In Memoriam: Marcello Costa

We honour the legacy of Marcello Costa, who passed away in Adelaide on the 14th of April, 2024.  

At the 2023 meeting of the Australasian Neuroscience Society, Emeritus Professor Marcello Costa was honoured with a Distinguished Achievement Award for his contributions to neuroscience, with particular reference to the enteric nervous system.  Born in Turin, Italy, in 1940, after completing his medical studies and PhD in 1967 Marcello moved to Australia in 1970 as a postdoctoral fellow in the laboratory of Geoff Burnstock at The University of Melbourne. Between 1973 he spent time as a Research Fellow at The University of Helsinki and The University of Turin, before accepting a position as a lecturer in Human Physiology at Flinders University. In 1986 Flinders University recognized his service by creating a Personal Chair in Neurophysiology, and in 2013 he was appointed the Matthew Flinders Distinguished Professor in the College of Medicine and Public Health, and Professor of Neurophysiology. 

Marcello was a founding a member of ANS and was granted Lifetime Membership in 2010, and the Australasian Neuroscience Society Medallion for "individuals who have provided outstanding service to the Society". ANS has established the annual Marcello Costa Award in his honour. The recognitions bestowed by ANS add to the many he has received in his career, including the Centenary Medal in 2001, being inducted as an Honorary Bragg Member of the Royal Institution of Australia, and receiving the Federation of Neurogastroenterology and Motility Societies Lifetime Achievement Award in recognition of his research and mentorship in 2018. In 2020 he was made an Officer of the Order of Australia (General Division) "for distinguished service to higher education, and to medical research, in the field of neurophysiology, and to professional scientific bodies." 

Having retired from academia in 2021, Marcello had been revisiting memories of his early childhood in Italy, and of his parents who prevented the deportation of a young Jewish girl by the occupying Nazi forces. He is happy to share this moving oral and pictorial history of his family here. 

Marcello was very supportive of the establishment of ASAN, and donated $10,000 to help it with its mission of promoting autonomic neuroscience.

His legacy donation will also support the annual Marcello Costa Excellence in Autonomic Neuroscience Award.

In Memoriam: Geoff Burnstock

A personal memory by Marcello Costa

Geoffrey Burnstock was one of the founders of Australian autonomic neuroscience research. 

He had migrated, as a Senior Lecturer, from England in 1959. In 1964, he took up the Professorship of the Department of Zoology at the University of Melbourne (Figs 1 and 2 in downloadable document). His emigration was motivated by the promise of greater freedom. In a radio interview with Robyn Williams in 2012, he said “In England, if you want to do something new, the first response is usually, 'It can't be done’…whereas in Australia the first thing they say is, 'Give it a go mate’.”

London-born Geoff was educated at King’s and University colleges. As a student of JZ Young in the Department of Anatomy and Embryology at University College London (UCL), he finished his PhD in 1957. He was a post-doctoral fellow at Mill Hill, then at Oxford, joining the formidable ‘don’ of smooth muscle physiology, Edith Bulbring, a refugee from Nazi Germany (Figs 3 and 4). He published, with her and his fellow PhD student, Mollie Holman, Excitation and conduction in the smooth muscle of the isolated taenia coli of the guinea-pig. 

His full biography has been covered by North and Costa and by Spencer and Costa. Spencer and Costa also document his remarkable collaboration with Mollie Holman’s group at Monash University. Both Geoff and Mollie can be regarded as the founders of Australian autonomic neurosciences (Fig 5), together with Mike Rand, Professor of Pharmacology at the University of Melbourne (Fig 6). Geoff also wrote “Against the odds: an autobiography” (A private publication, printed at Lavenham Press, Lavenham, Suffolk). His early PhD student, John Furness, wrote his obituary, edited a special issue of Autonomic Neuroscience  and helped to identify some colleagues in the current figures.

The Department of Zoology at The University of Melbourne in the 60s and early 70s attracted a remarkable team of young researchers from all walks of science and life (7, 8, 9). I was attracted to join him in 1970 after meeting him at a conference a year earlier in Venice. As a medical student in Turin, I had known of his work with some of his early students, Graeme Campbell and Max Bennett (Fig 10), who each published a chapter with him in the Handbook of Physiology (Campbell G, Burnstock G (1968) Comparative physiology of gastrointestinal motility. In: Code CF (ed) Alimentary canal. American Physiological Society, Washington, DC, Handbook of Physiology, vol IV, sect 6, pp 2213-2266; Bennett MR, Burnstock G (1968) Electrophysiology of the innervation of intestina1 smooth muscle. In: Code CF (ed) Alimentary canal. American Physiological Society, Washington, DC (Handbook of Physiology, vol IV, sect 6, pp 1709-1732). With them, he had discovered that the inhibitory transmission from enteric neurons was not mediated by either noradrenaline or acetylcholine, the two known neurotransmitters in the autonomic nervous system, but by non-adrenergic non-cholinergic (NANC) neurons. Over the next several decades, he set out to demonstrate that the transmitter of these NANC neurons is ATP, hence ‘purinergic’ nerves (Fig. 10).

Despite incomplete evidence for it, which made some of his Melbourne students sceptical, he stuck to his idea. In the 1970s, in a spirit of friendly criticism, I coined in the term ‘maccaronergic nerves’ to counteract his diagram of ‘purinergic nerves’ (Fig 12). He took this in good spirit and often used my diagram in his talks. Most of us younger researchers retained a healthy scepticism of the purinergic hypothesis. Yet Geoff remained a good mentor for all of us and often reminisced with nostalgia about those early times at the Zoology department in Melbourne. He generously realised that some of us wished to collaborate independently. He and I published only a short letter to the editors and a short monograph (Adrenergic Nerves, Fig 13, since translated into Russian!). I worked with John Furness from the day of my arrival in Melbourne in 1970. 

Geoff’s interest in a multitude of comparative aspects of the autonomic nervous system spanned tissue culture, histochemistry, ultrastructure, pharmacology and electrophysiology in molluscs, fish, frogs, lizards, sheep, all small laboratory animals and, of course, humans.

Since his work with Mollie Holman in Melbourne, noradrenaline had been accepted as the neurotransmitter of sympathetic nerves to the vas deferens, but, in the 1970s, Geoff acquired evidence for ATP being released from these nerves. He then proposed the novel idea of co-transmission which, within a few years, became a fertile general principle in neuroscience (Figs 14 and 15) and an influential meeting in Sweden with Tomas Hokfelt.

In 1975, Geoff returned to England as Head of the Department of Anatomy and Embryology at University College London, where he retired in 1997.  Geoff continued his efforts to convince other biomedical scientists of the importance of ATP as an extracellular signal in addition to adenosine and cAMP. Collaborating with a pioneer of molecular biology, Eric Barnard, to clone a P2 receptor, cDNA, he addressed the issue of the nature of receptors for ATP and purines in general. He distinguished the receptors since named P2X and P2Y (Burnstock G. A basis for distinguishing two types of purinergic receptor. In Cell membrane receptors for drugs and hormones: a multidisciplinary approach (eds R. W. Straub & L. Bolis), pp. 107–118. New York, NY: Raven Press).

The biography I wrote with Alan North contains a detailed summary of subsequent work by Geoff and other well-established molecular biologists, such as David Julius (San Francisco) and John Wood (UCL) (see also North).

When Geoff arrived in 1975 at the Melbourne University Department of Anatomy and Developmental Biology, there were three professors; when he retired in 1997, there were 26 full professors.

As we note in our biography, “This strong drive could easily come over as self-promotion, but it was fuelled also by his genuine passion for discovery across a broad swathe of biomedical science”. 

While President of the Australian Neuroscience Society in 1994, I took the risk of asking him to deliver the plenary lecture in 1995. The criticism that he was not a proper experimental scientist, but a self-promoting entrepreneur of science, was soon confounded by everyone realising his genuine drive to foster research in the broadest way possible.

Geoff participated in the first ENS meeting at Flinders in 1983 (Figs 16, 17, 18) and in the second in Adelaide in 2014 (fig 19, 20, 21, 22).

On retiring in 1997 from UCL (fig 23) he created the Autonomic Neuroscience Institute at London’s Royal Free Hospital 

Geoff was Editor-in-Chief from 1985 to 2016 of The Journal of the Autonomic Nervous System (later Autonomic Neuroscience: Basic and Clinical), founded in 1978 by Chandler McCluskey Brooks. He was editor-in-chief of the journal Purinergic Signalling, founded by him in 2004, until his death on June 3, 2020, and served on the editorial boards of more than 30 journals. Prolific, he published more than 50 papers annually. 

He was the first President of the International Society for Autonomic Neuroscience (ISAN), founded in 1994 and would certainly have become a member of the current Australasian Society for Autonomic Neuroscience (ASAN).

As a result of his extensive collaboration with clinicians, a drug to be used for chronic cough was called gefapixant—the first three letters being a tribute to him.

He was celebrated by his Australian friends in 1989 (Fig 24). I was often a guest of his family (Fig 25) and met at a number of meetings with close clooeagues (Fig 26). Retired at 88, he and Nomi moved from London, back to Melbourne in 2017. Geoff maintained close contacts with colleagues at the university. They had spent every summer at Nomi’s family home on the beaches at Paraparaumu, New Zealand, where we were their guests in 2011 (Figs 27 and 28). 

He came to John Furness’ celebration in Melbourne 2011 (Fig 29). He was celebrated by the Australian Academy of Science (Fig 30).

I was privileged to be the youngest colleague invited to the small family celebration of his 90th birthday in Melbourne (Fig 31).

When we had first met in Venice, Geoff had shown me pictures of his wood carvings. A few years ago, he left me, as a legacy of our friendship, a small token of his art (Fig 32).

For several years after he left Australia and when I had moved to Flinders University as a foundation lecturer in Physiology under Laurie Geffen, Geoff asked me, every year, to join him at the UCL, appreciating that the likelihood of that happening diminished as I set roots in Adelaide. 

This very brief biography ends with a quote from Geoff’s interview with Robyn Williams in 2012 “My philosophy is, if you can't do it one way, you find another”. He always did, until his peaceful death in Melbourne in 2020.

Image:  Mollie Holman & Geoff Burnstock [detail]. Photo provided by the Burnstock family

In Memoriam: Mollie Holman

A personal memory by Nick Spencer

Much of the strength today in Australian autonomic neuroscience can be traced back to a time when Mollie Holman began her seminal research in autonomic neuroscience at Oxford University, then moved back to Australia and developed her laboratory and Neuropharmacology Group at Monash University.

Mollie Holman was born in 1930 in Launceston, Tasmania. She graduated in 1952 from Melbourne University with a Bachelor of Science degree, majoring in Physics. In 1955, Mollie completed her MSc also at the University of Melbourne, her thesis was entitled ‘Pharmacology of Bioelectricity’. Formally, Mollie was recognised as a biophysicist. 

After completion of her MSc, Mollie moved to Oxford University in the mid 1950’s to study for a DPhil under the supervision of Professor Edith Bülbring in the Department of Pharmacology. It was during this time at Oxford where Mollie met a young Geoff Burnstock. Mollie and Geoff became close research colleagues and collaborators, initially under the critical eye of Prof Bülbring. Their first paper together, published in 1958, involved a beautiful series of experiments using sharp intracellular microelectrodes to determine the spread of excitation of smooth muscle action potentials along the syncytium of taenia coli.  

Perhaps most notably at Oxford, Mollie and Geoff were recognised for their pioneering work on the smooth muscle of the vas deferens, where they recorded neuroeffector transmission in response to sympathetic nerve stimulation. Together they discovered that brief electrical nerve stimuli applied to the hypogastric nerves elicited excitatory junction potentials (EJPs) in the smooth muscle. There was a conspicuous lack of agreement between Geoff and Mollie with regards to the interpretation of their results with reserpine (to deplete noradrenaline from sympathetic nerve terminals). Mollie was confident that the neurotransmitter underlying the EJPs was attributed to release of noradrenaline. However, despite reserpine treatment to block noradrenergic transmission, EJPs were still elicited following stimulation of sympathetic varicose nerve terminals, or in the presence of adrenoceptor antagonists. Geoff was convinced early on that adenosine triphosphate (ATP) or a related purine was a co-transmitter with noradrenaline. In stark contrast, however, Mollie, did not share Geoff’s enthusiasm for purinergic co-transmission. I once asked Mollie why she was unconvinced that ATP or a related purine could be a neurotransmitter at autonomic neuroeffector junctions. Her reply was: “I don’t think we depleted all the noradrenaline.”  During my PhD, Mollie remained sceptical of the notion of co-transmission of noradrenaline with ATP or a related purine. Years later, Mollie did say: “she was prepared to keep an open mind” with respect to a purine being a neurotransmitter. It wasn’t until about two decades after Geoff and Mollie’s first experiments that it was revealed that indeed ATP is a co-transmitter with noradrenaline. David Westfall’s laboratory and others had clearly measured release of ATP with noradrenaline following sympathetic nerve stimulation. 

Mollie graduated in 1957 with her Doctor of Philosophy from Oxford University. Then in 1958, she was offered a lectureship at The University of Melbourne, in the Department of Physiology. In 1963 she moved to the Department of Physiology at Monash University. Initially appointed as a Senior Lecturer, she was then appointed Reader in 1965 and Professor in 1970.  

Mollie had an extraordinary eye for electrophysiological detail. She had the patience and temperament to endure hours of late-night recordings. She had an encyclopaedic knowledge of the autonomic nervous system, always asking the most pertinent and relevant questions in seminars. During my PhD candidature, I would meet with Mollie one-on-one and present her with my latest data. Mollie had an exceptional ability to ask the most appropriate questions – always offering great advice to trouble-shoot experiments that may have proved challenging. 

One of the most significant discoveries that revolutionised autonomic neuroscience started when Geoff and Mollie began working in Australia with Max Bennett and Graeme Campbell on the guinea-pig tenia coli. Their paper in 1964 showed that a neurotransmitter was clearly released from enteric neurones in the gut that involved a neurotransmitter that was neither acetylcholine nor noradrenaline . With respect to the inhibitory junction potential (IJP) they elicited, it was stated in their paper: "It seems more likely that they are due to the release of an inhibitory transmitter from intramural nerve fibres. It is possible that some of the peripheral extensions of the sympathetic nerves are resistant to both guanethidine and bretylium. However, on the basis of present evidence, we favour the view that the inhibitory responses to transmural stimulation which persist in the presence of these drugs are mediated by intrinsic nerves which are distinct from the sympathetic and parasympathetic systems."  It was Geoff’s team that went on to propose that ATP was the non-adrenergic, non-cholinergic (NANC) neurotransmitter underlying the IJP in the gut in a classic publication of 1970. The work of Geoff and Mollie in their laboratories at Melbourne University and at Monash University respectively in Australia had uncovered a new class of enteric neurone. They had completely changed existing views by demonstrating that ATP (or related purine) could be either an excitatory or inhibitory neurotransmitter in smooth muscles of different visceral organs. 

The research that Mollie undertook with Geoff on sympathetic neurotransmission and the possible role of ATP ignited numerous international collaborations, and many of the world’s top scientists came to Australia to work with them both. Together, Mollie and Geoff truly stimulated autonomic neuroscience in Australia.  

Mollie attracted many top scientists to her laboratory at the Department of Physiology at Monash University, which made many extraordinary contributions to autonomic neuroscience. This firmly ingrained Australia on the international radar as a mecca for electrophysiology of visceral smooth muscle organs. A large number of national and international leaders came to Monash in the 1960’s and 1970’s to work with Mollie and her group. One of her laboratory’s greatest accomplishments was the first intracellular electrophysiological recordings from neurones in the gastrointestinal tract with microelectrodes. Mollie recruited David Hirst to her group and together with Ian Spence successfully distinguished two types of neurones in the enteric nervous system of guinea-pigs (Hirst et al., 1974).  These neurones were coined “AH” neurons and “S” neurones because of their distinctly different synaptic inputs. Coincidently, in the northern hemisphere, Alan North’s laboratory was also recording from enteric neurones with microelectrodes and also characterised two distinct populations of nerve cells, which his lab called Type 1 and Type 2 neurones and published in 1973. It should be acknowledged that Dr Yokoyama had recorded from myenteric neurones using extracellular electrodes in 1966, although there was some question whether these recordings were from muscle or nerve cells.

Mollie attracted the young postdoc Joe Szurszewski from the Mayo Clinic, USA. When I visited Joe’s laboratory in 1995 (at the start of my PhD), Joe said that the intention of his visit to Mollie’s lab was to record action potential collisions along peripheral nerve axons. Instead, Joe discovered synaptic potentials in the inferior mesenteric ganglia and together with Peter Crowcroft discovered in 1970 the first evidence of a peripheral reflex from the gut wall to sympathetic prevertebral ganglia. Tim Hibberd, now a senior postdoctoral researcher at Flinders University, has published in recent years major advances on these intestinofugal neurons (Hibberd et al., 2020).  

In the early 1970’s The Department of Physiology at Monash University was a buzzing department, especially in peripheral and central neuroscience.  Mollie developed the Neuropharmacology Group, which consisted of many top scientists, including David Hirst, Robert Bywater, Elspeth McLachlan, Tim Neild, Grahame Taylor and Joel Bornstein. This was a spectacular time in autonomic neuroscience. The Group was very special, being composed of academics who were all interested in smooth muscle and other targets of the autonomic nervous system and their underlying nerve pathways. 

It is difficult to put into words to describe how valuable it is to be supervised by highly experienced scientists, who can provide the necessary guidance to teach the important skills essential to form one’s own laboratory. I was the last PhD student that was fortunate to be supervised by Mollie. Robert Bywater was my co-supervisor. Mollie and Robert taught me not only how to record from smooth muscle and enteric neurons, but most importantly how to properly interpret electrophysiological recordings with confidence and clarity the how to “ask the right questions”. Recording and interpreting high-quality electrophysiological recordings requires hours of experience. It is not something found on the internet or a short YouTube video. Knowing how to “read” electrophysiological recordings is something that is developed after hours of practise under guidance from experts who know how to discriminate minute synaptic potentials (that maybe only a few hundred microvolts) or smooth muscle junction potentials (that vary wildly depending in amplitude). The skills Mollie and Robert taught are never forgotten and remain deeply ingrained today. 

Mollie’s laboratory inspired Robert Bywater and Grahame Taylor “down the corridor” to make the first intracellular recordings from the colon. These studies were of great significance because Robert and Grahame’s work on the mouse colon led to extensive work on what has become today one of the major motor patterns studied in the colon – the colonic motor complex (CMC). This motor pattern is being used increasingly around the world today, because a plethora of transgenic mice are available.

After being infected with a thirst for scientific enquiry, I left the guidance of Mollie and Robert in 1998 to commence a postdoc at The University of Nevada. There, I used my skills developed from Mollie and Robert and introduced the group in Reno to the CMC, originally identified by Jack Wood in 1973. In recent times, there have been major advances in our understanding of the neuronal mechanisms underlying the CMC, using imaging and electrophysiology recordings of the enteric nervous system. Today, as gut-brain research has escalated to unprecedented levels, the mouse colon and the CMC are extensively studied in countless laboratories around the world. Much of the energy that ignited electrophysiological research into colonic motility in mice came from Mollie’s laboratory. 

John Furness was a PhD student of Geoff Burnstock in 1969. He worked on the guinea pig colon at The University of Melbourne with intracellular electrodes and in 1970 concluded that: “the muscle cells of the distal colon of the guinea-pig are influenced by three sets of nerves: cholinergic excitatory, adrenergic inhibitory and intrinsic inhibitory fibres releasing a non-adrenergic transmitter substance.” These findings confirmed earlier evidence by Geoff and Mollie for the existence of non-adrenergic and non-cholinergic inhibitory neurons in the taenia coli. Although John did not work directly with Mollie, John had a major role in the invitation Marcello Costa received in early 1970 from Geoff to join his lab. Marcello was a recent medical graduate from The University of Torino, Italy. He said that the day he arrived in Geoff’s laboratory in Melbourne, John and Marcello performed their first experiment. That moment paved the way for an extraordinarily productive partnership that continued for another 17 years after both Marcello and John joined the newly formed Medical School at Flinders University. I think it is fair to say that enteric neuroscience is perhaps strongest in Australia more so than any other nation, largely as a result of the partnership between John and Marcello and the collaborations that developed from their initiatives.

It has been an honour to have Marcello work in my laboratory (performing many hands-on experiments) with extraordinary productivity over the past 13 years. It is interesting to note that over Marcello’s 50-year research career, his most productive period in terms of publications has been from 70-80 years of age. This shows Marcello’s remarkable stamina and his insatiable desire for scientific endeavour. The past decade has seen a very dynamic and exciting research era with Marcello and other close colleagues at Flinders University, including Simon Brookes, David Wattchow, Damien Keating, Phil Dinning, Taher Omari, Tim Hibberd and many others who have collaborated closely, now combining and extending their expertise with other local and international colleagues in autonomic neuroscience. 

In 1996, Mollie became Emeritus Professor at Monash University. In 1998, she was awarded an Order of Australia for service to scientific research, particularly relating to the autonomic nervous system and the control of smooth muscle, and to education and university administration. In 2001, Mollie was awarded the Centenary Medal - for service to Australian society and science, and in 2007, she was awarded the David de Kretser Award for contribution to Faculty of Medicine, Nursing and Health, Monash University. Mollie passed away on 20th August 2010 in Melbourne, Victoria, Australia. She is deeply missed. On a deeply personal note, I will never forget the knowledge and critical thinking skills Mollie and Robert passed on and how they always found time to give assistance when needed.

Many laboratories active in Australia in the field of autonomic neuroscience today can be traced back to a point when they either worked with, or had some research collaboration with, Mollie. The ineffaceable legacy of Mollie continues to flourish, highlighting how important is the continuous branching of good science forming an engaging network, via mentoring, collaboration and teamwork between dynamic scientists across multiple generations.

Image:  Mollie Holman & Geoff Burnstock [detail]. Photo provided by the Burnstock family