Randal Halfmann, PhD

Randal Halfmann obtained his Ph.D. in Biology at MIT, then started his own lab at UT Southwestern Medical Center as an NIH Early Independence Awardee. While there, he discovered that self-propagating protein aggregates known as prions function to enforce cell fate commitment in organisms ranging from budding yeast to humans. In 2015 he joined the Stowers Institute, where his lab investigates both the mechanisms and biological consequences of protein supersaturation and self-assembly. His work is elucidating how protein self-assembly controls the granularity of protein activity in biological space and time, in phenomena ranging from signal transduction to cellular memories to aging. Recent breakthroughs from the Halfmann lab include the development of technology to detect and characterize protein self-assembly in living cells (2018), elucidation of the molecular etiology of Huntington’s Disease proteopathy (2021), and discovery that our innate immune system is powered by protein supersaturation (2022).

An overarching goal of modern biology is to understand how biomolecules compartmentalize cellular processes at mesoscopic spatiotemporal scales -- that is, greater than the sizes and fluctuations of individual proteins, but smaller than the sizes and lifespans of cells. These emergent properties of biomolecules somehow orchestrate gene regulation and signaling. The relatively recent appreciation that proteins can order themselves via liquid-liquid phase separation in vivo marked a turning point in our understanding of how cells work. An intrinsic feature of phase separation is nucleation, the energetically unfavorable event that dictates the probability of the new phase occurring de novo at any point in space and time. Whereas the implications of phase separation in organizing protein activities in intracellular space are now being feverishly uncovered in research labs around the world, the fact that the nucleation barriers inherent to phase separation can also control protein activity temporally over cellular and organismal time scales is only beginning to assimilate into biological discourse. The Halfmann Lab is making those discoveries. We seek to uncover fundamental relationships between nucleation barriers and directional cellular changes that abound in biology. These collectively underlie physiological and pathological phenomena ranging from cell differentiation and development on the one hand, to neurodegeneration and aging on the other. The central tenet of our research holds that nucleation barriers render living proteomes perpetually high energy, or supersaturated, with respect to ordered protein assemblies such as amyloids, and this provides a driving force for inevitable and irreversible declines in cellular phenotypic potential.