It’s not unusual for a biologist to study crickets, the chirping insects. But James Holehouse, an assistant professor of biology, has a strong research interest in cricket, the sport that involves bowlers, overs, and sticky wickets. 

And while many biologists study the laws of evolution, Holehouse has also taken deep dives into the U.S. legal code, a hodgepodge of rules and regulations nearly as complex as the tree of life. 

Holehouse, who earned his master’s degree in theoretical physics and his doctorate in quantitative biology at the University of Edinburgh, started at WashU this fall as a member of the Rules of Life Initiative. He applies theoretical and computational approaches to topics that cross the boundaries of physics, biology, and sociology. 

He spoke with the Ampersand about the hidden connections between sports and science, the importance of randomness, and his new role at WashU.

How did you get your start in biology?

As a doctoral student, I shifted from studying theoretical physics to another challenging topic: gene regulation and expression. I was especially interested in the role of randomness. Randomness plays an important role in gene expression and gene regulatory networks. Even in a stable environment of genetically identical cells, gene expression from one cell to another can come down to chance.  There is still much we don’t know much about how regulatory systems evolve to deal with all that noise.

Biology and physics may seem distantly related, but my background gave me a toolkit for solving problems. Biology is a great testing ground for a lot of new physics. 

Can you give an example of how you study randomness in biological systems?

I recently wrote a paper in Proceedings of the Royal Society B that offered a new perspective on how biological transience—manifested in the reality that organisms are born, live, and then die —affects the behaviors of inherently random cellular function. A lot of the processes that allow cells to function are marked by substantial degrees of randomness. Just by chance, one cell might have 10 copies of a particular protein while its neighbor only has two. I use mathematical modelling to make the case that random variation might be an asset to an organism because it opens the possibility for cells to have different beneficial functions. If you can understand how such fleeting randomness affects an organism, you could find important regulatory mechanisms that you’d never see if you ignored or discounted the noise. 

In addition to biological topics, you’ve also studied the evolution of legal codes and the laws of cricket and rugby. What’s the connection? 

My work spans the breadth of living systems. Biological systems and human-built systems have a lot in common. In particular, they both need robust regulation. 

Take cricket, for example. The rules of the game diversified in 1939. There was a stark increase in the depth of cricket law, sandwiched between two periods in which the laws evolved more slowly. It’s analogous to the Cambrian explosion in evolution, which began about 538 million years ago.

I believe both biological and human systems follow universal principles, and I'm trying to identify those principles and understand how patterns manifest themselves across the tree of life. Do cells organize the diversity of their proteins in ways that are similar to how cities organize a diversity of occupations? Does the size of the regulatory genome increase with cell size just as human laws scale with population size? These sorts of questions are fundamental to my work.

I generally focus on a single concept of inquiry at a time, and I use many different model systems to investigate those concepts.

What are your plans for WashU?

My lab will focus on the science of regulation. I’m especially interested in studying how gene regulatory networks evolved to deal with different types of biological noise and randomness. For my research program to flourish, I’ll need to be surrounded by a wide variety of researchers with different skills and insights. That’s why I’m so excited to be part of the Rules of Life Initiative. It’s a great way to get people interacting across departments.

I’ve already started talking with other members of the Rules of Life Initiative as well as established faculty members from the wider university. They’re all brilliant. For anyone who takes interdisciplinary science seriously, WashU is an ideal place to be. 

Header image: Human-derived cells captured through fluorescence microscopy. The technique uses fluorescent dyes to highlight cellular structures, revealing details that are otherwise difficult to see. (Image: ZEISS Microscopy, CC BY 2.0)