Dr. Blackwell comes to us from the snowbound Boston area. His lab is located in the Joslin Diabetes Center, which is part of the Harvard Medical School Department of Genetics. Dr. Blackwell received his PhD in Microbiology and Immunology from Colombia University. He has been a professor at Harvard for over twenty-years and has seen major changes occur both technologically and philosophically in the biological research field. The Blackwell lab focuses on research in healthy aging and lifespan by studying the model organism C. elegans, which is a type of worm. The lab specifically focuses on understanding oxidative stress responses and collagen development profiles in relation to lifespan. A simplified way of thinking about how collagen and extracellular matrix relate to lifespan is that as one grows older, the collagen and extracellular matrix slowly breakdown and are not as quickly repaired when injured. This is seen most prominently in cartilage-based injuries. Cartilage is made of collagen and extracellular matrix. A knee injury affecting the cartilage will heal much faster in young individuals than older individuals.
Dr. Blackwell’s talk focused on his work in C. elegans and the changes in extracellular matrix controlled by the SKN-1 gene, over the organism’s lifespan. In C. elegans the SKN-1 gene plays a key role in promoting longevity through various pathway regulation including, proteasome maintenance, stress resistance, immunity and lipid metabolism. One of the more surprising findings from these studies was the observation that SKN-1 was also involved in regulation of extracellular matrix genes and the resulting collagen expression profiles that change as the organism ages. SKN-1 dependent extracellular matrix remodeling is critical for lifespan extension in C. elegans. Several longevity interventions that delay aging are, in part, successful due to enhancing the function of extracellular structures.
Q: Our readers might not be familiar with the C. elegans model organism. Can you explain why you choose to study C. elegans and how well the information obtained from this model translates to mammals?
KB: It is the simplest multicellular animal with tissues that can conceivably be compared to humans. It was originally chosen in the 1970s as a model organism. Some of its advantages are that it reproduces in a few days and it self-fertilizes, which can make genetic manipulation much easier. It is a great organism for studying aging, because you can do so much to it genetically, and you can see the effects of aging in a short amount of time. With respect to translatability, I think there is a tendency to always question that. But worms and humans share the most fundamental processes, and the most basic wiring is there. So for testing an idea or delving into the unknown, C. elegans is a great organism to start with.
Q: You talked about the dauer state. Could you describe that in more detail? Is it similar to hibernation?
KB: You can think of it as similar to a hibernation state or a spore. The difference is that hibernation is not a developmental state, it is a metabolic state. The dauer state is an actual development state that the animal can go into for a period of time and then emerge to reenter the reproductive life cycle almost as if it had never been a dauer.
Q: If we were to convert the C. elegans dauer state into human years, how long would that be?
KB: When the organism comes out of dauer, it still has an entire adult lifespan ahead of it. It’s a bit like those space movies where they do cryopreservation. In C. elegans, this stage can last months. So to translate that for humans, it would easily be several years that could be endured in this stage.
Q: You mention collagen levels and that the profile changes as one ages. If one could find a way to retain the “young” collagen profile, would you stay young?
KB: What I wanted to clarify, is that some collagens are only found during certain developmental processes, while other collagens are only expressed in adults. So what you would need to do is actually find the regulator, which controls the expression of these collagens.
Q: Is there anything equivalent for collagen profiles in humans?
KB: Humans have a much more complex profile of collagens, so it is hard to draw direct comparisons literally. However, I think the remodeling of the extracellular matrix and collagen is important in human aging. As an example, collagen decreases in the skin with age, as does the elasticity, and as elasticity decreases this further drives a decrease in collagen levels. The extracellular matrix is certainly an area that could use further studies on the effects of aging on the matrices to evaluate what changes occur over time.
Q: You mentioned how fat particles were increased in the worms when the germ-line producing cells were removed, and that this increased lifespan. Do you think this phenomenon translates to humans?
KB: That hasn’t been thoroughly investigated as there would be minimal volunteers for such a study. However in the movies and in “Game of Thrones”, the eunuchs are often portrayed as being inclined toward being overweight (only kidding). What may be more applicable would be the application of the Mediterranean diet, which affects lipid signaling in a specific way. This diet may mimic some of the lifespan increases without the surgical interventions. Studies continue to evaluate what effects certain diets have on lipid signaling.
Q: I’ve noticed you’ve been in academia for over twenty years. What changes, both positive and negative, have you observed?
KB: One of the positive observations is that everyone needs to know more, and therefore, academia is much more interesting. Twenty years ago one’s dissertation was more narrowly defined, and you were so limited technically that you could actually have a successful PhD with minimal exposure to other fields. I find that this is not true anymore. The fields have begun to overlap, and this is much more exciting. In the aging field, you need to understand multiple organisms, systems biology, cell metabolism, cancer etc. There are so many intersecting fields.
One of negatives is the funding situation. It is a flat funding situation that hasn’t adjusted for inflation. The current scientific community isn’t organized for a flat funding situation. Some reorganization and some re-evaluation is needed. If you want a viable scientific community, you have to keep pace with the changes in technology and the changing fields; the government needs to invest in science at a level that can foster growth as they remain the main source of funding for the scientific community. Another negative is that we are currently training too many people for too few academic jobs and not properly preparing them for this.
Q: If we training too many people for too few jobs, would you suggest training less people?
KB: I think that one answer may be to create other types of training positions, and to expose the scientists to additional avenues outside of academia. Another might be to encourage positions that are more permanent and that come after a postdoc position but before a tenured professor, especially for those that enjoy bench science. It is imperative that we continue to fund basic science, seeing that most of the pivotal translational discoveries, be it siRNA or CRISPR, have come from basic research. We must continue to allocate funding toward basic science as it’s the foundation that translational research is built upon.
For more on Dr. Blackwell’s exciting research on aging in C. elegans, check out the Blackwell Lab Website.