Har Gobind Khorana, the modest teacher

Har Gobind Khorana. Photo: nobel.org prize

On January 9, 2022, it was the 100th anniversary of the birth of Har Gobind Khorana, a pioneering biologist in chemistry and synthesis, decipherer of the genetic code and beloved mentor. His friend Uttam L. RajBhandary, professor of molecular biology at the Massachusetts Institute of Technology, once said that Khorana sincerely believed in Otto Loewi’s motto: “We must be modest except in our goals” – a statement amply confirmed in his statement. life – story.

Khorana was born in 1922, in British India, to a poor family who placed great importance on education. In 1945, after obtaining his bachelor’s and master’s degrees in chemistry from the University of the Punjab, he received a scholarship from the Ministry of Agriculture to complete a doctorate. Initially it was to focus on fungicides and insecticides, but the need to accommodate WWII veterans prompted the Indian High Commission to reorient its research towards organic chemistry.

After completing her doctorate and saving part of her stipend, Khorana funded her own post-doctoral position under the supervision of Vladimir Prelog. He later recalled that Prelog had taught him to see beauty in chemistry, work and effort. In addition to publishing two articles, Khorana learned German to better understand cutting-edge chemical research.

In 1949, he returned to a newly independent and chaotic India, where, despite his qualifications, he was unable to find a job. But his ties to the scientific community earned him a job at Alexander Todd’s lab in the UK. There he contributed to the synthesis of the building blocks of DNA.

The history of the discovery of heredity is long, beginning with Gregor Mendel in the 19th century, but many concepts common today, such as the double helix structure of DNA, were in fact being developed in Cambridge in the time of Khorana. stay here.

Imagine that DNA is a twisted ladder. Each rung of the ladder is made up of one of four possible bases: adenine (A), cytosine (C), thymine (T) or guanine (G). The spine, or the two poles of the ladder, is made up of sugar molecules linked to each other by phosphate bonds. So when you break DNA, you will find that its individual chemical units are sugars, phosphate bonds, and bases.

Khorana and her colleagues at the Todd Lab created these building blocks through chemical reactions. It was a big step in unraveling the puzzle of heredity.

Gordon Shrum, the director of the University of British Columbia, invited Khorana to open his laboratory there in 1952. The university did not offer many facilities, Shrum thought that “research in organic chemistry was the least. expensive to run, requiring only test tubes ”. With Shrum’s encouragement, Khorana decided to focus on the synthesis of oligonucleotides (short portions of DNA).

This topic was essential for advancing the study of genes and for synthetic biology. This work would also pave the way for understanding mRNA – the polymer molecule at the heart of Pfizer-BioNTech and Moderna COVID-19 vaccines.

To build on this work, Khorana moved to the University of Wisconsin in 1960 and tackled the defining problem of his day: how does the base sequence in DNA specify the sequence of acids. amines in protein? He referred to the challenges he faced on this path in his Nobel Prize lecture (1968), which he began with these words:

“Recent advances in the understanding of the genetic code are the result of the efforts of a large number of workers professing a variety of scientific disciplines. Therefore, I think it is appropriate that I attempt a brief review of the major stages in the subject’s development before discussing our own contribution which has been a group effort throughout.

One of the first hurdles was that Khorana’s team needed large amounts of DNA and RNA. Their solution was to use an enzyme called DNA polymerase to speed up the reactions by which oligonucleotides are made. In the process, they discovered the fundamental properties of DNA and DNA polymerase which are important in passing genetic information from one generation to the next. They also discovered that RNA is a necessary intermediate step between DNA and protein synthesis.

Proteins are made up of polypeptides; each polypeptide consists of a chain of amino acids. Over time, Khorana’s team succeeded in streamlining a process of synthesizing polypeptides outside the cell using a defined DNA template. After that, they moved on to testing the repeat trinucleotide hypothesis.

According to the hypothesis, based on the work of Marshall Nirenberg, DNA gives a cell instructions to make amino acids using three bases at a time. A set of three of these nucleotides was called a codon.

To test, Khorana’s team synthesized DNA fragments with two alternating bases, so that they had two codons. For example, a fragment with T and C alternating could have two types of codons: TCT and CTC. Through a series of logically progressive experiments, they were able to determine which codon corresponded to which amino acid.

Ultimately, they were able to map the oligonucleotides and their corresponding amino acid sequences. This work dovetailed perfectly with the results of Nirenberg’s experiments, proving their validity.

In this way, Khorana, Nirenberg, Robert Holley and many other scientists together built the Rosetta Stone of biology: the codon table. It is a basic tool that scientists around the world use today to identify, study and manipulate genes.

The codon table. Image: Scott Henry Maxwell / Wikimedia Commons, CC BY-SA 4.0

Khorana continued to open up new fields of study throughout his career. After joining the Massachusetts Institute of Technology in 1970, he synthesized the first completely artificial gene and then incorporated it into a living organism, providing the first demonstration of synthetic biology. This proof of principle has led to many applications, including the engineering of microbes to clean up oil spills, gene therapy, and synthetic genomes. He also contributed to the then nascent field of signal transduction and helped understand how vision works.

In keeping with Loewi’s motto, Khorana has always been modest except in his goals. Or, as he once said, “I’m always working on big problems.”

Deepika Calidas is a biochemist. Her last position was as a postdoctoral fellow at the Johns Hopkins School of Medicine.

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