The nucleus of a typical human cell is just millionths of a meter across, yet the DNA inside is well over a meter long -- long enough to contain the entire human genome. With DNA so tightly folded and packed, it's a wonder any genes are accessible at all.
Terumi Kohwi-Shigematsu of Berkeley Lab's Life Sciences Division has learned how the bundle of DNA and proteins called chromatin rearranges itself to allow gene expression in cells known as thymocytes. The answer involves two principles that have fascinated her since her school days: biological structures and biochemical reactions.
When she was 16 her father, a Japanese official, moved their family from Tokyo to the Washington, D.C. area. In high school there, she recalls,
"I was fascinated that living things could be entirely made out of chemicals."
She majored in chemistry at Washington College, then got her master's degree in physical chemistry at Johns Hopkins University by using x-ray crystallography to study DNA molecules. But because she wanted to "study biological systems from broader angles, not restricted to the few molecules that could be made into crystals" -- and because in living things biological molecules interact dynamically -- she returned to Tokyo University for graduate studies in biochemistry.
There, DNA's different forms focused her twin interests in chemistry and structure. "At the time everyone assumed DNA remains double-stranded in living cells, but I believed DNA is dynamic and takes other forms."
She was 24 years old, at the turning point of her career. Encouraged by her thesis advisor, she proved that a simple chemical, chloroacetaldehyde ("It has a nice smell," she says, "but it can give you lung cancer") reacts with single-stranded DNA and is an excellent tool for examining protein-DNA reactions.
Meanwhile, in a neighboring lab, only one other graduate student, Yoshinori Kohwi, was also dedicated enough to work through the hot summer months without air conditioning. "We found each other alike, and we decided to get married."
With Ph.D.s in hand, the newlyweds faced a problem. "Nori was offered a tenured university position, but as a female in Japan I knew I would not get an independent research position." She applied to the National Institutes of Health and won a Fogarty Fellowship to study in the U.S. Kohwi decided to accompany his wife to the Hutchinson Cancer Research Center in Seattle, where both took postdoctoral positions.
When they later moved to the Burnham Institute in La Jolla, the institute hired an immigration lawyer to help have her government visa's strict requirement to return to Japan waived. "If I had returned," she says, "I would be a housewife by now."
After 13 years in La Jolla, Kohwi-Shigematsu and her husband decided to explore a different research environment at Berkeley Lab. Here they have worked both together and independently to unravel the secrets of DNA.