Legends in our Field: Har Gobind Khorana (1922-2011)

Kadambini Alva P.

Dr. Har Gobind Khorana, a name etched forever in the history of Science, was best known for deciphering the mechanisms by which RNA codes for synthesis of proteins. He was jointly awarded the Nobel Prize in Physiology/ Medicine along with Robert W. Holley and Marshall W. Nirenberg “for their interpretation of the genetic code and its function in protein synthesis.”

The illustrious career of this Indian-American scientist had a very humble beginning. Born in a small village (Multan) of British India (Now Pakistan) to a poor family, Khorana began his early education under a tree, which was the only school in his village. His hard work, talent, and scholarships paved way for his higher education. He obtained his bachelor’s (1943) and master’s degree (1945) from the Punjab University (Lahore) and then went on to pursue his Ph.D. in organic chemistry at the University of Liverpool, England on a prestigious government fellowship. In 1948, Khorana was awarded a doctoral degree for his work on the chemistry of melanins and indoles under the mentorship of Roger Beer.

A lot of the chemistry literature Khorana came across during his PhD was in German language and so for the next phase of his career he wanted to do research in a German-speaking country and be proficient in the language. So, he joined the lab of Vladimir Prelog (a future Nobel laureate in chemistry,1975) at the Federal Institute of Technology (ETH) in Zurich. Here he worked on the chemical structure of Erythrina alkaloids (used as arrow poisons). While this unpaid postdoctoral stint lasted less than a year, it had a major influence on his philosophy, work ethics, and the research he pursued in the future. It was during this time that he came across a lesser known class of compounds called carbodiimides which proved to be of great importance in his future work on nucleotide cofactors. It was also during this time that he met Esther Elizabeth Sibler, whom he married later. On returning to India from Zurich in 1949, Khorana faced the challenge of finding a job in a newly partitioned country.

Fortunately, with his contacts from ETH, he was able to receive a three-year fellowship to work under Alexander Todd (another future Nobel laureate in chemistry, 1957) at Cambridge University in 1950. Here Khorana worked on peptides and the possibility of using carbodiimides to synthesize pyrophosphates. It was an exciting time for him to work here as he was exposed to path breaking research viz. Todd’s work on chemical structure of nucleic acid, Fred Sanger’s sequencing of insulin, and John Kendrew and Max Perutz’s X-ray analysis of myoglobin and hemoglobin. This environment of scientific breakthroughs and discoveries inspired Khorana to apply his chemistry expertise to the field of Biology.

In 1952 Khorana accepted an offer to set up a non-academic research laboratory at the British Columbia Research Council (BCRC), Vancouver as it gave him the freedom to pursue his own research. His work here on use of carbodiimides to form pyrophosphate bonds, coenzyme A, ATP, and many other compounds of biological interest was groundbreaking and brought him international recognition. His achievements in applying synthetic organic chemistry to biological problems made him a pioneer in this field.

In 1960, Khorana moved to the Institute for Enzyme Research in Wisconsin, where he did his Nobel Prize winning work on deciphering the genetic code. He discovered the codons for amino acids serine and leucine and generated synthetic oligonucleotides. His group was the one to assemble the coding region of the yeast alanine tRNA gene and thus the first synthetic gene. He described the amplification of synthetic genes in a series of steps which was redefined 15 years later as PCR. His research laid the framework for synthetic biotechnology, which is today commercialized by many companies in form of providing customized synthetic oligonucleotides for amplifying DNA, sequencing, site-specific gene modification, and many other applications.

In the final phase of his academic career, Khorana worked at the Massachusetts Institute of Technology (MIT). He shifted his research focus to biological membranes, protein transport and began investigating the molecular mechanism that controls cell signaling pathways which he pursued until his retirement.

Throughout his career, Dr. Khorana received many national and international honors and awards. He is the only Indian to have received the prestigious Nobel Prize for his contributions to Medicine. He also has many national and international fellowship programs instated in his honor. Despite all odds and obstacles in life, Khorana achieved outstanding success in his endeavors through determination, focus and consistent hard work and yet remained humble. He believed that “We must be modest except in our aims”. Dr. Khorana passed away on 9 November 2011, at the age of 89 but his legacy will continue to inspire every generation of scientists.

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