Podcasts

NB: First of all, for listeners who might not know about your subject area, can you just explain a little bit about your research?  

CH: Yeah, of course. So, I'm a professor of paediatric haemato-oncology. So essentially that's a blood cancer in children. My research really focuses on the commonest childhood cancer, which is acute lymphoblastic leukaemia, which is a cancer that affects predominantly young children.  So, the kind of peak age of leukaemia is between the ages of two and five. Actually, leukaemia is one of the huge success stories of modern medicine from a kind of universally fatal disease back in the 1950s - a child presenting with leukaemia today has an over ninety percent chance of long-term cure, proper cure, you know, back into a completely normal life. But of course, to do that cure the treatment is pretty intensive and it's very long and it's very arduous. So actually we treat children for up to two and a half to three years with chemotherapy, and of course, because the peak age is when you're aged two to five, you're in a period of really rapid growth and the kind of chemotherapy and treatments that we use will kill leukaemia cells. Fantastic. But also, potentially have an effect on your normal developing cells in the body. And so we know that a lot of kids have long term side effects from their treatment. So, the research in childhood leukaemia now, and the research that we do in my group really are to try and develop what we call kinder and gentler treatments. So we still get the really good cure rates. But actually these are much more specific and targeted agents that will kill leukaemia cells while sparing normal cells in the body and allowing those cells to develop normally. So there's a lot of advances in that field - and we work very specifically on actually treating leukaemia that has spread to the fluid around the brain. Because you can imagine brain cells are super precious and you don't want to damage any brain cells while you kill leukaemia cells. And so we work a lot on trying to understand how to develop new treatments for leukaemia that spread to the fluid around the brain. So, really exciting times.  

NB: And you mentioned the brain there. I've read a little bit about new Drug Administration techniques involving the blood brain barrier and finding ways to get through the blood brain barrier, the BBB. Is that part of your research? And if so, could you tell us a little bit about that?  

CH: Absolutely. We're very interested in the administration of drugs. Leukaemia is a cancer of white blood cells, and actually white blood cells normally traffic from the blood into the fluid around the brain called the cerebrospinal fluid. And in a way, you can think of that fluid around the brain a little bit like kind of moat around a castle or something. So actually we don't really like immune cells to go into the brain tissue because immune cells cause inflammation. And obviously you don't want your brain to be inflamed and swollen. So we actually inject our chemotherapy into that spinal fluid. So these poor children during their treatment for leukaemia, which is curative - which is fantastic - they get between ten and twenty-six spinal taps, where we directly inject the chemo into that fluid. And of course, that's really I mean, it's quite effective, which is great, but it's actually obviously quite unpleasant. We generally put the children to sleep and do it under general anaesthesia, but in fact they then hate the general anaesthetics, and it's a huge burden for the families. And of course, it's a huge burden for the NHS as well, doing lots and lots of expensive surgical procedures to try and get this chemotherapy administered over these two to three years. So we're really working on new ways that you might be able to get drugs into that spinal fluid without having to do the direct spinal taps and actually inject it in there. So partly, we're looking for drugs that you can just take by mouth orally, and that will then cross from the blood into that cerebrospinal fluid. And there are certain physical properties of drugs that you can predict. They'll be much more effective at doing that. But we're also recently - we’ve actually been looking at giving drugs, what we call intranasal, so up the nose. And actually children are quite familiar with that because that's how they get their flu vaccination each year. They get a little squirt of flu vaccine up the nose, and the blood vessels from the nose go very directly to the brain. So you can actually get much higher concentrations of the drugs in the fluid around the brain. So we haven't tested that in patients yet, but we're using that in what we call our pre-clinical models, our models in the lab. And that's looking pretty effective as well. So we're really on the quest for new agents to treat brain leukaemia that 1; you don't have to inject intraspinally; and 2,   don't affect normal brain cells. And that's the holy grail to have that combination of not affecting normal brain cells, just being very specifically laser targeted towards the leukaemia cells, but also that you don't have to give via that spinal injection.  

NB: You said the word “burden” there. I thought you were going to say a burden on yourself, a burden on your own peace of mind. Do you feel that when you're working with sick children? How do you keep going with this work without taking too much of it on board in yourself?  

CH: Yeah, that's an interesting question. I think I don't so much see that. I mean, obviously it can be incredibly upsetting. You know, one of the great joys of working in childhood cancer, if you like, is that you may have formed such an amazing relationship with the patients and the families because you're on such a journey with them. You know, you start with a child who's incredibly sick, come to the hospital, you then give them treatment. And then of course, in leukaemia, because that treatment lasts two and a half, three years, you see these children grow up in front of your eyes. And in fact, after the first kind of four to six months, they're often back at nursery or school. And obviously they're coming to the hospital quite often, but they're, they're growing and developing into these people with real personalities, and you get to know them so well. And I suppose that you feel as a doctor in that, that you're, that you have a really powerful role in terms of explaining things to the families, helping them understand the treatment, empowering them to really help them look after their, their children. So I wouldn't say in that way, it's not - it's more empowering than stressful. But of course, you know, there are stressful times and, you know, it's wonderful that we cure nine and a half out of ten children. But of course, for every child that you don't cure, that's an absolute tragedy and doesn't just affect the family, but the whole healthcare team are very affected by that. And I think one of the things in childhood cancer is that we work as very, very supportive, multidisciplinary teams where we all support one another through that. So the burden is not just on an individual doctor; there's the whole nursing team, the medical staff, the allied health professionals, the dieticians, the psychologists. We all work really closely with these families, and so I suppose in that way we kind of try and share that burden. And we always kind of have debriefs and things. If anything doesn't, doesn't go well.  

NB: And you're in a sort of fostered safe space.  

CH: Yeah, exactly. Exactly.  

NB: Would I be right in saying that progress for these things, these new administration methods and new drugs is slow. How do you measure progress when it's a long game? Success might take years to actually reach a patient at their bedside.  

CH: Yeah, it's a good point. I mean, progress is slow, although I would say that in childhood leukaemia it's very interesting - progress has been very steady and stepwise. So there's a very interesting pattern if you look in childhood leukaemia, that if you look in the 1940’s - the first cure for childhood, or the first treatment for childhood leukaemia, was published in 1944, I think. And it was a folic acid antagonist that produced very temporary remissions but did, otherwise, prior to that, was absolutely, universally fatal. And in the 1950’s, about ten percent of children survived. In the sixties, it was twenty-five to thirty, then the seventies. And we've gone stepwise up to this level around ninety percent. We did that by increasing the intensity of the treatment. So we started off with a couple of drugs. Then we added another one, another one, another one. And children because they're quite resilient, can actually cope with that as long as you schedule them properly, give them in the right orders and give them breaks if you need to. And so we learned how to use these, what we call combination treatments. Now, we couldn't do that very effectively back in the 1940’s and 1950’s, because this is a cancer of immune cells. So you wipe out not just the leukaemia cells, but the normal immune system. And so you would wipe out the leukaemia cells, but then the child would die of infection. And we didn't have good enough antibiotics. But as we developed better, what we call supportive care, which is antibiotics and antifungal agents and other things to treat the children if they got infections, then we were able to ramp up the intensity of the treatment. But actually when we got to about ninety percent, we got stuck because all the chemotherapy obviously has side effects. They may be rare. Some of the fatal ones are quite rare. But actually when you add them all up, the chance of dying from a side effect, from the treatment was pretty much exactly the same as the chance of dying from leukaemia coming back. So we couldn't go anywhere further from with the treatment in terms of making it stronger, because then actually you're more likely to die from the treatment than the leukaemia coming back. So we reach this what we call equipoise, where we couldn't really do anything and we got stuck. But then the new era of what we call immunotherapy came along where we can actually use the patient's own immune system or to actually fight cancer cells. And that caused a huge leap forward in that therapy, because it's very specific and very targeted to the cancer cells. (It) means that you can reduce all those side effects (that) you see from the chemotherapy but actually kill it and kill the cancer in a much kinder and gentler way. So, that's been a really big advance and that's been quite quick and rapid the adoption of that treatment. So it's gone from a kind of research idea through to something that we're actually using in children now, over 5-10 kind of period really. So that's been a really rapid advance. 

NB: Forgive the simplistic question - I've haven't experienced cancer. What is chemotherapy? What is it doing to the body?  

CH: Yeah, sure. So chemotherapy. When you talk about treating cancer there used to be two things that you could do. You could do what was called chemotherapy or radiotherapy. But now we have a third thing which is immunotherapy - immune system therapy. So these are now three categories of treatment. Radiotherapy involves shining X-rays at cancer and X-rays kill dividing cells. So you do a targeted beam of X-rays that you precisely direct so that the beam intersects at the point where the cancer is and kills the cancer cells and hopefully doesn't kill too much stuff around it. Very effective, but a little bit imprecise sometimes. Then chemotherapy is basically using drugs to kill cancer cells. And, and most chemotherapy essentially targets the proteins and molecules in the cells that cells need to divide into. So we know that cancer essentially is uncontrolled proliferation of cells. So you have normal cells - normally they will stop growing at some point. But a cancer cell - the cell goes gets something wrong when it replicates and starts dividing. Making one cancer cells becomes two, two become four, four become eight. And then it works up to millions, if not trillions of cells. And it doesn't know how to stop growing. And we have agents that we know, drugs that will come in and interfere with that replication of the cell and tell the cells to stop growing. 

NB: If you get it early enough.  

CH: If you can. So, most of the time it's much easier if it's actually not spread around the body and you're not having to try and get that drug into every site in the body and tackle – it’d be like fighting a fire. You know, it's much easier to fight it when it's a small fire than when it's spread all over a building, and you're having to fight on many, many different fronts. And so chemotherapy is essentially drug therapy. And then immunotherapy is essentially using the body's own immune system to fight to fight the cancer. Sometimes you infuse what we call antibodies, which are things that fight infections, but instead of them targeting infections, you get them to target the cancer cell, and they latch onto the cancer cell and kill it. Or you can actually take the body's own immune cells out, take it to a lab, add in a special – what we call a kind of construct that allows it to express a receptor that will go back in the body and hunt out the cancer cells. It sounds very science fiction, but it is actually happening today. We're treating children with these - children and adults with these therapies.  

NB: You've spoken about the benefits of team science rather than working in silos. What does team science actually look like in practice in your world?  

CH: Yeah, that's a great question. Science has got a kind of - I suppose it's got two models. So one model is scientists competing against one another to be the best to make the first discoveries, to break boundaries. And competition can be very useful in that space. It gives you real motivation, you know, to be the best, to be the first, to all get together on a collective effort to find some new discovery and say, “we've got to do this before the Americans do it”, or the next lab does it or whatever. And I always think of that a little bit like what I would call a kind of rock star scientist, the kind of person who says, “I am the best. The world expert.” But there's another approach to science, which is to say, okay, here's the problem. Not one person can't solve this problem on their own. You can't possibly have all the skill sets that you need to bring all the different information and techniques we have at our fingertips now. So I think in the olden days, you know, science was simpler. You worked in the lab, and you had chemicals and you mixed them together, you know. Now we have artificial intelligence. We have genetic engineering. We have data from the patients. We have all these different aspects to help us answer one problem. And in order to bring all those different things together, you need people with different skill sets. You can't possibly be skilled in all the best person in all those different areas. And so team science approaches really bring in diverse skill sets to work on a very defined problem. And you kind of leave your ego at the door, if you like, and you say, “we're going to all work together on this and we'll all share the credit for that.” I often think of that a little bit like a kind of symphony orchestra. So, you know, to be the absolute best symphony orchestra, it's not only about your lead violin or your conductor or your lead soloist. Actually, if you've got an out of tune person at the back playing the drums, that's going to really affect your sound. You also need a brilliant auditorium. You need people to do your PR, you know, and tell people (…) to come to the concert. You need to have the people at the front desk welcoming people in. All of that is part of the experience of delivering this really high-quality product. And I think science is really like that too, you know, so we don't just need the leaders, the PI’s who are having the initial idea. You need the people at the bench side to do that. You need the people in the wash up to wash up your glassware and bring it up so that you can do the experiments using good equipment. You need your professional services to help you with all the kind of administration of the grants and things. So everyone works together to develop and deliver a really excellent outcome. But actually, I think now it's recognised that all research benefits from that approach, not just rare diseases. Actually bringing the right people and the right skill sets together to answer a problem and working collaboratively on that. And I think a lot of research funders are now recognising that as well in the way that they reward research and fund research. You know, they accept that to solve the really hard challenges we have now, you really need interdisciplinary research; you really need team approaches to these big challenges.   

NB: You don’t only work with your immediate teams, but you also collaborate internationally as well. Why do you think global collaboration is especially important?  

CH: So I mean, in childhood leukaemia, it's relatively easy to make a case for global collaboration. So although as I said at the beginning that childhood leukaemia is the commonest childhood cancer, thankfully it's still rare. So in the UK, we have four hundred children roughly a year with acute lymphoblastic leukaemia. If we're curing ninety three percent of them, you've only got a handful of children each year where the leukaemia comes back. So if you want to try and investigate why it comes back into some children and not others, you know, if I was just doing work in Glasgow, I'd have two or three children, not even that - probably one child a year that I could look at their data and look at their tumour and their biology and try and work it out. If it was in the UK, I'd maybe have 40 or 50 children, not even that. But if I then team up across Europe, I then have a much larger cohort of children. So actually our childhood leukaemia trial that we're running at the moment actually involves fourteen countries across Western Europe, all teaming together so that we have enough patients in order to personalise children's treatment according to their specific type of leukaemia they have.  

NB: I can see that AI and supercomputing are becoming prominent tools in treatment and in your research. In simple terms, what do these approaches do, or what are they going to be able to do that hasn't been previously possible?  

CH: Yeah. I mean, we're not a big AI supercomputing group, but obviously I think it touches all parts of kind of biomedical research now and certainly machine learning and using the power of supercomputing. So I think if we look back, we sequenced the human genome - what was those 25 years ago now? And it took several years and multiple labs and now we can send our leukaemia cells off that we get from a patient to a company and get a whole genome sequence in just a few days for just a few hundred pounds. So it’s an amazing evolution in our ability to characterise tumours. And we can do that not just with the genomes, the DNA sequence of the tumour, but we can look at the proteins in the tumour, what we call the metabolites, all the all the different molecules in the tumour. We can look at the RNA, which genes are being switched on and off in the tumours - and we can do that in individual cells. So we can take a cancer sample, and we can divide each cancer cell. We can look individually at what's happening. And that generates crazy amounts of data. So you know, you've got thousands and thousands of genes and proteins and metabolites and no human brain can really have - I mean, you could do it if you spent ten years looking at these pieces of data, making connections and drawing connections on a map. But no human brain can really process data fast enough to just do that visually, just by looking at the results and saying, well, that maps with that or that connects with that. Whereas using machine learning and artificial intelligence and supercomputing techniques, you can feed data in and ask it to search for patterns and connections. And it can do that really fast. So it'll make sense of huge amounts of data for you. In the end, you still need to interpret that. They'll come out with, well, it looks like this is happening and that's happening and that's happening and that might be related to that. And then you have to kind of look at that and say, “okay, right. So how does that make sense? What might be going on there? How will I test that?” 

NB: You have to scrutinize it,  

CH: And then you have to translate it back into the lab to say, “Okay, this looks important. What happens if I interfere with that process? Does it actually do what I what the computer has predicted it will do?. So you still need the lab to test the predictions that the machines make, but they help you get so much faster and much more accurately to the kind of predictions that allow you to then advance the science.  

NB: I want to ask you about the Scottish Health and Biomedical Institute or the SHBI.  

CH: Oh, yes.  

NB: What problem is the SHBI trying to solve and why now?  

CH: So this is a really exciting new project.  I would say just some of the things that we've just been discussing about, you know, the huge advances in biomedical science, the amount of data we can generate, the ability for machines and AI to help us understand that data and make links that the human brain wouldn't have automatically made. And then the ability to interrogate that means that we're really in a in a new era of science, I think. And where I think it really adds value is that up until now, because we've had to simplify systems in order to understand them, I think we've got into an approach to biomedical science where we essentially look at individual diseases in forensic detail. So I was telling you about looking at every individual cell in a cancer. You know, not just looking at the cancer in bulk, but teasing out every individual cell. And you can get really laser focused down on what's happening at the cellular level in any disease. But of course, all these cells live in the body, and they're bathed and they're given nutrients and energy and things from the bloodstream, from all these other, you know, your lungs bringing the oxygen in, your heart's pumping the blood around. And every individual person has a unique combination of what's going on in their body when the disease develops, so the disease doesn't develop in isolation. It doesn't develop in a test tube. It develops in your own body. And so actually, when we're trying to understand diseases, I think for a while we got very interested in kind of precision medicine and looking down to more and more narrow levels and looking at the level of individual genes in the cells and saying, “well, we could personalize medicine by finding a cure for the gene that's gone wrong in that cell” or whatever. But actually, you can zoom out a little bit and actually say that personalised medicine, you really need to personalise it for the person's whole body. So a lot of people who get cancer, for example, might have other diseases. They might have heart disease, they might be overweight, they might have chronic inflammation. And these things will be affecting how their cancer is behaving in the body. The cancer will be exposed to different growth factors, to different levels of oxygen, to different nutrient levels in different patients. And so this is very, very complex. My description is quite complex. You can see there's a lot of complexity there. And I think people have shied away from understanding that complexity up until now. But these new advances mean we can embrace that complexity and really try and understand complex disease processes. And we know in Scotland, we have the highest incidence of cancer in the UK and the worst cancer outcomes in the UK, same for cardiovascular disease, etc.. And that's driven really by what we call health inequalities, by multimorbidity, by people having more than one disease at the same time. So one of the key aspects of the Scottish Health and Biomedical Institute is to try and address these problems that we have here in Scotland, but also elsewhere in the world and in the UK of chronic ill health, multimorbidity, etc.. But looking up till now, when we've looked at poor health, we've really looked at a social and political level. You know, we all know that in order to prevent cancer, we should eat five fruit and veg a day, we should exercise, we should not be obese, we should not drink alcohol, we should not smoke, etc.. And those are very good pieces of advice. But of course, if you then get ill and you've done that stuff, you actually need something that will actually help treat your illness in you as an individual. And so understanding how those factors play out at a disease level is really important. And we think that there's not enough discovery science trying to work out why you're more likely to die of breast cancer if you're from a black ethnic minority, for example. You know how best to treat someone with these new immunotherapies if they have problems already with their immune system and inflammation, etc.. so we're bringing together the best scientific minds in Scotland in biomedical research into one team effort, if you like, to try and understand the complexity of disease at a kind of more organism level rather than at a cellular level. And that's essentially the idea behind SHBI and quite a unique idea, I think.  

NB: And so looking ahead, maybe ten or twenty years, what does success look like for you for patients, for research culture, for collaboration, and for Scotland and beyond?  

CH: Yeah. Interesting. Personally for me, I've always made it a career goal to try and develop a new treatment for brain leukaemia. So we're not giving these children up to 25 or 26 spinal taps and injecting the chemo. I've always said to my research group, if we get to that point, I'll retire. And that's motivation for them to go for it. So that's a very personal goal. But I think for Scotland, for the wider scientific community, I would really like us to be able to treat diseases in people that take account of everything they're experiencing and not just treat them as a series of single problems. Like you've got heart disease, you've got lung disease, you've got cancer. But actually here is a treatment that's specifically designed for you and your situation. And I think that would be amazing because I think at the moment drug treatments are a bit one size fits all. So the analogy that I use actually is there was a really interesting period of time where car manufacturers only tested seatbelts across against standard sized male dummies. So they were eighty kilograms male dummies. Seatbelt testing, of course, protected seventy kilograms eighty kilograms males, but did not protect women or other groups at all. And it was only when they opened their eyes to that saying, hang on a second, we should be testing against other types of people, that we then had much safer seatbelts. Well, I think it's a little bit like that at the moment with medicines we design. We design medicines and we put them through clinical trials but we when we put them through the clinical trials, we have a lot of what we call exclusion criteria, which mean you can't take anyone who's got any other illnesses or any other medicines. And so you design your drugs for the perfect patient who's otherwise healthy and just has this single problem going on. And I want to get to a place where we're designing drugs that fit everyone of every shape and size in our society.  And I think that will lead to real advances in health care.  

NB: Is there a name for that? Is it personalised health care?  

CH: So it is personalised medicine, absolutely, yes. But I think up till now, we've been thinking of personalised medicine in terms of just looking deep enough into a cell so that we can get exactly the right drug for that disease, but we actually need to zoom out and look at the right drug for that person as opposed to that disease in that person. It's a subtle distinction, but it's really important. And I guess that's where technology comes in as well. Yeah, technology, machine learning, just being able to embrace that complexity allows you to then, um, really try and be much more holistic about how you treat. 

NB: Holistic is the word.