Q&A with Jolanda Van Leeuwen

Tell us a bit about yourself. Where did you grow-up? Where did you go to school (and beyond)?

I grew up in a village in the “Groene Hart”, an agricultural area in the middle of the Netherlands. Already as a child, I loved learning new things and reading; every Wednesday after school, I would walk to the public library to borrow a fresh stack of books. I spent my Saturdays and school vacations working in one of the greenhouses and whenever possible, I would go ice skating on one of the canals or lakes.

Describe your scientific background (What turned you on to biology/science in the first place)

Because no one in my family had attended university, it was not obvious that I would. But I was doing quite well in school and decided that I wanted to give it a try, although I wasn’t sure what to study. Because my impression of studying biology was that I would have to learn the Latin names of all plants by heart, I decided against that (I was probably wrong in this assumption ). But I liked exact sciences, so I decided to study chemistry instead, at Leiden University, which was close to home.

My interest in biology came later. During a research project at Leiden University, I synthesized ruthenium-platinum complexes that could have potential anti-tumor activity, and my professor suggested that I would go to Italy to test this at Trieste University. There, I used cultured human cells and mice to investigate the anti-tumor and anti-metastatic potential of my compounds. The results were not very promising, but I did realize that I found biological research more interesting than chemistry.

For my PhD research, I wanted to combine my background in chemistry with biology and decided to join the molecular toxicology lab of Nico Vermeulen at VU University Amsterdam (the Netherlands). There, I adapted the budding yeast to mimic human drug metabolism and used these ‘humanized’ yeasts to investigate the molecular mechanisms underlying drug toxicity. I became interested in genetics when I started to use various mutant strains to investigate the role of particular genes in toxicity. For my postdoc, I thus decided to join the labs of Charlie Boone and Brenda Andrews, pioneers in high-throughput yeast genetics, where I developed high-throughput genomic assays to study genetic interactions. In my own lab, we have further expanded on this research by using cultured human cells, in addition to yeast, as model systems to study genetic interactions.

What does your lab study both broad and specific?

One of the main aims of our research is to improve our understanding of genetic suppression. Sometimes people can be perfectly healthy despite carrying mutations that in most other individuals would have led to a serious genetic disease. A possible explanation for this is that these resilient individuals carry additional mutations that may protect them from the detrimental effects of the disease mutation, a phenomenon called genetic suppression. Identifying these protective mutations may help us understand the mechanisms underlying the genetic disease and could identify avenues for therapeutic intervention. But we currently lack the expertise to identify the protective suppressor mutations among the millions of mutations scattered throughout the genome of these resilient individuals.

With our research, we aim to improve our understanding of genetic suppression, so that we can find and predict mutations that protect against genetic diseases. We are mapping thousands of suppressor mutations in both yeast and cultured human cells. We then use the identified suppressors to define general principles of suppression and train computational models that can predict suppressors for disease genes.

How has your research changed over time?

Initially we were mainly using deletion and knockout alleles, that completely inactive genes, in our research. But if you look at natural populations, the most common variants are missense variants and variants in non-coding parts of the genome, and not complete loss-of-function mutations. We are thus more and more focusing on these more subtle variants, that can have very different suppression interactions than deletion or knockout alleles.

We have also been slowly moving towards the field of human genetics. CRISPR-Cas9 technology allowed us to screen for genetic interactions in cultured human cells, something that was previously only possible at scale in yeast or bacteria. Also the large databases with genome sequences of hundreds of thousands of individuals that have been established in the past decade have changed our research. We can use these genomes to validate our findings from model systems, or to generate new hypotheses that we can then test in vitro.

What types of projects interest you?

All projects! But I especially love projects that use new technology that allows us to answer questions that were difficult to tackle previously.

What technologies do you apply to your research?

We do a lot of genome editing and high-throughput screens. For our yeast work, we have two robots, Tom and Jerry, that help us generate and cross mutant strains and measure their phenotypes individually. In cultured human cells, we use pooled screens with various CRISPR-Cas9 genome editing tools to generate single and double mutants and determine their fitness.

What attracted you to the Department of Systems Biology?

The people and the research. I think the atmosphere in the DSB and at UMass Chan in general is quite unique, with a strong focus on collaboration rather than competition. I did my postdoc in a very collaborative environment, the Donnelly Centre at the University of Toronto, and I was looking for a similar environment. I also think the department has just the right amount of diversity in research models and approaches – enough diversity so that everyone’s research is complementary to the overall research portfolio of the department, but enough similarity to stimulate collaborations.

How important have good mentors been in your research career?

I have been very lucky to have had supportive mentors at every step of my career. My postdoc mentors, Charlie Boone and Brenda Andrews, have been extremely important in my development as an independent researcher. They taught me to think and dream big; to not accept boundaries, but to push them. I still turn to them for advice when I encounter new challenges.

What is your goal as a mentor?

My ultimate goal as a mentor is to become almost obsolete . To have equipped my trainees with all the skills and knowledge necessary to become independent researchers. I think a large part of that involves building the confidence of my trainees, sometimes even more so than teaching technical knowledge. To achieve this, I try to create an environment where everyone feels comfortable to take risks and challenge ideas. In the end, this benefits both the trainee and our research.

What do you like to do outside of work?

I love wildlife watching. My favorite vacation is spent in the jungle looking for and photographing wildlife. Closer to home, I love skiing and hiking.