The Science of Smell: Q&A with Aashish Manglik, MD, PhD

Aashish Manglik, MD, PhD, focuses his research on understanding how the human body senses and responds to external stimuli — both in the hormones and signals that drive our physiology and the medications we take. 

Recently Manglik, an associate professor in the School of Pharmacy’s Department of Pharmaceutical Chemistry, and his team succeeded in mapping the 3D structure of odorant receptors (ORs), special proteins found on the surface of our cells in our nose that detect odor molecules and send signals to our brain, forming our sense of smell. 

The human body has about 400 different types of ORs that aren't yet fully understood. We asked Manglik how helping to uncover the fundamental principles of our smell perception could improve understanding of how other proteins in the body recognize small molecules, including potential new drugs. 

Q: Why is it important to study our sense of smell? 

A:  My lab is focused on how information from the outside world gets into our bodies or cells. Across biology, this process is facilitated by proteins on the surface of our cells that detect external stimuli — everything from light to medications and hormones.

G protein coupled receptors (GPCRs), which are the largest group of drug targets in our bodies, are critical for enabling us to see, smell, taste, and even allowing our hearts to recognize adrenaline in the blood. They play a crucial role in neurotransmission and many other physiological functions. 

The challenge is that many proteins in our body are tuned to sensing one specific thing, but it’s estimated that we can detect an enormous variety of odorous molecules — potentially hundreds of thousands, if not millions. That presents a really interesting problem, to be able to discriminate such small differences from a chemistry perspective, and we’re working to understand how our olfactory system accomplishes this task. 

Erin Lubin

Manglik with structural models of G-protein-coupled receptors (GPCRs).

As pharmacologists or drug discoverers, we’re still not perfect at predicting why a certain small molecule binds to its target protein. Chemical detection by our sense of smell is one example where that problem is really clear. While we are studying our sense of smell, the fundamental problem is the same if you're trying to develop a new medication for hundreds of other GPCRs involved in many diseases. 

Q: Are you incorporating AI into your research? 

A:  Yes, we use various AI methods all the time. Our main goal is to understand the three-dimensional shapes of these receptors and how odorant molecules fit inside them. We use approaches such as cryo-electron microscopy (cryo-EM) that were pioneered [at UCSF] in part by people like [School of Medicine Biochemistry and Biophysics Professors] Yifan Cheng, PhD, and David Agard, PhD, to get high-resolution images of these structures. 

AI helps us augment or extend our conclusions from experimental data, particularly through advances like AlphaFold [an AI method for predicting protein structures].  

Q: What are some of the biggest challenges in visualizing and characterizing odorant receptors? 

A:  One major challenge has been producing enough of these receptors to study their structures. In other areas of pharmaceutical chemistry, obtaining protein structures has become routine. But for odorant receptors, many believed it was nearly impossible to generate enough to get a three-dimensional image. We  overcame a lot of those challenges,  and we're continuing to innovate towards a general solution for this bottleneck.

Q: Tell us about your recent NIH grant and what you aim to accomplish with it? 

A: We have two NIH grants focused on understanding olfaction — one based at UCSF and another at Duke University. These are highly collaborative grants involving [Duke University Professor] Hiroaki Matsunami, PhD, and [City of Hope Professor] Nagarajan Vaidehi, PhD. Our first NIH grant focuses on methods to produce these proteins. That initial success paved the way for a second grant, which I now lead, aimed at obtaining more 3D structures of odorant receptors, to understand how they recognize various odor molecules. 

Q: How is interdisciplinary collaboration advancing your research? 

A:  No single lab can do everything. As researchers hyper-specialize, we need collaborations to achieve a deeper understanding of any given problem. Locally, we collaborate with [Department of Bioengineering and Therapeutic Sciences Assistant Professor] Willow Coyote-Maestas, PhD, MS, on deep mutational scanning — a method that allows us to ask how every amino acid in a protein connects to its function. That approach has been highly successful in our work on odorant receptors. 

We also work with [Department of Pharmaceutical Chemistry Professor] Brian Shoichet, PhD, on docking methodologies to discover molecules that interact with odorant receptors. And we work with researchers like [Department of Biochemistry and Biophysics Professor] Jeremy Reiter, MD, PhD, and [UCSF Weill Institute for Neurosciences Psychiatry professor] Mark Von Zastrow, MD, PhD, to explore signaling biology, helping us understand how receptors interact with cellular signaling pathways. 

We really benefit from thinking all the way from atomic-level detail, like what we do in my lab, to what the physiology of these systems are, to their cell biology. All of that requires a highly collaborative approach to science that we hope will start to unlock mysteries in our sense of smell.