Dr James Kinross
Dr James Kinross is a Senior Lecturer in Colorectal Surgery and a Consultant Surgeon at Imperial College London. We caught up with him to find out more about his career and research…
1. Can you tell us about your career path, and how you got to your current position as Senior Lecturer in Colorectal Surgery and Consultant Surgeon?
I went to medical school at St. Mary’s Hospital London which later became Imperial College School of Medicine. After qualifying I was accepted into a basic surgical training programme at St. Mary’s. One of my professors at the time asked if I had ever considered a career in research. I had not, but after taking time to thinking about it, I found myself undertaking a PhD on the gut microbiome and surgical outcomes. People genuinely thought I was mad for choosing this area of research because back in 2005, no one really cared about the gut microbiome. It was during my PhD when I really started to understand the significant implications of the gut microbiome to human health and I became much more interested in the translational applications of the gut microbiome. I also became very interested in nutrition and how we can engineer the microbiome through what we eat. That led me onto a postdoctoral clinical scientist training post, that meant that I then became an Academic Surgeon and ultimately, that culminated in my current position as Senior Lecturer in Colorectal Surgery at Imperial College London.
2. Why did you specifically decide to look at the gut microbiome and surgical outcomes?
Surgical injury or any kind of injury that leads to sustained blood loss causes physiological shock. The gut is the first place that blood is diverted away from, because in times of crisis the body will send that blood to the brain or the heart. We became interested in this idea that if you hypo-perfuse the gut, you might end up modifying the gut ecology in some way. This is really important because the bacteria are likely to influence the degree of systemic response that results from that injury.
It then followed that for elective surgery at least, we could pre-emptively engineer the microbiome to improve surgical outcomes. We initially looked to see if galacto-oligosaccharides could in some way optimise the growth of mucosal commensal bacteria and prevent the metabolic and inflammatory complications of intestinal ischemia, but that turned out to be more difficult than anticipated. In times of critical illness, giving these sorts of complex sugars can have unexpected outcomes and sometimes it can make matters worse. But that was my original PhD, my work has now evolved into a number of different avenues including disease prevention, improving perioperative outcomes, engineering the microbiome to improve outcomes for chronic diseases and lastly biomarker discovery.
3. What led to your interest in the gut microbiome and colon cancer?
To me, it is almost intuitive that the microbiome influences cancer risk yet until quite recently, the microbiome has almost been completely ignored in this field. The idea that they may also be important in therapy is still really an emerging concept. For me, I always have to ask “why would they not be involved in some way?”.
The problem we have in the colon as opposed to the fore-gut, is that the colonic ecology is so much more complex, so highly individualised and it can be affected by a large number of environmental factors. Moreover, it’s quite hard to access and all of these things make it more difficult to study. It was interesting to me that if we could demonstrate that the microbiome was mechanistically linked to cancer causation, this would represent a completely new therapeutic target that we could use to improve cancer outcomes.
It was clear from the very beginning that people were trying to apply a bottom up scientific approach to the problem. The work done in H. pylori and gastric cancer has been very clear cut as there was a clear driver organism that was very strongly associated with gastric cancer risk, but that is not the case with colon cancer. The problem is much more intricate in the colon, and deciphering how such a complex microbial network interacts with the host organism to drive cancer is a big challenge.
Early studies on the gut microbiome and colon cancer were very naïve, as they were done in a small number of patients, and typically only looked at the faecal microbiome and they weren’t really understanding or studying the gut microbiota in a longitudinal way. Therefore, as a clinical scientist I could see a lot of room for improvement.
4. What role does the gut microbiome play in the aetiology of bowel cancer?
If you look through literature, there are a couple of recurring candidates for causation with Fusobacterium nucleatum being at the top of the list. These bugs seem to be strongly associated with cancer and have some sort of mechanism that explains why they may or may not initiate cancer. The problem with these bugs is that they are invariably found in the general population and probably around 20 – 25% of patients demonstrate high abundance of Fusobacterium nucleatum. The association is therefore not that clear, and it is not yet established if they are ‘driver’ bugs. We hypothesise therefore that the driver species are probably replaced by the evolving mucosal and luminal ecology of the gut, and by the time the cancer has formed (this is the point at which most studies study cancer) they are replaced with ‘passenger’ organisms. Increasingly, the data is showing that it’s likely that it is the genotype of the cancer that determines the passenger mucosal microbiome signature that we see.
That tells us that although these bugs seem to come up time and time again in literature, they are probably not necessarily causative. That doesn’t necessarily mean they’re not valid targets for developing novel therapies for treating colon cancer, but it just means that if you’re trying to prevent cancer, they may not be the best targets.
We have therefore studied diet in low-risk and high-risk populations (rural Africans, Western population, high-risk indigenous population). In these groups we find that the diet-microbiome link is very strong and it’s the metabolic network of these bugs that is the most important risk factor in determining whether you’re likely to get colon cancer. When we crossed over the diet between rural Africans and African-Americans for example, we found that bile acid secretion goes up by 400% in rural Africans who have an Americanised diet and their short chain fatty acid excretion dropped massively. These things are reciprocal and this is important as it means you can modify cancer risk through diet, in a relatively short period of time. But equally, it may be that there isn’t a single target or bacteria that if we knocked down, would lead to a significant reduction in our risk of colon cancer.
We all know from epidemiological studies what a healthy diet for the gut looks like. The microbiome is the critical mediator that determines whether our diet is going to be good or bad for us and therefore this poses the question whether we can engineer the microbiome so that we can get the very best out of the diet we’re consuming. Or could we possibly supplement with secondary metabolites that may have some benefit?
5. Evidence also suggests that our gut microbiota affects the efficacy of anticancer therapy. Can you elaborate on this?
The molecular toolbox of the gut microbiome is vast and incompletely mapped. In a human population, we definitely don’t know in a lot of detail how the microbiome influences these drugs. What we are yet to determine is the complex network between these drugs on chemotherapy efficacy or toxicity. They have got a very broad series of mechanisms of action so they might influence translocation, immune function, metabolism, enzymatic degradation or they might have some form of other indirect effect that we don’t yet quite understand so this is definitely an area that warrants further research. However, this is a very exciting concept as it means we now have a vast new set of targets we can utilise for cancer therapy.
6. How would this understanding of the host-chemotherapeutic microbiota axis help us to formulate cancer treatment therapies in the future?
We need to better understand an individual’s individual ecology, both before and after treatment. If we can do this, it may mean we can more effectively target treatment stratify therapy. The key thing about the gut microbiome is that it is modifiable and the strategic shift is towards a “drugable microbiome” i.e. we make drugs to target the bacteria in the gut rather than the host. So, you may not need to change the therapy but you could change the microbiome and there are a number of different ways in which we could potentially do that. For example, one interesting avenue that is being studied a lot at the moment is looking at how we could utilise faecal microbial transplantation in modifying the gut microbiome. However, this is quite a blunt tool, and we may be able to give highly selected commensal strains engineered to produce the molecular candidates we need. This is likely to be a very important role for probiotics in the future.
7. The iKnife technology has been used to improve the precision of colon cancer surgeries. Can you tell me a bit more about the iKnife technology and how this has helped in research?
The iKnife technology works by coupling two existing processes including surgery using electricity and mass spectrometry. The iKnife delivers high level of electricity on the tissue surface and this produces gas fumes as a by-product. We used to just dispose of these fumes as a waste product but my colleague, Professor Zolta Takats, decided to pass this smoke through a mass spectrometer. Within that smoke phase, there is a lot of interesting data on lipid chemistry and as it turns out, cancer actually has a very reproducible lipid chemistry and this tells us a lot about the molecular biology of that cancer. This can be used to help us identify what type of tissue is present.
Initially the technology was used as a margin detection tool – as a surgeon can you be sure that you’ve resected the entire tumour? There are trials going on for use in breast cancer and other types of cancer to establish this application. But since its initial concept, the technology has been diversified significantly including its applications in microbiology. Bacteria have lots of lipids in their cell wall, so actually the same technology can apply the same methodology for point of care for microbiology testing. We are able to get pretty robust data on classes and taxa of bacteria but also on what these bacteria are doing –functional information about signalling molecules and also clinically relevant information like antibiotic resistance.
There is currently a big programme of work trying to develop automated processes for the deployment of this technology in the microbiology lab because it takes seconds to get data as opposed to days if we were using traditional culturing techniques. There are also clinical trials to ascertain whether we could do things like measuring the gut microbiome during endoscopy.
8. What does a typical working day look like for you?
Invariably it is long, but it is always interesting! My day usually starts quite early and I’m usually at the hospital by around 7am. On an operating day, I will first clear my email tray, see my pre-op patients and operate for the day and this takes me to around 5pm. After that, I will do a ward round, see all my post-op patients and any other in-patients that I have. Most of my clinical practice is minimally invasive and robotic, and I predominantly treat bowel cancer so most of my patients are bowel cancer patients but not exclusively. One day of the week I will have other clinical duties and this includes things like running clinics and going to meet with cancer multidisciplinary teams. Every 7 weeks or so, I will be the on-call emergency consultant and will have to treat everybody and anything that comes through the door of our wonderful hospital, which is always challenging as we are a major trauma unit.
My week is divided between about 60% clinical practice and 40% academic work. I manage and run my own research group, so I am constantly in group meetings or if I’m lucky then I’ll get to spend some time in the lab. I also have academic responsibilities at the college so I have to manage and teach medical and graduate students, run various other educational courses as well as supervise all my PhD students. Because I am an academic, I also have to go and meet my collaborators and sometimes this means travelling internationally. I’d say I’m out of the country at least once a month. All of this, of course, has to be balanced with spending time with the family as well!
9. What do you like to do in your spare time?
Obviously my children come first so I live through them and their hobbies. My son is a massive Manchester City fan and my daughter loves to paint. But I also enjoy cycling a lot. I find endurance exercise to be good for clearing the head, you can’t multi-task and it just makes you feel amazing afterwards. So, this Summer I am cycling over the alps, and I can’t wait!
10. What inspires you?
What inspires me is my patients. I feel very privileged to be able to do what I do and it’s a great honour to be able to look after people when they are unwell. My patients are truly extraordinary and they are the reason I get out of bed every morning.