Har Gobind Khorana

Har Gobind Khorana was born on January 9, 1922, in Raipur, a small village in the Multan district of Punjab, then part of British India and today in Pakistan ^[1]. His father, Ganpat Rai Khorana, worked as a patwari, a village clerk responsible for agricultural tax records. The family had little money, yet the father insisted that all five of his children learn to read and write. Khorana later recalled that his family was practically the only literate household in a village of about one hundred people ^[1].

His earliest schooling took place outdoors, under a tree, with a single teacher serving the village. From there he moved to the D.A.V. High School in Multan, where a teacher named Ratan Lal encouraged his curiosity about the natural world ^[2]. Scholarships carried him to Punjab University in Lahore, where he earned a bachelor's degree in 1943 and a master's degree in chemistry in 1945, studying under the supervision of Mahan Singh ^[1].

In 1945 the Government of India awarded him a fellowship to study abroad. He sailed for England and enrolled at the University of Liverpool, where he completed a PhD in organic chemistry in 1948 under Roger J. S. Beer ^[1]. The move began a long migration through the world's chemistry laboratories, and he never again lived in the country of his birth.

After Liverpool, Khorana spent a year in Zurich at the Swiss Federal Institute of Technology, working on alkaloid chemistry in the laboratory of Vladimir Prelog, who later won a Nobel Prize of his own ^[2]. Money was scarce, and Khorana lived frugally, but he often described the Zurich period as formative for his scientific taste and standards. In Switzerland he also met Esther Elizabeth Sibler, whom he would marry in 1952 ^[1].

A short return to India brought no job offers, so in 1950 he went back to England, joining the Cambridge laboratory of Alexander Todd, a leading authority on nucleotide chemistry ^[3]. There Khorana turned his attention to nucleic acids and to phosphate ester chemistry, the field that would define his career. In 1952 Gordon Shrum recruited him to the British Columbia Research Council in Vancouver, Canada, offering modest facilities but complete scientific freedom ^[1].

The Vancouver years proved remarkably productive. With coworkers, Khorana developed practical methods for building nucleotides and their derivatives, and in 1959 he and John Moffatt announced a chemical synthesis of coenzyme A, a molecule central to cellular metabolism ^[2]. The achievement made his reputation international. In 1960 he moved to the Institute for Enzyme Research at the University of Wisconsin-Madison, where he became co-director and, in 1964, Conrad A. Elvehjem Professor of Life Sciences. He became a naturalized citizen of the United States during his Wisconsin years ^[3].

Any account of Har Gobind Khorana achievements begins with the genetic code. By the early 1960s scientists knew that DNA stored hereditary information in sequences of four bases, and Marshall Nirenberg had shown that a synthetic RNA made only of uracil directed the production of a protein made only of phenylalanine. What remained unclear was the full dictionary connecting the sixty four possible three letter codons to the twenty amino acids ^[4].

Khorana's contribution was chemical precision. His Wisconsin group synthesized DNA and RNA molecules with exactly known repeating sequences, such as alternating pairs of bases, then observed which proteins these templates produced in cell free systems ^[4]. The experiments confirmed that the code is read in groups of three, that the triplets do not overlap, and that the message runs in a fixed direction. Combined with the binding assays of Nirenberg's laboratory, this work assigned meanings to all the codons, including the signals that stop protein synthesis ^[2]. For this achievement Khorana shared the 1968 Nobel Prize in Physiology or Medicine with Marshall Nirenberg and Robert Holley ^[1]. The same year he received the Albert Lasker Basic Medical Research Award ^[3].

He did not pause. Khorana next set out to build an entire gene from bottled chemicals, a project many colleagues considered impossibly ambitious. In 1970 he moved to the Massachusetts Institute of Technology as Alfred P. Sloan Professor of Biology and Chemistry, and in 1972 his team announced the total synthesis of the gene for a yeast alanine transfer RNA ^[5]. By 1976 the group had synthesized a bacterial tyrosine transfer RNA gene complete with its regulatory start and stop signals, and demonstrated that the man made gene functioned inside a living Escherichia coli cell ^[5]. The chemical strategies developed along the way, including early forms of oligonucleotide synthesis and the primer based copying methods that foreshadowed the polymerase chain reaction, became foundations of biotechnology ^[6].

In his later decades Khorana changed fields again, applying chemical and molecular tools to membrane proteins. His MIT laboratory carried out detailed studies of bacteriorhodopsin, a light driven proton pump from salt loving microbes, and of rhodopsin, the light sensing protein of the vertebrate eye, clarifying how such proteins fold and signal within cell membranes ^[6].

Khorana married Esther Elizabeth Sibler, a Swiss national, in 1952, shortly before the couple settled in Vancouver. He credited Esther with giving his wandering life a sense of purpose and stability at a moment when he felt out of place, neither at home in India nor settled abroad ^[1]. They raised three children: Julia Elizabeth, Emily Anne, and Dave Roy ^[3].

Colleagues describe a man of unusual modesty and discipline who avoided publicity, rarely gave interviews, and preferred long walks, hiking, swimming, and music to academic ceremony ^[6]. He listened more than he spoke, and he was known for spending years, sometimes decades, on problems that others thought too hard to attempt. Students remembered his habit of working alongside them at the bench well into his senior years ^[5].

The family also knew sorrow. His daughter Emily Anne died in 1979, and Esther died in 2001, losses that Khorana bore privately ^[3]. Despite decades of American life he retained quiet ties to his origins, and he supported efforts to help young Indian scientists gain research training abroad.

Khorana remained on the MIT faculty for the rest of his career, retiring formally in 2007 after thirty seven years at the institute ^[5]. Honors accumulated steadily: election to the National Academy of Sciences in 1966, foreign membership of the Royal Society in 1978, the Willard Gibbs Medal, the Gairdner Foundation International Award, and the National Medal of Science, presented in 1987 for his work on the genetic code and gene synthesis ^[3].

He continued to influence science through his students and postdoctoral fellows, many of whom became leaders in chemistry, biology, and the emerging biotechnology industry ^[6]. In 2007 the University of Wisconsin-Madison, the Government of India, and the Indo-US Science and Technology Forum jointly created the Khorana Program, an exchange scheme that sends students between the two countries for research training, honoring his path from Punjab to the American Midwest ^[7].

Har Gobind Khorana died on November 9, 2011, in Concord, Massachusetts, at the age of 89 ^[4]. He was survived by his children Julia and Dave. Obituaries around the world noted that a scientist who had begun his education under a village tree ended his life having rewritten the chemical language of heredity.

Among the essential Har Gobind Khorana facts is this: the tools of modern genetic engineering trace directly to his laboratory. The chemistry his groups developed for stitching nucleotides into defined sequences made possible synthetic genes, DNA probes, site directed mutagenesis, and the custom oligonucleotides that every molecular biology laboratory now orders routinely ^[6]. Techniques he explored in the 1960s and 1970s echo in genome sequencing, in the polymerase chain reaction, and in the synthetic biology of the twenty first century ^[4].

His intellectual style left a mark as deep as his results. Khorana believed in mastering a problem completely, moving into new fields without fear, and letting the work speak instead of the worker. Nirenberg, his fellow laureate, and later colleagues at MIT often pointed to the gene synthesis project as an example of scientific courage: a decade long effort with no guarantee of success, carried through by patience and rigorous chemistry ^[5].

For readers of any Har Gobind Khorana biography, his story also carries a social meaning. A child from a family of very modest means, educated first outdoors in a small Punjabi village, became one of the central figures of twentieth century biology through public scholarships and open scientific institutions ^[1]. Universities in India and the United States name lectures, fellowships, and buildings for him, and the Khorana Program continues to move young researchers across the same route he once traveled alone ^[7].