*Please note this interview’s responses are paraphrased responses.
Introduction
Dr. Edward Glasscock, Ph.D., runs the Glasscock Lab at Southern Methodist University. Dr. Glasscock received his Ph.D. from the University of California, Berkeley and completed his medical training at the Baylor College of Medicine. The Glasscock Lab at SMU explores the fascinating field of cardiorespiratory neurogenetics by exploring the genes and mechanisms that underlie epilepsy and Sudden Unexpected Death in Epilepsy (SUDEP). The Glasscock Lab's research involves utilizing genetic mouse models of epilepsy, pharmacology, histology, molecular analysis, and a wide array of in vivo, ex vivo, and in vitro electrophysiological techniques.
Dr. Glasscock, I'd like to begin our interview with the question of how did your interest in pursuing research that explores the genes and mechanisms underlying epilepsy and Sudden Unexpected Death in Epilepsy (SUDEP) begin, and how has it developed over the years?
Dr. Glasscock mentions that in college, he found that he was fascinated by the concept of a single genetic change causing disease. This fascination soon defined an experience at one of his lab rotations at UC Berkeley. He expressed that the lab's interest involved studying genetic modifiers of seizure susceptibility. Essentially, the lab's work aimed to answer the question of how gene mutations interact with one another to make disease more or less harmful. Dr. Glasscock centered his Ph.D. studies around this very concept and soon observed an incredible finding in Drosophila melanogaster flies that provided the inspiration and basis for the Glasscock Lab's research today.
Dr. Glasscock outlined the experiment's results involving Drosophila Melanogaster flies and mentioned how intriguing it was that a gene mutation in one fly suffering from seizures could be suppressed by introducing a second mutation. He mentioned this finding essentially conveyed the concept that two genetic wrongs can produce a right.
Dr. Glasscock spoke about his time conducting his post-doctoral research at Baylor College of Medicine, where he completed additional research pertaining to this topic of genetic modifications impacting disease, utilizing mouse models as opposed to Drosophila flies. The first project Dr. Glasscock was involved in consisted of taking mice with a calcium channel mutation resulting in non-convulsive seizures and breeding them with mice that carried a potassium channel mutation which produced convulsive seizures (generalized tonic-clonic seizures) that often resulted in death. He conveyed the incredible finding he came across as he mentioned that the double mutant mice carrying both mutations had significantly fewer seizures that were no longer lethal. Essentially, the double-mutant mice fared better regarding seizure severity and death due to seizures. Based on these findings, Dr. Glasscock wondered what was causing mice to die from seizures, and this question introduced the concept of Sudden Unexpected Death in Epilepsy (SUDEP) into his work. He postulated the question of what genetic interactions predispose individuals to be at risk for seizures resulting in death. To further explore this question, Dr. Glasscock began studying and recording the heart's activity in the same potassium channel mutant mice, which exhibit seizure-related death. He conducted this experiment in order to observe if any cardiac dysfunction was present during the interictal (i.e., non-seizure) period and during seizures.
At the end of his postdoctoral training, Dr. Glasscock transitioned to an assistant professor faculty position at the Louisiana State University Health Sciences Center, where he constructed his lab around studying brain and heart dysfunction that possibly predisposes individuals to die from seizure-related death. Additionally, he decided that a study of respiratory function in mouse models was essential to his research involving seizure activity, explaining how breathing and cardiac activity are interconnected. Alongside monitoring heart activity, Dr. Glasscock began combining them with simultaneous breathing measurements in mice as well. These in vivo recordings of heart and brain activity were collected by implanting electrodes in the mice, and the respiratory function of mice was monitored using whole-body plethysmography, a technique that involves placing the animals in airtight chambers and recording their respiratory waveforms by measuring the micro pressure changes associated with inhalation and exhalation.
Dr. Glasscock expressed that he wanted to explore further how these organ systems of the heart, brain, and lungs talk to one another and where failure or defects occur in that communication, leading to Sudden Unexpected Death in Epilepsy.
Now, the Glasscock Lab has developed new genetically modified mouse strains that enable the introduction of gene mutations in a tissue-specific fashion for the purpose of identifying that tissue's contribution to dysfunction. Essentially, these mouse strains, termed conditional gene knockouts, allow for selective disruption of a gene in a particular organ or cell type while preserving normal gene expression elsewhere. Utilizing conditional gene knockout strategies in mice, Dr. Glasscock's Lab selectively deletes genes in the brain, heart, and lungs and observes how the tissue and organ systems' functions and communications are affected in relation to these anatomically restricted mutations. This explanation leads to the groundbreaking research the Glasscock Lab conducts and the next topic of our interview.
Dr. Glasscock, your lab also focuses on better understanding how epilepsy can alter the brain's control of cardiorespiratory function, thus increasing the risk of SUDEP. How has your research in this specific area of Cardiorespiratory Neurogenetics helped you better understand the general patterns and mechanisms underlying the area of Cardiorespiratory Neurogenetics as a whole?
Dr. Glasscock remarked that regarding the study of seizures, many focus on the brain and heart's interactions. With this focus in mind, Dr. Glasscock explained how he soon found that harmful and potentially lethal cardiac arrhythmias were occurring during seizures, noting how seizures can cause detrimental cardiac patterns. To connect the respiratory function component to this finding, Dr. Glasscock also began to develop methods that allowed him to measure breathing measurements in mice during seizures. He found that the seizure-related cardiac arrhythmias he had previously observed were always preceded by respiratory abnormalities, suggesting breathing dysregulation could be triggering the cardiac dysfunction during seizures. This series of experiments and studies contributed to the overall concept of studying the relationship between the brain, heart, and lungs during seizures, an area of research which Dr. Glasscock's Lab has continued to explore.
Dr. Glasscock mentioned that his lab utilizes Kcna1 conditional knockout (cKO) mice, which deletes the Kcna1 gene in tissue- or organ-specific patterns. The Kcna1 gene encodes the voltage gated Kv1.1 potassium channel alpha subunit protein, the same potassium channel targeted in Dr. Glasscock’s aforementioned experiments. The lack of Kv1.1 globally (i.e., throughout the body) produces frequent tonic-clonic seizures, which end up being lethal in about 75% of animals. One of the main strategies of the Glasscock Lab involves using cKO approaches to selectively delete Kcna1 in the heart, brain, or lung organ systems of mice. This strategy helps the lab understand the implications of these genetic modifications on the neuro, cardiac, and respiratory systems in mice prone to severe tonic-clonic seizures.
One of the many incredible aspects of research is the ability to find new discoveries amidst a discovery currently being explored. What are some avenues of cardiorespiratory neurogenetics research you feel your lab's work is paving the way for? Would you mind sharing some studies or findings from your lab's work that encapsulate the context of this question?
Dr. Glasscock remarks that the impact generated from studying the relationship between these organ systems in relation to SUDEP and seizures centers around identifying new therapeutic approaches for preventing SUDEP as well as providing new diagnostic measures to better predict the risk of SUDEP. Dr. Glasscock explained an interesting finding his lab came across, which revealed a functional disconnect between the brain and heart activity in mice that experience seizures due to global KO of the Kcna1 gene. He expressed that this finding was surprising, as he had expected that mice that were predisposed to dying from seizures would have an overactive brain and heart connection; instead, they found the opposite. Additionally, Dr. Glasscock explained that his studies analyzing the communication between the brain, heart, and lungs in his SUDEP-prone mice have led to the observation that the most significant abnormality exists in the pathway of the heart's flow of information to the brain. Essentially, the greatest defect in brain-heart-lung communication in SUDEP-prone mice appears to be in the afferent sensory pathway of the heart to the brain, which shows greatly reduced information flow, rather than the efferent motor pathway of the brain to the heart. Moreover, Dr. Glasscock found that there is enhanced communication from the brain to the lungs prior to seizures occurring, suggesting a possible measure that could be used to predict seizure onset.
Dr. Glasscock expresses that these patterns his lab has observed in Kcna1 mice KO represent potential patterns underlying SUDEP in patients, as the mice are viewed as a valuable preclinical model of human SUDEP recapitulating the essential core features of SUDEP in humans. These observations of enhanced communication between the lungs and brain and an absence of communication between the heart and the brain are examples of discoveries that have allowed Dr. Glasscock's Lab to further explore, anatomically and physiologically, where the primary defects in SUDEP-prone Kcna1 KO mice present in the body.
Another interesting finding from Dr. Glasscock's Lab showcases that the potassium channel mutant gene responsible for producing tonic-clonic seizures in these mice is present in the heart as well as the brain. When Dr. Glasscock began studying Kv1.1 more than ten years ago, it was widely presumed that the potassium channels were present in the brain but not in the heart. In addition to detecting Kcna1 gene expression in the heart by various methods, Dr. Glasscock’s lab used a variety of in vivo and in vitro electrophysiology techniques, observing that when this gene is deleted in the heart, an absence of function exists, resulting in changes in arrhythmia susceptibility and the production of abnormal cardiac action potentials.
In relation to the previous question, I'd also like to talk about your work identifying new therapeutics to prevent SUDEP and better biomarkers to predict that certain individuals are at high risk for SUDEP. How do you believe your research in these two areas will impact the field of preventive care regarding epilepsy and being high risk for SUDEP?
Dr. Glasscock mentions that he hopes his lab’s work will provide an idea of what organ system is driving SUDEP. Dr. Glasscock hopes these observations will help doctors recognize which organ system needs to be targeted for a therapeutic purpose. He explains that a collaborative project that his lab is currently exploring involves a mathematical analysis of communications between the brain, heart, and lungs, focusing specifically on the directionality of information flow between these systems. This type of analysis would allow identification of whether dysfunction leading to SUDEP occurs primarily in the direction of the brain to the lungs or in the direction of the lungs to the brain. Dr. Glasscock hopes this type of mathematical analysis will reveal biomarkers that can be used for surveillance to identify conditions that put patients at high risk for SUDEP. Additionally, he hopes these biomarkers serve to help better stratify long and short-term risks for SUDEP in epilepsy patients, allowing a better understanding of one's predisposition to SUDEP through their lifetime.
As our interview comes to a close, I'd like to focus our interview on the topic of the collaborative nature of research and research labs. A research lab presents a collaborative environment; often, lab members will work on their own independent projects that contribute different findings to the lab's overall focus. How do you believe the collaborative nature of research applies to your lab?
Dr. Glasscock expresses that he has organized his lab so that each member has an area of expertise that they can further explore and connect to the lab's overall focus. The beauty of this environment, he believes, exists in the creation of innovation at every corner of the lab, and these diverse, vast amounts of expertise present themselves as a helpful factor in allowing members to collaborate on projects to answer questions and reveal observations others might not have realized. The overlapping niches of knowledge presented in the Glasscock Lab create a narrative of collaborative innovation that helps propel the lab into new discoveries in the field of cardiorespiratory neurogenetics.
About the Author
Apurva Veeraswamy is a sophomore at Southern Methodist University concentrating in Biological Studies and Public/Global Health.
References
Edward Glasscock, Ph.D. SMU Dedman College of Humanities and Sciences.
https://www.smu.edu/Dedman/Academics/Departments/Biological-Sciences/People/Faculty/Edward-Glasscock
Glasscock, E. Research. Glasscock Lab. http://glasscock-lab.mozello.com/research/
Dr. Edward Glasscock, Ph.D., runs the Glasscock Lab at Southern Methodist University. Dr. Glasscock received his Ph.D. from the University of California, Berkeley and completed his medical training at the Baylor College of Medicine. The Glasscock Lab at SMU explores the fascinating field of cardiorespiratory neurogenetics by exploring the genes and mechanisms that underlie epilepsy and Sudden Unexpected Death in Epilepsy (SUDEP). The Glasscock Lab's research involves utilizing genetic mouse models of epilepsy, pharmacology, histology, molecular analysis, and a wide array of in vivo, ex vivo, and in vitro electrophysiological techniques.
Dr. Glasscock, I'd like to begin our interview with the question of how did your interest in pursuing research that explores the genes and mechanisms underlying epilepsy and Sudden Unexpected Death in Epilepsy (SUDEP) begin, and how has it developed over the years?
Dr. Glasscock mentions that in college, he found that he was fascinated by the concept of a single genetic change causing disease. This fascination soon defined an experience at one of his lab rotations at UC Berkeley. He expressed that the lab's interest involved studying genetic modifiers of seizure susceptibility. Essentially, the lab's work aimed to answer the question of how gene mutations interact with one another to make disease more or less harmful. Dr. Glasscock centered his Ph.D. studies around this very concept and soon observed an incredible finding in Drosophila melanogaster flies that provided the inspiration and basis for the Glasscock Lab's research today.
Dr. Glasscock outlined the experiment's results involving Drosophila Melanogaster flies and mentioned how intriguing it was that a gene mutation in one fly suffering from seizures could be suppressed by introducing a second mutation. He mentioned this finding essentially conveyed the concept that two genetic wrongs can produce a right.
Dr. Glasscock spoke about his time conducting his post-doctoral research at Baylor College of Medicine, where he completed additional research pertaining to this topic of genetic modifications impacting disease, utilizing mouse models as opposed to Drosophila flies. The first project Dr. Glasscock was involved in consisted of taking mice with a calcium channel mutation resulting in non-convulsive seizures and breeding them with mice that carried a potassium channel mutation which produced convulsive seizures (generalized tonic-clonic seizures) that often resulted in death. He conveyed the incredible finding he came across as he mentioned that the double mutant mice carrying both mutations had significantly fewer seizures that were no longer lethal. Essentially, the double-mutant mice fared better regarding seizure severity and death due to seizures. Based on these findings, Dr. Glasscock wondered what was causing mice to die from seizures, and this question introduced the concept of Sudden Unexpected Death in Epilepsy (SUDEP) into his work. He postulated the question of what genetic interactions predispose individuals to be at risk for seizures resulting in death. To further explore this question, Dr. Glasscock began studying and recording the heart's activity in the same potassium channel mutant mice, which exhibit seizure-related death. He conducted this experiment in order to observe if any cardiac dysfunction was present during the interictal (i.e., non-seizure) period and during seizures.
At the end of his postdoctoral training, Dr. Glasscock transitioned to an assistant professor faculty position at the Louisiana State University Health Sciences Center, where he constructed his lab around studying brain and heart dysfunction that possibly predisposes individuals to die from seizure-related death. Additionally, he decided that a study of respiratory function in mouse models was essential to his research involving seizure activity, explaining how breathing and cardiac activity are interconnected. Alongside monitoring heart activity, Dr. Glasscock began combining them with simultaneous breathing measurements in mice as well. These in vivo recordings of heart and brain activity were collected by implanting electrodes in the mice, and the respiratory function of mice was monitored using whole-body plethysmography, a technique that involves placing the animals in airtight chambers and recording their respiratory waveforms by measuring the micro pressure changes associated with inhalation and exhalation.
Dr. Glasscock expressed that he wanted to explore further how these organ systems of the heart, brain, and lungs talk to one another and where failure or defects occur in that communication, leading to Sudden Unexpected Death in Epilepsy.
Now, the Glasscock Lab has developed new genetically modified mouse strains that enable the introduction of gene mutations in a tissue-specific fashion for the purpose of identifying that tissue's contribution to dysfunction. Essentially, these mouse strains, termed conditional gene knockouts, allow for selective disruption of a gene in a particular organ or cell type while preserving normal gene expression elsewhere. Utilizing conditional gene knockout strategies in mice, Dr. Glasscock's Lab selectively deletes genes in the brain, heart, and lungs and observes how the tissue and organ systems' functions and communications are affected in relation to these anatomically restricted mutations. This explanation leads to the groundbreaking research the Glasscock Lab conducts and the next topic of our interview.
Dr. Glasscock, your lab also focuses on better understanding how epilepsy can alter the brain's control of cardiorespiratory function, thus increasing the risk of SUDEP. How has your research in this specific area of Cardiorespiratory Neurogenetics helped you better understand the general patterns and mechanisms underlying the area of Cardiorespiratory Neurogenetics as a whole?
Dr. Glasscock remarked that regarding the study of seizures, many focus on the brain and heart's interactions. With this focus in mind, Dr. Glasscock explained how he soon found that harmful and potentially lethal cardiac arrhythmias were occurring during seizures, noting how seizures can cause detrimental cardiac patterns. To connect the respiratory function component to this finding, Dr. Glasscock also began to develop methods that allowed him to measure breathing measurements in mice during seizures. He found that the seizure-related cardiac arrhythmias he had previously observed were always preceded by respiratory abnormalities, suggesting breathing dysregulation could be triggering the cardiac dysfunction during seizures. This series of experiments and studies contributed to the overall concept of studying the relationship between the brain, heart, and lungs during seizures, an area of research which Dr. Glasscock's Lab has continued to explore.
Dr. Glasscock mentioned that his lab utilizes Kcna1 conditional knockout (cKO) mice, which deletes the Kcna1 gene in tissue- or organ-specific patterns. The Kcna1 gene encodes the voltage gated Kv1.1 potassium channel alpha subunit protein, the same potassium channel targeted in Dr. Glasscock’s aforementioned experiments. The lack of Kv1.1 globally (i.e., throughout the body) produces frequent tonic-clonic seizures, which end up being lethal in about 75% of animals. One of the main strategies of the Glasscock Lab involves using cKO approaches to selectively delete Kcna1 in the heart, brain, or lung organ systems of mice. This strategy helps the lab understand the implications of these genetic modifications on the neuro, cardiac, and respiratory systems in mice prone to severe tonic-clonic seizures.
One of the many incredible aspects of research is the ability to find new discoveries amidst a discovery currently being explored. What are some avenues of cardiorespiratory neurogenetics research you feel your lab's work is paving the way for? Would you mind sharing some studies or findings from your lab's work that encapsulate the context of this question?
Dr. Glasscock remarks that the impact generated from studying the relationship between these organ systems in relation to SUDEP and seizures centers around identifying new therapeutic approaches for preventing SUDEP as well as providing new diagnostic measures to better predict the risk of SUDEP. Dr. Glasscock explained an interesting finding his lab came across, which revealed a functional disconnect between the brain and heart activity in mice that experience seizures due to global KO of the Kcna1 gene. He expressed that this finding was surprising, as he had expected that mice that were predisposed to dying from seizures would have an overactive brain and heart connection; instead, they found the opposite. Additionally, Dr. Glasscock explained that his studies analyzing the communication between the brain, heart, and lungs in his SUDEP-prone mice have led to the observation that the most significant abnormality exists in the pathway of the heart's flow of information to the brain. Essentially, the greatest defect in brain-heart-lung communication in SUDEP-prone mice appears to be in the afferent sensory pathway of the heart to the brain, which shows greatly reduced information flow, rather than the efferent motor pathway of the brain to the heart. Moreover, Dr. Glasscock found that there is enhanced communication from the brain to the lungs prior to seizures occurring, suggesting a possible measure that could be used to predict seizure onset.
Dr. Glasscock expresses that these patterns his lab has observed in Kcna1 mice KO represent potential patterns underlying SUDEP in patients, as the mice are viewed as a valuable preclinical model of human SUDEP recapitulating the essential core features of SUDEP in humans. These observations of enhanced communication between the lungs and brain and an absence of communication between the heart and the brain are examples of discoveries that have allowed Dr. Glasscock's Lab to further explore, anatomically and physiologically, where the primary defects in SUDEP-prone Kcna1 KO mice present in the body.
Another interesting finding from Dr. Glasscock's Lab showcases that the potassium channel mutant gene responsible for producing tonic-clonic seizures in these mice is present in the heart as well as the brain. When Dr. Glasscock began studying Kv1.1 more than ten years ago, it was widely presumed that the potassium channels were present in the brain but not in the heart. In addition to detecting Kcna1 gene expression in the heart by various methods, Dr. Glasscock’s lab used a variety of in vivo and in vitro electrophysiology techniques, observing that when this gene is deleted in the heart, an absence of function exists, resulting in changes in arrhythmia susceptibility and the production of abnormal cardiac action potentials.
In relation to the previous question, I'd also like to talk about your work identifying new therapeutics to prevent SUDEP and better biomarkers to predict that certain individuals are at high risk for SUDEP. How do you believe your research in these two areas will impact the field of preventive care regarding epilepsy and being high risk for SUDEP?
Dr. Glasscock mentions that he hopes his lab’s work will provide an idea of what organ system is driving SUDEP. Dr. Glasscock hopes these observations will help doctors recognize which organ system needs to be targeted for a therapeutic purpose. He explains that a collaborative project that his lab is currently exploring involves a mathematical analysis of communications between the brain, heart, and lungs, focusing specifically on the directionality of information flow between these systems. This type of analysis would allow identification of whether dysfunction leading to SUDEP occurs primarily in the direction of the brain to the lungs or in the direction of the lungs to the brain. Dr. Glasscock hopes this type of mathematical analysis will reveal biomarkers that can be used for surveillance to identify conditions that put patients at high risk for SUDEP. Additionally, he hopes these biomarkers serve to help better stratify long and short-term risks for SUDEP in epilepsy patients, allowing a better understanding of one's predisposition to SUDEP through their lifetime.
As our interview comes to a close, I'd like to focus our interview on the topic of the collaborative nature of research and research labs. A research lab presents a collaborative environment; often, lab members will work on their own independent projects that contribute different findings to the lab's overall focus. How do you believe the collaborative nature of research applies to your lab?
Dr. Glasscock expresses that he has organized his lab so that each member has an area of expertise that they can further explore and connect to the lab's overall focus. The beauty of this environment, he believes, exists in the creation of innovation at every corner of the lab, and these diverse, vast amounts of expertise present themselves as a helpful factor in allowing members to collaborate on projects to answer questions and reveal observations others might not have realized. The overlapping niches of knowledge presented in the Glasscock Lab create a narrative of collaborative innovation that helps propel the lab into new discoveries in the field of cardiorespiratory neurogenetics.
About the Author
Apurva Veeraswamy is a sophomore at Southern Methodist University concentrating in Biological Studies and Public/Global Health.
References
Edward Glasscock, Ph.D. SMU Dedman College of Humanities and Sciences.
https://www.smu.edu/Dedman/Academics/Departments/Biological-Sciences/People/Faculty/Edward-Glasscock
Glasscock, E. Research. Glasscock Lab. http://glasscock-lab.mozello.com/research/
