Birth Centenary: Prof Khorana: the Pioneer of Chemical Biology

 

Professor Har Gobind Khorana was born on January 9, 1922, in the village of Raipur, Multan district in the Punjab region, which is now part of Pakistan.  He was the youngest of the five children of a Hindu agricultural tax clerk (patwari) of the British colonial Government, which was dedicated to educating his children. His family was “practically the only literate family in the village inhabited by nearly 100 people.” He did his matric from DAV school, Multan and Bachelor’s and Master’s degrees (Chemistry) in 1943 and 1945, respectively from Government College, University of Punjab, Lahore.  His motivation was his school teacher Rattan Lal who had profusely influenced his educational impetus. 

Partition Not a Hindrance in Completing Ph.D.  

In 1945, he moved to Liverpool University, UK after being awarded a Government scholarship. He got his Ph.D. in Organic Chemistry in 1948 under the mentorship of Prof Roger JS Beer. He managed this academic excellence despite a very tough time for him and a very difficult situation for his family losing their home due to the tragic Partition. He came back to India in 1948 to meet his family. 

After not getting a job, he decided to move to German-speaking Federal Institute of Technology in Zurich, Switzerland to work on Alkaloid Chemistry in the laboratory of Professor Vladimir Prelog. His stay was short due to lack of any financial support and he had to survive on his savings. He secretly took up his residence in a laboratory until some financing came through.

Luckily, he received a research fellowship at the Cambridge University, a centre for the study of proteins and nucleic acids in the laboratory of Alexander Todd, on peptide and nucleotide research where James D. Watson and Francis H C Crick would discover the double-helix structure of DNA, and Prof Khorana was drawn to the field. 

In 1952, Prof Khorana moved to the British Columbia Research Council, Vancouver, Canada, to start his own research group which had people from 27 countries. In fact, the Director of that Council had come from Canada to interview him and assured him that he would have all the freedom to do what he wanted. 

Nobel Prize Recognition   

In 1960, he moved to the Institute of Enzyme research, University of Wisconsin, Madison, USA, as a co-Director and a member of the Biochemistry Department. He started working on Genetic code and chemical synthesis of coding regions of Gene for various tRNAs, which led him to share the Nobel Prize in Physiology or Medicine in 1968 at a relatively young age of 46. 

He was also awarded Padma Vibhushan, the second highest Indian civil award in 1969. He successfully used his previous knowledge for synthesis of nucleotides, pyrophosphate bonds, coenzymes and ATP. For this, he was much appreciated and came in contact with many eminent biochemists like Paul Berg, Arthur Kornberg, Fritz Lipmann and many more, who spent time as summer interns in his laboratory. He became an American citizen in 1966. He generated synthetic oligonucleotides and amplified these molecules biosynthetically with DNA polymerase. He assembled the first synthetic Gene and developed what some call a “Bio-brick” leading to the  field of synthetic Genes and synthetic Biology. 

Delineating Genes     

In 1971, he finally moved to Massachusetts Institute of Technology, Cambridge, USA. There, he described the amplification of genes in a number of steps. His work was successfully adapted by Professor Karry Banks Mullis by using thermo-stable; TaqDNA polymerase. He coincidently shared the 1993 Nobel Prize in Chemistry with his post doctoral fellow Dr Michael Smith for his novel and valuable Molecular Biology tool of the site Directed Mutagenesis (STM). Curiously, he had a rare distinction of being associated with the father-son duo of Arthur Kornberg and Roger Kornberg, both Nobel laureates. The latter was specifically advised by his father to work in the laboratory of Professor Har Gobind Khorana.

He was considered as one of the pioneers of doing interdisciplinary research in Chemistry, Biology and Physics. He could undoubtedly be called the founder and early practitioner of the current discipline of Chemical Biology. Prof Khorana’s lab also turned out leaders in academia and industry. 

In 1972, Prof Khorana reported a second breakthrough: the construction of the first artificial gene, using off-the-shelf chemicals. Four years later, he announced that he had gotten an artificial gene to function in a bacterial cell. The ability to synthesise DNA was central to advances in Genetic Engineering and the development of the biotechnology industry. “He left an amazing trail of technical development for current life sciences,” said Dr. Thomas P. Sakmar, a Professor at Rockefeller University and a former student. 

He was also conferred the National Medal of Science USA award in 1987. He switched later to another new and emerging area of membrane research and signal transduction.  He identified mechanisms by which integral protein functions and mapped their interactions with phospholipids of bilayer structure at a molecular level. He was very much attracted to light sensitive bacteria, particularly purple membranes of Halobacterium halobium bacteriorhodopsin and eventually, mammalian rhodopsin. This was the ultimate problem tackled by him. 

Humble Yet High Thinking 

Prof Khorana was a very modest, humble and yet a very demanding and great scientific thinker.  He always showed what excellence in science is and recognised it in others. He always avoided publicity. He was fond of music, swimming and long walks of solitude to think about his research problems. He used to carry a pen and notebook to write his scientific thoughts and problems. On the day of his Nobel Prize announcement he was the last one to hear about it since he was at his rented cottage to write his manuscripts with no telephone, TV or radio with him. His wife, Esther, had to drive and inform him about it. He remained at MIT for over 30 years until his retirement in 2007 and he remained professor emeritus. Till his last moments he was thinking about science. He died on November 9 2011 at the age of 89 at Concord, Massachusetts, USA. 

Research Helping Scientists On Health Concerns like COVID-19  

He is truly a symbolic figure showing how education and hard work can overcome socio-economic and intellectual boundaries. His success was indeed hard earned and quite improbable one.  He was always loyal to people who helped him. His path breaking research has been still helping many scientists on major health concerns like cancer and current pandemic of COVID-19. 

In 1952, he was recruited to the British Columbia Research Council in Vancouver to join a group working on nucleic acids. He developed a new method of synthesising nucleotides, and achieved international recognition for synthesising coenzyme A, which is involved in converting fats to energy.

His move to Canada coincided with his marriage to Esther Elizabeth Sibler, whom he had met in Switzerland. “Esther brought 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,” he wrote.

His wife died in 2001. Their daughter Emily Anne died in 1979. His survivors include another daughter, Julia Elizabeth, and a son, Dave Roy.

In 1960, Prof Khorana moved to the  Institute for Enzyme Research at the University of Wisconsin, where he did the work that led to his Nobel Prize. His lab included researchers from 27 countries with expertise in basic chemistry, Molecular Biology, Enzymology and Biochemistry, a multidisciplinary effort unusual for its time.

Prof Khorana became an American citizen in 1966. He joined the M.I.T. faculty in 1970 and retired in 2007.

An unassuming man, he shied from the spotlight and did not like talking on the phone. In the weeks before he received the National Medal of Science, a stack of message slips piled up on his desk with increasingly urgent messages that the White House had called and that he should call back. With the ceremony date fast approaching, a representative of the White House tracked down Prof Khorana at a scientific meeting and told him he would be receiving the award. Prof Khorana assured him he 
would attend.