In the first in a new 'In Conversation With...' series, Professor Jeremy Pearson MBE, Associate Medical Director at the BHF, talks to Professor John Martin, Emeritus BHF Professor of Cardiovascular Science, about his life and career, and his ardent and enduring belief in a international and multidisciplinary approach to research.
Professor Martin was BHF Chair between 1990 and 2008 at UCL, and he retains the title of Professor of Cardiovascular Medicine there. Professor Pearson caught up with John over Zoom in March 2021 from his home in West Cork, Ireland.
'John Martin is still bringing his enquiring mind to bear on fundamental aspects of clinical science. Indeed, early in our talk John made it clear he defines himself primarily as a clinician scientist. This is underpinned by several of his other qualities, including a fervent belief that multidisciplinary research is needed to solve problems that will never be successfully tackled otherwise, and the need for multinational collaborations to bring the best minds together – he is a steadfast Europhile.
John started his medical degree in the 1970s in Sheffield at a later age than most of his contemporaries and by an unusual route, after exploring the possibility of becoming a priest and studying Philosophy in Spain. His interest in platelet biology was kindled in Sheffield by Eric Preston, then a consultant and later Professor of Haematology. It was to shape the whole of his career.
At the time it was known that platelets were produced from bone marrow megakaryocytes but the process was obscure. John measured the distribution of platelet volume in the blood and found that it was log normal, rather than Gaussian as for other cell types. Recruiting Tony Trowbridge (an applied mathematician in Sheffield) to the cause he published the first of a series of papers with him noting that this distribution was characteristic of particles produced by physical fragmentation and concluding, with supportive experimental evidence, that platelets are produced in the pulmonary circulation by fragmentation of trapped circulating megakaryocytes. This novel idea was counter to the prevailing view that platelets were produced by extrusion from megakaryocytes in the bone marrow. Though it is often still unmentioned in textbooks of haematology, Martin’s theory has slowly gained ground and recently been extended by others to show in addition the presence of resident megakaryocyte precursors in the lung, with implications for cell-based treatment of thrombocytopenia.
A chance encounter at a conference in Istanbul with David Penington (Professor of Medicine at Melbourne University), where they discussed platelet science over coffee, produced a little while later an unexpected invitation to join Penington’s department as a Senior Lecturer. John accepted and there he began clinical studies to understand the relationship between platelet numbers, density and volume in health and disease – paving the way to his most highly cited paper (Lancet 1991) showing that mean platelet volume is an independent risk predictor for future myocardial infarction. Larger platelets were known to be more reactive, but the findings in the Lancet paper raised more fundamental questions in John’s mind about the features of megakaryocyte biology that determine platelet size. This is something he is still trying to solve, in collaboration with stem cell biologists now that in vitro systems for producing platelets from stem cell-derived megakaryocytes are being refined.
In 1990, soon after returning to the UK, John was recruited to KCL, to set up and lead its new department of Cardiovascular Medicine. Moving to KCL had been initiated by collaborative links John had established with the Wellcome Foundation and their labs in Beckenham, where John Vane and Salvador Moncada were carrying out research that contributed to the Nobel Prize-winning identification of nitric oxide as an endothelium-derived vasodilator and powerful inhibitor of platelet aggregation. The Foundation also had space at King’s College Hospital, which housed John’s new department, and the BHF agreed to fund the Chair.
The major development in John’s research at this time had originally started at Beckenham. In a typically imaginative series of experiments he showed that early atherosclerotic intimal lesions could be created rapidly in rabbit carotid arteries solely by placing a loosely fitting silastic collar around the artery, without detectable flow changes or endothelial damage, leading to the novel hypothesis that disruption of blood flow through the adventitial vasa vasorum was a necessary and sufficient cause for lesion formation. This was confirmed in later BHF-funded experiments at KCL where the adventitial vasa vasorum was directly occluded or removed, with evidence that the arterial media became relatively hypoxic. Setting up a collaboration with Seppo Yla-Herttuala in Finland, John explored the possible role of locally generated VEGF (known to be expressed in response to hypoxia and induce angiogenesis in tumours), demonstrating its increase in the media in the collar model. Expecting that exogenous VEGF, delivered adventitially inside the collar, would aggravate lesion formation they were surprised to find exactly the opposite. Further experiments showed that this was due to VEGF-induced nitric oxide synthesis, proving a novel non-angiogenic role for VEGF as a cardioprotective agent. This pioneering work provided a stimulus for subsequent efforts by Professor Yla-Herttuala and others to develop VEGF-related gene therapy in humans to restore blood vessel function in ischaemic tissues – a quest that is still highly active but has yet to progress beyond early phase clinical trials.
In 1995 Salvador Moncada moved from Beckenham to UCL to direct a new institute [The Wolfson Institute for Biomedical Research] and UCL sought to attract John Martin as well to bring them together for mutual benefit. The BHF agreed to the transfer of the Chair and John moved in 1996.
This period in John’s research career saw the emergence of cell-based approaches to cardiovascular regenerative medicine. Preclinical studies, particularly in mice, had suggested that injection of autologous bone marrow-derived mononuclear cells could dramatically enhance cardiac repair after myocardial infarction or in heart failure. These results were already being seized on as justification for uncontrolled treatments carried out in hospital-hotels in exotic locations for fee-paying customers seeking a wonder cure. With Dr (now Professor) Anthony Mathur at Barts, John strongly advocated the need for randomized controlled clinical studies in humans and they were amongst the first to carry them out. They enlisted many European co-investigators to increase patient recruitment, culminating in the largest trial to date, funded by an EU FP7 grant, which reported last year but even this lacked statistical power and there was no evidence of benefit (or harm). I asked John whether this sounded the death knell for this approach, and whether he now thought there might be more promising avenues to improve cardiac repair. He responded that it was important to publish the negative result and despite the challenges (given a background of improving survival in heart failure) of finding sub-groups who might benefit he believed the technique could still be of value in patients with dilated cardiomyopathy.
John has relished his time at UCL, which has been a fertile ground for new cross-disciplinary initiatives in clinical research in areas ranging from intensive care to obstetrics, all with platelets as key players. Much of this has additionally involved European colleagues and EU funding. UCL also supported John’s entrepreneurship: he is a vocal proponent of the value in protecting and exploiting intellectual property and founded a company (Ark Therapeutics, which was listed on the London Stock Exchange) embedded in his labs to maximise translational opportunities for novel gene- and small molecule-based therapies in vascular disease.
John also led the formation of the thriving Yale-UCL Collaborative, initially cardiovascular in flavour but now operating across several faculties and disciplines, which holds joint workshops and has a graduate student exchange programme. The Collaborative brought John into contact with Günter Wagner, an evolutionary biologist at Yale, where informal sharing of ideas re-energised John’s long-standing fascination with the evolutionary origin of platelets. Megakaryocytes (which are highly polyploid cells generated by rounds of endomitosis) and platelets only exist in mammals. Haemostasis in other animals is controlled by nucleated thrombocytes generated in bone marrow. What happened to make the switch from thrombocytes to platelets and what were the evolutionary consequences? Martin and Wagner published a provocative hypothesis-generating paper in 2019 suggesting that the immediate evolutionary advantage was a more effective haemostatic system, and that a critical consequence was that this in turn enabled the evolution of eutherian placentation with its extensive fetal-maternal blood interface, requiring highly efficient haemostatic control to prevent blood loss during pregnancy and at birth. John has just submitted a grant application to use the latest sequencing tools to understand differences in gene expression between megakaryocytes with different levels of ploidy and compare these with gene expression in avian thrombocytes – in the hope that this will lead to identification of candidate genes or epigenetic pathways that control polyploidization. The second highly ambitious aim is to use this knowledge to artificially “evolve” polyploidy in avian thrombocytes.
Our wide-ranging and highly enjoyable conversation was conducted by Zoom to his house by the sea in rural West Cork, where he has been sequestered during lockdown. It revealed several less obvious aspects of John’s character that contribute to his personality and success. I mentioned at the beginning of this article his Europhilia, manifest in his many European collaborators and colleagues and also by his important role in the European Society of Cardiology’s relations with EU policy makers in the last decade to encourage their commitment to actions to reduce the burden of cardiovascular disease. However, his personal commitment to Europe is best summed up in a quote from a UCL blog (“I am now a European first, a Yorkshireman second, and British third”) and by his leaping up during the conversation to find and show me proudly his new Irish passport, acquired by virtue of having an Irish grandfather. There is also much more to Professor Martin than clinical science. He writes published poetry and short stories (a collection is called The Origin of Loneliness), and paints – though this is for personal satisfaction rather than public consumption. Perhaps inevitably, the Yale-UCL Collaborative now holds an annual poetry competition. I wondered if isolation on the beautiful Irish coast had led to new poems, but as for many of us lockdown has inhibited rather than stimulated John’s creative writing.
John designed and had engraved glass windows fitted on the corridor side of his new UCL office in 2001, with apparently enigmatic inscriptions. The left repeats “De Motu Orbis Terrarum”, with “Copernicus”; the right repeats “London Cracow Padua” with “UCL BHF 2001”. The Latin phrase references Copernicus’ iconoclastic view that the earth revolved around the sun, and deliberately echoes William Harvey’s “De Motu Cordis” – a similarly iconoclastic view. Both worked in Padua and their ideas were not well received in their home cities (Cracow and London). John hoped these windows would encourage young researchers to persevere even in the face of opposition to their ideas. If you look at the current design of the ESC’s Gold Medal (its highest personal award for lifetime achievement) the two Latin phrases appear on one side, with “Ars Longa Vita Brevis” on the other. The design was introduced in 2000, and you can guess who proposed the inscriptions. In 2008 the medal itself was awarded to Professor Martin.
John’s research has always been driven by searching for answers to big questions and framing hypotheses to test them experimentally, I’m sure influenced by his original training in philosophy. The starting point has often been a “vision” (his word) brought on by a conversation with a colleague or friend that has been rapidly converted into action. Indeed on one occasion in a pub a scribbled design on a piece of paper led directly to a patent. His evident enthusiasm for all he does shows absolutely no sign of diminishing. For example, he has set up and chairs a new charity that can source investment to deliver clinical trials rapidly, and which has already achieved multimillion pound backing from UKRI and other investors for an ongoing trial of a repurposed anti-glycemic drug for COVID treatment.
We finished our conversation with a brief reflection on what the BHF Chair had meant for John. He was very clear – he was extremely grateful, because it gave him the freedom to be creative in his research.'