“It’s my ambition that someday the word ‘topoisomerase’ will be in the dictionary,” says Professor Jim Wang, Mallinckrodt Professor of Biochemistry and Molecular Biology, who is retiring after 28 years at Harvard. He coined the word eight years after his discovery of the first topoisomerase in 1971, by shortening the term for topological isomers, which refers to different geometric shapes of a molecule. “Topoisomerases are enzymes that pass DNA strands or double helices through one another. In their presence, linked DNA rings or loops can come apart, and different topological forms of DNA can interconvert.”
For those unfamiliar with topoisomerases, Wang explains, “You have at least six of them. Otherwise, you’d be a mess, believe me. I can tell you what happens to our mice that lack just one of them.” Without one form, the embryos never develop; without another, brain development is defective and there are no live births; mice lacking a third form die young.
Topoisomerases also come in handy when you’re sick. They’re just as necessary for the life of bacteria. In fact, Cipro and “a whole zoo of antibiotics” work by targeting bacterial topoisomerases. In 1985, Leroy Liu, then a faculty member at Johns Hopkins and one of Wang’s former graduate students, found that many anti-cancer drugs target topoisomerases in fast dividing cancer cells. Liu’s findings led to two new drugs: topotecan in the U.S., and irinotecan in Japan.
Wang admits that he’s come long way from his undergraduate studies in chemical engineering. “Early on I focused on the chemical properties of DNA and now I’m manipulating the genes of mice.” He came to the United States in 1960, earned a master’s in chemistry from the University of South Dakota, and received his PhD in physical chemistry from University of Missouri. He spent his postdoctoral years at the California Institute of Technology, and from there he taught at University of California at Berkeley until he came to Harvard as a tenured professor in 1977. His colleagues sprinkle conversations about him with phrases like “brilliant but humble,” “dignified,” “Nobel-Prize quality,” “pioneering,” and “marvelous.”
The trajectory of his career began during his postdoctoral work. Ten years previously, when Watson and Crick discovered the double helix structure of DNA, they noted an “entanglement problem” that nature must solve in order for cells to replicate DNA during cell division.
As Wang explains it, the problem begins with the sheer quantity of DNA. Fitting the six feet of DNA inside each cell into the nucleus is like stuffing miles of strings inside a basketball. It must twist, and then twist on its twists. “You can imagine that the string gets tangled,” he says. “The problems inside a cell are worse, because DNA doesn’t just sit there.” For cell division, the strands of a parent DNA double helix are separated, duplicated, and then segregated into daughter cells. During transcription, trailing strings of mRNA also enter the picture. If DNA were prone to tangle, now the tangles should really get entwined. “That’s a fundamental problem that that nature must solve,” Wang emphasizes.
Realizing the immensity of this problem, as late as the 1970s some scientists still doubted that the double helix could really represent DNA’s structure in solution or in the living cell. But Wang not only verified the helical structure, he measured it. “Jim carried out a remarkably elegant experiment and found a very simple solution to measure the helical repeat of DNA in solution,” says MCB Professor Richard Losick, the Maria Moors Cabot Professor of Biology. “He would later teach it to undergraduates in an introductory course. When I taught the course and introduced a lab, I had them repeat Jim Wang’s experiment. Hundreds of undergraduates have now confirmed the structure of DNA in solution by the Wang method.” DNA in solution was shown to make a full helical turn every 10.5 base pairs, close to the number 10.0 in the Watson-Crick model.
As well as confirming the structure, Wang also elucidated important features of supercoiled DNA, how the helical DNA “twisted ladder” can itself be coiled. “It took many years to understand the different compacted forms of DNA that exist in nature and how nature goes about both creating and using them,” explains Simon Lynch, a postdoctoral fellow in his lab from 1989 to 1994 and now Director of Research at Cumbre Pharmaceuticals. “Jim’s early contributions launched whole new sub-fields that encompass both pure and applied research.”
Wang next tackled the problem of how DNA avoids entanglement. “The topoisomerases are nature’s magicians,” he says. “You can find linked or knotted DNA rings in nature, and these enzymes will separate or untie them just like magic. You add a tiny bit of topoisomerase and, zoom, a fishnet of DNA rings all come apart.”
He went on to discover the science behind this apparent magic. “To take two linked rings apart, you break one, move the other one through the cut, and then rejoin the cut,” he says. “A topoisomerase breaks a DNA strand and forms a link with it at the same time; the DNA-linked enzyme then finishes its job by rejoining the DNA strand. It’s a very clever enzyme, because it only transiently breaks DNA to solve the entanglement problem.”
One type of topoisomerase breaks one DNA strand to allow another strand to go through. A second type breaks both strands and escorts them through another double helix. “It’s amazing machinery. I’m very happy we figured out the way this works a few years ago,” he reflects. Over the course of 40 years, Wang wrote or contributed to 250 research papers and two books, which MCB colleague Nancy Kleckner, the Herchel Smith Professor of Molecular Biology, calls “definitive works in the field.”
Wang’s colleagues fondly recall his love of problem solving. “I asked him what he thought about an idea I had,” recounts Losick, “and he asked for time to think about it. He had an entire page of calculations showing me why I couldn’t possibly be right. Well, that remains to be seen! But I’d put my money on Jim more than me.”
Mark Ptashne, who helped recruit Wang to Harvard in 1977 and is now at the Memorial Sloan-Kettering Cancer Center, shares an experience of his own. “Jim had an idea contrary to my idea. He designed an experiment that disproved his own idea. Then he did another experiment that he thought disproved my idea, too. He does science for the right reason, trying to find out the truth about how things work.”
In the future, Wang predicts scientists will discover that topoisomerases play key roles in many biological processes including aging, but he thinks that “the baton has been passed” and he will no longer be continuing research in this field. He hopes to spend more time practicing classical Chinese poetry, and he is moving to Seattle, Washington, to be near two grandchildren, but not to flee the Boston winters. “I can be happy anywhere,” he claims.
Other than his ambition to have topoisomerase become a familiar word, Wang smiles. “I believe in retirement. Whether I like it or not, I will have to find out. I’m an experimentalist. That’s what I do.”