Ankur Jain didn’t always know he wanted to be a biologist. During his undergraduate studies at the Indian Institute of Technology Kharagpur, he originally focused on engineering, but soon realized that he wasn’t actually that interested in understanding how human-made things work. Instead, he wanted to study the mechanisms that make things tick in the natural world, he says. Jain ended up graduating with a degree in biotechnology and biochemical engineering in 2007, and moved to the United States to pursue his doctorate in biophysics and computational biology at the University of Illinois Urbana-Champaign.
During his PhD, Jain focused on developing better techniques to study what proteins do in cells. “The machines inside the cell—the proteins—they often act in conjunction. Maybe one protein alone does not do its task, but [it does when] it’s bound to something else,” he says. “The question is, what is it working with? What are its partners in crime?”
One method for determining protein partners is a pull-down assay—anchoring one type of protein to beads in a column and identifying which other proteins bind to, or are “pulled down” by, it. But this technique runs into difficulty when proteins have multiple partners.
To fix this problem, Jain led the effort to develop a single-molecule pull-down (SiMPull) assay in which protein A is attached to a slide, while proteins B and C are tagged with fluorescent peptides. By overlaying fluorescent microscopy images of single-molecule resolution, this technique can determine whether protein A can bind to B and C at the same time, or only separately. Jain later used this technique to study the components of mTOR complexes, which play important roles in normal cell growth but also in many diseases, including cancer.
After receiving his doctorate in 2013, Jain took a postdoctoral position with biochemist Ronald Vale at the University of California, San Francisco. During this time, he pivoted to studying the internal organization of cells. Many intracellular structures are enclosed in membranes, but others aren’t, Jain says. “Just like oil and water separate from each other, there are compartments inside the cell which don’t have a physical boundary surrounding them, but still maintain their identity.”
Jain wasn’t initially studying this phenomenon, called liquid-liquid phase separation, in any particular disease. But in 2014, the Ice Bucket Challenge, which highlighted amyotrophic lateral sclerosis (ALS), took the internet by storm. Jain learned that some forms of familial ALS are associated with abnormal nucleotide repeats in a specific gene. He noticed that these disease-associated patterns in patient’s DNA—and the RNA it is transcribed into—looked similar to the synthetic DNA and RNA he was making to study RNA aggregation and phase separation.
In a 2017 Nature paper, Jain demonstrated that RNA molecules with repeat expansions, including those associated with diseases such as ALS and Huntington’s, bond with each other in specific ways, forming gels and undergoing phase separation to create structures called RNA foci. While RNA foci had been observed in the cells of patients with repeat expansion disorders, this study revealed the mechanisms by which repeat expansions in DNA lead to RNA foci and suggested that these abnormal RNAs, and not just abnormal proteins, may be involved in driving disease.
Vale tells The Scientist that he was “very impressed with the originality of [Jain’s] work as a graduate student . . . and that spark of original thinking and independence came through in his postdoc as well.” On top of that, Vale adds, Jain is “just a really wonderful person to interact with and do science with.”
In 2018, Jain joined the Whitehead Institute at MIT, where he continues to study the role of RNA foci in neurodegenerative disease. This year, he was named a Pew Biomedical Scholar, and he says he plans to use the accompanying funding to investigate the role of polyamines in RNA aggregation.
Among his other projects, Jain recently teamed up with Jing-Ke Weng, an MIT biologist who studies plant metabolism, to screen plant-produced small molecules for their abilities to inhibit the aggregation of RNAs and proteins relevant to human neurodegenerative disorders. This collaboration is scientifically promising, but also enjoyable for the scientists involved, Weng says. Both he and Jain are “quite interested in the fundamental mechanisms of how things work, how molecules behave in the cells,” he adds. “We just happen to be trained in very different disciplines. So when we meet and discuss, we have a lot of fun.”