The Oxford-AstraZeneca vaccine against Covid-19 is based on the principle of merging DNA from two viruses, one of which allows the vaccine to enter cells and the other elicits an immune response.
In 1972, Paul Berg, who died at the age of 96, became the first person to combine the DNA of two organisms in this way. Recombinant DNA has become a fundamental tool in biomedical research and drug discovery, allowing drugs such as human insulin to be grown in bacteria and tailored vaccines to be developed.
For his discovery, Berg shared the 1980 Nobel Prize in Chemistry with Fred Sanger and Walter Gilbert, who independently discovered methods for DNA sequencing.
The announcement of Berg’s successful experiment splicing DNA from the common gut bacterium Escherichia coli (E. coli) with DNA from a monkey tumor virus caused alarm within and outside the scientific community. Berg’s goal was to use the technology to study how mammalian cells produce proteins. A first step would be to infect E. coli with the modified virus. But what if such cloned viruses escape and infect humans?
While excited by the possibility of the new research, Berg acknowledged, as he later wrote in the journal Nature, that “full pursuit of these goals could have unforeseen and detrimental consequences for human health and the Earth’s ecosystems.” He immediately interrupted his research program.
Berg chaired a committee of the US National Academy of Sciences that edited the “Berg Brief,” which was published in July 1974 in three leading scientific journals on cancer viruses “until attempts were made to assess the dangers.”
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 organizing the conference, open to social scientists and journalists as well as academics, held in February 1975 in Asilomar, California.
After days of heated debate, participants agreed to lift the moratorium and replace it with a set of policies that balanced what was allowed with the perceived risk.
The result was significant as it showed that the scientific community could regulate itself without the need for government intervention.
The controversy raged for several more years: in the late 1970s, Berg traveled the length and breadth of the United States, meeting with councils and university councils to try to persuade them to ban recombinant DNA research.
A decade later, he was proving his skills as a scientific diplomat in the equally heated discussions surrounding the launch of the whole human genome sequencing project. A back-cover calculation had suggested it could cost $3 billion.
Many scientists feared that such a “space shuttle” venture could siphon off funding from individual curiosity-driven projects. Although Berg was not personally involved in the sequencing, within a year he had helped shift the question, “Should we do this?” to “How should we do that?” Today, an entire human genome can be sequenced in hours for a few hundred dollars.
Berg was born in New York to first-generation immigrants from what is now Belarus. Harry Bergsaltz, who made fur trimmings for clothing, and his wife Sarah (née Brodsky) settled in Brooklyn. Paul was the first of three boys born there, an older child had died. In his Nobel autobiography, he credited Sophie Wolfe, the lab technician at Abraham Lincoln High School in the Brighton Beach neighborhood of Brooklyn, with sparking his passion for discovery.
She ran a popular after-school biology club. “She never gave you answers,” he later said. “She would come back with a guiding question that might help you figure it out for yourself.” Two others who attended the school in the same decade also won Nobel Prizes: Berg’s mentor and colleague Arthur Kornberg and crystalgrapher Jerome Karle.
Berg’s university education was interrupted by three years of military service in the US Navy, but in 1948 he graduated from Penn State University with a degree in biochemistry. He then earned his PhD from Western (now Case Western) Reserve University in Cleveland, Ohio, on how vitamins support the action of metabolic enzymes.
His subsequent research with Kornberg at Washington University in St. Louis, almost by accident, led him to the discovery of the enzymes that connect amino acids to adapter molecules called transfer RNAs, which in turn assemble the amino acids into proteins based on a messenger RNA template. As a result, he became “increasingly concerned with how genes work and how proteins are made.”
In 1959 he moved in with Kornberg to establish a new biochemistry department at Stanford University in California, which he headed from 1969 to 1974. It was there that his team carried out their Nobel Prize-winning work. Using enzymes to cut open the circular DNA molecules of E. coli and the simian virus SV40, they engineered them so that the complementary “sticky ends” regenerated a circular DNA molecule including E. coli genes.
Berg continued his lab at Stanford for 20 years after receiving his Nobel Prize, directing the Beckman Center for Molecular and Genetic Medicine from 1985 until his retirement in 2000. Initially he opposed any involvement in commercial ventures. But in 1980 he agreed to co-found the biotechnology research institute DNAX, which was later acquired by the life sciences firm Schering-Plough. The institute’s researchers used the technology developed in Berg’s laboratory to produce antibodies and other molecules of the immune system.
After his retirement, he continued to attend his department at Stanford, and his thoughtful, liberal, and collegial approach inspired every new generation of scientists. Cultured and sociable, he enjoyed sports, art, music and good food, especially with his family.
In 1947 Berg married Mildred Levy, a nurse, amateur musician and conservationist, and they had a son, John.
Mildred died in 2021. Berg is survived by John and his younger brother Jack.
• Paul Berg, biochemist, born June 30, 1926; died February 15, 2023