Small-Molecule Talk with Alison Ondrus

New assistant professor of chemistry Alison Ondrus says she's excited to apply the tools of traditional chemistry to the study of biological problems and thinks Caltech, with its small, interdisciplinary environment, is the perfect place to do it.

Ondrus received her PhD in organic chemistry in 2009 from MIT, where she learned to synthesize structurally complex molecules. From there, she became interested in biology and began studying the Hedgehog signaling pathway as a postdoctoral scholar at the Stanford University School of Medicine. The Hedgehog family of proteins is responsible for many basic functions in animals, including development and organization of the overall body plan. Mutations in Hedgehog pathway genes can lead to congenital deformities as well as both juvenile and adult cancers.

At Caltech, Ondrus plans to use her chemistry background to continue studying the Hedgehog signaling pathway and address mysteries about how essential small molecules, such as cholesterol, control Hedgehog activity during the development of embryos, a process known as embryogenesis.

Your PhD was in synthetic chemistry. What does this involve?

In synthetic organic chemistry, you build complex molecules from scratch. You start with a hypothesis for how to make an interesting molecular structure in the most convergent, elegant, efficient way possible based on the reactions that you choose. From there, you go to the lab and try to build the molecule.

How did you go from synthesizing chemicals to studying biological pathways?

I'd spent a lot of time just looking at the structures of molecules and appreciating the richness of structure, so when I had an opportunity to see how the same principles translated to biological activity, a new world opened up. I started finding myself thinking more and more about all of the small molecules that are already present in our own bodies. I've always been fascinated by human health and human development, and I started to question how these molecules participate in normal physiology and disease. I started reading to try to find examples of where people had at least circumstantial evidence that small molecules played key roles in regulating a biological pathway, in particular in human health.

Through my reading, I came across the really fascinating pathway that I now study—the Hedgehog signaling pathway.

Why is the Hedgehog signaling pathway important?

Hedgehog is important in almost every aspect of how an embryo becomes a human form, and its deficiencies showcase its importance. It's responsible for establishing our body plan, from our left-right symmetry to how many digits we have. As you can imagine, defects in the pathway lead to really acute phenotypes because it's so fundamental in these early processes. The pathway also plays a role in various cancers, most notably basal cell carcinoma—skin cancer—the most prevalent form of cancer in humans.

We know that certain small molecules that are based on cholesterol can turn the pathway on or off, but we don't know what enzymes produce these molecules, where they're localized, or how they interact with the Hedgehog pathway. Elucidating these cellular processes is essential to understanding how the pathway controls things like body patterning and brain development, and how that can go wrong and lead to cancer.

If we can understand what components of cholesterol metabolism are necessary for Hedgehog activity, then we can start to address much more specifically some of these medical conditions and intervene in ways that we haven't yet considered.

How will you go about studying cholesterol in the Hedgehog pathway?

I'm going to merge the synthesis part of my background with my understanding of signal transduction to ask questions about cholesterol and related molecules, and their role in regulating the Hedgehog pathway. Small molecules are often the missing link in hypotheses regarding Hedgehog pathway signal transduction. You may have two proteins in the pathway that communicate via these very specific small molecules, but without having chemical tools to ask questions in a precise way, the mechanism remains unknown. What are the exact structures of these molecules? How do they perform this communication? Something that's unique about our lab is that we can synthesize the specific cholesterol molecules needed to answer these questions.

What do you like about Caltech?

At Caltech, there are really no barriers. Nobody says you can't do something or that an idea is too unprecedented. There's a cultural acceptance that doing new things is fundamentally exciting and valuable. That's what I really appreciate about Caltech.

What do you like to do in your spare time?

I love yoga and riding my bike, and reading both Eastern and Western philosophy. I just finished listening to the audiobook of The Structure of Scientific Revolutions by Thomas Kuhn, which I recommend to anyone.