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Wednesday, March 14, 2007

Nobel Laureate: Paul Berg

The Nobel Prize in Chemistry 1980.

"for his fundamental studies of the biochemistry of nucleic acids, with particular regard to recombinant-DNA"

Paul Berg won the Nobel Prize in 1980 for his work on developing recombinant DNA technology. This is the only Nobel Prize that has been awarded for that achievement.

Berg is credited with creating the first recombinant DNA molecule back in 1972 (Jackson et al. 1972). He combined a fragment of a bacterial plasmid with a piece of DNA from a simian virus (SV40). The goal was to understand the structure and organization of the small SV40 virus—the main focus of research in Berg's laboratory. Berg was hoping to create a recombinant DNA vector that would introduce foreign DNA into mammalian cells where it could be expressed. Here's part of the original press release ...
Berg was the first investigator to construct a recombinant-DNA molecule, i.e. a molecule containing parts of DNA from different species, e.g. a chromosome from a virus combined which genes from a bacterial chromosome. His pioneering experiment has resulted in the development of a new technology, often called genetic engineering or gene manipulation, which has already had important practical applications, e.g. the manufacture of human hormone with the aid of bacteria. Berg performed his experiment, however, as part of an incisive analysis of the chromosome of an ape virus (called SV 40) Viruses contain DNA (or sometimes RNA, another nucleic acid). They cause disease by introducing foreign genetic information in a cell and in this way disturbing its chemical machinery. As DNA molecules from viruses are relatively small, they are excellent objects of investigation for the study of the relationship between the chemical structure and biological function of DNA.
Following the creation of the first recombinant DNA molecule—but after a lag of a few years—Paul Berg was successful in his attempt to construct mammalian cloning vectors. His lab was the first to express a cloned foreign gene in mammalian cells. In this case it was the recently cloned rabbit β-globin gene.

The original recombinant DNA molecule constructed in 1972 was not immediately propagated in living cells out of safety concerns. At the time, it was unclear whether the cloning of a potential cancer causing virus (SV40) presented a health hazard. Berg and others voluntarily stopped research in this field until they could sort out the safety issues.

The voluntary moratorium in 1973-74 led to the famous Asilomar Conference where the issue was debated by a group of prominent scientists. This was such an important event that a 2004 article by Paul Berg on the Asilomar Conference is included in the Nobel Prize website [Asilomar and Recombinant DNA]. The result of the debate was a decision to proceed with caution and a number of safety protocols for working with recombinant DNA were put in place.

Almost all of the safety concerns proved to be exaggerated and the recombinant DNA regulations have been quietly dropped over the years. Even in 1980, when Berg received his Nobel Prize, he was able to express some frustration at how the concerns of scientiests were perceived. Nevertheless, there's a common perception among scientists that their behavior in the mid-1970's was not only ethical but highly successful. That point of view is expressed in the 2004 article ...

What did the actions taken by the scientific community achieve? First and foremost, we gained the public's trust, for it was the very scientists who were most involved in the work and had every incentive to be left free to pursue their dream that called attention to the risks inherent in the experiments they were doing. Aside from unprecedented nature of that action, the scientists' call for a temporary halt to the experiments that most concerned them and the assumption of responsibility for assessing and dealing with those risks was widely acclaimed as laudable ethical behavior. If the Asilomar exercise was a success, it was because scientists took the initiative in raising the issue rather than having it raised against them; that initiative engendered considerable credibility instead of cynical suspicion of what was to follow. The public's trust was undeniably increased by the fact that more than 10% of the participants were from the news media. They were free to describe, comment on and criticize the discussions and conclusions at the end of the conference. All the deliberations, bickering, bitter accusations, wavering views and the arrival at a consensus were widely chronicled by the reporters that attended and subsequently by the rest of the media and subsequent commentators.
While much of that may be true, it tends to ignore the consequences that we had to live with for a decade. By 1980 it was clear that recombinant DNA posed no danger but by then all the strict rules and regulations were in place and compliance was enforced by law. At that point the opinions of the experts didn't matter. The public was scared and they were determined to ignore scientific evidence in order to restrict research. We've also forgotten the serious attempts by uninformed governments to stop recombinant DNA research altogether.

The cynical point of view is that the public's trust in science declined in the 1970's because scientists were pushing ahead with highly dangerous research that could destroy the world.

So, what are the lessons of Asilomar? Here's how Berg describes it in 2004 ..
Is "the Asilomar model" appropriate for resolving or contributing to some of the "hot button" issues confronting scientists and the public today? For example, are the deep divisions about fetal tissue and embryonic stem cell research, somatic and germ-line gene therapy and directed genetic modification of food crops amenable to deliberation and resolution? I believe the Asilomar model would not succeed in dealing with those issues today to the extent it did 30 years ago with recombinant DNA for the following reasons. First, the public's awareness of the recombinant DNA breakthrough was sudden and unanticipated. It was more than just another interesting scientific advance because it brought with it potential dangers to public health. Furthermore, the implications of risk came from the scientists conducting that research, not from some investigative reporter or disaffected scientist; that was most unusual, even historic. There seemed to be an urgent need for consensus on how to proceed and a plausible plan on how to deal with issues, both of which were provided by the scientific community. Action was prompt and seen by the public to have been achieved by transparent deliberations and with considerable cost to their own scientific interests. The issue and its resolution were complete before an entrenched, intransigent and chronic opposition developed. Attempts to prohibit the research or reverse the actions recommended by the conference threatened but never generated sufficient traction to succeed.

By contrast, the issues that challenge us today are qualitatively different. They are often beset with economic self-interest and increasingly by nearly irreconcilable ethical and religious conflicts and challenges to deeply held social values. An Asilomar type conference trying to contend with such contentious views is, I believe, doomed to acrimony and policy stagnation, neither of which advances the cause of finding a solution. There are many forums for airing opposing views but emerging with an agreed upon solution from such an exercise is elusive and discouraging.

The Asilomar decisions emerged from a consensus of opposing views. Although the recommendations were clearly "inconvenient", the participants had a stake in having the science move forward and not in leaving the rules for conducting the research to be set by others. By contrast, there is little prospect for consensus in our society on the ethical issues concerning fetal tissue and embryonic stem cell research, genetic testing, somatic and germ-line gene therapy, and engineered plant and animal species and hence little incentive to seek a compromise. Compromise in those instances may only be achievable by political means, where majority rule prevails.
In other words, the lesson of Asilomar is that when politicians and the general public learn enough about an issue to start forming an opinion, the views of scientists are usually ignored or rejected. It's better to keep them ignorant until you can get some reasonable laws passed. Not a very happy lesson.
Jackson, D.A., Symons, R.H., and Berg, P. (1972) Biochemical method for inserting new genetic information into DNA of Simian Virus 40: circular SV40 DNA molecules containing lambda phage genes and the galactose operon of Escherichia coli. Proc. Natl. Acad. Sci. (USA) 69:2904-2909 [PubMed]


Torbjörn Larsson said...

Paul Berg made a cogent analysis in an issue I don't know much about.

"In other words, the lesson of Asilomar is that when politicians and the general public learn enough about an issue to start forming an opinion, the views of scientists are usually ignored or rejected. It's better to keep them ignorant until you can get some reasonable laws passed."

The immediate question becomes better for whom? At the risk of becoming trite, I think that ethical codes and committees should be a continuing effort, involving other interested parties. Perhaps it won't stop politicians interest in meddling, but it would make the cases when they circumvent experts and regular procedure stand out.

Other problems would be the conflict in the aspects of wanting to suppress information to the public and the goal of informing, or the risk for undercutting the gained trust Berg discusses. My naive feeling is that it is better not hiding the issues. The public won't be interested in the success of that approach but in discussions about risks, assumption of control and 'scandals' that follows.

I think the discussions behind the EU's chemicals regulatory system, REACH, shows why that is so. The public feels powerless against some of the interests driving regulatory issues. (And as usual a compromise was reached that didn't give long-time satisfaction to all parts, guaranteeing that the issue will return to haunt us.)

Steve LaBonne said...

The real problem with Asilomar is that people talked as though there were "issues" when in fact there weren't any. There were only purely hypothetical, far-fetched fears based on elaborate worst-case scenarios, totally unsupported by either evidence or theory (many of the molecular biologists raising the unjustified fears would have done well to talk to talk to some epidemiologists first, who would have been able to calm their nerves.) That by the way is pretty much the opinion that was forcefully articulated many times over the years by Watson, who was involved from the outset just as Berg was and who came to bitterly repent going along with the early alarmism.

If scientists would simply refrain from shooting off their mouths about imaginary "risks" that they can't back up with any evidence (while of course being open about genuine risks in which there are solid reasons to believe), then there need be no temptation to try to (wrongly) exclude appropriate public input and oversight.

Steve LaBonne said...

Back to Berg himself- when I was a grad student at Northwestern back in the late 70s, Berg was one of the distinguished scientists brought in by our department under a foundation-funded program to spend a few days interacting primarily with us students. I remember being impressed that such an august personage turned out to be so kind, gracious and genuinely interested in spending time with the grad students.

Larry Moran said...

I second the opinion of Paul Berg. He happened to be in Toronto when the Nobel Prize was annnounced and he was very kind and gracious to everyone, including reporters. It was exciting to be around someone who had just become a Nobel Laureate.