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Fred Hutchinson Cancer Research Center computational and molecular biologist Dr. Arvind “Rasi” Subramaniam has received a five-year, $920,000 CAREER Award from the National Science Foundation to develop computational models of how cells cope with stalled protein synthesis. Cells rely on proteins for all their functions, and Subramaniam's research will shed light on how protein synthesis goes awry in diseases such as cancer.
CAREER Awards support early-career faculty poised to make important scientific advances and serve as academic role models in research and education.
“It gives us an opportunity to explore a direction we would otherwise find very hard to do with traditional funding mechanisms,” said Subramaniam, who has also obtained National Institutes of Health funding to study the same process in human cells. “The NSF is more willing to fund projects that are not directly medically relevant. It’s fantastic. A precise understanding of biology is what we want, but you can’t start with a complex disease system. This gives us a really nice way to test our intuition using rigorous computational models.”
The creation of proteins is fundamental to life.
“All the cells in our body rely on proteins to do everything that happens inside them,” Subramaniam said.
Our genes encode all our proteins. Transforming genetic information into a functional protein is a process that can be divided into two main steps. First, molecular machines create a molecule known as messenger RNA based off a gene’s sequence. Then, different molecular machines called ribosomes read the mRNA molecules and assemble proteins using amino acids, proteins’ building blocks.
As ribosomes march along the string-like mRNA molecules, they can occasionally get stuck. Subramaniam studies how cells sense and deal with these stuck ribosomes. Using computational methods, his team has produced preliminary work that suggests it’s not so much the ribosome stalling as the ribosome traffic jam that ensues as the machines pile up behind a stall, which tells cells there’s a problem that needs to be dealt with.
“The goal of this specific project is to describe the process of how ribosomes move, and what happens when they get stuck, in precise quantitative terms,” Subramaniam said.
Being able to attach numbers to the model will deepen scientists’ understanding of how protein synthesis can go awry and the mechanisms that cells use to respond to it. A qualitative view of the process might mean merely knowing which molecules cells rely on to sense stalls on mRNAs. A quantitative model would include calculating the exact amount of proteins produced, which is a starting point for predicting how the process gets hijacked by diseases such as cancer, he said.
Computational models can also provide examples of unexpected outcomes that can be tested experimentally. Subramaniam’s discovery that ribosome traffic jams could be important arose in just that way. The work supported by the CAREER Award will alternate between computational modeling and experimentation, as results from each approach inform the other. To pursue this mix of approaches, Subramaniam, who holds appointments in both the Basic Sciences Division and the Herbold Computational Biology Program within the Public Health Sciences Division, expects to draw on the complementary expertise of his experimental and computational colleagues.
Subramaniam is also excited to continue and extend his teaching and outreach activities as part of the CAREER Award. With Hutch colleagues Drs. Trevor Bedford, Jesse Bloom, and Phil Bradley, he put together an interdisciplinary graduate course in computational biology for students in the Fred Hutch/University of Washington Molecular and Cellular Biology graduate program. He also hopes to introduce high school and undergraduate students to computational methods through the Hutch’s various internship programs.
“Most of these students come from an experimental, wet-lab background. This is a chance for them to learn about computational biology,” he said.
