Dianna E. Willis, Ph.D., studies the mechanisms that underlie how nerves grow and repair themselves and the chronic pain that can develop when these mechanisms go awry. She joined the Burke faculty in 2009 and is the Director of Pain Research. Along with John Cave, Ph.D., Dr. Willis co-directs BMRI’s Summer Student Research Program, which offers undergraduate students the opportunity to work in a lab and participate in cutting-edge research. When she’s not busy running experiments or training the generation of scientists, Dr. Willis finds time to participate in mud runs and triathlons.
As an undergrad, did you know you wanted to be a scientist?
I really thought I was going to go to med school. When I was an undergrad at the University of Pittsburgh, I worked in a hospital and also spent some time in a lab. Over the course of doing both of those things, I realized I really much preferred the lab work rather than working with patients—which I think is a good time to figure that out and not two years into med school.
Were you working in a neuroscience lab?
Most of my early work was on microbiology and immune work, actually. I made antibodies and things like that. Really as an undergrad in many ways you’re just a pair of hands and so I did a lot of different things—but I knew I enjoyed being at the bench and doing hands-on work.
You’re now the Director of Pain Research here at Burke. How did you get into this area of research?
As a post-doc, I worked with Jeff Twiss at the Nemours Biomedical Research Institute at the Alfred I. DuPont Hospital for Children in Wilmington, DE and we were working on axonal regeneration. Say, you damage your sciatic nerve, which enervates your leg and your foot. As part of the peripheral nervous system, the sciatic nerve has the capacity to repair itself—unlike if you break your back and damage your spinal cord, or damage your brain, there’s only very limited capacity for repair [in the central nervous system]. I studied what intrinsic capacity of these neurons allows for their axons to repair.
What we started to see were changes that happen after injury that facilitate regeneration. The problem is that once that repair has been successful, that neuron doesn’t go back to what it looked like before the injury—it doesn’t reboot. Our question now is: are some of those changes that occur after injury, that are good for repair, at a certain point do they become maladaptive? Do they lead to chronic neuropathic pain? That’s one of the prime interests in our lab right now.
What is neuropathic pain?
If I hit my toes with a hammer, that’s normal pain—called nociception. It’s a good thing that tells us not to hit our toes with hammers. The problem is when pain becomes pathophysiological. Now, instead of having pain when I step on a tack, I have pain when I draw the covers over my legs at night. Neuropathic pain means painful response to stimulus that normally would never cause pain or in the absence of any external stimulus at all.
When did researchers first recognize neuropathic pain as something distinct from regular nociceptive pain?
Neuropathic pain has been an interest of labs for several decades but now we’re getting closer to the fundamental biology questions. I think now both clinically and from a society standpoint people are understanding these are real syndromes and there’s actually biology behind it—it’s not all just in your head. And that has helped to lead to greater funding and increased interest in research into neuropathic pain causes and treatments.
What are you trying to understand about neuropathic pain?
One of the first steps in neuropathic pain is what they call peripheral sensitization, which lowers the threshold at which peripheral neurons fire. If I damage my sciatic nerve, those neurons can change to the point where they alter their firing points—the point at which they send signals to the brain. But that’s not the only change that happens. If peripheral sensitization is allowed to progress long enough, you get central changes as well. The neurons in my leg talk to neurons in my spinal cord, which talk to neurons in my brain, and those neurons talk to other neurons that send signals back down. It’s a loop system. If the first part of the loop has been sensitized so long it can also change everything up the stream and down the stream.
There are so many steps to the repair process we have to figure out. How fast do we have to fix the first part of the loop before it propagates the damage? And if we aren’t fast enough, how can we fix the loop to return the system to normal? Right now, my lab is primarily interested in how we repair the first neuron in the loop.
Why is neuropathic pain so hard to treat?
Of the thirty-plus clinical trials for neuropathic pain, every one of them has largely failed. In large part, it’s because it’s really such a systemic issue. It’s also a heterogeneous patient population. Neuropathic pain patient A may not be the same as neuropathic pain patient B and C—their pain syndromes result from a variety of reasons and may be fundamentally different.
The other thing is that pain is not a quantitative thing. It’s not like measuring blood pressure. It’s subjective. In our mouse models we use measures of temperature and mechanical sensitivity. So we poke their foot and see at what point they withdraw from the stimulus. When you’ve done something to give them neuropathic pain, it’s a much lower threshold. Of course you’ve gotta figure out how to translate a behavioral measurement like that in a rodent to a human population.
One focus of your research is local protein synthesis. Can you explain why local protein synthesis is important in pain?
If you think about the distances covered by a single neuron of the peripheral nervous system, like the sciatic nerve—that’s a long distance between the cell body and the axon. The dogma, for year and years, was that everything that the axon and the growth cone (the tip of the axon) requires comes from the cell body and gets trafficked out there. So when that axon is growing and it encounters a signal of some kind and has to decide to go towards or away from it, the dogma would say, the axon has to send a signal back to the cell body and the cell body has to send a protein that the growing axon needs. That never made any sense. When encountering a dynamic situation it seems a lot more favorable for the axon to be able to respond autonomously.
So the question we have is: Can the axon make some of its own proteins to respond to environmental cues? We went about studying whether or not the templates and machinery required for protein synthesis are present in the axon. And indeed they are, particularly after injury. We’ve shown in several cases that to prevent these RNAs from getting out there and to prevent local protein synthesis means you attenuate regeneration. It was really the first suggestion that local translation in the axon provides a fundamental role for repair. I think the dogma is changing but it’s been a hard sell for a lot of people.
So what’s next?
In a perfectly functioning axon that hasn’t been damaged, what role might local translation play in that cell? We don’t know that yet.
Some people also question whether this is strictly the domain of the peripheral nerves—do other neurons of the body also do this? We have an ongoing set of projects in our lab looking at axons in motor neurons particularly as it revolves around motor neuron diseases like ALS and spinal muscular atrophy.
Ten years from now, what do you hope we’ll know about neuropathic pain?
I hope we will have at least a more fundamental understanding of what causes neuropathic pain so that we can target therapeutics to non-nociceptive pain. And from a more clinical aspect, how can we identify what mechanism has driven the neuropathic pain in a specific patient? If there are multiple mechanisms that drive neuropathic pain and multiple types of neuropathic pain patients, we better figure out how to line those up. Remember those old tests in school where you had to draw the line from something in this column to something in that column? We want to be able to do that—draw the line from what we understand about mechanism in the lab to a specific type of patient.
You co-direct the Summer Student Research Program here at Burke. How did that come about?
Burke has always taken summer students, but on a lab-by-lab basis—there was no official program. We decided before last summer to formalize the program. We had four official students in the program last year, and expanded to ten this year. Those ten students are really some of the cream of the crop in terms of their application packages, their letters of recommendation. And we probably have another 10 to 15 students outside the program who also do summer research here.
What do you try to teach your summer students?
I think an important thing to do for these students is not just teach them how to pipette. Fundamentally scientists are here to think, and so you can’t just tell them add this and this to the tube—you have to tell them why. And beyond the science, we try to teach our students the process of being in a lab. Why is it important to keep a good notebook? Why is it important to be a good lab citizen? Why is it not a good idea to ever use the last of something and not replace it? So they understand that what they do have real ramifications for the lab.
We do a seminar series for the students where once a week we have a faculty member come in. They talk about their research and things like that, but they also talk about how they got into science, what they like about it, what they don’t like about it. It’s a job like anything else, so of course there are going to be things you don’t like about it. Each faculty gives a different perspective to these students. We all get here from different directions.