Halfmann Lab

Randal Halfmann, Ph.D.

Associate Investigator

Assistant Professor, Department of Molecular and Integrative Physiology
   The University of Kansas School of Medicine

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For kids raised in a city, sometimes a trip to the science museum is needed for them to feel immersed in biology. For kids raised in the country, it’s all around them. For Randal Halfmann, Ph.D., who grew up on a cattle farm 10 miles out of Coleman, Texas (population 4518), his “biological exploratorium” was the great outdoors. “I was surrounded by livestock and exposed every day to plants,” says Halfmann, who was active in his high school’s Future Farmers of America (FFA) organization. “For college I never considered any place other than Texas A&M, where my dad went.”

There, supported by a FFA scholarship, Halfmann majored in genetics and was mentored by plant geneticist David Stelly, Ph.D. Halfmann completed an honors thesis in Stelly’s lab on chromosome doubling in cotton and was named an A&M University Scholar. He describes his college years as all-engrossing. “I found myself thinking about chromosome doubling strategies even when I wasn't in the lab.” 

Stelly encouraged Halfmann to apply for a National Science Foundation (NSF) fellowship and pursue graduate work at the Massachussetts Institute of Technology (MIT). Early on at MIT, Halfmann briefly considered focusing on RNA biology, which was trending in 2004, but a seminar he had attended at A&M about “the protein folding problem” continued to stick with him. In a nutshell, the problem deals with the question of how amino acid sequences “know” how to each fold into their own unique shape. Halfmann then heard a talk by MIT and Whitehead Institute faculty member Susan Lindquist, Ph.D., who was studying particles of misfolded proteins known as prions. Halfmann was hooked; he joined the Lindquist lab.

At the time, prions had an unfavorable reputation, as their accumulation in the brain caused mad cow disease and its human counterpart Creutzfeldt-Jakob disease. Plus, toxic amyloid filaments seen in the brains of patients with neurodegenerative disease resembled prion proteins. Halfmann’s graduate work over the next five years didn’t refute the involvement of prions with disease processes, but it helped salvage their negative reputation.

For example, two of his publications from the Lindquist lab, a 2009 Cell paper and a 2012 Nature paper, demonstrated that prions aren’t “all bad” but that several proteins in perfectly normal yeast can aggregate into prion forms. More amazingly, “prionization” of some of these proteins helped yeast adapt to environmental change.

Before these studies, few prions were known. “But we found at least nineteen of them, and it seemed that some cells lived quite happily with them,” says Halfmann. “That suggested that there was a lot of biology unexplored.” This work helped spur investigation of adaptive cellular behaviors aggregated proteins might foster, an idea elaborated in Halfmann’s 2014 lay article entitled, “The Bright Side of Prions.” 

By the time he earned his doctorate degree, Halfmann was headed for an academic career. With Halfmann’s impressive 2010 resume and graduate training in a prestigious lab, he bypassed the traditional postdoctoral training and instead sought an independent position at The University of Texas Southwestern Medical Center.

There, working closely with Zhijian (James) Chen, Ph.D., and supported by competitive awards, Halfmann ran his own lab until 2015. During that period he began to confirm that prionization of some proteins actually helped yeast cells cope with environmental challenges.

In a 2013 Cell paper, he reported that alcohol exposure made a particular yeast transcription factor aggregate or polymerize into prion form. That shape change in turn altered gene expression such that yeast banded together to become multicellular, a form more tolerant of environmental stress. More excitingly, daughter cells of prion-containing yeast inherited their parent’s prions and the traits they conferred. And in a 2014 collaboration with Chen, also published in Cell, he reported that prion forms of other proteins function as part of innate immune responses in mammalian cells.

“Since then others have shown that the prion-like particles exist in human cells and are even taken up cell-to-cell,” Halfmann says. Overall, the reconsideration of prions that has occurred over the last decade is revolutionary. It means that, in both yeast and humans, cells can inherit or acquire adaptive responses via protein structures, not just by DNA.

Halfmann became a Stowers Assistant Investigator in 2015 and continues to study protein conformation transitions, primarily in yeast. Attracted here in part by colleagues like Kausik Si, Ph.D., who also saw a bright side of prions very early on, Halfmann says the choice was unambiguous given the support the Institute provides new investigators. “Stowers is a small but unusual place,” he says. “They put science first and remove obstacles that might keep scientists at other places from doing what they do best.”

So it seems natural that someone who skipped a postdoc would land in a nontraditional environment. Ironically, the move to Kansas City has made Halfmann more conventional. “I always told friends, ‘You don’t have to do a postdoc,’ ” he laughs. “But as soon as I accepted the job here I realized, I’m going to need them!”