Dr. Danica Chen comes to us from right across the bay at UC Berkeley, where she is an Assistant Professor in the Department of Nutritional Science. Dr. Chen completed her doctoral studies at UC Berkeley and then decided to give the East Coast a try, doing her postdoctoral work at MIT. She received numerous awards including the prestigious Ellison Scholar award, and is a member of the QB3 consortium. Currently her laboratory focuses on the SIRT protein family, specifically on SIRT3 and SIRT7.
The Chen lab has been exploring the role that these proteins play in hematopoietic stem cells (HSC) in relation to metabolomics and how this impacts aging. Her lab’s most recent studies discovered that SIRT3 reduces oxidative stress under a calorie restrictive diet, via deacetylation of SOD2, a protein which has been shown to play a role in aging and age associated diseases. Overexpression of SIRT3 in aged HSCs proved beneficial, and this research is being further explored for possible translational options. SIRT7 appears to have similar but more dramatic effects on the aging process, playing a role in mitochondrial regulation, through repression of mitochondrial and ribosomal proteins. This reduced mitochondrial and ribosomal protein expression allows for clearance of aggregate proteins, which is further enhanced when SIRT7 is over-expressed in HSCs. SIRT7 knockout mice develop fatty liver disease, which is reversible upon re-introduction of SIRT7 into the liver. These findings are very exciting and offer several new pathways to pursue regarding therapeutic development for various aging-related diseases.
Q: You mention how HSCs become less effective with age, have there been any studies done on patients or animals that have been irradiated and had their HSC replaced, from the angle of how this effects their lifespan?
DC: That is a great question. I’m not aware of the data, but of course we don’t want to do this to healthy individuals. Unfortunately these studies are difficult to do, and in addition there would be many confounding factors as it would be a very traumatic procedure.
Q: You have mentioned that overexpression of SIRT7 increases protein aggregation clearance, are there studies examining what the SIRT7 levels are in aggregation diseases (ie Huntington’s disease), and if an increase in SIRT7 has any beneficial effect in these diseases.
DC: That’s a very good question. I think it would be very interesting to examine the levels in protein aggregation models. SIRT7 studies are just emerging and we still have a lot to learn. Currently, there are three different SIRT7 KO mouse models which all show various defects. Before we can develop drugs, we need more studies on these models to see if an increase in SIRT7 would be beneficial. There is data to show that SIRT7 decreases with age, but we would need to know if upregulating SIRT7 would be beneficial. These studies are certainly possible and offer exciting possibilities.
Q: Is there a way to naturally increase SIRT7 levels, without possible drug treatments?
DC: Yes, in one experiment we subjected the cells to nutrient starvation, and saw a modest increase in SIRT7 levels. We also treated the cells with stress inducers and saw some modest increases. An equivalent in humans might be calorie restriction.
Q: Have they looked at people on calorie restriction diet? Would the samples would be hard to get, how would you be able to obtain the tissue?
DC: So that would be an interesting experiment, but there would need to be people willing to volunteer their tissue. For HSCs, there is a way now to harvest the cells from blood, you don’t need to go into the bone marrow. Instead, you can use growth factors to coax the HSCs to come out into the blood, and then collect the blood. The cells are able to repopulate themselves, so it isn’t detrimental to the patient.
Q: You mentioned in your talk that the SIRT3 knockout (KO) mice did not show any phenotypes until age two. With that concept in mind, would it be possible to make a conditional KO of SIRT3, where one would turn “on” the SIRT3 at old age and observe if this would restore normal stress response. Also what would be the next steps in exploring this mechanism for models?
DC: Yes, I think that would be a fantastic model. We currently have the SIRT3 conditional model, and we can potentially cross with the Cre mice and make that model. We can now work with models that were not previously easy to make, like rats. We need to know if these changes are conserved across species, as we want to know if this would work in humans. Since there are no current drugs available that regulate the SIRT3 or SIRT7 a large amount of work needs to be done before we will know if this approach will be an effective treatment in humans.
Q: Can you talk a bit about what it is like to be an Assistant Professor and what advice would you give to those who might be in that position soon?
DC: Focus is one of the most important things. You have a clock, and sometimes you want to forget about that clock and just enjoy the process. But you do have a clock, so just focus on a few things and getting the research out. Also some people always try to aim for papers in high profile journals, and sometimes it just doesn’t work out. It’s okay, just move on and get it published. Focus on writing good papers, even if they are not in high profile journals. I think the biggest transition when starting as an assistant professor is going from a bench scientist to a laboratory manager. Learning how to interact with the students and how to be a good mentor are really important skills.
Q: Can you discuss what it has been like to mentor students and what is one of the most essential parts of that?
CD: Yes, graduate students always ask me what my mentoring style is. Everyone is different and so you need to spend weeks to months to get to know the students and understand their needs. Communication is very important.
Q: What advice do you give postdoctoral students who are making decisions on if to pursue academia or industry?
CD: I think for myself, I was always open minded to just try you best, enjoy what you are doing, and see what happens. If you want to be in academia, it will happen. You just need to be persistent.