Order from Chaos

The more Caltech biochemist Shu-ou Shan learns about how proteins are made, the more she marvels that life exists at all.

Proteins make up the molecular machines that enable cells to function. They catalyze chemical reactions, transport molecules, and serve as structural components in membranes. For all of their diversity, however, all proteins begin as chains of amino acids that must be folded into complex three-dimensional shapes before they can perform the functions they were created to fulfill.

Shan, a professor of chemistry in Caltech’s Center for Molecular Medicine, and her team focus on these first few moments of a protein’s life.

What the researchers have found is that protein biogenesis is anything but simple.

Quantifying a Complex, Competitive Process

Many nascent proteins must be folded, modified, and paired with partner proteins within seconds to minutes of being born. Conversely, about a third of new proteins delay their folding and instead must be escorted to their cellular destinations before they assume their designated structures and functions. Further complicating this sequence of events, the “assistant” proteins that help young proteins accomplish these tasks compete with dozens of other helper proteins. Diverse assistants crowd around the cell’s protein synthesis machine, called the ribosome, until their specific wards emerge. Shan compares this process to trying to perform a highly choreographed dance in the middle of Grand Central Terminal during rush hour, and yet somehow it works out beautifully.

“It’s almost miraculous that things happen correctly most of the time,” Shan says. “I want to understand how these different factors, when put together, manage to coordinate with one another in space and time, and how seemingly random and competitive processes instead lead to robustness and specificity. This is the intellectual puzzle that fascinates me the most.”

“It’s almost miraculous that things happen correctly most of the time. . . . This is the intellectual puzzle that fascinates me the most.”
- Professor of Chemistry Shu-ou Shan

While she pieces together this puzzle, Shan also hopes to help put cell biology on the same quantitative and predictive footing as sciences such as chemistry or physics, her original scientific focus. “In physics, you can write a set of equations based on first principles and predict that you’re going to find Uranus traveling through this exact spot on this exact day,” Shan says. “Biology is still very far from that, but if we are going to think about successful biological engineering and predictable molecular therapy, biology needs to move to that level of quantification.”

Shan’s goal is to describe every protein biogenesis pathway her group studies in energetic, kinetic, and molecular detail and to build mathematical models that not only explain the pathways but also predict how genetic mutations and other factors could affect them. Using this knowledge, she aims to develop techniques to intervene with and modify individual pathways to affect human health.

“Many diseases associated with aging, for example, are rooted in mistakes in protein biogenesis,” Shan explains, “so understanding these pathways could inform new and effective approaches to intervention.”

Fresh Perspectives

Shan’s research takes place at the nexus of biology and chemistry, and she finds Caltech, with its strong culture of collaboration across traditional fields, to be the perfect place to pursue her interdisciplinary approach to science. “Being at Caltech has forced me to come out of my comfort zone and talk to scientists who come from different backgrounds and have very different perspectives,” Shan says. “This is good for my science, because here my science can be more creative.”

Shan also has been impressed by Caltech’s students, especially the graduate students. Many who join her laboratory have studied physics and chemistry and have an interest but no background in biology or biochemistry. “They take a huge risk by entering a new field and having to learn many things from scratch,” Shan says. “But not being bogged down by conventions in biology also allows them to analyze problems with a fresh perspective.”

The graduate students in Shan’s lab also have proven to be resourceful. She credits them with helping turn her research ideas into reality. When her lab needed a single-molecule-resolution microscope to study a protein they had isolated, for instance, a graduate student built a system from the ground up.

“Our undergraduate and graduate students are our backbone,” Shan says. “They are the ones who actually do the work on the bench and make remarkable things happen.”

To support research in Caltech’s Center for Molecular Medicine, contact Janny Manasse, senior director of development for the Division of Chemistry and Chemical Engineering, at (626) 395-1530 or at jmanasse@caltech.edu.

Giving Priorities