Rachel Wolfson in the lab. Image: Anna Olivella and the Harvard Brain Science Initiative
When it comes to senses, most of us focus on the familiar five — vision, hearing, smell, taste, and touch — that play a vital role in helping us move through the external environment.
More recently, however, scientists have become interested in a sense known as interoception, or our ability to sense the internal state of our bodies.
Rachel Wolfson, assistant professor of cell biology in the Blavatnik Institute at Harvard Medical School, began studying interoception as a neurobiology fellow at HMS. Now, she is continuing this work in her own lab, which she launched last fall.
As a gastroenterologist and a scientist, Wolfson is interested in how our brains sense and interpret information coming from the gastrointestinal organs, including how neurons in these organs translate mechanical and chemical cues into signals the brain can understand.
Her research aims to unravel the basic biology of this gut-brain connection — and she hopes that her work can eventually inform the development of better treatments for patients with gastrointestinal issues.
In a conversation with Harvard Medicine News, Wolfson discussed why she started studying interoception, how her clinical experience informs her research, and what she plans to tackle first in her lab.
Harvard Medicine News: How did you become interested in interoception?
Wolfson: In graduate school, I became fascinated by how cells sense nutrients and other stimuli in their environment, and how these stimuli turn into signals that cells can understand. After leaving graduate school, my interest shifted to how organs sense their environment, with a focus on organs in the gastrointestinal system.
This shift was in part because of my clinical experience as a medical student. I would go from room to room and hear patients talk about experiencing abdominal pain. In fact, abdominal pain is the second most common reason for emergency room visits behind chest pain, so it’s an important clinical problem. Sometimes abdominal pain is caused by a specific gastrointestinal condition, such as inflammatory bowel disease, but often, it is a side effect of other medical conditions. While it may not be life-threatening, it does affect a person’s quality of life.
Making Sense of Interoception
Yet we don’t have great medications to target abdominal pain. And that’s because we don’t understand the sensory neurons that mediate this pain.
I’ve always been motivated by basic science questions, but I especially like basic science questions that have clinical implications. Studying how organs in the gastrointestinal system sense their environment seemed like a nice intersection of my skills and interests.
HMNews: What are you planning to study in your lab?
Wolfson: I started my research on the gastrointestinal system in the lab of David Ginty [the Edward R. and Anne G. Lefler Professor of Neurobiology] here at HMS. We built mouse genetic tools that allowed us to identify, label, and manipulate five subtypes of neurons that innervate the colon. Through this work, we were able to understand the properties of those neurons, including the types of forces they detect and communicate to the brain.
Now, my lab is going to dive in and think about these neurons on a molecular level. In particular, we want to understand how these neurons respond to the many kinds of sensory stimuli in the gastrointestinal system. These include mechanical forces like stretch as well as small molecules made by the microbiome, bacterial and viral infections, and inflammation. I think this is a fascinating topic because it’s at the intersection of neuroscience and cell biology. To study it, we will need to go inside these neurons to see what proteins they express and how those proteins control signaling pathways and local cellular responses.
The gastrointestinal system is a nice place to start, but eventually we’d also like to study the sensory innervation of other internal organs.
HMNews: What do you like about working at the intersection of neuroscience and cell biology?
Wolfson: I have always identified more as a cell biologist than a neuroscientist, and I think there is a ton of fascinating cell biology within neurons that we don’t understand. The idea is to study neurons as cells and to think about how they are functioning from a cell biology perspective. To do this, we’re combining skills from both fields.
The benefit of being in a cell biology department is that we can study the proteins expressed in neurons, including their interactions and downstream signaling pathways — which is distinct from what many people in neuroscience departments are doing. Also, I like being in a department where there are a few people doing neuroscience plus people across the spectrum of cell biology studying topics like metabolism and transcription. When we present our work, we hear different questions and ideas than if we presented solely to a neuroscience audience. It can challenge us and push our research program in new directions, and it opens up different kinds of collaborations.
In fact, one of the reasons I wanted to stay at HMS is that I love the inter-lab collaboration here, both within and across departments. Basically, anything you can think of that you want to do, there’s somebody nearby who has expertise in it.
HMNews: How do you think about the potential of your work to help patients?
Wolfson: Often, abdominal pain or disorders of the gut-brain axis happen because there’s something going wrong with the neurons that innervate the gastrointestinal system — for example, they’re firing when they shouldn’t be, which leads to hypersensitivity or pain. There’s lots of basic biology to learn here, but by studying the proteins inside these neurons, we are hoping to identify new drug targets that can lead to the development of more specific therapies with fewer side effects. For instance, if we knew that a patient with inflammatory bowel disease was experiencing pain because of a specific subtype of neuron in the colon, then we could treat their pain more effectively by targeting that subtype.
HMNews: Why is it important to you to continue your clinical practice?
Wolfson: When I’m in the hospital seeing patients, I’m constantly inspired by how many things we don’t know. That feeds back to my research, and I hope that my research also feeds back to my clinical practice. I see GI patients in the clinic who have many of the symptoms that we’re interested in treating down the line, so I think it can be helpful crosstalk. I also think it can be helpful for my patients to hear about what we’re doing in the lab. Even if we don’t have solutions for them right now, we can tell them, “This is why we don’t understand that, and these are the things we’re working on.”
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HMNews: What do you love about being a physician-scientist?
Wolfson: I love that we are given the freedom to think about things that are interesting and that have potential impacts on human health. I enjoy basically every aspect of coming up with questions and designing creative experiments to explore them. I love when a scientific paper or a clinical interaction with a patient inspires us to ask something new. I love doing experiments, seeing the results, and sharing the findings.
As we’re doing all that, we are learning about the world around us, and we are finding out things that could have an impact on people’s lives, which I find extremely rewarding.
This interview was edited for length and clarity.
