In Memoriam: Gary Mawe

Abstract

Dr Gary M. Mawe

Professor of Neurological Sciences

University of Vermont

1956–2024

On 17 February 2024, the field of enteric neuroscience lost a highly respected colleague, mentor and friend. Dr. Gary M. Mawe, PhD, Professor of Neurological Sciences at the University of Vermont Larner College of Medicine, passed away peacefully after a long illness.

Gary was an internationally renowned neurobiologist who devoted his career to the study of the gastrointestinal (GI) system. His unquenchable curiosity and enthusiasm for both science and life led him to pursue numerous interests and passions. His pioneering studies of the neural mechanisms regulating gallbladder motor function, enteroendocrine serotonin signalling in health and disease, and inflammatory neuroplasticity of the enteric nervous system were recognized and praised by the scientific community.

Gary's work was continuously funded by the National Institutes of Health (NIH) for his entire research career. Over his distinguished career, he published more than 130 peer-reviewed primary scientific articles and coauthored more than 14 review articles and chapters, including those published in Nature Reviews Gastroenterology & Hepatology (Mawe & Hoffman, 2013; Spohn & Mawe, 2017) and Journal of Clinical Investigation (Mawe, 2015), that have become central references in understanding gastrointestinal autonomic biology. The comprehensive review of the enteric nervous system (Sharkey & Mawe, 2023) written with his collaborator of over 20 years, Dr. Keith Sharkey, will certainly stand as his Magnum Opus. This project started in the Fall of 2019 when Keith was on sabbatical leave in Vermont. Although Gary was unwell at the time of writing this article, his fascination in the field remained as strong then as it ever was, and he enjoyed the hours of discussion it generated. Gary was extremely proud of his publications and worked very hard to ensure impactful comprehensive work. This virtual issue of The Journal of Physiology compiles all of the published work. Gary aimed for his primary research to be submitted and published in The Journal of Physiology and each of these manuscripts beautifully illustrates his lasting impact on the field of gastrointestinal physiology.

Gary received numerous awards recognizing his contribution to the field, including the Janssen Award for Basic Research in Gastrointestinal Motility in 1996, the Basmajian/Williams & Wilkins Award of the American Association of Anatomists in 1997 and the University Scholar Award, Graduate College, The University of Vermont in 2003. In 2023, he received the American Neurogastroenterology and Motility Society Dodds-Sarna Award, honouring an investigator who made major contributions to the field of Neurogastroenterology and Motility.

At the time of his death, Gary was the Samuel Thayer Professor of Neurological Sciences and Adjunct Professor of Pharmacology and of Medicine, at the University of Vermont where he was also the director of the anatomical gift program. He was also adjunct professor of Physiology and Pharmacology at the University of Calgary, and adjunct professor Adjunct Professor of Anatomy, Biochemistry and Physiology at the University of Hawaii.

Gary grew up in Pittsburgh with his seven brothers and sisters and was a dedicated Steelers fan. He received a BSc in Biology from Penn State University, although he joked his true major was Nitty Lion football. After a year as a research assistant in the laboratory of Dr. William C. DeGroat at the University of Pittsburgh, he began his PhD at Ohio State University under the supervision of Jacqueline Bresnahan and Michael Beattie and graduated in 1984. During these years, he gained strong training in the anatomy of the autonomic nervous system.

Gary pursued his postdoctoral studies under the mentorship of Dr. Michael Gershon in the Department of Anatomy and Cell Biology at Columbia University College of Physicians and Surgeons in New York City where he launched his career studying the enteric nervous system. During this period, his draw to the physiological sciences was finally fulfilled when he learned sharp electrode intracellular electrophysiology. He supplemented his training at Columbia with a strong interaction with many trainees in the laboratory of Dr. Jackie Wood at the Ohio State University, including Dr. Michael Schemann. Merging anatomical, pharmacological and physiological approaches to define the function of the enteric nervous system became the approach that defines his career. He used this approach first to study serotonin. When investigating the actions of serotonin in enteric ganglia, he made the novel discovery that enteric neurons express more than one type of serotonin receptor, which led to the development of new drugs for the treatment of disorders of brain–gut interaction (Mawe et al., 1986). It is also when he was at Columbia University that Gary began his work on the gallbladder (Mawe & Gershon, 1989), a niche from which he launched a successful independent career.

With his NIH FIRST Award in hand, Gary joined the Department of Anatomy and Neurobiology at the University of Vermont (UVM) in 1988. On his drive to Vermont, he found himself in the middle of a small-town 4th of July parade between the trucks and the bands. In a fashion unique to Gary, he waved to the crowd knowing that he had found his new home.

Gary had three major research directions over the span of his career, all of which produced significant findings that have shaped the field of neurogastroenterolgy and motility.

After his move to UVM, Gary worked hard to establish himself as an independent scientist. It was a productive period for his lab with a series of influential papers on the neurophysiology of the gallbladder. Gary's first studies focused on the neurochemical, electrical or synaptic properties of gallbladder and sphincter of Oddi neurons and the ionic properties of gallbladder smooth muscle. He was particularly proud of three landmark single author manuscripts he published in The Journal of Physiology (Mawe, 1990; Mawe, 1991; Mawe, 1993). Using a combination of intracellular and voltage clamp recordings and immunohistochemistry in wholemount guinea pig gallbladder, he was able to determine that all gallbladder neurons received nicotinic input from vagal preganglionic fibres, and that hormonal cholecystokinin and norepinephrine from postganglionic fibres acts presynaptically on vagal fibres to respectively increase or decrease cholinergic release from vagal terminals (Cornbrooks et al., 1992; Gokin et al., 1996; Guarraci et al., 2002; Hemming et al., 2000; Hillsley et al., 1998; Jennings & Mawe, 1998; Mawe & Ellis, 2001; Mawe et al., 1997; Mawe et al., 1994; Talmage & Mawe, 1993; Talmage et al., 1996; Talmage et al., 1992). He expanded his program to investigate neural control of the sphincter of Oddi and biliary tree and discovered co-ordinated neural control of the sphincter from the gallbladder and duodenum (Ellis & Mawe, 2003; Gokin et al., 1997; Hillsley & Mawe, 1998; Kennedy & Mawe, 1998; Kennedy et al., 2000; Manning & Mawe, 2001; Mawe & Kennedy, 1999; O'Donnell et al., 2001; Talmage et al., 1997; Wells & Mawe, 1994; Wells & Mawe, 1993; Wells et al., 1995). In addition to his studies of various inputs to the neurons in gallbladder and duodenal ganglia, Gary also started to investigate the properties of the gallbladder smooth muscle (Balemba et al., 2008; Balemba et al., 2006; Bartoo et al., 2008; Lavoie et al., 2010; Parr et al., 2003; Petkov et al., 2005; Pozo et al., 2002) and interstitial cell of Cajal-like cells (Lavoie et al., 2007). Work from his lab also showed that, contrary to conventional wisdom, gallbladder muscle dysfunction precedes, and probably contributes to, the onset of inflammation during the development of gallstone disease (Lavoie et al., 2012). The purple elements of Fig. 1 were all characterized in publications by Gary and his group a.k.a. the Green Mountain Gallbag Company.

Although Gary consciously moved away from serotonin in his early independent career, that changed the day a postdoctoral trainee grabbed serotonin from the refrigerator to test its effects on guinea pig sphincter of Oddi neurons (Hillsley & Mawe, 1998). This small action assured Gary that it was okay to work with serotonin again and opened the flood gates to a research pursuit focused on the pathophysiological changes in neuroepithelial serotonin signalling. In his renewed foray into serotonin, he was not alone, but instead embarked in one of his longest and strongest collaborations with Dr Keith Sharkey of the University of Calgary. They used animal models of intestinal inflammation to investigate changes in mucosal serotonin signalling and took those finding to study serotonin signalling in human digestive diseases, including inflammatory bowel disease and irritable bowel syndrome. Gary studied the distribution and functions of serotonin receptors that are targeted in therapies for irritable bowel syndrome and showed that a common effect in digestive disease is a downregulation of the serotonin selective reuptake transporter (Coates et al., 2004; Costedio et al., 2008; Costedio et al., 2010; Faure et al., 2010; Linden et al., 2003). While Gary was trying to understand the mechanisms responsible for these changes, he also investigated novel treatment strategies that could alleviate the symptoms of motor dysfunctions and dysmotility. Gary and his collaborators discovered that serotonin type 4 (5-HT4) receptors are expressed in the epithelium of the colon, and that luminally restricted 5-HT4 agonists accelerates recovery from colitis, reduces visceral hypersensitivity, and has a protective action in the normal and inflamed colon (Hoffman et al., 2012; Hurd et al., 2023; Konen et al., 2021; Mawe et al., 2022; Spohn et al., 2016). More recently, Gary's work emphasized on how intestinal microbes can affect serotonin signalling and potentially modulate central nervous system responses including behaviour by exploiting the tryptophan-synthesizing properties of certain bacteria, as well as the powerful properties of tryptophan metabolites (Legan et al., 2022; Legan et al., 2023). Clinically translational studies represent a key part of Gary's scientific legacy in GI disease. He was one of those rare basic scientists who was able to develop a common language with clinicians to enable successful collaborations.

Collaborations with Gary were not only fun, but also very productive, as proven by his work with his longtime friend Keith Sharkey. Together with their combined teams, they evaluated how the reflex circuits in the intestines change in response to intestinal inflammation (Gulbransen et al., 2012; Hoffman et al., 2011; Hons et al., 2009; Hons et al., 2012; Krauter et al., 2007; Krauter et al., 2007; Linden et al., 2003; Linden et al., 2004; Linden et al., 2005; Lomax et al., 2005; Lomax et al., 2007; Roberts et al., 2013; Strong et al., 2010). These studies provided a detailed description of the various changes in enteric neurons that occur during periods of intestinal inflammation, including neuronal hyperexcitability, enhanced fast synaptic neurotransmission and altered neuromuscular transmission (Fig. 2). Importantly, they discovered that many of the inflammation-induced changes persist beyond the recovery of inflammation implicating neuroplasticity as a strong potential contributor to dysfunction in functional bowel disorders.

Gary's excitement for science and life was contagious. He was a distinguished and brilliant scientist yet a humble and kind man who treated his mentees as equals. He was generous of his time and genuinely enjoyed sitting with his students or postdocs at the electrophysiology setup or at the fluorescence microscope. His explanations of what they were seeing would be marked by some laughs, a slap on the shoulder and a ‘Cool, huh?’. Once he would find the answer to his quest, whether it being the perfect recording or fluorescent cell, he would cheer the room with his classic ‘Now we are cooking with gas’. Sitting with Gary at his computer to discuss results, write manuscripts or grants and develop new ideas was another truly stimulating experience. Gary had a gift to distill advanced concepts into their simple elements. A model mentor, he made sure members of his ‘team’ enjoyed working together and cared for each other.

He was an outstanding mentor to over 90 undergraduate and graduate students, postdoctoral fellows, medical and surgical residents, and clinical fellows. Under his supervision, each student contributed to make important discoveries in the field of enteric neurosciences. He never stopped standing by his mentees. Once you entered Gary's lineage, you became an important part of his scientific and personal world. He loved to introduce his students, postdocs and mentees to as many people as possible in the field and to give them the opportunities to speak at meetings. Generations of students and postdocs are feeling fortunate to have been trained by Gary and being part of the academic family that he fostered. Not surprisingly, many are now successful independent investigators who are continuing to propagate Gary's legacy. Once a Mawe Lab member, always a Mawe Lab member.

Gary was also an informal mentor to almost everyone in the field of Neurogastroenterology. He was constantly writing letters of support for promotions and awards, often with second farcical copies sent just for the eyes of the subject. His light-hearted conversations with young investigators at international meetings were followed by sage advice about how to navigate a career in science. This mentorship will continue to have a lasting mark on our field.

Teaching was one of Gary's true passions. Gary was a gifted speaker and teacher who was always ready to share his knowledge and new ideas with everyone. He took pride in teaching at all levels of training and across numerous disciplines. He was loved and respected by his students. His way of telling stories and wondering about the complexity of living systems fascinated and captured the attention of any audience. He broke down complex biological concepts to their fundamental elements with a talent unique to those who find wonder in the broader perspective.

A unique educator at the Larner College of Medicine, Gary co-directed and taught Human Gross Anatomy courses with his colleague, Dr. Victor May, for 34 years. Wearing his signature Hawaiian shirts, he gave animated lectures filled with humour and funny facts. During dissection laboratories, he enjoyed going from one table to another, helping students identify ambiguous structures at the same time as telling stories to lighten the laboratory routines. His lively teaching style was appreciated and he received several teaching awards over the years. His talents made Human Gross Anatomy one of the top-rated courses at the University year after year.

In addition to his lectures at UVM, Gary spent a week each summer at the Lake Itasca Biological Field Station as a Visiting Professor for the University of Minnesota Graduate Program in Neuroscience from 1990 to 2004. There, he used the complexity of the guinea pig ileum enteric nervous system to teach concepts in neuropharmacology to first year graduate students.

From 2015 to 2023, he delivered lectures on the histology, anatomy and physiology of GI tract, and made clinical correlations with GI disorders prevalent at in the Department of Anatomy, Biochemistry & Physiology at University of Hawaii John A. Burns School of Medicine (JABSOM) with the appointment as adjunct professor in 2015. The students at JABSOM made a great impression on Gary and their appreciation of his instruction and his love to learn was one of the main reasons he would plan those annual trips. Of course, he also enjoyed the warm people and lovely culture of the islands and looked forward to the annual senior luau which he arranged to coincide his visits.

Gary believed in the importance of service to the profession and to the field. He was a tireless advocate for increased funding and support for research in GI physiology and neurobiology, working to raise awareness of the importance of this field of study. He was passionate about biology in general, and by the gut in particular. He loved ‘preaching the gospels’ of the enteric nervous system, the gallbladder and of serotonin, and the world is now filled with his generation of his converts.

As a recipient of numerous NIH funding awards for the entirety of his career, Gary served the NIH extensively, as a reviewer on a variety of committees and study sections. In addition, he served many foundations, including most notably the Science Foundation of Ireland, Natural Sciences and Engineering Research Council of Canada, and Crohn's and Colitis Foundation of Canada.

Gary was also member of numerous Editorial Boards and Scientific Advisory committees. He had leadership roles as Councilor of the American Neurogastroenterology and Motility Society (ANMS) and as Chair of the ANMS Research Committee. He was Reviewing Editor of The Journal of Physiology and made a lasting impact on the journal. Gary also served on the Editorial Board of American Journal of Physiology: Gastrointestinal and Liver Physiology, and was the Associate Editor for Autonomic Neuroscience: Basic & Clinical. He served on the Editorial Board and was Reviews Editor and Chair of the Journal Management Committee for Neurogastroenterology and Motility. Gary was a member of the Scientific Advisory Boards for the International Foundation for Functional Gastrointestinal Disorders and the Councilor for the Nerve–Gut Motility section of the American Gastroenterology Association, and he served in an advisory capacity for many international conferences and symposia. Gary also served on the Rome Foundation Basic Science Committee (2012–2019) and, together, Gary and Beverley Greenwood-Van Meerveld Co-Chaired the Fundamentals of Neurogastroenterology – Basic Science Committee for Rome V Foundation, to be published in 2026.

Gary was the quintessential Renaissance Man. Whatever he was curious about, he pursued with an endless enthusiasm. In addition to his unbound curiosity, he was very creative and tremendously energic, and strived to not compromise that part of his life. He was an amateur astronomer, an avid nature photographer and an artist. Between capturing the perfect images of flying fireflies in Spring, running waterfalls in Summer, colourful foliage in Fall and snowflake photographs in Winter, he also dabbled in making weathervanes and Calderesque hanging mobiles.

Although he loved everything about Vermont, outdoors and nature, he equally felt at home in urban settings where he would take pleasure in finding obscure museums, original art exhibits and lively music festivals. When in Rome, Gary was most excited about visiting the Capuchin crypts, which includes various alter pieces made from the skeletal remains of capuchin monks. He took many photographs that he used as teaching material for his gross anatomy classes.

He loved to cook and bake. He used a systematic – and scientific – approach to test numerous iterations of a recipe until it reached his idea of perfection from smoked pulled pork, salmon or nuts to homemade pizza. He tested them all. He also loved to bake cakes or cookies, with very imaginative names, for every lab member's birthday, or for no particular occasion. He celebrated manuscripts, grants and graduations with memorable gatherings at his house, which included some carefully selected homecooked meals and a group picture in front of Camel's Hump – his favourite mountain in Vermont.

Perhaps not surprisingly, he proudly listed in his curriculum vitae his award-winning coffee cake from the 1983 Ohio State Fair. This prize is also a testament that Gary has jumped between high-level science and outside interests through his entire life. In his 20s, after winning the First Place and Best of Show, Men's Cooking price at the televised blue ribbon award ceremony, he went on his way to present his latest research findings a neuroscience meeting.

It is very hard to imagine that Gary would have ever known a stranger; he was a friend to everyone he encountered. In 1989, shortly after he moved to Vermont, Gary was invited to present his early findings on the neural control of gallbladder function at the inaugural Little-Brain Big-Brain meeting in Munich. This biennial young investigator meeting, which continues to this day, has earned a strong reputation over the years as a meeting that resulted in fruitful collaborations and life-long friendships. This was certainly true for Gary who deeply cherished the memories and the friendships he made through Little-Brain Big-Brain.

Gary had a deep sense of friendship corroborated by genuine humanity. He was a generous colleague who knew how to listen just as well as he knew how to teach. His optimism and enthusiasm were infectious. At meetings, his wide smile attitude was an invitation to share stories over a cup of coffee or a frothy pint. Using his great sense of humour, he would fill the conversation with cheerful anecdotes. Gary was always happy to share his experience, take informal mentorship roles with senior colleagues or sponsor junior faculty. He actively promoted the highest values of equity, diversity and inclusivity. He built lifelong friendships and mutual respect with them, always making time in his busy schedule to discuss scientific questions, challenges, career decisions and life.

He welcomed friends and colleagues into his life, introducing them to his students, sharing his passions with them, and gifting them a photograph of snowflakes or fireflies, a mobile or homemade raspberry jam. Gary had a knack for remembering the smallest details about his friends’ lives. He remembered birthdays, anniversaries and other special events, and, often seemingly out of nowhere, he would send you an email or note just to keep in touch. He was often responsible for organizing an email spam campaign on the birthdays of his colleagues. For his collaborators and friends, knowing Gary has been one of the greatest gifts of their life.

Gary was modern pioneer in the field of Neurogastroenterology and Motility with ground-breaking publications and concepts that will have had a lasting impact. In addition to being a distinguished scholar, he was an exceptional mentor and educator and was one of the most recognized and accomplished faculty at the University of Vermont, as well as its greatest ambassador.

Although Gary was passionate about his research and his hobbies, he was most especially dedicated to his friends and his family. Therefore, he left an indelible mark in the hearts of everyone he touched, far beyond in the neurogastroenterology community. Gary enriched our lives; his wisdom, humour and friendship will be painfully missed by all.

Photo Credit: Gary M. Mawe