What aspects of your life as a researcher do you most enjoy?

As an experimentalist, I love the cycle of planning and doing an experiment to test a hypothesis, getting results (often unexpected), and then reconstructing the hypothesis. What attracts me most is learning something new. As a lab or institute leader, it is somewhat different. What I liked most was helping others learn to be totally honest in the face of their own results. We scientists are often fooled by what we think we see in data, and sorting out what a result really means is important.  So, the goal is to help others understand what their own research tells them. Of course, it can be depressing to realize that an experiment did not mean what you thought it would, thus a supportive leader needs to be enthusiastic, whatever the result!

Tell us about one of your favorite papers from your lab and/or from another lab

I was always drawn towards the use of genetics because it provides a clean, reproducible logic for biology, which can otherwise be pretty messy. The creation or isolation of mutants helps sort out complex pathways of dependencies, and tests hypotheses.

My favorite paper of all time is Lee Hartwell’s 1974 paper [1] in which he describes the cell cycle as a series of dependent events (and some independent events) that ensure cell division. He established the entire cell division cycle with the brilliant use of conditional mutants that arrested with landmark phenotypes under non-permissive conditions. It is a classic paper that instilled in me a deep respect for genetics, and for organisms in which genetic approaches can be applied rigorously. Both yeast and worms allow that.

It follows, then, that my favorite among my own lab’s papers is based on a genetic screen: one performed in C. elegans to identify factors involved in creating and positioning heterochromatin in the interphase nucleus. We used an integrated repetitive array that would express GFP upon derepression and bind its product, so we could monitor heterochromatin by microscopy. My student, Benjamin Towbin, now a professor at the University of Bern, did a genome-wide RNAi screen in worms and came up with 29 strong regulators of heterochromatic silencing, and two that regulated position. We spent years following up on this screen, which generated further Cell papers. Not surprisingly, Towbin et al., 2012 [2], is one of my favorite papers. 

What do you see as the main ‘impacts’ of research in your field?

Since histones and chromatin factors are conserved across eukaryotes, most of our chromatin studies in worms and yeast have direct parallels in mammals. For instance, the role of histone H3 lysine 9 methylation in stabilizing repeats by preventing transcription in C. elegans [3] has strong parallels in mice and man, with implications for genome instability in aging and cancer. Note that retroviral and repeat element transcription is a trigger of inflammation and innate immunity response in human disease. 

Similarly, the role of chromatin remodeling and DNA dynamics at sites of DNA damage in yeast has also influenced research in mammals. We showed early on in yeast that telomeres and sites of DNA double-strand breaks cluster together in the nucleus, and in some cases shift to the nuclear pore. This localization depends both on the chromatin context of the lesion and on sumoylation [4], and helps determine the repair pathway to be used. 

What are the most important new technologies in your field in the past 10 years? Has theoretical modeling played an important role?

Studies of chromatin and nuclear organization depend on high-throughput sequencing-based technologies like Hi-C, DamID, ATAC-seq, CHIP-seq, as well as high-resolution imaging of single proteins, nascent RNAs and DNA. These have driven the field forward. They allow us to be more quantitative, less anecdotal, and to generate biophysical models of chromatin dynamics. 

Indeed, the field of 3D chromatin folding is well-suited for theoretical modeling, because at its root is a polymer fiber that behaves according to physical rules. Modeling has helped us predict how a chromatin fiber compacts, moves, and how that might be affected by nucleosome shifting or removal – not to mention the long-range folding of DNA into loops. We even modeled how a resected double-strand break can find its homologous template for repair [5]. 

Whereas theoretical modeling can provide explanations and hypotheses, one still needs genetics and quantitative cell biology to test them. This explains my commitment to systems in which genetic manipulation can be performed in a controlled and efficient manner.

What do you consider your most important contributions as an institute director or outside of the lab?

During the first 20 years of my career – until I was 45 or so – I simply avoided facing the issue of the low numbers of women in Swiss academic science. I concentrated on my research and made the most of the opportunities that opened for me. Fortunately, I had excellent (male) mentors, who supported my career aspirations. Then a series of things happened: I became head of a research institute, and a bit later, chairwoman of the Gender Equality Commission for the Swiss National Science Foundation. Through the latter, I learned that the number of women professors at Swiss universities had only increased from 6% to 11% during a 20-year period (1993–2013). Clearly the hiring of professors was imbalanced, particularly in STEM fields. But worse than that, it seemed that something in the Swiss academic system discouraged women from taking leadership roles, given that women made up ~50% of the PhD students, and 40% of the postdocs. I could no longer look away.

The rectors of the seven Swiss universities had tried to make recommendations or “non-binding quotas” about hiring women, with limited effect. I myself was biased against quotas, for I thought they might work for a while, that is, to “reset” a system, but then might evoke a backlash. I imagined resentment growing against female colleagues, if it looked as if candidates were hired based on gender, rather than their professional qualities. So, we took a different approach. With the Gender Equality Commission, I created a highly competitive program of early-career development grants for women only, and made the criteria for applicants very flexible with respect to age and overseas stays. The use of the funds was also quite flexible. The goal was to support women in independent postdoc-level positions for 5 years, to help them bridge into positions of responsibility, i.e. professorships, targeting the period when many dropped their careers. Studies showed that this was often due to the difficulties of combining family and research. We coupled the funds with mentoring and networking programs. The scheme ("PRIMA") was very successful, and the initial goal of 12 grants per year grew to 15 or 20, chosen from up to 180 applicants annually. Alas, the program has since been stopped, a bit after I left my post.

I learned a lot through this experiment; indeed, PRIMA could not alone resolve the gender problem. I learned that academic research environments must embrace fairness and respect as guiding principles. Members of minority groups need to feel wanted, respected and integrated in order to prosper. To help such scientists advance their careers, we needed networking programs, especially in the fields where women represent a low percentage of the professors. Finally, we need social structures that allow mothers (and fathers!) to feel at ease in the scientific workforce. Parents deserve to feel confident that their children have good childcare. We have not achieved all of this, but I am nonetheless happy to have helped 80 to 100 women who might otherwise have dropped out of Swiss academia. Obviously, I am convinced that women make academic science a better place to be!

References

1 Hartwell L.H. et al. (1974) Genetic control of the cell division cycle in yeast. Science183, 46–51. https://doi.org/10.1126/science.183.4120.46

2 Towbin, B.D. et al. (2012) Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. Cell 150, 934–947. https://doi.org/10.1016/j.cell.2012.06.051

3 Zeller, P. et al. (2016) Histone H3K9 methylation is dispensable for Caenorhabditis elegans development but suppresses RNA:DNA hybrid-associated repeat instability. Nat. Genet.  48, 1385–1395. https://doi.org/10.1038/ng.3672

4 Gasser, S.M. and Stutz, F. (2023) SUMO in the regulation of DNA repair and transcription at nuclear pores. FEBS Lett. 597, 2833–2850. https://doi.org/10.1002/1873-3468.14751

5 Gehlen, L. et al. (2011) How broken DNA finds its template for repair: a computational approach. Prog. Theor. Phys. Suppl. 191, 20–29. https://doi.org/10.1143/PTPS.191.20

More information on the Molecular Oncology Lecture at the FEBS Congress

Susan Gasser will deliver the Molecular Oncology Lecture at the 48th FEBS Congress in Milano, Italy on Sunday 30th June 2024 on ‘Loss of heterochromatin drives increased genome instability in aging and cancer’: 2024.febscongress.org/

Top image of post: by Chen from Pixabay