James Hurley is a professor of biochemistry, biophysics, and structural biology in the Department of Molecular and Cell Biology. The Hurley lab is interested in fundamental questions of how the interactions between proteins and membranes determine cell and organelle shape and the evolution of shape over time; how protein-membrane interactions turn on and off the signals that control essential cell processes; and how pathogens such as HIV-1 subvert and co-opt these interactions. The roots of the Hurley lab’s research program are in the use of structural approaches—including x-ray crystallography, hydrogen-deuterium exchange, cryo-electron microscopy, and cryo-electron tomography—to reveal the structures and dynamics of membrane-interacting proteins across multiple resolution and scale regimes.
QB3-Berkeley: Are there any papers forthcoming from your lab that you’d be willing to tell us a bit about?
James Hurley: We have a very exciting project that recently appeared in Nature. That paper has to do with lysosomes and autophagy, which is a major topic in my lab. And it also has to do with the use of cryo-EM, which is the major approach used in this research. In this paper as we asked the question: When cells are fed, and they don’t need to transcribe the genes to do more autophagy and make more lysosomes, how do they turn that off? It turns out to be staggeringly complicated; to understand this, we did a biochemical reconstitution and looked at a set of cryo-EM structures that are detailed enough for a side chain placement. The structure ends up involving 36 different polypeptide chains that are there just to make that decision as to where you go with this transcriptional switch.
Another theme of my group’s work is integrating cell biology and structural biology. This project is part of initiative called the Alliance for Therapies in Neuroscience; we were also able to receive funding from Genentech for this project because of the prospects that can be helpful in dealing with intractable neurodegenerative diseases that involve excessive buildup of aggregates within cells and are too slow or defective clearance of those aggregates. So, by increasing lysosomes by increasing autophagy, the idea is that we can speed the clearance of these dangerous materials and save your neurons. There are also potential implications for cancer research that we’re excited to follow up on as we move forward with this project.
QB3: It sounds like this is a project that utilized Cal-Cryo@QB3-Berkeley?
JH: Yes! All of the work was completed at the Cal-Cryo core research facility.
QB3: You’ve worked on several large training grants. What do you like most about working with trainees at UC Berkeley?
JH: We’ve just gotten a fundable score on a new grant called the biophysics training program. It replaces a long running program that Dave Wemmer ran, which was called the molecular biophysics training grant. This training grant is the mainstay of support for the QB3 biophysics program. Many of the first- and second-year students in the biophysics graduate program—probably at least half—are supported on this grant.
In my previous role, at the intramural program of the NIH, I didn’t teach, and I didn’t write grants for the first 20 years of my career. But when I got that chance, I came to Berkeley expressly to work with grad students. And that’s very special because as a mentor to grad students, you’re such a formative part of their scientific development, and you get to see the transition in their training: It’s almost like a switch flips at a certain point and they become independent thinkers.
My favorite mentoring experience so far was with a student named King Carter, who was MCB student could have easily been a biophysics student. Carlos Bustamante, also a QB3-Berkeley faculty affiliate whose lab is in Stanley Hall, was King’s co-mentor. King was a first-generation college student, so no one in his family had attended college, much less grad school. His family immigrated from the Philippines when King was eight and he came up through the SF State University through a program called the Minority Access to Research Careers (MARC). King had a great deal of determination, and he graduated with a fantastic first-author paper, which was a very elegant piece of work. He’s now doing a postdoc at the NIH Intramural Program, and he was last year’s MCB student commencement speaker. I’m so proud of students like King and the other students I’m able to mentor here at Berkeley.
QB3: What advice would you give to prospective students who are interested in your field?
JH: This, like many fields, is in rapid transition, and artificial intelligence and machine learning are having a huge impact. Structural biology has been such a productive field—there are nearly 200,000 structures that have been solved experimentally, mostly by X-ray crystallography, some by NMR, others by cryo-EM. And two years ago, Google’s DeepMind came up with algorithm, AlphaFold 2 that was able to use this training set to largely solve that prediction problem. Much of the activity in structural biology has been subsumed by these prediction algorithms. I think this was a bad development for some people in structural biology, but I believe it’s great for people like me, who are interested in integrating structural and cell biology and interested in understanding hierarchically, how biomolecules come together in the cell, to give rise to the emergent phenomenon that we know of as life. And life starts at the cellular level. It’s very exciting to me that we are now in a position to go from the principles of physics and chemistry to the principles of life in a rigorous way. So, I would say to students: Don’t be scared of AI taking your job. Learn how to make AI work for you—not displace you. And come to Berkeley if you’re admitted to one of our excellent programs. This is the place to be.
QB3: What do you like to do when you’re not working?
JH: I like to spend time outdoors with my wife and son and our dog. We do quite a bit of kayaking, and we bring the dog kayaking, so everyone’s together out on the water. We do quite a bit of cycling as well. That’s not quite as dog compatible, but it is compatible with my son who is on the Berkeley high mountain bike team. He rides a little faster than me these days, but we do like our riding time together.
QB3: What is the best part of being part of QB3 Berkeley?
JH: The heart of QB3-Berkeley is Stanley Hall. It’s the QB3 core research facilities. It’s the training programs. And it’s the entrepreneurial activities and support. My life as training grant director is certainly easier by the capabilities that QB3-Berkeley has developed like the terrific Graduate and Postdoc Career Development office, and the SQB seminar series, which we worked into including as part of our training program. As I mentioned previously, the QB3-Berkeley core research facilities are vital to us; we use Cal-Cryo@QB3-Berkeley on a weekly basis. And I am involved in starting companies, most of which have not gone directly through the QB3 startup vehicles, but I have utilized QB3’s Startup in a Box once and I’m gearing up for the next round. As soon as the market gets a little better, I plan to launch another company, and perhaps we’ll participate in one of QB3’s startup programs with this new company.