April 2002
Patenting Human Genes

Putting it All Together

Measuring Cosmic X-ray Fireworks

Understanding Gene Functions Through Mutation

New Fellowships Integrate Teaching and Research

Pursuing Answers to Big Questions

Commentary: The Mentoring Mindset

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Bryn Mawr College
A quarterly newsletter on research, teaching, management, policy making and leadership in Science and Technology

Understanding Gene Functions Through Mutation
By Karen Kreeger

Nancy Craig ’73

For Nancy Craig ’73, one of the most important of Bryn Mawr was the support she had as a woman in science. "There was no one asking in an unbelieving way, 'Oh, you're a chemistry major?’" she says. "And goodness knows I've encountered that. There is still an element of incredulity about women doing science." But at Bryn Mawr this simply was not an issue, "and that's why I found it such a powerful place," she says.

Craig recalls a high-school teacher of English, German and Latin who was instrumental in helping her decide where to go to college. She believed California was too provincial and that Craig should look outside of the state. "She's the one who told me about places like Bryn Mawr and advocated that I should look more broadly," says Craig. "I was never even east of the Rockies until I flew over them to come out to school."

After graduating from Bryn Mawr, Craig had to decide whether to go on to medical school or graduate school. She realized that she was more interested in how and why people got sick than in treating disease. Craig went on to graduate school at Cornell University studying how bacterial cells respond to DNA damage and how viruses grow in those cells. She earned her Ph.D. in biochemistry in 1980.

Jumping Genes

Craig accepted a postdoctoral fellowship at the National Institute of Mental Health and in 1984 joined the Department of Microbiology and Immunology at the University of California, San Francisco, as an assistant professor. She started working on a type of mobile DNA called transposons. These are pieces of DNA that move to different locations within a cell and sometimes between cells. Transposons — so-called jumping genes — were discovered in the late 1940s by Nobel laureate Barbara McClintock.

Craig has been at Johns Hopkins University School of Medicine in the Department of Molecular Biology and Genetics since 1992. She was also awarded an investigatorship with the Howard Hughes Medical Institute in 1992, which she still holds.

Currently Craig runs a lab that includes about 10 graduate students, postdocs and technicians. "I've heard people say that science is a lonely endeavor," she notes. "It's almost archetypal. But in fact it's a very interactive job. I could characterize my job as running a small business. I have to teach, coordinate and facilitate, and all of that is very people-oriented."

For Craig, the most gratifying part of her job is understanding how nature works. "I don't work at the bench anymore, but I'm still grabbed by these questions," she says.

Transposable Elements

Craig’s basic research on transposons and how, at the molecular level, they make the jump within and between cells has far-reaching implications. Although she doesn’t work directly with HIV, Craig’s studies of transposons increase our understanding of how HIV replicates and moves from cell to cell. Retroviruses like HIV are actually transposable elements — copies of them go into new cells, where they join DNA and become integrated into human chromosomes.

Transposable elements are also useful as research tools to ascertain the functions of genes. Craig works with a bacterial transposon called Tn7. "We've been able to make many types of Tn7s and put a molecular tag in the middle of the element, such as genes for antibiotic resistance, to follow the transposon when it moves," she explains.

Usually Tn7 is very selective about where it inserts and in which types of DNA it will insert, but Craig's lab has made a version of Tn7 that is not so picky — that is, it can be inserted into many different places in a genome. Craig and Jeff Boeke, a yeast biologist at Johns Hopkins, have made tens of thousands of yeast mutants using Tn7. With this technique, they were able to associate the changed behavior of a particular mutant with a Tn7 insertion at a particular site, allowing easy identification of the mutated gene. Knowing how a mutated gene’s behavior is altered often provides important insights into the function of that particular gene when it is not mutated.

"We're interested in applying this technique to bacteria to study what kinds of genes are important," Craig says. For example, E. coli, the common human gastrointestinal-tract bacteria, has about 4,300 genes. E. coli has been studied intensively for 50 years, yet the functions of 30 percent of its genes remain a mystery. "Sorting out who does what is important, and to do that we can use insertion mutants made with Tn7," she says.

Another distinctive feature of Tn7 is that it can preferentially hop onto bacterial plasmids that move between cells. This phenomenon underlies the dissemination of antibiotic resistance genes contained within the transposons. "Imagine you have an awful infection in the gut because of a pathogenic strain of E. coli, and you're prescribed tetracycline," Craig explains. "There might be other bacteria around that carry transposons having tetracycline-resistance genes on them. If those antibiotic resistance genes can move into your pathogenic E. coli by hopping onto a plasmid, then those E. coli will also become resistant to tetracycline. So it's the movement of transposons between cells that underlies this terrible problem of antibiotic resistance." Tn7 itself carries resistance to one of the drugs that is often prescribed for urinary tract infections — trimethoprim, which is one of the drugs in Bactrim.

Career Advice

Craig has been greatly gratified by her career thus far, and advises up-and-coming scientists to "do what you really want. I see far too many students today who ask, 'What area of research would be a good career choice for me, in terms of what's "hot"?' I think, especially in science, you simply have to be fundamentally motivated about a problem because it fascinates you."

Craig says that Bryn Mawr provided her with a wonderful foundation. Part of that is the excellent education she received. But another important part is "this very powerful sense of self as a person, and I guess that's particularly an issue for going into such a male-dominated field," she concludes.

About the Author

Karen Young Kreeger is a science journalist who writes on biomedical and women’s health topics, as well as careers in science. Her most recent work has appeared in Bioscience, Genome Technology, Muse and The Scientist.

 
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