In Memoriam: Marcello Costa (1940–2024) – a pioneer of the enteric nervous system

It is with sadness that we announce that Marcello Costa, our dear friend and colleague, passed away peacefully at his home in Seacliff (Adelaide, South Australia) on Sunday 14 April 2024. Professor Marcello Costa (AO, FAA) was a pioneer and leader in the field of autonomic neuroscience, specifically the intrinsic neural circuits of the enteric nervous system. From the mid-1970s to 2023 he led a series of studies characterising enteric neuronal pathways, particularly those related to gastrointestinal motility. His work traversed many disciplines including anatomy, histology, physiology and pharmacology through to electrophysiology. His papers often combined multiple approaches well before 'multi-disciplinary research' became fashionable. In later years he led the development of methods to objectively analyse gastrointestinal motility patterns, combining multi-dimensional maps of diameter, length and pressure with recordings of smooth muscle electrical activity. His quantitative accounts of complex motility patterns far surpassed the descriptive summaries that had previously characterised this field. His work was driven by a goal to demystify how cells of the gut work together to give rise to simple, adaptive behaviour patterns. Marcello was born on 9 January 1940 in Turin, Italy. In his childhood, he spent a lot of time at the family's apartment in the High Susa Valley to the west of Turin. Here, he developed a life-long love of mountains. He and his family (mother: Verbena, stepfather: Augusto and older brother: Giorgio) moved to Buenos Aires, Argentina, in 1949. He attended the High School San Martin and the public Italian High School of Buenos Aires, finishing school in early 1960. Later that year, Marcello moved back to Turin to study medicine. However, between these moves he fitted in joining an expedition to explore the continental icepacks of Patagonia, venturing into barely mapped territory. A few months later, Marcello undertook another trip with his brother Giorgio, climbing mountains in Peru and descending the Ucayali and Amazon rivers. His time at the Universita di Torino was intense. Not only did he become heavily involved in student politics (elected as Leader of the Student Centre Left Party) but he also trained in mountain climbing with the Gervasutti School of the Torino Alpine Club, played guitar in a jazz band and joined the student choir. He also undertook a research internship in the Departments of Anatomy and Histology under the supervision of Giorgio Gabella. Using a newly discovered technique (the 'Falckh–Hillarp method') to visualise monoamine transmitters (Falckh et al., 1962), Marcello undertook microscopy studies that led to 11 publications between 1965 and 1970 and award of his MD (Gabella Daniela followed a few months later. On arriving at Melbourne University, Marcello met John Furness and they discovered many shared interests and ideas. Together, they extended studies on peripheral aminergic innervation. This was the start of a long and productive collaboration which continued until 1988. There was a brief interlude when Marcello's funding ran out and he had to return to Europe in 1973. Fortunately, he was soon invited back to Melbourne, within the year, but in 1974 Geoff Burnstock announced that he would be moving to University College, London. The group at Melbourne University dispersed; John Furness was offered a lectureship in Anatomy and Histology in the new Flinders University School of Medicine in Adelaide. In 1975 Marcello accepted a lectureship in Human Physiology also at Flinders University, where he remained for the next 47 years. He retired as Mathew Flinders Distinguished Professor in 2021, at the age of 81, retaining his links as Emeritus Professor. At a young age, Marcello was given a small microscope; this opened up an intriguing new world of tiny objects. As a teenager he sold his beloved bicycle in order to buy a better microscope, capable of resolving bacteria. He spent many hours entranced by different types of protozoa moving in pond water. This early love of microscopy may have prepared him for his research as an intern under the critical eye of Professor Giorgio Gabella. He carried out an extensive series of histochemical studies localising amine transmitters in the autonomic nervous system, working with Giorgio Gabella (Gabella Wattchow et al., 1988). Later, methods for maintaining the intestine for several days ex vivo in organ culture were developed by Marcello and his colleague Simon Brookes, allowing the application of retrograde tracing of neurons in both animal and human tissue (Brookes Waterman, Costa Waterman, Tonini this was a huge advance over previous descriptive analyses (Cannon, 1902). Interestingly similar maps were developed at nearly the same time in two other laboratories (Bercik et al., 2000; Bouchoucha et al., 1999). In 2008, Nick Spencer joined Flinders University and soon after Marcello joined Nick's laboratory, for the next 13 years until his retirement in 2021. This was an incredibly productive and dynamic era – a time of great energy, vision and innovation. It was also Marcello's most productive publication period. It was a true honour having Marcello perform hands-on experiments in the laboratory of N.J.S., right up until he retired at 81 years of age. This period also involved extensive collaboration with Phil Dinning and Lukasz Wiklendt, where Marcello combined intraluminal pressure maps with spatio-temporal maps of wall movements and focal recordings of electrical activity (Fig. 1) (Costa et al., 2021; Dinning et al., 2011). During this time in Nick's laboratory, Marcello produced a series of at least 30 key papers, detailing interactions between neurogenic and myogenic mechanisms in the small and large bowel of several species with remarkable quantitative precision. Marcello had a clear vision on how to translate his research into the clinical world. Live specimens of human gut could be obtained (with appropriate permits) from surgeons operating in the same building. This pathway was established by David Wattchow, a colorectal surgeon who did his PhD with Marcello and John Furness. David's efforts made it possible for many studies in animal tissue to be tested in human tissue over ensuing decades. Specimens were taken from the healthy segment of the small or large intestine resected in the treatment of malignancy. In the laboratory they were studied anatomically under the microscope (Wattchow et al., 1995) or physiologically in organ baths (Carbone et al., 2013) in the labs of Simon Brookes and Nick Spencer. Several surgical trainees carried out PhD studies on these specimens, supervised by Marcello. Marcello was impressed by the work of Dr Anthony Bauer from Pittsburgh, USA, who had shown in animals that anti-inflammatory drugs were candidates to treat post-operative ileus (Bauer windsurfing to Kangaroo Island, Yorke Peninsula and along much of the 100 km length of the Coorong lagoon. He appreciated art and created a series of YouTube videos on the history of art and perspective. Last, but not least, Marcello was also a family man. He and Daniela have a son, Andre, who is now a successful academic at the University of Adelaide. Marcello was also the father-in-law of Kat, grandfather of Harry, Orlando and Heidi, and brother of Giorgio. Marcello received many awards and accolades during his long career. These included appointment as Fellow of the Australian Academy of Sciences in 1989. In 1992, he was honoured with the title of 'Cavaliere della Repubblica Italiana'. In 2001, he was awarded the Australian Centenary Medal. In 2018, Marcello was awarded the inaugural Lifetime Achievement Award by the Federation of Neurogastroenterology and Motility Societies and, in 2020, he was appointed as an Officer of the Order of Australia. The latter honour is given by the Governor General of Australia for contributions to Australian society. However, perhaps his greatest accolade was the respect and affection of the many people who he personally interacted with, in his many areas of interest. In the world of university and science he influenced undergraduates, medical students and many leading scientists in neuroscience and neurogastroenterology. Many of his colleagues referred to him as a 'renaissance man' on the basis of his mastery of multiple fields of knowledge, combined with a deep culture and education. His belief in the value of scientific understanding was unbounded. His own work added enormously to that store of knowledge but, in addition, he encouraged many researchers, junior and senior, in their quest for discovering new knowledge. Marcello was not only a great scientist, ambassador, teacher, public advocate and family man, he was also our friend and inspiration. We miss him deeply. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests declared. N.S.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. S.B.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. D.W.: Conception or design of the work; Drafting the work or revising it critically for important intellectual content; Final approval of the version to be published; Agreement to be accountable for all aspects of the work. Australian Research Council Centre of Excellence in Advanced Molecular Imaging (Imaging CoE): Nick J. Spencer, DP190103628; DHAC | National Health and Medical Research Council (NHMRC): Nick J. Spencer, 1156427.