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If you look at the successful scientists, and if you could follow the path of their day-to-day decisions of how to proceed on a research project, you’ll find that, more often than not, they hit a decision point or crossroads where they have to make a decision: “Do I go this way, or that way?” In many cases, they have no way of foretelling, but what you find is that successful scientists, more often than not, choose the path that leads to major breakthroughs.

I sometimes refer to it as a “nose” for the right way to go; intuition is another way to say it. They sort of “smell out” what is the best way to go. They make mistakes, there’s no question about it, but what you find is they choose the right path, or the rewarding path, more frequently than not.

The second area that is most important [to being a successful scientist] is when you get a result that is inconsistent with what you had imagined or supposed or expected. And then the question is how you deal with that kind of outcome. There are people who, sometimes, just don’t believe that result and try to find other ways to test their notion until they find there was something wrong with that first negative result.

Third, and most important, is resiliency—the ability of scientists to come back in the face of an uninformative result in a particular experiment. People tend to think scientists know exactly the result they’ll get, and they go on to the next thing. More often, things don’t work. And you go home rather discouraged. Good scientists come back the next day with new ideas and renewed enthusiasm and confidence, and they keep plugging away, varying the conditions, trying to find the right way—and, then, suddenly, it succeeds!

When I counsel students, I talk about this capacity for resiliency, for persistence, for perseverance—the ability to continue to pursue your ideas and not to be discouraged by intermittent failures. Because science is not easy. It’s hard work, and notebooks are filled with experiments that didn’t work.

You must have the passion to come in and work long hours, oftentimes without succeeding. But the passion drives it. I don’t think any semi-successful scientist can lay claim to anything if they didn’t have a passion for discovery. It can be very discouraging. People who are easily discouraged will, oftentimes, give up before getting to the success.

When I was a graduate student, I wanted to do research more than anything. I spent long hours at the lab. My wife was a nurse at MacDonald House [MacDonald Women’s Hospital, part of University Hospitals of Cleveland]. She got off at midnight, and I was often there from eight, nine in the morning until midnight. I’d come home for dinner; we lived close by. Then I’d go back to the lab. I worked evenings. I worked on weekends, always trying to move ahead and solve the problems that were left the night before.

When I talk to other scientists who I think are successful and who have achieved something notable, that’s what they’ll say: You have to have that passion.

You can develop that passion by role models, but one of the things that does the most to promote that passion is early successes. Because the taste of success, the taste of triumph—or, at least, having something come out that’s worthy of somebody’s note—is like a drug. Success is a very heady experience. I used to say that, in many cases, it’s a bigger high than taking drugs. You have to experience that to develop that passion.

Some of early success is luck, some of it is not. Some of it is from failure—getting around that failure. Often it comes from a pat on the back and encouragement from people you respect and admire. This brings you along during those rough periods.

As a teacher, I’m often trying to encourage research people in my lab. I’ve developed different tricks. One of my favorites is to discuss an experiment with them and to bet on the outcome. I often take what I’m reasonably convinced will be the losing side. If the experiment goes well, I get to pay off. The researcher gets a little boost.

Most good scientists that I know of are competitive. In a way, doing science is solving a puzzle. So there’s a race. Who solves the puzzle first gets a lot of credit. That’s not the only motivation, but once you’re engaged, the credit you get for a breakthrough or discovery is something you seek. Being first is not only an honor, it’s where the rewards come from.

[The novel Arrowsmith, by Sinclair Lewis, helped inspire the young Paul Berg to take up science.]

A young scientist, who had his own ideas about the problem of yellow fever, had to buck tradition and an arrogant superior. He was constantly being prevented from following his leads and ideas. He eventually overcame that. So it was the young, aggressive, upcoming scientist who took on the older guy and won the battle. It was like any other inspirational thing you might read, like a war hero or a baseball player who wins in spite of all adversity. At that age, it had a big impact on me. It portrayed medical science as an honorable and rewarding activity, especially if you could make a contribution that was going to save lives and cure disease.

[In 1953, Francis Crick and James Watson discovered the double-helix structure of DNA.]

I spent a year working at the Salk Institute and, as a member of one of the advisory groups, I got to know Francis Crick pretty well. Our interactions were mostly talking science—talking about a lot of things.

My foremost role model at Western Reserve was Harland Wood, the chief of the biochemistry department. He was a very unusual character and person. He could be gruff on the outside and intimidating to many. But deep down, his passion for science came through clearly. Almost until the day he died, he was working in the lab. I think, when he turned eighty, he published more papers in the previous year than any group of people in his department. He was just amazing.

When he was a graduate student, he never took no for an answer. If he had an idea for an experiment, and the equipment and tools didn’t exist, he invented them. So he was one of those people you couldn’t help but admire. He was wonderful. He was often in the lab in the evenings, and he would come in and we would sit around and shoot the bull and talk about experiments, talk about results and what other people were doing.

He certainly promoted his graduate students—and me in particular—so that we got chances to meet the other leading scientists at meetings. He was just a remarkable guy, and everybody who knew him, loved him. So you couldn’t help but try to emulate him, or at least try to live up to his standards.

I had already gotten the Nobel Prize before he died. That was certainly something he was proud of. He tried to recruit me to come back to Case Western Reserve early on, but I was really well established at Stanford. We always had a good relationship. I invited him to Stanford many times.

When I came to his eightieth birthday party [in 1987], we had a lot of fun together. I have a lot of photographs that I enjoy looking at.

Case once asked me to participate in the groundbreaking exercise for a new building, and I arrived at five-thirty or six in the morning after an overnight flight from California. He met me at the airport. He took me to breakfast. He found a place for me to take a nap. We had a wonderful day.

When my research group had switched from work with microbes to mammalian cells, we had an idea for a new kind of technology to help us probe new questions. We came up with an idea of how to introduce new genes into mammalian and bacterial cells. Somebody then said to me, “You know, what you are doing is dangerous.” And my first reaction was, “That’s bunk!”

After discussing it in more and more detail, I was more and more convinced that he was overestimating any risk. But then I began to ask, “Could I actually say that the experiment I was about to do had zero risk?”

“Zero risk,” in this case, means no danger to people in my lab, people working in the same area, and the local community. The hypothetical risk posed was that we might create a microbe that would carry within it genes that could cause cancer in animals. We had no idea if those genes could cause cancer in humans. Now we know it doesn’t. I was pretty confident that what we were doing was not going to be dangerous—except that I couldn’t say that I was absolutely sure it wouldn’t.

You don’t need a very high ethical standard to be concerned about doing something that can cause serious damage to the people around you and to the environment or the community. I began to think about finding another way to answer the questions and not put people in jeopardy.

That was essentially my thinking, and I talked to a number of people—people whose opinion I respected. They all more or less shared that kind of view. We just put that experiment off on the side and went on to do other things.

In the meantime, somebody else discovered a better way, an easier way, to do what we had done, making recombinant DNA. They reported this in a scientific meeting and got a similar kind of response: If you put genes that might cause serious diseases—toxins, drug resistance, cancer—into bacteria, and these bacteria live inside the intestinal tract of humans, such experiments could be dangerous. People suggested that such experiments could create some kind of an epidemic of various serious problems.

That concern emanating from a scientific meeting was published in Science magazine and conveyed to the National Academy of Sciences. The president of the academy knew that I had encountered the same kind of concern the year before, and he asked me if I would advise the academy on how to proceed and what kind of advice it should provide. I met with a small group of prominent scientists and discussed the pros and cons, dangers and benefits, and we came to the conclusion that we didn’t have enough information to decide as to the extent of the risks.

Consequently, we recommended that we would express our concerns and uncertainty in a letter in the scientific literature and make suggestions how we might proceed. It came to be called the Moratorium Letter, because it called on scientists working in this field to defer certain kinds of experiments until we could better assess their potential risk.

I was the chairman of the committee that published this letter, so I became identified with this whole concept of scientists questioning the safety of their own experiments and taking up the responsibility to define or devise a response. Ultimately, we had the Asilomar Conference, which I chaired, so again I was the front man in an effort to devise a way to assess a potential risk when the research was highly valuable and important. Our conference came out with suggestions of how to proceed. I think the public and everybody accepted it.

The question is: What drove the scientific community to respond in the way that it did? Not everybody agreed with our position. There were many who thought we were overestimating the risks. Some believed there was no risk and we were standing in the way of the progress of science.

On the other hand, the public gained an enormous amount of confidence in scientists, because they began to trust us. After all, we were the ones who called attention to it and took up the task of trying to find a way to deal with the risk. We came up with plausible regulatory procedures, which actually impeded our own research. All of that was viewed as being exemplary, ethical behavior.

Remember, we all wanted this science to move forward. We wanted this science more than anything, because we saw the huge promise, but most of us felt it was inconceivable that we would say, “We don’t care if there’s a risk. We’re just going to go ahead and do our favorite experiments.”

Perhaps people attribute too high an ethical motivation on our part. But most of us were trying to figure out ways of doing this research while minimizing any risk. I don’t think anyone else would have done differently. Nobody would go ahead and do things that they know could cause enormous problems for other people or society.

There were certainly a lot of scientists who wanted to get on with it. However, after a lot of discussion and soul searching, and devising ways to minimize the risk that wouldn’t impede the research, the scientific community was persuaded that we had provided a sensible way to proceed.

The Asilomar meeting, which I’ve written a paper about for the Nobel Foundation, really was a historic event. But if you ask now if it’s a model for being able to resolve other kinds of science public-policy issues, the answer is probably not. That was a unique occasion. The issue was clearly safety. Safety could be evaluated in terms of the kinds of risk you could imagine. You could develop data or explore existing data that assessed the magnitude of the risk.

On the other hand, today, we’re debating embryonic stem cells—not an issue of risk. That’s an issue of faith, religion, and values. There’s no way those kinds of differences can be resolved by getting together and talking. We’ve been doing that for three years. It’s been impossible to shake people from their bedrock faith that stem cells are immoral.

[Responding to the Bush administration’s choking off of most federal money for stem cell research, several states and universities are working to fund the research independently.]

Here in California, on the November 2 ballot, we have an initiative for the State of California to issue $3 billion worth of bonds to support stem cell research. Three billion dollars. Three hundred million dollars a year.

I’m sure there’s going to be a lot of people out there who will be arguing about whether we can afford it, first of all; second of all, why should the state be funding what is “immoral.” And then the question comes out: Who defines it as immoral?

I believe embryonic stem cell research is an imperative. I think we must move on it, because of the potential it has for being able to alleviate life-threatening diseases for hundreds of thousands of people.

I don’t regard the embryonic stage—from which stem cells are derived—as a person. Many of those that do, make a religious argument: that life begins at conception. If you believe that, you have to kill a person in order to obtain stem cells.

An early blastocyst—which is an early stage, after an egg is fertilized and before it ever attaches to the uterine wall—has no potential to actually form a person. Besides of which, all of these embryos are in IVF clinics sitting in deep freezes. There are like ten thousand embryos being discarded down the drain a year.

Which is the more moral position: to extract the value that such a blastocyst represents in the form of stem cells and the potential it has for cures? Or is it more moral to flush it down the drain? That’s where the issue has come down.

Remember, this structure is about 120 cells. It is probably four or five days post-fertilization. It’s not attached to the uterine wall. It’s sitting in a petri dish—impossible to give rise to a person. So to attribute to it a humanity is no more than saying skin cells are people. Genetic information supplied by my skin cells can give rise to a person. So the argument is one of religion. And if people believe deeply that destroying a blastocyst is tantamount to murder, those people will never be sanguine about embryonic stem cells.

In the end, it’s going to be our democratic process. If the majority of people believe that this sort of research should go forward, it will go forward. And an Asilomar-type conference isn’t going to change those people’s minds.

I believe the public is ill-equipped to decide what information scientists should seek to know. By contrast, it should have a huge role in deciding how the information we acquire is used. To emphasize, the public must have a huge say in the application of scientific knowledge, but not in its acquisition. Some say that, because the public is funding science, it should be able to decide against certain areas of scientific discovery. There is an unfortunate concern that is expressed as, “Please don’t open doors. We don’t want to know what’s on the other side. We’re better off not knowing.” If people believe that ignorance is better than knowledge, then we’re in bad shape. Knowledge alone is neutral. For me, the question is: How is that knowledge used? Society has a responsibility, as do scientists, in seeing that information is used wisely.

[Dr. Berg comments on the increasing commercial opportunities that are emerging from academic biomedical research.]

World War II brought collaborations between academic scientists and war industries to a new level. Here there is little debate about whether these interactions served the public interest. Not surprisingly, following their wartime industrial affiliations, many sought to continue them when they returned to their academic settings.

This was a principal factor in the development of Silicon Valley. The emergence of venture capitalists and Stanford’s accommodating policies of having its faculty actively involved in the industry that was growing up around it is now legendary. The history of this development is being studied and emulated all over the world.

Industry profited from the proximity to an academic environment that provided talent, knowledge, and prestige. Here in California, as in the East Coast’s Boston-to-Research Triangle corridor, high-tech industry grew rapidly, closely linked to the academic centers they surround. The public—elected officials, chambers of commerce—touted the benefits of this linkage and judged it to be a very definite public good.

Until the 1970s or so, the biological sciences were naifs in this game. During the 1950s, which saw the blossoming of biochemistry and the emergence of molecular biology and genetics, there was, to my knowledge, little or relatively little involvement of academic biologists with industry. With the exception of the occasional consultantships, most life scientists looked with skepticism at industrial research in their fields, and industry saw little reason to support the arcane research being done at the cutting edge. Venture capital and life-sciences-based industries other than drug companies were unheard from or about.

In the mid-1970s, however, scientists in academia and industry, as well as investors, began to appreciate the impact of advances in molecular biology. “Genetic engineering,” the catchy media label for molecular biology-molecular genetics, caught on as a potential new route to commercially attractive products.

Basic scientists, who had never thought of patents, were suddenly energized to patent their discoveries, while others were encouraged to start companies. Both industrial and investment companies created scientific advisory boards that sought to take advantage of the intellects and fame of leaders in the life sciences.

But the interactions between academia and industry didn’t go into high gear until after Congress passed the Bayh-Dole act of 1980. That legislation obliged those receiving federal research funds to make strong efforts to promote the commercialization of their discoveries. This, I believe, transformed our research universities and institutes and their scientists into more engaged participants of the industrial enterprise.

From that time forward, faculty researchers were expected to be aware of the potential commercial value of their work, and their institutions were obliged to create the infrastructure that would facilitate patenting, marketing, and licensing their faculty’s discoveries.

It didn’t take long to realize that the Bayh-Dole mandate had the potential for being a “cash cow” for the institutions and the scientists. Those institutions that already had an office of technology licensing—OTL—were off to a fast start; a good example was Stanford’s prompt patent applications for recombinant DNA technology and, shortly thereafter, Columbia’s patents of a method for transforming mammalian cells. Substantial income at a few institutions—for example, Stanford, the University of California at San Francisco, Columbia, MIT, Harvard and a few others—whet the appetites of most others.

The unintended consequence of this new focus is to restrict what had been, by and large, a culture of free exchange of research tools amongst scientists to one of restricted access—restricted in this case means paperwork, at least, and occasionally onerous protracted negotiations with licensing offices rather than with the scientists who were involved.

A particularly frustrating consequence is the restricted access to databases: Patents are being sought which make protein and DNA sequences proprietary and therefore more difficult for others to explore their ramifications.

Having become an integral part of the academic research enterprise, university OTLs have made commercial gain a driver of research choices, even to the point of encouraging scientists to enhance patent and licensing opportunities. All this has happened with the full blessing, encouragement, and assistance of university administrators. For, after all, isn’t capturing additional sources of income an inviting goal? New educational and research initiatives are increasingly evaluated as to whether they will enhance the university’s competitiveness with the industrial sector.

I believe that if we value unfettered basic research as the prime function of the academic setting, then it is fair to ask if the extent of current commercial interactions distorts that mission and promotes the public interest.

We all appreciate that the vector of innovations and breakthrough discoveries depends heavily on the investigator’s intellect, experience, curiosity, and hunches, and little on financial rewards—except prizes. Although I cannot quantitate the extent to which that vector will change in this new climate, listening to colleagues at Stanford, elsewhere, and, increasingly, in Europe and Japan, I fear that research is veering increasingly toward more commercial ends. Is this good or bad? Is this in the long-term public interest?

I suppose it depends on how we interpret the public interest. Short term, the public benefits from the products that are emerging from federally funded research. In the area of biomedicine, many of the new technologies and products will benefit human health. Agriculture and industry are also making great progress in developing new food products and plant-derived materials. Industrial processes are also being revolutionized. So the public interest is well served.

But isn’t the long-term health and viability of the academic research as the generator of basic knowledge and the innovator of ideas that challenge the zeitgeist also in the public interest? The question is, what’s the right balance for society?

I believe that the public interest extends beyond the immediate commercial benefits. It must also be on guard against weakening the enterprise that we rely on to generate the knowledge and skills needed to sustain the effort in the long run.

[Dr. Berg is worried about neither the effects of eating genetically modified food nor the effects of the production of genetically modified food.]

Let’s put it this way. “Worried about it” is in terms of the following: I am confident that the methodologies that are being used to validate the safety and the environmental impact are enough to convince me at least that the kinds of what-ifs that people raise are overly exaggerated.

That’s not to say that, if somebody starts to make a new kind of product, I would accept it right away. No. I think it needs adequate testing to provide the same kind of convincing evidence that a drug does when it passes FDA approval. In this particular case, there’s the added concern about environmental damage. That has to be looked at. But once the expert people who assess those two kinds of activities give it a bill of health, I can’t deal with people who just keep raising fantasy fears.

I learned a long time ago that there is no end to what-ifs. You could sit with any reasonably intelligent person, and they will raise more what-ifs than you ever could have imagined. Each one of which is a major blocker to any kind of progress.

The whole idea is to do the best we can to assess the risks all around, comparing them to the benefits. If the risks are enormous, with the benefit being small, obviously you would say to go very, very slow before you go forward. If the risks are only imaginary or small, and the benefits are huge, then I think it tips the balance the other way.

For me, life is opportunities. There are a lot of challenges out there, not all scientific ones. Right now, I’m very much involved in what I’m calling the political or public policy aspects of science. It hurts me greatly to see the way public policy issues are debated.

People grant Nobel Prize winners with infinite intelligence, wisdom, and insight. That’s so overblown that it’s been an amusement to me. In a Nobel Prize winner’s specialty, they’re incomparable. Outside that specialty, they’re plain old ordinary folks with the same kind of dumb ideas and dumb viewpoints, without any greater insight into critical problems than anybody else. It annoys and surprises me the way people stand in awe of a Nobel Prize winner. Sometimes it’s truly embarrassing.

People are either expecting or believe that you have these superhuman powers, which none of us have! There are a lot of smart guys out there, a lot of smart people. In fact, Harland Wood should have gotten a Nobel Prize—and never did. That doesn’t diminish him or the contributions he made, because the Nobel system wasn’t able to deal with someone like Harland Wood. The significance and importance of his work wasn’t appreciated until many years later. There are more great scientists who have not won the Nobel Prize than there are who have. Also, there is the problem that, if more than three people were involved in a major discovery, nobody gets it.

People will come up and say, “Can I shake your hand? I’ve never shook hands with a Nobel Prize winner before.”

That’s my view on it. I don’t think I can take it too seriously. It was wonderful to get the prize, because it’s a recognition, but the expectations it generates are unrealistic.

I handle that by trying to convince people that their expectations are totally wrong. I’m quite up-front about it. I once had an experience at a dinner party. I sat next to a woman from Hollywood. She’s quite a prominent woman. We had a wonderful conversation. My son was in the theater business, and we talked a lot about theater. We talked about art. She happened to be a major art collector. We had a wonderful evening, and, when she left, we acknowledged that we enjoyed talking to each other. She came running back five minutes later and told me she was terribly upset, because I had never mentioned that I was a Nobel Prize winner. And I said, “What difference did that make?” After all, we had a wonderful conversation. We had a terrifically stimulating discussion, so what difference did it make? Of course, she wanted to go home and be able to tell her bridge club or whatever that she had had dinner with a Nobel Prize winner.

As told to Joseph Malcolm McClain