Molecular Human and the Multi-Omics Revolution: with Dr. Karsten Suhre and Dr. Anna Halama
Glycans and Neurodegenerative Diseases: A New Perspective on Alzheimer's with Prof. Ronald SchnaarPodcast published on 6/14/2023 • Show notes written by Vanja Maganjic & Rina Bogdanovic
Let me say that the world of glycans and their functions, as in human physiology, and human disease is really advancing rapidly. I think there are going to be new discoveries and action taken on old discoveries that are going to help out in lots of immune diseases and cancer, maybe neurodegenerative diseases, but glycans are everywhere. And that we are working hard as an international community to discover, to the extent that we can build up that infrastructure to keep the discovery moving forward.
35 minutes reading time
The longer lifespans we enjoy come shadowed by age-related diseases, notably Alzheimer's. This episode shines a light on the often-overlooked glycans, complex carbohydrates that play a pivotal role in healthy brain function. Our understanding of Alzheimer's causation has evolved, moving beyond just 'trash accumulation' to include problems with 'trash clearance.' Discover the potential of glycans in healing spinal cord injuries, the hurdles in identifying early biomarkers and delivering drugs to the brain. We delve into the essential role of gangliosides, a unique class of glycolipids, and separate science from media hype around Alzheimer's prevention. Ronald Schnaar is the Professor and Interim Director of the Department of Pharmacology and Molecular Sciences and a Professor of Neuroscience at Johns Hopkins University School of Medicine. Listen in as he unpacks his extensive research in neuro glycobiology and the practical hurdles in the path of Alzheimer's research and prevention.
- Why Study Glycobiology? What Drew Ronald to Glycobiology [02:41]
- Understanding the Crucial Role of Glycans in Cell-to-Cell Interaction [05:18]
- Study on Gangliosides in Context of Nerve Cell Insulation [06:29]
- Congenital Disorders of Ganglioside Biosynthesis: Symptoms and Treatment Options [12:03]
- The Potential Role of Glycans in Repairing Spinal Cord Injuries [18:17]
- The Evolution in Our Understanding of Alzheimer's Disease [20:45]
- Challenges of Studying Alzheimer’s Disease [27:23]
- International Research Collaboration for Study of Alzheimer’s Disease [31:09]
- Dual Causes of Alzheimer's: A New Perspective [32:37]
- Are Mice Good Models for Neurodegenerative Diseases? [34:42]
- The Challenge of Translating Research into Clinical Application [38:40]
- Challenges of Drug Delivery to the Brain [40:45]
- The Future of Glycan Biomarkers of Alzheimer's Disease [42:23]
- Alzheimer’s Prevention: Sifting Fact from Fiction in Media Coverage [45:58]
- Ronald’s Future Research Plans and Focus [51:27]
- Ronald’s Final Message to Our Listeners [54:44]
About the guest
Ronald Schnaar is a Professor and Interim Director at the Department of Pharmacology and Molecular Sciences and a Professor of Neuroscience at Johns Hopkins University School of Medicine. He directs discovery research programs and multi-institutional collaborative projects in the field of Glycobiology. His research addresses the functions of glycans, the major structural determinants of cell surfaces, with the related goals of expanding knowledge of human physiology and revealing new opportunities for therapeutic development. His biomedical research focuses on the roles of glycans and glycan recognition in the physiology and pathology of the nervous and immune systems. He has performed and directed glycobiology research for nearly 50 years. His biomedical research team discovered that gangliosides, major glycans of nerve cells and axons, function in axon-myelin interactions, including the stabilization of axons and the control of axon regeneration after injury. His team identified glycans on human neutrophils that initiate neutrophilic inflammation and glycans in airways that regulate human eosinophilic and mast cell (allergic) inflammation. In their latest studies, his team discovered a unique glycan in the human brain that regulates debris clearance and has implications for Alzheimer’s disease progression. Dr Schnaar has served as the Editor-in-chief of the journal Glycobiology, co-editor of the textbook Essentials of Glycobiology, President of the Society for Glycobiology, Steering Committee Member of the Consortium for Functional Glycomics, and Director of the Lung Inflammatory Disease Program of Excellence in Glycosciences, a multi-institutional NIH-funded program to harness glycan recognition to treat asthma and other inflammatory lung diseases.
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Articles, books, and other media discussed in the show
Find more information about congenital disorders of ganglioside biosynthesis and Alzheimer’s disease:
Ronald’s work relevant to this conversation:
"So in your brain, all of the nerve cells communicate with each other by sending out long threads called axons that carry electrical signals that then can communicate with other cells, and like wires, they have to be insulated to work properly. And that insulation that wraps the axons is called myelin. And what we found, it was a surprise to us, but it’s just the way it works is that the protein it's called Myelin-associated glycoprotein, or MAG, that recognises gangliosides. It is on the myelin and the gangliosides are on the axon. And that's one of the ways that this wrapping, this insulation stays on the axon. And we were able then to identify the structures involved. And then, in mice where we can manipulate the genes. We changed genes in the mice so that they couldn't produce the gangliosides recognised. And what do you know, those mice had problems maintaining their myelin, they became crippled. As they age their myelin falls off, and their axons degraded, that's what happened. And they were dragging their hindquarters around. So we discovered that gangliosides are recognised by a protein called MAG and that this interaction is responsible for stabilising the insulation wrapping around axons."
"We learned that Alzheimer's is a disease of the accumulation of trash in the brain. This trash is misfolded proteins, proteins that should have a function but instead, get crumbled and build up. And there are two classes of those called plaques and tangles of different proteins that build up in the brains of Alzheimer's patients. And it still is a strong hypothesis that these plaques and tangles result in the death of nerve cells. So pharmaceutical companies focused on stopping the plaques from forming, that's the first thing that happens. And they got some drugs that would stop or diminish plaque formation. And they tested them in patients that had Alzheimer's symptoms, and they failed to help, which was a big disappointment. So what did we learn from that?"
"I think that part of being a discovery biomedical researcher is a very high level of optimism. We are going to solve these problems, they're not going to get solved by themselves. As an international team, biomedical discovery researchers are working to get the knowledge that's going to lead to cures, we just have to have that faith. It's not a word used for science, but it's with faith, and optimism, that we are going to be successful. And we have, we have been for many diseases, we're doing much better now."
Rina Bogdanovic [00:05] Hello, hello, and welcome back to GlycanHub - the podcast in which we explore health, disease, and longevity through the lens of glycobiology. My name is Rina, and I am your host. We are living longer than ever before, but unfortunately, our health span (or how long we live in good health) doesn't tend to align with our lifespan (that is the length of life overall). As our average lifespan increases thanks to advancements in medicine and healthcare, we are seeing a rise in age-related diseases leading to a decline in quality of life during our later years. Unfortunately, a common cause of cognitive decline among older individuals are neurodegenerative diseases, of which Alzheimer's is the most common. Today's episode is an expedition into the fascinating and somewhat mysterious landscape of our brain, more specifically the role glycans play in its structure and function. My guest today will introduce us to the way glycan research reframed our understanding of the cause of Alzheimer’s disease. We will discuss the difficulty of identifying early biomarkers of Alzheimer’s, the challenges of drug delivery to the brain, as well as how our understanding of the structural role of glycans in the nervous system could aid in mending spinal cord injuries in the future. We'll also touch upon how to discern the reliability of science reported in the media, particularly concerning Alzheimer's prevention. My guest today is a seasoned expert in the field, having devoted over four decades to the study of glycobiology. He is a Professor and Interim Director of the Department of Pharmacology and Molecular Sciences, and a Professor of Neuroscience at Johns Hopkins University School of Medicine. His research focuses on Sialoglycans in the control of nervous system proteinopathies. Cell-cell interactions in inflammation as it pertains to respiratory health, and asthma in particular. A warm welcome to Ronald Schnaar.
Ronald Schnaar [02:39] Thank you, delighted to be here, Rina.
Why Study Glycobiology? What Drew Ronald to the Field
Rina Bogdanovic [02:41] So before we start talking about your research, I want to learn more about what it was that initially drew you to glycobiology. It is a field that is often overlooked and neglected. And so I'm just curious, what was it that initially attracted you to it? And what is it that still keeps you interested today?
Ronald Schnaar [02:59] Interestingly, what got me into this field is still what I do today. And this was many years ago when I was a young graduate student and hadn't decided what I wanted to research yet. And I saw a talk by another graduate student. And what he showed is that some artificial beads he made that had sugars attached to their surface, interacted with human cells. And he’d put one sugar on, the cells would ignore it. If he’d put another sugar on, the cells would crowd around. And I thought to myself - Oh, my goodness, they're communicating with cells, they're speaking a cell language, and I want to do that. And so I actually began working in glycobiology and one of the leaders in the field, Saul Roseman, was at the institution, Johns Hopkins, where I was doing my graduate work. And I requested that he allow me to join his team. And we worked on glycans and cell recognition, which, as you know, is still what I'm doing today. We have advanced over the years a lot, but it's the same field.
Rina Bogdanovic [04:26] So I'm curious, how many years has it been that you have been researching in this field?
Ronald Schnaar [04:31] Over four decades. So I've watched the field grow around me. I've watched the tools become available, and I've watched the knowledge expand remarkably. In the days when I started, we knew that sugars could be recognised in nature because some pathogens like the influenza virus bind to sugars. But we didn't know that, we kind of intuited, but we didn't know that our own cells could recognise sugars or what that was about. And since then that field just exploded, and we know a whole lot about it now, it's very interesting.
Understanding the Crucial Role of Glycans in Cell-to-Cell Interaction
Rina Bogdanovic [05:18] Could you tell me a bit more about what is meant by cell-to-cell interaction? And what have you learned is the role of glycans in that interaction?
Ronald Schnaar [05:29] We're social animals, inside and out. And inside, we have trillions of cells, different kinds of cells. And as part of an efficient functioning organism, those cells have to recognise each other and respond appropriately. We don't respond the same when we run into our grocer as we do when we run into our grandmother. And that's because we recognise them as being different. The surfaces of cells are covered with glycans, it's the face of the cell. So it's sensible that cell recognition - that is the ability of cells to recognise and respond appropriately to each other, has to do at least in part, with what glycans are there. And cells can molecularly take a snapshot of that, and respond accordingly.
Study on Gangliosides in Context of Nerve Cell Insulation
Rina Bogdanovic [06:29] Just to make it clear, this cellular interaction is present in essentially every organ, every part of our body. But you have primarily focused if I'm not mistaken, on inflammation and neurobiology. And one of your, to me, very interesting areas of research was on gangliosides. Could you explain what they are and what their role is in the brain?
Ronald Schnaar [06:56] Sugars are attached to the surface of your cells, they would float off if they weren't attached. They can be attached to lipids, which are embedded in the surface of your cells. And then the sugar sticks out or the proteins and when they're bound to lipids are called glycolipids or glycosphingolipids. And some of those that have our, for humans and other mammals, our favourite sugar at the outermost terminus, or outermost point of the glycans is called sialic acid, especially well suited for recognition. If it has a sialic acid, those glycolipids are called gangliosides. Now they're everywhere. They're in every cell in your body. But in the brain, they dominate. In your liver, most of your glycans are on glycoproteins and your brain most are on glycolipids, we really don't know why that is. But when I started investigating recognition function of molecules, there were two great reasons why I focused on ganglioside. One is that unlike glycoproteins, which can be very large and have a whole bunch of different sugars attached to them, the sugars can be different along the chain. You purify it and see what it does, functionally, cells make it kind of difficult to interpret. Gangliosides are individual, single chains of sugars on a single lipid, and you can separate them that way. And then you can test them for what they're doing. So the brain, and I can get them easily to test. And our team did that. And we began looking for recognition. How do we do that? We assumed because there was no evidence that in order for a sugar to be able to generate a response, it has to be recognised. So if this is your sugar, there had to be something out there that recognised it, that would result in some kind of response. So we took that and purified those individual gangliosides from the brain, and we tagged them so that we could follow them experimentally. We asked - Is there anything in the brain that binds these? And in fact, we found things and the one that we focused on was a protein that specifically binds to just two of the major brain gangliosides based on their structure, and we found out what it did. And let me back up. So in your brain, all of the nerve cells communicate with each other by sending out long threads called axons that carry electrical signals that then can communicate with other cells, and like wires, they have to be insulated to work properly. And that insulation that wraps the axons is called myelin. And what we found, it was a surprise to us, but it’s just the way it works is that the protein it's called Myelin-associated glycoprotein, or MAG, that recognises gangliosides. It is on the myelin and the gangliosides are on the axon. And that's one of the ways that this wrapping, this insulation stays on the axon. And we were able then to identify the structures involved. And then, in mice where we can manipulate the genes. We changed genes in the mice so that they couldn't produce the gangliosides recognised. And what do you know, those mice had problems maintaining their myelin, they became crippled. As they age their myelin falls off, and their axons degraded, that's what happened. And they were dragging their hindquarters around. So we discovered that gangliosides are recognised by a protein called MAG and that this interaction is responsible for stabilising the insulation wrapping around axons. And if you're missing it, you’ve got problems, and especially your long axons, like the ones from your spine to your toe. So your mobility fails, but others do as well.
Congenital Disorders of Ganglioside Biosynthesis: Symptoms and Treatment Options
Rina Bogdanovic [12:03] Now, you said you engineered these defects in mice. But do such diseases exist in humans as well?
Ronald Schnaar [12:12] They do. After we made these discoveries, it was timely, because the genetic revolution was providing the tools to sequence genes and find out which genes had problems and genetic diseases. And sure enough, the very gene that we knocked out in mice that resulted in their lack of ability to move their hind quarters, turned out in a human, rare human disease, called human spastic paraplegia, which has the same outcome. People who are missing this gene have problems with their mobility, and most of them ended up in wheelchairs. So we were able to know why now, these people had that. Interestingly, we had some hints in the mice that they had deficits in their intellectual abilities, not as easy to measure in mice. But the people who have this gene missing, the humans that have these genes are intellectually impaired. They have low IQs across the board. So the gangliosides, which we know are very prominent in the brain, these structures are involved in both motor and behavioural maintenance, development and maintenance in humans.
Congenital Disorders of Ganglioside Biosynthesis
Rina Bogdanovic [14:01] Just in general, when it comes to congenital disorders of ganglioside biosynthesis. How frequently do these appear in the population?
Ronald Schnaar [14:11] They're rare, they're inbred errors. In certain populations, they pop out. And in particular, we knocked out some of the very terminal sugars on gangliosides and that's what causes paraplegia and mild intellectual disability. But there's a knockout or a mutation that occurs in humans even further earlier, that knocks out essentially all of the major gangliosides. Those kids are in bad shape, I visited with them. This is a disease that comes on very early. Severe intellectual disability, none of them are conversant. And they have very limited communications. It's a terrible disease and they are unable to walk, they have motor disabilities as well. So the question was, how many people have this? Well, in this community called Old Order Amish, which is a small community in the middle of the state of Ohio, in the United States, they're probably 100 of these patients. So in that community, it's a very major problem in this tiny community, they have 100 children who live to their mid to late teens that have this disease. But in general, we're talking about worldwide, probably only hundreds of cases, maybe 1000s of cases.
Rina Bogdanovic [16:01] And so I imagine the treatment options are not very vast.
Ronald Schnaar [16:05] Zero, essentially. We could discuss that, we’ve discussed that as teams of physicians caring for these patients, and those of us that have knowledge in the area. And the attempts, at one level, the easiest attempt is to try to feed back the missing gangliosides. That's tough because it's hard to get things that you eat into your brain. The other option here is genetic engineering. And I think that may have some promise. Interestingly, and maybe people listening to this would like to know about this, that there have been diseases of gangliosides, especially the breakdown of gangliosides, where the enzyme is missing to break them down. They build up in your brain, and you die at a very young age. This has essentially disappeared by genetic counselling. We know the gene, we can identify if you have it or not. It's recessive, which means both your mom and dad have to have it. So those of us in communities like the Ashkenazi Jewish community, that had a lot of this disease called Tay-Sachs disease, well, we all get tested. And then we know and we know to look. You know, I know that I don't have the gene at all, so my children can't have it. But if my wife had it, we could have done testing, amniotic testing, and know whether our kids have this devastating, horrid disease. So communities that are willing to do that, can wipe out these diseases by genetic counselling.
The Potential Role of Glycans in Repairing Spinal Cord Injuries
Rina Bogdanovic [18:17] When it comes to your research and gangliosides, what has been the focus other than looking at these congenital disorders?
Ronald Schnaar [18:28] We're very interested in the broader functions. Again, we're talking about molecular recognition. In this case, we were able to find out the myelin-wrapped axons. Now it's interesting, you may know and your viewers may know, when you have injuries to the nervous system, they tend not to heal, the neurons don't grow back. One of the reasons is that molecules in the myelin that are used to insulate those axons actually are telling the axons to be stable and not regrow. So for example, we know that myelin-associated glycoprotein sends that signal through gangliosides. And so we were able then to devise an approach of administering to in this case, rats that we had caused a spinal cord injury, an enzyme that would change their gangliosides. And in that case, release the inhibition and let the axons grow back. So this is the kind of approach we're taking. Discovering the interactions, and then every time we discover an interaction, the question is, what do we do with that and can it alleviate disease?
Rina Bogdanovic [19:58] Just to put it in perspective for our listeners, how long does it usually take from doing these types of experiments with mice in the lab, to potentially applying this to people with spinal cord injuries in real life?
Ronald Schnaar [20:11] There are a lot of levels of complexity. But decades is a good rule from the discovery of a target to delivery, therapeutic delivery to humans. And for better or for worse, the economics have to be there. You know, it takes a billion dollars to develop a drug. So you have to also have the economics to support that.
The Evolution in Our Understanding of Alzheimer's Disease
Rina Bogdanovic [20:45] Absolutely. Now, another concern that's rising related to the fact that we are an ageing population is an increase in neurodegenerative diseases and dementia. Now, a lot of your research has also focused on Alzheimer's disease. And so I'm curious, how would you say our understanding of Alzheimer's has changed or developed in recent years?
Ronald Schnaar [21:09] It's a great question, and it has developed. So what did we learn earlier? We learned that Alzheimer's is a disease of the accumulation of trash in the brain. This trash is misfolded proteins, proteins that should have a function but instead, get crumbled and build up. And there are two classes of those called plaques and tangles of different proteins that build up in the brains of Alzheimer's patients. And it still is a strong hypothesis that these plaques and tangles result in the death of nerve cells. So pharmaceutical companies focused on stopping the plaques from forming, that's the first thing that happens. And they got some drugs that would stop or diminish plaque formation. And they tested them in patients that had Alzheimer's symptoms, and they failed to help, which was a big disappointment. So what did we learn from that? Well, as you may know, Alzheimer's builds up for many, many years, decades, things build up in your brain, well before you have symptoms. And the concept now is, by the time you're having symptoms, it's probably too late. Or it's too late to go in and block plaque formation. It may not be too late to clear out other trash in the brain actively. But we can't just when we have a patient come in with Alzheimer's symptoms, stop new plaques from forming in treatment. So that's one thing we learned. The other thing that has driven some of our research is that with the power of genetics, which I mentioned earlier. We've now gone as a field into large populations and explored their entire genetic code. And then asked which of these people are susceptible to Alzheimer's and which of these people get old but never get Alzheimer's and compared their genetic makeup. And well, what was found surprisingly, again, not in retrospect, is that a lot of these genes showed up in cells called microglia. These microglia are a kind of immune system of the brain. They're specialised cells only in the brain, and what's their job? Clean up trash. So it's like - Oh, there's a problem with trash cleanup. And so one of the driving forces of our recent work is that a gene called CD33 was found to be associated with people that are more susceptible or families more susceptible to Alzheimer's disease. And it turns out that CD33 puts the brakes on microglia and stops the trash truck. And if you have a genetic makeup, so you make lots of this break, CD33, you're more susceptible to Alzheimer's disease. Rarely, do some people have a gene that the product doesn't have any breaks, and they're less susceptible to Alzheimer's disease. So this is one pathway we're interested in, why? Turns out CD33 is a glycan binding protein. That's what led us into this field.
Rina Bogdanovic [25:38] Have you also been able to explain why it is that if this is a genetic issue when it comes to microglia, why does it occur progressively as we age?
Ronald Schnaar [25:48] As you could imagine, the day the trash strike starts in New York, things are okay. A week later, things are still kind of, okay, a month later, you can't get around anymore. So this is a long-term progressive buildup in the brain. And this is, by the way, another opportunity for therapeutic approaches to Alzheimer's disease. Since the failure of the plaque-stopping drugs, one thing that scientists have been trying to do is discover markers. That is molecules that we can measure in our blood, for example, that tell us if you are in the very early stages of Alzheimer's disease. Now, essentially, the only way to prove somebody has Alzheimer's disease is after they die. And you will look at the histology in their brain. We can guess they have early Alzheimer's because of cognitive symptoms. But wouldn't it be great if we knew that this process, that the trash collectors were on strike, even before the trash started to build up? Then maybe we could go in and do something. And that's the hope.
The Challenges of Studying Alzheimer’s Disease
Rina Bogdanovic [27:23] Could you also explain, when it comes to conducting these studies, I guess when it comes to human tissue, it's usually post-mortem that you acquire it. So what are some of the challenges when it comes to studying Alzheimer's and acquiring human tissue?
Ronald Schnaar [27:40] To us, that's a barrier. When I began this work, there were a few brain banks around the world that can provide donated tissues. And this depends on families who care about furthering the science over the very long term. We talked about decades, this isn't going to help the next person in line but it might help down the road. Their willingness to approve tissue donations. Now, recently, I was fortunate to have collaborated with a group right here at Johns Hopkins called the Lieber Institute that has perhaps the world's largest bank of human brain tissue for various neurological diseases. And what happens and, you know, this is tough to think about but what happens is when somebody dies and their brain is donated, they have a quick system where they can study the histology of the brain, get information about the diseases, if any, and categorise - and as I mentioned, Alzheimer's can be diagnosed post mortem. So they have non-Alzheimer's brains and Alzheimer's brains at different stages. And now we can begin to probe what's different and know what's different and associated with that. We're doing studies with microglia. And now we can actually make human microglia from stem cells in the laboratory. And we're finding out how we can rev up their trash collection or reverse the inhibition that they get from CD33. So together by understanding the molecules in Alzheimer's that aren't folded and how we can alter and rev up microglia, we might get, what we call a lead molecule, a molecule that we can define, that we think can resolve some aspects of Alzheimer's. Then it’s a long road to animal testing, and then a long road to safety and a long road to human trials. And there are pitfalls at every step. Somebody says this - the probability that we're going to learn something new, that's useful, is very high. The probability that we, a small laboratory, are going to come up with a cure for Alzheimer's is very low. But as a team, the 1000s of us around the world that are working on these problems, are going to come up with the information that's going to allow us to move forward and make this something historical, if not for our children, for our grandchildren.
International Research Collaboration for Study of Alzheimer’s Disease
Rina Bogdanovic [31:09] Do such initiatives exist already, when it comes to collaboration around the world for Alzheimer's?
Ronald Schnaar [31:14] Collaboration in biomedical sciences is international. Always has been, I was just, if I may, an aside, I was just reading about some important studies on glycans that lead to breakthroughs and recognition that were going on in the 1940s. And a key connection was made between an investigator in Sweden and an investigator in Australia, when they met at a conference in Cambridge, in 1949. This is how science works. So the important aspect of accelerating discovery is bringing more people in to do it, and providing the resources they need to do it. And for that, there are national efforts through funding agencies in each country. And there are private agencies like the Alzheimer's Foundation, Cure Alzheimer’s, and I'm sure they are around the world and raise funds to inject into the field to further key discoveries.
Dual Causes of Alzheimer's: A New Perspective
Rina Bogdanovic [32:37] Now, just going a little bit backwards. We mentioned the accumulation of misfolded proteins, we mentioned waste clearance, now I think more traditional, at least the way I was taught was mainly to blame the accumulation of misfolded proteins. But now, would you say that the cause of Alzheimer's is dual in that it is, for people who are more predisposed to the disease, they likely have an issue with a higher accumulation of waste proteins and then a lower waist clearance?
Ronald Schnaar [33:10] I would say that that's the case. And genetics on that is pretty strong. Alzheimer's certainly doesn't have one gene that causes it, we already know that. But it may have more than one genetic association or pathway that leads to this. In every case, Alzheimer's in particular has this buildup of plaques and tangles in the brain that we can see by histology and quantify, so we know what stage of Alzheimer's they’re in. But it's only post-mortem. So we're convinced, you know, there's a lot of debate since the inhibitors of plaque formation failed. There's been a lot of debate. Did we get this all wrong? Is this what we call an epiphenomenon? Coincidental? I'd say the field right now still has somebody in it that says yeah, let's forget about plaques and tangles. But almost everybody that I know that studies this area feels that plaques and tangles are the end product that results in nerve deaths.
Rina Bogdanovic [34:31] Now, much of your research uses mice as models of disease, and they are the most frequently used animal. How accurately would you say that the mouse brain can replicate human disease?
Are Mice Good Models for Neurodegenerative Diseases?
Ronald Schnaar [34:42] The answer is sometimes yes and sometimes no. The brain is a pretty privileged site. We have lots of protection around it, from our skull of course, but even inside. We have membranes and a blood-brain barrier. And we really don't let pathogens get into our brains. So things have stayed pretty much the same over the course of evolution. So that, for instance, myelin-associated glycoprotein MAG, as I mentioned earlier, and its finding gangliosides, we were able to show that mice and humans have the same disorder, if the key molecules in that connection are missing, and it is the same. It's different in the immune system. It's different outside the brain. Microglia are part of the immune system. And even though it's different from the immune system between mice and men, why is that? Well, it turns out that over evolution, one of the biggest challenges to our survival has been our ability to fight pathogens, pathogens and we are having a war. And so we have immune systems that use glycans to drive immune responses. Eventually, pathogens learn that, they mimic our part of the immune glycan repertoire to change our response so they can get away with proliferating inside our bodies. So then we evolutionarily change over time, those of us that don't have the same sugars are less susceptible to those diseases and survive, to have families. And since between rodents and humans, there's been a lot of changes in glycans. And there's been changes in glycan binding proteins. We kind of have the same systems in place, but the details are different. Let me give you an example. We have a molecule on some of our immune cells called SIGLEC8, it controls our allergic responses and is involved in things like asthma, we discovered the sugar it binds to in the human airways. And mice don't have SIGLEC8, I mean, we don't use numbers for most of mice molecules like that. We call it Siglec-f. And when we look for molecules that bind SIGLEC8 in mouse airways, they don't exist. So between mice and humans, we've changed a lot in the immune system. So I gave a lecture once, entitled, mice aren't always men. So here's the story, for the most basic biological processes, like genes, like making proteins, we are like bacteria. So bacteria are good models. We’re like yeast, we’re like mice. So across species, we can do these studies. For other areas that have evolved more rapidly, like glycans, there are areas that are very different. And so just like I said, glycans and recognition in the brain are the same in mice and men. Glycans and recognition and allergic inflammation are different in mice and men. It has to be tested in every case.
The Challenge of Translating Research into Clinical Application
Rina Bogdanovic [38:40] Now, you said you were working with stem cells, and growing microglia in the lab. I'm curious when it comes to therapeutic potentials, how can our knowledge of currently what you've discovered about inhibitory signalling in microglia in Alzheimer's disease, how can this be used for therapeutic purposes?
Ronald Schnaar [38:57] This is the dream. It's not a fantasy. There are actually companies thinking about this now, it's just the beginning. But here's the way it works in microglia. Microglia have sugar-binding protein on their surface. It's not doing anything. And the microglia are going around collecting trash. They come into contact with a particular sugar that we identified in the human brain. And now it says stop, put the brakes on. So what can we do about that? Well, if we know this exact shape, and how it fits, we could maybe make something small enough to deliver to your brain that instead of this going in, this small thing sticks in it. It doesn't signal. It just blocks it. And now it's like this wasn't even there. And your microglia says - Okay, there's nothing stopping us, we're gonna go pick up the trash. That's the fantasy of this. There are many steps yet to prove it. At the cell level, can we actually manipulate the ability of microglia to phagocytose stuff that eats the trash? And we do this by having microglia in a petri dish, and we give them tiny fluorescent particles or even fluorescent plaque. And we looked at them under the microscope over time, and we watched them gobbling it up.
Challenges of Drug Delivery to the Brain
Rina Bogdanovic [40:45] Now, you've mentioned the levels of protection of the brain. So could you maybe explain a bit further for our listeners - what are the main challenges when it comes to drug delivery to the brain?
Ronald Schnaar [40:57] Actually, there are two ways that we can deliver drugs to the brain, the reasonable way and the very difficult way. The reasonable way is, if you eat something, it goes into your bloodstream, or you inject it into your vein, and it goes into your bloodstream, and then it spontaneously moves across the membranes called the blood-brain barrier. And this happens, some molecules have the properties appropriate to make it to the brain, and others don’t. So part of pharmacology, part of drug development, is working on shapes and additions to molecules, to get them to be just the right flavour, to move into the brain. The other way we can deliver things to the brain is to implant a pump and pump it right into your spinal cerebral spinal fluid. That's highly unusual. And that kind of approach, for example, might be used in acute spinal cord injury, to deliver drugs to the site of injury inside the blood-brain barrier, where you're going to just treat for, you know, a month or three months and then withdraw the treatment.
The Future of Glycan Biomarkers of Alzheimer's Disease
Rina Bogdanovic [42:23] Now, when it comes to the work that's been done on biomarkers of Alzheimer's disease, what role do glycans play there? Is there much work when it comes to glycan research in that area?
Ronald Schnaar [42:35] It's just the very beginning. There's a lot of work going on in glycan biomarkers, you may know, that's been in cancer. And that's because cancer cells early on were realised to have different glycans on their surface. So there's been a lot of investment worldwide in research of blood glycans and how they relate to cancer development. So the technology is there to do that. There's even in the United States, a group called the Alliance of Glycobiologists funded by the National Institutes of Health to do just that in cancer. So now that people are looking for markers in Alzheimer's disease, that same approach that's been developed over the years can be applied. Early days.
Rina Bogdanovic [43:40] Especially as we've mentioned, Alzheimer's develops over decades.
Ronald Schnaar [43:43] Yes, right.
Rina Bogdanovic [43:45] In an ideal scenario, you can detect it 20-30 years before you develop symptoms.
Ronald Schnaar [43:49] Wouldn’t that be great? I think that the likelihood. So the other aspect of this is that, as I mentioned, changes in the CD33 gene, are associated with an enhanced likelihood of Alzheimer's. It isn’t an on-off switch, it makes them more susceptible. And now each and every one of us can get our whole genome sequenced. And many of those genes, hundreds of 1000s of them are involved in making glycans, or in protein, they recognise glycans. So that's another way we can begin to look at this is - how about those glycan genes? Are those different? And if they're different in disease, what does that imply? What are the structures that are made by those genes? And is there something we can test and then just do something?
Rina Bogdanovic [44:50] I’m very optimistic but it's saddening to hear that it's still very early days. It's going to take a long time.
Ronald Schnaar [44:57] Yeah. I think that part of being a discovery biomedical researcher is a very high level of optimism. We are going to solve these problems, they're not going to get solved by themselves. As an international team, biomedical discovery researchers are working to get the knowledge that's going to lead to cures, we just have to have that faith. It's not a word used for science, but it's with faith, and optimism, that we are going to be successful. And we have, we have been for many diseases, we're doing much better now. My mother's having her 99th birthday party next month. So when we look back, there's been a lot of advances, we just have to have faith that we're going in the right direction, and we're gonna keep doing what we're doing.
Alzheimer’s Prevention: Sifting Fact from Fiction in Media Coverage
Rina Bogdanovic [45:58] If I'm not mistaken, it sounds like one of the best treatment options for Alzheimer's will be prevention in the long run. What are the preventative measures that are currently available for Alzheimer's?
Ronald Schnaar [46:09] Oh, none. Unfortunately. If we knew those, we'd all be doing it. And yeah, I know that I get my news feed too, I get those tips that if you eat this, or if you sleep on this side of the bed, you're less likely to get Alzheimer's. But frankly, there are no treatments that changed the course of Alzheimer's at this time. And there are lots of people interested in this terrible disease as well as other neurodegenerative diseases. And we have to take the longer view on that as scientists say, we're gonna dig, dig, dig.
Rina Bogdanovic [46:55] Thank you for opening the topic regarding media, and maybe even some bad science being promoted or fake news regarding Alzheimer's. So for our listeners, who are maybe reading these types of articles and are struggling to distinguish between what is real and what is just done for clickbait, could you maybe give some advice on that?
Ronald Schnaar [47:19] Yeah, you have to go to a reliable source. And knowing what that is, isn't always easy. But there are reliable sources. So at our level, quality science is judged by our peers, and other scientists in the area, and then published in reputable journals, but how do you know what reputable journals are? These are collected by organisations that have the expertise on hand to know what's real and what's not. In your area of the world, there are Alzheimer's Associations, in the US called the Alzheimer's Association, as well as national sources, like the National Institute of Health in the United States. And certain high-level media-connected research institutions have put out newsletters. And they have the expertise on hand, people with high standards for evaluating science like you Rina, that look at the science and bring forward things that are real, and don't bring forward things that aren't. So if you read that rutabaga would cure Alzheimer's, and you go to the Alzheimer's information page at NIH, and there's nothing about rutabagas there, you know, it's not real. So over time, these things fall away. And the real stuff ends up being at these sites that you can trust. And so find those sites, if you're interested in potential. You know, the unfortunate thing is that even in our field, glycobiology, people will take advantage of those who are desperate. People who have a loved one with cancer. People who have a loved one they are losing to Alzheimer's disease. And that Desperation can lead to a mindset of - I'll try anything. And there are organisations out there that are happy to take your money and they'll send you a package of anything. And it can give you some hope over the short term. But unless it's been tested, tried and true, it's a waste of money. And I would avoid those, that would appear like good opportunities.
Rina Bogdanovic [50:24] Frequently I see on social media articles about certain types of vegetables that help you prevent Alzheimer's. I think it's just very important for our listeners to understand that these studies that would need to be conducted for this to be scientifically proven, would have to be longitudinal over decades. And nothing, as far as I know, has been done in that area.
Ronald Schnaar [50:47] Yeah. And I think that those tips go under the category of it can't hurt.
Rina Bogdanovic [50:52] Yeah.
Ronald Schnaar [50:55] Sure, eat more vegetables. Now, you know, some of these things can hurt. Dan Hurley wrote a book called Natural Causes, talking about so-called nutraceuticals, some of which can actually hurt you. So you really got to be careful. Easy access, sometimes you just kind of pay a lot of money. And they either do nothing or can be harmful.
Ronald’s Future Research Plans and Focus
Rina Bogdanovic [51:27] I think we're nearing the end of our conversation. So I want to focus now on asking you what are your current goals in your future research. What is going to come out of your lab?
Ronald Schnaar [51:42] So there are two interacting areas that overlap that we're really interested in. One is going deeper into the structures, the glycan structures that are driving these changes. And the two areas that we're thinking about are, as I mentioned earlier, allergic inflammation, microglia, and Alzheimer's, those are the two areas we're working on. And in both those areas, we have the capability of deconstructing the molecules we get from human airways, or the human brain, and breaking them down to their minimum active components, and determining exactly what that structure is. And if we're going to be able to build deliverable molecules for therapeutics, that's one thing. So when we get those in my laboratory, what do we do with them? As I mentioned, we put them on microglia. We can’t do that in my laboratory, because we don't have the capability. But we collaborate with a group in Chicago that isolates fresh, allergic immune cells, from their patients in their Clinical Immunology division, and we send them these molecules, and they test them on those cells. So that's the combination, find structures that we can identify, and then put them on cells that matter. And, that's all preclinical work. Unfortunately, we really can't do that in rodents, because they don't have the same glycans. And like in binding proteins, as humans, we have to go after human tissues and human cells. So that's where we're aiming in the next - That's our five-year plan. That's me knocking on wood for good luck.
Rina Bogdanovic [53:49] I will certainly be very excited to see what new research you bring out. I'm curious, do you consider any other animal models besides mice for this research?
Ronald Schnaar [54:01] I don't personally. Certainly, there are primate models that can better replicates not perfectly replicate the glycan repertoire of humans. It turns out, even though the great apes are our closest cousins, evolutionarily, there have been some major changes in glycobiology, especially with the cyclic acids that are involved in our recognition. There was a big change about half a million years ago, where we just went our own way.
Rina Bogdanovic [54:44] And so to conclude this conversation, do you have a final message that you would like to say for our listeners?
Ronald’s Final Message to Our Listeners
Ronald Schnaar [54:51] I think that first of all, let me say that the world of glycans and their functions, as in human physiology, and human disease is really advancing rapidly. I think there are going to be new discoveries and action taken on old discoveries that are going to help out in lots of immune diseases and cancer, maybe neurodegenerative diseases, but glycans are everywhere. And that we are working hard as an international community to discover, to the extent that we can build up that infrastructure to keep the discovery moving forward. We're enthusiastic about it. And we hope that the resources that come in to further this enterprise are maintained and we can continue in the next generation of scientists, and the next can continue to make these discoveries important to the health of you and your families, me and my family for that.
Rina Bogdanovic [56:11] Thank you, Ron. It was really nice talking to you.
Ronald Schnaar [56:13] Great talking with you too Rina. Take care.
Rina Bogdanovic [56:15] I hope this conversation helped you better appreciate the sheer complexity of Alzheimer’s disease. I also hope that you are not leaving this episode disheartened, but rather encouraged by the collaborative effort of scientists and clinicians worldwide to develop better diagnostic methods, more effective treatment options and potentially, one day, a cure. If you would like to access more information about this conversation and Ron’s previous work, follow the link in the description to the show notes for this episode. Equally, if you want to find out more about GlycanAge, head on to glycanage.com where you can access a whole list of our scientific publications, blog posts, testimonials and of course this is where you can order your GlycanAge test kit. Watch out for our next episode where I will be joined by Gordan Lauc, I believe this will be his third time on our podcast. Gordan is a Professor of Biochemistry and Molecular Biology at the University of Zagreb, his research focuses on IgG glycans, particularly in the context of chronic inflammation and biological age. We will discuss what glycan studies can tell us about COVID-19 symptoms and recovery. Please don't forget to leave ratings and reviews for this episode and engage with us on social media. Thank you for listening and have a great day.
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