Dave Pagliarini, UW–Madison associate professor of biochemistry, has been selected to lead the Morgridge Institute Metabolism Initiative, which will provide leadership, infrastructure and community building to this growing UW–Madison research area. Pagliarini, an expert on mitochondria structure and function, reflects on some of the opportunities ahead.
What first attracted you to mitochondria as your research focus?
- I stumbled into this field as a graduate student when I discovered, unexpectedly, that the protein I was studying localized to mitochondria. I then spent my postdoctoral years at Harvard Medical School and the Broad Institute using systems biology approaches to identify all of the mitochondrial proteins. It became clear from that initiative that a good 25 percent – about 300 proteins – has no established biological functions. This was a striking discovery, given that most scientists thought of this organelle as a well-defined machine. Defining this whole system enabled us to more efficiently and rapidly identify causative mutations for human diseases and to begin defining the functions of these “orphan” mitochondrial proteins — goals that will remain at the forefront of my lab’s research at Morgridge.
What are the human health implications of your work?
- Our insufficient understanding of how these organelles work has obscured the nature and cause of many mitochondrial diseases. For instance, many patients with mitochondrial disease do not have mutations in the suspected genes, telling us that other proteins must be necessary for the affected process. Alternatively, many other diseases arise from mutations in proteins with no known function, making it difficult or impossible to understand the metabolic mechanism of the disease. My group is working hard to elucidate the functions of these orphan mitochondrial proteins, and is working closely with clinicians and geneticists to identify new causative mutations in mitochondrial disorders.
What would you consider the ‘sweet spot’ for the Morgridge metabolism initiative?
- I believe that we have a special opportunity to be a leader in defining the basic molecular and mechanistic underpinnings of metabolism. Other places have taken a very disease-centric approach to metabolism by creating centers dedicated to studying, for example, obesity or diabetes. Those centers have served the scientific community well, but I believe that basic science approaches most often lead to discoveries that have the greatest long-term impact. Recent work has revealed that there are so many more fundamental aspects of metabolism to be discovered, which is very exciting. The Morgridge initiative will be at the forefront of this exploration.
One of your early goals will be attracting talent to Wisconsin’s metabolism community. What are your guiding principles for the search?
- Bringing the right new investigators to Madison is clearly the most important element for this initiative as we position ourselves as true leaders in metabolism research. Identifying individuals of special talent is of course a key piece, but it goes way beyond that. I believe that much of the best science today is done collaboratively and across disciplines. As such, it is essential that we hire investigators of the right substance and temperament for this kind of work. We need to establish a culture of open and active communication where we are constantly trying to identify areas ripe for new and, perhaps, unorthodox collaborative opportunities. New investigators who embody these values will be the ones to benefit most from — and will most effectively strengthen — our already excellent community of metabolism researchers. I’m quite energized by the challenge of identifying and recruiting these types of individuals to campus.
How can the Morgridge Institute best make contributions to this research space?
- We’re in a time when science funding is hard to attain. When that happens, the first thing to get cut is creative, exploratory research — the kind of high risk/high reward science that has the greatest discovery potential. Everyone becomes more conservative out of necessity, and the work tends to become more formulaic. I think Morgridge can help promote more exploratory science on campus through its mission and its unique resources. Morgridge also has the flexibility to recruit investigators who flourish in this kind of research environment. We’d like to recruit people who speak multiple scientific “languages,” who can think across different disciplinary boundaries, and who know how to effectively harness all the free data we have at our fingertips to help construct exciting new hypotheses. Hiring the right people and positioning them to be aggressive and adventuresome in their research will be a key competitive advantage for us as we emerge as leaders in this space. Finally, Morgridge can serve as a nucleus for the great metabolism work already happening on the UW–Madison campus; it will become a natural gathering place for our collective efforts. This is a special chance to add to Madison’s legacy in metabolic research!