Discover Dialogue: Biochemist Paul Berg

I'm an experimentalist, and the only way I can tell you if it works is to try it

By David Ewing Duncan|Thursday, April 28, 2005

Paul Berg, Cahill Professor of Biochemistry, emeritus, at Stanford University, won the Nobel Prize in Chemistry in 1980 for his pioneering work in recombinant DNA technology. In the early 1970s, he created the first hybrid molecule of DNA containing genes from two different organisms. That process now forms the backbone of genetics and the biotech industry. Berg also led a remarkable effort among scientists in the 1970s to voluntarily halt certain experiments in recombinant DNA until he and his colleagues could agree on guidelines that would minimize the risks of releasing bioengineered organisms into the environment.

You’re 78. Why are you still so active?

B:  There are things that really trigger a strong sense of injustice in me, and frankly, the bills pending in Congress to ban cloning for stem cell research were one; the one provision that really got to me was the provision that says no person in this country can have access to the stem cell therapy that was developed using the cloning technique. I couldn’t imagine how a bunch of guys sitting in Congress could sit there and say, “We’re offended by this technology, so therefore we’re going to prohibit 290 million people in this country from having access to a therapy that could save their lives.”

Why do you think Californians strongly supported their stem cell initiative?

B: I suspect there is widespread agreement that the president’s policy in restricting research on embryonic stem cells to lines that existed before 2001 is ill advised and that California should support a program that is forward looking, just as it has over many years in environmental and social programs. There must also have been a realization that advances in the biomedical field would be a boon for the state’s economy.

Was too much promised in terms of cures?

B: By its nature, science is an uncertain business, and predicting outcomes and results with certainty is foolhardy. I believe that the availability of embryonic stem cells provides a new and powerful approach to understanding the genetic and cellular basis of disease and for that reason is likely to lead to new knowledge and better treatments for those who are afflicted with those burdens. I’m convinced, however, that we are far less likely to find cures or new therapies without research on stem cells.

How do you deal with the tension between the need for pure research and the demand for results and cures?

B: The general public and members of Congress are less interested in hearing about the science and more interested in hearing about what the science can do. They want to hear more about what you’re going to cure. What I say to them is that I’m an experimentalist, and the only way I can tell you if it’s going to work is to let me try it. But if you’re going to prevent me from trying it, we’ll never know.

Why don’t they get it?

B: I’ll tell you an anecdote. Thirty years ago, when recombinant DNA was being threatened with prohibition, some quite well known senator gets up on the Senate floor and says, “I don’t profess to be able to understand this at all. I never got past high school chemistry, so I couldn’t possibly understand this science. But I want to say that this is the most dangerous research ever conducted in the United States, and it should be prohibited.” He confesses his ignorance, says he doesn’t know anything about it, and comes to an amazing conclusion anyway.

What do you think people are afraid of?

B: I characterize the paranoia under the phrase “What are we opening the door to?” What-ifs are easy to generate. You can sit down with a group of reasonably intelligent people and hypothesize all kinds of outcomes. So some of them generate fear. For example, the word cloning. What do you think resonates in the minds of the general public when a scientist says he wants to clone stem cells? Well, right away they associate it with cloning people. But we’re all agreed we shouldn’t clone people. Cloning stem cells has nothing to do with cloning people. But the word cloning just triggers fear. What do you see? The Boys From Brazil, Star Wars. People don’t understand that the Human Genome Project could not have been accomplished without cloning DNA. They don’t know that you can’t have vaccines unless you clone viruses. They don’t know cloning is like a copying machine.

Will Congress ban cloning?

B: There is a bill that has been passed twice in the House of Representatives. When it was passed, I was at a luncheon, and Bill Frist, the Senate majority leader, was there. I asked him, “What do you think about the House passing this?” And he said that they really didn’t understand it. I said: “You’re kidding. You mean these Congresspeople voted on what is a very important issue and they didn’t know what they were voting on? Well, surely in the Senate, which prides itself on being this formidable deliberative body with highly intelligent people, surely it’s not going to happen there?” He said, “It’ll pass in a breeze.” It hasn’t, but that response tells you a lot.

You have been involved in controversies before about groundbreaking discoveries that people thought might be dangerous. What happened in the 1970s?

B: Well, we were in the midst of experiments aiming to use an animal virus to introduce new genes into human cells and into bacterial cells. Our aim was to study how “foreign genes” worked in these inappropriate hosts. But some people thought that bacteria carrying tumor genes would be dangerous for humans.

The viruses caused cancer in some animals, and there was a fear that if you combined the DNA from the viruses with bacteria that are out there in the world, you would cause a cancer epidemic.

B: That was the fear. And someone at Cold Spring Harbor Laboratory found out about this experiment and called me up and said, “You’re going to do the most dangerous experiment, and you can’t do that.” I was at first annoyed and told him to go to hell. But then after sorting things out, I decided that I couldn’t know if the experiment we were doing was 100 percent safe.

So you gathered a few scientists together under the National Academy of Sciences banner and you wrote a letter, the Berg letter.

B: I contacted Jim Watson, Dave Baltimore, Norton Zinder, Dan Nathans, key people in the field. We got together at MIT and discussed that question, and  we concluded that we didn’t really know if there is any danger. So we decided that the only honest thing to do was to write a letter to our friends saying that some of this kind of work is of enormous value, but some may turn out to be risky. So why don’t we just put some experiments on hold? That is what generated the whole idea of the moratorium.

You suggested halting all experiments?

B: We actually identified only three experiments that we thought deserved caution. We didn’t see any harm in taking Escherichia coli genes and putting them into E. coli. That’s an experiment you can do in your kitchen sink. But putting drug-resistance genes into microbes that cause disease doesn’t sound like a great idea. Putting genes that produce toxins into a bacterium that inhabits humans doesn’t sound like a great idea. Putting DNA that has cancer genes into an organism that inhabits people might not be a great idea. So why don’t we all agree to put those kinds of experiments on hold until we can review this whole field to see how to deal with the potential risks?

So 150 scientists from around the world gathered at Asilomar in California?

B: Yes, and we argued for three days, and some were opposed to any regulations, but most thought we ought to say something. So the conference came out with a measured response, which said, we really don’t know the magnitude of the risks. However, to minimize any risks, the conference concluded that if there are risks they could be managed in this way: All but a few experiments had to be done in special facilities that ensured against escape of the experimental organisms, what we called physical containment. In addition, we proposed graded levels of what we call biological containment, meaning you use special viruses, special organisms that reduce the potential for escape from the lab.

Had anything like this happened before?

B: No. That’s why it had so much pizzazz.

What was the response?

B: The public applauded the scientists for taking the initiative to deal with the concerns.

Then there was a backlash?

B: It was only eight months later, after the guidelines came out, that people began to say that the scientists were like the fox guarding the chicken coop. But the Asilomar Conference did gain the public’s trust. And there has been no untoward incident in billions of experiments.

Weren’t you also criticized because you dealt only with the safety issues and not the ethical questions?

B: Here is something that people have legitimately criticized—we did not address ethical issues, we did not address how you deal with, say, bioterrorism. They weren’t left off the agenda by accident; it was deliberate. Having only three days, we focused on the science, the magnitude of risks, and how we could do the science safely.

So it was all about safety?

B: The issues were public health, how to do the experiments safely.

Today, though, it’s mostly about ethics.

B: Yes, and it’s much more difficult. How can you have a meeting with people who come to it with a deep abiding faith that a fertilized egg is a person, and a blastocyst created by nuclear transfer is a person, and the destruction of that blastocyst to harvest stem cells is murder? You can’t.

But people use bioengineered drugs.

B: It’s amazing that people are willing to use all of the drug therapies that are developed using genetic engineering that are produced in bacteria, or yeast, or God knows what, and they’re worried about genetically modified foods.

Has there been talk about holding another Asilomar for stem cells?

B: People who have to deal with contentious issues always ask: Why don’t we have another Asilomar? It sounds like a magic mechanism for resolving problems, but it won’t work for resolving all contentious issues. We were dealing strictly with safety in 1975, but it’s very difficult to resolve issues that involve differing religious and ethical perspectives. I don’t think you can resolve those kinds of issues in an Asilomar-type setting.

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