Diversity Our Strength
Photo by Andre Furtado on Unsplash
First published at UiB.no on May 15, 2020
Most research institutions recommend that you do a research stay abroad during your doctoral or postdoctoral period. A research stay will help you to establish and develop international collaborations, and give new impetus for your own and the home institution scientific work. It also allows for personal development, by exercising independence, acting on curiosity, learning of different cultures and practicing a different language - it is all a part of the package. Sylvia Varland is a member of the Arnesen Lab at University of Bergen and she recently came back from a 2-year research stay at the University of Toronto, Canada. Learn more about her scientific adventure and cultural experiences.
Researcher Sylvia Varland was seeking new challenges with a potential stint abroad, after graduating with a PhD in Molecular Biology from the Arnesen lab at University of Bergen in 2016. She had long been interested in precision medicine and wanted to combine it with her background in molecular biology. “In my doctoral work I was studying the metabolic regulation of N-terminal acetylation, one of most common protein modifications in human cells”, says Sylvia”. “By applying functional genomics, I wanted to learn more about this protein modification from a genetic perspective and its impact on human diseases”.
Systematic analysis of genetic interactions
The year before Sylvia Varland had, with support from the Meltzer Research Fund, given a talk at the International Conference on Yeast Genetics and Molecular Biology. At this conference, she learned about a groundbreaking study on how genes within a cell interact in groups. University of Toronto Professors and Charles Boone and Brenda Andrews, and Professor Chad Myers of the University of Minnesota-Twin Cities led the study, which took more than 15 years to complete. In this seminal work, they mapped all possible genetic interactions within the budding yeast Saccharomyces cerevisiae. Then they created a global genetic interaction network that mapped a wiring diagram of cellular function.
Mobility fellowship a key stepping stone
Sylvia found the systems approach in the landmark paper by Boone, Andrews and Myers groups very fascinating. “Molecular biologists, like myself, are used to dissecting cellular processes into molecular modules and building blocks. However, we all know that biological systems are extremely complex”, says Sylvia. “We know that N-terminal acetylation deficiency can give rise to disease. However, we do not know how the enzymes affect each other. When a NAT enzyme is completely absent or not working properly can the other NAT enzymes take over?”, she continues enthusiastically. With future genetic work in mind and looking for new challenges, Sylvia contacted Professor Boone about a potential collaboration. The Canadian response was all positive and she started the process of securing funding. Sylvia Varland received the prestigious International Mobility Grant from the Research Council of Norway to study the genetic basis of N-terminal acetyltransferses – the enzymes that perform N-terminal acetylation. With the financial support she needed along with a Marie Skłodowska-Curie actions - Seal of Excellence, Sylvia found herself moving to Canada, the land of Maple Syrup and ice hockey.
Unique expertise not available in Norway
The Boone Lab shares an open concept space with Professors Brenda Andrews in the renowned Donnelly Centre for Cellular and Biomolecular Research, which is affiliated institution of University of Toronto. Donnelly researchers are encourage to think beyond the boundaries of single research fields and collaborate across different disciplines to drive scientific progress. This scientific strategy has provided the Donnelly Center with a unique expertise within biological and biomedical research. “What I found particularly impressive was how the Donnelly Center pursued interdisciplinary initiatives and how this lead to innovative technology development”, says Sylvia. It was the discovery of insulin in 1921 that paved the way for medical research in Toronto. Today this multicultural city is a hotbed for biomedical entrepreneurship, which was possible by combining basic and clinical research with biotechnology and capital investment. “Many startups have been launched as a direct result of research made at the Donnelly Center”, she continues.
Figure 2: Life at the Donnelly Center. Sylvia Varland celebrates May 17th, the Norwegian Constitution Day, in the cell culture lab (upper left). Adrian Drazic juggling cell lab work and the Ice Hockey World Championship (upper right). Two scientists, five weeks, a May 17 celebration and a Ice Hockey World Championship later Sylvia can show the samples ready for Illumina sequencing (lower left). Agar plates ready for SGA and an SGA triple mutant plate (lower right). Photo: Sylvia Varland
The awesome power of yeast genetics
Yeast is not only used to create beer, but is also an ideal model organism for genetic research. One reason is that yeast can easily be genetically manipulated. However, it is one thing to create two deletion strains, cross them, and evaluate the growth of the resulting double mutant. It is a completely different story to construct more than 23 million double mutants. How is it even possible? Professors Boone and Andrews are in the forefront of functional genomics studies in yeast. They developed the synthetic genetic array (SGA) analysis, which automates yeast genetics and enables the construction of genome-wide sets of recombinant mutants. In particular, SGA can generate all possible double mutants for a mutant form of a particular query gene. For this specific work, the Boone and Andrew lab has a sophisticated facility for automated yeast genetics that is unique in the world. It includes custom-made robotics for pinning yeast mutant arrays, for yeast transformation and for automated preparation of samples for high content imaging. There is no other facility with a comparable capacity for manipulating and imaging high-density yeast arrays, which are ultimately analyzed using robust computational pipelines. Sylvia was able to take advantage of their setup to study trigenic interactions of selected NAT enzymes. For this, she constructed a small-scale library of double NAT mutant strains that were crossed with a genome-wide yeast deletion collection comprising nearly 6,000 strains. But Sylvia did not stop her scientific endeavor to learn more about the NAT enzymes with the relatively simple yeast organism.
CRISPing away to better understand genetic basis of human disease
The discovery of CRISPR technology has revolutionized the field of functional genomics and genetic interaction mapping, enabling comprehensive mapping in human cells. To translate insights from the global yeast genetic interaction network to human cells, Boone, Andrews and Myers paired up with Professor Jason Moffat also at the Donnelly Center. He has created genome-scale CRISPR technologies for functional genetic analyses of all human genes. Specifically his lab has designed various CRISPR lentiviral libraries, where the TKOv3 library targets 18,053 protein coding human genes. Sylvia took part in the genetic interaction network project, which focuses on systematically mapping genetic interactions in various cancer HAP1 knockout cells by performing genome-wide CRISPR screens. Dr. Adrian Drazic, who co-discovered the actin N-terminal acetyltransferase NAA80, joined Sylvia for 3 months. Together they screened several genes encoding NAT subunits. “Genome-wide CRISPR screens provide a wealth of information, which will shed new light on the function of N-terminal acetylation”, Sylvia says.
A research stay gives both scientific and personal experiences
At the end, do you have any tips for researchers that are pursuing a stay abroad, and would you do it again?
“The first challenge is to secure funding. Do not underestimate the time it takes to plan, write and self-evaluate a proper proposal. Read the guidelines thoroughly. Many postdoctoral grants do not focus solely on the project, but they also put a lot of emphasis on career development. For example, the Marie Curie fellowships focus on Excellence, Implementation and Impact. What is the impact of your fellowship? I received valuable inputs from my PI Professor Thomas Arnesen and the Division of Research and Innovation at UiB to improve my application. One way that the mobility grant facilitated my career development was that I further developed my project management skills. Maybe more importantly, during my research stay at the Donnelly Center I connected to a broad international network of researcher in molecular genetics and computational biology.
Figure 3: Canada can offer fantastic wildlife and scenic landscapes, as Lake Louise in Banff National Park. Photo: Sylvia Varland
For me it was important to not only focus on scientific merit, but also get the Torontonian experience. Thus, my research stay was also a great personal experience. I decided to move in with two female professionals working within media and communication. One of them was a local Canadian and the other a British Expat. Together we explored Toronto, the city that never sleeps. From Canadian thanksgiving with mandatory pumpkin carving, Saturday brunches, sour beer at the Bellwoods Brewery, and Shakespeare in the park to the unforgettable atmosphere in Toronto when the Toronto Raptors won the NBA. I also joined the Norwegian Club of Toronto. Here I met some fantastic people with very different background than myself. Canada has many beautiful and scenic landscapes to offer. I used this opportunity to experience the wildlife in breathtaking Rockies, taste lobster at Prince Edward Island and do the cranberry plunge at the Muskoka lakes farm”.
“I am very appreciative of the Norwegian Research Council for supporting my research activities in Toronto”, says Sylvia. “My research stay at the Donnelly Center has broaden both my scientific and cultural experience. The City of Toronto's motto Diversity Our Strength also holds true for science. I strongly believe that the scientific community benefits from being inclusive and open to new ideas, often from completely different disciplines”, she continues.
Going forward, Sylvia Varland wants to combine her molecular biological skills with her newly acquired knowledge of functional genomics to understand effects protein modifications have on human disease.
Personal 3-year Mobility Research Grant (3,300 000 NOK).
“The NatFUGE project: Exploring N-terminal acetyltransferases using FUnctional GEnomics”
The NatFUGE project was supported by the Research Council of Norway through a FRIPRO Mobility Grant (Project 261981) which was co-funded by the European Union Seventh Framework Programme under Marie Curie grant agreement no 608695.
Recommended reading material
A global genetic interaction network maps a wiring diagram of cellular function. [Mapping genetic interaction]
Costanzo et al, 2016, Science (PMID: 27708008)
Global Genetic Networks and the Genotype-to-Phenotype Relationship. [Review]
Costanzo et al, 2019, Cell (PMID: 30901552)
Systematic mapping of genetic interactions for de novo fatty acid synthesis. [CRISPR]
Aregger et al, 2019, BioRxiv
Systematic genetic analysis with ordered arrays of yeast deletion mutants. [SGA]
Tong et al, 2001, Science (PMID: 11743205)
Spotlight on protein N-terminal acetylation. [Review]
Ree, Varland and Arnesen, 2018, Exp Mol Med.