Connell Lecture Series: Dr. Michael Rosen

Written by Cindy Yimei Wan

Dr. Michael Rosen is the Chair of the Department of Biophysics at UT Southwestern Medical Center and an Investigator of the Howard Hughes Medical Institute. Dr. Rosen was invited to give a Connell Lecture on March 9th, 2022, during which he shared recent work from his lab on the role of phase separation in chromatin organization in eukaryotic nuclei. I had the valuable opportunity to speak with Dr. Rosen before the lecture to learn about his path towards a career as a scientist, the work being conducted in his lab, and his philosophy regarding research and mentorship.

Dr. Rosen grew up in Michigan in a household of scholars: his father is a professor in the Department of Psychiatry at Michigan State University, and his mother, until she retired, was a professor of English education at the University of Michigan-Flint. With both his parents and all of their friends being academics, science was a strong theme throughout his life. “I always loved science, from my earliest memories,” Dr. Rosen recalls. “[I] loved dinosaurs and loved running around in the creek catching frogs and critters from the water.” Up until high school, Dr. Rosen really enjoyed math and thought he might become a mathematician. However, his interest in science ultimately won out. He attended the University of Michigan for his undergraduate studies and earned degrees in both Chemistry and Chemical Engineering. In 1993, Dr. Rosen earned his PhD in Chemistry from Harvard University under Stuart Schreiber. “Like everybody in science, I wasn’t sure what I was going to do with that science background. Through graduate school…my friend, Tom Wandless, who is now a professor at Stanford, used to joke that I was going to open a McDonald’s and he was going to open a bike shop.” Although Dr. Rosen did consider other paths, such as biotech and pharma, he ultimately saw himself becoming an academic. In particular, he was drawn to the independence of academia. For Dr. Rosen, the fun of science is coming up with new creative ideas and insights – the “Aha!” moments.

Following his PhD, Dr. Rosen was a postdoctoral fellow at the Lunenfeld Center at Mount Sinai in the labs of Tony Pawson and Lewis Kay, which he remembers fondly: “It was the very early days of signal transduction…Tony had just discovered the SH2 domain a few years before [my wife and I] were there, so there was this incredible buzz going on [about how] we were onto the next great advance in science.” He started his independent laboratory in 1996 at the Memorial Sloan-Kettering Cancer Center in New York before moving to the UT Southwestern Medical Center in 2001. In the beginning, his research group focused on investigating signalling pathways that regulate actin assembly, using structural techniques such as NMR and X-ray crystallography. However, recent efforts have shifted more towards studying biomolecular condensates and their formation via phase separation, which is a physical process by which macromolecules separate into coexisting dense and dilute phases.

It was actually one of those “Aha!” moments that first led his research group towards the study of phase separation. In 2008, Dr. Rosen’s group was studying how Neural Wiskott-Aldrich Syndrome protein (N-WASP) activated the Actin related protein 2/actin related protein 3 (Arp2/3) complex to nucleate actin polymerization in eukaryotic cells. Mutations in WASP, the founding member of the protein family to which N-WASP belongs, lead to Wiskott-Aldrich syndrome, a disease where defective actin cytoskeletal rearrangement leads to immune dysregulation. Interestingly, his group determined that two N-WASP proteins appeared to activate one Arp2/3 complex, rather than one N-WASP to one Arp2/3 as was thought at the time (1). An important implication of this finding was that the assembly of many N-WASP molecules together would increase the likelihood of activating Arp2/3. Naturally, Dr. Rosen’s group became interested in factors that could assemble N-WASP into large oligomers. As N-WASP proteins have proline rich regions that bind SH3 domains, they intuited that mixing N-WASP with SH3 domain proteins could be a “recipe to oligomerize”.

A graduate student in Dr. Rosen’s group at the time, Hui-Chun Cheng (now an assistant professor at National Tsing Hua University), mixed N-WASP with Nck, a cytosolic protein containing three SH3 domains, and saw the solution take on a strange cloudy appearance. Initially, they thought it may have aggregated or precipitated – however, when they spun down the solution to clarify it, there was no pellet of aggregated protein, and moreover, shaking the tube would make the solution go cloudy again. In fact, they had driven the system to phase separate. Not long after, a seminal paper from Tony Hyman’s lab was published, showing that P granules in the C. elegans embryo are phase separated droplets. Everything clicked: N-WASP and Nck were undergoing the same process. In 2012, Dr. Rosen’s lab published a paper in Nature showing that phase separation of N-WASP, Nck, and phosphorylated nephrin stimulate Arp2/3-mediated actin assembly (3). Notably, they demonstrated for the first time that the concentrations required for phase separation are directly related to the valency of the interacting species. Biomolecular condensates are now a major focus of Dr. Rosen’s lab. Recently, they have been interested in the structural mechanisms driving chromatin phase separation (4), which Dr. Rosen finds very cool.

In terms of his approach to supervision, Dr. Rosen aims to foster an environment that is supportive without being restrictive. Back when Dr. Rosen was a student and postdoctoral fellow, he was a member of larger labs where he had a lot of freedom to pursue his own research interests. Now, as a supervisor, he tries to give the people in his own lab the same freedom to guide their own projects and explore their own directions, while accounting for their individual needs. “It means making their own mistakes,” Dr. Rosen says. “But I believe people learn better from their mistakes than being told exactly what to do.” His main word of advice for current trainees is to understand that they have the opportunity to push their project in directions that genuinely interest them. “It’s your project, it’s your science, [and] it’s going to be your discovery… We try to instill in our graduate students [that] it’s your opportunity to do something wonderful.”

You can learn more about Dr. Rosen’s research at https://www.utsouthwestern.edu/labs/rosen/research/.

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References

  1. Patrick, S. B. Cheng, H-C. Ismail, A. M., Panchal, S. C., Doolittle, L. K., Kim, S., Skehan, B. M., Umetani, J., Brautigm, C. A., Leong, J. M., & Rosen, M. K. (2008). Hierarchical Regulation of WASP/WAVE Proteins. Mol. Cell. 32(3), 426-438. https://doi.org/10.1016/j.molcel.2008.10.012.
  2. Brangwynne, C. P., Eckmann, C. R., Courson, D. S., Rybarska, A., Hoege, C., Gharakhani, J., Jülicher, F., & Hyman, A. A. (2009). Germline P granules are liquid droplets that localize by controlled dissolution/condensation. Science 324(5935), 1729–1732. https://doi.org/10.1126/science.1172046.
  3. Li, P., Banjade, S., Cheng, H. C., Kim, S., Chen, B., Guo, L., Llaguno, M., Hollingsworth, J. V., King, D. S., Banani, S. F., Russo, P. S., Jiang, Q. X., Nixon, B. T., & Rosen, M. K. (2012). Phase transitions in the assembly of multivalent signalling proteins. Nature483(7389), 336–340. https://doi.org/10.1038/nature10879.
  4. Gibson, B. A., Doolittle, L. K., Schneider, M., Jensen, L. E., Gamarra, N., Henry, L., Gerlich, D. W., Redding, S., & Rosen, M. K. (2019). Organization of Chromatin by Intrinsic and Regulated Phase Separation. Cell179(2), 470–484.e21. https://doi.org/10.1016/j.cell.2019.08.037.

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Correction: In the original article published on May 12th, 2022, the author described mutations in N-WASP and other WASP family proteins leading to Wiskott-Aldrich syndrome, when in fact only mutations in WASP cause the disease. The post has since been updated with the correct information on May 16th, 2022. The author apologizes for the mistake and thanks Dr. Rosen for the correction suggestions.



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