I had been interested in science, at least at some level, from an early age, but it wasn't until high school, in a suburb of Kansas City, Missouri, that I started thinking of it as a career possibility. Going to college at a small liberal arts school in Missouri called Truman State University, I believed that my interest in science would lead me to become a physician. I took biology and chemistry in preparation for medical school, but somewhere along the way I discovered that I could have a career in scientific research.
When I graduated in 1998, I entered the PhD program in cell biology at the University of Missouri. At that point, I did not have much of a plan, but knew I wanted to continue working in cell biology. I was intrigued by the idea of learning the underlying mechanisms of how a cell works and how they are affected by different disease states.
I joined the lab of Antony Cooper, who had initiated a project to study the degradation of proteins that fail to fold correctly in the endoplasmic reticulum (ER), the organelle where all secreted proteins begin their journey. It was a genetics- and biochemistry-oriented approach, using yeast cells, to study a process thought to be involved in numerous diseases. At the time, Antony was just starting out and working in a field that was still not defined. I found this tremendously exciting because there were opportunities for discoveries everywhere.
Not in Kansas (City) Anymore
When I completed my PhD, in 2003, I knew I wanted to continue doing research, so I interviewed for postdoctoral positions in a couple of labs — one in Boston and one in New York. Having spent my entire life in the Midwest, I wanted to try some place different. I chose David Ron's lab in the Molecular Pathogenesis Program at the NYU School of Medicine. David's lab studies cellular and organismal adaptations to the stress of unfolded proteins, primarily within the endoplasmic reticulum.
At the time, the Ron lab was considering an additional direction, exploring how cells respond or adapt to misfolded protein stress within mitochondria, the powerhouse of the cell. I saw this as another opportunity for discoveries in an area of basic cell biology that was relatively wide open. As mitochondria are required for numerous, essential functions — including ATP production, the regulation of programmed cell death and a variety of metabolic outputs — I thought the study of this putative signal transduction pathway would be interesting in itself, but might lead in any number of directions.
Working with David, I started by addressing a simple cell biology question: How do mitochondria sense the presence of unfolded proteins, and, how, then does the cell integrate this information into ongoing gene expression programs? Similar to the endoplasmic reticulum and cytoplasm, mitochondria have a dedicated molecular chaperone network, which maintains the organelle's folding capacity, facilitates protein folding, and protects against the accumulation of deleterious, aggregation-prone proteins.
Much like the accumulation of unfolded protein stress in the ER, stress in mitochondria is sensed and a signal is transduced to the nucleus, where molecular chaperone genes are turned on to facilitate protein folding. However, as the cell is compartmentalized, these chaperones are targeted specifically to mitochondria. Initially, studying mitochondrial protein folding did not seem like much of a stretch from the lab's previous work, but we quickly realized the process of signaling from the mitochondria to the nucleus was much different.
“ There's clearly mitochondrial dysfunction going on in cancer cells. SKI provides a fantastic environment to gain a better understanding of this dysfunction and how cancer cells adapt to it. “
Cole Haynes, Cell Biologist
Over the course of our study, we found a number of components that make up a signal transduction pathway termed the mitochondrial unfolded protein response. We ended up reporting, in Developmental Cell as well as in MolecularCell, on a genome-wide RNAi-based screen for genes involved in signaling the mitochondrial unfolded protein response.
Up to this point, the majority of the work had been done in the worm, C. elegans, a system amenable to genetic discoveries. Interestingly, all of the identified components are present in mammals, which naturally started me thinking about diseases like cancer where maintenance of mitochondrial homeostasis might play a big role.
Part of an Exciting New Team
After more than four years working in David's lab, I felt it was time to start my own lab. Given the importance of mitochondria in numerous aspects of biology and disease, I had a number of ideas for my own research, and seriously considered two institutions: The Scripps Research Institute in La Jolla, California, and Sloan Kettering Institute (SKI).
When I interviewed with Alan Hall, the chairman of the Cell Biology program here at SKI, it seemed like he was putting together an exciting and energetic group of researchers. It didn't take me long to decide that I wanted to be a part of that group and by that point I had grown accustomed to living in New York City and really enjoy all the city has to offer.
My laboratory at SKI continues to be interested in molecular mechanisms and signaling pathways that protect mitochondrial function, particularly at the level of protein folding and protein homeostasis. There is a fair amount of research into the workings of mitochondrial chaperones or proteases; however, how different biological scenarios impact the mitochondrial folding environment and the dependence on maintenance of the environment is relatively wide open.
Now that we have identified the components in this signaling pathway, we intend to explore its function in aspects of biology where mitochondrial biogenesis and/or dysfunction are prevalent. Our interests range from aging, to germ line development, and to cancer.
One of my major goals is to further our understanding of the stress responses that cells mount to protect and maintain mitochondria and to understand how these function at the molecular level. Ultimately, we hope to develop strategies to manipulate these components as potential therapeutic strategies. For example, inhibition of such mechanisms to reduce mitochondrial folding capacity may slow cancer cell proliferation, while boosting signaling and increasing the organelle's folding capacity may allow cells to better deal with the unfolded protein stress and mitochondrial dysfunction associated with aging.
There's clearly mitochondrial dysfunction going on in cancer cells. Working at SKI, which is part of Memorial Sloan Kettering Cancer Center, provides a fantastic environment to gain a better understanding of this dysfunction and the means by which cancer cells adapt to it.
With all the alterations in mitochondria observed in a wide range of cancer cells, including increased reactive oxygen species, mutations in mitochondrial DNA as well as the shift in metabolism away from mitochondrial-dependent respiration, the organelle's protein folding environment is almost certainly stressed. This suggests a dependence on pathways that promote efficient mitochondrial protein folding.
The initial work was done in worms, so there is a pretty big stretch between that and cancer patients. But we'll start with studies in cell culture and see if the components we found in worms are functioning in a similar manner in human cells and go from there.
Last updated: December 21, 2009