HAR GOBIND KHORANA: THE HUMBLE GENIUS

[COVID-19 SERIES#4]

In these times of the COVID-19 pandemic, genetic manipulation and testing are increasingly in focus. On one hand there are rumors that the causative Corona virus is man-made, while on the other there are efforts to crack the genetic code of the virus and develop a vaccine as soon as possible. In the backdrop of this situation one name which comes to mind is that of Dr. Har Gobind Khorana, the first researcher of Indian origin to win the Nobel Prize for Physiology or Medicine.

A Google doodle honoring the researcher

Dr. Khorana was born on 9^th January, 1922 in the village of Raipur in Multan (present Pakistan), where his father was working as a clerk. His family was the only literate among the 100 or so living in the village. After schooling, he was offered a scholarship at Punjab University, Lahore to study chemistry. However, he was so shy that he refused to attend the scholarship interview and almost took up English. Nevertheless, he got the chemistry scholarship and completed his Bachelor course in 1943 and Masters in 1945.

Soon thereafter, he won a scholarship to study organic chemistry at the University of Liverpool. He obtained his Ph.D. in 1948 under the supervision of Roger J.S. Beer. Subsequently, he went to Zurich, Switzerland for post-doctoral research. There, he joined the Eidgenössische Technische Hochschule (ETH) working under Vladimir Prelog, a chemist who won a Nobel Prize in 1975 for his work on stereochemistry. However, within a year Gobind ran out funds and secretly lived in the lab to avoid expenses. Subsequently, he was forced to return to India.

However, in India the young scientist became jobless. But then Lady Luck smiled again and he won a three-year fellowship with Alexander Todd at Cambridge University. While at Cambridge, Gobind was exposed to Sanger's exciting advances in protein sequencing, Perutz's and Kendrew's breakthroughs in protein crystallography, and Todd's work on the chemical structures of nucleic acids. This innovative environment drew Dr. Khorana, a synthetic organic chemist, to the newborn field of Molecular Biology. The iconic Cambridge University would in 1953 be the site where James D. Watson and Francis H. C. Crick would discover the double-helix structure of DNA.

In 1952, Dr. Khorana had the exciting prospect of setting up his lab by the British Columbia Research Council in Vancouver. There, he started work on nucleotides and nucleic acids. He used a carbodiimide (dicyclohexylcarbodiimide) to form pyrophosphate bonds, which eventually led to the first synthesis of coenzyme A and ATP. 

In 1952 he married Esther Elizabeth Sibler, whom he had first met in Switzerland. The couple had three children, Julia Elizabeth, Emily Anne, and Dave Roy. He credited her with bringing a “consistent sense of purpose into my life at a time when, after six years’ absence from the country of my birth, I felt out of place everywhere and at home nowhere.”

In 1960 Khorana accepted a position as co-director at the Institute for Enzyme Research at the University of Wisconsin at Madison, USA. He became a professor of biochemistry in 1962 and was named Conrad A. Elvehjem Professor of Life Sciences at UW–Madison. Most of his significant work which led to the Nobel Prize were performed here. In 1966 he accepted the US citizenship.

He generated synthetic oligonucleotides and amplified these molecules biosynthetically with DNA polymerase. Using the oligonucleotide CUCUCU, he discovered that the triplets CUC and UCU encode the amino acids leucine and serine, respectively. This work corroborated the studies of Marshall Nirenberg, who had previously shown that a UUU triplet encoded a phenylalanine residue. Gobind, with his characteristic humility, would always note that Nirenberg's work inspired his own investigations of the genetic code.

In 1968 he won the Nobel Prize for Physiology or Medicine with Marshall W. Nirenberg and Robert W. Holley for research that showed the order of nucleotides in nucleic acids, which carry the genetic code of the cell and control the cell's synthesis of proteins. He would often rent a room or cottage without a phone, radio, or TV so that he could think and write without distraction. His wife, Esther was forced to drive an hour to inform Dr. Khorana that he had won the Nobel Prize.

In 1970 Dr. Khorana joined the Massachusetts Institute of Technology as the Alfred P. Sloan Professor of Biology and Chemistry. After a long and fruitful career at MIT he would retire in 2007.

While at MIT, using DNA ligases, Gobind's lab assembled the coding region of the gene for the alanine tRNA. By 1976, Gobind had added the required regulatory elements needed to express the gene in a living bacterial cell and demonstrated that the synthetic tRNA functioned identically to the naturally expressed gene. This seminal work defined the conceptual and technical framework for biotechnology and, nearly 45 years later, is still the strategy used to assemble synthetic genes and genomes.

Gobind's mentorship involved rigorous intellectual training and hard work. It did not matter if none of the experiments worked (at least for the impossible problems!), but complete “24/7” engagement was expected. One possibly apocryphal story involved Saturday morning donuts that Gobind would bring to the lab. Rumor had it that he had identified everyone's favorite type of donut and would bring only one each. At the end of the day, he would check the remaining donuts and determine who had come in over the weekend!

Dr Khorana won eminent honors from all over the world. Among others, he was awarded the Louisa Gross Horwitz Prize, Lasker award, Willard Gibbs Medal, Gairdner Foundation Annual Award, Paul Kayser International Award of Merit and the National Medal of Science. An unassuming man to the last, he was sent numerous letters for his National Medal of Science award, which were unanswered. Ultimately, a White House representative tracked him to a conference where he got the assurance from Dr. Khorana that the researcher would attend the felicitation ceremony. 

Dr. Har Gobind Khorana passed away on 9^th November 2011, in Concord, Massachusetts, at the age of 89. In 2002, the government of India was requested to grant him its highest civilian award, the Bharat Ratna. Unfortunately, the country is yet to pay this colossal legend a worthy obituary.