Everything Is Physiology: A Q&A with Michael Caplan, MD, PhD

If you asked 100 people “What is physiology?” you would get about 112 definitions. But, in my mind, there are two main ways of explaining what physiology is. For me, physiology is the branch of biomedical science that connects the properties of molecules to the properties of higher-order biological systems. In other words, how does looking at each level of resolution teach us something about other levels of resolution? For example, understanding what a mutation in a potassium channel does can teach us about how that channel functions in the heart.

We are a branch of science that tries to look at all levels of resolution simultaneously, to integrate the very high-resolution understanding at the molecular or cellular level with the 40,000-foot view at the organismal level. It’s physiologists who are trying to understand how all the bits and pieces come together to try and make a functional, complicated living machine.

The other definition is that physiology is the branch of science that tries to understand how molecules determine function. Physiology can be viewed as trying to understand biological function at the level of molecules, cells, tissues, organs, and organisms, and how all of these different components talk to each other to make an integrated biological system.

By either of these definitions, pretty much anyone at the medical school could call themselves a physiologist, and I’m okay with that. I believe that a lot of what goes on around here, whether or not it happens in our department, is physiology. Physiology is the broadest umbrella of all of the basic biomedical sciences and incorporates a lot of the things that go on in clinical departments and basic science labs.

Physiology is the foundational science on which all of medical science is built. Anyone who is trying to understand how an organ works or how it goes wrong is applying physiology in one way or another. Understanding how all these body systems are governed, how they interlink, and how we can intervene to try and make them better—that’s all built on understanding physiology. All of the organ-based science at the medical school and all of the clinical work that brings together a knowledge of organ function is predicated on physiology.

There have been huge advances. For example, the discovery of a family of ion channels called PIEZO channels, led by a scientist named Ardem Patapoutian, PhD, advanced our understanding of how our body senses touch and physical pressure. These are touch sensors that not only determine our body’s ability to sense touch, but also our ability to sense internal stretch. Your body knows how much you’re breathing because of these mechanically sensitive ion channels. Your body knows that your bladder is full because of them. Patapoutian won the Nobel Prize for this fascinating and important work.

Similarly, the scientist who shared the Nobel Prize with Patapoutian, David Julius, PhD, won for figuring out a lot about a different family of ion channels, called TRP channels, that determine things like our body’s temperature—they help our body know how hot it is. There’s a whole family of temperature sensors that your body uses to keep track of that fundamental physiological variable.

There’s also a whole new field in physiology called interoception. Your brain is constantly keeping track of what all of your organs are doing. The body is able to sense all sorts of parameters of organ function, and our organs are constantly talking to our brain to tell it how we’re doing. It’s sort of a sixth sense.

For example, if you’re very thirsty and you drink a glass of water, within seconds you are no longer thirsty. But that water hasn’t even been absorbed into your system yet. How does your body know that you’ve drunk a glass of water if that water hasn’t had the opportunity to enter your bloodstream and change your blood chemistry? Beautiful work from a Cal Tech researcher named Yuki Oka, PhD, showed that there are sensors in your gut that detect what you are eating and drinking, and that they tell your brain even before you absorbed them. Understanding how organs talk to the brain is a new and critically important branch of physiology.

Our department is looking at a lot of different systems at a lot of different levels of resolution. We have several people studying sensory physiology—the physiological systems that help the body be aware of what’s going on inside it or around it in the outside world. And that includes interoception. There’s also a lot of work in the department being done on cell signaling and the properties of cell membranes.

We have researchers interested in hunger and thirst, in how insulin secretion is regulated, and in how metabolic factors control decision making. We have a lot of interest in the brain, including the formation and regulation of neurological synapses and how the blood-brain barrier is controlled.

When it comes to disease, our researchers are studying how mitochondria contribute, the metabolic factors affecting tumor growth, how obesity alters brain function, and how to treat polycystic kidney disease.

And we also develop new techniques. We have researchers pioneering fascinating and exciting new electron microscopy methods that allow us to see through huge volumes of tissue at an incredibly high resolution.

I would like to continue to promulgate and expand our connection to clinical sciences to ensure that people in all of these departments recognize that we are open to collaboration. We also want to do our best in terms of teaching both medical and graduate students to make sure that we do justice by the science of physiology and show how central and fundamental it is.

My goal for the department is also to continue to bring in exciting new people to think about different ways to view physiology. For example, we’ve had long talks with Andrew Goodman, PhD, and the Department of Microbial Pathogenesis, which he chairs, because he and his colleagues have done wonderful work on the microbiome, which can almost be seen as another organ. My group has shown that signals from the microbiome can regulate blood pressure. Others have shown that they can regulate appetite.

So, I want to think about ways to collaborate with microbial pathogenesis, with immunobiology, and with all of the basic science and clinical departments to connect physiology to all of these different approaches that are looking at how life works. Physiology is the central integrating station for all of it.