Har Gobind Khorana (1922–2011): Pioneering Spirit

One of the great chemists of the 20th century died on November 9, 2011. H. Gobind Khorana, a founder of what we now call chemical biology and a pioneer at the dawn of the age of molecular biology, was 89 (see Image 1). Gobind was a creative and insightful chemist, with many landmark achievements to his credit, including the first practical synthesis of nucleotides and coenzymes in the mid-1950s. He had a pioneering sense of the power of multidisciplinary work and he continued to reinvent himself at regular intervals for more than 50 years. He shared the Nobel Prize for Physiology or Medicine in 1968 (with Robert W. Holley and Marshall W. Nirenberg), at age 46, for contributions toward elucidating the genetic code—one of the great scientific achievements of the age of molecular biology. Energized by the Nirenberg and Matthaei experiment from 1961, where a cell-free extract produced a protein made entirely of phenylalanine when poly-U was added, Gobind’s group at the Institute for Enzyme Research at the University of Wisconsin–Madison worked around the clock in double shifts to synthesize all of the possible triplet trinucleotides, thus providing a firm basis to establish the complete codon assignments and to determine how the code was read. Gobind pursued this punishing schedule even though work on the genetic code in the early 1960s represented a digression of sorts from studies aimed at refining procedures to synthesize even longer polynucleotides. In 1972, Gobind described the total chemical synthesis of a functional tRNA gene in an unprecedented and still unsurpassed achievement in chemical biology, which was published in an entire issue of Journal of Molecular Biology in December 1972—15 consecutive articles, 313 consecutive pages. The achievement was even more striking if we stop to consider that when the project was initiated, in 1960, there was no reliable method to synthesize more than a di-nucleotide in reasonable yield, nor was there a way to sequence DNA. The report of ‘‘nearest-neighbor’’ analysis by Arthur Kornberg—a test to confirm the sequence of the bases during replication—was all that Gobind needed to commit to the work [1]. And once Gobind committed, there was no turning back—ever. By the time I had met Gobind for the first time, at the Massachusetts Institute of Technology (MIT) in 1984, he was 62 years old—already a giant from an earlier time. He gave no impression at that initial meeting that he was satisfied with his achievements or finished with his work. And in fact, he wasn’t. He would be active for 23 years more and would publish seminal work on transmembrane signaling and energy transduction. I remember vividly that first meeting, and I guess that anyone who has ever met Gobind would remember him. He was not necessarily what you would expect given his achievements. He seemed to have time; he listened and had no air of pretense at all. He was a professor who did not profess; an expert who did not claim to know all there was to know. He preferred to be on the receiving end, to acquire more information to store, synthesize, and later recall using his prodigious memory. Of course, I already knew about his work on the genetic code and gene synthesis when we met. And I had studied the curious photo of him from 1966 at the Cold Spring Harbor Symposium on the Genetic Code that was reprinted in Recombinant DNA: A Short Course [2]. Wearing a grey suit and dark tie, Gobind is facing the camera and is caught just as he had apparently reached up to sweep back his hair (see Image 2). Standing about two paces to the right are Francis Crick and Marianne Grunberg-Manago, but they are looking past Gobind into the distance. Gobind, at least in earlier years, must have been easy to underestimate and overlook. And though an unassuming and humble man, at times shy, he was definitely not reserved or impersonal. With an intellectual audacity that propelled him forward, Gobind would study and seek out the leaders of each successive field of interest and then, in most cases, leap beyond them while leaving a trail of highly accomplished colleagues (perhaps 250 postdoctoral fellows and students over the years), who would often go on to become leaders in whatever field he had jettisoned earlier. Image 1. Portrait of H. G. Khorana. Image credit: Karina Åberg. doi:10.1371/journal.pbio.1001273.g001