Tim Raine is a consultant gastroenterologist at Addenbrookes Hospital in Cambridge and an honorary faculty member of the Wellcome Trust Sanger Institute. He is a mucosal immunologist, and alongside translational science work, he is also heavily involved in clinical trials and guideline development. Despite his relative youth, Tim has been in and around ECCO for many years and is well known to the ECCO Community. After chairing both Y-ECCO and GuiCom, he is now a member of SciCom, reflecting the breadth of his involvement with IBD. I had the opportunity to discuss his work with ECCO and his journey into life as a clinician-scientist.
Tell us about your journey into gastroenterology and IBD. Were you born a gastroenterologist or did you come to it by accident?
I certainly wasn’t born a gastroenterologist, or even a doctor. After leaving school I wanted to do a science degree but thought all the most interesting courses were medical sciences. As part of a pre-clinical medicine undergraduate degree, I found immunology impossibly hard – in common with just about all my cohort – so I really wanted to try and understand it better. I ended up spending my final undergraduate year in an immunology lab, where I really fell in love with the subject. I was then torn between going on to study clinical medicine or doing a PhD in immunology, but luckily enough there was a programme in Cambridge that allowed me to do both. So I joined a strange bunch of individuals looking to spend a total of eight years of pre-qualification study.
I was able to progress my clinical work alongside a PhD which took me into the effects of intestinal infections on the function of tissue-resident T cells. After qualifying, I spent a period of time in the States before returning to London, where I was able to undertake junior doctor jobs alongside post-doctoral research. At that time I wanted to keep studying tissue-resident immune cells, but absolutely wanted to work in human biology and also enjoy the challenges and rewards of working with patients. Gastroenterology struck me as a perfect opportunity where we are visualising and biopsying the tissue all the time in a range of really interesting and life-affecting pathologies, with patients of all ages and sorts.
Besides, all the gastroenterologists I met were really positive, encouraging and seemingly very happy people. This was particularly true in the IBD Community, as we all know. And I liked the rhythm of gastroenterology, with outpatient work and endoscopy. I was able to return to Cambridge to continue my gastroenterology training alongside further post-doctoral research. I worked on developing approaches to using novel sequencing techniques to allow interrogation of immune cell behaviour using endoscopic biopsies from human gut – and the dysregulation of this in IBD. Gradually over time I settled into this dual role combining clinical work with IBD patients with translational science work with patient samples, all of which then led very naturally into an interest in interventional clinical studies and developing novel therapeutics.
Mentors, role models and collaborators – how important has this been for you? What advice would you give young IBDologists trying to get guidance on their own trajectory?
Everyone always stresses the importance of a mentor for the simple reason that this is completely true. I was lucky enough to enjoy really strong mentorship at all stages of my training, from my PhD and early clinical years, through to my IBD training and consultant career. Prof Miles Parkes shaped a lot of what is great about IBD research in the UK (and further afield) and he was an absolute inspiration and source of advice and support. Prof Arthur Kaser arrived in Cambridge around about the same time I returned and was a huge supporter in terms of lab space, advice and knowledge. And there were many, many others, to whom I am indebted. So it’s never just one mentor, but a series of individuals whose help, support and advice is essential at different stages.
What advice would I give? Honestly, I don’t think I’m in a position to give advice, but if I was to make a suggestion, it’s that the mentor–mentee relationship isn’t always obvious or essential to define (although it’s great to grab formal opportunities when offered). Maybe these relationships are more of a general extension of human interactions – we all are surrounded by others that we get to know and hopefully get to like and we can support and help one another. So yes, grabbing onto the tail of the “big name” may feel like an obvious move, but maybe the support and advice that we all need can be found in other, less obvious places where boundless expertise and wisdom is to be found. Just be open and receptive to advice from all sources, and develop a sense of what advice works for you and think about how to repay or support those who offer the advice and support.
You have undertaken fundamental “basic” research, clinical research and trials whilst being an active clinician. How do you balance these three? Do you sleep? With all the money in the world, what would you focus on?
Well, I’ve learnt to compromise. I guess the risk is that you end up being less good at any or all of these activities than someone who focusses exclusively on one. So the challenge is always to work out what added value you might bring as someone with a toehold in other camps. Your patients may not know that they want to see a doctor who is active in clinical trials, but others may indeed want to take part in a trial. A much larger group will value being cared for in a centre where staff are actively participating in advancing the field, with the added expertise and confidence that comes from this reverberating through the team. And our colleagues in laboratory research teams have amazing skills and knowledge, but they will value being able to discuss and refine these with someone who “speaks their language” and can also offer some clinical context. We can help them to shape questions and work out what questions need prioritising. Put another way, I think having an academic interest that strays too far from your clinic is a recipe for frustration that has to be guarded against.
Your question about funding is a tricky one. Whilst it would be great to see ever more funding going into IBD research, I actually think that we do have to focus study design on issues and questions that really matter and having “all the money in the world” might not be the best way to find a cure for IBD. But we need to talk about cure and I think there are some really fundamental questions that we are now just beginning to have the tools to scratch, in particular around how the GI flora interact with the immune system and shape the response to therapeutics. For all the time we spend talking about “combination therapy”, I think the true combination therapies of the near future will involve the addition of targeted modulation of intestinal microbiota alongside our existing approach of targeting the immune system.
As a SciCom Member you are involved in developing both the scientific programme and the ECCO Grants. Omics and systems approaches are flavour of the month, and the explosion in hypothesis-free approaches has in some cases taken over from old-fashioned hypothesis-led studies. To be provocative – the hypothesis in IBD research is dead isn’t it?
Hard to disagree. Omics sound great and suggest endless possibilities of “big data”. And for sure we are seeing real progress here. But there are several limitations, not just financial but also around sample acquisition and even things as mundane as good phenotype data collection. It’s an old truism but these approaches are hypothesis generating; to prove these hypotheses we still need experiments designed around testing and rejection of the null hypothesis. These experiments may be lab or animal based, or indeed clinical trials. We do need to start thinking about trials more as large science experiments and not just as very expensive ways of generating a p value for a binary outcome. So what would I like to see more of? Proper science embedded within drug development programmes around the phase II stage. And more open sharing of these findings. That’s a big ask given the way that this stage of drug discovery is funded and the intellectual property associated. But we are seeing companies starting to share, e.g. transcriptomic datasets from prior trials to support testing of hypotheses unrelated to their drug. We need mature conversations around how to collaborate and support this kind of sharing more systematically, and better incentives to create the frameworks for collaboration.
You have been a member of several committees (including this one). What have you gained from being part of ECCO Committees? What are your proudest achievements at ECCO?
Goodness, I’ve met some fantastic people – and had the privilege to discuss ideas with them as well as getting to know many of them as friends. That’s easily the biggest personal gain. What am I proudest of? Well, guidelines get a mixed reception. We know lots of clinicians around the world value them and turn to them, often working in non-expert centres. And ECCO Guidelines are held as amongst the most highly regarded IBD guidelines in the world. I’m very proud to have been a part of this. In particular, I’m proud of helping move ECCO Guidelines to a position of ever more rigorous assessment of the evidence and further from eminence-based processes. But some will say that guidelines that fetishise RCT level evidence can lack colour and utility in the real world, whilst others will question why we need guidelines at all. I think during my time with the Guidelines Committee we managed to make some real progress on balancing and responding to these demands, and the new Crohn’s Guidelines which I’m helping to lead the development of will, I hope, be ECCO’s best and most useful guidelines yet.
Related to this, GRADE (Grading of Recommendations Assessment, Development, and Evaluation) guidelines are scientific but perhaps dogmatic, particularly in IBD, where treatment is less algorithmic. How do you see ECCO Guidelines adapting to the situation we find ourselves in, with a range of medications but without the knowledge or tools to use these with precision?
For a long time we put RCTs at, or near the top of, an “evidence pyramid” and regarded cohort studies, for example, as being small, retrospective and dirty. But actually we are now seeing the limitations of RCTs: they often recruit patients quite distinct from most clinical practice and there simply aren’t enough IBD patients on the planet to power all the RCTs that we could design if we wanted to start testing every possible head-to-head comparison across a range of patient subgroups. At the same time, we are seeing more and more well-designed, massive cohort studies, often with prospective data collection at a near whole-population level. So I think we need to start thinking about how we combine alternative sources of evidence – RCTs, yes, but also these massive cohort studies, network meta-analyses, data from other indications and scientific inference – and bring this all together in a document that can be accessible and useful to the clinician seeing patients. And yes, at times we have to acknowledge imprecision in our current tools and suggest ways of working and managing patients amongst all this uncertainty. Some might refer to this as the “art” of IBD, as though it’s the opposite of science, but actually I think it is science – in all the complexity, uncertainty and imprecision of human biology – and we can and should approach this with a scientific mindset.
With all of this, and a family, do you have time to switch off? How do you switch off?
My wife is also a senior physician in the same hospital, so life can get pretty dominated by work at times and our diaries get pretty ugly. But kids are a complete leveller. They honestly don’t care one bit about our work, and nor should they! They’d be much more impressed if I could swim two lengths underwater (I can’t) and much more excited if I took a day off to take them down to the river. Spending time with my kids is switching off – that’s absolutely what drives me.
Thank you, Tim. We are really grateful for the insights into both your life and your perspectives on the state of play in IBD today.