Bioscience Ethics at 50: Asilomar and the beginning of genetic engineering

In 1973 the Gordon Conference on Nucleic Acids took place at New Hampton, Hampshire, where advances in recombinant DNA technology were discussed.

One researcher, Paul Berg (who went on to a very distinguished career and died only recently) was working with SV40, a cancer-producing simian virus (as an aside, SV40 had been accidentally injected into many polio vaccine recipients in the 1950-1960s).  Berg pioneered using restriction enzymes to cut DNA loops and then using other enzymes to rejoin them, creating new combinations of genetic material. Others at the same time were working on similar “recombinant” technology.

Here’s a video of Berg discussing his work and his belief that a “moratorium” of this technology should be called. Partial transcript of the video:

The point was that we were going to be propagating SV40 genes in E. coli. The concern was that E. coli is a natural inhabitant in humans, and the worry was whether we could inadvertently infect humans with the E. coli we were propagating, potentially leading to cancer. This concern sparked intense debate. Depending on where you stood on the issue, you were either vociferous about it or dismissive, saying, "Forget about it. It's not serious."

After many conversations, I became convinced that I could not dismiss the risk and make it zero likelihood. So, I decided to put the whole thing on the shelf, and for a while, the issue died down.

About a year later, Janet Mertz, a graduate student in my lab, discovered that EcoRI made cohesive ends. She found that she could take any two DNAs and join them together. This breakthrough allowed Stan Cohen and Herb Boyer to begin making recombinants using E. coli plasmids, checking for drug resistance, and showing they could create chimeric DNA molecules.

They presented their work at a Gordon Conference, which sparked a similar reaction among a small minority of the audience. Some expressed alarm, saying, "Oh my God, you guys could really make some dangerous things." At that conference, Maxine Singer and Dieter Soll, the co-chairs, were persuaded to draft a letter to the academy, published in Science. The letter highlighted the great promise of being able to create new kinds of DNA molecules while also addressing the possible dangers and risks.

When the president of the academy received the letter, he asked, "What do I do with it?" Maxine suggested, "Call Paul Berg, because he's thought about this problem."

The papers presented at the 1973 Gordon Conference alarmed the proto-molecular biologist conferees, who voted to send a letter to Philip Handler, President of the National Academy of Sciences, about the possible consequences of the new technology. The letter read:

Guidelines for DNA Hybrid Molecules

Those in attendance at the 1973 Gordon Conference on Nucleic Acids voted to send the following letter to Philip Handler, president of the National Academy of Sciences, and to John R. Hogness, president of the National Institute of Medicine. A majority also desired to publicize the letter more widely.

We are writing to you, on behalf of a number of scientists, to communicate a matter of deep concern. Several of the reports presented at this year's Gordon Research Conference on Nucleic Acids (June 11—15, 1973, New Hampton. New Hampshire) indicated that we presently have the technical ability to join together, covalently, DNA molecules from diverse sources. Scientific developments over the past two years make it both reasonable and convenient to generate overlapping sequence homologies at the termini of different DNA molecules. The sequence homologies can then be used to combine the molecules by Watson-Crick hydrogen bonding. Application of existing methods permits subsequent covalent linkage of such molecules. This technique could be used, for example, to combine DNA from animal viruses with bacterial DNA, or DNA's of different viral origin might be joined. In this way new kinds of hybrid plasmids or viruses, with biological activity of unpredictable nature, may eventually be created. These experiments offer exciting and interesting potential both for advancing knowledge of fundamental biological processes and for alleviation of human health problems.

Certain such hybrid molecules may prove hazardous to laboratory workers and to the public. Although no hazard has yet been established, prudence suggests that the potential hazard be seriously considered. A majority of those attending the Conference voted to communicate their concern in this matter to you and to the President of the Institute of Medicine (to whom this letter is also being sent). The conferees suggested that the Academies establish a study committee to consider this problem and to recommend specific actions or guidelines, should that seem appropriate. Related problems such as the risks involved in current large-scale preparation of animal viruses might also be considered.

(signed) MAXINE SINGER  DIETER SOLL

From this initial burst of activity, scientists reached a consensus that the as-yet unnamed science of Genetic Engineering should be put under a moratorium. Experiments were to cease until the ramifications could be discussed and amelioration put into place.

The conference meeting was held at Asilomar, in Southern California, in February 1975. The outcome was a set of guidelines for handling recombinant DNA, physically (biological containment facilities) and experimentally (using only hosts that would die outside a laboratory). 

That was 50 years ago.

I wasn’t a “Genetic Engineer” in those days. I’m old, but not that old. I learned about the conference in 1979, as I studied genetics for my degree. 

The burgeoning field of genetics had a vertical take off between the first “restriction enzymes” in the early seventies and the routine gene engineering of the 21^st Century. In fact, the modern understanding of heredity is less than two hundred years old: The understanding that for all sexually reproducing species – plant or animal - two parents provide heritable material to an embryo, which can then pass down half its own heritable material to its offspring.

A brief timeline:

1. Mendel's experiments showing that various plant characteristics were not “blends” of their parents’ characteristics: 1865

2. The concept of evolution set down in writing by Darwin. The Descent of Man published on February 24, 1871

3. Mendel’s experiments verified (and rediscovered) by Hugo de Vries, Carl Erich Correns and von Seysenegg, 1900

4. Proof of DNA's role in heredity:  The Hershey-Chase experiment, which demonstrated that DNA, not protein, was the genetic material, 1952

5. Discovery of DNA structure: The double helix structure of DNA was identified by James Watson and Francis Crick in mid-March 1953, with their paper published on April 25, 1953

6. Experiments showing DNA replication: The Meselson-Stahl experiment providing experimental proof of DNA's semiconservative replication: 1958

7. The first paper describing a restriction enzyme published by Hamilton O. Smith, Thomas Kelly, and Kent Wilcox. The isolation and characterization of the type II restriction enzyme Hind II from Haemophilus influenzae: 1970

8. The Human Genome Project:

• Started in 1990

• Declared complete on April 14, 2003 (covering about 92% of the genome)

• "Complete genome" level achieved in May 2021

• Final gapless assembly finished in January 2022

Recombinant technology has moved on at a tremendous rate since the seventies. Several other conferences have been held including this year at the "Spirit of Asilomar and the Future of Biotechnology" conference in February 2025, and work continues.

The Asilomar conference marked the first significant time that researchers stopped and thought, “Just because I can, it doesn’t mean I should.” Scientific Ethics have been in the news again and again after 1975 and there are very good reasons for that.

Another thing that has been in the news over the past few years, as well: the possibility of “lab leaks.”

What did people in 1974 know about lab leaks?

“This [genetic manipulation] would call for technical re-education of the average microbial geneticist or molecular biologist, whose manipulation of bacteria chills the blood of anyone accustomed to handling pathogens.”

Thank you, Professor E. S. Anderson of Colindale. [Nature (250(5464), 278–280. doi:10.1038/250278b0]

For background, reading, please see Paul Berg's video and/or my earlier posts on Asilomar,

https://peromyscus.blogspot.com/2013/06/genetics-library-project-political.html

https://peromyscus.blogspot.com/2015/03/genetic-engineering-birds-do-it-bees-do.html