Barbara J. Meyer: 2018 Thomas Hunt Morgan Medal

Abstract

The Genetics Society of America’s (GSA) Thomas Hunt Morgan Medal honors researchers for lifetime achievement in genetics. The recipient of the 2018 Morgan Medal, Barbara J. Meyer of the Howard Hughes Medical Institute and the University of California, Berkeley, is recognized for her career-long, groundbreaking investigations of how chromosome behaviors are controlled. Meyer’s work has revealed mechanisms of sex determination and dosage compensation in Caenorhabditis elegans that continue to serve as the foundation of diverse areas of study on chromosome structure and function today, nearly 40 years after she began her work on the topic.

FROM the beginning of Barbara Meyer’s scientific career, her work has led to insights that now stand as textbook paradigms. In graduate school, Meyer helped establish λ-phage as an important model for transcription and gene regulation. As a postdoctoral researcher and junior faculty member, she identified the sex determination master switch in C. elegans and characterized the dosage compensation complex (DCC) that equalizes the expression of X-linked genes between the sexes, opening areas of research that her laboratory and many others continue to work on today.

In his nomination letter for the Morgan Medal, Gary Ruvkun describes Meyer’s career as taking “an astoundingly unique intellectual trajectory” that has led her to remain at the cutting edge even after decades of work. “She is still a champion with a killer forehand,” writes Ruvkun.

A retrospective survey of Meyer’s career could give the impression that every step was carefully orchestrated from the beginning, but, according to Meyer, that is not the case: “I didn’t plan my career,” she says, “it just kept happening.”

In fact, Meyer did not start her academic career with plans to become a biologist. In high school, she found biology the least appealing of her science subjects, with classes that were largely based on rote memorization. In her college years at Stanford University, Meyer disliked most laboratory courses, and she considered attending medical school rather than graduate school. However, once she became involved in independent research, she realized it had actually been the prefabricated experiments and predetermined answers that made the laboratory courses dull. That tipped the scales in favor of graduate school.

At first, her graduate studies did not go according to plan. Meyer started at University of California, Berkeley with Harrison Echols, but she ultimately transferred to Mark Ptashne’s laboratory at Harvard University to pursue her interest in understanding how some viruses determine whether to replicate and lyse their host cells or become dormant, a process known as the lysis–lysogeny decision. It would have been entirely understandable if Meyer had struggled to reach her research aims after changing advisors and moving to a university across the country, but it was then that she started to become recognizable as the prolific scientist she is today. In Ptashne’s group, Meyer dissected how λ-phage “decides” to switch between lytic and lysogenic growth, revealing key aspects of how a relatively simple gene regulatory system can exert precise control.

Meyer published 12 papers based on this research and received faculty job offers from Caltech and Massachusetts Institute of Technology (MIT) just as she finished her PhD. But rather than reap the immediate rewards of her success, she decided to push herself in a completely new direction: “I thought, it was time to prove to myself that I could start a research area from scratch,” Meyer says.

MIT generously held her position for 3 years while she worked as a postdoctoral researcher with Sydney Brenner at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England. Brenner’s laboratory had captured Meyer’s attention because they were beginning to work with the nematode worm C. elegans, which was then a promising new genetic model organism.

Like phage “choosing” between growth modes, worms face a developmental choice between two distinct fates—hermaphrodite and male—and Meyer became interested in how this decision is made. Using C. elegans offered huge potential for understanding the regulation of development, but in these early days of worm genetics there were few tools available for the type of mechanistic work Meyer planned. Applying molecular genetics used for studying viruses to worms would take her into uncharted territory.

But the decision paid off. Switching to a relatively untested model meant investing considerable time and effort, but Meyer has ended up with a powerful system that has continued to provide major insights across her career, from her postdoctoral research years to her years at MIT, to her eventual return to her native California for a position at University of California, Berkeley, where she became a Howard Hughes Medical Institute Investigator.

At the time that Meyer first turned to the worm, it was known that C. elegans “counts” the number of X chromosomes to determine sex. Hermaphrodites have two (XX), while males have only one (XO). Prior genetic work had indicated that the ratio of X chromosomes to sets of autosomes (X:A) is the key factor that specifies sex in worms. Even tiny differences in the ratio can be detected: a worm with an X:A ratio of 0.67 is a fertile male, but a worm with an X:A ratio of 0.75 is a fertile hermaphrodite. Meyer sought to understand how this finely tuned system works at the molecular level, and how the worm compensates for one sex having twice as many X chromosomes as the other.

Meyer’s group first showed that C. elegans compensates by turning down expression of genes on both hermaphrodite X chromosomes by half (Meyer and Casson 1986). By investigating mutations that were preferentially lethal in hermaphrodites, they uncovered key molecular players in this phenomenon and established that dosage compensation was set in motion by the same signals that controlled the sex determination pathway—a fact that opened the door for the group’s identification of the master switch.

The breakthrough that set the stage for this discovery was moments away from being missed. A technician had been about to pour down the drain what looked like a useless flask of mutant nematodes that had reverted to wild type when Meyer shouted across the laboratory, “Save the culture!” After a closer examination, they discovered that the flask contained worms with a spontaneous suppressor mutation in what would prove to be the master sex-determination gene, which she named xol-1 (for XO lethal) (Miller et al. 1988). “That’s when I realized our research directions were going to work out,” Meyer says. She knew that by screening for mutations that suppress the death of the XO-lethal mutant, they could eventually find almost everything in the pathway.

Following the last-moment rescue of that culture, Meyer’s group has, over the years, developed an explanation for how the worm senses tiny differences in the X:A ratio. The key is a molecular battle for control of the xol-1 promoter. Expression of xol-1 triggers male development; when it is repressed, the worm develops as a hermaphrodite. The signal that turns xol-1 on or off is the relative levels of factors encoded on the autosomes vs. the levels of other factors encoded on the X chromosome. That is, xol-1 expression is activated by autosomal transcription factors and repressed by opposing X-linked transcription factors (Carmi et al. 1998; Powell et al. 2005; Farboud et al. 2013). A second layer of control is provided by an X-linked RNA binding factor that prevents proper splicing at a xol-1 intron, generating a nonproductive transcript (Nicoll et al. 1997). Interestingly, a similar concept of autosomal signal elements and opposing X signal elements was proposed by Calvin Bridges in 1921 for sex chromosome counting in Drosophila (Bridges 1921), but it was ultimately found that flies do not actually use such a system. Bridges had the right idea but for the wrong organism.

Less than a year after publishing their initial findings on the critical role of xol-1 in specifying male fate, Meyer’s laboratory reported their discovery of an X-linked gene that controls hermaphrodite development and dosage compensation in XX worms (Nusbaum and Meyer 1989). The expression of this gene, which they dubbed sdc-2 (sex determination and dosage compensation), is repressed by XOL-1 in males and encodes a protein that is recruited to the X chromosome, where it triggers assembly of a large complex involved in repressing X transcription (Dawes et al. 1999). By painstaking dissection of the structure and function of this DCC over the years, Meyer’s team has made surprising and impactful discoveries that touch many areas of chromosome behavior and gene regulation (e.g., Mets and Meyer 2009; Brejc et al. 2017).

The DCC turned out to resemble condensin, a highly conserved protein complex that is integral to many aspects of chromosome organization and segregation during meiosis and mitosis. In fact, the DCC shares 4 of its 10 subunits with condensin complexes involved in mitosis and meiosis (Chuang et al. 1994; Lieb et al. 1998; Mets and Meyer 2009), while other DCC subunits do double-duty with complexes involved in histone methylation (Pferdehirt et al. 2011; Brejc et al. 2017). To achieve mass repression of the entire X, the worm seems to have co-opted the machinery used for multiple aspects of large-scale chromosome management.

Recently, a collaboration with Job Dekker (the recipient of GSA’s 2018 Novitski Prize) revealed a key aspect of the mechanism by which the DCC represses transcription: chromosome-wide remodeling. Dosage compensated X chromosomes have a highly organized structure including self-interacting domains that resemble the recently discovered mammalian toplogically associating domains (Crane et al. 2015). This marked the first discovery of a specific machinery and DNA target sequences regulating formation of toplogically associating domain structures, opening up the burgeoning field of higher-order chromosome structure for new mechanistic insights.

Meyer’s colleagues are not surprised by her scientific success. Cynthia Kenyon, now a vice president at Calico Labs, was a postdoctoral researcher in the Brenner laboratory with Meyer and says Meyer’s approach to science is reflected in all aspects of her life: “She does everything to perfection, actually. Her work is beautiful, as is the way she presents her work, her house, her furniture, cooking, garden, everything,” says Kenyon.

Meyer herself cites laboratory members and collaborators as being critical to her success. Over her career, she has mentored more than 70 graduate students, postdoctoral researchers, and PhD research specialists. The first student to graduate with a PhD from Meyer’s laboratory was Anne Villeneuve, now a professor at Stanford University. Says Villeneuve, “She has been a friend and a mentor to me all along. She’s somebody who was always encouraging to me and somebody I could call as a sounding board if I’m trying to figure out how to navigate something.”

Reflecting on her own navigation of science, Meyer says, “It hasn’t been linear, but the questions we address have become more and more tractable as we develop more powerful tools and discover more answers. We continue to let the genes and molecules lead us into new and deeper mechanistic and evolutionary directions.”