This Week's Citation Classic

This week's citation classic is A.S Sarabhai, A. O. W. Stretton, S. Brenner and A. Bolle. 1964. Colinearity of the gene with the polypeptide chain. Nature 4914:13-17.

Following Crick and Watson's big breakthrough, the biology world sparkled with new hypotheses regarding the nature of the gene and the genetic code. The DNA molecule's structure implied a number of these hypotheses, but without empirical confirmation, they were nothing but speculation. One of these hypotheses was that the linear sequence of bases in a DNA strand coded for a complementary linear sequence of amino acids constituting the protein product of that gene. While this is the most obvious and parsimonious hypothesis, one need not think hard to imagine other possibilities.

Sidney Brenner was not reluctant to give his students difficult thesis problems. His graduate student, Anand Sarabhai was given the task of demonstrating colinearity of gene and polypeptide chain. For a graduate student to be given such a fundamental, but risky, problem is quite exceptional. Luckily Sarabhai was up to the task. He obtained phage T4 nonsense mutants from Dick Epstein of Geneva. Epstein called his mutants amber mutants, after the mother of Harris Bernstein, a Caltech grad student. German speakers will identify the connection; bernstein is the German word for Amber.

Sarabhai writes: "These mutants (it was believed) did not make a full polypeptide in a normal cell but did so in a suppressor-positive cell. What was not known was whether the amber mutations kept terminating and releasing the synthesized peptide or simply got jammed at the amber site. I told Dick that I could test this in Cambridge quickly. What I found was that the amber mutants kept terminating and releasing the polypeptide, so that you got large amount of fragments of polypeptide of lengths dictated by the position of the amber mutations in the gene. This broke open the co-linearity problem." J. Biosci. 2003, Vol. 28, p. 668.

Analysis of the broken fragments allowed Sarabhai to define 8 segments of the polypeptide chain that are in the same order as the segments on a defined genetic map. Thus Sarabhai, a graduate student, made a fundamental contribution to biology. DNA sequence = amino acid sequence.