The Bioinformatics CRO Podcast

Transcript of Episode 2: Chris Ponting

Grant: So welcome to The Bioinformatics CRO podcast. I’m Grant Belgard, and joining us today is Chris Ponting. Chris, would you like to introduce yourself? 

Chris: Hi Grant. Yes, my name is Chris Ponting. I’m from the University of Edinburgh. I’m the chair of medical bioinformatics here. 

Grant: Lovely. And Chris was also my PhD supervisor many years ago. And then my supervisor for a second time, a couple of years after that. 

Chris: Well, you’ve gone on to greater things than I have, so well done. 

Grant: Oh, I don’t know about that. So, yeah, I just wanted to talk about some of the things that you’ve gotten into in recent years, especially your move to ME and CSF. I’d love to hear about that and what your thoughts are on the comparisons that are being drawn to post-COVID syndrome. 

Chris: That’s really interesting and a story that really goes back many years. So I was at university with a guy called Simon McGrath and some years later he got ME, myalgic encephalomyelitis. And it destroyed his life or at least his expectations and hope for the future. I felt for many years that I could do nothing about this as a scientist. And then recently I was just thinking that perhaps the techniques of population genetics might be interesting and useful. So I dipped my toe in it, and eventually after some years, some discussions, and bringing together many people from across the United Kingdom, we were awarded just this year over 3 million pounds to start a genetic study of myalgic encephalomyelitis, ME. 

Chris: In the middle of that, of course, COVID comes along. It was apparent to many beforehand and certainly more now that there are some interesting overlaps between post-COVID syndrome or long COVID or whatever you want to call it.

Chris: And after all, many people with ME report a viral infection before they come down with their syndrome. And this is exactly what’s happening now with long COVID. Now I don’t wish to say that long COVID is ME, it isn’t, but some people may resolve from long COVID into ME, which in this country as an adult, you need to have symptoms for over four months.

Chris: But watch this space! Basically, I know some people are doing some, or the beginnings of some genetic studies of long COVID. And it’s going to be fascinating to compare the genetic signals for ME, with the genetic signals for long COVID. Are they different? Are they the same or do they overlap, but not completely, et cetera.

Grant: Have there been any genetic studies of ME that have been broken out by the kind of proximal cause. So if it were a viral infection, have there been genetic studies broken out by the subtype of virus and so on?

Chris: So you would have thought that there would be plenty of genetic studies and well-powered ones involving many people. And you would think so because in this country, in the United Kingdom, around a quarter of a million people suffer from ME. But there are not. There aren’t any well-powered genetic studies anywhere in the world. So we know, nothing about the genetics of ME. We know that there is evidence that it is inherited, which gives us some support for our case that we should do this genetic study. But we know almost nothing about what will eventually be seen, obviously, as being a whole set of different conditions, which have different contributions made by the environment and from different parts of our chromosomes. It will be one of these complex disorders and teasing everything apart will take time. But given that there’s no effective treatment for people with ME, we really have to start with the genetics because we know almost nothing as researchers in ME.

Grant: And why do you think it’s been so neglected? 

Chris: It’s been neglected essentially because of this lack of information. The ignorance that we, as researchers, have towards it. We know almost nothing. It’s multisystem, which is difficult.

Chris: If it was affecting only one system, then we would know what to do, but, for some people it manifests mostly in muscles, others in the brain, others it may be perceived as an immune response problem, for many people it’s all three or more. So that’s a problem, but also there’s been a problem with its diagnosis. It’s a diagnosis by exclusion, meaning that it’s not particularly easy to diagnose. And that means that often people are not diagnosed. Indeed in the United Kingdom, the time taken on average to be diagnosed is about eight years. It’s neglected because we know very little. So “Let’s start finding out” is my view. 

Grant: And are there any countries that have been ahead of others on looking into this or has it been very well neglected across the board?

Chris: So it’s neglected a disease across the world. There are many countries where it’s not recognized at all by health professionals. And there are many health professionals across the world who think of people with it, with ME, as malingerers or who make up their disorder for whatever reason. It is the most devastating of diseases. In terms of quality of life, it’s so much worse than almost everything, including many cancers and multiple sclerosis, et cetera. Why anyone anywhere would make up such a disorder. I just don’t know.  It’s almost Victorian in our approach to this disease in the sense that when we look back on this, maybe in 10 to 50 years time, we will understand what it was. And think “why on earth did we overlook it and disbelieve all of these people for so many years.”

Grant: So I guess this feeds into another question, which is what do you think we need to do differently in biomedical science? And there are probably many answers to this, but. 

Chris: So one thing is we need to listen. If we’re studying a disease, then the person with the disease is often the expert on it. They have lived the experience of the disease. If they say that it fluctuates in different symptoms, that’s what it is. So listening and acting upon the experiences of people. And it’s not just their lived experience, but also they’ve become experts in the literature. They often, in my experience coming in from the outside has been, many people with ME, despite the fact that they are fatigued and they have post exertional malaise, and often can’t do things even things like brushing their teeth, but they do get involved and read the literature and are experts in it. And so I’ve often gone to my friend or others of people with ME and asked their advice as to what we should do scientifically.

Chris: And we should also pay attention to the fact that there are many scientists who have ME, many people who, in multiple different professions who have long COVID. I see nowadays that such experience can be thought of as being negative, that somehow subjectifying their experience, because it is they who are suffering, actually is not valuable. We need to be dispassionate in our observation of disease. And actually, I don’t think that’s right. 

Grant: That’s really interesting. So if I were to push you a little bit out on a limb and ask you to speculate, what do you think we might learn about the disease, if you had to give your best guess about ME CSF and it’s overlap with long COVID and so on? You don’t have to answer this.

Chris: I don’t mind answering questions, which are all speculative. I think as scientists, this is what we do. We do speculate, but in the knowledge that many things that we speculate about, we have no evidence for.  We put forward hypotheses, which is a part of speculation, and often we try and work out whether those are false. So one answer to your question is that I would not be at all surprised if it were to turn out that there was a mitochondria component. So, as you know, the mitochondria is the energy of the cell, so the battery of the cell. And if something were to go wrong with that, it would affect many different systems. It would affect the immune system. It would affect the nervous system. It would affect muscle, et cetera. And, and that would make complete sense to me if that was going wrong. 

Chris: But I actually think it will be many things. There have been people with ME, who’ve been diagnosed with ME, who have surgical operations on their neck and have had many fewer symptoms since then–not a large number, a smaller number. And I need to say that it is a procedure that is fraught with risks, so anyone thinking about it should go to their GP, their practitioner. But it is highly likely that there will be many different contributions made. And this is not easily understood because the medical model is that if you have a set of symptoms, it will be one thing.  But from genetics, we know that many different things can break and manifest in the same way in a person.  And there are many different ways in which the clinician can be hoodwinked by symptoms into thinking that symptoms are one thing and they’re many. So I am willing to speculate on the basis of evidence and thus far, we have none. So from our genetics, we will have some, I hope. And from there we will draw up the hypotheses and hope that many of the experts in those different fields will take on the challenge of seeing whether those are false or indeed real. 

Grant: And can you talk a bit more about your genetic study, and, you know, the design and when you might expect the results?

Chris: I think the results will come in about two and a half years from now.  What we will have done by then is to look at the DNA differences in 20,000 people with ME in the United Kingdom: differences with respect to the general population. We’re lucky in this country because we have something called the UK Biobank where half a million people have had their DNA changes read out. And so all of that’s been done. We don’t need to look at those, who we would call controls. We only need to look at the 20,000 cases of ME. Now we had no idea how long it would take us to get to 20,000 and we haven’t yet formally launched, but we have a registration page on the Decode ME webpage, and 20,000 people with ME in the United Kingdom have registered for this study, which is outstanding.

Chris: And the work that’s been put in by charities and digital marketing companies, et cetera, to get us to that point, even before we launch is fabulous, which gives me confidence that we really will be able to go quite fast in the early stages. What we’ll find, I don’t know. Maybe we find nothing–possibly–but we should look.

Grant: That’s outstanding. What are your thoughts on how communication from scientists has been handled with COVID-19? With, you know, many preprints going out, there have been a number of preprints that have influenced the discussion among the general public that wouldn’t pass muster on review and so on.  On the other hand, certainly science has moved much, much more rapidly with this than I think anything we’ve ever seen before in a positive way as well. What are your thoughts on that and on how politicians have kind of adopted, in many cases, scientists to agree with whatever they want to push? In the state of Florida, for example, our governor recently had a series of conference calls with some scientists who had somewhat fringe views on the pandemic and what should be done about it. But what are your thoughts on all that? 

Chris: Well, I think it’s really interesting because previously I think the public thought of scientists has been quite a homogenous bunch with the same views. Um, and that’s not true at all. People think of things in very different ways. And those kinds of controversies and conflicts in ideas really have not been exposed to the general population before. But now that they are because we’re seeing people on the same day writing letters to the same place to say, I believe in X and others saying, I believe in not X and that is causing confusion, but it actually reflects the reality.

Chris: I think the more it is understood that there are differing points of view and the more that you air them, the more people can weigh in and give their views, the better. And that is happening. Although you implied that peer review, which takes preprints into the publication domain, isn’t perfect. And just because it gets published, doesn’t mean that it is correct. And in fact, it’s the goal of scientists to demonstrate that what was known previously was either imperfect or incomplete. And also I don’t think the general public understood. 

Chris: Now your question also makes me say that the politicians who are considering the scientist views really are not qualified to understand the science, which is a shame. Why is it that scientists don’t become politicians? If we had a cohort of scientists who were members of different legislatures.

Grant: I guess Germany does, right? 

Chris: It does. They’ve had a very coherent response to COVID, but our country in the United Kingdom–and I think in the United States, it’s the same–there are almost no scientists. And I think that’s a huge deficit because the greater expertise, and the breadth of expertise that there is in parliament here, I think the better laws will be made and the better decisions would be taken. At the moment, we have the situation where people who have taken arts degrees–which are great–are making essentially scientific decisions. And I’m not sure that that has led to good outcomes here in the UK. 

Grant: So if you’d be willing to speculate again, the UK seems to be undergoing a second wave now, right? How do you expect that to play out? I mean, obviously there are a lot of decisions every day that you have to make about how you and your own family will respond to this.

Chris: I think it’s incredibly hard for every single person to judge what they should and what they shouldn’t do, and it’s leading to a huge amount of anxiety. We went to a restaurant as a family last night for the first time in a huge while. But of course we were worried about that. Should we have done that? Are we infectious? Are others infectious? Should we wear a mask? We did. Unfortunately, I think this is going to be the situation for others. 

Chris: Someone asked me yesterday, “how long is this going to last?” I mean, how do I know? I’m not an expert. I’m not a virologist or an epidemiologist, but I answered. I said, “I think we have another two years of this. I don’t think we are going to be saved early by a vaccine or several. We don’t know whether a vaccine like that is going to have great efficacy across the whole population.” So the best thing to do is to try not to infect people. And people are finding this hard because they lose their freedoms. They are used to traveling the world. They are used to doing X, Y, and Z and hate the idea that they’re being told that they can’t do it anymore. But a better idea is to protect other people. And I’m an optimist that feeling of protection others will eventually prevail. 

Grant: I do think there’s been a bit of a move in that direction even here. I would say a few months ago was probably the height of people screaming at each other because they didn’t want to wear a mask or whatever. But I think over time, people are realizing that the virus is real. You know, certainly if you go out when sick and so on you’re kind of in A-hole.

Chris: We needed to be tested because one of the household had symptoms. And so we went to a drive-in testing facility locally. And that was a sobering experience: watching the line of cars, watching the expense that the state has put into testing so many people, getting your results back within 15 hours was amazing.

Grant: That’s fantastic. That’s unheard of here. 

Chris: It’s not half an hour as it is in airports in Germany, et cetera, I mean, in Italy, but that was a sobering experience. I think, for us all. And it brought it home to us how widespread this is. That yes, maybe one in a thousand people are infected at any one point, but that is a huge number. 

Grant: What are your thoughts on–I don’t know if you’ve looked into this. You don’t have to answer if you haven’t. But, what are your thoughts on the prevalence of long COVID, and the longer term consequences? I mean, it seems, there are a lot of contradictory numbers about, you know, exactly how different studies are conducting surveys and differences in definition and so on.

Chris: This is a great example of where science doesn’t know. It doesn’t know how to define “recovered” for people with COVID. And if we don’t know how to define people who are recovered, then we don’t know how many people are ill still after, however many months. So we have to set down our structures, our frameworks, our concepts, and that’s beginning to happen. And upon those, are new studies that are going to be determining the proportion of people who are unwell still. Now there will be people who’ve been in hospital and intensive care who will still be ill. Um, and they are often going to have other conditions and they will be very poorly for a long period of time. And then there are people who are going to be unwell essentially for the rest of their lives, just as people then me off and. 

Chris: Your question is really how, what is the proportion of people who have been infected will be affected with ME like symptoms for the rest of their lives? It could be small. It could be of the order of 1%, which is the mortality rate as well. 1% of everyone is a large number. So if it’s 10%, it’s 10 times that large number. And we would have in that scenario a whole stratum of our society who would be unable to work, unable to look after themselves in many cases. A quarter of people with EM are bedbound or housebound. And if that’s the case with some people with long COVID eventually, then that would be the case. 

Chris: It’s a horrifying thought that that might be the case. But people with ME look upon that as something that might be an opportunity for ME to be understood, but more importantly, with a huge amount of empathy and a fellow feeling that they’ve always been left alone by society. And through no fault of anyone, they might be joined by a large number of others, which will mean that society will have to pay attention, which they haven’t for so long. But I haven’t answered your question. Your question was, what’s going to be the health burden in the future? And the margins of error of an estimate are too large to know at the moment. I don’t know.

Grant: Yes. Speaking of COVID, have you attended any virtual conferences? 

Chris: I was a co-organizer of a conference over the last two days. I think most people are Zoomed-out, being on Zoom or whatever calls, throughout the day. People, including myself, by the end of the day were just exhausted.

Chris: That conference actually, however, had some energy to it. We made use of breakout rooms and that was sort of randomly done. We allowed, you know, people to interact in ways which were less formal, and we paced it I think quite well. At least the feedback said so, but conferences are going to change quite clearly. 

Chris: I go back to the ecological case that conferences actually have not been very good for our environment for many years and I’ve contributed to that. So we will continue to communicate in that way virtually at conferences. And I think that’s a good thing. We will miss one another. We will miss, you know, looking one another in the eye and having a beer or whatever, but that’s a small price to pay really for everything else that’s going on at this moment. and what’s already happened over the last few decades.

Grant: Why do you think zoom is so fatiguing? And everyone has the same experience. You know, you can be at a conference all day and it’s fine, but if you’re on back-to-back zoom calls for three or four hours, you’re exhausted.

Chris: I think in a conference you can zone out. You can kind of do what aquatic mammals do and switch your brain off and sleep. Well not sleep, you know we don’t sleep in conferences, but you can at least zone out for short periods of time and then come back in and focus. If you’ve got a bank of 20 people staring at you, you shouldn’t really do that.

Chris: And so you don’t and you fix on what’s going on, and I think that’s very tiring. So at the beginning of lockdown, when we have back-to-back Zooms throughout the day: eight or whatever per day. I had to change that. I had to move to being more spread out. And as winter comes here, we’re going to have to organize ourselves so that we can go out in the middle of the day and actually see some sunlight and get some exercise. So we’re going to have to plan our days differently. 

Grant: So I guess on a completely different note do you want to talk about your novel or will that be more of a surprise?

Chris: I’ve forgotten that I told you about a novel. I basically finished a novel. I’ve not sent it to anyone. The first version was read by my wife and she was rather scathing, probably quite correctly. So there is now the second version, which is probably a bit more thoughtful and explanatory. And it’s a dystopian novel. It does derive from a genetic story, but it takes a whole bunch of quite broad subjects from the ongoing ecological disaster that we’re in. And it has a theme that I thought was not particularly topical at the time, which was viruses. But now that it’s done, it’s complete, viruses of course now de rigueur. And so people might think that, I took inspiration from the COVID pandemic, but actually this wasn’t the case. 

Chris: The idea is that it is the human race on the earth that is the virus that is infecting our biosphere and so many species are being driven to the wall by our infection on the planet. It’s not a particularly nice idea. It’s not a particularly new idea. I go on to say that there’s more to it than that. It is that the men of the human race that are culpable. So there is a character–giving some of the plot away cause it’ll never be published obviously. 

Grant: You could always self-publish. You can get anything out these days. 

Chris: I could self publish. Yes. There’s a character, a woman who basically realizes that one way of putting a handbrake on the ecological disaster is this essentially to try and hobble males of the human race. So she introduces a virus to do so, which targets the men only and in so doing it does two things: it hobbles the males, and reduces the ecological disaster. But unfortunately viruses will do what viruses do well, which is evolve. And so, the virus then begins to jump to other animals and to women.

Chris: And causes a devastating effect on the whole of the human race, which has only countered–I’m telling you the whole story now–it’s only countered by the introduction into the germline of a mitochondria-like entity, which targets the factors that have led the males to be hobbled. And basically immunizes some people but these are only women to the effects of this virus. And so we have basically a matriarchy, whereas previously we had a patriarchy. 

Grant: That sounds really interesting. I would love to read it. 

Chris: I’ll give you a copy. I’m going through it one last time at the moment. 

Grant: That’s great. So maybe that feeds into one question I like to ask, which is: what would you do if you weren’t a scientist? Would you be a novelist or something else? 

Chris: Absolutely. I’ve already started thinking about my next one–if I’m going to write a next one. I’ve actually enjoyed writing a lot because it is freeing. As a scientist, I have to write facts, the facts as I understand them. As a novelist, you can write anything, and that freedom to venture anywhere in your mind is wonderful. You’re not constrained by the evidence that’s out there. So I’ve really enjoyed doing that, but it also takes quite a lot of rigor to do and to plot out all of the different characters and the themes, et cetera. So this is what I’m doing now for what might become a second, which is on the theme of clonality.

Chris: The idea is that–I haven’t written a word of this–that a male clones himself, thinking that he will gain immortality. But actually all that he does is introduce another male into the world. Who’s much younger than him. And he finds it to be quite a challenge to his sense of superiority.

Grant: Interesting. And I’m guessing it’s not in the same world as the first novel. It’s a totally separate world.

Chris: Yes, both of which are empty of COVID-19. 

Grant: And what’s your process like for that? I mean, do you dream up all the characters and the plot and so on before you start writing or is it very iterative between the writing process and kind of picturing the world?

Chris: So those are the two processes I’ve adopted. The first was organic: organic growth that just percolates up in your brain and that leads to all sorts of conflict in your mind and inconsistencies in the plotline. So I had to go through the plot again and again and again, to try and make it consistent. That took a long, long time. So what I’m now doing is trying to ensure that the plot is cogent, well-thought-out, the characters are three dimensional, and their interactions with one another are well-described even before the first word is written. So let’s see, the first way of working led to a full draft. The second way of working hasn’t yet generated a single word. So let’s wait to see. 

Grant: That’s great. So what do you think is the most interesting thing happening in biomedical research today? You don’t have to pick one, you can pick a few.

Chris: I think the most interesting thing that’s happening in research is how it’s becoming much more immediate in its effects on the population because of COVID-19. There are researchers now who have generated findings last week, who put them up as preprints this week will know that through the media they will become known by millions of people tomorrow. That immediacy of effect is changing the way that researchers are considered by the population, by governments. But it’s also changing the way that scientists themselves are thinking how they can do that science and what effect and impact they have on others. 

Chris: A lot of science is done without thinking about “what is the impact? What is the benefit, the immediate benefit?” These are blue sky science, and that’s a good thing. So I think hopefully once COVID blows itself out, there might be a long lasting impact on the idea that scientists should engage more with the population, work out what are the issues that vex them most, and also work on things that are more impactful. So that to me is interesting, more sociological than anything. 

Chris: What was interesting before that, of course, was the advent of CRISPR: this idea that as scientists of model organisms from flies to mice, to human cells, we can go in and edit and cut and paste and change DNA. And in that intervention ask, “what does this letter do out of our 3 billion? What does that letter do?” And really, we hadn’t had that ability before. And that really was game changing almost within months everything changed in genetics. 

Grant: And where do you think that’s headed? What do you think will be the most impactful thing that comes out of CRISPR and related technologies?

Chris: I think. All of those technologies are now giving insights into the world of molecules that we had never had before. What do I mean? I mean that we’ve been able to observe. We’ve been looking at cells and molecules and watching them go by and prodding them and seeing what their response was. But never really have we been able to intervene directly in a very targeted manner and have alongside the edited cells, the other cells, the wild type cells, and then compare them one to another and actually see what is going on.

Chris: That may not seem to be a big deal, but absolutely it is. And it’s taking biology, I think, one step closer to other types of interventional science, for example in physics and chemistry, where previously biology was much more observational. 

Grant: Do you think we’ll still be eating meat as widely as we do today in a generation?

Chris: No, we won’t be eating meat, if we’re still around a generation from now. I don’t believe so. There will be a proportion of our population–as ever–that will take up a large slice of our resources of the world, but most people I don’t think will be eating meat in a generation. At least my vegan daughter would hope that we don’t see as much meat then as now.

Grant: And do you think CRISPR and related technologies might play a role there?

Chris: I have to be careful here: I have colleagues who work in this area. Is CRISPR going to have a long lasting effect on livestock? It is going to have an effect and absolutely is being used currently to improve–as some would call it–on livestock traits. Is it going to last for more than a generation? I don’t think so. But whatever prediction I make, of course, doesn’t matter because I’m just one person. And once another generation has turned, I will have shuffled off my own mortal coil. So I can say whatever I want now. 

Grant: And have you seen what Meatable and similar companies are working on now? It’s a little bit of genetic engineering, but…

Chris: Yeah, I don’t know much about this. 

Grant: Moving to lab-grown meats to get away from animal-derived. 

Chris: My, my question would be what are the resources that are required to generate those lab grown meats? It may be that there are issues there that would need to be, considered quite carefully. The best thing is simply not to eat meat or drink milk. I’m not a vegan, right. I’m just saying that’s the best thing for our world going forward. If everyone were to make that same decision, the whole world would be such a better place. 

Grant: Certainly. In, I guess, probably even still the very early stages of a very great extinction event. Yeah. And practically speaking, do you think that there’s much chance of avoiding that or are we so far along at this point?  

Chris: As a human race, we’re not avoiding ecological disasters at all. We’re observing them and not learning from what has happened over the last few decades. It’s a train crash that we’re observing year on year. And I’m constantly reminded by people in my family who say “Yes, COVID is a huge thing, but the biggest thing, the greater thing than that, is the ongoing ecological disaster.” And I played my part in that. I think everyone in my generation needs to stand up and retell exactly what we’ve done and then ask ourselves what we need to do in the future.

Grant: This is depressing, but true, right? Um, so what do you think is your most controversial opinion in science? 

Chris: So we have evidence that we’ve published that 90% of the human genome does not alter who we are and what we do. And that if there were to be any changes in that 90%, it wouldn’t affect us at all.

Chris: Many people I’ve talked to who are scientists, or who are not scientists, are absolutely outraged by this idea. The scientist cannot believe that the molecules that we have in all of cells, or parts of molecules would not generally do anything. But that’s what the data says. I have to look at the data and come to a conclusion. We’ve looked at the data in a particular way that no one else has. And absolutely. It makes sense.  It comes to that conclusion, and others, using different approaches, come up with something similar.

Chris: So interestingly. We as humans would like to be sort of perfect objects, where you know, the genetic codes in our chromosomes are, in some way, perfect machines. It’s not true at all. In fact, you know, that there is an evolutionary argument, which is well-established, that as a population we’re pretty poor at getting rid of bad mutations. So we carry them in our population and pass them down through the generations often, more often than other species. So we’re certainly not the epitome of all animals now in that respect. So I think that’s a really interesting view of the human genome. And not one that, as I said, every single scientist and every single member of the general public would agree with. 

Grant: That’s interesting. You’ve certainly ended up in a very different place than where you grew up as a child, moving to England and then Scotland and so on from Uganda. Where do you think you’ll retire? 

Chris: That’s a great question. Where I’m allowed to retire by my family. Where would I like to retire? I spent two years on the West coast of Canada. And the countryside there, the variety of countryside from rainforest to arid desert in just a hundred miles or so, is outstanding and outstanding beauty. Great people: the Canadians. And I quite like that. I won’t be allowed of course. We’ll have many more family ties inside the United Kingdom. But I can always think of that as a dream and wonder whether that’s going to happen or not. 

Chris: Um, England? Unfortunately I’m less fond of England than I was. So I’m not going to retire there. Politically I think it’s not a place that I recognize as the one that I grew up in. 

Grant: Do you expect that by the time you retire, Scotland will even still be part of the UK? 

Chris: Well, this is a big question as to what’s going to happen with Scotland. The current opinion polls are that if there were to be a referendum now, Scotland would go independent. The separation of Scotland from the rest of the United Kingdom would take a very long time, just as the separation of the United Kingdom from the European Union, which I regret hugely, will take far longer than anyone has ever thought. And that will happen with Scotland. 

Chris: We share a border, which is, you know, you can not see the border, you just pass through it. It’s just like a state line in the US and that would just have to change, particularly if Scotland were to become again part of the European Union, which most people in Scotland would wish. 

Grant: Just logistically it seems like it would be difficult for them not to. It’s such a small, well, it would be such a small country. 

Chris: It is a small country. It’s, you know, 5 million or so, but that’s sort of similar size to other members of the European Union. And such countries have benefited hugely from being part of that Union. And I think sometimes we focus too much on large versus small equating them to important to not. And Scotland’s always been at the edges of the United Kingdom and made much of that. I think it might do so again. 

Grant: Great. Is there anything else you want to say before we wrap up? 

Chris: Not really Grant. It’s a pleasure talking to you. And I wish that I could ask you as many questions as you’ve asked me today. So we should catch up separately. 

Grant: Yeah. Definitely. 

Chris: And I wish you well, you and your family well, obviously. I don’t think so. I’ve covered quite a lot of ground and probably some ground that I’m happy to stay in, but I’ve not covered before politics, et cetera. 

Grant: Thank you for joining us, everyone. Hope it was a nice conversation.

Chris: I’ve enjoyed it a lot Grant.