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William D. Willis, Jr., M.D., Ph.D. Memorial Lecture: An Interview with Gary Lewin

1 June 2021

PRF Interviews


At the International Association for the Study of Pain (IASP) 2021 Virtual World Congress on Pain, to take place June 9-11 and June 16-18, IASP will present awards to honor the achievements of up-and-coming as well as more established investigators (these awards were originally to be presented at the 2020 World Congress on Pain in Amsterdam, which was canceled due to the COVID-19 pandemic). In advance of the meeting, PRF spoke with each of the winners. Here, in this interview, we chat with Gary Lewin, PhD, winner of the inaugural William D. Willis Jr., MD, PhD, Memorial Lecture award. Read more about the award here.


Lewin is a professor and group leader at the Max-Delbrück Center for Molecular Medicine (MDC) in Berlin, Germany. Lewin has had a long-standing interest in the development, plasticity, and function of the somatosensory system. With Lorne Mendell he discovered a role for nerve growth factor (NGF) in chronic inflammatory pain, which has inspired development of humanized antibodies directed against NGF, drugs that may soon reach clinical application. His group pioneered the study of touch transduction and discovered the first mammalian proteins necessary for normal touch sensation. In the last 10 years his group has continued to elucidate the role of novel proteins in touch and pain transduction. In addition, for more than 15 years his group tried to take advantage of the extreme physiology of African naked mole-rats to discover molecular tricks to resist hypoxia, remain healthy in old age, and suppress pain.


Here, Lewin chats with Lincoln Tracy, a research fellow from Monash University, Melbourne, Australia, to discuss his path to pain research, his work in identifying the molecular mechanisms underlying mechanosensation, and how a chance encounter with naked mole-rats spawned an entirely new research direction for him. Below is an edited transcript of their conversation.


What first got you interested in science?


That's always a difficult one to answer, I think. I grew up on a small island, the Isle of Man. It's a very beautiful place. I was always a big fan of the outdoors, and in school I was interested in biology. When I went to university, I studied both zoology and physiology. I was more interested in physiology, and after the first year of zoology, I found it wasn't my thing. At a bachelor’s level, zoology is a very descriptive subject – one has to know a lot about a lot of different animals. It really focused on taxonomy and phylogeny, which was difficult to put in the context of physiology at the beginning. So I switched to pharmacology. I've always been interested in how the body works and how we can use pharmacology as a tool to cure diseases.


How did you transition into pain research?


After my bachelor's I was looking around for a PhD position. I was very interested in neuroscience. We had a great lecturer who introduced us to the gate-control theory of pain very lucidly. So somatic sensation was really intriguing to me. I was lucky enough to be accepted into Steve McMahon's lab in London, where I did my PhD. That's the first time I started doing neurophysiology. My PhD focused on regeneration and neuronal plasticity rather than pain.


But I was fortunate to end up in a very nice group of people. Steve McMahon was a postdoctoral fellow with Pat Wall, and during my PhD, I had the privilege that Pat moved over to our department and took a lab next to ours in his emeritus years. On many Friday evenings after work, we would go down to the pub and have a drink. Pat was a very charismatic character, so we learned all about the history of the specificity theory versus the gate-control theory of pain. I was surrounded by legends in the pain research field like Pat, Clifford Woolf, and Maria Fitzgerald, who were all people I encountered during my PhD.


At that time, Steve McMahon ran a spinal cord seminar at University College London, which we regularly attended. I remember seeing some great lectures there, including from Dale Purves. It was a very lively neuroscience community and somatosensory community in London at that time. I was lucky to be nurtured in that environment.


What is the overall aim of your research?


There are two veins of research in my lab. I have a core interest in sensory mechanotransduction – trying to figure out what molecules enable sensory neurons to detect mechanical stimuli. This was something that had barely been looked at in the late 1990s, and it's what I started my group on. It’s an area we’re still actively involved in today. We are probably at the tip of the iceberg because we know that many neurons essential to mechanotransduction use more than just Piezo2.


A very simple comparison is the nematode worms; we know a lot about sensory touch in nematodes. These worms have just six sensory neurons, which are all basically the same, but they need at least 17 different gene products for those sensory neurons to function properly. Now, how those gene products, which include ion channels, matrix proteins, and cytoskeletal proteins, come together in the nematode worm is still not completely understood. The fact that such a simple organism with one cell type has 17 proteins shows how far away we are in the mammalian system from understanding the whole picture.


The second focus of the lab is on naked mole-rats, which happened almost by chance. We are interested in the extreme biology of the naked mole-rat. For example, a mole-rat is extremely long-lived for a rodent. Compared to a mouse of the same size, it can live for up to 37 years. These animals are highly social and live in an organized way. We recently showed that they communicate with each other with unique dialects. There are also several fascinating aspects of their physiology, like being able to survive complete anoxia [loss of oxygen supply] for 18 minutes.


Why is it important to understand the molecular mechanisms behind mechanosensation?


In the clinic, people don't complain of thermal pain – they mostly complain of mechanical pain. Either they have ongoing pain or they have pain that is triggered by very mild stimuli that shouldn't normally trigger pain. So mechanical stimuli are really the most important drivers of chronic, or pathological pain. Consequently, how mechanical signals are transduced is very important to understand.


For example, my group discovered a molecule called STOML3, which is a membrane protein that regulates Piezo ion channels. STOML3 is upregulated after nerve injury and is required for mechanical hypersensitivity. If you take animals that don't have STOML3, they do not develop neuropathic pain. Small molecules that can inhibit the function of STOML3 can acutely treat neuropathic pain in animals with a nerve injury.


We are interested in the "druggability" of mechanotransduction approaches. The more we understand which components are responsible for either physiological or pathological sensations, the more we can develop targeted small molecule therapies that engage those targets and modulate pain at its source. We can already do this, in the sense that we routinely use local anesthetics in the clinic to block peripheral nerves, which is a well-established way of treating chronic pain. However, this is just impractical.


For example, if you go to the dentist and get a nerve block, all the sensation in your face is gone for several hours, and it's not so pleasant. That's because we're blocking all signals that are coming from the peripheral nervous system, regardless of the neuron types they're coming from. We showed that using a STOML3 antagonist can block signals at their source, but because we have not identified all the molecules that are required for the transduction process, there are a lot more opportunities out there to develop small-molecule therapies that could, in principle, be used to treat acute and chronic pain.


How did you end up working with naked mole-rats?


That came about by chance, really. In the early 1990s I discovered that nerve growth factor [NGF] can produce long-lasting mechanical hyperalgesia. That was an important finding, as it showed that NGF could be a target for therapy. Then, in the early 2000s, I was working in the mechanotransduction space but had a reputation in the pain field because of my NGF discovery. A mutual friend of mine wanted to introduce me to Thomas Park, who had established naked mole-rat colonies in his lab in Chicago. He had injected these animals with capsaicin, and they did not react to it. That was kind of strange because we knew at that point that capsaicin is a chemical that produces a painful sensation in all animals except birds. He wasn’t an expert on pain, so our mutual friend put us in touch.


At that point, my lab had been established for six or seven years, and I was transitioning from doing lab work to being more of a supervisor. So the mole-rats became my summer project. Thom would come over to my lab in Berlin with four or five mole-rats in his bag, and we would try to figure out what was going on. For example, we recorded from sensory neurons and investigated whether they responded to capsaicin. This work expanded over time, and we found that not only were the animals insensitive to capsaicin, but they were insensitive to acidic pH. They were also insensitive to the effects of NGF, which for me was like a big bright light turning on.


The more I got to know about the naked mole-rat – the more I saw them and worked with them – the more interested I got in their biology. That's when Ewan St. John Smith came to my lab, and we started to think about expanding into other areas. In 2005 we started getting colonies going. We've had them in the lab for about 16 years now and have about 250 animals in separate colonies.


Can you say more about how you developed that line of research over time?


I was actually very lucky. We put out a paper showing there was selective pain insensitivity in the naked mole-rat. And the questions that arose from those days was how and why. These are still questions that we're trying to answer. Although I’m a neurophysiologist by trade, I decided to get into molecular biology to learn how to make our own knockout mice. We quickly realized that the naked mole-rat was a great candidate for molecular biology work because evolution had led to changes in the nociceptor system that were, in principle, accessible to us by using molecular techniques.


A great example of this was when Ewan came to the lab and we tried to figure out how naked mole-rats are insensitive to protons of a simple acidic solution. If you put lemon juice on the bed of a nail it stings for quite a while; that’s your typical acid-induced pain. But the naked mole-rat, being completely insensitive to this, was kind of interesting. So Ewan showed very nicely that the protons in acid block Nav1.7 [a voltage-gated sodium channel that, when missing in humans, results in complete insensitivity to pain].


One thing that really excited me about that finding is that it was an example of how evolution had figured out that Nav1.7 was important for pain before we even knew it existed. The ancestor of the naked mole-rat appeared around 30 million years ago, meaning that the naked mole-rat as we know it emerged about 20 million to 25 million years ago, probably with the same kind of pain insensitivity phenotypes that we see in modern naked mole-rats. It is interesting because their selection for pain insensitivity occurred via proteins that we now know are targets for drug therapy. The mole-rat was able to shut down massive pain by changing one part of the protein. Later on, we also showed that the NGF receptor, TrkA, is hypofunctional in the naked mole-rat. It’s down to probably two to three amino acid changes in TrkA that are only found in a naked mole-rat, again, probably arising 25 million years ago. And again, the same protein is essentially the same target for therapy that we've now developed 25 million years later. It's very striking how detailed studies on the naked mole-rat kept revealing proteins that were already targeted for pain therapy. It may still be the tip of the iceberg; there are more things that we may be able to discover.


The studies we did early on made me a huge enthusiast of using evolution as a biomedical driver to try and find new mechanisms that might be of interest. This is a nice melding of my training in pharmacology with my initial botched studies in zoology. I feel I come with a completely different view of evolutionary biology than your typical zoologist, who is interested in diversity and evolution, and how traits evolved in large groups of animals or plants. I'm much more interested in trying to exploit how biology and evolution have selected for traits, and to use that time during evolution to understand and develop new therapies. That's how evolution works; adaptive changes occur over huge amounts of time.


What else can we learn from naked mole-rats and other rodent species?


Studies into other rodent species are ongoing. We recently started to look at the phylogeny of algogen resistance, and we published this recently. My idea is that if it’s happened once, it could happen again. In this study, we screened different rodent species for three different algogens. We found that capsaicin sensitivity occurred twice in the phylogeny, while acid insensitivity occurred quite often.


Another trait that we're looking at is animal communication. We know the naked mole-rat is highly developed in terms of a social system, and this social system is cooperative. We believe the animals' vocalizations actually contribute to that cooperativity. But the African mole-rat family is very nice because many species are social and some are solitary. This means we can contrast between animals that live alone and animals that live in closer groups. We can also ask whether the brain is different in animals that are solitary compared to animals that are social.


Sociality is one reason why humans have become so successful – because we're able to work cooperatively, and there is some feature of our brain that is important for cooperativity. We believe the mole-rat might be a good example of convergent evolution, where the mechanisms of sociality in the naked mole-rat could be similar to the mechanisms that underlie our sociality.


What are some of the challenges associated with your research?


Using non-model organisms is challenging, as there are fewer tools available. For example, you can’t make a knockout mole-rat. What we’ve chosen to do instead is to transfer genes from a mole-rat into a mouse, and it actually seems to work. If you take the mutations in the mole-rat TrkA receptor and put these in the mouse, our preliminary data show that mice display less hyperalgesia to painful stimuli than they would normally.


There are now probably 30 labs around the world that keep naked mole-rats – there are labs in China, Russia, Japan, the US, and throughout Europe. Basically, all continents have a naked-mole-rat lab now; it’s almost an established model organism, which is very gratifying to see. It's not easy to work with naked mole-rats, but it certainly has become quite popular because of the variety of adaptations that they reveal.


Within your field of research, what is something that we don’t currently know that you hope we will learn in the next five to 10 years?


One of the big things we would like to understand is how neurons in the naked mole-rat can survive hypoxia and extreme hypoxic conditions. We know that mitochondrial damage is one of the major reasons why cells die after hypoxia. Somehow the mole-rat has managed to save its mitochondria from hypoxic damage – they’re able to shut them down into a dormant state that enables them to recover once oxygen comes back. But I don’t believe the naked mole-rat has invented another protein or gene to do this. What experience tells us is that naked mole-rats have the same set of genes as we do but have adapted them for different purposes. I think it’s very likely that the gene, or genes, used by naked mole-rats to protect themselves from hypoxia also exist in humans, and they can be manipulated. Understanding this would be a real game changer.


What does winning the William D. Willis Jr. Memorial Lecture award mean to you?


It's a great honor. I actually knew him. Pat Wall and Bill Willis were initially on opposite sides of the fence in terms of the gate-control theory versus specificity. It's kind of funny to be a recipient of the prize, since I was in the Pat Wall school of thought. But Bill Willis was a very productive neurophysiologist, a very productive pain scientist, who made very important contributions to the field, especially on the central mechanisms of hyperalgesia. So it's funny and a great honor at the same time to be the first recipient of the award.


If you could have a dinner party with anyone from history, who would you want at the table with you and why?


I'd love to go and have dinner again with Pat Wall. When I was hanging around Pat Wall, I was a young whippersnapper – I was just 20 or 21 years old. I think now, with my experience as a researcher, it would be great to talk to him again. I also think it would be cool to have him at the same table with his least favorite contemporary from Hopkins, Vernon Mountcastle, who did seminal work on the touch system.


Lincoln Tracy is a researcher and freelance writer based in Melbourne, Australia. You can follow him on Twitter @lincolntracy.

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