Latest / Polymath World Channel / Polymath World # Episode 46 - Dr Denis Alexander
Transcript
- Polymath World (00:00.888) Hello and welcome to the Polymath World channel and I'm delighted to be joined by a really fantastic scientist who's done amazing work and also someone who's become quite a friend in the last two years. We're going to be dipping into molecular immunology and genetics and all kinds of things which you know are my favorite subjects today. I'm delighted to be joined by Dr. Dennis Alexander. Thank you so much for joining me today. Denis Alexander (00:21.913) Good to be here. Polymath World (00:23.914) Excellent, so you are a molecular immunologist, you've worked in genetics and the interface of genetics and medicine. I'm really excited to dig into your story, but can we start from the very, very beginning? Were you really interested in science as a child and did you always know that that was what you wanted to get into? Denis Alexander (00:43.449) Well, I had a mother who actually read physiology at Oxford in the early 1930s, so a few years ago, and she was one of the women, one of the first women actually to study physiology in Oxford. It was a bit of a man's world until little later on in the 20th century. And she was always a great enthusiast for science and physiology. And she ended up teaching physiology in a girls' school, actually, and then she often... kind of lend me all kinds of stuff from school. don't know if she was supposed to do that, interesting things that got me engaged in science. I also had a wonderful microscope that was inherited from my grandfather who I never met because very sadly he died in 1917 in the midst of the so-called Spanish flu in the First World War. Actually it was 1918 I think and yeah we inherited his microscope and so I love looking at creepy crawlies. under the microscope and fishing things out of the pond. I think all those sort of things did get me interested in science from quite an early age. Polymath World (01:49.07) And was it the life sciences most of all that captivated you then rather than physics or chemistry? Denis Alexander (01:58.072) I think it was really. think I've always been interested in creepy crawlies and although having said that, I did get interested in chemistry through making bombs in the back garden. we had ammonium nitrate. My mother was a great gardener and we had quite a big garden, about an acre of garden. And when my parents were around, like, you know, I had my mates around when I was little and we used to kind of explore things that were hanging out in the tool shed and places and we discovered. Somehow I discovered that if you mix 50-50 ammonium nitrate with, or I guess it's sodium nitrate, no ammonium nitrate I think, mix it 50-50 with sugar and pack it into something and make a long fuse, it can make a really good bang. And I was excited by that and we did that quite a bit, experimented with other chemicals as well. So that got me into chemistry. And so I think getting into chemistry and then getting into biology, you put them together, what do you have? have biochemistry. Perfect world. Polymath World (02:55.406) Yes, you found your niche. what was your education like? Describe your education journey for us. Denis Alexander (03:04.887) Well, I had what in those days was considered sort of a normal track for our family. It's funny thinking back now, but anyway, when you're growing up, you just fulfill the expectations of the maid by your parents and your nearest and dearest. So I went to prep school. I went to public school day. I was never a border. Both my brothers, in fact, had been borders, but they were probably a bit older than I was. And then from Epson College I went to Oxford, got an open scholarship to Oxford and did four years of biochemistry there in Oxford. So that was the kind of track. And the reason I say it's a bit funny thinking back now because it was never discussed what university I would go to or whether I would go there. It was always assumed I was going to go to Oxford and that's what you do. And both my brothers have been there and my mother had been there. and my grandfather had been there and my uncles and so forth and so on. It was simply a kind of assumption and I sort of slightly shudder now thinking back at that but you know that normality is shaped by what you're brought up to expect in your family environment and so in that way I simply that's what I did. I still had to work hard to get there but you know it was simply the expectation. Polymath World (04:22.444) Yes, and so did you study biochemistry then at Oxford? Denis Alexander (04:26.637) Biochemistry four years, yeah four years, it was quite a new degree. I'd only been going a couple of years when we there and they were still sorting out some things. Actually I learned at school that biology, well love biology, love chemistry and then I learned about biochemistry and I thought wow that's so wonderful to combine these two things together and then they said you need maths to do biochemistry and so they pushed me into maths six form and I did not like maths actually. Polymath World (04:32.695) Yeah. Denis Alexander (04:54.105) and I complained bitterly and then in the end my mother went to see the headmaster and said this boy does not like maths but he likes to do biology and so that's how I got into the biology sixth form thanks to my mother so I was still quite young so in those days you could flip around a bit and I don't know anyway that's what I did so I ended up three and a half years in the sixth form of HINC so I'm going to have be up Polymath World (05:07.916) Hahaha Polymath World (05:18.088) It sounds like you quite a lot to your mother already in your journey. What era is this that you are doing your biochemistry degree? Denis Alexander (05:28.089) I did buy a chemistry rock for 64 to 68. Yes. Polymath World (05:31.722) Okay, so it really is quite an explosive period for biochemistry at that time, isn't it? Denis Alexander (05:35.993) Yes, explosive, maybe that's the right word, but yes, indeed, it was a good time to do it. My tutor was Arthur Peacock. Arthur Peacock was a biophysicist working on DNA structure and so I him for four years. He was also fascinated by irreversible thermodynamics, which he tried to teach us and that I wasn't so, didn't feel so warmly towards that, but I love the biochemistry. I loved Polymath World (05:44.332) Wow. Denis Alexander (06:04.088) I like sort of things which are complex systems where all the bits, you know, you can work out how they join up together. That's the good thing about biochemistry. You can make sense of the system. I never liked anatomy because in a sense you're learning a whole row by row, a whole list of things. And I couldn't see much point in that. But biochemistry, could see how things would join up. You could make sense of A going to B to C to D and all that kind of thing. And I found that, and I still do, very attractive. Polymath World (06:11.822) Mm. Polymath World (06:31.662) Yes, we've spoken to Kenneth Miller on this channel and he was talking about that era as well. This is the structural biology boom. know, Fred Sanger has won the Nobel Prize in 58 for sequencing the amino acid sequence of insulin and inventing that process. Obviously, the molecular biology revolution is well underway there. Were there any... particularly the interesting or exciting problems you working on when you were doing postgraduate study. Denis Alexander (07:06.168) Prescrinder's study. Well, I was interested in doing neurochemistry and there wasn't a lot of neurochemistry going on at Oxford at that time. And so I asked my tutor, I said, where's a good place to do neurochemistry? he said, my lad, you should go to the Institute of Sun Country. That's where there's good neurochemistry. I said, yeah, that sounds good. And now again, I slightly shudder at the way things were so informal. He said, do you want to do a PhD there? I said, yeah, why not? He said, well, I've got a friend I'll phone him up and... you know, we'll see if they got a PhD in studentship. He phoned him up, he phoned up Richard Dick Rodnight, who later became professor of neurochemistry at London University. He phoned up Dick and he said, oh Dick, I've got a lad here who wants to do a PhD. Have you got any PhDs going? He said, sure, I've got two. When would you like to come? And that was that. I I come, I slightly shudder at the thought of it now. You know, I hate to mention these things, but it was all very informal. Polymath World (07:36.182) you Polymath World (07:55.342) gosh. Denis Alexander (08:04.496) And funnily enough, I showed up a little bit late, as I often do, I show up late to things. And I showed up the day after the other guy got there first. So he got the first pick at the project. I had no idea what project I was going to do. In those days, you just showed up and they gave you a project. So there were two projects. And the other guy who showed up first got the project about working on phosphorylated proteins in brain tissues. And, you know, if you let them stimulate brain tissues, then... what happens to phosphorylated proteins. And he got that project and I thought, dear, that sounds really interesting. And then the project I got was to analyze the structure of the sodium potassium pump. That's the pump that you need to restore. And once you get a nervous impulse where you've got the sodium ions rushing in and potassium ions rushing out, and so then you have to restore that using the sodium potassium pump in order to restore the electrical gradient across the nerve. Polymath World (08:37.282) Thank Polymath World (08:43.725) Well. Denis Alexander (09:00.892) and at that time it was very poorly understood, the structure was not known at all. And so I was given the challenge of trying to work out the structure of the sodium-potassium pump, which I think back again was a huge project, but actually went quite well. Polymath World (09:18.04) Gosh, it must have been really quite amazing being on the frontiers of such a new discipline. Denis Alexander (09:25.272) It was quite new. I mean, wouldn't say it's totally new. was, I suppose, been going about, neurochemistry goes back a while actually. And the reason I think of that is when my mother died, we went around the whole, all of us, family went around the house and was sorting out her belongings in the usual kind of way. And then we came across this bunch of papers. My sister said, oh, that's, they're just papers that's thrown away. said, a minute, wait a minute. And it turned out to be my mother's physiology essays from Oxford. and which I kept, said, no, this will be really interesting. Essay is written in 1931 to 1934. And they give you a kind of picture of science in those days and physiology. And I came across an essay, guess what, on phosphorylated proteins. So, and I kind of felt almost spooky about this since I spent much of my life working on phosphorylated proteins. And then coming across this essay, you know, dated 1933 or thereabouts. And so of course the Polymath World (10:11.171) Wow. Denis Alexander (10:25.752) understanding of what they did was fairly minimal at that time but still you know progress was being made and so in a way neurochemistry goes back to the earlier part of the 20th century really as people began to look at the chemistry of living things so biochemistry sort of evolved itself during the course of the 20th century. Polymath World (10:37.698) Yeah. Polymath World (10:46.284) Hmm, fascinating. What did you do after your PhD? Denis Alexander (10:51.764) After my PhD, I decided I would, at that era, okay, so we need to describe the 1960s. It was an era of travel, of wanting to do something for the world. Of course, then that developed into the hippie trail and people going out to India and you got the Beatles and Sgt. Pepper's lonely club band, what was it called? That one and all this kind of culture going on at that time. Anyway, I went to help develop. Polymath World (11:13.207) Yes. Denis Alexander (11:20.246) new university departments in the Middle East. I felt that I had an easy life. I've been given a lot. I've been, you know, doing all these wonderful things. I didn't want to leave science, but I wanted to use science to help people in countries which at that time, the science was really just getting going. And one of the countries in that category was Turkey. And Turkey at that time had only 10 universities and it had developing research programs, but they were pretty early days, to quite honest. There wasn't a lot of research going on and they did need, they were welcoming to foreigners who might want to come and help and go on the faculty and start teaching science and doing research, setting up new labs, that kind of thing. And so in fact, we ended up, because I got married during my time doing my PhD in London, and we went off and we had our first married home was actually in city of Ankara. capital city of Turkey. So that's where we set up for the next nine years. Polymath World (12:23.202) Hmm. And what was your, so it's obviously you were teaching, but what kind of research were you doing out there? Denis Alexander (12:30.615) Actually, the first two years I wasn't doing any teaching at all. It was really a postdoc. I mean, it's really my first postdoc position. And they welcomed to have some of this is a Haji Tepe University, one of the three universities in Ankara at that time. And so the only thing I knew about was, you know, how to work in neurochemistry. was anything I knew about. So I set up a neurochemistry project. I carried on working actually on the structure of the sodium potassium pump. By that stage, what I'd shown in my PhD was there's one main big subunit, which is called the alpha subunit now. And it was quite clear that there was another subunit, at least one more involved. In fact, there are three, as it turns out. But we knew there was another subunit. And I spent a couple of years trying to analyze and isolate that subunit. And we did all this work on ox brain. And the good thing about ox brains, Ankara is a good place to go for ox brains. So what you do is you get up early in the morning and go down to the slaughterhouse and you can get your brain quite easily. You know, get a couple of brains and freeze them down quickly to get them back to the lab. And that's the material I was working with. So what we call it now, kind of in those days, we call it bucket and spade biochemistry. You it's what you take a big tissue of some kind and you analyze it and you purify it and you mess around. And yeah, that's what I did. Polymath World (13:35.48) you Polymath World (13:48.398) No, Polymath World (13:56.898) How were you assessing the structure of the sodium potassium pump? Were you using crystallography? Denis Alexander (14:02.584) Not at all, no, not in those days, no, this was way before. Well, was coming along, crystallography was coming along, but coming back to the Institute of Sarkarotry, it was definitely a biochemistry lab. Fortunately, fortunately it's a phosphorylated protein, that's why I got in phosphorylated proteins. So we had to make, by the way, our own ATP, ATP radioactive 32. Can you imagine? You couldn't buy it from radioamish in those days, so we took it in turns in the lab to synthesize Polymath World (14:26.978) Gosh. Denis Alexander (14:32.438) ATP32 starting off with five millicuries of inorganic radioactive phosphate and ending up with one millicury of ATP32. and yeah, and your badge, your radioactive badge would tend to get pretty black during that week. So you didn't want to do it too often. Anyway, so really it's a very fast reaction. They'd already built a fast reaction vessel and they knew that it was a sodium activated, what we call kinase now. of some kind and basically what happens is that in the sodium potassium pump the hot radioactive ATP32 sticks its radioactive phosphate onto the alpha subunit of the sodium potassium pump and it's not a normal, it's an unusual chemical bond, it's called an acyl phosphate bond and it has certain properties that you can then identify as an acyl phosphate, we call it a high energy phosphate bond. And that is an intermediate, very rapid intermediate. It's very rapidly dephosphorylated in a potassium catalyzed way. So you've got sodium catalyzing the phosphate going on to this A cell phosphate intermediate, and then potassium quickly takes it off. And that gives you the energy which shifts the conformation of the pump in such a way that it therefore acts as a like an ion channel. It pumps the ions in two different directions. Only recently has the total structure of that pump really been worked out, again with X-ray crystallography and so forth. But that was 50 years later, it took a long time to do that. So in those days, all we knew was that this is sodium catalyzed event, we could isolate it. And then of course, once I got hot P32 on this protein, then I could purify it. So like I say, bucket and a spade, biochemistry, just put down columns and columns and more columns and more columns. curifying finally on a polychromy gel. And in those days we didn't even have slab gel electrophoresis. We had these tubes. Okay. So it's called tube electrophoresis. And that was challenging because then you had to get it out of the tube and you had to chop it up into little slices and put each slice separately into the radioactive counter. So was pretty, it was hard work actually. So, and, but it was great fun. I enjoyed it a lot. And yeah, so we found out in fact, Polymath World (16:47.918) haha Denis Alexander (16:54.347) that the molecular weight, according to the lecture of Freisitz, and it's a fairly rough way of assessing the molecular weights, we calculated the molecular weight was, I think it was 102,000 thereabouts. And it turned out, which I think is more by luck than anything, that it was pretty much exactly what the alpha-cell unit molecular weight is. By the time you've got Clonen in sequence, then you can work out the exact molecular weight. And we were very close actually, but. Like I say, I think it was a bit of luck there because the accuracy of those two gel and atrophoresis calculations were not great. Polymath World (17:32.879) Well, I'm curious. Obviously you are learning all the tools of the trade and you're getting your hands dirty while you're doing all of this. But you are known really for molecular immunology. So what was it that brought the move from doing that kind of biochemistry and sort of some of the structural stuff over into doing molecular immunology? Denis Alexander (17:59.543) Yeah, there's a bit of a jump in between actually, which is part of the answer to your question. And in 1980, I got recruited to go to the American University of Beirut in the Lebanon. In fact, the late 1970s got very political, very difficult in Turkey. There was nearly a civil war. There were fights in my campus. By that time, I'd gone to the Middle East Technical University, a very left-wing campus, and there were fights between all the different left-wing groups and There was martial law quite often and so forth. Anyway, we thought, yeah, we eventually left Turkey in 1980. And then I, out of the blue actually, I got recruited to go and help set up something in the American University of Beirut Medical Center called the National Unit of Human Genetics. And that was totally different from the research I've been doing before. But I wanted to do something that would be more helpful medically to the local population. And the Lebanese, as many countries in that part of the world, tend to marry their first cousins quite often, which is not a good idea genetically. And so you can see various genetic diseases there quite often, which you would only see very rarely in this country. And so the National Unit of Human Genetics was set up to do research in that area and to also do prenatal diagnosis. We had the first prenatal diagnostic clinic in the Arab world, actually outside of Israel, that was the first one. And so it was an amazing place really to do research. Again, politically it was not a great time to go in retrospect, but of course we didn't know that at the time. Well, it was not terribly stable, but it got worse as we were there. But we quickly found a whole bunch of stuff that we'd never have found working in other places. So was clinically... fascinating, interesting place. We were able to do some help to some of the poor little kids who had genetic diseases. In many cases, you know, when you give a diagnosis to a child with a bad genetic disease, the prognosis is pretty bad actually. But simply finding out what it is can be a real comfort to the parents, at least they know more what's going on. In other cases, in fact, Denis Alexander (20:24.008) it can be really encouraging for them because you can manipulate the diet in some ways and the baby will be fine and be cured. Sometimes it can be a good news story all the way around medically as well. I could tell you one example of that if you like. Kind of interesting. Well, we had one little baby who used to come to the, several times the baby was brought into the American University Hospital with lactic acidosis. There are many reasons for lactic acidosis. Polymath World (20:38.89) Yes, yes please. Denis Alexander (20:53.142) baby very poorly, not doing well, failure to thrive, treated in the hospital, went home again, few weeks later, will be coming in again, same problem and so forth. So each time the baby came in, we had a tiny, tiny little bit of blood, just enough to get a little white blood cell pellet out of it, white blood cells so you can then do enzymology and you can screen, you know, a couple of, maybe two or three enzymes each time. And the first couple of times the baby came, all the enzymes we looked at were normal. So I did a big literature search and those days was no internet, obviously no online thing. So it's a question of trawling through McCusick, the great Bible of genetic diseases, trawl through that. And I came across this disease, which I'd heard of before, called fructose 1,6-difositase. And if you have that genetic mutation, that means you don't have that particular enzyme and you cannot metabolize fructose properly. and it gets switched down another pathway into lactic acid, lactic acidosis. I thought, okay, let's set that up. Next time the baby comes, we'll give that a shot. Anyway, we set it up and baby came in, tried the enzyme, completely lacking. It was the 31st case in the world, in the world, of fructose 1, 6-dipositase deficiency. And so that was a pretty rare disease. But of course, in that case, and then what we discovered was... the parents were actually feeding this poor baby honey because there's a kind of cultural tradition in Lebanon that, you know, if your baby fails to thrive, you feed him honey, you see. Well, of course, honey is full of fructose. And so they were killing their baby without realizing it. And so all we had to do is tell the parents, look, stop the honey, avoid mature fruits, which has lot of fructose in, baby will be fine when the baby was fine. So that was a good news story. And we were able actually to do Polymath World (22:32.056) Yeah. Polymath World (22:44.909) Wow. Denis Alexander (22:48.054) The parents were first cousins and we did a whole study on I think four generations to the family, maybe three generations to try and detect heterozygotes so that it could be genetic cancelling about not marrying people who are fellow heterozygotes which would obviously raise the possibility of having a homozygous offspring. So that was a good news story, yeah. But they weren't all good news. Polymath World (23:12.322) These were early days of, I suppose, genetic counseling, something that the NHS wants to sort of build up a lot more these days. Denis Alexander (23:24.498) Yes, yes, mean genetic cancer had been going on for some time, but in those days it was becoming better informed. Of course the families we were looking at in Lebanon mostly had a history in the family of a particular disease and therefore there was grounds for giving them genetic counseling based on that, especially if you could detect heterozygous, not always possible in every case. In the case of fructose 1,6-stifosinase, that was out of the blue. That had never been described before in the Lebanon tool. That was the first case, as I mentioned, in Lebanon and the 31st case in the world. So it depends on what it was. In fact, two weeks after we got there, again, a story would be too long to tell, but basically we discovered a new human mutation. A baby had come into, or a small child had come to the hospital. and the doctor thought that he had seen a cherry red spot in the retina. That's classic sign of Tay-Sachs disease, which you don't get in Lebanon, you get a similar disease in Lebanon. And so we looked at the urine in that case and turned out the lysosomal enzymes were very, very high. So it wasn't a lack of the enzyme, which is hexosaminidase. It wasn't a lack of that. was actually... very high levels of all the lysosomal enzymes and yeah so it was an extraordinary thing and we we've ended up it took a couple of years to really work on that and it was from a Palestinian family in one of the Palestinian refugee camps in Beirut and we went in the in the refugee camp four of us went down on our white coats we got complete family history. Key thing there is to get the granny on site we got the granny on site and she just says right and she orders everybody to give blood and go out to everybody in the whole camp and get all the relatives. And we got a whole four generations worth of relatives and we analyzed the whole lot. I mean, we were able to trace this particular mutation all the way actually from the granny, all the way through the family. Anyway, so it's a long story and it turned out to be a novel human mutation. So we got three papers out of that. So it was good for that point of view as well. you know, that Denis Alexander (25:41.885) and able to give some genetic counseling as well, although very sadly the whole family were dispersed after this really invasion in 1982. Polymath World (25:51.927) And you had to leave the Middle East after not too long as well. Is that when you were brought over to Cambridge? Denis Alexander (26:01.064) Actually what happened was we evacuated three times from Beirut and the first two times the fighting quietened down a bit and we went back in. But the third evacuation was we realized it was time to go. Okay, what happened was the President Reagan, US President at that time, a deal with Maggie Thatcher, our own Prime Minister, so that US planes would take off from a base in fact near Cambridge as it happens. to go and try and kill Colonel Gaddafi and they missed and they killed his little adopted child and of course as you can well imagine the Arab world was an uproar about that and so they started killing western, well they killed three western people in revenge and two of them, one of them in fact was the director of the language school where my wife was teaching English at the time and so the writing was on the wall and Yeah, so the embassy calls up and said we're arranging evacuation and anyway, we had to be out in two days. So we actually left, literally left the experiments on the lab bench and cleared up in a hurry and drove back from Beirut back to England. We no job, no house and not quite sure what happens next. So what happened next actually was I got a job at the Institute of Psychiatry in London. Polymath World (27:14.542) you Polymath World (27:21.208) one. Denis Alexander (27:26.581) just a temporary job as it turned out, I mean, I was like a visiting fellow and that was really like going into Nirvana, know, because it's well funded, you know, you could just write up on the wall anything you want in the way of consumables, you could get anything you want within 24 hours instead of 24 weeks or something. And so very different from working in a developing country or something like that. anyway, and that's how I came into molecular immunology. because I knew something about kinases and phosphatases and phosphorylated proteins. That's how I got a job there. And so I ended up working on phosphorylated proteins in T cells and one of the white blood cells. And that's what I did then in a job that ended up with three and a half years. And now that I managed to get a toehold back in research life here in the UK. And that's how I got a job in Cambridge basically. So it's all happened that way. And that's how, so I have to thank President Reagan. for getting me into molecular immunology because that's what happened historically. And that's how I came up to Cambridge and got a job at the Bakerham Institute which is a research campus just outside Cambridge and that's how I ended up in molecular immunology. Polymath World (28:30.102) haha Polymath World (28:44.62) Yes, and you're a fellow of St Edmunds College at Cambridge University and you ended up ultimately being the director of molecular immunology at the Babraham. The Babraham is an incredible place. Could you maybe give us some highlights of some of your research and work there, the kinds of things you got to work on? Denis Alexander (29:07.123) Well, by the way, I was never director of molecular biology. so I was, I mean, just to be clear. funny enough, we started out with departments when I first went there. And then it went from evolved, this is the organizational system evolved from departments to what do we have next? We programs, and then we had a program. And then after that evolved to laboratories with a big L. And so it's kind of a, anyway, they're all basically the same people every time. So I was Polymath World (29:10.894) Sorry, I'm like an emoji. Denis Alexander (29:37.363) Chair of the Programme of Molecular Immunology. So my lab was called the Laboratory of Lymphocyte Signaling Development. yeah, so we had a lot of interesting projects going. The one project we had, which was going on all the 20 years I was there, was based on a molecule called CD45. You we immunologists are very exciting people. We call our molecules by numbers. So I used to say to my... Polymath World (30:04.342) Yeah. Denis Alexander (30:06.941) I used to say to my wife, know, she said, what do I tell people that part is? You always say, what does your husband work on? And I said, just tell them I'm working on CD45, you know, that'll shut them up. They won't ask any more questions after that. CD45 is this wonderful big molecule, which is a transmembrane molecule. And it's got a huge ectodermane, the bits sticking outside the cell, which is alternatively splice, you've got all these variants and the inside part. and that's the reason I got into it, is a tyrosine phosphatase. So by the time I'd left the Imperial Cancer Research Fund, it was clear that when an antigen binds to the antigen receptor and then initiates a cascade of signals inside the cell that lead down to the nucleus, leading to the activation of a T cell and then its replication. So that initiation is the coupling mechanism happens through the phosphorylation of a whole series of tyrosine residues in the cytoplasmic tails of the antigen receptor. And that became, was really clear. So I knew that CD45 must be having an important role in that. And of course, the initial thought we had was that CD45 was actually dephosphorylating those particular phosphotyrosines. But it turned out, in fact, that wasn't quite the case. There was something a little different, which turned out to be even more interesting actually. that there's a tyrosine kinase called LCK and it has an inhibitory tyrosine, phosphorylated tyrosine and it's C-terminus. When that's inhibited, the kinase doesn't work properly and so therefore the antigen receptor doesn't work properly and therefore your immune system doesn't work properly. Okay, so there's a cascade of events there. So the lack of a regulation of a phosphorylation event can switch off your immune system. That's good to remember. So we discovered that LCK, Tauracin-505 was a substrate for CD45, which is that Tauracin phosphatase. And what was then unexpected was we then did an experiment, started working a lot on transient mice. And we thought, well, okay, so we got hold of some other mice with LCK, which had been mutated at that Denis Alexander (32:35.38) particular tyrosine, so it didn't have it. So that was a mouse colony with that particular mutation. They had some problems, but they didn't have cancer or anything like that. We also had from colleagues, collaborators here in the University of Cambridge, Nick Holmes and the Department of Orthology had made a CD45 knockout mouse colony. And that mouse colony is completely immunocompromised. It's just like children get, you know, they have no immune system basically because what you're doing is you're switching off all that integration of signals that come from not only the T cell antigen receptor in T cells but also the B cell antigen receptor in B cells. So they're completely switched off. So we thought okay so why don't we cross the CD45 knockout mice, no CD45, and then we'll cross them with the LCK mice and so we should be able to restore Polymath World (33:07.662) you Denis Alexander (33:34.044) since the LCK mice, don't have that regulatory tyrosine at the end, that C-terminus. So we should be able to restore all the immune system in the CD45 knockout. That's what we did. And what happened was quite unexpected actually. And what happened was the mice that we've now got CD45 knockout, LCK mice, Lick mice, they all started getting cancer from the age of six, eight, nine, 10 weeks. And they were dead by 16, 18 weeks. And they got T-acute lymphoblastic leukemias. So that part of the lab swung the research into cancer research. I always remember we sent some of the cells down to a clinician here around the corner here at Adibert's hospital, working in the area of oncology. He said, when I look at these cells in the mouse, they look exactly like a human T-acute lymphoblastic leukemia. Okay, so what was going on there, to cut a long story short, it turned out LCK has another phosphotericine, which we knew about autophosphorylation, which it activates it. And what was going on was that when you don't have CD45 present, that auto-activating autophosphorylation site goes through the roof. It was super activating LCK and it was converting LCK-teracin kinase into an oncogene and causing cancer. That's a short summary of a long story. Anyway, that was one of the interesting kind of outputs which took many years actually to get that far and then we discovered how well how that was working at the molecular level in terms of the initial events that were going on in terms of causing that cancer so that was kind of an interesting model. Science is totally unexpected yeah you never know what's going to happen next which is fun. Polymath World (35:19.991) Yes. Polymath World (35:24.524) Yeah, yeah, absolutely. We've had Professor Bob White on this channel and I believe he started the Faraday Institute for Science and Religion with you. Is that correct? Denis Alexander (35:37.876) We co-founded it together, that's right, we're both fellows of Cinnamon's College and we co-founded it together, yes. Polymath World (35:39.958) Yes. Polymath World (35:44.353) Yes, and you've mentioned Arthur Peacock already, who is a giant in the academic field of science and religion. So that's quite a heritage, that's quite a legacy you had there. I first came across you because I picked up a book I saw in a bookshop called Creation or Evolution, Do We Have to Choose? And I thought, that's an interesting book. It's probably controversial with some people. Why not give it a read? So the 2000s must have been quite interesting. You've been doing your science research in Cambridge and yourself and Professor White have this vision to start a much better thought through, I think, and academically credible and viable centre in Cambridge for studying how science and religion interrelate and their answers to the big questions. Could you explain just something about what your heart was behind setting up the Faraday Institute? Denis Alexander (36:50.42) Yes, indeed. So the BBSRC, that's the research council for whom I used to work at the Baybram Institute, they had, they used to have a very early retirement age of 60. know, 60 is really young, okay. So I tell my American friends that and they look totally shocked. anyway, so psychologically, I was already beginning to think, what am going to do after the age of 60? Hopefully I'll still live a few more years after 60 and have something to do. So. Polymath World (37:03.907) Wow. Polymath World (37:17.92) Yes. Denis Alexander (37:19.796) I started winding my lab down. didn't write any more grants and just kept things going. The lab had grown to about 40 people actually. So we had five project leaders, which were fine. But my own research group was about 15, I think. I was winding them down. And then at the same time, there were certain shrill voices out there in science. Richard Dawkins was one of them. And Bob White and I both got... Polymath World (37:46.67) you Denis Alexander (37:48.252) a bit tired of hearing this idea of a kind of conflict between science and faith. We thought that was very, just didn't fit the data really historically or in contemporary thought. And we got a bit of fed up with that. And so we thought, well, why don't we start up an institute, you know, which would do research on the relationship between science and religion. And so, and I needed a job, okay, after I retired at the age of 60. Actually, what happened was the BBSRC changed its mind. They switched to a retirement age of 65 or something about two years before I was about to retire. By that time, I was psychologically already geared up to that I was winding my lab down. Anyway, so that's what happened. So and we thought, well, why don't we have a science religion institute? And the obvious place to have one is in a Cambridge College because it's interdisciplinary. You know, we've got all the disciplines there and science religion brings in history and know, philosophy and sciences obviously and everybody and theology. So that would be a good place to have one. And so we approached the governing body and they were happy enough to say, just as long as you fund it, okay, get it funded, then, you know, just carry on. And that's what we did really. So I became the first director when we set up the Institute. We got a grant from the John Templer Foundation. was a very short grant actually, only 30 months, but they gave us some matching funds. enough to keep us going for five years in the first instance. And so we set up in January 2006, I became the first director because, know, was, Bob White was still at his chair in geophysics. So he was busy with that. And I was still carrying on a bit of work at the Abraham, but left that eventually. And that's how we got going really. And the aim has always been to do research, academic research in the field of science religion. but also some dissemination work to have people going out to schools and churches and whatever different places to give lectures about the relationship between sons and faith. So that's how we got going really in 2006. Polymath World (40:01.39) 2006, that's an extraordinary time because I think The God Delusion by Richard Dawkins comes out then. Obviously, it's five years after 9-11, so discussion about science and religion is not particularly well thought through or friendly. You have the Intelligent Design Trial at the end of 2005 over in the US, so that's quite an extraordinary time to be making a better conversation. Could you tell us something about some of your books in this area? I know, I believe you gave one of the GIFT lectures as well. So tell us something about your books and your published works in science and religion. Denis Alexander (40:42.035) Yes, I mean just on your first point you mentioned there by the way, of course we didn't know that 2006 was going to be such a great year for starting up an institute on science religion. We'd already planned it, you know, for the previous two years. 2005 we got a grant and so forth. So yeah, and we have to thank Richard Dawkins very much for stirring up an interest in this whole field. Not always for reasons that we would agree with, but still has started good conversations and And I think a lot of people immediately started coming to our events. We were quite surprised by the level of interest actually. And the surprise was partly because we didn't think there'd be that number of people interested, but we really had some amazing numbers of people. We came along quite early actually. And so that was, I think in many ways, thanks to people like Richard Dawkins and the new atheists and all those sort of people. We didn't come out to particularly confront them or we've never done You know, we've never done debates, that sort of thing. We're more of an academic institute in that way. But I think if you look at the cultural background, and I think those of New Atheists were helpful, actually, in arousing interest in this particular field. To come to the second part of your question there on books. Yes, actually, I wrote my first book on science of faith when I was doing my PhD, which I know is a bit crazy, really. So I wrote it when I was 25. and then 26 it was called Beyond Science. And the way that happened was I had a brother, older brother, who's long since died, and he started up a publishing house, which moved to Oxford called Lion Publishing. And they were interested in books that would relate faith to all kinds of academic areas and so forth. And he said to his younger brother, me, he said, we need a book on science religion, which is sensible. you know, which is, you know, where the science is correct and not like somebody who's crazy, creationist and that sort of thing. anyway, and that's what happened. So, and that was published in just, just after we got to Turkey, I think. So I can never do a book launch. But, excuse me, it actually did quite well. The reason it did well, I think mainly was because of no competition. There were very few sort of sensible books on science religion in those far off days. Denis Alexander (43:06.675) and so there was creationist books out of the United States were a few books Arthur Peacock was just also publishing his first book etc but anyway it did quite sell quite a lot of copies because there wasn't much else on the market anyway that's how I think about it yeah so then I wrote a book when I was in Beirut called Rebuilding the Matrix Science and Faith at the end of the 20th century unfortunately The Century was not long enough and so eventually got published in 2001 and the subtitle was Science of Faith in the 21st century. I think we had to change the title and it got a bit big and anyway I'm not very good at writing short things. The Giffords came later on so the Giffords lectures I gave in 2014 was it? Yeah I think it was, something like that, no 2012 was it? Something like that, 2012 anyway. Polymath World (43:44.376) Hahaha Denis Alexander (44:03.603) Yes, I gave the Gifford Lectures, which is whole series of lectures. You know, it's not one, it's a whole series and did those up at St. Andrews University. And that I did. Well, the book that came out of it was called Jean's Determinism and God, and that was published by Cambridge University Press. And a number people said it's too technical, it's too academic. We didn't really understand it. We want you to write a more popular version. So I Polymath World (44:18.455) Yes. Denis Alexander (44:32.434) was in correspondence actually with LAM Publishing about writing a lot of version and then, and then I noticed my contract with Cambridge University Press that said any other book relating to this one, we have to have first option or first refusal or something like that. Anyway, so I wrote to Cambridge University Press and said, oh, I know you don't do popular books, so I need to tell you that I'm in correspondence about this other book. And they wrote back and said, oh, well, you know, it depends how you define popular. And so Polymath World (45:00.269) Hahaha Denis Alexander (45:01.186) and they sent us a summary. Okay, so I sent them a summary and a few weeks later I had a contract. So that second book that came out was called, Are We Slave to Our Genes? A more popular title anyway. And that came out during the pandemic. again, not an easy one to launch in the middle of the pandemic. But yeah, I've had a few other books as well, but those are some of them. Yeah. Polymath World (45:12.342) Mm-hmm. Yes. Polymath World (45:22.722) No. Polymath World (45:27.916) Yes. I really enjoyed these books tackling the questions of determinism and what our relationship between our genes and us and what that relationship really is. I thought they were really tremendous. And you did become a bit of a lightning rod for a while with the creation and evolution book. I remember people writing counter books and counter blogs to what you're saying. It was really quite fantastic. Denis Alexander (45:57.331) I felt a little bit like Richard Dawkins. Richard Dawkins has got all these books written against him. And then once I've done creation, evolution, we have to choose. You're kind of piggy in the middle already, because on one hand, you've got the creationists who think you're terrible and they write books, contradicting everything you say, etc. On the other hand, you've got people who go, well, we don't believe in creation anyway, and they just say, you kind of get it from both sides really. Polymath World (45:57.454) Yes. Polymath World (46:22.166) Yes, yes you did. Now I'm very biased. I think the Faraday Institute is absolutely wonderful and everything there is first rate and you've had some key lectures there by people who've been on this channel like Simon Conway Morris and Martin Rees and Kenneth Miller and it's a really fantastic place for taking the conversation seriously and looking at it academically. I know we've run a bit over time here, but I hope we can get you back on for another conversation sometime perhaps. But in the meantime, if people want to find out more about you and the Faraday and your works, where should they go? Denis Alexander (47:07.334) Well, they can go straight to the Faraday website. If you Google Faraday Institute, you'll find it easily enough, I think. And there's another one, a Faraday, which is to do with batteries. Okay, you're not particularly interested in batteries and don't go to that one. And there you'll find all our activities. You can sign up for a monthly newsletter if you're interested in tracking what's going on. There's a summer course coming up, first week of July. Polymath World (47:21.272) Ha ha. Denis Alexander (47:34.042) Is it the first week of July thereabouts anyway? All the details are up on the website. Summer courses we've done right from the beginning actually. We've been doing them now for 20 years and I've been to every one of them and I'm always excited by the summer courses because there we have a good lineup of speakers and it's really quite an intensive week of covering many aspects of the science phase discussion. at an academic level and we get people coming from all over the world to those. So I do recommend that and there other courses and activities. So I also recommend the Faraday papers if you like a kind of introduction, nice brief 4,500 word introduction to different aspects of the Science Faith discussion. You'll find those up there. They're all free PDFs. You download them. There's a good one coming out soon, being published later on this week actually about The Christian roots of scientific laws. Quite an interesting topic. So, yeah, so visit the website. Polymath World (48:30.038) Yes, I've enjoyed those too. Just a final question before we go. For those who are students who are watching this, who are looking to get into something like molecular immunology or they want to take that medical research slant for their career on the genetic basis of disease and those sorts of things, what advice would you give to students who are just at the beginning of their journey? Denis Alexander (48:58.13) I think you're talking about undergraduates here. yeah. Well, I would obviously start with a PhD. Some people do a master's first, one of your master's to get them into it. But I think the PhD is the way to go. Now, not everybody does a PhD. Some people join up with a company and work as research assistants in a lab. You can do that way. But I... Polymath World (49:00.93) Yes, or people who are looking to go into research in those fields. Denis Alexander (49:27.514) I'd recommend doing a PhD in biochemistry, or microbiology, cell biology, all those areas. I think now all these different labels we use, I mean, if you go to any laboratory around the world in the molecular biological sciences, to be honest, they look pretty similar. They look as if they've been designed by the same architect. When I go walking into a lab in India or China or Australia, which I do, by the way. And so, yeah, I would certainly start with a PhD. And some people do a PhD and that can really tell them that this is not the career for them. If you want to do an academic career, it's a tough course these days. A lot of competition, lot of writing grants, community funding going. But if you're up for that and you don't mind that aspect of it as well, it's a good way to go. And I think PhD is the way to find out. That's the way you find out if this is the kind of career for you or not. Polymath World (50:26.366) Excellent. Thank you so much for your time today, Dr. Alexander. It's always a pleasure speaking with you. Denis Alexander (50:31.218) Very nice to talk to you. Thank you. Thank you.