemistry by mutational techniques rather than having to follow the demanding, fussy chemical approaches that characterized the ﬁ eld. Perhaps I too could become, as Chargaff later remarked, an unlicensed biochemist, using clumsy, random mutations to explore the china shop of metabolism. At Caltech, I joined the seminal group that had adumbrated the one gene, one enzyme motto. Apparent counterevidence had been assimilated into the theory. For instance, a mutation affecting the isoleucine and valine pathways was found to affect a single enzyme common to both. A problem remained, however: Max Delbruck insisted that the theory Arginine; Beadle; metabolic organization; Neurospora; pyrimidine *This article is dedicated to the memory of two mentors: Herschel K Mitchell, who gave me opportunity and independence, and Norman H Horowitz, who gave me background and insight into Neurospora biochemical genetics. http://www.ias.ac.in/jbiosci J. Biosci. 32(2), March 2007, 197–205, © Indian J. Academy of Sciences Biosci. 32(2), March 2007