Bedside-to-Bench-to-Bedside: The Keys to Successful Collaboration in Neuroscience Research

Podcast Transcript

Alex Rae-Grant, MD:  Neuro Pathways, a Cleveland Clinic podcast for medical professionals, exploring the latest research discoveries and clinical advances in the fields of neurology, psychiatry, neurosurgery, and neuro rehab.

It's no secret that the cures for today's most daunting brain and spine diseases are likely to start at the lab. What's key is a strategy to swiftly transfer lab findings to the bedside. In today's episode of Neuro Pathways, we're discussing critical collaborations between researchers and clinicians who have taken neuroscience bench research to clinical trials and development of novel therapeutics. I'm your host, Alex Rae-Grant, neurologist in Cleveland Clinic's Neurological Institute.  

Today I'm very pleased to be joined by Dr. Bruce Trapp. Dr. Trapp is the chairman of the Department of Neurosciences in Cleveland Clinic's Lerner Research Institute. Bruce, welcome to Neuro Pathways.

Bruce Trapp, PhD:  Well, a pleasure to be here and thank you Alex and the NI for inviting me to participate in this.

Alex Rae-Grant, MD:  Bruce, I've known you for quite a while, but before we get started, why don't you help our listeners get to know you a bit more. Where are you from and how did your career lead to the Cleveland Clinic?

Bruce Trapp, PhD:  Yeah, well originally I'm from Northern Illinois, about 90 miles west of Chicago. Got my education in Chicago, my PhD at Loyola University School of Medicine, and then I went to the NIH in Washington DC, or Bethesda, specifically. Spent nine years there. First faculty position was Johns Hopkins in the Department of Neurology, and then 26 years ago I came to the Cleveland Clinic to chair a new department, the Department of Neurosciences.

Alex Rae-Grant, MD:  Well, I'll tell you what, with 20 years plus leading the Department of Neurosciences at Lerner, can you start the discussion by telling our listeners the prominent research role that you and your team have played at Cleveland Clinic?

Bruce Trapp, PhD:  Yeah, I think one of the philosophies I brought back in 1994, some time ago, in starting a basic neuroscience department, was that I wanted to focus on human disease. It was not a popular thing back in those days to have a basic science department focus on human disease, but it's probably one of the main reasons I took the job at the Cleveland Clinic. Again, my research interests being multiple sclerosis, MS, the Mellen Center had one of the biggest MS programs in North America if not the world. So this just opened an opportunity to really jumpstart a clinical research program in MS that included the Department of Neurosciences and hopefully that I could then recruit people in other CNS or peripheral nerve diseases as part of the faculty.

Alex Rae-Grant, MD:  We know your team's led neurosciences for a number of years in multiple fronts, particularly in MS. Can you talk about some of the many successes, including recent identification of a new subtype of MS?

Bruce Trapp, PhD:  I think if we look back from the beginning of this program, and I'd like to just mention that one of the things that have made us successful is our autopsy program. So we study MS by studying MS, and that takes an awful lot of coordination with the neurologists at the Mellen Center, radiologists in the Radiology Institute and BME.  But probably the first major impact we made was to describe neurodegeneration in MS, and I always thought it was a disease of myelin and the axons were spirit. That's what all the textbooks showed, and we, as well as others, we weren't the only one, but we really catalyzed this effort to describe neurodegeneration and MS, and that loss of neurons or axons was probably the major cause of permanent neurological disability in the disease. And so that was a seminal finding, I think the number-one cited paper in all of MS research still, and that was published in '98, a long time ago.

But then we have carried on that entrance trying to figure out how neurons and axons may die in MS. Are there therapeutic targets there that we could treat? We know the anti-inflammatory therapies do very well. They slow the disease but they don't stop it. So we're looking for additional targets, additional therapies, and the neuron and the axon is that therapy. So our most recent observation, we always thought the neurodegeneration was a consequence of demyelination, but we presented data last year in a subgroup of MS patients that they had neurodegeneration without demyelination. So providing the first evidence, or among the first evidence, that separates demyelination and neurodegeneration. And so now we're trying to figure out the potential mechanisms of that neuronal loss.

Alex Rae-Grant, MD:  And I know that we in the MS field struggle with the degenerative component, and how to work on that and how to explain that to our patients. Why are their MRI scans pretty steady and they feel the relentless decline? So I know that's a very important field of endeavor. Let me ask you, when we think about the collaboration, it's moving from the basic sciences to research to treating patients. How do you see that pathway connecting and moving forward?

Bruce Trapp, PhD:  You often hear this bench-to-bed theory of doing MS, and I think we have a modification of that here. It's really bench to the patient, but we start with the patient, and that's where my interactions with the Mellen Center and the neurologist there, so they have a great command of this disease and they ask their patients if they would donate their brain and spinal cord to our research program. And I think we've done about 180 some now. And this has made a huge difference in our understanding of the brain. So I look at our research as going from patient to bench and then back to patients. So the best way to study MS is to study MS and that is to get our hands on these brains and spinal cord and try to figure what's going on. We've been very successful in that. We've identified targets. I don't think we have no drugs in clinic yet, but we're in the pipeline to try to do that. Either to stop the neuro degeneration or to repair the myelin, which are the two major new targets out there right now.

Alex Rae-Grant, MD:  We know at the clinic it's really a multidisciplinary set of approaches to things. How do you see that working between the research side and the clinical side, that multidisciplinary component?

Bruce Trapp, PhD:  It's an absolute necessity today, particularly if you're going to try to have relevance to the clinical disease. We absolutely need the neurologists, so they do more than sign up these patients, they see our data that we generate. And their input into the interpretation of that data is really why we can publish in the New England Journal of Medicine and not the Journal of Neuroscience. Well, there's nothing wrong with the Journal of Neuroscience, but without this input from the clinicians, we would not have the same impact, not only in generating the data, but interpreting and putting it in context of the disease. The same can be said with the Imaging Institute and BM members that do all the brain imaging. We're leaders in brain imaging here. We're trying very hard to figure out what these brain images mean as far as pathology. And we're sitting on the cutting edge. So this recent paper we had, there was individuals from Mellen Center, the Imaging Institute, BME and neuroscience, all on the same paper. So it's teamwork. You've got to work together. Same common goal. And I've been very fortunate to be in an atmosphere where everyone plays together quite well on that team.

Alex Rae-Grant, MD:  So I think what's interesting in MS, or one of the many interesting things, we had heard all along that it's a white matter disease and now we know that the gray matter is critically involved. And where you thought it was an inflammatory disease and now we know that it's a degenerative disease. We used to think it was a T-cell disease and now we know it's a B-cell disease as well as many other effectors. So what we're learning is overturning what we used to think we knew. Is there a lot of things that you've learned that changed your mind about MS over time?

Bruce Trapp, PhD:  Well, yeah. I mean, I really was trained as a myelin biologist and interested in the cell biology of myelin, did a lot on inherited diseases of peripheral nervous system, but MS is a different disease and we don't know what causes it. We know that MS has the immune component that's very important. We have 17 or 18 FDA-approved therapies now to reduce inflammation, demyelination, but we don't stop the disease. And so there's things about it we don't know, and of course gray matter pathology is one of them.

We and others have described the demyelination of the gray matter, the cortex, cerebral cortex, being very important. Unfortunately we do not see that in routine imaging scans. Fields are making progress in that, so I'm hope they'll see something soon, but we have no way of judging what that cortical lesion load is in the MS patient. And now evidence that neurons may degenerate without demyelination, How do you have a marker for that? So we keep learning. I think we have to keep studying the MS brain and we have to model aspects of that so we may be able to learn pathways, but I think we're now starting to see in the pipeline, across the country, not just from our stuff, targets being identified and drugs coming into phase-one therapy that either will be neuroprotective or will promote repair, which are the two new targets for the field.

Alex Rae-Grant, MD:  Obviously you look ahead as to what's the next three to five years for your lab and for the collaboration. Are there some new things you can point our audience to that you're planning on the horizon?

Bruce Trapp, PhD:  Well, these patients that have very little brain demyelination and neurodegeneration, we're trying to get at the mechanisms of neurodegeneration. So we're very deep in the trenches to that right now, using some very novel technologies like single-cell RNA sequence to 10x technology. We're just getting into that right now, so hopefully this may provide us some insight into what are some of the mechanisms of neurodegeneration independent of the deep myelination possibly that's going on, and we could get some therapeutic targets. We're still trying to develop imaging modalities. We're not doing the imaging, but we're doing the pathology on that that can identify demyelination in the white matter and in the cerebral cortex.

The other thing that was part of our endeavors towards the myelocortical MS was they had MRI changes. Couldn't distinguish them from typical patients. The only difference was the MRI changes in the white matter were not demyelinated, so we know there's false positives for that if you assume that these images are demyelinated most of the time, but not all the time. Important. It's very important. If we're going to develop remyelinating therapies, we have to have an imaging baseline of demyelination when we put the patient on the drug. And if we have a 20% error, which our data would say at least occurs, you're never going to see a beneficial effect if you use white-matter MRI imaging, or it's going to be extremely difficult. So we've got to improve. I'm optimistic. The hardware's improving tremendously, and this is a very young science. MRIs haven't been around since, what, early 80s? So plenty of room for expansion and improvement there.

Alex Rae-Grant, MD:  So we're always learning new things and moving forward.

Bruce Trapp, PhD:  Always.

Alex Rae-Grant, MD:  So you've shared some great insights with us, Bruce, but before we sign off, anything else you particularly wanted to share with our audience about this whole field?

Bruce Trapp, PhD:  Well, yeah, I mean, I think there's two points that I look back now on since I've been here that really have helped us succeed, and I mean us in a group. And one is being associated with the NI and having these wonderful neurologists, neurosurgeons, neuroradiologists, to really help integrate our data into the disease. And without that support, we'd have never made the impact or the discoveries, I don't think, that we have done. And the second thing is the Lerner Research Institute has provided an awful lot of support for our program. We've been the model system. I mean, I think there are many there now, but when we started in the mid-90s we were the model system that the Cleveland Clinic would want to see as integrate programs in human disease. And so I'm very proud of that and proud of the colleagues, Rich Rudic, Bob Fox, Dan Ontaneda. And now it's just another string of neurologists that keep keeping us going and I've been very fortunate to be associated with those folks.

Alex Rae-Grant, MD:  We've been very fortunate to have you with us, Bruce. Well, thank you for joining us and we'll look forward to seeing how your work continues to develop and hopefully it'll help with the care of patient neurological diseases for many years to come. Thanks.

Bruce Trapp, PhD:  Thank you.

Alex Rae-Grant, MD:  This concludes this episode of Neuro Pathways. You can find additional podcast episodes on our website, clevelandclinic.org/neuropodcast, or subscribe to the podcasts on iTunes, Google Play, Spotify, SoundCloud, or wherever you get your podcasts. And don't forget you can access real-time updates from experts in Cleveland Clinic's Neurological Institute on our Consult QD website. That's consultQD.clevelandclinic.org/neuro. Or follow us on Twitter @CleClinicMD, all one word. That's at C-L-E Clinic M-D on Twitter. Thank you for listening. Please join us again soon.