The Oxford-AstraZeneca vaccine against Covid-19 was built on the principle of stitching together DNA from two viruses, one to enable the vaccine to enter cells and the other to provoke an immune response.
In 1972 Paul Berg, who has died aged 96, became the first person to combine the DNA of two organisms in this way. Recombinant DNA has become a fundamental tool of biomedical research and drug discovery, making it possible to grow drugs such as human insulin in bacteria as well as to develop tailor-made vaccines.
For his discovery Berg shared the Nobel prize for chemistry in 1980 with Fred Sanger and Walter Gilbert, who independently discovered methods of sequencing DNA.
The announcement of Berg’s successful experiment, which spliced DNA from the common gut bacterium Escherichia coli (E coli) with the DNA of a monkey tumour virus, raised alarm both inside and outside the scientific community. Berg’s goal was to use the technology to study the way mammalian cells produced proteins. A first step would be to infect E coli with the modified virus. But what if such cloned viruses escaped and infected people?
While excited by the possibility of the new research, Berg conceded, as he later wrote in the journal Nature, that “unfettered pursuit of these goals might have unforeseen and damaging consequences for human health and Earth’s ecosystems.” He immediately paused his research programme.
Berg chaired a committee of the US National Academy of Sciences that issued the “Berg letter”, published in three leading scientific journals in July 1974. The letter called for a worldwide, voluntary moratorium on any recombinant research involving antibiotic resistance genes, bacterial toxins or cancer viruses “until attempts have been made to evaluate the hazards”.
It also called for an international meeting to reach agreement on these issues. Berg was among a group of senior scientists who took the lead in organising the conference, open to social scientists and journalists as well as scientists, held at Asilomar in California in February 1975.
Over days of heated debate, the participants thrashed out an agreement to lift the moratorium and replace it with a set of guidelines that tailored what was permitted to the level of perceived risk.
The outcome was significant in demonstrating that the scientific community could regulate itself without the need for government intervention.
The controversy rumbled on for some years: in the late 1970s Berg travelled the length and breadth of the US, meeting councils and university boards to try to talk them out of banning recombinant DNA research.
A decade later he exercised his skills as a scientific diplomat in the equally heated discussions around the launch of the project to sequence the entire human genome. A back-of-the-envelope calculation had suggested that it might cost $3bn.
Many scientists feared that such a “space shuttle” enterprise could suck funding away from individual, curiosity-driven projects. Though not personally involved in the sequencing effort, within a year Berg had helped to move the question from “Should we do this?” to “How should we do this?” Today a complete human genome can be sequenced in hours for a few hundred dollars.
Berg was born in New York, the son of first-generation immigrants from what is now Belarus. Harry Bergsaltz, who made fur trim for clothing, and his wife, Sarah (nee Brodsky), settled in Brooklyn. Paul was the first of three boys born there, an older child having died. In his Nobel autobiography he credited Sophie Wolfe, the lab technician at Abraham Lincoln high school in the Brighton Beach area of Brooklyn, with firing his passion for discovery.
She ran a popular after-school biology club. “She never gave you any answers,” he later said. “She would come back with a leading question that would perhaps help you go find out on your own.” Two others who attended the school in the same decade also won Nobel prizes: Berg’s mentor and colleague Arthur Kornberg, and the crystallographer Jerome Karle.
Berg’s university education was interrupted by three years of wartime service in the US navy, but in 1948 he graduated from Penn State University in biochemistry. He then did a PhD on the way vitamins support the action of metabolic enzymes at Western (now Case Western) Reserve University in Cleveland, Ohio.
His subsequent research with Kornberg at Washington University in St Louis led him, almost by accident, to discover the enzymes that link amino acids to adaptor molecules known as transfer RNAs, which in turn build the amino acids into proteins following a messenger RNA template. As a result, he became “increasingly preoccupied with how genes act and how proteins are made”.
In 1959 he moved with Kornberg to establish a new biochemistry department at Stanford University in California, which he chaired from 1969 to 1974. There his team carried out his Nobel prizewinning work. Using enzymes to snip open the circular DNA molecules of E coli and the monkey virus SV40, they engineered them so that the complementary “sticky ends” reformed a circular DNA molecule including E coli genes.
Berg continued to run his lab at Stanford for 20 years after winning his Nobel prize, directing its Beckman Center for Molecular and Genetic Medicine from 1985 until his retirement in 2000. Initially he resisted any involvement with commercial companies. But in 1980 he agreed to co-found the DNAX biotechnology research institute, later acquired by the life sciences company Schering-Plough. Researchers at the institute went on to use technology developed in Berg’s laboratory to produce antibodies and other immune system molecules.
Even after retirement he continued to visit his department at Stanford and his thoughtful, liberal, collegial approach inspired each new generation of scientists. He was cultured and gregarious, enjoying sport, art, music and good food, especially with his family.
In 1947 Berg married Mildred Levy, a nurse, amateur musician and supporter of nature conservation, and they had a son, John.
Mildred died in 2021. Berg is survived by John, and by his younger brother Jack.
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