Mapping Out the Neurons That Contribute to Headache and Pain: A Conversation with William Renthal

By Neil Andrews | October 9, 2023 | Posted in

“Migraine is a complex disorder that will take a multidisciplinary approach to solve. So, regardless of your training, your skill set can likely help us understand some of the remaining migraine mysteries.” – William Renthal

Editor’s note: William Renthal, MD, PhD, is director of research at the John R. Graham Headache Center at Brigham and Women’s Hospital, Boston, US. He is also an associate professor of neurology at Harvard Medical School. In addition to being a neurologist who cares for patients with headache, he is also a researcher whose lab is focused on investigating the cell types and cell states underlying chronic pain and headache.

In this Migraine Science Collaborative interview, Renthal chats with MSC executive editor Neil Andrews to discuss his path to research and medicine, the focus of his lab, the findings from his work so far that he is most excited about, and much more. The interview has been edited for clarity and length.

How did you become interested in doing research?

The summer after my freshman year in college, I worked in the laboratory of Dr. Eva Lee, who is not only a transformative cancer biologist but also an amazing mentor. I was really taken aback by how passionate she was about cell biology and the ways she could leverage this insight to help cancer patients.

She and her husband co-discovered the first tumor suppressor gene and continued to make important discoveries while I was in her lab. I think the culture of innovation Dr. Lee crafted in her lab ignited a spark of curiosity in me that continues to this day.

When I was in college, I was also fortunate to get to work with Dr. Brent Iverson, a chemist at the University of Texas at Austin. He was interested in designing small molecules that could interact with DNA and slow down cancer cells from growing. This work introduced me to the exciting world of chemical biology and its incredible potential for both probing new biology and treating disease.

William Renthal

William Renthal

In addition to being a researcher, you are also a doctor. Why did you go into medicine?

I found that the research I was really excited about was always related to some type of disease condition. But I honestly wasn’t 100% sure when I applied to MD/PhD programs whether I wanted to be a practicing physician, a full-time scientist, or some combination of the two. In medical school, I was really surprised by how much I enjoyed every rotation I did; whether it was OB/GYN, surgery, neurology, or psychiatry, I wanted to do all of them. But I ultimately decided to become a neurologist because it seemed like the perfect place to help patients and their families through challenging diseases while getting to apply my curiosity for how the brain works to neurological disorders with limited treatment options.

How did you get into pain and headache specifically?

When I was a PhD student, I worked in a lab with Dr. Eric Nestler, who is a psychiatry researcher. I became very interested in how mood, sleep, and pain can affect various neurologic and psychiatric conditions, and vice versa. I had also been reading about pain during my time in grad school.

When I became a resident, I was mainly doing inpatient work, so there wasn’t much exposure to headache or pain management. But a couple of things from personal experience inspired me to pursue headache and pain medicine. One is that I was playing tennis with a friend and I ran backwards to return a lobbed ball, but instead crashed into a pole and injured my rib. While this crash could have made for a funny YouTube clip, it instead left me in constant pain for weeks. I was struck by how silently disabling it is to be in chronic pain while trying to study, work, or do simple activities of daily living. In addition to this experience, both my wife and daughter have migraine, and have to experience disabling pain on a recurring basis. So I decided to apply my clinical and research training to improve our care and treatment options for patients with pain and migraine.

Let’s talk about your lab. What is its overall goal? What are you trying to figure out?

We are trying to understand the molecular features present in nociceptors, how they change in different pain conditions, and how to use this information to develop tools to stop these neurons from transmitting pain signals to the brain.

We approach this overall goal with a number of complementary techniques such as single-cell RNA sequencing, epigenomic profiling, proteomics, spatial technologies, and optogenetics. Together, these approaches will help us describe both the molecules present in nociceptors and the cell types with which nociceptors interact to transmit noxious information from the periphery to the brain, where the perception of pain is encoded. Improved understanding of nociceptors and how they function will facilitate the design of more effective and safer pain and headache therapeutics.

Now I’ll ask you to brag a little bit. In terms of both headache and pain, what do you think are the most important discoveries you and your colleagues have made so far?

One of the things I’m really excited about is our efforts to build a comprehensive cell atlas of the different types of human peripheral sensory neurons, at single-cell resolution, to compare gene expression profiles of those neurons across species, and then to develop tools to help the community better understand these large datasets [see MSC related news story].

We recently posted a preprint of a harmonized cell atlas that includes most of the published single-cell RNA-sequencing datasets from dorsal root ganglion and trigeminal ganglion cell types across six different species, including humans. This resource will help other groups who are interested in which cell types express a given gene or help them annotate their own single-cell RNA-sequencing data. We use this resource every day in our lab, so I hope other groups find it helpful for their research as well.

In addition to helping to molecularly profile sensory ganglia cell types across species, our group has also explored how these cell types change in animal models of pain and headache. We have found that certain pain conditions, especially conditions involving nerve injury, can lead to dramatic transcriptional changes that are needed to promote nerve repair. So we have made some good progress identifying sensory ganglion cell types and how they change in pain or migraine, but much more work is needed in these areas before patients will be able to benefit from these insights.

Where is migraine genetics heading? Many genetic variants, known as single nucleotide polymorphisms, or SNPs, have been linked to migraine, but what are the next steps after learning about these variants?

This is a great question. I think the first step is to understand which genes and cell types are affected by these genomic variants. Migraine is a problem that affects both the peripheral nervous system and central nervous system, so where is, and which cell types drive, migraine susceptibility? Is migraine caused by dysfunction of neurons in your brain? Neurons in your peripheral nervous system? Non-neuronal cells such as astrocytes or vascular smooth muscle cells? There is evidence both from patients and animal studies that dysfunction in even one of these cell types can cause migraine or migraine-like symptoms, so it may be that an individual’s set of genetic variants differentially affects one or more cell types in their central and peripheral nervous systems, with the effects of this summing in a unique fashion to drive their migraine syndrome.

My long-term vision is to use genomic information from my patients in addition to their history, exam, and imaging data to design a personalized treatment plan. While we can now easily sequence a patient’s genome for a few hundred dollars, we still do not know much about how migraine-associated variants actually affect the central and peripheral nervous system cell types involved in migraine pathophysiology. My lab and many others in the field are working hard to try to improve our understanding of migraine genetics, which I’m really optimistic can now advance quickly thanks to the incredible high-throughput genetic research tools that are now available.

What other areas of headache research are most exciting to you these days?

I’m really excited about advances in neuroimaging. While this isn’t my direct area of research, advances in imaging resolution, and in cell type-specific imaging ligands, position this space well for making important contributions to our understanding of migraine pathophysiology.

I’m also really excited by both basic and emerging clinical data evaluating the role of other neurotransmitters and neuropeptides involved in migraine. Given the success story of CGRP [calcitonin gene-related peptide] inhibitors for treating migraine, I’m optimistic that modulating the activity of other neurotransmitters and neuropeptides secreted by trigeminal nociceptors could also be helpful for treating migraine.

I wanted to ask you about the landscape of headache treatment. Many people still don’t get enough relief from current therapies. Will that be the case, say, a decade from now? What are your thoughts about the prospects for better treatments for people who are still struggling?

Migraine treatment over the past five years has been absolutely transformed. Those patients who respond well to CGRP inhibitors know what we’re talking about. There are people who had migraines every day for a decade, who then start on a CGRP inhibitor and become nearly headache free. That type of transformation shows the importance of mechanistic research in this field. I am optimistic that we’re going to have more of these CGRP-level successes in the coming decade.

In parallel with improved treatment options, I am excited about new precision diagnostics that can help patients start on the right treatment faster. Any migraine patient knows that our current treatment process is trial-and-error, and it can be a long time before patients find a treatment option that works for them.

Is there anything else you would like people who are reading this interview to know about the headache field?

Get involved! There are a lot of ways to contribute regardless of your interest or background. We need more headache specialists and other healthcare providers who understand how to treat headache properly. We also need people who are interested in understanding phenotypic differences between patients, so that we can start to understand more quickly who would be better for one treatment versus another. While I love genetics, we wouldn’t need to sequence every patient’s genome if we could understand features during a history and physical exam that could predict treatment response. We also need more basic researchers to help us understand the principles underlying migraine.

Migraine is a complex disorder that will take a multidisciplinary approach to solve. So regardless of your training, your skill set can likely help us understand some of the remaining migraine mysteries.

Thank you so much for the interview.

I’m happy to do it! Thank you for your interest and for allowing me to share how exciting headache medicine is.

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative. Follow him on Twitter @NeilAndrews

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Neil Andrews is a science journalist and editor based in New York City. He has over two decades of experience covering science and medicine for expert and non-expert audiences alike. He is also the executive editor of the Migraine Science Collaborative, where he manages the day to day operations of the site. Previously he was the executive editor of the Pain Research Forum.

When not thinking and writing about neuroscience, Neil spends much of his free time on his Peloton and exploring NYC. He is also on a quest to satisfy his coffee cravings by visiting every independent coffee shop in the city. Follow him on Twitter @NeilAndrews.



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