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Remembering Har Gobind Khorana

 Gobind Khorana with Julius & David Adler in 1966 while at UW-Madison Biochemistry
Gobind Khorana with Julius & David Adler in 1966 while at UW-Madison Biochemistry

Adapted from Aseem Z. Ansari, Marsha Rich Rosner, and Julius Adler (Cell, 147. 12/23/11)

Gobind Khorana traversed boundaries, both scientific and cultural. He pioneered the use of chemistry and physics to answer fundamental questions in biology. In particular, he helped decipher how RNA encodes protein, and how light is perceived. His research earned him the Nobel Prize in Medicine in 1968. Although deeply modest and unassuming, Gobind would often remark, ‘‘I only work on big problems.’’ Indeed, only such challenges were worthy of Gobind’s extraordinary intensity, creativity, and focus.

Gobind is an icon for science sans frontiers. He was an early practitioner of what is now known as Chemical Biology. He pioneered new synthetic routes for nucleotide cofactors and oligonucleotides and then used these synthetic molecules to help elucidate the genetic code. He assembled the first synthetic gene, laying the foundation for Synthetic Genomes and Synthetic Biology. In 1971, after he joined MIT, he described the amplification of synthetic genes in a series of enzymatic steps. 15 years later, these were enhanced with a thermostable DNA polymerase, and became PCR. At MIT, Gobind took on lipids and membrane proteins, focusing on rhodopsins until his retirement in 2007.

From India to UW. The elegance of Gobind’s work has inspired generations of chemists and biologists around the world, but has been singularly profound in India. There, Gobind symbolizes the fact that education and talent can overcome socioeconomic and intellectual boundaries.

Gobind began his education under a tree in a small village of a hundred families, who were mostly illiterate. Fortunately, his talent was recognized early, and he went on to Punjab University in Lahore. Although he almost became an English major, he graduated with a Masters in Chemistry and then won a rare fellowship to pursue a Ph.D. in organic chemistry at the University of Liverpool in England.

After obtaining his doctorate in 1948, Gobind enthusiastically moved to Eidgenössische Technische Hochschule (ETH) in Zurich to join the group of Vladimir Prelog, a chemist who won a Nobel Prize in 1975. In less than a year, he had to leave Zurich because his savings ran out. During his brief tenure at the ETH, however, Gobind serendipitously encountered the little known work of Fritz Zetzsche on carbodiimides, which later was crucial in Gobind’s synthesis of nucleotide cofactors and ATP.

Gobind failed to find a position in India, but then received a three-year fellowship with Alexander Todd at Cambridge University. There, Gobind learned of Sanger’s exciting advances in protein sequencing, Perutz’s and Kendrew’s breakthroughs in protein crystallography, and Todd’s own work on nucleic acids. This innovative environment drew Gobind, a synthetic organic chemist, to the newborn field of Molecular Biology.

In 1952, Gobind began his independent scientific career as a nonacademic researcher at the British Columbia Research Council in Vancouver, Canada. His seminal scientific contributions can be grouped into two phases. The first focused on nucleotides and nucleic acids, using carbodiimides to form pyrophosphate bonds, which eventually led to the first synthesis of coenzyme A and ATP. Soon, Gobind wrote to Van Potter, a leading cancer biologist at UW-Madison, asking if he would test his synthetic ATP in rigorous biochemical assays. Van Potter not only obliged with the experiments, but also succeeded in bringing Gobind to the Institute for Enzyme Research, a vanguard of chemical biology at UW-Madison.

 photo of Khorana with Nirenberg during the 2009 Steenbock Symposium
Khorana with Nirenberg during the
2009 Steenbock Symposium
UW and MIT. From 1960 to 1970, Gobind was a member of our Department, and Co-Director of the ‘‘Enzyme Institute’. During this period, he generated and amplified synthetic oligonucleotides. Using the oligonucleotide CUCUCU, he discovered that the triplets CUC and UCU encode the amino acids leucine and a serine, respectively. Marshall Nirenberg had previously shown that UUU encoded phenylalanine, and Gobind, with characteristic humility, always noted that Nirenberg’s work inspired his own.

Gobind next set his sights on synthesizing a complete gene. Ultimately, he synthesized the coding and regulatory regions of a tRNA gene, and demonstrated that it worked in bacteria. This tour de force defined a framework for biotechnology and, 40 years later, is still used to assemble synthetic genes and genomes.

The second phase of Gobind’s career began after he left Madison for MIT. There, he focused on the mechanism by which intrinsic membrane proteins function and how they interact with phospholipids in the lipid bilayer. His interests led him to bacteriorhodopsin and, eventually, mammalian rhodopsin.

The strategy he chose was a forerunner of contemporary systems biology: sequence the protein, mutate every residue, express and reconstitute the proteins in a native biological context, and then meticulously monitor the phenotypic perturbations. Gobind and his co-workers elucidated how bacteriorhodopsin, and latter mammalian rhodopsin, pumps protons across the membrane when activated by light.

Khorana with Khorana students 2009 Steenbock Symposium 
Khorana with Khorana students at the
2009 Steenbock Symposium
The Khorana program. Inspired by Gobind’s story, UW-Madison launched the Khorana Scholars Program. This program places American and Indian students in leading laboratories in the other country, for a transformative summer research experience (see the article on page 20 of this newsletter). In 2007, the year Gobind retired from active research, Gobind generously lent his name to the program. During his last visit to UW-Madison, Gobind met the 2009 scholars. His joy at meeting the future generation of scientists and their passion for science was palpable.

The respect and warmth felt by Gobind’s academic family was readily evident in the periodic ‘‘Khorana Symposia,’’ which were held in various parts of the world. The last such gathering was in 2009 at the 33rd Steenbock symposium on Synthetic Gene to Synthetic Genomes. Many of the scientists that spoke, in describing their current work, noted how Gobind shaped their thinking and how his contributions continue to propel new fields, such as synthetic and chemical biology. As a tribute to Gobind, UW-Madison has made these talks publicly accessible at http://www.biochem.wisc.edu/seminars/ steenbock/symposium33.

 Masayasu Nomura and Hikoya Hayatsu with Gobind Khorana during the 2009 Steenbock Symposium
 Masayasu Nomura and Hikoya Hayatsu with Gobind Khorana
during the 2009 Steenbock Symposium

A devoted family.
Gobind had a deep interest in nature and its beauty; he actively sought solitude in natural settings to think deeply and critically about science. His beloved wife Esther, whom he lost in 2001, ensured that he was free to focus exclusively on science. Gobind tragically lost his daughter Emily in 1978 but is survived by his loving children David and Julia, who cared for him in his final years.

Har Gobind Khorana pursued his work with a single-minded intensity but remained humble to the end. His innate curiosity and appreciation of life (as well as that quick laugh, that slight tilt as he craned his head to listen, and that quizzical look) will remain with those who were fortunate to be his friend. In a collection of his papers published a decade ago, he quoted from Otto Loewi, who could have describing Gobind himself: ‘‘We must be modest except in our aims.’’

 Table of contents from The Journal of Molecular Biology Vol 72 Issue 2 December 28, 1972
The entire Journal was devoted to papers authored with Khorana (as well as the first two in the next issue)

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