Q&A with CBI Fellow Isabel Larus

Isabel Larus is a Chemical and Systems Biology PhD student at Stanford and part of the Chemistry/Biology Interface (CBI) Training Program at Sarafan ChEM-H. CBI is an interdisciplinary training program that supplements traditional degree-granting PhD programs at Stanford. The program aims to help scientists speak multiple scientific languages spanning chemistry, biology, engineering, and medicine, and enable them to tackle the most challenging and important problems facing human health. Larus sat down to talk with us about her time in the CBI program and how she became interested in the science of protein folding in health and disease.

What question are you trying to answer with your current research project?

A protein’s 3-D shape, or conformation, is like the structure of a machine built for a specific task. Think of a protein like a transformer robot—when in robot form, it has one function, but in car form, it does something else. Many proteins can switch between two or more shapes. In some cases, a protein can switch into an extremely stable shape – so stable that it can drive other copies of the same protein to change shape as well, like a domino effect. This process is called self-templating, and these cascading changes can serve as a cellular “memory” that can alter future cellular behavior. Through self-templating, a cell can remember something that happened to it in the past by storing that information in assemblies of highly stable protein shapes that persist after the initial domino cascade. Self-templating was once thought to be rare, causing severe neurodegenerative diseases, but we now have examples of this behavior in all domains of life and know that it can be part of both healthy and disease processes. 

Despite these findings, we still don’t know how many proteins can engage in this molecular “memory” or what properties enable a protein to switch into a shape that starts the domino chain reaction. With this project, we set out to systematically test over 15,000 human proteins to uncover which ones are capable of this “molecular memory” behavior, hoping to shed light on what makes a protein able to switch and self-template.

So, you are trying to understand the biophysical rules that cause proteins to fold in different ways and how those rules may change with certain diseases? 

Yes. We want to identify the features that give certain proteins the ability to engage in this kind of conformational “memory” behavior, and to understand how disease-related mutations might alter these templating properties. To do this, we’ve built a tool that allows us to systematically screen all human proteins, giving us thousands of examples to look for patterns. So far, our results suggest that this capacity is much more common than previously thought. That opens the exciting possibility that conformational templating is not only linked to harmful events, such as aggregation in neurodegenerative diseases, but may also play roles in normal, beneficial cellular processes.

How did you become interested in protein biophysics, in the first place?

I became interested in protein folding early on during an introductory biology class. Proteins are initially synthesized as a linear chain of amino acids, but for them to be functional, they need to fold into a specific three-dimensional shape, like origami driven by physical interactions between amino acids. I was intrigued by how the biophysical process of protein folding can have such massive outcomes for an organism and drive a variety of diseases from Alzheimer’s Disease to cystic fibrosis. When I decided to do my PhD, I came to Stanford University and rotated in the Jarosz lab, which studies the role of protein folding in evolution, disease, and development and how alternative protein conformations can change the function of cells, in both good and bad ways. I liked the people and the mentor, and the lab was a good scientific fit for me. Understanding the role of protein folding in disease seemed like an interesting chemical-scale problem and big unmet need in society, and that really excited me!

How did you become interested in the CBI Program at Sarafan ChEM-H?

In order to make big contributions to problems in the life sciences right now, you need to bring in diverse perspectives and approaches from the physical sciences as well as the life sciences. That’s what drew me to the research in my home program and to CBI. I wanted to be part of an interdisciplinary community that is focused on using diverse approaches to tackle big problems related to human health. I also wanted to be part of a community of peers and mentors who are all motivated by the same things. 

What advice do you have for people thinking about applying to the CBI program or starting grad school?

Take advantage of the opportunities to meet your peers and engage in their science, not only to build your professional network outside of your home program but also to learn about other science and engage with the community. 

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Daniel Jarosz is an Associate Professor of Chemical and Systems Biology and of Developmental Biology at Stanford University. He is also a member of Bio-X, the Maternal & Child Health Research Institute, the Stanford Cancer Institute, the Wu Tsai Neurosciences Institute, and a Faculty Fellow at Sarafan ChEM-H.