Measuring Up

In 1963, Nancy Hopkins sat down in a Harvard lecture hall for an hour that would change the course of her life. The lecture was on genetics, and the speaker was none other than James Watson, the charismatic co-discoverer of the structure of DNA. In that hour, Watson spoke about the molecule and its genetic code, which was still being unraveled.

Hopkins, then a junior at Radcliffe College, was deciding on a career path. “I was trying to escape my destiny, which was to marry and have children by the time you were 30,” she says. It was also a time in her life when she was looking for meaning. Watson supplied it. “He was able to convey that really everything biological was the product in some way or another of this one molecule and its particular nucleotide sequence,” she says. “It was one gigantic puzzle; all of biology was somehow in there.” DNA and the new science of molecular biology might even get to the root of thorny questions about human behavior or solve a problem like cancer.

More than 50 years later, Hopkins, the Amgen Professor of Biology emerita at MIT, is winding down an extraordinary career in which she made important contributions to molecular biology and helped catalogue the genes required for a fertilized egg to develop into higher organisms. Along the way, she took a courageous stand against gender bias in academic science at MIT and beyond. Hopkins not only instigated an investigation that grew into the landmark 1999 report on the status of women at MIT, but she devoted time to making sure it got results. “With her guts and her passion, she is really an example of how to be an activist,” says Sangeeta Bhatia, director of the Laboratory for Multiscale Regenerative Technologies at MIT and part of a generation of MIT women whom Hopkins has inspired. “I probably wouldn’t be here were it not for the changes she had implemented.”

Her determination is wrapped in charm and good humor. Hopkins, who officially retired in 2014 but still has an office at the Koch Institute for Integrative Cancer Research, continues to help younger colleagues address remaining obstacles to gender parity. She’s also devoted the past few years to another cause: urging cancer biologists to focus on preventing disease.

23 Fish

After Watson’s fateful lecture, Hopkins decided to study molecular biology and joined his lab at Harvard. Watson encouraged her to pursue a career in the field, which then had few women. She worked as a technician for Harvard biologist Mark Ptashne as he tried to use a simple virus called bacteriophage lambda to isolate a protein called a repressor, which inhibits gene expression. Hopkins and Ptashne succeeded in isolating the protein, a major advance in molecular biology. Technicians were not named on papers at the time, though, so her contribution was not credited.

Eventually, Hopkins completed her PhD at Harvard, spent two years working with Watson as a postdoctoral fellow at Cold Spring Harbor Laboratory, and in 1973 was recruited to lead her own lab at MIT’s newly formed Center for Cancer Research. She spent the next 15 years or so working on unraveling the biology of tumor-causing viruses. Though she made some key discoveries, Hopkins struggled for recognition and support. “Once I was on my own, I found it difficult,” she says. She thought the problem might be working on cancer, which was closely aligned with the male-dominated field of medicine.

Wanting a change, she turned to a field where women were succeeding: developmental biology. A prominent German scientist, Christiane Nüsslein-Volhard, had uncovered a large number of genes involved in fruit fly development, for which she would eventually win the Nobel Prize. During a sabbatical in Germany in 1989, when Nüsslein-Volhard’s lab was switching to studying zebrafish, Hopkins thought it might be possible to use the diminutive striped fish to study one of her long-standing interests, the genes underlying behavior.

She quickly saw that zebrafish research wasn’t advanced enough to support that goal. But Hopkins found the fish entrancing. In a matter of hours, she watched the eggs divide and the cells grow into bodies with heads. By the next morning, tails were wiggling. It was all transparent and clear as day. “It starts with this fertilized egg and the next day it’s a fish; I mean, it’s breathtakingly beautiful,” she says. And the fish had a backbone; until then, most large-scale studies of genes and development had been done in invertebrates.

Hopkins saw an opportunity to answer a big question: what genes are necessary to construct a vertebrate embryo from a single fertilized egg? Nüsslein-Volhard and others had been pursuing similar projects in invertebrates using an approach called forward genetic screening, which can help uncover gene functions that scientists wouldn’t otherwise find. The idea is to randomly introduce mutations into the DNA of thousands of organisms, screen for mutant organisms with a certain characteristic (such as failure to develop properly), and then map the genes affected in those mutants. Hopkins wanted to identify a catalogue of genes without which an organism fails to develop.

Taking this approach with fish would require new tools. Hopkins returned to MIT with a goal and 23 fish in a tank, but shifting the focus of her career in her late 40s was no easy feat. With a project too risky for traditional grant funding, she began with $30,000 a year from a friend, followed by small grants from the National Science Foundation. Then she applied for funding allocated to MIT from the pharmaceutical company Amgen and got $8 million to develop a genetic screen.

Other labs were using chemicals to randomly mutate zebrafish DNA. Hopkins created mutations by inserting new DNA into the genome. The genetic sequence of the inserted DNA also acted as a flag signaling its position, making it much easier to know which gene was affected. As luck would have it, Hopkins’s previous work with cancer viruses made the work possible; her lab was able to use a similar type of virus—one made of RNA, called a retrovirus—to randomly disrupt zebrafish DNA.

Getting the first mutants was exciting; Hopkins still has the champagne bottles she broke out. But the goal was to scale the project up, which meant breeding tens of thousands of mutated fish to isolate a few hundred of the genes involved in development. Hopkins needed to find lab members willing to commit to a slow and time-consuming process. The payoff would come at the end, when they could divide up mutants of interest and launch their own labs to use the tool they’d created.

“She was so enthusiastic when I met her,” says Shuo Lin, now a researcher at University of California at Los Angeles, who came to the project as Hopkins’s first postdoc and helped develop the retrovirus technique. Lin had never worked with zebrafish before and admits he didn’t know what he was getting into. “I just liked her, to be honest,” he says. Adam Amsterdam, who arrived as a student and stayed as a postdoc and then a research scientist, was also critical to making the project work. Lab manager Sarah Farrington painstakingly tracked every single fish. The lab had weekly goals: Hopkins diligently recorded their progress on a bulletin board and insisted that results be rechecked. “It was a rough slog for a few years,” Amsterdam says. Rather than letting them stop to explore interesting genes as they came up, Hopkins kept the lab focused on the big picture.

By 2004, the lab had identified 315 zebrafish genes, about 25 percent of those needed for the animal’s development, and Hopkins was elected to the National Academy of Sciences. Generating zebrafish mutants—they would ultimately identify more than 500—yielded other observations, including a set of genes related to cystic kidney disease that Zhaoxia Sun, who is now at Yale, discovered as a postdoc. Some mutants developed tumors. In 2002, Hopkins began a long-term collaboration with the lab of Jacqueline Lees, a professor of cancer research at MIT, to study tumor-causing—and tumor-suppressing—genes in zebrafish.

“Her work really catapulted the zebrafish model forward as a top discovery tool to uncover genes that regulate development and cancer,” says David Langenau, a researcher at Harvard Medical School. Hopkins’s lab became a repository of mutant fish that were freely accessible to researchers from around the world who came to study them or had embryos sent to their own labs. Eventually, the lab froze sperm from the entire collection for posterity.

Battling Invisibility

Early in her career, Hopkins thought she knew why so few women chose to go into science: because running a lab was time-consuming and hard to combine with motherhood. (She herself had made the difficult decision to forgo having children to focus on science.) But she came to realize that this wasn’t the whole story. While some scientific colleagues were supportive, “there was a kind of invisibility,” she says. “You would do experiments and publish them, and it was like you were invisible, your work was invisible, what you said was invisible.”

Initially, she blamed herself for not being aggressive enough. Then she noticed that other women’s discoveries were being coopted by men, who won the resulting accolades and leadership positions. She had hoped leaving the cancer field would help, but in the early 1990s, Hopkins had to fight to get 200 more square feet of lab space for her zebrafish, even though she was a senior scientist. That is when she found herself becoming a crusader against gender inequity. She famously took a tape measure and compared the size of her lab to those of male colleagues. She found she had less space (1,500 square feet) than the average for male junior professors (2,000 square feet) and far less than fellow full professors who were male (3,000 to 6,000 square feet). Around the same time, she had been removed from teaching a class she’d spent years co-developing—MIT’s first biology course—when her male colleague took it over. “I decided that I was going to dig in my heels and fight back,” she says.

In 1994, over lunch at a corner table at the Kendall Square Rebecca’s, Hopkins showed biology professor Mary-Lou Pardue a letter she’d drafted to MIT president Charles Vest about the discrimination she’d observed. Pardue immediately wanted to sign it too. They drew up a list of other tenured women in the School of Science to speak to first (there were only 15, alongside 202 men). “We were sort of scattered about,” says Institute Professor Sallie (Penny) Chisholm, who had a joint appointment in the Schools of Engineering and Science. Once they began talking, nearly all of them united in an effort to document and address long-standing inequities. “Nancy’s role was to lead and to keep the group together,” says Chisholm. “There’s no question in my mind that without her it wouldn’t have happened.”

A committee led by Hopkins produced an internal report in 1996; she also worked on the groundbreaking Report on Women in Science in 1999, which Lotte Bailyn pushed to make public. These reports laid out how women were increasingly excluded as they tried to move up the career ladder. Vest embraced the results, and the reports and subsequent Institute-wide follow-ups led to changes at MIT and universities around the nation.

MIT began working to recruit more women to the faculty, appoint more women to committees and leadership roles in departments and the administration, remove the stigma around taking family leave, and offer day care and other services for parents. And when Vest stepped down as president in 2004, he was succeeded by biologist Susan Hockfield, the first woman—and first life scientist—to lead the Institute. Those changes happened thanks in no small part to Hopkins’s persistence. “There’s a whole generation of women, including myself, who look at her and say, ‘Okay, that’s how you do it,’” says Sangeeta Bhatia.

Hopkins says the MIT report changed the national conversation on gender because it had the support of MIT’s leaders, who were willing not only to admit their bias but to turn words into actions. “They changed policies; they built day care on campus, which was unimaginable. Having children became normal, having family leave became normal,” she says. “Those were monumental breakthroughs. Putting women in the administration, realizing you really needed them to be in powerful positions, was critical. These things really changed everything.”

But while Hopkins would have liked this movement to set everything right for women, she acknowledges that it hasn’t. A 2011 follow-up report for the Schools of Science and Engineering found that MIT had become a more supportive place for women, but that issues still remained with hiring, promotion, and child care. Today, 20 percent of MIT’s tenured faculty members are female. The 34 in the School of Science account for 17 percent of the school’s tenured faculty—up from 7 percent in 1994—but all seven scientists granted tenure in the School of Science on July 1 are men. In some fields (such as math), fewer women pursue PhDs; in others (such as biology), women are well represented as students but their numbers fall at the faculty level. One problem, identified in a 2014 PNAS study by Jason Sheltzer and Joan Smith, may be a lack of women hired as postdocs at elite laboratories. “MIT hires women [faculty] at the same rate as the applicant pool. If they aren’t applying, we must be doing something wrong,” she says. “What is it?”

Another concern is that the gains women have made in academia aren’t reflected in scientific advisory boards, venture capital funding, and executive leadership in biotech. “When you work at something, as MIT did, things change,” Hopkins says. “When you don’t, nothing happens. This was the big lesson we all learned. Time alone doesn’t change anything; people change things.”

Hopkins made headlines again in 2005 when she walked out of an academic conference after economist Lawrence Summers, then the president of Harvard, asked whether innate differences between men and women caused the dearth of women in science and engineering. Comments like these, she believes, ignore the well-documented effects of bias. One thing she learned from studying gender on campus is that women on the faculty “had to be perfect,” she says. “If they made one error, they were out.” What’s more, she realized that work by a woman would be perceived differently from identical work by a man. Acknowledging that was deeply painful. “You have to face the reality that that is truly how your colleagues see you. They don’t think you’re very good; that’s the underlying horror of this gender bias,” she says. “Every day, you thought you were interacting on the same level, but you were not.”

Recognizing the role of cognitive biases helped Hopkins understand the kinds of steps needed to make workplaces fair. We don’t yet know how to make people less biased, she believes, so it’s important to continuously measure the effects—such as unequal representation and salaries—and create policies to correct them. To that end, she’s been working with Bhatia to track gender imbalances in entrepreneurship among MIT alumni and faculty. Bhatia hopes the data can spur further changes in the steps universities take to help members of the community make a bigger impact.

Rethinking the War on Cancer

Even after retiring, Hopkins still has her hand in several projects. Notably, she’s returned to the cancer field from a new angle. At a conference a few years ago, an epidemiologist said that up to 70 percent of cancer deaths worldwide are preventable. The statistic is commonly cited in public health, but it was news to her—and would be, she suspected, to many molecular biologists.

Hopkins, who herself was successfully treated for breast cancer, knew that some cancers were caused by behaviors such as smoking. But the statistic forced her to see the problem differently. If cancer prevention could have such dramatic results, why was the field so singularly focused on developing drugs?

At every turn, cures for most cancers have been elusive. When Hopkins left the field in the late 1980s, scientists were optimistic about the emerging science of oncogenes (human genes that, when mutated, lead to cancer). More recently, drugs have been developed to target specific genetic mutations. They have been helpful in some cancers, but cancer genomes, it turns out, are chock-full of mutations and rapidly develop new ones. Excitement is now shifting to cancer immunotherapy; but again, the most promising results are limited to a few cancers.

Hopkins doesn’t question the value of this research, but she believes that prevention is just as important. In 2012 and 2013, she spent several months on a sabbatical at the epidemiology department at the University of Texas M.D. Anderson Cancer Center to learn about the impact of anti-smoking campaigns, screening tests, and other public health measures. She teamed with Koch Institute director Tyler Jacks and Edward Scolnick, a core investigator at the Broad Institute and professor of the practice in biology, to organize the Koch’s first symposium on early detection and prevention of cancer in 2016.

“I think she’s absolutely on the right track,” Scolnick says. While he believes that research on cancer genetics is important, “some of that money that goes into the cancer field should be reprogrammed for prevention and early detection, because the impact will be far greater.”

Today, Hopkins is still interested in the big problems that lured her as an undergraduate. But the solutions look a lot more complex than they seemed in Watson’s lecture hall. Then, the DNA code seemed to hold answers to fundamental questions about life. Now, she realizes that phenomena as complex as human behavior “won’t be explained in a simple way by a small list of genes.” Indeed, she thinks some of her most profound discoveries have come from observing gender biases in her own colleagues. And she’s realized that we can do as much today to tackle cancer through changes in behavior and health care as we can by studying cells and genes.

Asked what she hopes her scientific legacy will be, Hopkins cites early work in understanding gene expression and her better-known role in making zebrafish a widely used research tool. But then she wryly dismisses the question. “In time, most science just gets absorbed,” she says, and the contributions of all but a few legendary scientists are forgotten: “At the end of the day, it’s Darwin, Mendel, Watson, and Crick.” And then she adds pointedly, “And Franklin.”

She’s speaking of Rosalind Franklin, whose critical contributions to identifying the double helix structure of DNA were not always recognized. If Hopkins is indeed remembered in the future, she suspects it will be for helping to make science a place where women are less invisible than Franklin has been—and find a more welcoming environment to make their own mark.  

Courtney Humphries is a contributing editor for MIT Technology Review and a freelance writer covering biology, health, and culture for a variety of publications.