Unit 3: Genetics: Nancy Hopkins
Interview: Nancy Hopkins

hopkins.jpg Nancy Hopkins, the Amgen Professor of Biology at the Massachusetts Institute of Technology, is a molecular biologist, a scientist whose specialty is genetics at the molecular level. She graduated from Radcliffe College and attended graduate school at Yale and Harvard, receiving her Ph.D. in Molecular Biology and Biochemistry from Harvard. After postdoctoral work at the Cold Spring Harbor Laboratory, Dr. Hopkins joined the faculty at MIT. Her research has ranged widely, from gene regulation in bacterial viruses to cancer viruses to embryonic development of the zebrafish. She was also a coauthor of the Fourth Edition of the classic textbook The Molecular Biology of the Gene.

How did you get interested in molecular biology?

When I was a junior in college and trying to decide what to do with my life, I signed up for the introductory biology course. The second lecturer was James D. Watson, and by the end of his first class, that was it—I wanted to be a molecular biologist. I was convinced that out of DNA was going to come the answer to every question in biology.

By that time, spring of 1963, we knew what a gene was, and the genetic code had been figured out. But how were genes regulated? That was the hot question. The French researchers François Jacob and Jacques Monod had recently done a brilliant genetic analysis of gene control in bacteria. They had come up with the hypothesis that the proteins encoded by certain genes could bind to DNA and repress the expression of other genes. But there was no direct evidence for this.

What was your first exposure to research?

I arranged to work in Jim Watson's lab, though I didn't know how to do much of anything. At first I was really just a science groupie. I hung around the laboratory, absorbing the atmosphere. There was a feeling of tremendous excitement in the air. At the same time, I saw that scientists worked 60-70 hours a week, and I worried that a career in science would require me to give up my other interests. So I was drawn to the idea of being a scientist, but a bit repelled by it, too.

However, I really wanted to know how genes were regulated, and I had become obsessed with the question of whether the repressor hypothesis of Jacob and Monod was correct. So I went off to graduate school at Yale hoping I could work on that problem. Unfortunately, I couldn't find a faculty sponsor; everyone said the problem was too hard.

After a year I gave up and went back to Harvard to work as a technician for Mark Ptashne, who was trying to isolate the repressor protein of a bacterial virus called lambda. I didn't care as much about getting a Ph.D. as I did about being involved in isolating a repressor. So I worked in Mark's lab while he isolated the repressor, and we showed that it could bind to DNA—clear evidence that Jacob and Monod were right. That was a day I'll never forget! Having had my fun (as Jim Watson put it), I then enrolled in graduate school at Harvard.

Tell us more about viruses and about the research you did as a graduate student.

Viruses are tiny entities, made chiefly of nucleic acid and protein, that multiply inside cells. Lambda is a type of virus, called a phage, that grows inside bacteria. It has genes that enable it either to replicate and kill its host or to shut down and hide out in the host. Lambda's repressor plays a key role in regulating its genes and determining which pathway is taken.

For my Ph.D., I showed that there were specific sites on lambda DNA where the repressor attached. If one made mutations in those sites—damaged them—the repressor didn't bind, and then the phage didn't behave normally.

What did you do after graduate school?

I was very interested in cancer and wanted to move on to work on animal viruses that were known to cause cancer. For my postdoctoral training, I worked on DNA tumor viruses, and then when I went to MIT I turned to RNA tumor viruses of mice. (These viruses have RNA rather than DNA as their genetic material.) We used genetics to identify genes that made various strains of the viruses differ in their ability to cause cancer, or made them cause different types of cancer.

Are viruses involved in human cancers?

Some viruses can cause cancer in people; for example, papilloma viruses can cause cervical cancer. But viruses aren't thought to be responsible for the major cancers in this country—those of colon, breast, prostate, and lung. Furthermore, in healthy people exposed to cancer viruses, the immune system probably prevents cancers from developing.

After 17 years with cancer viruses, you made a major change in research area. Tell us about that.

In my work with phages and cancer viruses, I'd learned that I loved using genetics to figure out how genes function to produce biological processes. By this time, it seemed possible that, with the new DNA technologies, you might be able to use genetics to dissect one of the most complex processes in biology: the development of a vertebrate animal. For years we had had the idea that molecular genetics held the key to the mysteries of embryonic development—how a heart develops, for instance, or even why you look like your mother; we just didn't believe we would be able to make much progress in our lifetime. But now we were no longer limited to the genes of viruses; we could get our hands on individual genes of eukaryotic cells, of complex animals.

A revolution in developmental biology started with an organism that had been an important object of genetic study since early in the 20th century, the fruit fly Drosophila. German researcher Christiane Nüsslein-Volhard and American Eric Wieschaus had shown that one could use a large-scale genetic approach to identify the genes required for the development of a fly embryo. The strategy was to treat flies with a mutagen—something that makes changes (mutations) in DNA—and then look to see how the descendants of the treated flies developed. Essentially, you're damaging one gene or just a few genes at a time and asking, "What happens when I take these genes away?" The amazing success of this Drosophila research raised the question of whether you could do the same thing for a vertebrate animal. Many people thought it would be too hard.

Why is this sort of genetic study so hard?

Because animals have so many genes. If you have to screen all the genes one by one, or even a few at a time, it's a lot of work. For the Drosophila project, the researchers had to breed about 20,000 families of flies altogether and then examine about a million embryos and larvae, one by one, to find the defective ones. Imagine doing such an experiment with vertebrate animals!

Undaunted, Nüsslein-Volhard was setting up to repeat her fruit fly study with the zebrafish, a vertebrate first proposed for genetic study by a phage geneticist, George Streisinger. So I took a sabbatical in Germany to learn about zebrafish.

What's good about the zebrafish?

The zebrafish is good for genetic analysis because it will breed year-round in the lab, and it's conveniently small and hardy. Moreover, its early development is extremely fast: It develops from a fertilized egg to a free-swimming little fish in only five days. This fish is a juvenile, a larva, but it already has a beating heart, functioning digestive organs, a vision system that can focus on swimming prey (Paramecium), and the brain and muscles needed to catch and eat them. And its development is easy to follow, because for the first five days, the animal is transparent!

How does your experimental strategy differ from Nüsslein-Volhard's?

We invented a method to make mutations in fish using a virus rather than a chemical. Some viruses can insert DNA copies of their genes at many places in their host cell's DNA. If the inserted viral DNA lands within a host gene, the gene is damaged—it is mutated. Making mutations by insertion greatly simplifies the task of identifying the mutated genes and cloning them (making many copies for further study), because the inserted DNA serves as a tag. (Ironically, it was a variant of the mouse virus I had studied for 17 years that worked for us!) Having devised a method, we were in a position to find the genes that are needed to make a 5-day-old zebrafish.

What progress have you made?

Our method has really worked. We are now rapidly identifying essential developmental genes and cloning them. It's the most exciting project I've worked on. Many of the genes we've found so far are ones not previously known to be important for development. And these genes turn out to have close relatives in the human genome. This is good news. In fact, we hope that the human versions of some of the genes we find will someday be used for regrowing damaged organs in people.

You spent several years investigating discrimination against women at MIT. How did you get involved?

Reluctantly! I began with a strong belief that science was a merit-based occupation. But, as time went on, I couldn't help observing how women's scientific contributions were valued differently from those of men, how women themselves were valued differently. In part what drove me to action was that I needed more room for my fish! Trying to get a little more space, I was working my way up through the administrative layers of MIT, and finally I worked myself right up to the president. But before I complained to him, I thought I'd check out my perception of the situation with other women on the faculty. This turned out to be easy to do, because there were then only 15 women among the 212 tenured science faculty at MIT. I was surprised to learn that almost all of these women had reached the same conclusions I had.

So we went as a group to ask the administration to let us study the problem, to let us collect data about the distribution of space and resources. Doing the study was fascinating. We found that subtle discrimination in the individual case is often invisible. But when we looked across all 15 women—and remember these were very outstanding scientists—their experiences formed an undeniable pattern which one could understand was a subtle but damaging type of gender bias.

We wrote up our report, MIT accepted it and corrected all the documented inequities, and everybody was happy as a clam. But it didn't stop there. We soon learned that our results had ramifications far beyond MIT. When a short summary of our study was published in the faculty newsletter, the New York Times picked it up, and we soon heard from hundreds of other women, at all sorts of institutions, who had independently come to the same conclusions we had. I was invited to the White House, where the President and First Lady thanked MIT for doing this study. The problem is clearly a long-standing one relating to the role of women in society. Changing that situation will take time. But MIT's recognition of the problem turns out to have been a monumentally important step for women scientists.

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