Dr. Claudio Hetz was originally trained as a biotechnology engineer at the University of Chile and earned a PhD in Biomedical Sciences at Serono Pharmaceutical Research Institute in Switzerland. He then went to Harvard University for his postdoctoral training. Dr. Hetz joined the University of Chile in 2007 and is currently a professor in the Faculty of Medicine and adjunct professor at Harvard. He is also the co-director of the Biomedical Neuroscience Institute. He has received numerous important awards for his research including the TWAS-ROLAC Young Scientist Prize as an outstanding young scientist in Latin America. Dr. Hetz was also a finalist in the Eppendorf and Science Award in Neurobiology and was awarded the Cell Biology Society and Bios-Chile prize as the best young scientist in Chile. In 2014, he was selected by the LatinAmericanScience.org and Qué Pasa magazine as one of the 30 most influencing scientists in Latin America.
Dr. Hetz’s lab focuses on understanding cellular strategies involved in adaptation to chronic endoplasmic reticulum (ER) stress. The ER has many important cellular functions, and can be described a sophisticated machinery for protein folding and secretion. ER stress engages an integrated signaling pathway known as the “Unfolded Protein Response” (UPR), which aims to reestablish protein homeostasis through transcriptional upregulation of genes involved in protein folding, quality control and degradation pathways. Recent evidence in model organisms indicates that ER proteostasis is impaired during aging. Dr. Hetz’s lab is currently developing a systematic approach to underscore the effects of targeting the UPR in several brain diseases, such as prion disorders, amyotrophic lateral sclerosis (ALS), Huntington’s disease, Parkinson’s disease, and Alzheimer’s disease, using genetic manipulation of the pathway in mouse models in addition to developing gene therapy strategies to alleviate ER stress.
During this talk, Dr. Hetz described the role of ER stress in protein misfolding disorders, and discussed possible strategies to target the UPR with therapeutics. The UPR signals through the activation of several ER stress sensors including IRE1α. Upon activation, IRE1α catalyzes the splicing of the mRNA encoding the transcription factor XBP1 leading to the expression of a potent transcription factor termed XBP1s. Dr. Hetz demonstrated how XBP1 regulates the proteostasis network and autophagy. Based on the link between XBP1 and autophagy, his laboratory also tested the potential use of trehalose, a drug that induces mTOR-independent autophagy, in the development of amyotrophic lateral sclerosis (ALS). Treating mutant SOD1 transgenic mice (ALS model) with trehalose significantly extended their lifespan, increased survival of motor neurons (neuron type affected in ALS), and also mitigated disease progression and ALS phenotypes.
SAGE sat down with Dr. Hetz to further discuss his work.
Q: Have you tested XBP1 in a normal aging model instead of a disease model?
CH: No this is something that we would like do in my lab as collaboration, and that is why I am here [at the Buck]. We have already discussed this idea with Brian Kennedy. We would like to test the UPR pathway in lifespan and healthspan. Currently, nobody knows if XBP1 expression will decline with age, and we are testing this idea now.
Q: How did you find out about trehalose and its role in autophagy?
CH: After we found out that the protective effect of XBP1 is linked to autophagy, we also found that trehalose was reported by others to increase autophagy through a TOR-independent pathway. People already tried trehalose in other systems. We think that FOXO1 activity is related to the mechanism involved in trehalose-induced autophagy, but we still don’t know the whole mechanism.
Q: What are the follow up experiments?
CH: We are measuring the impact of autophagy in brain diseases using genetic tools. Right now we want to screen for new compounds that induce autophagy because trehalose is not very strong. You need a really high dose of trehalose. Right now we are developing a program to generate a library of natural compounds derived from Chilean plants that we are going to test in disease models using high-throughput assays.
Q: Do you have plans for future collaborations with the Buck?
CH: We have discussed this for a long time. I along with the Institute of Biomedical Sciences at University of Chile really want to establish an alliance with the Buck. Brian has visited our country several times, maybe more than 10 times. Our government disclosed a program to create a center in Chile, and one of the topics of the program is aging and aging related diseases. One of the requirements to create this program is to associate ourselves with an international center, and of course the Buck is the best. So we developed the program project together with the Buck and we just applied last month. Right now, we are waiting for the result. If we can get it, it will be really nice because we will start great collaborations, and will share postdoc and students between the two institutes.
Q: How big do you think the new center is going to be?
CH: The center has two aspects. One is a clinical center for brain diseases related to aging, and the other is a research center with preclinical models. We will have PI’s that focus on mitochondria bioenergetics, regeneration, genetic studies, proteostasis, and we also want to develop interventions for these diseases. The center will cover a lot of branches, but only focus on the aging brain. We hope that the size of the center will be 100 people at the end, including PIs, students and postdocs. We are really excited!
Q: What is the science environment like in Chile?
CH: We have a small science community. But it is open to the international community. Half of the funding we have is coming from international foundations, such as the Michael J. Fox foundation, MDA, AD Association, for example. Even though it is a small community, it is very open and very collaborative. The micro-environment is really good. The problem might be that each of us is specialized in a specific topic because we don’t have a lot of people covering the same topics. But again, it is easy for you to know who you want to talk to. I am really happy to work in Chile. You can see your impact in the training of the new generation of scientists day by day.
Q: How easy is it to get government funding in Chile? Is the funding increasing or decreasing?
CH: The government funding is increasing but still is below average for developed countries. The approval rate is about 40%, which is pretty high. But we only spend 0.4% of our GDP on funding. We should get 0.8% for a developing country. It is a discussion that happening right now in Chile. Since the country is small, the 0.4% is not bad.
Q: You are a very successful scientist. What advice would you give to those who want to pursue academic career?
CH: I think you need to think about what your main question is and how you can contribute with something novel with impact. Make sure you follow your passion and you put creativity into your work; this will make the difference. Science is a way of living. You also really need to have good networks. Collaboration is important because it will make sure that your work is going to be multidisciplinary and conceptually deep.
Q: You have a really big lab. How do you manage so many people?
CH: I have learned a lot about how to manage people by making mistakes, listening to people and sharing experiences with my colleagues. This is certainly more difficult than doing experiments. I think you have to spend a lot of time with them outside of the lab, listen to them and understand their potential. All people are different, and you can´t expect the same of all the researchers in your group. If you identify someone with great potential, put more energy in making sure they develop. They need to have a good reason to be at work, because science work is not easy: the experiments are difficult, and the process of getting a paper out is painful and frustrating. You need to help them find the moments of pleasure during the daily experiments. The pleasure can be day-to-day through simple discussions of good results or of good speculations. Ultimately, they need to have fun intellectually. Also I never ask my people to work all the time. I want them to have their personal lives, because that way when they are at work they are more productive. This is why I try to make sure we start working early so then can go home early and do other things that will nutrient their spirits and refresh ideas. If you push too hard, then it is easier to get frustrated because if you don’t have a personal life, when the experiment fails, your life fails. People need to know that sometimes things don’t work (most of the time) and that’s life…that’s part of the job. You really need to maintain the positive energy.
For more on Dr. Hetz’s research, check out the Hetz Lab Website.