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Past, present and future: Academic life from the lens of Dr. Phil Hieter
Writing by Deepesh Panwar from the Brumer Lab, Michael Smith Laboratories
This is the second article in our Past, Present and Future series, where we explore the journeys of inspiring faculty whose work is shaping the future of research. In this instalment, we feature Dr. Phil Hieter. Dr. Hieter is a professor at the Michael Smith Laboratories and the Department of Medical Genetics at UBC. He earned his PhD from Johns Hopkins University and completed postdoctoral training at Stanford University. Dr. Hieter’s research focuses on how changes in genome structure and sequence contribute to tumorigenesis. His lab uses genetic and biochemical approaches in the model organism Saccharomyces cerevisiae (baker’s yeast) to investigate the molecular components required for chromosome transmission. The overarching goal of his work is to translate basic findings in yeast to better understand the mechanisms of genome instability underlying human cancer, and as a means to identify novel cancer drug targets.
1. How has your research evolved and impacted your field?
Research evolves gradually over time, with occasional punctuated moments of significant change. As an undergraduate, I worked in a basic biochemistry lab and lacked a strong perspective on high-level science. That experience, however, made me realize how much I enjoyed bench research, which was formative.
After completing my undergraduate degree in 1975, I was torn between pursuing medical or graduate school. To buy time and gain perspective, I took a technical position that allowed me to interact with researchers and explore options. During this period, I attended a talk by Phil Leder on antibody diversity that fundamentally changed my perspective on science. I reached out to him and subsequently joined his lab at the NIH as a PhD student while concurrently completing my graduate coursework at Johns Hopkins in Baltimore.
In Phil Leder’s lab, we embarked on an ambitious project that relied on cross-species DNA hybridization from mouse to human antibody genes. We successfully achieved the cloning of the human kappa and lambda light chain genes, generating genetic probes that were then used to study gene rearrangements during B-cell development in human leukemias. Much of this work was only possible due to access to advanced experimental tools and restriction enzymes not commercially available at the time.
After completing my graduate studies, Phil encouraged me to pursue something new, which led me to join Ron Davis’s lab at Stanford in the early 1980s as a postdoctoral fellow. There, the focus was on DNA transformation in yeast, cloning centromeres and origins of replication, and using yeast genetics to understand eukaryotic biology. This marked a significant transition in my career, from mammalian molecular biology to yeast genetics. Coming from a different background, I found it exciting to learn and use genetics to generate mutants and link phenotypes with biochemical pathways.
During this time, I also had the opportunity to interact with Lee Hartwell who was on sabbatical at Stanford (and who 20 years later was awarded a Nobel Prize for his work on cell division cycle genes in yeast). His work inspired me to carry out a large-scale genetic screen to identify centromeric DNA and to develop assays to monitor chromosome transmission during cell division in yeast. This led to me starting my own lab at Johns Hopkins Medical School in 1985, just as medical schools began to recognize that eukaryotic model systems like yeast could help us understand human biology. I began my work establishing genetic screens and identifying a large reference set of mutants defective in chromosome transmission, which provided genetic entry points for mechanistic studies of centromeres, sister chromatid cohesion, and the regulation of mitosis.
In the early 1990s, we began identifying the human orthologs of the yeast Cell Division Cycle (CDC) genes that encode the “Anaphase Promoting Complex”. We were able to map the human CDC27 gene to the 800 kb region that included the BReast CAncer (BRCA1) gene implicated in that cancer’s progression in humans, making it a candidate gene for about a month. Although it turned out not to correspond to the mapped BRCA1 mutation, the experience highlighted the power of evolutionary conservation from yeast to human.
In the late 2000s, our lab shifted focus solely from mechanistic studies to the inclusion of applied research, leveraging our foundational work to develop cancer drug targets. For the past 15 years, we’ve been exploring how chromosome instability and genetic vulnerabilities in cancer cells can be exploited through synthetic lethal approaches. The journey has unfolded with twists and turns, as each new effort has brought both challenges and opportunities, and opened doors to unexpected collaborations.
2. What major challenges have you encountered during your research career?
In the early stages of my career, I was fortunate to work with inspiring mentors, so I didn’t feel an unusual amount of external pressure. One major challenge, though, was my postdoctoral transition to Stanford as I entered a completely new research area and system. I tackled it by working hard and staying open to new opportunities.
Another significant turn in my career that brought its challenges was moving to UBC in the late 1990s. It was a challenging transition, moving from a medical school to a more general academic environment. It required relocating my entire research setup and adapting to a new institutional environment. In 2000, I also became Director of the Michael Smith Laboratories, which meant balancing administrative responsibilities with research, a rewarding yet demanding role.
3. Are there any research topics in your field that you believe are currently undervalued? Where do you see these areas heading in the next 5–10 years?
There are three categories I’d highlight: two are associated with work we currently do in my lab, while the other is broader and more conceptual.
The first is an under-appreciation of the continued value of model organisms, including yeast, worms, flies, zebrafish, and mice, well into the future. Because of the strong evolutionary conservation of gene function and the complementary set of powerful experimental toolboxes, the utility of model organisms spans basic biology, human health, and even agricultural science.
Second, I believe that synthetic lethality as a research approach is currently undervalued. Since it was first proposed in the late 1990s, only one drug targeting Poly ADP Ribose Polymerase (PARP) in BRCA1-mutated cancer has made it to clinical use. Progress has been slow, which has created skepticism in some circles. Meanwhile, immunotherapies have gained substantial momentum and funding. Despite this, I believe a form of synthetic lethality, that converts a protein target to a cytotoxic form, holds great potential, particularly through small-molecule inhibitors that target specific genetic vulnerabilities in cancer cells. I’m optimistic this area will mature significantly over the next 5–10 years.
Lastly, there is too often a lack of appreciation for fundamental, curiosity-driven research without immediate applications. Yet, history has repeatedly shown that major innovations such as DNA sequencing, PCR, next-generation sequencing, and CRISPR all arose from basic science. Furthermore, because biological mechanisms are highly conserved across evolutionarily diverged species, gene function information is often transferrable across organisms. Funding agencies and government decision-makers must be continually reminded of this. While applied research is important, it’s invariably built on the foundation of decades of basic research from the scientific community at large.
4. What advice would you offer to someone beginning their research career in your area?
The advice I give to early student scientists is: choose an important problem, and then find a mentor, collaborators, and environment that supports you in solving it. Build relationships and seize opportunities. As a student, you will develop deep expertise in a specific area, but as you move between labs or institutions, you’ll learn new tools and methods. The key is to connect the dots across seemingly unrelated fields – the constellation of different experiences and expertise gained along your career path, and the connections you build between them, make you unique.
For example, my own journey took me from antibody research to yeast genetics; completely different systems with different mindsets. But I was always looking for underlying links, and that openness led to new collaborations and research directions I couldn’t have imagined at the outset.