I was born 14 may 1954, and my childhood in Carnforth, Lancashire was idyllic. At the time I would have said it was unremarkable, as are most things when not viewed by comparison. The near-total freedom I enjoyed seemed perfectly natural. The town was an unpretentious railway town in North Lancashire, England. My father was the local lawyer; my mother left her work as a telephonist when she married, as was the custom. And I was their only child. They were good enough not be overly protective and I survived as much foolhardy behaviour as most young people. I was neither pushed nor discouraged in schoolwork and again saw that as entirely normal. Appreciation of my parents came to me much later, with the recognition that other people saw them as special people in the community. My world was a simple one of building tree houses, lighting fires, mock (and occasionally real) combat with other groups of children. But I was always concerned with improving things: a better catapult, a hotter fire, a bigger explosion. I had an encyclopaedic knowledge of the melting temperature of metals; molten lead was a joy; an ambition to create the 2800OF necessary to melt iron was sadly never fulfilled. I learnt that it was possible to create something akin to a hand grenade by compressing thousands of the tiny ‘caps’, as supplied for toy guns, between two large bolts threaded onto a single nut, then hurled at a brick wall. The result was a neat hole in a nearby garage door. Fortunately, before the inevitable calamity, life evolved.
Aged 11, I started at Lancaster Royal Grammar School. The school was good and undoubtedly the single most formative experience in my education. But it was not idyllic. There will be others who recall their trials with school meals; the UK was not at the top of the culinary league in the 1960s and the Lancaster Royal Grammar School kitchen was not the cordon bleu of the nation. When a good meal cropped up there was no question of equal shares: the older boys, in charge of the table, would take the large majority. Again, without a comparator, I saw this as the way of the world. But that blissful childhood was over.
I was good at most subjects, with the exception of English. Lack of talent was reinforced by lack of effort and sadly this dichotomy in my abilities grew until I eventually came to recognise the importance of communication, a decade or two later. Actually, my ethos was not out of keeping with that of the school; little time was wasted on things other than sport (particularly Rugby Football) and University Entrance (particularly entrance to Oxford or Cambridge). This rather blinkered approach to life did exact its penalty in due course. But I was comfortable at the time. The school had some good teachers; several were truly excellent. I remember in particular Gary Sleightholme, who taught me chemistry. The accent was on finding simplicity in complexity, which is of course the essence of molecular biology. I have heard many scientists describe their first appreciation of this, at the hands of some esteemed mentor in a famous research institution. But for me (and I suspect for many others) I’m pretty sure it was the school. Of the two acceptable school options, excellence in sport or Oxbridge entrance, the pathway for myself was the latter, by default. For various reasons I didn’t think I’d enjoy either Oxford or Cambridge, but never had quite the bravery to refuse the entrance examination, which I duly took. Most of the questions were opaque to me, but I remember creating and solving a set of equations relating to a complex chemistry problem. When several variables cancelled out and the answer was simple integer, I felt confident of success. Beyond this I hardly managed a single answer. But rather to my own surprise, and greatly to that of some at the school, a telegram arrived announcing an open scholarship to Gonville and Caius College, Cambridge. This was to study medicine.
I remember that decision, as follows. I had intended to study chemistry; my chemistry teacher was inspiring and, as I was told by my parents, a distant relative had been a successful pharmaceutical chemist. But it wasn’t to be. The Headmaster, John Lorraine Spencer MA, a rather ethereal figure, who somewhat incongruously wore a gown as he walked about the rough and tumble school, appeared one day in the chemistry classroom. ‘Ratcliffe,’ he said, ‘may I have a word?’ I duly followed him with some trepidation to his study. ‘Ratcliffe,’ he said, ‘I think you should study medicine.’ His views were never to be taken lightly. ‘Yes sir,’ I responded, and the University application form was altered without further exchange. I have never been sure whether he thought I would be a good doctor or a bad a chemist, or really whether he was right or wrong in the end.
But I was pleased with myself. Even though I didn’t want to go, I had got the Scholarship to Cambridge a year early and there was a little time to kill. The previous obsession with explosive dynamics resurfaced, in a slightly more dangerous guise. I had always wanted to be good at sport, not chemistry; but though the spirit was strong, the flesh was weak. Now, however improbable, I saw a potential solution; motorsport. I took a job in the analytical laboratory of a local textile firm and earned enough money to buy a racing kart (not a go-kart). Here was a real thrill; the acceleration over a short span was truly mind-blowing. It suited my basic interest in combustion. I learnt to ‘mechanic’ it (the most important bit) and drive tolerably, though not brilliantly well. It held prestige amongst a set of peers I admired. Though I never possessed a powerful motorcycle I had the gear to tune them for my friends. Mercifully for my poor parents, this period came to an effective end when I finally took up the place at University.
As might be predicted from this preparation, medicine at Cambridge was not an unqualified success. I am not going to go into detail; suffice it to say this was not the fault of the University, or the College, or my tutors. Though I readily saw the potential in a different approach to life, it was simply too far away from two-stroke racing engines and the associated culture. Though I made good friends, I couldn’t quite adjust. The saving grace was that the clinical three years of the six-year course were generally undertaken elsewhere, usually in London. This offered a second chance.
The clinical medicine course at St. Bartholomew’s Hospital was well organised and I found much of it, particularly the process of medical diagnosis, very interesting. There were other good things. I met my wife Fiona there; Fiona was also a medical student. But, after Cambridge, I wasn’t taking any chances with examinations. I wasn’t quite sure what I wanted to do, but I wanted the freedom to choose. Still lacking those skills in Rugby Football, the easiest route to first choice in a House Physician job (and hence it seemed, to everything beyond) was a good performance in the final examinations. In these, the majority of marks were awarded through ‘multiple-choice’ questions. Now, as most of those who have set these examinations will know, there are only certain types of information that are suitable for the exercise. Besides, even when a question is not set properly it is possible to discern what question the examiner is trying to set and answer it. I greatly enjoyed the medical course in a wider sense and flirted with a career in most every speciality covered in the curriculum, but I applied the above logic to the examinations with a brutality that still makes me blush. The result, in the main examination, was substantially more marks than any other student. Perhaps naively, I had not seen the difficulty that this might create. I was surprised by a summons to meet with the sub-dean. Most likely drawing on his experience as a former member of the Hospital Rugby Club, he could think of only one explanation; I had acquired copies of the examination papers in advance of the event. The interview has forever made me sympathetic to the cause of minority groups in police stations. In the end however, he was good enough to recognise that without a confession, the evidence was at best circumstantial and I was duly appointed to the House Physician post of my choice, on a ‘firm’ specialising in Gastroenterology and Nephrology.
During that time, Larry Baker, the Consultant Nephrologist, kindly suggested that I should become a Nephrologist myself. As with the Headmaster at Lancaster Royal Grammar School, I didn’t doubt his wisdom and planned my career accordingly. Others were more cautious: Nephrology is an expensive speciality, and the UK National Health Service was not well resourced. I well remember being told by one of leaders in the speciality that there would only be two consultant positions coming up between then (circa 1980) and year 2000, so I had better distinguish myself, somehow. The first statement turned out to be untrue; but the second was chastening. As a busy trainee Nephrologist there was no real opportunity for laboratory research. So, as the necessary route to distinction, I took to writing medical case reports. In most scientific circles this would not be seen as a useful, let alone a distinguished, training. Later, I became adept at re-arranging my publication list, so this phase of my scientific development was less apparent. Later still, I have come to see it as critical. What is important in embarking on a research career is selecting the question; once the question is clear, answers may follow. For most of us this is the joy of academic research; we are free to pick our questions. I moved from London to Oxford to complete my clinical training in Nephrology. The experience of surveying the patients of London postgraduate and Oxford hospitals for case histories from which something new might be securely deduced, was without doubt a key experience. It didn’t directly inform the question I eventually chose, but it taught me how to look for potentially soluble problems amidst a mass of insoluble distractions.
There were a few false starts. I thought it would be possible to understand the physico-chemical properties of myoglobin that led to myoglobinuric kidney failure, using isolated perfused kidneys. I learnt kidney perfusion from Brian Ross, who had developed the technology under Hans Krebs, but myoglobin even at massive concentration had no effect on the preparation. I then thought it would be possible to use 31Phosphorus NMR measurements of cellular energetics to understand why the kidneys are susceptible to injury in shock and joined George Radda’s laboratory to study this, but the spatial resolution of the method was not sufficient. I thought it would be possible to understand why the kidneys make erythropoietin (the hormone that stimulates red blood cell production) in response to blood loss, but not to reduction in blood flow. I hadn’t properly considered the technical difficulty of measuring intra-renal haemodynamics and oxygen fluxes, under those conditions. So, none of these problems were solved, but they brought me progressively closer to the ‘oxygen sensing’ question.
Most of my colleagues in Nephrology worked on quite different topics in immunology, genetics or the control of blood pressure. The combination of a slightly awkward, non-compliant nature that led me to avoid these subjects, and the experience of looking for soluble problems, derived from that case-report era, brought me to the question. The sensitivity and precision of regulated erythropoietin production by the kidneys in responses to changes in blood oxygen content must, I felt, reflect an answerable and important question as to the nature of the underlying ‘oxygen sensing’ process. Not everyone agreed; recombinant erythropoietin was being used to great effect in kidney patients, why worry about its regulation? But I was convinced there would be an answer and that it would be interesting. Besides, the identification of the erythropoietin gene opened a new possibility to trace the transduction pathway from the erythropoietin gene locus ‘outwards’ to the putative oxygen sensor.
I had finished my clinical training in Nephrology and there was a decision to make; should I move from Oxford to take up one of those rare opportunities to become a Consultant Nephrologist in the National Health Service, one with supposedly protected research time? Or should I stay amongst friends in Oxford? By now I had made, at least in part, a cultural adjustment towards the ‘Oxbridge’ environment. A combination of kind personal assurances of support from David Weatherall and John Ledingham in the Department of Medicine, miserably heavy rainfall when I travelled to look at a Consultant position at a hospital in Wales, and extreme good fortune in an interview at the Wellcome Trust, conspired to convert what was surely a truly impossible ambition (to solve the problem as a working Consultant Nephrologist) to one which, as a well-funded Wellcome Trust Senior Fellow in Clinical Science, might just be possible.
But there were still problems to overcome. I had no technical knowledge at all of molecular cell biology. At the time, I wasn’t greatly concerned, though looking back, the level of ignorance must have raised a few eyebrows amongst my colleagues. This attitude owed a lot to my early experience as a junior doctor. The National Health Service was in perpetual crisis. My years as House Physician coincided with the end of the Callaghan government, and the UK’s ‘winter of discontent.’ Practically everyone was on strike and nothing worked. As far as I could see, in the eyes of the all-powerful senior staff, the solution to each and every problem within the hospital (and on occasion outside it) was that the House Physician or Registrar (the next grade up) would sort it out. Against this background, it had never before struck me that total lack of knowledge was a barrier to engagement with a problem. But now, even I could see that some external means of acquiring skills in molecular cell biology was necessary. I invested in a copy of Benjamin’s Lewin book Genes III and went to see a friend, John Bell, who I had met as a House Physician at the National Hospital for Nervous Diseases in London. John was generous in giving me a bench place, to work on erythropoietin regulation, in the midst of his crowded HLA immunogenetics laboratory. This was critical and set me up. So, here is my advice to the aspiring clinician scientist, take your time, look around carefully, pick your own question, then find a friend to help.
In fact, I had a number of friends who helped, most importantly David Weatherall, who, after my initiation in John’s laboratory, gave me some laboratory space of my own within his newly commissioned Institute of Molecular Medicine. In the adjacent bay was Richard Jones, to whom I owe a lot. Richard taught me much of the gene regulation technology we used in the early stages of the work. Carole Beaumont (on sabbatical with Richard) taught me tissue culture. Martin Johnson at Cambridge made transgenic mice for me, an attempt to derive the erythropoietin producing cells in kidney by expressing ‘T’ antigen at the erythropoietin locus. By now, there was growing confidence in the project, at least locally; a series of excellent trainee Nephrologists, Tan Chorh Chuan, Chris Pugh, Patrick Maxwell, John Firth, Jonathan Gleadle came, or were steered my way. Ben Ebert joined the laboratory as a Rhodes Scholar from the US; Masaya Nagao joined us from Japan. All were taking a risk, as I had no track record in the field.
It was a busy time. Fiona had also moved from London to Oxford. We married in 1983 and she was by then a trainee anaesthetist. During that critical period when I was finishing my own Nephrology training, deciding what to do and then setting up the laboratory, she bore our four children: Anna, Alice, Robert and David. I occasionally brought the very young children to the laboratory and entertained them with tricks with the dry ice, another iteration of my own childhood theme of explosives. I interfaced week-end experiments with family walks and trips to the seaside, and generally thought I was managing well. It is only in retrospect that I see the sheer enormity of Fiona’s task, managing her own training, the children and the household, almost single-handed. I owe so much to her fortitude.
There had been many unsuccessful attempts to understand the nature of the oxygen sensing process through pharmacological interventions on erythropoietin response to hypoxic stimuli. But identification of the erythropoietin gene gave us a new opportunity. It had been established that the erythropoietin gene was regulated by transcription. So, we argued, working from the gene it should be possible define oxygen-regulated control sequences at the locus and then dissect our way through the transcriptional and signal transduction pathways to the putative oxygen sensor. Nevertheless, despite a lot of talent and enthusiasm in the laboratory, none of us had a biochemical training. And beyond the identification of the oxygen-regulated control sequences by gene transfer, the most obvious approaches to dissecting those pathways were biochemical. As Richard Jones explained, the new molecular approaches based around the gene had opened research questions in cell biology to amateurs like myself, who had come into the laboratory with no training in biochemistry, but there were limitations to this. Even the environment David Weatherall had created with his Institute of Molecular Medicine could not address this deficiency. We spent a lot of time discussing alternative genetic approaches to the problem. One of these led directly, but unexpectedly, to our first breakthrough.
It had long been assumed that the extraordinary sensitivity of erythropoietin to reduction in blood oxygen reflected the function of a high specialised oxygen sensor that was specific to the erythropoietin producing cells themselves. Erythropoietin is produced by cells in the kidneys and to a lesser extent the liver. We had spent a lot of time trying unsuccessfully to culture these cells from the kidneys of the erythropoietin – T antigen transgenic mice. In the end, it was cell lines from the liver, shown by Franklin Bunn and colleagues at Harvard to produce erythropoietin in response to hypoxia, which opened the molecular approach. We and others used these cells as the vehicle to define the oxygen-sensing control sequences at the erythropoietin locus. But then there was my biochemistry problem; how to get to the target, that oxygen sensing mechanism lying further upstream. Another scientist in the Institute, Dave Simmons, was successfully using ‘expression cloning’ in Cos7 cells to identify surface receptors and cell adhesion molecules. I thought I would use this technology to identify upstream components of the oxygen-sensitive pathway by gene transfer. This would be from Franklin Bunn’s oxygen-sensitive hepatoma cells to the Cos7 cells, which I believed would not be intrinsically oxygen sensitive as they do not make erythropoietin. To my great surprise, control experiments – designed to check the absence of oxygen sensitivity prior to gene transfer – clearly showed the same oxygen sensitivity of those control sequences isolated from the erythropoietin locus, in Cos7 cells.
This of course disqualified the intended experiment but changed everything in my scientific life. It was the first evidence of a widespread human oxygen sensing system, manifestly operating beyond erythropoietin. The implications were clear, there must be other targets in non-erythropoietin producing cells, which are also regulated with great sensitivity by oxygen levels. We found the first of these: enzymes encoding specific isoforms glycolytic genes that are also upregulated in cancer, connecting us with the cancer metabolism and oncology communities. Although the work didn’t immediately attract so much attention, and there were initial difficulties in publication, from that moment we were confident we were on to something important. Nevertheless, the lag between the tremendous excitement running through the still small group of scientists working on this problem, and interest developing in the general scientific community, was very striking. It still colours my advice to young scientists; when deciding what to do, try very hard to ignore the interests and prejudices of those around you, they will likely be a very long way behind the curve. However, the field grew steadily as more and more people found new pathways that responded to HIF (Hypoxia Inducible Factor, the transcription factor binding those oxygen-regulated sequences, which was discovered by Gregg Semenza). However, I think all of us were surprised by the extent of the HIF transcriptional cascade and the extent to which so many responses to hypoxia (low tissue oxygen levels) had previously been overlooked. Many of the new responses to hypoxia were fascinating in their own right, but our intention had always been to work our way upstream to the oxygen sensing mechanism itself and our attention shifted back.
By now we were an established group in David’s Institute of Molecular Medicine and we took advantage of everything it had to offer. Half of an entire floor in the building was given over to the Institute’s coffee room. David had clearly been impressed by this much championed facility at the Laboratory of Molecular Biology in Cambridge. Coffee was made in advance, dispensed with impressive efficiency and consumed in armchairs of exactly the correct design and spacing to support conversation. The room was carpeted. For those considering institutional design, every detail of this matters. We sat there with anyone who would listen and speculated (mainly unproductively) about what the mechanism of oxygen sensing might be, and (a little more productively) on experimental strategies that we might use to define it. With every visitor I considered their work from the perspective of its potential to solve the oxygen sensing problem, my problem. We tried to harness a whole range of gene transfer and expression cloning methodologies, we examined model organisms for conservation of the pathway, hoping to harness genetic methods in flies, nematodes worms, or even yeast. I was impressed by George Stark’s use of somatic cell genetics for dissection of interferon response pathways. Morwenna Wood and Emma Vaux, two highly competent trainee Nephrologists, spent vast amounts of time engineering Chinese Hamster Ovary cells to express hypoxia inducible transgenes encoding cell surface markers, and then selecting mutants with defective responses to hypoxia. To their enormous credit, they did isolate valuable mutants, but it proved difficult to identify the defective genes beyond those encoding components such as HIF that we already knew about.
In the end, it was a mixture of genetic and biochemical approaches that brought us step by step towards the solution. Each advance was incremental, to use that favourite word of editors when declining manuscripts. Defining the regulatory domains in HIF that mediated oxygen sensitivity of the complex, demonstrating the physical association of those domains with the von Hippel-Lindau protein (pVHL), showing the function of pVHL as a ubiquitin ligase that degrades HIF, the discovery of prolyl hydroxylation as the mechanism governing oxygen-regulated association of pVHL with HIF, evidence that the enzymes catalysing HIF prolyl hydroxylation belonged to the 2-oxoglutarate dependent dioxygenase family, identification of the actual enzymes and their oxygen sensitivity, were all incremental steps. I was one of those fortunate enough to be called to Stockholm for our contributions to this work, but there were many others whose work contributed to, and was informed by, the timely publication of all those incremental advances.
The final steps, involving the identification of the actual oxygen sensing 2-oxoglutarate dependent dioxygenases that catalyse the prolyl hydroxylation of HIF, were taken together with my friend and colleague Christopher Schofield, with whom my laboratory continues to enjoy great collaborations. Chris (Professor of Organic Chemistry at Oxford) brought the biochemical perspective that I lacked to the work. But the original collaborative work was not a large-scale biochemical purification, which I had previously envisaged being necessary at some stage in the programme. Rather, based on his earlier structural analyses of 2-oxoglutarate dependent dioxygenases and related enzymes, Chris was able to predict genes that might encode the putative oxygen sensing prolyl hydroxylase. Meantime one of our earlier exploratory ventures, hatched in the Weatherall coffee room, had involved identifying the HIF orthologue in Caenorrhabditis elegans and, very importantly, raising an antibody against the protein. This enabled us to assess mutants for their impact on the proteolytic regulation of the HIF by hypoxia, but so far none had shown an abnormality. One of Chris’s predicted 2-oxoglutarate dependent dioxygenases was represented in the libraries of mutant C. elegans that were so beautifully catalogued and efficiently provided by the nematode worm genetics community. Worms bearing mutant alleles of the relevant gene were identified via WormBase and duly ordered.
I have a vivid recall of one morning in March 2001; Andy Epstein, a PhD student in the lab burst into my office, exclaiming, ‘here’s your gene, Egl9’. Three different alleles of the mutant Egl9 gene, previously characterised by the Nobel Laureate Bob Horvitz on the mechanistically agnostic basis of defective expulsion of their eggs, all showed upregulation of their HIF, irrespective of oxygen levels, as would be predicted for a defective enzyme whose oxygen-dependent catalysis of prolyl hydroxylation was physiologically deployed to signal oxygen levels. We were rapidly able to confirm this and identify three human orthologues. Jonathan Gleadle, one of the trainee Nephrologists who joined the laboratory and did some of early work defining HIF-target genes, had returned to the group after completing his clinical training. Jonathan identified the human orthologue of Egl9 on the basis of a highly conserved catalytic domain and called their products the PHD (prolyl hydroxylase domain) enzymes. Those findings completed that journey I embarked on as a young Nephrologist, from erythropoietin to oxygen. The high points in that journey were exciting, very exciting; the low points I tend to forget. The experience was addictive, and I am always looking for the next of those ‘eureka’ discovery moments.
Though the work provided an answer to a question, defence of oxygen homeostasis is clearly more complex. Severe hypoxia is fatal within minutes and oxygen homeostasis must be maintained over much shorter and longer timescales than those mediated by the transcriptional pathways we have so far unravelled. For instance, the oxygen sensitive signals by which the carotid body controls breathing, part of the work for which the Nobel Prize for Physiology or Medicine was awarded to Corneille Heymans in 1939, are still not understood at the molecular level. The laboratory works on these and other as yet unsolved problems in the physiology of oxygen homeostasis. Although we were at first surprised to find that the HIF system operated generally in mammalian cells, and was not restricted to erythropoietin producing cells, we were then surprised that it was apparently restricted to animal life, there being no obvious HIF orthologue in non-metazoan species. It is now clear that species in all four eukaryotic kingdoms deploy enzymatic protein oxidations coupled to protein degradation to signal oxygen levels in their cells. However, the oxidations are of different types and coupled in different ways to the signalling systems, raising questions as to the origins of these systems, their inter-relations and whether they also function in human oxygen sensing. I also became interested in cancer, in particular the implications of oncogenic ‘switching’ of very extensive interconnected physiological pathways, such as occurs when the pVHL ubiquitin ligase is inactivated and the HIF system is unphysiologically activated in kidney cancer. I imagine that this paradigm, in particular the mechanisms by which the developing cancer ‘accommodates’ adverse components of the oncogenically-activated pathway will be important in understanding the disease. For these reasons, supported by loyal staff who have stayed with me for years, the laboratory remains as active, or at least as hopeful, as ever, and I remain as addicted as ever to the discovery process.
But there have been new experiences. I worked with small and large companies on the development of HIF hydroxylase inhibitors for the treatment of anaemia, and perhaps other ischaemic/hypoxic diseases. This is an interesting experience for an experimental scientist used to near-total control of an experimental research programme. It is very satisfying to see the work progressing towards a medicine, though somewhat alarming not to have that control. But there is the same unpredictability. Given that the field started with the regulation of erythropoietin, it is no surprise that the 2-oxoglutarate analogues being developed as HIF hydroxylase inhibitors will induce erythropoietin production and correct the anaemia of erythropoietin deficiency. But given the extent of the HIF transcriptional cascade that became apparent, I don’t think the scientific community would have predicted that this could be done without a major dysregulation of other responses to hypoxia, as appears from current clinical experience to be the case. I learned a certain respect for those taking the risks that are intrinsic to the medicine development process.
In 2003, I was approached about taking on the Headship of the Department of Clinical Medicine. John Bell had succeeded David Weatherall into this chair and was now moving (as David had) to the Regius Chair. I hesitated, knowing very well that University administration was not a natural suit. But the Department was interesting. Under the successful tenure of David and John it had grown well beyond the norms of a University Department, more the size of a small University, with a research budget that would come well up the UK university league. It was and is (in accordance with the name) a Department of Clinical Medicine but encompassed an extraordinary range of disciplines ranging across structural biology, large-scale human genetics, clinical trials, epidemiology, molecular cell biology, to tropical medicine and the teaching of clinical medicine within the National Health Service. An expectation was that the senior professorial staff would contribute to the Acute Medicine Rota and teach medical students in that context. With my training in Clinical Nephrology and continuing practice in both Nephrology and Acute Medicine for much of the period I have just described, I could actually do this. My perception was that this was slightly to the surprise of a number of the other medical and nursing staff working in the relevant service; it certainty filled some of my post-docs in the laboratory with horror. They felt that this sort of ‘high tension’ medicine should only be performed by highly professional, and very good-looking staff in surgical scrubs, as they had seen on TV. I have never been completely sure as to which attributes, they felt to be lacking in myself. However, clinical medicine was only part of the experience. Across all its domains the Department encompassed more than 2000 staff, including many working in tropical South-East Asia and Sub-Saharan Africa. Academic management of this scale is a challenge, by and large I learned not to attempt it. I learned a lot about people, particularly creative people. In the Department, as in the laboratory, the most surprising things (to me) turned out to have their value. I learned tolerance and firmly believe that science is, or should be, one of the great unifying forces in a world of diversity. Of course, a persistent problem was balancing Departmental matters with the running of the laboratory, and I’m grateful to many on both sides of that equation who ensured at least a modicum of success. But I avoided further progression in academic management, and after more than a decade in the position, looked for opportunities that might give me more time in the laboratory and new scientific horizons.
It was therefore a piece of good fortune when, in 2015, Paul Nurse approached me about a position at the shortly-to-be-opened Francis Crick Institute, to develop its interface with clinical practitioners and clinical medicine. Here, I thought my unusual experience of different sides of medicine might be useful. And there were new scientific horizons. The key point about the journey that I have just described is that it is the selecting of the research question that matters. The purpose of bringing clinical practitioners to a major biomedical research institute such as the Crick is that they will ask new questions, not necessarily clinical ones, simply different ones. I combined the Crick position on a 50/50 basis with running my laboratory in Oxford as a member of the Ludwig Institute of Cancer Research and felt I had things under control, at least until one morning in October.
I had heard mention of the Nobel in discussions of the merits or otherwise of the work on oxygen sensing, but the news that morning was a surprise. I had reached that all-too-familiar crisis point in writing a grant application with colleagues from Finland and had been writing most of the weekend. In the frenzy of activity, I had quite forgotten the significance of the first Monday in October. But my personal assistant, Catherine, does not forget things. It was Catherine who pulled me out of the Monday morning laboratory meeting to take the call from Thomas Perlmann and then replaced my strong coffee with a calming mug of tea when I returned to finish the meeting. A great deal of champagne was subsequently consumed in the laboratory throughout the day and, as television viewers observed, standards of safety became lax. Many have recounted the rather surreal experience of being bestowed with omniscience, overnight. Even the children (now grown up) thought I might have a useful opinion on things, for a short period of time. But the experience in Stockholm is worth restating.
The attention to making Nobel Week a celebration, and a happy time in every way possible way, was truly remarkable. Every event was managed to perfection, every microphone tuned precisely, all electronic projection flawless. The King was majestic, the Queen was gracious and Princesses stunning. Breakfast in the Grand Hôtel, overlooking the Stockholms ström, is one of most pleasurable experiences on the planet. The week’s hectic schedule was efficiently managed by our attaché Jane Viol. It even seemed my motor-racing aspirations had been considered; our driver Bo Cravell was an ex-rally champion. There was just one hiccup. The family travelled to Stockholm with our new-born granddaughter, her mother (Anna) and father (Rupert) having hastily obtained a passport. At the point of maximum tension, dressing for the ceremony, it emerged that it would not be possible to accommodate the baby at the five-hour banquet, in any way whatsoever. My wife Fiona took the matter seriously. After 37 years of marriage, I did not doubt the outcome. I carried on wrestling with buttons on the formal attire. I think Miss Elizabeth Merryn Everleigh is youngest to attend that magnificent Nobel banquet, safely tucked away under that very grand staircase through which we had entered the Hall. What a day.
This autobiography/biography was written at the time of the award and later published in the book series Les Prix Nobel/ Nobel Lectures/The Nobel Prizes. The information is sometimes updated with an addendum submitted by the Laureate.
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