Bobbi Pritt, M.D. (00:05):

Hello, I'm Dr. Bobbi Pritt, a clinical microbiologist and laboratory leader at Mayo Clinic, and your host for today's episode. I'm excited to be here today with Mayo Clinic Laboratories CEO and president, Dr. Bill Morice, to get the latest news. We will then be speaking with Dr. McKeon and Dr. Anastasia Zekeridou about testing for autoimmune neurological conditions. Bill, welcome back.

William Morice II, M.D., Ph.D. (00:29):

Yeah, always good to be back, Bobbi.

Bobbi Pritt, M.D. (00:32):

Yeah, you know, I love talking with you about what's new and noteworthy. And one of the first topics I wanted to bring up was this interesting topic of Mayo Clinic Laboratories investing in Pathology Asia Holdings and LifeStrands Genomics to advanced diagnostics and precision medicine. And I thought we could start with you telling us a little bit about this collaboration.

William Morice II, M.D., Ph.D. (00:53):

Yeah, I'd love to. As we've talked about in the past, Mayo Clinic Laboratories under Mayo Clinic, has evolved in our structure such that we can still be strategically aligned with our department, with you and all the great things happening within DLMP, but also thinking about how we build bridges with other healthcare organizations in more meaningful ways, really to help extend the knowledge that we have about diagnostics and their contribution to healthcare to other parts of the United States, but also other parts of the globe. And so, what has been announced is a partnership that we've been working on for several years with a company which is based in Singapore, Pathology Asia Holdings, which actually has laboratory activities across Southeast Asia, Vietnam, the Philippines, Malaysia, and also in Australia and New Zealand. So, across the region. And we've been talking with them for some time because, as the healthcare advances there, it's a huge population, a huge part of the world.

It's an opportunity for us to think about how we can help improve patients' lives and healthcare. One of the laboratories they have, LifeStrands Genomics, which is an advanced DNA testing laboratory, has labs actually in Malaysia, Singapore, and Australia. It's really an opportunity for us to A, participate in healthcare and, and diagnostic medicine and laboratory medicine in a more meaningful way in a new geography. Because as you know, that's literally halfway around the world. So to have them send things back to us doesn't work particularly well here in Rochester. Number two is really for us to learn also because as the different parts of the world are facing many of the same healthcare challenges, but also different ones and also healthcare delivery systems are different even across Southeast Asia, Indonesia being an island country much different than Singapore, which is a very small country.

So it's a way for us also to learn about how we can be more relevant in thinking about diagnostics and how they help shape healthcare. And of course, you know, I had a lot of experience with that with, with COVID having to think about, globally, about a single test there, but just about how healthcare is delivered. So, it's a great opportunity for us to really take that next step as Mayo Clinic in helping improve patient lives.

Bobbi Pritt, M.D. (02:57):

Yeah, that's a really exciting opportunity. Can you tell us a little bit about how the collaboration will help clinicians and patients living in that geographic region?

William Morice II, M.D., Ph.D. (03:05):

Well, a couple different ways. I think number one, we know a lot about how to use laboratories to really help improve healthcare systems. We've talked about that a lot. So, some of that knowledge will start to diffuse then through the Pathology Asia hospitals so they can start to just think and learn from us. Second is we will eventually start to think about, what are some tests that we have developed here in Rochester and in Florida and in Arizona as well, and how some of those might actually be introduced into that market and those markets in a way that's really relevant for the people living there, right? So, it's both the knowledge about how to use labs, it's new tests coming in, and not just new tests, but new tests with that knowledge that they really use most effectively. And again, that's the beauty of it.

I mean, gosh, you know this better than I do in your realm of infectious disease, as you start to bring those diagnostics into new places, you start to see new challenges and new opportunities to innovate. That's really what we're hoping to accomplish here, is to really, not just improve, but also help grow that ecosystem of innovation in that region as it pertains to diagnostics.

Bobbi Pritt, M.D. (04:06):

Yeah, it's very interesting. There are a number of infectious diseases that have some geographic restrictions, including those that are only found in parts of Southeast Asia, for example. So, interested to see where that will lead.

William Morice II, M.D., Ph.D. (04:18):

Not just infectious diseases. You know, the cancers that I studied, like T- and NK-cell leukemias, much more common in that part of the world. And I had the opportunity to write for the Blue Book, and we don't really understand why those differences exist. So, this is a way for us to grow collective knowledge as well.

Bobbi Pritt, M.D. (04:32):

Well, you know, we kind of tied those two things together. There are some infections found in Asia and Southeast Asia that actually cause cancer. And so, who knows? There might be some pathogens leading to certain types of cancers, or not.

So, I look forward to hearing more about that as the collaboration progresses. And then the other topic I wanted to bring up was an article that was just published by some collaborators at Mayo Clinic. It's actually two studies on advances in DNA detection. The first study really focused on how to detect a broad range of DNA mutations in noncancerous human tissues across the genome. And then there was a companion paper that was also published that used deep whole-genome sequencing to detect these rare, single-letter DNA changes that were present at really low levels, below 1% in a tissue sample. And I was just reflecting on how we're going to continue to see more of these technologies and the advances in understanding genomes and doing more of this genome analysis for patient care. I really wanted to get your thoughts on, how do you think these types of discoveries really impact clinical care?

William Morice II, M.D., Ph.D. (05:39):

Well, that's a great question. You know, and I had just had the opportunity a couple weeks ago to provide some input to Washington, D.C., on behalf of ACLA to the federal government, when they were wondering why they've seen this increase in molecular testing over time. And it really allowed me to think back to next-generation sequencing, which did not exist when I got done with training, or if it did, it had not been introduced into clinical medicine, all the discovery that happened from that. And now, I think as we're sitting here today about the tests that we provide for patients, both, you know, for somatic mutation, for cancer, for infectious disease now as well with the work you're doing on CSF and metagenomics. These advances first gain insights into human health and eventually then transition into clinical diagnostics derived from that knowledge of human health.

I think that will be another next wave, is how do we start to think about disease at the cellular level? For our careers, personalized medicine has been about the individual, but even within every individual, I mean, we are a complete mosaic of different cell types. And I think we're going to get more and more. And again, it really circles back even to our first conversation. The more that we're doing these activities globally, the more we can learn collectively about the human condition and find ways to understand it, diagnose it, and treat it.

Bobbi Pritt, M.D. (06:51):

Yeah. Well, you know, as a microbiologist, I'd be remiss to not include the human microbiome, because we're a mosaic of different organisms that make up our entire body and live in various parts of our body. So, you know, we're seeing the same thing, too, with sequencing, doing whole-genome sequencing on our collective flora. In sheer numbers, microorganisms outnumber human cells. So together, I think it's going to be a lot of interesting discoveries on what that means for patient care.

William Morice II, M.D., Ph.D. (07:20):

Yep. Lots to discover still in human health and in the world. Lots to understand and then lots for us to talk about. So, we'll have lots to talk about going forward.

Bobbi Pritt, M.D. (07:29):

Wonderful. I look forward to it. Well, thanks again for joining us, Bill.

William Morice II, M.D., Ph.D. (07:32):

My pleasure, as always.

Bobbi Pritt, M.D. (07:39):

Welcome to the deep dive. We're going beyond the headlines today with Dr. Andrew McKeon and Dr. Anastasia Zekeridou, who are both neurologists and co-directors of Mayo Clinic's Neuroimmunology Laboratory. We're going to dive into how their laboratory has driven testing advances. Thank you both so much for being here today.

Andrew McKeon, M.B., B.Ch., M.D. (07:59):

Thank you, Dr. Pritt.

Anastasia Zekeridou, M.D., Ph.D. (07:59):

Thank you for having us.

Bobbi Pritt, M.D. (08:01):

Let's start with some basics. Can you start by explaining what autoimmune neurological conditions are, and why they could be challenging to diagnose?

Andrew McKeon, M.B., B.Ch., M.D. (08:11):

So, autoimmune neurologic conditions are disorders characterized by an immune attack on the nervous system, which can manifest in many different ways, anything from brain disorders all the way down to autonomic nerve disorders of the gut. And these have largely been defined by the presence of an antibody biomarker, and that's often how these disorders are initially characterized. But, as we've learned over time, there are also seronegative disorders that, and these antibody-negative disorders are sort of a focus of research for us as well.

Anastasia Zekeridou, M.D., Ph.D. (08:46):

I think some of them might present, for example, as seizures or cognitive disorders or psychiatric symptoms, or some of them might have MRI lesions that are actually necessitating a biopsy. So, I think that if we don't have the diagnosis through the antibody test, so a lot of the patients might get diagnosed, for example, with dementia or a neurodegenerative disorder, or just epilepsy or a psychiatric illness. But it's very important to distinguish between those, because practically, some of the autoimmune neurological diseases, when treated early and when treated appropriately, they will have very good outcomes. For example, patients with an MDA receptor encephalitis, they might present, initially at least, young women with psychiatric presentations, but having the antibody has helped define those patients as autoimmune encephalitis. And even if they spend months in the neuro ICU or in ICU care, they can actually have very good outcomes.

Bobbi Pritt, M.D. (09:46):

Well, that's good to hear. And it sounds like diagnosis is incredibly important then. So, what makes Mayo Clinic's approach to developing diagnostic solutions for these conditions unique?

Anastasia Zekeridou, M.D., Ph.D. (09:57):

I think part of the paradigm that we have here is that we're very interconnected between the laboratory and the clinic. For example, four out of the five lab directors are autoimmune neurologists in the Neuroimmunology Lab. So, we see patients in clinic, then we come and do the diagnostic testing here, but also are involved in research in like discovering new antibodies, seeing how these antibodies actually work and what are the treatments that we can offer to our patients. There is a lot of this interconnectivity that starts from the patient where we see them, we identify the problem, we try to identify what this is related to bring it to the lab, and then do the research behind it in order to support our treatment and then bring it back to the patient. So, a lot of autoimmune neurologists and laboratorians working together here.

And also, the autoimmune neurologists, we are involved in the validation of tests. So, if there is a test, for example, that has been discovered somewhere else, a new antibody, we can see what is the clinical significance. Can we bring it back to our lab? Is it important for our patients? So, there is a lot of this connectivity and collaboration between us and also researchers outside of our group as well.

Bobbi Pritt, M.D. (11:16):

Yeah. Dr. McKeon, what are your thoughts on this?

Andrew McKeon, M.B., B.Ch., M.D. (11:19):

I think that, in the absence of kind of antibody testing, it can be very difficult for us to determine what's going on with patients. And so historically, a lot of these patients were thought to have just some poorly differentiated neurologic disorder and often the assumption culturally in medicine was that most patients with central nervous system problems that were not strokes were basically neurodegenerative and that there wasn't really much hope for treatment of these patients. Slowly initially, and then kind of exponentially over time, then these antibody biomarkers became available, and that really helped us define this field of autoimmune neurology. And, we really haven't looked back since.

Bobbi Pritt, M.D. (12:01):

I think that's wonderful. It's what, more than 30 years of your focused work in autoimmune neurology and the fact that you have practicing neurologists as laboratory leaders doing research and development I think is a really unique model and one that's been very effective.

Andrew McKeon, M.B., B.Ch., M.D. (12:16):

Yeah, it has indeed. Really, it is kind of truly bench to bedside and back, and whatever direction you want to go with that. There's a lot of back-and-forth between the different components of our service and what we do. And also, you know, we have very strong collaborations worldwide. We also have a lot of insight into the testing offered by other labs. And so we've brought up a lot of tests that are offered by other people, you know, or that have been discovered by other people. And we're always very quick to want to bring those in and harmonize those with the tests that we do to really offer the most comprehensive and sensitive and specific evaluations that we can for any disease state.

Bobbi Pritt, M.D. (12:55):

Yeah, sure. You want what's best for the patients. Well, Dr. Zekeridou, I wonder if you can comment on this approach that connects patient care research and lab testing. And you've touched on this already a little bit, but how does this accelerate discovery and innovation in your mind?

Anastasia Zekeridou, M.D., Ph.D.  (13:12):

I think it's important to realize that when you have a patient in front of you in clinic, I think that also motivates you a little bit differently. Like, you want to give them the answer. You want to be able to go back to them with a treatment plan or with an answer for what has been going on. A lot of our patients have been not properly diagnosed for years before they come here. So, I think this patient contact has the motivation aspect of it, but it also helps recognize the nuances. Like you can actually really get to the deep dive, understand what's going on and really try and separate, what does this patient look like? Is it similar to another patient that I have seen? All of those things actually work together. And I also think that sometimes the other thing that happens with our lab is that you will get a phone call from an outside provider just wanting to discuss a patient that had antibody testing in our lab.

And even though we don't directly see this patient, I feel that we get involved a little bit in their care by understanding their stories, trying to help the clinician. So, all this clinical approach, either if patients are only at Mayo or outside of Mayo, it really helps motivate us and also really focus the research and really keep our eye on the goal, which is, what can we do to get the patient better?.

Bobbi Pritt, M.D. (14:29):

I love that approach. I think that's wonderful. Dr. McKeon, do you have anything to add?

Andrew McKeon, M.B., B.Ch., M.D. (14:35):

I suppose one aspect of it is that maybe we haven't discussed is the importance of serum and spinal fluid testing. And so, we don't just rely on one specimen type, and we have to try to integrate that into our thinking as far as which specimen type is best for each analyte. So there's some differentiation in our profile-based approach, based around kind of which specimen type is best to detect one over another.

Bobbi Pritt, M.D. (15:01):

Sure. And you've been really instrumental in creating those testing algorithms and guidelines. And I believe that many of the clinically relevant antibodies that are available to patients were actually discovered at Mayo Clinic in the Neuroimmunology Laboratory. Can you tell us a little bit about that?

Andrew McKeon, M.B., B.Ch., M.D. (15:17):

Yeah, sure. Well, dating back to the 1970s, Dr. Vanda Lennon, who founded the lab, was involved in seminal work around myasthenia gravis and actually identifying that this was an autoimmune disease. And then was involved in discovering the acetylcholine receptor-binding antibody. And that was really the kind of the foundation of the clinical component of the lab here at Mayo. But then there were kind of several big discoveries using similar technology. The radioimmunoprecipitation assay for another disease called Lambert-Eaton Syndrome for a calcium channel antibody. And then another acetylcholine receptor, this time an autonomic one relevant to autoimmune dysautonomia, that she discovered. And then there was a kind of a pivot to using tissue-based assays, so basically a mouse brain assay, that we could see IgG binding to the tissue and then really helped to characterize a lot of autoimmune neurologic diseases, everything from cancer-related paraneoplastic disorders to mimics of multiple sclerosis, known as neuromyelitis optica.

And then since then, many antibody markers of autoimmune encephalitis and related disorders. If I had to highlight one, I would say the neuromyelitis optica story in relation to Mayo Clinic is really probably the best known one, but also one where we went from literally antibody discovery to a curative therapy within 20 years in patients who otherwise were left with kind of a diagnosis of untreatable multiple sclerosis and became wheelchair bound and blind. Really, quite an incredible story.

Bobbi Pritt, M.D. (16:52):

That's amazing. You know, I love the stories. I think that really brings it home for the people that are listening. Do you have any other specific examples of how our lab discoveries have really just changed the way that patients are diagnosed and treated?

Andrew McKeon, M.B., B.Ch., M.D. (17:06):

There are several of the realm of autoimmune ataxias, autoimmune encephalitis, and autoimmune movement disorders. Dr. Zekeridou actually described one a few years ago against phosphodiesterase enriched in the basal ganglia in patients presenting with an autoimmune basal ganglia disease of the brain. So these patients have movement disorders, specifically chorea and dystonia, which otherwise looked like a kind of a garden variety dystonia that is idiopathic that we sometimes see in adults. But, she identified this one and, it was happening in a very specific circumstance of patients who had cancer that were treated with these immune checkpoint inhibitors that really unleashed a very vigorous T-cell response against their cancer, but unfortunately unleashed autoimmunity in these patients also. That's kind of an example, but there are many.

Bobbi Pritt, M.D. (17:56):

Yeah, that's great. Dr. Zekeridou, do you have any examples you'd like to add?

Anastasia Zekeridou, M.D., Ph.D. (18:00):

I think those are great examples. I was going to say that some of the diseases initially were targeting a lot of patients. We would find an antibody that would be more common. And then as the years progress and we find more and more antibodies and like Dr. McKeon has a pipeline, a research pipeline, finding antibodies now in even smaller populations. And some people might argue, do we really need all of those? But, I would argue that we do. Because in a single patient you can make a huge difference by giving them an answer and knowing how to treat them. For example, I think we had a patient that both of us saw in clinic with an autoimmune tremor. None of us, I think, had seen an autoimmune tremor looking like this before. Most of the people that present with this tremor would have been what we call an essential tremor, but the story didn't make sense.

And then, this patient actually, we saw him, he had an antibody staining when we did our tissue indirect immunofluorescence assay, and then we actually saw him in clinic. We looked for a cancer. We found a lymphoma. So, we managed to treat him both for the cancer, for the autoimmune disease, and he went back to normal. Eventually, we identified his antibody as well, so this might help other people, but this is an exceedingly rare situation. But at the end, it really made a huge difference for this patient. So I think now as we work through our way, like the Aquaporin-4 was a great example, but then we find more and more rare antibodies, but I think that this make a huge difference for the patients that have them. We can actually focus our treatment, because an antibody is not only a diagnostic tool, but it really helps us get a glimpse, at least, in the pathophysiology, what is the best treatment? Where do we go from there?

Bobbi Pritt, M.D. (19:41):

Those are great examples. It must be really rewarding to then see the patient and know that you're actually providing, through your diagnostics, your research, an answer for them to make their lives better. Thank you both so much for sharing those examples and also sharing your expertise with us today and joining us on this podcast.

Andrew McKeon, M.B., B.Ch., M.D. (20:00):

Well, thank you for the opportunity, Dr. Pritt.

Anastasia Zekeridou, M.D., Ph.D. (20:01):

Thank you for having us. Thank you.

Bobbi Pritt, M.D. (20:08):

Let's wrap up with the top takeaways and how to learn even more on the topics we discussed. In today's news segment, Dr. Morice shared more about a new collaboration to expand access to advanced diagnostics, and we discussed a Mayo-led study advancing the detection of DNA mutations. You can find links in the show notes to more information on both topics. And then during our deep dive, Drs. McKeon and Zekeridou talked to me about Mayo Clinic's Neuroimmunology Laboratory and how it's advancing patient care. To help you learn more, we've included links in the show notes of a recent story about how their work is transforming the approach to testing, and also an overview of autoimmune neurology tests offered by Mayo Clinic Laboratories. Thank you for joining us today. If you haven't already, make sure to subscribe so you never miss an episode. Next time, Dr. Peter Lucas will join me to explore strategies that Mayo Clinic's Department of Laboratory Medicine and Pathology in Rochester is using to drive innovation. I hope you'll be able to join us.