Bringing order to disorder: Jhullian Alston, PhD

Alston holds up a tray of tubes.
Alston selects buffers for single-molecule assays of disordered proteins. (Photos: Michael Goderre/Boston Children's Hospital)

Proteins typically fold into orderly, predictable three-dimensional structures that dictate how they will interact with other molecules.

Jhulian Alston, PhD, is drawn to intrinsically disordered proteins, whose key feature is a lack of structure. They are difficult to study and far less explored.

“They’re floppy, they don’t have specific folds, they can’t slot into each other like Legos as folded proteins do,” he says. “Yet, they are active and can interact with other proteins or nucleic acids.”

Though the name “disordered” suggests these proteins are diseased or dysfunctional, they’re legitimate players in many cell functions. They’re found throughout the evolutionary tree — from yeast to flies to humans.

“There’s evolutionary pressure for certain proteins to remain disordered,” says Alston, a postdoctoral fellow in the Boston Children’s Hospital lab of Taekjip Ha, PhD. He speculates that the lack of structure keeps them dynamic and flexible, able to expand or contract to respond to different conditions or interact with specific molecules.

Disordered proteins are known to be involved in disease. One that Alston studied previously is critical for packaging the SARS-CoV-2 genome. Others, when genetically mutated, are associated with cancer and neurodegenerative conditions.

Bringing physics to protein biology

Intrinsically disordered proteins are often studied with biophysics techniques such as single-molecule spectroscopy, which can analyze molecules’ configurations with nanometer precision, and computer simulations that predict the behavior of a protein and its interacting partners. Alston gained considerable expertise in these techniques during his PhD work at the Washington University School of Medicine.

In the Ha lab, within the Program in Cellular and Molecular Medicine (PCMM) at Boston Children’s, Alston is applying single-molecule techniques to study disordered proteins produced through the fusion of two different genes. These proteins, the result of a chromosomal abnormality, drive some childhood cancers.

Alston in the lab with Taekjip Ha discussing the contents of a flask.
Alston and his mentor, Taekjip Ha, discuss bacterial growth conditions for protein expression.

Alston’s current focus is PAX3-FOXO1, a fusion of two proteins that leads to alveolar rhabdomyosarcoma, a soft-tissue pediatric sarcoma. Using a single-molecule technique called FRET, he is studying how the fusion leads to new behavior, including new DNA and protein interactions that ultimately lead to cancer. He hopes to design peptides that can bind to PAX3-FOXO1 and prevent it from driving cancer.

From animals to proteins

Alston didn’t initially expect to be doing biophysics. He started out working with animal models, studying rats with nerve injury and prostate cancer as an undergraduate at the University of Maryland, Baltimore County (UMBC). As a postgraduate at the NIH National Institute of Diabetes and Digestive and Kidney Diseases, he knocked out genes with CRISPR in the worm C. elegans.

Alston at the lab bench, writing in a notebook
Taking notes on experiments.

But proteins captured Alston’s interest. He had heard of unfolded loops in proteins, but not the idea that they had biological functions. He wanted to understand the precise interactions that occur between proteins and study them in a quantitative fashion. His mentor at the NIH, John Hanover, suggested he do a PhD in biophysics.

Alston’s work was initially supported by an NIH National Cancer Institute Predoctoral to Postdoctoral Fellow Transition Award and the Burroughs Wellcome Fund’s diversity in science program. Now, he’s received another big boost with his selection as an HHMI Hanna H. Gray fellow. Through this program, which supports early-career researchers from a variety of backgrounds, Alston will receive up to $1.5 million over the course of up to eight years.

His big-picture goal is to find ways to target a variety of intrinsically disordered proteins with drugs. “About 40 percent of protein regions in humans are disordered, and we lack the ability to target them,” he says. “The ability to target disordered regions will open up drug discovery across the board.”

Alston studying an image on the computer.
Alston analyzing single-molecule FRET data as part of his research on PAX3-FOXO1.

Paying it forward

Meanwhile, Alston has been giving back. As an undergraduate in UMBC’s Meyerhoff Scholars Program, he benefited from having many role models at a time when he needed them. He has gone on to mentor other trainees who are underrepresented in STEM fields through the NIH’s Network of African American Fellows, as a graduate student at Washington University, where he chaired the Association of Black Biomedical Graduate Students, and currently as secretary of the Harvard Black Postdoctoral Association.

Looking forward to a day when he has his own lab, Alston wants to create a space where people of all backgrounds feel welcome. “Science is best when lots of different viewpoints are involved,” he says.

Read more profiles of our researchers and learn more about the PCMM.

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