Har Gobind Khorana did not know when he was born. “The correct date of my birth is not known,” he wrote in 1968, continuing: “that [the date] shown on documents is January 9, 1922.” We do not know where that date came from. Though the family owned some ancestral land, his parents were poor, and Indians of that era and from that economic background rarely kept exact records of births or other such events. Not unexpectedly, no childhood photograph of Khorana is known to exist, and the few stories that are known about his childhood may well be apocryphal rather than a record of facts.

Khorana was born in Raipur, then a village of about a hundred people near the ancient city of Multan in Punjab in what is now Pakistan. The village was near what is now Kabirwala; otherwise, it has disappeared from maps though there are people still living in the area. None of Khorana's family remains there today. During the time of India's Partition in 1947 and the violent chaos that followed, they had all migrated to India, initially mainly to Delhi. Other than being Khorana's birthplace, nothing of significance has been recorded of Raipur.

According to his grandnephew, Alok Khorana: “family lore speaks of a mischievous child who liked to steal sugarcane from the sugarcane fields. Gobind described our ancestral home as consisting of a kitchen and bedrooms in one corner, with a courtyard housing cows and horses on the opposite end.” The family is believed to have owned that ancestral home for centuries. As far as can be told, the ancestral home does not survive. The family lost all their landed property during Partition as was typical for Hindus and Sikhs who fled Pakistan and Muslims who fled India.

Gobind's father, Ganpat Rai Khorana, was a patwari, that is, a village agricultural taxation clerk at the lowest level of the administrative system of British-ruled India. We know little about Ganpat Rai, except that he insisted on educating all his children. Khorana later recalled: “Although poor, my father was dedicated to educating his children and we were practically the only literate family in the village.”

On the evening of December 10, 1968, on the seventy-second anniversary of Alfred Nobel's death, a slightly built Indian American man, only 44 years old, stood before King Gustaf Adolf of Sweden on a stage in the Konserthuset Stockholm (the Stockholm Concert Hall). By the king's side were Princess Christina and Prince Bertil of Sweden. The slightly built man was Har Gobind Khorana, and he was there to receive his share of the Nobel Prize in Physiology or Medicine. Accompanying him was his Swiss-born wife, Esther Elizabeth.

The Prize ceremony was followed by a formal banquet with about 1,300 guests. The menu included lobster and avocados as a starter, lamb with creamed mushrooms as the main course, and pineapple ice cream and cake for dessert. To drink, they had a choice of Pommery & Greno Brut or Château d’Yquem 1962. Afterward the Khoranas sipped Courvoisier. It was a joyous occasion.

In 1968, as today, the Nobel Prize was the greatest honor that a scientist can receive. Khorana received his prize for his role in solving the most important problem of molecular biology of his era: the nature of the genetic code. By the mid-1950s it had become clear that a string of four DNA nucleotides (adenosine [A], cytosine [C], guanine [G], and thymine [T]) in genes determined, by the order of their occurrence, the string of amino acid residues in protein molecules that carried out most of life's activities. These amino acid residues were of 20 types. But which sequence of DNA nucleotides specified which amino acid residues? This translation was carried out according to the genetic code. It turned out, as Khorana definitively established, that a triplet “codon” of nucleotides specified each amino acid residue. He established exactly which triplet of nucleotides specified each amino acid residue.

The problem of the genetic code had moved to the center of attention in molecular biology in the late 1950s, shortly after Francis Crick and James D. Watson established that DNA had the structure of a double helix with nucleotides strung along the two backbones that faced each other along the central core of the double helix.

If 1979 had been a year of transcendental success because Khorana had finally succeeded in creating a synthetic gene that could function within a cell, it followed a year that had brought him great personal sorrow. His younger daughter, Emily Anne, succumbed to leukemia on July 12, 1978, after a protracted illness. She was 23 years old and her mortal remains were interred at Henniker Cemetery in Henniker, New Hampshire, where the Khoranas had bought a cabin.

The family was devastated, though they knew Emily's death was coming. Friends mourned with them across the world. In Liverpool, Gobind's old mentor, Roger Beer found it sadly ironic that Khorana, who had done so much to reveal the secrets of life, had been helpless when cancer attacked his young daughter. He could well have asked: What was the point of all this biological research?

Emily's death dominated 1978, but was not the only tragedy that year. On June 26, 1978, George Kenner, who had had a history of depression, died by suicide. After teaching at Cambridge for a number of years, he had moved to the University of Liverpool in 1957, where he became Heath Harrison Professor of Organic Chemistry and, after 1976, Royal Society Professor. When the Khoranas visited Beer at Liverpool over the years, they had also kept up with George and his wife, Jill. While Kenner had had a superb research career studying protein synthesis, eventually he succumbed to his depression and took his own life in a remote area in the hills of Wales where he loved to hike.

Following Kenner's death, the University of Liverpool Department of Chemistry instituted the George Kenner Prize and Lectures. The first of these lectures was held on October 28, 1980. Todd introduced the lecturer who, appropriately, was Khorana, speaking on the final complete synthesis of a functional gene (“Synthesis in the study of biological function of nucleic acids”). Todd also presented Khorana with an engraved bowl designed by Denis Mann of Caithness Glass, a well-known glass artist (see Figure 8.1). Khorana stayed with the Beers as usual. It must have been a bittersweet reunion: Kenner had been a friend to all of them.

The Nobel Prize brought Khorana fame, but it also brought even higher expectations. Though he may not have minded the fanfare, psychologically, all the attention took its toll. A short time after returning to Madison from Stockholm, he suddenly disappeared from his laboratory apparently in a state of mental exhaustion, possibly depression. For several months he was unavailable. Laboratory members tracked him to Vancouver, where he was recuperating, but showed little interest in an immediate return. Friends said that he sat by the water for hours every day staring into the distance. But, soon, a crisis emerged within the laboratory as a dispute burst open between two factions that refused to work together. RajBhandary duly reported the problem to Khorana and it finally had the effect of making him return to establish peace. The laboratory could start functioning again.

Laboratory members also recall that wherever Khorana went—and he gave many seminars in the late 1960s—he was repeatedly asked whether he had finished synthesizing a gene. Was it done yet? When would it be done? He must have felt immense pressure though, after that initial retreat to Vancouver, it would not manifest itself publicly.

He had brought the pressure on himself. In the early 1960s, when not even the sequence of a single gene was known, he had announced his goal of the total synthesis of a functional gene. He was always explicit that the drive to decipher the genetic code was a mere detour from that pursuit even though it had brought him fame and a share of a Nobel Prize. Synthesizing the gene was a much more challenging—and, therefore, intellectually satisfying—problem:

On August 15, 1947, India gained independence from the British who left it almost bankrupt after centuries of colonial plunder, most recently to finance its war against Germany and the Axis powers. The following spring, Khorana completed his Ph.D. at the University of Liverpool. The terms of his scholarship, because it had been funded by the Government of India, required him to return to India. But Khorana did not want to return, at least not immediately. He wanted a year's postdoctoral stay in Europe. Ostensibly, this wish was motivated by a desire to learn German well enough to navigate effortlessly the vast German scientific literature on organic chemistry. He later claimed: “I wanted very much to spend a period of time in a laboratory in a German-speaking region of Europe.”

In the chaos in continental Europe that followed World War II, laboratories in Germany or Austria were not viable options. That only left Switzerland as a possible destination in German-speaking regions. It is probably not a coincidence that this was where Esther lived. In fact, there is ample reason to believe that learning German alone does not explain Khorana's preference for Switzerland over India in 1948. It was mostly an excuse or, at best, a rationalization.

The Eidgenössische Technische Hochschule in Zürich

As his intended destination, Khorana chose the Eidgenössische Technische Hochschule (ETH) in Zürich which, as he later correctly noted, had “had a great tradition in organic chemistry.” He then applied for a year's funding from the new Government of India but, given its dire financial straits, he was not surprised when the application was turned down. However, according to him:

In the early 1970s, even as the functional tyrosine suppressor tRNA gene was being synthesized in his laboratory, Khorana began seriously considering moving on from DNA. He was not alone among prominent researchers in molecular biology—we must remember that he did not call himself a molecular biologist—looking for research pastures beyond DNA, areas in which it was likely that there still was low-hung fruit to gather. Crick moved on to study consciousness. Nirenberg also moved on to neurobiology, to the study of neuroblastomas (tumors in the nervous system), a field to which he eventually made important contributions.

Khorana was also attracted by the prospect of a molecular neurobiology. That he chose to focus on membrane proteins seems to have been partly due to the influence of Efraim Racker, an Austrian-born biochemist, whose laboratory he visited at Cornell University in 1973. He set up a collaboration with Racker, which began with rather modest expectations. As he explained later:

That Khorana should turn his attention to membranes in the context of the early 1970s is not very surprising. They were becoming fashionable for a variety of reasons.

Most importantly, membranes surrounded all living cells. They seemed to be the locus of many physiological activities including energy production. Protein molecules within them were implicated in signal transduction.

Settled in Madison, Khorana began to expand his laboratory and start new projects. Two of the young scientists who joined the laboratory in 1962 were Uttam RajBhandary and Dieter Söll. RajBhandary, who became a lifelong friend and eventually also moved to MIT in concert with Khorana, came from Nepal where he was born in the Kathmandu valley. He received a B.Sc. in 1952 from the University of Patna in India and an M.Sc. from Presidency College, Calcutta (now Kolkata), also in India. Subsequently, he earned his Ph.D. from the University of Durham (in a unit that is now part of Newcastle University) under the supervision of Professor (later Sir) James Baddiley, who had been a graduate student with Todd at Cambridge and had been the first person to synthesize ATP artificially (though the reaction was more complex than the one-step procedure that Khorana later devised in Vancouver).

RajBhandary's thesis project had been the synthesis of Coenzyme A but, in 1961, Moffatt and Khorana had beaten him to that goal. Disappointed, RajBhandary went back to Nepal for six weeks to take stock of the situation. Returning to Durham, he completed a thesis in 1962 on the chemistry of molecules that form part of bacterial cell membranes. Khorana had known Baddiley from his time at Cambridge and had asked for his help in expanding his laboratory. Baddiley had recommended RajBhandary and the latter joined Khorana's laboratory as Senior Project Associate.

Khorana had handed RajBhandary his laboratory notebooks with the records of exploratory experiments on what was then called soluble RNA but was about to be recognized as transfer RNA (tRNA) which played a cen-tral role in the synthesis of proteins in the cell. These became the focus of RajBhandary's research during a long and productive career, even though Robert Holley at Cornell University beat him to the goal of first sequencing a tRNA molecule in 1965. (Sequencing the tRNA molecule earned Holley a share of the 1968 Nobel Prize in Physiology or Medicine along with Khorana and Marshall Nirenberg, whose work will be discussed at some length below.)

“Total synthesis,” explains the Introduction of Classics in Total Synthesis, “is the chemical synthesis of a molecule, usually a natural product, from relatively simple starting materials and is to be distinguished from partial synthesis or semisynthesis which designates the synthesis of a given molecule from an advanced precursor related to it, which may or may not be a natural product itself.” Total synthesis marks the complete chemical mastery of a complex molecule; if the molecule is of biological provenance, it shows how chemistry can take over the process of creating it. The biological molecule can now be synthesized in the laboratory, then redesigned to fit new functions as needed, and dealt in the same way as chemists deal with inorganic matter.

The modern history of total synthesis begins in the early nineteenth century with the synthesis of urea by Friedrich Wöhler in 1828. It was the first synthesis of an organic substance using only inorganic reagents. The synthesis of acetic acid in 1845 and glucose in 1890 were other nineteenth-century milestones. Throughout the latter half of that century, almost all organic chemists tried their hand at total synthesis, typically of dyes and small organic molecules of biological provenance and economic interest.

In the twentieth century, total synthesis became a Holy Grail of organic chemistry with attempts directed at increasingly complex molecules including organic substances. Toward the end of the twentieth century, the editors of Classics in Total Synthesis estimated that more than 20 Nobel Prizes were earned through this enterprise. The list of recipients reads like a Who's Who of chemistry, including Emil Fischer (1902), Adolf von Baeyer (1905), Otto Wallach (1910), Hans Fischer (1930), Leopold Ruz̆ic̆ka (1939), Robert Robinson (1947), Alexander Todd (1957), Vladimir Prelog (1975), and Elias J. Corey (1990), among many others besides Har Gobind Khorana (1968).

Khorana was unique among organic chemists because he directed his whole research focus on total syntheses of biologically salient macromolecules of increasing complexity ending with the synthesis of a complete functional gene in 1979. In the process, he perfected methodologies that were widely recognized as major technical breakthroughs in organic chemistry and in the emerging discipline of molecular biology.