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Douglas Cyr's research in protein folding and trafficking and his contributions towards understanding the disease mechanisms of cystic fibrosis caught our attention. Curious to know more, BioTechniques contacted him to find out about the ambition, character, and motivations that led to his success.
Creating Knowledge
What are the current goals of your lab?
My lab has two major focuses. The first is to understand differential susceptibility to proteotoxicity in neurons that occurs in protein conformational diseases—such as Huntington's disease—or those caused by prions. These disease proteins are toxic in some situations, but not in others. We are working with a model that suggests the levels of protein quality control factors vary between neuronal cell types. With this model, we intend to identify the components of the quality control networks and see if variations in their activities account for the differential susceptibilities.
The other main focus of the lab is to understand the folding defects that cause cystic fibrosis (CF) and the machinery that recognizes them so that we can bring about a cure for this disease. We have contributed to the understanding of the protein folding pathway of the CF transmembrane conductance regulator (CFTR)—which is mutated in CF patients—by identifying folding defects, along with the machinery in the endoplasmic reticulum that recognizes and targets them for degradation. We are developing approaches to manipulate the activity of that machinery using small molecules under development for treating CF. We are testing these compounds to discern the mechanisms by which they function and create data for the development of therapeutics, which has led to a natural convergence of basic biology and some of the translational research being done.
As a side project, we are testing a new idea in the field that there are chaperone dependent ubiquitin ligases that function in protein quality control. Right now we know there are some molecular chaperones that form complexes with ligases to help target misfolded proteins for degradation, but it looks like there are also novel proteins that can directly recognize misfolded disease proteins and target them for degradation. We are trying to identify those cellular factors and determine their mechanisms of action.
Have you ever reached a conclusion in an unexpected way?
When I was a postdoctoral fellow at the University of Munich, we were looking at mechanisms for protein translocation across membranes. We isolated mitochondria and looked for proteins that crossed the mitochondrial membrane to get stuck inside. One substrate we worked with seemed to get lost from our assay system. The signal just disappeared. We couldn't figure out what happened to it or where it went. We scratched our heads for a few months until we finally ran an experiment showing that this substrate was going into the mitochondria and then coming back out again. With our assay, we could only detect things that were inside the mitochondria, so we lost the signal under certain conditions. This observation led to the realization that protein translocation reactions were reversible and provided some basic insights into the mechanism. We published these findings in Science in 1994.
What is the most important research question in your discipline at the moment?
We are just beginning to assemble the catalog of components that function in protein quality control, but we don't know how they are organized or how the activity of chaperone networks is regulated during stress. I would say that regulation of protein quality control networks to modulate or suppress the accumulation of toxic or misfolded proteins is an important emerging area.
What challenges do you currently face?
It has always been a challenge to find good hard-working people to join the lab. We are always looking for students, postdocs, and good people at any level.
There is also a challenge in balancing career and family, and ensuring my priorities are such that I can sustain my career at a high level while maintaining a high-quality personal life. To do this, I have to sacrifice both on a career level and on a personal level. I always want to make sure that everything balances out in the end. If the sacrifices and cuts are made too much on one side, both will fail. But if I can work hard in one area for a certain amount of time to achieve a goal and then balance out the other side, I can have a sustained career.
What has been the highlight of your career?
We have made a lot of observations and contributions, but to me that is expected for this line of work and wouldn't qualify as highlights. Not everyone can do something they like every day, but I really enjoy my work. I would say that the highlight of my career is my career. I am a basic scientist. It is a privilege to come to work and create knowledge.
