Obituary: Alfred Hershey

Alfred Hershey and his friends Max Delbruck and Salvatore Luria shared the 1969 Nobel Prize for Physiology or Medicine for their pioneering research in the 1940s and early 1950s which established bacterial viruses (or phage) as a powerful experimental system to explore the molecular basis of life.

These three were the founder members of the "phage school" and played quite different roles in this rather nebulous movement. Delbruck was its guru and driving force, Luria the ideas man, while Hershey was the consummate professional, whose work combined acute scientific insight with innovatory experimental skill.

Hershey was born in Michigan, in 1908, received his degrees at Michigan State University, and served on the faculty of the Bacteriology Department of the Washington University Medical School in St Louis from 1934 to 1950. He then joined the staff of the Carnegie Institution of Washington in its Genetics Research Unit located in the old whaling port of Cold Spring Harbour, lying about 30 miles from New York on the north shore of Long Island. He was to spend the rest of his life there, becoming Director of the unit in 1962 until his retirement in 1974, and then continuing to live there with his wife Jill in a house just above the Cold Spring Harbour laboratories.

There is a particular experiment of Hershey's that will go down as one of the seminal biological contributions of this century. This is the so- called Hershey-Chase experiment (Martha Chase was Hershey's research assistant at the time), which was instrumental in convincing the scientific community that genes were made of nucleic acid.

As late as 1952 there was still a fierce debate going on as to whether it was a protein or nucleic acid component of living organisms which constituted the genetic material. Hershey considered that the phage system was an ideal one with which to study this question and he and Chase began a study of the contributions of the protein and nucleic acid components of phage particles to phage heredity. In order independently to follow the fate of these two components during phage infection they labelled the proteins with radioactive sulphur and the nucleic acids (in this case DNA) with radioactive phosphorus.

The doubly labelled phages were then allowed to absorb and infect sensitive bacterial cells. A short time later the culture was vigorously mixed using a high-speed blender. After a short centrifugation this blended culture was separated into two parts, the infected cells and the supernatant liquid, and radioactive assays performed on each.

The results of these assays showed that 80 per cent of the phage proteins were sheared from the bacterial cell surfaces and found in the supernatant liquid, while 80 per cent of the phage DNA remained associated with the infected cells, which despite the blending were still able to go on and produce new phage progeny.

Hershey and Chase suggested that the most plausible interpretation of these results was that the role of the phage proteins was to encapsulate and protect the phage DNA, to mediate the attachment of the phage to sensitive bacteria, and to act rather like a syringe that squirts the DNA into the host cells. On the other hand, the DNA was the material of heredity and determined the growth characteristics of the infected cells as well as the genetic make-up of the progeny phage.

The results of this experiment were published in 1952, and the paper was enormously influential in convincing biologists that nucleic acid and not protein comprised the genetic material, and in a remarkably short time this became the accepted belief.

In retrospect it seems surprising that the conclusions of the paper were accepted so readily, as the results showed that 20 per cent of the phage protein did stay with the infected cells after blending and could have crucially influenced the infective process. While reflecting on this experiment some years after he had retired, Hershey acknowledged that he had been surprised by the short time it took for the conclusions of the paper to be accepted. "I wasn't too impressed by the results myself," he said. "But of course the reason for its final acceptance was the beautiful structure of DNA that came up soon after this time, in 1953, which made DNA so irresistible intellectually, whatever the facts might be."

Nothing Hershey worked on either before or after 1952 matched the impact of the blender experiment, but throughout his career he broke new ground in a great variety of disciplines. He initiated "suicide experiments", whereby the lethal effects of radioactive decay occurring in different parts of a micro-organism could be studied. He also performed some of the earliest experiments which demonstrated that genetic recombination could take place during intracellular phage growth, a result which was the forerunner of much of the genetic engineerlng that goes on today.

Then, following the blender experiment, he went on to demonstrate that viral growth occurs in two stages; the first being the replication of the nucleic acid and the synthesis of capsid proteins, and the second being their assembly into mature viruses. And in the later years he became a DNA physical chemist, examining the biophysical properties of phage DNA and showing that the molecules of heredity were long polymers of definite size; and he developed new ways of measuring the molecular weights of these long molecules and treating them in controlled ways so as to fractionate the pieces.

In between all this he found time to edit the highly influential book The Bacteriophage Lambda (1971) and for a time even flirted with theoretical studies on the population biology of recombining phage particles.

An intriguing aspect of Al Hershey's research is that it was often in fields in which he had no experience or training. As he admitted, he was a born dilettante. When he was well into his seventies I taped a conversation with him in which he was reminiscing about his career, and in answer to a query as to what aspects had given him most satisfaction he thought for a while and replied: "I can't distinguish too much.

"Of course I was very excited by the blender experiment because I realised that other people were going to be excited by it. But as far as my own private interests were concerned I always liked what I was doing. Of course there are depressing periods when nothing appears to be happening. But whenever anything was happening, and even when nothing was happening, it was fun just to do phage experiments.

"Later when I began playing around at being a physical chemist I enjoyed very much doing work on the structure of DNA molecules, something which I would never have dreamed of doing before I started. But that's the nice thing about doing research. Whatever you do is novel, so you always have this sense of novelty even if you are only using a new gadget. That's nothing to be proud of, but it's fun. And if you get some results with a new gadget, then it's doubly fun."

That's a joyous postscript to a research career.

Hershey clearly enjoyed doing his own experiments and, although colleagues did spend time working in his laboratory, and he collaborated with them and with friends at other locations, he was never the centre of a large research group. His wide influence came partly as a result of his published research, but also through the many review articles he wrote over the years. These were classics of their kind with their mixture of critical assessment, insight and wit, and were a great source of education and enlightenment to generations of molecular biologists.

Scientific conferences didn't much appeal to him, and he attended very few. Also he didn't enjoy travelling. I think the only time he left America, apart from attending the Nobel celebrations in Stockholm, was a visit to one of the early phage meetings held just outside Paris in 1952. After the meeting he and Jill spent some weeks touring around Europe, but he never felt inclined to repeat the exercise.

Outside the laboratory his main relaxation was sailing. He owned a day- boat moored at Cold Spring Harbour, which he and Jill sailed exuberantly in Long Island Bound, as many of their friends can testify. Also for many years he and Jill kept a sailing cruiser on the great lakes in North America where, sometimes accompanied by their son, Peter, they would spend a month each summer leisurely exploring the waterways, and where he would unwind before returning to the scientific scene.

After retirement Hershey gave up any direct involvement with research. His enthusiasms turned in other directions, particularly to classical music, which became more and more of a comfort as he grew older. Friends continued to visit him, and he was happy to talk about contemporary scientific questions, but his interests were elsewhere.

He would however still sometimes appear at the garden parties which are a feature of the summer conferences at Cold Spring Harbour. Those old enough to know him would go up and pay their respects, and maybe share a joke and a beer, while the younger scientists would be told that the spare and frail figure on the lawn was the mythical Hershey. He was one of the last survivors of a different scientific era.

Hershey was elected to the National Academy of Sciences in 1958 and to the American Academy of Art and Sciences in 1959, and during his career received many scientific honours in addition to his Nobel Prize.

Neville Symonds

Alfred Day Hershey, biochemist: born Oswosso, Michigan 4 December 1908; Assistant Bacteriologist, Washington University School of Medicine, St Louis, Missouri 1934-36, Instructor 1936-38, Assistant Professor 1938- 42, Associate Professor 1942-50; staff, Genetics Research Unit (Department of Genetics), Carnegie Institution of Washington 1950-97, Director 1962- 74; Nobel Prize for Physiology or Medicine (with Max Delbruck and Salvatore Loria) 1969; married 1945 Jill Davidson (one son); died Syosset, New York 22 May 1997.