“CURIOSITY-DRIVEN EXPLORER”: Clifford Brangwynne, Princeton University professor of chemical and biological engineering, has been selected as one of 19 new Howard Hughes Medical Institute investigators. He will receive roughly $8 million over the next seven years to pursue his ongoing explorations into uncharted realms of biomedical research. (Photo Courtesy of Clifford Brangwynne)

By Donald Gilpin

Clifford Brangwynne, associate professor in chemical and biological engineering at Princeton University, has been awarded roughly $8 million from the Howard Hughes Medical Institute (HHMI) over the next seven years to explore uncharted territory in biomedical research, the HHMI announced this week.

From a background in materials science as an undergraduate at Carnegie Mellon University and applied physics at Harvard University, where he earned his PhD, Brangwynne has leapt into a new field of biology where he has explored a world of protein groups making transitions that could unlock the secret of turning genes on and off. “The central players in the drama of gene regulation are these floppy proteins,” Brangwynne said. “They form little dew drops that decorate the genome and control its function.”

Noting the potential for manipulating these phase transitions to alter biological programs that control cell function during development, Brangwynne continued, “There’s still some healthy skepticism, but we now have enough examples that most people agree that these phase transitions are important or even essential. They may even figure in pathologies where proteins clump up, like Alzheimer’s disease.”

One of 19 new HHMI investigators, Brangwynne sees the “no strings attached” award as a huge boost to his research work. “What it really means to become an HHMI investigator is that some really impressive scientific luminaries at HHMI and their advisory board think that I am going to continue to do great research,” he said. So it’s a wonderful vote of confidence in me and my research, which emboldens me to push into totally new territory.”

Brangwynne went on to explain, “Science is just like other creative fields, where we have these ‘gut feelings,’ or intuitive senses for what are the most interesting and fruitful areas to dig into. Being an HHMI investigator means that my scientific instincts are much less resource-limited. I can take more risks and follow my nose into promising new territory.”

HHMI is the nation’s largest private supporter of academic biomedical research, spending more than $650 million in the U.S. in 2017. “We selected these scientists because they know how to ask hard and interesting questions with skill and intellectual courage,” said HHMI Vice President and Chief Scientific Officer David Clapham. “We believe they have the potential to make breakthroughs over time.”

Twenty-eight current or former HHMI scientists have won the Nobel Prize,
making big leaps forward in HIV vaccine development, micro biome and circadian rhythm research, immunotherapy, and the genome editing tool known as CRISPR/Cas9, among other fields.

A faculty member at Princeton since 2011, after working as a postdoc at the Max Planck Institute in Germany, Brangwynne discussed his excitement in his recent discoveries. “Going under the hood of nature and seeing it in a new way blows any other adventure out of the water,” he said.

“Understanding how phase separation impacts the genome is just thrilling. Our genes are not only a record of where we’ve been — i.e. our genetic heritage, but also where we are, our phenotypic characteristics like height and eye color, and where we are going — i.e. what diseases we are likely to get, at what age we will die, etc. It’s like a blueprint for the past, present, and future of physical selves.

“And the concept that this fundamental concept of physics is important, our discovery that liquid-liquid phase separation occurs throughout the cell, and the likely possibility that the process is in a dynamic interplay with this flow of genetic information, and that by engineering phase behavior we can control this information flow, is just about as cool as it gets. But our hope in science is always that the reality is even more exciting than we at first imagined, and so we’ll see where this line of inquiry leads us.”

Brangwynne talked about learning “to embrace uncertainty, pushing into the unknown, and the idea of being comfortable with being uncomfortable,” as he emphasized his focus on “the stewardship of opportunity” and the moral responsibility to take advantage of opportunities that arise.

He described his hopes for his ongoing research. “Neurodegenerative diseases are some of the most devastating. Instead of causing a problem with your liver, kidney, or intestine, diseases like Alzheimer’s are eating away at your mind, the core of who a person is. It turns out that many of these kinds of diseases are all about proteins clumping together, and how this occurs is closely coupled to the phase separation process which is occurring all the time in all of our healthy cells. I’m excited by the possibility that our work on liquid condensates in the nucleus will shed light on these disease processes.”

Describing himself as a “curiosity-driven explorer,” Brangwynne concluded, “I view my research — and life in general — as an incredible adventure, and I’m eager to see where it leads.”