Modeling Translation: the Mathematics of Making Proteins
Arvind “Rasi” Subramaniam, Computational Biologist
Dr. Arvind “Rasi” Subramaniam has always been interested in understanding the fundamental aspects of how things work. He studies one of the most essential processes of biology: how cells turn the genetic information contained in DNA into proteins, the components that make cells function. This interest in fundamental biology puts him in good company in the Basic Sciences Division, although his research career actually began in theoretical physics.
Theoretical physicists attempt to predict the behavior of the universe by developing mathematical equations that explain how things interact. While pursuing his Ph.D., Subramaniam worked on understanding the interactions of subatomic particles in two dimensions, an area of research that is essential to the development of quantum computers. While the fields of physics and biology may seem very different, basic scientists in each discipline have much in common: They all seek to understand how things work and interact at their most fundamental level.
"A basic science perspective gives a concrete framework to think about the complexity around us. Without it, you can describe what you see but not understand it at a deeper level. Without conceptual models of how various molecules interact inside cells, it would be extremely difficult to understand a complex disease like cancer," Subramaniam said.
Toward the end of his Ph.D., he wanted to move away from theoretical work into research that could have an impact in the near term. He happened to attend a few talks in the then up-and-coming area of systems biology and became interested in applying his background in mathematical modeling to biological systems.
But the journey from physics to biology wasn’t easy. Out of grad school, Subramaniam didn’t even know how to pipette, a day-one skill for measuring small volumes of liquid taught to any biologist-in-training. Undeterred, he sought out a mentor who considered his background an asset and was willing to show him around a biology lab.
Subramaniam did his postdoctoral research at Harvard University, where he was co-mentored by Drs. Phillippe Cluzel and Erin O’Shea. He studied a process called translation, whereby cells make proteins, their building blocks, using the information contained in their genes. This process is achieved using biological machinery called ribosomes, without which your cells would be lifeless blobs of fat.
Given the importance of ribosomes to overall cell functioning, it is no surprise that abnormal ribosomal activity can have many severe health consequences. For example, individuals with decreased ribosomal function have a fivefold increased likelihood of getting cancer. However, tumors also need ribosomes to become more malignant. A cancerous cell that divides indefinitely but does not produce more proteins cannot grow into a tumor.
As someone with a background in theoretical physics, Subramaniam finds the study of translation a particularly interesting problem.
“Translation is a rapid consumer of a cell’s energy and nutrient stores. This means you can try to understand the process by thinking about how a fast and energy-efficient system should work,” he said.
Given that fact, computational models of translation can be optimized and compared based on their efficiency. The same way physicists develop equations to describe the interactions of planets and subatomic particles, biologists can develop equations to describe interactions between molecules.
“It’s challenging to do almost any biological research today unless you have some proficiency in computational techniques.”
When he started this line of research, Subramaniam realized that mathematical models of ribosomal functioning used widely in the translation field had not been thoroughly tested. His research aims to experimentally test and improve the computational models of translation and ribosomal function to better understand how these processes are affected in disease.
As we are faced with increasingly complex questions about human health, computational modeling can be an important tool, as it allows researchers to describe biological phenomena accurately and make specific predictions that can be tested and refined. This is why Subramaniam thinks it is important for young scientists to develop computational skills and why he helps teach an introductory course on computational biology to students in the joint University of Washington-Fred Hutch Molecular and Cellular Biology graduate program.
"It’s challenging to do almost any biological research today unless you have some proficiency in computational techniques," he said.
Following his postdoc (and learning to pipette), Subramaniam wanted to build on his work studying translation. He recalled O’Shea pushing him to apply for a faculty position at Fred Hutch. When he was given an offer, she told him, “You have to go there. You'll do your best science.”
O’Shea, who is now president of the Howard Hughes Medical Institute, told him that at Fred Hutch he would have the chance to work at the bench, a rarity for faculty.
As of 2015 he’s been running his own lab, furthering our understanding of one of the most essential aspects of life. Whenever he needs a bit of inspiration, he likes to join some of his colleagues on a run around Lake Union or a hike in Snoqualmie Pass and talk science.
“Being at Fred Hutch is even better than I imagined," he said. "It is very inspiring. My colleagues are amazing biologists doing exciting research. I feel fortunate that I get to learn molecular biology directly from them rather than in classroom lectures."
— By Matthew Ross, March 10, 2020
