AUTHORS: Dr Sanketh Rampes and Dr Anvarjon Mukhammadaminov
In this series the Medspire team interviews doctors about their career, their specialty, the choices they have made and their advice for doctors and medical students.
Today, the subject is professor James Spicer, professor of experimental cancer medicine at King's College, London, and an honorary consultant of medical oncology at Guy's and St Thomas' Hospitals. Professor Spicer runs the Phase I trials programme at King's Health Partners, and leads the King's Experimental Cancer Medicine Centre. His research focuses on the development of new cancer drugs and the care of patients with lung cancer, with a special focus on novel immunotherapies.
A podcast of this interview is available here:
How did you get to where you are today?
My career has been about a journey rather than a destination, and that's probably just as well, because the journey was slightly circuitous at times. I was not actually a medical student the first time around.
When I left school I was interested in life science, particularly in molecular life science, but wasn't totally convinced that patients were creatures I wanted to spend very much time with. That came later on, with maturity.
My first undergraduate degree was biochemistry, which was a four-year course in Oxford. The fourth year allowed us to specialise in areas of interest, and I found myself picking options around the growing field of molecular medicine.
Around that time, diseases like cystic fibrosis and Duchenne muscular dystrophy were being characterised at the molecular level. A lot of this work grew out of the molecular genetics of them - benign, haematological conditions like sickle cell disease and thalassaemia, and the work of David Weatherall, who went on to found an institute that became the IMM in Oxford.
So that was really the beginning of molecular medicine, and it was inevitable that I segued from the ‘molecular bit’ to medicine.
By the time I graduated, I was thinking seriously about whether I should be applying to medical school. That is quite a serious consideration when you've just finished four years as an undergraduate. It was very hard to find graduate entry programmes in those days.
It would be another five years of study, so I baulked at that decision. It was the late 80s. The economy was booming, and pretty much anyone could fall into a well remunerated job in finance.
So that's what I did, for three years. I worked for an American investment bank called JP Morgan, which is a very effective outfit. It was a lovely place to work, full of fantastic, bright, motivated people - a bit like medicine. I was happy enough there, but by the time I reached my mid-20s, I was looking around.
I realised that wasn't my niche for life, and thought increasingly about what was, by then, an even more exciting world of molecular medicine. So I took the plunge, and packed up my desk in Throgmorton Street - just behind the Bank of England - one Friday.
On Monday morning I signed on as a med student across the river at Guy's. I trained there as an undergraduate, and then, after house jobs, went around most of the hospitals in London, doing general medical training.
Then I came back to Guy's and St Thomas' for my oncology specialist training, which is closely linked with St George's Hospital - a lovely rotation. I inevitably found myself being interested in drug development, which in oncology is very driven by an understanding of the molecular aspects of the disease - if you can call cancer ‘one disease’.
I went back to the Marsden to train in Phase I trials and drug development. Then I was recruited to set up that activity at Guy's and St Thomas'. I've been there for about 15 years.
What made you switch to medicine?
I found myself in my mid-20s reflecting on ‘what it was all for’, which is not unusual. I was equipped and interested in some areas which could be relevant and make a contribution - however you define that in life.
I felt that contribution was going to come in the area that I have ended up in, rather than breaking through new barriers in finance, which never really ‘floated my boat’. I found myself in that role having a lot of fun and learning a lot, and meeting some fascinating people, who are in many cases still friends.
But when you have to really think about providing motivation when you get out of bed in the morning, you're always going to struggle to keep up with the pack, and that never really was ‘my bag’.
I got to where I really wanted to be just in time before I was getting too ‘long in the tooth’. I know some people start as so-called mature students in medicine quite late in life, and that's the right decision for some.
For me, it was just about the right stage and got me fully qualified and working as a doctor just before I left my twenties, which was fine for me and pretty standard in many parts of the world.
I got way more out of being an undergraduate medic having a slightly more sensible head on my shoulders, than I might have done at some stages when I was an undergraduate the first time around. I lived a pretty good life as an undergraduate, and probably wouldn't have survived the academic rigours of medicine the first time around.
So it all worked out well at that stage. Amazingly, if you would ask me to write my job description at that early stage, it probably would look quite like what I'm doing at the moment, which makes it all sound very well planned and organised. There's a lot of serendipity and ‘moving with the stream’ in careers in medicine.
Is there anything you learned as an investment banker?
It taught me not to be afraid of putting in the hours. I'm old enough now to have young adult children. One of the most valuable things they've learnt by example from me and my wife - who has a very different career but puts her heart and soul into it - is that ‘you reap what you sow’.
I certainly learnt that. If I was naturally brilliant maybe I could cut some corners. But most of us just have to work hard to get where we want - that's what I learnt.
What advice would you give doctors thinking about moving to banking or finance?
The other favourite switch has been to careers like law, and especially, management consulting. I'm always slightly nervous when I hear that suggestion from people, because medicine is such a ‘broad church’.
There are so many ways of finding your way in this discipline. It's too broad even to call it a discipline. If you think about the range of jobs that you can end up in, graduating in medicine, it's hard to understand how people can't find a niche for themselves.
Even if you don't like patients, there's always pathology. I always counsel caution in that context, particularly if you've invested years of your life as an undergraduate medic and then postgraduate training. It's a lot to turn your back on, especially when there are so many opportunities.
A lot of it's about this misapprehension that somehow the grass is greener in other careers. Having made the change in the direction I did, I know that it's not a bed of roses working in a very competitive, private sector where really the only thing that matters is return on investment and dollars.
It's not a huge incentive for me to get out of bed in the morning, either to earn money for myself, or particularly for somebody else, or some big corporation. So I would approach that particular switch with caution, unless there are very good reasons that you can't work in medicine any more.
What attracts you to oncology as a specialty?
I was always attracted to the science of medicine - I know that's not the case for all doctors. The population that apply and are accepted to medical schools like King's, tend to be those who have a scientific approach to medicine.
Certainly, that was my angle - I was interested in understanding the molecules of medicine. Another takeaway that I had from working in the commercial world, was that there you absolutely live or die by your social interactions.
Meeting people with different agendas, different problems, and different perspectives, I realised it was actually more interesting than I thought, having grown up being quite dry, academically. So that for me is the clincher - that medicine is a great combination of being a scientist and caring for patients.
I could have gone on to do a PhD in biochemistry, if that was all I was interested in. What leavens that in medicine - and still all these years later - is that sometimes it's a real joy. It really lifts the heart to leave your latest, slightly painful grant application, or recalcitrant postgraduate student, to see some patients in the clinic.
That's what we all learn to love through a career in medicine. That for me is the bit that came the latest, and was the final piece in the jigsaw, which made this the appealing career that it turned out to be.
What are the biggest changes you have witnessed in oncology?
There are two big transformations - even in my relatively young career. I've been a doctor for 25 years, and differentiated towards oncology for much of that. In that period, we've moved from an area where we were excited if we had a new chemotherapy drug in medical oncology - which is the use of systemic therapies or drugs as very broadly defined.
Back in the 1990s that was all we had - chemotherapy drugs with a very few exceptions like tamoxifen, the first successful endocrine therapy. We moved up very quickly through the gears, really in parallel with my young career. I can't take any credit for it at that stage, but I was extremely lucky to be ‘surfing a wave’. The first wave was the spectacular arrival of targeted therapy, just at the turn of this century.
So imatinib was the first so-called ‘magic bullet’ drug, which was designed to inhibit leukaemic cells that have a very specific molecular defect. That was very big news, even outside oncology, and that was the drug that hit the front page of Time magazine.
That opened up a tidal wave of targeted therapies, which very quickly rolled out from haematology into solid tumour oncology, and kept us all very busy and motivated through the first decade of this century.
Then, just then when we thought we were catching up with all the developments in the last decade, we've had another revolution, which is the new immunotherapies, which happened to be a particular interest of our unit at Guy's, and of many of my academic colleagues in King's College London.
In part, because King's has long been interested in immunology, and strong on the application of immunology to cancer - which is what immunotherapy is all about.
Where do you see oncology heading?
The personalisation of oncology. It’s a trend already. Bespoke medicine, according to the details of a particular patient's disease, is applicable in many areas of medicine, but really exemplified in cancer, where the disease itself is so diverse.
So we're dealing with a genetic disease. Not necessarily an inherited disease - that's not what I mean by genetic in this context. It's a disease that's driven at the level of the genome. So understanding what DNA sequence abnormalities are driving the cancer phenotype has been the key to understanding cancer biology.
That in turn has allowed us to identify, in some cases, extremely effective targets for new therapies. We're already at the point where we routinely profile patients' tumours genetically, if not completely genomically, just yet.
In most examples it's quite a focused genomic understanding that we need, in order to choose currently approved and available drugs, but there are more and more examples.
So in the lung cancer multidisciplinary team meeting, for example, where we discuss all the newly presenting patients with thoracic malignancies at Guy's that week, we need molecular pathology results for most of those patients, if they have advanced stage disease.
Those are the modalities that have cured more cancer patients than any medical oncologist like me to date. Here, I'm talking about the great majority, in some diseases, of patients with diseases with advanced stage. In other words disease that's spread around the body.
These are not patients who can be cured by a surgeon's knife or by a focused X-ray beam from a linear accelerator. So they're dependent on so-called ‘systemic therapy’, which is where I come in. In those areas in the thoracic MDT, for all lung cancer patients with the commonest histology, we now want to know quite a number of genetic results.
We want to know if there's an activating EGFR mutation, a mutation in KRAS, and rearrangement of genes like ALK, ROS1, and RET - whether there's an expression, or not expression of a immunotherapy target called PD-L1.
So that's just for standards of care for drugs which are routinely used and funded in the NHS. Regarding the portfolio of trials, there are fully 50 per cent of drugs in development in the world at the moment, which are in development for cancer.
There are a lot of trials going on around the world, and many hundreds in the UK. So to select patients for many of those trials, we need more molecular information.
So that's the trend which is already coming down the track, and as you may have heard, we're not far from having fairly routine genomic profiling for a large proportion of cancer patients across the NHS.
That will allow us to continue to extend the envelope of the population of patients, where we're not just taking a drug out of a draw, and giving it to everyone who's cancer label says breast cancer. We're actually interrogating their tumour and asking: 'We know it's breast cancer, but what's the best treatment?'
Medical oncology is a competitive specialty. What advice would you give medical students and doctors interested in pursuing this career?
First of all I would say, 'Go for it’. Why wouldn't I? It's given me everything that I had hoped for in a medical career. I may have ‘over-egged’ the science. In medical oncology, if you're not interested in science you are going to struggle. It's a new specialty.
The first medical oncologists appointed in the UK weren't really around until the late 1960s, so the discipline is historically driven by research. That's still generally the case, and most practising consultant level medical oncologists have a PhD at some stage.
That's not to say that there's not plenty more to offer. Some of my arguments are ultimate in holistic diseases to treat. There's nothing more all encompassing than a cancer diagnosis in many cases.
That allows the oncologist and their patient to get to know each other pretty well with a continuing relationship, not an episodic getting to know someone, giving them therapy, and saying 'Goodbye’. It would be great if we had that kind of practice, but unfortunately I don't have any interactions like that.
So that allows for a very rewarding clinical experience - that you get to know, and hopefully develop some trust with a patient. You go on a journey together, trying to make the best of their situation.
Increasingly, we have a lot to offer, and some patients do spectacularly well. It would be completely disingenuous to claim that we're providing a permanent solution for everybody - far from it.
So if you find having tough conversations with people about difficult situations like death and dying, then it's not a discipline for you.
Like many difficult things in life, if you do that well it can be uniquely rewarding. So there are many aspects that if you're made of the right stuff, if it suits you, that you would find rewarding about an oncology career - particularly medical oncology.
How did you become involved in research?
From the beginning, I was looking for an aspect of medicine that was driven by research, and I was clear from preclinical, undergraduate medical years that oncology was going to be my target. There wasn't much room for debate.
That decision made itself for me, quite early on. I realised that for many people it’s not the case that they've got a particular passion from the beginning of their medical career.
I guess most of us go through a stage where we're determined we're going to be a paediatric surgeon or something, but then we realise there's only about five of those in the whole of the country. So you have to think of a second best.
What does your role as professor of experimental cancer medicine at King's College, London involve?
The cancer centre, which is now one of the pre-eminent ones in the country, was growing very rapidly in the early 2000s. Yet there was a bit of a gap in what we could offer, particularly around newer therapies.
Guy's cancer centre has been at the forefront of clinical trials for a long time, particularly late phase trials - mostly the big, randomised trials that lead to approvals of new interventions. But until 2006, we didn't have any capability for testing new drugs in cancer. That's what I was brought in to fix.
We founded a new unit and treated the very first Phase I cancer patient there in 2007. Now there are four of us at a consultant level running a unit, which has got plenty of nurses, child practitioners, clinical fellows, and registrars helping us deliver these trials.
With some of the trials we're working with industry. A rewarding aspect of our role is that in some respects it’s a bit more outward looking than many NHS roles.
I can't come into work and interact only with King's and Guy's people all day, because 80% of new drugs are developed in industry, so if we're not talking to those guys, we're not going to be offering our patients the latest good therapies.
So that's what really underpins my research efforts - bringing newer drugs into the clinic, whether that's from biotech or pharma. The ‘icing on the cake’ is bringing some King's discovered therapy into the clinic, and we've got two of those in the Phase I clinic currently recruiting for a Phase I trial.
These are what I do, and what my job description is meant to capture. Working in a place like this, there are so many other areas for research. We work with many interesting laboratory based collaborators, maybe discovering new targets or developing new therapies.
In recent years, when everyone's life has been changed, even in the cancer centre, we've contributed quite a lot to COVID research, and particularly with an angle of how the disease can impact cancer patients.
Despite the fact we were very busy keeping the cancer service going, and trying to maintain access to trials through all of that, such is the momentum and energy of people around us that we were able to contribute quite a bit in that direction too, and I played a small part in some of those studies.
How do you select treatments that progress to the Phase I trials, and what interesting treatments have you come across?
Such has been the explosion of, or understanding of the biology, that there's a lot of candidate targets out there, and way too many candidate therapies than we can ever test. There just aren't enough patients to run all the potential trials that could be planned, even in one specialty like ours in oncology.
We have to be selective from the start, and that may be as straightforward and technical as picking a drug from a potential class, which is most potent. We're talking about binding affinities, but it's also about picking things which are most novel.
That's the excitement of being a Phase I trial in an academic environment. There are always plenty of drugs to test. Something that's really new and out there is often something which industry is rather reluctant to test, because of the risk involved, and because in part, risk is academically interesting - particularly if it pays off.
That can be a potent area for someone in my position to set up their stall, because those are the grants that get awarded. They are very novel, and potentially you're proposing something which may not be answered, despite the deep pockets in the pharmaceutical industry.
So those are the criteria that I apply. On the one hand what's the likelihood of its success? That's key from a patient's perspective - providing a spectrum of opportunities treatment-wise for our patient population.
We're delivering a service as well as a research agenda. Then finally, what can we really contribute to the world as academic trialists? A lot of that answer is around novelty.
What are the joys and challenges of working with industry?
There's many more joys than challenges. Lots of people imagine that industry is this voracious beast that doesn't care about the patient. There are famous artistic contributors to that world view. The Constant Gardener is a film about a rather infamous episode in which clinical trials disadvantage patients.
Those images stick in people's minds. But I often reflect on this, and I'm quite often asked about it. In quite a significantly long period of time, I've never had such an interaction with a colleague in industry, whether that's a big rather faceless global organisation, or a small start-up biotech run on a shoestring.
I've never had an uncomfortable relationship where the suggestion was that we do X, where I suggested Y, and that X was clearly not in the best interests of the patient.
Similarly, it's very uncommon that industry colleagues are seeking to bury unwelcome information. Generally speaking they may be too close to the problem if you like. If you're working in a small company that's only got one product, sometimes you need partners like us who have a portfolio of interests, who can really give the bad news that a drug isn't going anywhere.
We need to stop it, and that's explicitly an intention of early phase, Phase I trials. One major contribution we can make is to take a drug which is actually not doing what it should, to discontinue its development as soon as possible. Before too many patients are exposed to an ineffective drug, and before too much money is wasted trying to develop it.
Of all your ongoing research, which area or project excites you the most?
There are a number. It’s great to see, coming into our unit, therapies that have been discovered and developed at King's and Guy's - that's a fantastically holistic story.
For example, working with one of my close collaborators and King's colleagues, Professor Sophia Karagiannis, who is an antibody biologist, we are currently testing in the clinic the first ever IgE therapy for cancer. That's been pretty tough at times, but a very rewarding and revealing academic, as well as clinical journey.
It ticks those boxes of novelty. It's a crazy idea if you think about it for too long, and that's probably why pharma hasn't done it. We have treated people with these drugs, and we've seen signs of anti-cancer efficacy and tolerability, which many people didn't predict. So that's pretty rewarding.
Tell us about your work looking at the impact of COVID on cancer deaths, and the subsequent economic impact, published in The Lancet and the European Journal of Cancer.
I'm not going to take any of the credit for that work. I was rather peripherally involved, as someone who has done a lot of clinical oncology treating patients in all sorts of environments.
I have some very good colleagues who work in very diverse areas, and that again speaks to the wide ranging appeal of medicine in general, and oncology in particular. There are so many different areas you can make a contribution.
So in this context it's population-based science, which provides a lot of insight. Some of the work was driven by a very powerful epidemiological technique, where you can take databases, for example.
Cancer is a disease with which we have very good numbers, because all cancer cases are registered centrally in the UK. So we know a lot about what is the usual prevalence and incidence of cancers, and what's their usual stage distribution.
So with that, and with other NHS data, it was possible to study and extrapolate from some of the data on how cancer presents, which has been very much in the news.
What has been the impact beyond infectious diseases of COVID? Potentially one big impact was on cancer at the time of the ‘first wave’. One of the first things that happened during that lockdown, and the early surge of COVID cases, was that patients stayed home, even if they had worrying symptoms of cancer.
For example, in my lung cancer practice it's clear that we're seeing more patients who sat at home for a long time with breathlessness and cough, which otherwise they would have taken to their GP and had an earlier chest X-ray.
Over the last year, too many of them have waited until they couldn't wait any longer and were admitted as an emergency. Patients who present with a medical crisis like this are likely to have much more advanced disease, which will be much more difficult to treat - if it’s even treatable - and therefore are likely to have a much poorer outcome.
The research was looking at the self-evident fact that patients were presenting later. It was modelling from the relationship we already know, between stage and clinical outcome, what the likely impact on the morbidity, and particularly mortality, from some of the common cancer diagnoses was likely to be, purely as a result of the knock-on effects of COVID.
What advice would you give to doctors and students who are interested in becoming involved in research?
It's never too early to start. I remember as an undergraduate medical student assisting one of the surgeons on-call doing an emergency resection of an ischaemic small bowel in an elderly patient.
During the course of the operation there were some slightly strange appearances to the bowel mucosa. If you've seen an ischaemic bowel, it's pretty obvious that it's dead and that bit needed to come out, but then there was the normal mucosa a bit further away.
Then, in between, there were some rather strange appearances, which it turned out under the microscope were necrotic Peyer's patches, the lymphoid tissue in the mucosa of the bowel. These, it turned out, if you're right on the watershed blood-supply-wise, tend to be the first bits of the mucosa to die.
So this was an interesting appearance, and the surgeon said in passing: 'Maybe we should write up this case on how this appearance can be a bit misleading when choosing where to make the resection margin in this kind of emergency presentation’.
A couple of us on the firm thought that would be a nice thing to do, and maybe get ourselves an authorship on a paper. And that was my very first paper. ‘From small acorns’ - you never know where it's going to go.
So if you see and hear something interesting, why don't you make something of it? Most of your mentors throughout your career will be very encouraging, I know. Take the opportunities when they arise, and don't be afraid to be enthusiastic.
Don't be too cowed by the constant pressure of everyday learning, which we never forget as medical students. Just preparing for the next exam or viva is demanding of time, and we all have other things to do in our lives as well. If you're interested in research you will have to get used to making room for it.
I still do that today. There are so many other pressures, clinical, administrative, and otherwise in our working lives, which, from a time perspective, are always more pressing than finalising our latest manuscript or grant.
Those things just have to get done, somehow and some time, if you're ever going to make progress. There’s no substitute for applying your ‘shoulder to the wheel’ if you want to make progress in your own career.
What important lessons have you learned during your career?
The main thing is you ‘reap what you sow’ in working life, and in life in general. It's the same in a clinical career as in a research career. But if you take an interest in your patients and their problems, you do a better job for them.
If you have a big research component in your working week, that's something you will get so much more out of, if you go the extra mile. That's self-evident in a research world. It's rather different from a lot of medicine.
That's what makes a research academic clinical career quite demanding sometimes - your mindset that’s instilled into you at medical school is often quite reactive. Here is a constellation of symptoms and signs and investigations, now what's the answer and what are you going to do?
That's effectively what doing a ward round or being in clinic is about. Here's a pile of problems and you just keep churning away until you've answered them all to the best of your ability. Research is a bit different, because you arrive at your desk in the morning with a blank piece of paper, and unless you put pen to paper, nothing's going to happen.
It's not a reactive process - it's a proactive, creative process. I don't think I'm the most creative person intellectually - far from it. I don't think that's been a huge handicap. Taking hints and opportunities and making the most of them is a pretty good substitute for real, original thinking. That's been my philosophy.
Do you have any habits that have helped your career?
No. But I do have ways of thinking. It’s important to be self-critical and reflect on what you do. Constructively critical - you would never get anywhere if you were shooting yourself down the whole time.
But I think most people who are selected for medical training and survive it have an element of that. That's really important and it makes for an effective clinical practice, and for a more rewarding one. If I was working in a world where I thought there was only one answer to every clinical question, then that would be a pretty unrewarding world.
Having some ‘greyness’ and maybe some less good answers but no completely perfect ones - that's an important step to take psychologically, as you learn and practice medicine. So emphasising what, for a lot of us, is a natural propensity to be a bit reflective about what we do in life is something worth building on.
It's also important to have good life hygiene, by which I mean, if all you do is sleep, eat and come to work you're going to struggle, particularly in some of the more demanding clinical areas. So have some ways to offload and recharge.
For some people that's their family. For some people that's athletics or the arts. You have to have something for your own sake, and for the sake of those around you. People who are too single-minded can be quite boring.
Are there any role models who have had a lasting impact on you?
Here's a warning. Those charismatic clinical teachers who take you around the wards now, will never leave you. You will be reflecting on the words of wisdom you get from them for the rest of your career. I can think about specific clinical episodes from thirty years ago which still live with me.
Not because they were necessarily traumatic, but because they were great learning points. Actually, surprisingly, some of those role models who are senior physicians at Guy's Hospital only recently retired. They taught me, and certainly inspired me clinically.
Latterly, some of the senior oncologists who trained me as a specialist will always be there in my mind, and have very much contributed to the course of working life. Amazingly, because of the relatively short lifespan of our discipline, some of them were only the second generation of medical oncologists ever in this country.
So you're in touch vicariously with the entire history of a specialty, which is quite unusual, and rather a special thought. I won't name names - mostly because I know this is a general audience, but also because there are too many to name.
A nice tradition in life, and in particular at King's, is that when you're made a professor you have to give an inaugural lecture. It's a great opportunity to reflect on people who have influenced you and thank them, and that was an interesting process for me a few years ago. And to have some of them in the audience was quite sobering and fun.
What's your favourite book?
One of my great regrets is that I don't read novels very often. It's easy to make excuses, but whenever I have a spare moment it's reading something a bit more pressing, like the committee papers for the next morning.
The book that had the most impact on me, and perhaps even contributed to my career choices, was called The Ascent of Man. It was really popular anthropology. It was a history of the species almost from a physiological, but certainly from an archaeological, historical, and social anthropological basis.
It was written by an amazing broadcaster and academic called Jacob Bronowski, who in the early 1980s made what was then an impactful TV series, and this was the book that went with it. So it was a very approachable book with lots of pictures. Maybe that's why it appeals.
It was very much ahead of its time. He had a thesis of what it was that marks out our species for being a bit different. It being the optimistic early 1980s, it was more from that perspective - as the title The Ascent of Man implies. It was more from the self-congratulatory, ‘look what we've done as a species’ approach.
A more 2021 approach would be: what is it about humans that has been so devastating for the planet? But there are a lot of insights into just how the very basics of our anatomy, certainly our psychology, impacts how humans interact with the world, and how our thinking has evolved.
How even thoughts can be passed on from one generation to another, and do make for an ascent of sorts in technology and society - not always for the best. That insight for a budding physician was really inspiring, because ultimately we're here to study ourselves, human beings, either physically or mentally as doctors.
That book was influential on me as a teenager. Look it out, if you can find it. It's quite a read.
Medspire podcasts are produced by Dr Sanketh Rampes and Dr Anvarjon Mukhammadaminov, both full-time junior doctors. They aim to inspire the next generation of doctors and scientists by exploring the career journeys of leading clinicians and researchers.