The tiny, transparent worm Caenorhabditis elegans can be born either as a male, typically with one X chromosome, or as a hermaphrodite, with two. When Barbara Meyer began a professorship at MIT in the 1980s, she wanted to pinpoint the genetic pathway that determined the worm’s sexual fate. There was evidence that this process was tied to dosage compensation, a delicate balancing act that ensures X-chromosome expression is matched between the two forms—a condition necessary for survival not only in worms, but also in humans, fruit flies, and other animals in which one sex carries two X chromosomes, while the other carries only one.
Meyer suspected that the gene responsible would control the levels of X chromosome expression in only one form of the worm—either it would limit expression in XX C. elegans, or it would boost expression in individuals with only a single X—and failure to do so would result in the animal’s death. Her team, however, struggled to find such a gene. Then, one day, a “eureka moment” almost got thrown down the drain.
In one experiment, her team was growing hermaphrodites with a mutation in a sex-specific gene they knew was involved in X dosage compensation. At first, as expected, the nematodes were growing poorly and dying, but then a lab technician noticed that they suddenly looked healthy and started multiplying. Thinking that there was a problem with the culture, he started to discard the samples in the sink. From across the room, Meyer shouted, “Stop!”
She suspected that those healthy worms might contain the answer to her question, and she was right. There had been a spontaneous mutation in what turned out to be the master sex-switch gene, responsible for both determining sex and repressing the expression of X chromosomes in hermaphroditic worms (Cell, 48:25–37, 1987). “In that [culture], through serendipity, was the long-sought-after gene that I wanted,” Meyer says.
An unexpected path
Growing up in Stockton, a small city in California’s Central Valley, in the 1950s, Meyer never thought she’d become a scientist. She was fascinated by the sciences, which she encountered both through interactions with an uncle who was an aeronautical engineer and via a wide selection of nonfiction books. But when asked in high school to write an essay about what she envisioned as her future career, Meyer wrote that she would become a medical lab tech. “[I wasn’t] even dreaming that I’d be able to have a PhD,” Meyer recalls. In her town, “there was no model for being a scientist . . . certainly not for a girl.”
Meyer longed to escape Stockton, which she describes as a rather isolated place. She imagined traveling the world like another of her uncles, a globetrotter who would visit with exotic gifts from faraway places. She got her first travel opportunity after she was accepted into Stanford University, which allowed her to study abroad. She spent a semester at the Stanford campus in Stuttgart, West Germany, in 1969. On one of her visits to Berlin, where the infamous wall split the city in two, Meyer remembers encountering a distressing sight: soldiers shooting at people who were trying to escape across the border into the West. “When you see these kinds of things, it makes you happier thinking about science because there’s some logic to it, rather than watching people get shot,” Meyer says. “That compelled me even more [to go into science].”
After completing her undergraduate studies, Meyer joined the lab of David Clayton, a developmental biologist at Stanford’s California campus. There, she used herpes simplex virus and mouse mitochondria to investigate a nucleotide-forming enzyme called thymidine kinase. “That convinced me that I really wanted to do [research],” she says. “Whether I could or not was another question, but I really wanted it.”
While working in Clayton’s lab, Meyer decided she wanted to pursue medical research and applied to medical school. During the application process, several interviewers told her that they saw her more as a researcher than a physician, or that if they offered her a position in a medical program, she would simply get married, pregnant, and drop out, Meyer recalls. She was ultimately rejected.
That was a demoralizing experience, she says, but it turned out for the best. She had also applied to graduate school, and soon after her med school rejections, she learned she’d been accepted into a program at the University of California, Berkeley—where she would not only earn her PhD, but eventually go on to become a leader in the study of genetic switches.
A fateful switch
In graduate school, Meyer focused on viruses that infect bacteria. One such bacteriophage, the famous lambda phage, can live one of two lifestyles: a peaceful one, where it stays dormant in a host’s DNA, or a violent one, where it hijacks the host’s cellular machinery to replicate, then releases its progeny into the environment.
When Meyer started at Berkeley, she was intrigued by the factors that influenced how the lambda phage ended up on one of these two paths. At the time, scientists had discovered that the phage itself carried a repressor, a protein that inhibits gene expression by binding to DNA. They knew this protein was involved in determining a phage’s fate, but the mechanism behind its function was an open question. “The fact that there was a genetic switch that enabled that decision—I really wanted to understand that,” Meyer says.
Her advisor, Harrison Echols—a biologist who conducted pioneering work on bacteriophage lambda—thought that trying to understand the genetic switch was too difficult for her to pursue, Meyer recalls; as an alternative, he suggested she map out all the promoter sequences for RNA polymerases in the lambda phage’s DNA. So, she put her passion project on hold and began mapping polymerase promoters.
A few months later, she sat in on a seminar by molecular biologist Mark Ptashne, then a professor at Harvard University. Ptashne had been the first to isolate the lambda repressor protein, and his lab was in the process of investigating how it controlled the phage’s fate. According to Meyer, he too discouraged her from trying to tackle the question of the bacteriophage lambda’s genetic switch. “He said, you can’t possibly compete with us, so forget about it,” she recalls. But when she ran into him again a year later at a conference at Cold Spring Harbor Laboratory in New York, Ptashne asked her to sit in on meeting with a few members of his team, where he surprised Meyer by inviting her to his lab at Harvard to conduct the experiments on bacteriophage lambda that she was dying to do. “I had been dreaming about this for a whole year, and then this miracle happened,” she says.
After Echols approved the transfer, Meyer packed her bags and moved to Cambridge, Massachusetts. Within a few weeks of joining Ptashne’s lab, she had demonstrated that the lambda repressor regulated the transcription of its own genes in a test tube (PNAS, 72:4785–89, 1975). For her, this was an “aha” moment that led to a cascade of follow-up experiments and around a dozen papers during her PhD studies alone.
Working with Ptashne taught Meyer to be both a rigorous scientist and an expert communicator, she says. Ptashne is “a master at figuring out how to get messages across. . . . Plus, he had little patience, so your experiments had to be perfect for him to believe them,” she tells The Scientist. “I think that was all part of my education.”
Sex and death decisions
After completing her doctoral studies in 1979, Meyer wanted to find a research question that she could make her own—and a more complex organism in which to study developmental biology. For her postdoc, she moved across the Atlantic to Cambridge, England, to work at the MRC Laboratory of Molecular Biology. There, she joined the lab of Sydney Brenner, a biologist who later would win the Nobel Prize for his groundbreaking work on C. elegans.
Meyer chose to study the nematode because she was drawn by the question of how its sex is determined. “I was fascinated again by a binary developmental decision,” Meyer says. “It was the same idea [as with the lambda phage], but on a much huger scale.”
Jonathan Hodgkin, a nematode biologist who had been a graduate student in Brenner’s lab, had already identified a mutation that caused genetic males to become hermaphrodites, and vice versa. But Meyer wasn’t convinced that this mutation explained the sex switch, because there had been hints from previous research that the switch might be linked to dosage compensation of X-linked genes. Too much or too little X expression is lethal, so “I thought I couldn’t just look for sex reversal, because the animal I’m looking for might be dead,” Meyer explains.
Years earlier, biologists Victor Nigon and Robert Herman had shown that C. elegans embryos were sensitive to the number of X chromosomes relative to sets of non-sex chromosomes called autosomes in their genomes. By studying animals that carried two, three, and four sets of autosomes, they discovered that worms born with an X chromosome:autosome ratio between 0.5 and 0.67 would be male, while ratios between 0.75 and 1 would be hermaphrodites. (Other ratios would either be lethal or impossible to generate.) There had also been work by Thomas Cline, a geneticist who was then at Princeton University, that revealed a link between sex determination and dosage compensation in fruit flies.
Meyer decided to work backwards in the worms, screening for genes that were involved in dosage compensation. Eventually she found autosomal genes that, when disrupted by mutation, led to abnormal levels of X-chromosome expression (Cell, 47:871–81, 1986).
“Barbara is a brilliant and creative scientist,” says Cynthia Kenyon, the vice president of Calico, a San Francisco-based biotech company. Kenyon, who met Meyer while the two were both graduate students at Harvard in the 1970s, says that Meyer will “stop at nothing to figure out how to dissect a system of incredible complexity.”
Meyer continued her work on C. elegans at MIT in Cambridge, Massachusetts, where she started a professorship in the early 1980s. Anne Villeneuve, a Stanford University geneticist who was one of Meyer’s first graduate students at MIT, says she was inspired by Meyer’s boldness in the early days of her lab. “She had to have confidence in the system that she was building from scratch, and she had to believe that it was going to work out,” Villeneuve says. “Once it was built, everyone could see how cool it was.”
Her worm system led to the drain-dumping-turned-eureka moment, as well as to many other important insights into the molecular machinery involved both in dosage compensation and in other fundamental cellular processes, such as meiosis.
A brush with fate
During Meyer’s early days of working on C. elegans, Princeton’s Cline was but a faceless author on papers she’d read with great interest. She was amazed by the quality of the manuscripts, and because he was the only author on many of them, she suspected that he must have had a long career in academia—and thus was many decades older than her.
Meyer later learned that this was not the case: Cline was, in fact, only a few years her senior. The two met for the first time at a developmental biology conference in 1981 and bonded over their shared scientific interests. They started dating several years later, in 1986, and once their romance began, things moved quickly—within a month of getting together, they were married. “I fell in love with him from reading his papers,” Meyer says.
When the couple got married, they were professors in different states: Cline was in New Jersey, and Meyer in Massachusetts. Cline, like Meyer, was from California, and he wanted to return. Although Meyer loved MIT and the fast-paced lifestyle of the East Coast, managing her father’s health care from across the country was proving to be a challenge. After her father had a heart attack, Meyer and Cline moved back to their home state, where they both obtained faculty positions at Berkeley.
One of the defining features of the couple’s now decades-long relationship has been a common passion for science. Together, they have coauthored a handful of review articles, and to this day, they edit each other’s papers. “We’re each other’s best critics,” Meyer says. The two also share a love of hiking and have trekked along numerous, sometimes-treacherous trails around the world.
On one evening outing with Cline on Costa Rica’s Osa Peninsula in 1999, Meyer took a wrong step in the dark and fell off a 12-foot-high cliff. She landed on her back and shattered her ankle, but she considers herself lucky: there was a block of concrete right by her head, and iron rods jutting out from the space between her legs. “It makes me realize that anything can happen at any moment, and you better live your life well,” she says. “It made me think really hard about what could happen in the future—so I’m very good at troubleshooting in advance.”
That preparedness has served Meyer well both inside and outside of the lab. Throughout her career, she has juggled many tasks, from running her lab and mentoring countless students to organizing scientific meetings and serving on numerous advisory boards for universities, professional societies, and both governmental and nonprofit organizations. And, she’s still determined to crack more scientific mysteries—for example, to further unravel the biochemical mechanisms underlying dosage compensation and to understand how chromosome structure affects gene expression.
“There are quite number of big questions left,” she says.
Diana Kwon is a Berlin-based freelance journalist. Follow her on Twitter @DianaMKwon.