Unit Two: Bruce Alberts
The Cell

Interview: Bruce Alberts

Bruce Alberts first experienced scientific research by volunteering to work in a lab as an undergraduate. He went on to build a successful career investigating DNA chemistry, first at Princeton and then at the University of California, San Francisco, where he is a professor of biochemistry. Currently on leave from UCSF, Dr. Alberts is serving as president of the National Academy of Sciences in Washington, D.C. Under his leadership, the Academy has made the improvement of science education a top priority. Many biology students will have a chance to meet Bruce Alberts again if they use his classic text, Molecular Biology of the Cell.

How did you start in science?

I went to a large public high school in Illinois and really enjoyed my chemistry class. That's probably how I got so interested in science, but I don't think I really knew what science was. I do remember going to a career night at the high school where they invited parents and others working in various careers to come and talk about their occupations. I looked at all the occupations on the list that might use chemistry or science and there were two. One was medicine and one was chemical engineering, so I went to those two talks and decided I didn't want to be a chemical engineer, but thought maybe I would become a doctor. From my perspective as a 17-year-old, I didn't have any conception that there was an occupation of "scientist" for which you could get paid. I subsequently went to college at Harvard, where I took a lot of science courses because I was pre-med. But I still didn't get any hint from these courses about what doing science might be like.

So when did you begin to see that you could become a scientist?

During my junior year, Jacques Fresco, a post-doctoral researcher who was my tutor, asked me if I wanted to work in his lab during the summer. Since my girlfriend, now my wife, was going to Europe that summer, I had nothing else to do. I worked very hard all summer in his laboratory. The lab group worked on nucleic acids, and my project involved deciphering how errors in pairing between bases in DNA affect the helical structure of the DNA. I actually made a discovery that people were excited about, and the experience was completely different from the laboratory work that I had done in courses. We also used this discovery to analyze RNA—specifically, how helical structure forms due to base-pairing between certain regions of an RNA strand. So my research as an undergraduate that summer led to two papers, one published in Nature, the other in Proceedings of the National Academy of Sciences. Given the success of that one summer of work, and since it was so exciting to do this stuff, why go to medical school? I didn't even apply. I stayed at Harvard and did graduate work for a Ph.D. degree.

How did your parents react to that?

I think parents like their children to choose safe careers. Being a doctor had a good, solid image with my father, while it seemed like being a scientist had a shakier future. But although my parents were a little surprised, they were supportive.

Did your graduate work go as well as your undergraduate research projects?

Actually, my research career has been a series of ups and downs. My success as an undergraduate researcher gave me a false view of science—that it is easy. So I was extremely naive when I went to graduate school. My major professor, Paul Doty, told me I could pick my own research project. Overconfident, I thought I might as well tackle something very important, so I decided that I would solve the genetic code, which had not been deciphered at that point. I got the idea when I took a discussion course in molecular biology and we had to write a term paper proposing experiments. My experiments were my idea of how you might solve the genetic code using a method that turned out to be very cumbersome and would never have worked. But I got an A on the term paper, and I got excited about my idea. This is a very dangerous thing in science, when you get too excited about your own ideas! So when I started my research for the PhD, I tried to solve the genetic code using my term paper as the outline for my experimental plan. I spent three years on experiments that really didn't have a prayer of working.

What was wrong with your plan?

Basically, the problem was that I did this long series of experiments to solve the genetic code without first doing the control experiment that would have told me that the plan couldn't work. About the time I realized the problem, Francis Crick visited our group at Harvard and I explained to him what I had been trying to do. I'm sure Francis Crick doesn't remember this at all, but it is burned in my memory. As soon as I started telling him what my plan was, before I even got to the punch line that it didn't work, Crick asked if I had done the very control experiment that I had left out! I was really impressed that he saw the problem immediately, when it had taken me three or four years to see it. So, I had a lot of trouble with my thesis research, but I was able to shift to a different project to complete my PhD. And, most importantly, I didn't make the same type of mistake again.

In the medical center environment of UCSF, you and your colleagues are at an intersection of basic research in cell biology and biotechnology. How do you see the science-technology relationship?

I've actually lived through the explosive revolution that led to the biotech industry. When I first arrived at UCSF in 1976, Herbert Boyer invited my wife and me over for dinner, and during a walk he told me how he was going to start this company, Genentech. He asked if I would like to be involved, and I said no. I was too busy, and like most academics at the time, I wasn't interested in starting companies. Herb was unusual in that he was comfortable with the idea of applying what we knew in commercial ventures. But most of us also had not seen the potential benefits from technology based on gene cloning and other methods in molecular biology-how the different techniques could be combined to produce useful things for society. But here it was, this ability to make commercial quantities of rare proteins, such as human growth factors. The technology has revolutionized the pharmaceutical industry and has improved human health on a scale that I think even surprises Herb Boyer and the other pioneers of biotechnology. All that knowledge came from the basic research of scientists trying to figure out how cells work. In turn, basic biological research is benefiting from new knowledge in chemistry combined with engineering breakthroughs, such as machines that can sequence DNA very rapidly. As this illustrates, the whole enterprise of science builds up units of knowledge that can be combined in many ways. The progress of science and technology is ever accelerating; the more things you know, the more ways you can combine that knowledge.

Can you give an example of how such a synthesis of existing knowledge could give us a new breakthrough in cell biology?

We know a lot of facts about what is called cell signaling. We know that various growth factors and hormones bind to the outside of a cell and send signals inside. Right now, all the steps and variations make cell signaling look incredibly complicated, like a complete jumble that doesn't make sense. There seem to be too many signal pathways, with the complexity compounded by cross-talk between the pathways. We have lots of facts, but we don't yet understand the network properties of cell signaling. We can understand every piece of the puzzle of cell signaling, but until we understand how it all fits together in a network of communication and control, the whole picture won't come together and seem simpler. Solving the problem demands different ways of thinking about cells as complex networks, and I think this provides a role for new kinds of people in this field—perhaps people who would otherwise have gone into physics. I'm sure when we understand these cellular networks, we'll say, "How were we so stupid not to see that this is what the cell is doing?"

Sometimes these signaling and response systems run amok, with cancer being an important example. What are some of your thoughts about the cell biology of cancer?

I think this is another case where we already have a lot of knowledge but need to start putting the facts together in new ways. We now know that for a normal cell to become a cancerous cell, it has to be disturbed in a large number of different ways. A lot of check points have evolved in our cells, safety mechanisms that allow large multicellular organisms to grow and develop without the individual cells being selfish and growing out of control. Cancer therefore requires that several different defects occur in the same line of cells. For that to happen, there must be some breakdown in the cell's DNA metabolism—in its ability to repair DNA damage, for example. Different tumors can be caused by different defects in DNA metabolism. And yet the chemotherapy used to treat cancer is usually a kitchen-sink approach, a mixture of drugs. As we learn more about these defects in DNA metabolism, we'll be able to screen a particular tumor cell for the type of defect that it contains, and then take a much more tailored approach to chemotherapy. We will soon see some major breakthroughs in both our understanding and treatment of cancer. If I wasn't in my present job, that's exactly what I'd be working on right now.

Speaking of your present job, tell us a little about the National Academy of Sciences.

The National Academy of Sciences was chartered by Abraham Lincoln in 1863 to be an honorary society of scientists. The charter we received is unusual, because it requires the members elected to this honorary society to advise the government, without compensation, on matters involving science and technology. For example, committees set up by the Academy now do a lot of work on environmental questions, such as, "What is a wetland, and why should we protect wetlands?" "What is the best strategy for cleaning up radioactive waste that has accumulated around the nuclear weapons sites that are now being dismantled all over the world?" As another example, in 1991 the federal government asked us, in response to an earlier request by the governors of all 50 states, to facilitate the development of the first-ever national standards for science education in our nation's elementary and secondary schools.

What advice do you have for students with aspirations for research or other careers that involve science?

First, I think it's important for science students to get a strong background in the fundamentals of chemistry, physics, and biology. But there is much more to being a successful scientist than that. Enthusiasm and persistence are so important. There are a lot of times when you're doing science that things go wrong, as you've heard from my failures. Of the 30 or so graduate students I've had during my career, the most successful were the ones who persevered and worked even harder when their research wasn't going well. Otherwise, you never get past the rough spots. To succeed in science, you also have to get satisfaction from making progress in small steps. We don't make big discoveries every day. Sometimes it's a victory just to get a particular technique to work a little better. The only way to find out if you're good at science and enjoy it is to work at it for a while. And I don't think we're very good at predicting who will succeed in science. It depends a lot more on creativity, imagination, and persistence than on how many facts you can recall on an exam.

What if a student likes biology or some other science as an undergraduate major, but doesn't want to go to medical school or become a research scientist?

I think far too many science professors still have the idea that their most important teaching goal is to produce more scientists. That's one reason to teach science, but a much bigger reason is that we need more people with science backgrounds in many fields, not just in research careers. For instance, we need more people with science backgrounds in industry, in journalism, in government, and certainly as teachers in elementary and secondary schools. There are so many ways to use a science background successfully without being a research scientist or professor. I encourage students to keep an open mind about how they can put their science abilities to work in different careers. And I urge science professors to become much more inclusive in how they define the science community-to welcome not just academic scientists and researchers as part of their world, but the many others who are using their science education to improve schools, businesses, government, and other institutions.

Spreading both science and its values throughout our society has become the central mission of the Academy. Please visit us at www.nas.edu

©2005 Pearson Education, Inc., publishing as Benjamin Cummings