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Richard Weller 5:33
I'm Richard Weller, I'm an academic dermatologist at the University of Edinburgh in Scotland in the UK, I, my week is divided, I spend about half my time seeing patients. And half my time doing research I've been here for about I think just over 20 years now actually as an as an attending and an academic. Before that I worked through all over the place I trained in London, as a doctor started off doing my internal medicine in the UK then went to Australia, where I did Internal Medicine up in far north Queensland, up and up in Cannes. And I then came back to the UK, after about four years of internal medicine training, and I started my dermatology training, which was in the UK, the Institute dermatology in London. And I then have a very lengthy press, as you can see, got into research. And did three years full time research I went to I was in Germany in Dusseldorf. And I was done in the states in Pittsburgh. And finally, after an awful lot of times, traveling there rather than getting there, I made it to a permanent faculty, sort of a tenured post at the University of Edinburgh where I've been ever since.
Nick Jikomes 6:55
And so you're a dermatologist so so you're interested in skin, you treat people's skin, your research is focused on some really interesting stuff to do with skin. Just to kind of give people a base of information here, can you talk a little bit about skin on a basic level the sort of cellular anatomy of human skin and how that organization will allow us to think about what it's actually doing?
Richard Weller 7:20
Yeah, well, I suppose really relevant to what my research has been is the skin is how we meet the environment, I mean, the skin is this large epithelial surface. And this is where you interact with the outside city, your lungs, so does your gut phase or the the bits of your anatomy, which are an interface between you and the outside world. And that interface with the environment really is is key to the structure and function and evolutionary adaptations of skin. Now, I've worked in various different latitudes from here I am in in Edinburgh at 56 degrees north. I work down and UK, I might say also work down in Ethiopia at times and I was in Australia, I was in Pittsburgh. These are all very different environments that we humans have had to adapt to. And they're very different in terms of UV, of course, because I'm homosapiens us arose around 200,000 years ago, you know, we are the Naked Ape. We are raised in East Africa, Ethiopia probably homosapiens, around 200,000 years ago. And we evolved for a particular ecological niche we are at you look at these endurance athletes. These are men easy peasy and if super are men who do these mega distances and data that actually is a deeply human thing to do. Where we differ from our primate cousins, and particularly from our mammalian distant cousins is that we became a good endurance athletes in Africa. You can't catch a cheetah you can't catch a horse in a sprint. But over distance if you wait, what we are good at is we can trot for a couple of days, just jogging along for a couple of days, and catch those lovely furry, tasty antelopes and morsels and things. Because what we have done is we have shared our fur and we have developed sweat glands lots of sweat glands have really been being naked and sweaty, is what makes you human. That's the that's that's a particularly human feature. Sweating is the mark of of man and woman. And that allows us to shed heat, so my other mammals shed heat by panting and if you're covering distance, you can either breathe air in air out or you can pass And, but you can't, you can't do both together. Whereas we can jog along, mile after mile day after day, covering ground efficiently, and we can sweat. And that sweating allows us to shed the heat that's generated from all the exercise and running. But of course, when you said your first, you, you shed your protection from UV. And that has led to various evolutionary adaptations, which are also the mark of man. And those evolutionary adaptations have faced challenges as we've scattered around the world from our African homeland. And it really this is, this is skin color I'm talking about. So if you shave a young, lots of young primates, they actually have pale skin beneath it, they might have dark fur, but they've got pale skin beneath it, particularly younger animals, the great experts on this and like Nina Blonsky, is the real queen of this field of research. She's fantastic. She's over in Pennsylvania. And it's a lots of research here. But we having shed our burry UV protection, and then of course, exposed to UV. And so the other real mark of humans is that we developed on dark skin as protection against UV in Africa. So the other real hallmark of being human until very recently, until about 10,000 years ago, was having dark skin to give you UV protection. And that suited us well in our African homeland, where we lived until around well, if you're not African, that's where we lived until 60 or 70,000 years ago.
Nick Jikomes 12:00
So so there's a couple of ways that humans are pretty unique compared to other primates and mammals. So on the one hand, we became hairless. And this has to do with our adaptations that enabled us to do endurance running, which allowed us to travel which allowed us to hunt animals, types of animals and hunt in ways that you know, other predators can't. So our hairlessness comes down the skin also in parallel then, must have had other adaptations related to the ability to sweat and stuff. But then at the same time, you're saying, we went from being pale skinned as our, you know, an underneath the hair of a chimpanzee or another ape, they actually have pale skin, and we became dark skinned because, you know, on the one hand, we were gaining this ability to do endurance stuff and to sweat and to get rid of that heat, which unlocked you know, the ability to hunt animals over long distances. But at the same time, you say, that leaves us exposed to the elements, particular UV radiation. So you got hairlessness evolving in parallel with dark skinned nests. And then I'm really interested to learn more about the sweating component of this. So physiologically, like what is skin doing to allow us to do things like sweat to to help protect itself from the sun? And, you know, when we when we're, when we say that a dark skin phenotype has evolved? What is it going on sort of inside the cells and next to the cells that that is doing the protection?
Richard Weller 13:27
Yeah, what's what first of all, I suppose the first thing is the is the sweating thing. So I can't remember the numbers of sweat glands. But we have a great many sweat glands. And actually, those can be trained. So it my brother in law's a soldier and he was did a couple of tours in Afghanistan. Second one embedded with guns, you guys with the Marine Corps. And what they did before they get before they go out to Afghanistan is they go hot weather training first because it was really hot. And, and you your sweat glands, after a week or two can be trained to greatly increase the amount of sweat they produce. So a sweat isn't ultrafiltrate of plasma. That's why when you're sweating, you're, you need high water intake to make up for the fact that you're filtering your Plasma through your sweat glands. And that evaporation of sweat from the surface allows you to cope with really high temperatures, first of all, high temperatures outside and secondly, of course, heat generation from inside from doing from doing exercise. So that's the thing about about sweat. And if you go straight out, I remember there was a tragic case I was watching it as a New York journalist who left New York in winter to went and accompany a British guy who was walking down. I think denial from the source and tragically this American guy, fit healthy, athletic guy, going from New York winter to top of the Nile. That means to leave and, and died of heat exhaustion, I mean a really tragic event. And that was a classic, the person who was joining her been there for weeks and months and was adapted, his sweat glands had adapted to that environment. So that's that the skin pigmentation is, is interesting. And we've learned a great deal about skin pigmentation. I mean, in particular, in European groups, but, but it's the data is growing elsewhere, in the last five or 10 years, and we now are learning more and more about the genes which drive skin pigmentation. So there's a, there's a number of genes, there's 20, or 30 genes, which drives skin pigmentation. But actually, it's a few in particular, which have got a big effect. This is in terms of driving the pale skin variant of our natural original dark skin, which is what man has been for most of the time. And what we can see. So one of these genetic variants is called MC one r. So this is the genetic variant that leads to red hair. And if you look at genotypes around Africa, in the world, there's actually been strong selective pressure to prevent the NC y&r The pale, red haired gene, developing the pale red head variants in Africa, so you can look at genetic variation. I'm not a I'm not an a biological implementation, but this is what the experts in the field say. And there are strong restrictions, because you know, genes are continually developing variants, and it's small mutations might be beneficial, it might not be beneficial, selected in selected out. And it turns out, there's a strong restrictive control against those pale variants of MC one are arising in Africa. So there's been strong selective pressure to maintain dark skin until humans, which I suppose is a later part of the story, which we'll come to in a move out of Africa, and started ending up in places like here in Scotland and China and other places. So, yes.
Nick Jikomes 17:16
And so So, so there are these kinds of like trade offs. So in one environment in Africa, you want to have the dark skin pigmentation because you're exposed to lots of UV radiation in sunlight. You also have, you know, you basically said that there's plasticity in the sweat glands. So you want to be able to have your sweat glands quickly adapt to the environment, so that a, you can dissipate heat, if you're in a very hot environment, presumably, you know, be if you move out of that environment, you don't want to lose so much so that you can actually conserve heat. And then you've got, you know, you've got interesting things happening, presumably, that we have not talked about so. So why would so there's this restriction on evolution of lighter skin in a place like Africa, closer to the equator? Why is it that lighters can evolve as humans migrate north away from the equator? What What was the trade off there? Yeah,
Richard Weller 18:06
and that's a really interesting, quite interesting question. And the first thing I want to say, is we really amazing, we don't really know that much. It's kind of happened. It's obvious you look around, you can see it, can't you, but we're not really sure. There's got to be evolutionary fitness gains to dark skin in a sunny environment. Because, you know, we've had 200,000 years of restriction, maintaining that. And there's got to be evolutionary benefits, to pay off evolutionary fitness benefits to pale skin in a low light environment, because that has actually happened independently by different genetic routes, more than once. So the story goes that way. So those of us who are not African, are descendants of those small bands of Homosapiens, who left Africa around 70,000 years ago, and then kind of scattered around the world. So you know, 50,000 years ago, humans are getting as far as coastal migrations getting done as far down as Australia 50,000 years ago, coming up into up into northwest Europe, we think, of course, has been up. There's been a big ice age since then, Last Glacial Maximum 30,000 years ago. So we've got very scattered bits of information only because the ice came back 15,000 years ago, the original Americans crossed, you know, via Alaska and baringa, and then moved down into the Americas arriving down at the bottom of South America about 14,000 years ago. And those were dark skinned hunter gatherers. So they were the first people who scattered around the world. And then simultaneously, and really remarkably recently, in the Fertile Crescent, massive Potamia between the Tigris and the Euphrates Euphrates, and over and then, about 10,000 years ago, and at the same time, run the Yellow River Valley about 10,000 years ago, again, in East Asia or in China, independent pale skin variants arose. And they arose at the time that farming arose in both of those locations. So, East pale skin in East Asia, there's a kind of gradual accumulation of this sort of paler skin. In particular, the dominant genetic variant that leads to pale skinned in East Asia is this key tail G variant, back 10,000 years ago, and the strongly under selected for a variant that leads to pale skin in Europeans arises in the Fertile Crescent. That's, that's LC 24, a five variants, and again, arises about the same time and from So, what is interesting to me is that, and really, we're kind of working on at the moment. So actually, you know, humans have been at high latitude. Well, since a 50,000 years, certainly humans have been in Europe since about 50,000 years ago. And they had been up in China from long before 10,000 use that little 20,000 years ago. And also, farming had developed in various places. So you know, maize farming develops in Central America. Taro farming develops in Papua New Guinea. It farming occurs. Of course, in China, the Yellow River Valley, at the same time as pale skin evolves, is development of pig farming and millet and then rice. In the Fertile Crescent. It's it's sheep and goats and cows, and wheat. So what's interesting is that pale skin arises in high latitude human groups, low light human groups, who are farmers. And it seems that you have to have both of those things together. So the question is, you know, what is it about not just being a high latitude, but a high latitude farmer. So, um, and that, really, to me is one of the very interesting pieces of information as we start to look at what the benefits of pale skin in a low light environment can be. Now, as a dermatologist, of course, the view on sunlight has been quite simple sunlight bad, wear sunscreen, don't get skin cancer. And, and of course, that is true. We know that UV ultraviolet radiation is the major environmental risk factor. And we've known this for really 100 100 years. So it was it was first suspected that ultraviolet radiation, sunlight might be a risk factor for skin cancer in the late 19th century. There was a there was a famous German psychologist, German dermatologist called, was it God I've gotten which one it was no, who described Damon's House who's going to say live skin in Hamburg. Back in the 1890s. He noticed that sailors who live in a very high UV environment sailing from Hamburg all over the world at sea, sunlight bouncing off the skin, and he noticed there D wrinkled faces with skin cancers and he called it sailor skin. And you know, it's noticed in America, doctors in Minnesota, we're not seeing the same skin as doctors in Florida. And within the British Empire as was doctors in Australia who trained in Britain was seeing an entirely different kind of skin from what they saw in white Europeans in Australia. So it was suspected that UV might indeed lead to skin cancer. But the actual proof that UV was carcinogenic was produced by a chap called Finley graduate of my university Edinburgh, who 100 years ago back in 1928, not quite 100 years ago, did the classic experiments where he shone UV mice, and they got skin cancer and the mighty didn't shine UV app didn't get skin cancer that so that proved that it was indeed the UV rays, not the heat, not the diet, not that whatever that cause skin cancer. So we've known for up for 100 years that UV causes skin cancer, and that has been the message that all dermatologists have preached since then. But uv is carcinogenic to the skin, which it is. But of course, it forgets the bigger picture, which is what are the effects of UV overall on our health, not just the skin. And that's where I think the story has got very interesting. And that's where the story is beginning to change, and I think get more balance.
Nick Jikomes 25:22
Interesting. Before we dig into some of that, I mean, it's very, I didn't know this, I didn't know that light skinned phenotypes evolved multiple times. Or that there's this connection with farming, right? So you have to get to a high latitudes slash low light environment. And in addition to that, you basically have to become a more sedentary farmer compared to our hunter gatherer ancestors. And it's those two things that seem to define the niche, as you say that, that causes or that allows the light skinned phenotype to arise, you know, especially thinking ahead to some other things we're going to discuss related to nutrients and things like this. Does it have anything to do with diet? Do we think Do we know anything? Is there a connection there?
Richard Weller 26:09
Yeah, I mean, that's a really good question, will it? Well, it could be. And that's one of the things because what we're now trying to tie up, is these observational, I mean, all because evolutionary observational stuff, together with mechanistic stuff, what's the mechanism leading to this? So we're going to move on, I hope later to my work about sunlight and cardiovascular disease. Basically, sunlight appears via a non vitamin D pathway to reduce cardiovascular disease, now the biggest killer in the world. My suspicion is though, that in evolutionary times, I mean, I've, I've never, I've never run away from the saber toothed tiger or chased a woolly mammoth. But I have the feeling it's, it's probably a better workout than the most expensive gym in the world. Nothing like adrenaline or the fear of missing out on a good meal to make your workout faster, and no smoking and an active life. So I, I suspect that while now, cardiovascular benefits, strike me as probably the biggest benefits to sunlight. I suspect in evolutionary terms. That hasn't been the case. So we're really looking at what, what other things it could be. So several things happen, as you say, when you switch from being a hunter gatherer to a farmer. One is, is diet. Interestingly, because you switch from, well, you have a more sedentary life, and you switch presumably to more grains. It is interesting that the earliest farmers were smaller than hunter gatherers and appear. It wasn't an instant gain. Birth rates go up when you switch from being a hunter gatherer to a farmer and probably perinatal mortality. You're living a communities you're living very close by other people rather than being dispersed over the landscape. And the other thing is, really which which is one of the things that ties in with infectious disease. So most infectious disease is originally zoonotic comes from animals with which were in close proximity. So you know, COVID comes from bats TB comes from cows, through comes from chickens, measles, you know, there's a whole kind of series of animals and and bacteria and viruses which make that jump from one species to another and particularly virulent when they do that. So probably infectious disease arose when we switched to being farmers, because you're close by other people. So you can spread the disease around each other. And you're close to those animals that you are domesticating. And we've not really been able to see that for the last 100 years because we have fantastic treatments against infectious disease. We have the miracle of vaccination, which is the most incredible cost effective, effective means of I was in Pittsburgh, you know, the March of Dimes for polio vaccine famously was you know, Salk in Pittsburgh, just life dramatically life changing stuff. Still, we have we have vaccines, we have antibiotics, we have sewers, we have clean air Act's, you know, all of these structural in housing design and sewers and things and, and medical vaccines and antibiotics. treatments have really removed infectious disease from us as something that we're conscious of. And when COVID came along, that became really interesting, because suddenly here was an infectious disease to which we have no defenses. And we could see what happens with a new infectious disease as it arrives on a naive population homosapiens who has not been exposed to it. So um, we know that a lot of infectious diseases seasonal, you know, winter flu epidemics, colds and winter that has a strong seasonality to too many infectious diseases. And when COVID first came along, there's a strong seasonality to many non infectious diseases to which we'll move on to cardiovascular disease in particular. But our hospitals are busier in winter than summer, markedly busier in winter in the summer, and we just shrug our shoulders and say, yeah, it's winter, without thinking, why are our hospitals busier in winter than the summer, but to head I'll move on to that later. But heading back to infectious disease. So I was wondering if COVID would be seasonal, like influenza is, you know, a respiratory borne disease. And of course, at the beginning, you need 12 months to see seasonality. And at the beginning, you know, because I have to wait a year, maybe two years for the data is more robust. But But we realized early on that America, Johns Hopkins started collating all the data on COVID deaths within America. So America has 50 states, but it's 3200 counties. And the other great thing about America is it covers a huge geographical span, you know, it's the top to bottom is a long way, and very different UV environments. And Johns Hopkins was putting out on its COVID research database at county level COVID deaths within America. So these fantastic datasets. And I previously with my cardiovascular work, had been looking at the epidemiology of heart disease and sunlights stuff we'll move on to later. So I've been working with mathematical geographers, who are very good using satellite data. Anyway, a I mean, all these American amazing American institutions, we we, we use and thank you to the American taxpayer for providing them. So anyway, so anyway, a great organization. But he says this wonderful algorithms that can tell you how much you v is falling on any spot on earth, the wavelengths, the energy, everything else. And we've been using this for mapping blood pressure and seas and showing how you the high UV correlates with low blood pressure. But I thought, Well, look, could we do this looking at COVID, because we have COVID deaths at county level. And we have, we can calculate UV at county level. So I got together with the mathematical geographers, here in Edinburgh, none of us ever close and meeting in person because it was locked down, and we were all sitting at home like this, chatting away. That's it to die of COVID Several things have to happen, you have to meet somebody with COVID, you have to get infected, you have to get sick, you have to, and then and then you have to die in a state. And all of those are separate steps and separate risk factors affecting your likelihood of each of those steps in this pathway from being healthy American to dead Americans. You know, there's a lot of steps in that in that pathway. But you can actually pick that apart. So your risks of meeting somebody with COVID and catching it depend on the population density, but where you have population density at county level, clearly if and the amount of COVID in the population. So clearly, if you were living in Manhattan in 2020, February, March 2020, when it first arrived in the States, and you're shoved into the subway, and half the people there are coughing and hacking with COVID You are You are surrounded by COVID. If you're living in other news, North Dakota, driving your bodily column you through driving your truck around, meet a person a week, waiver them through the window, you know, and there's no COVID So, clearly very different risk factors, but the data is there. So you can you could calculate population density percentage of the population who have COVID Public transport use great web people meeting so you can put that calculation into your model. So that's your risks of catching COVID You then need to look at your risks of dying from COVID and we know that there are several demographic factors which alter your risks of dying of COVID. So, ethnicity is one darker skinned people had higher death rates, age is another poverty is another air pollution is another and all of that data is there and available. So you can put your second correction factor is which is to correct for your chances having a quad COVID of dying of COVID
and the third thing that happened This is in New England, everyone wears a mask. Because it's assigning a good citizen, and Louisiana, I'm generalizing, and I apologize. So as exceptions, it's we Seanna. Nobody wears the mask, because it's a sign of the devil, you have these huge, I'm afraid to say political, cultural differences in America, you also have at state level different policies, you know, Florida imposing very different policies to neighboring New York, and so on. So you put in a third random correction factor, which just corrects the kind of differences. Now, I am not a mathematical modeler, the code and the mathematics of this are far beyond me, which is why we simple dermatologists are good at making friends with people that can do the heart number crunching, but you can put in this model, and you can build it up. And so what we then did was we collated, and we cross match the deaths in the first three months of the COVID pandemic in America. So I think it was January to April of 20. And we could plot UV at each of these counties, versus deaths from COVID. Having done these really extensive corrections for confounders. And the final thing we did, I should say, is we excluded from our analysis, the 20% of American counties were enough, short wavelength UV, UV B, was falling to make vitamin D. So we wanted to show an effect of sunlight independent of vitamin D, because sunlight makes vitamin D, but not all sunlight makes vitamin D. It's only the short wavelength UVB. And what happens as light comes through the atmosphere is that the more atmospheric comes out, first of all, it reduces overall sunlight. But secondly, it particularly removes the shorter wavelength UV. So in Scotland, where I live up at 56 degrees north, there is no UVB to make vitamin D for six months of the year. Because that short wavelength uv is just removed from the atmosphere. And only really, for the three months either side of June, do we get enough short wavelength UV to make vitamin D. Whereas if you live down in the bottom of Florida, you know, you can make vitamin D all year long, because it's so far south. So we looked at these counties and this NOAA data and be excluded from the analysis, those southern counties where vitamin D would be formed.
Nick Jikomes 37:47
I see. So you're asking what's the relationship between your outcome with respect to COVID? And the amount of UV you're getting? If there is not enough UV around for vitamin D synthesis? So you're you don't you want to look at an effect that's independent of vitamin D.
Richard Weller 38:02
Exactly. So there is a sunlight, not vitamin D effect. And what we showed really quite clearly was that there was a straight line, dose dependent relationship, the more UV, I can't say that you were exposed to, because we don't know what people were doing. But the more UV in in your county, the lower the risk of dying for COVID. So we did that for America. Great. But we then thought, well, that's great. Let's do it again. So we then went to Italy. And we did it in Italy. And we then went to England, not Britain, which includes Scotland, but we went to England, and we did it for England. Now, each and long story short, each of those countries, we found exactly the same relationship, we had to repeat the analysis for each country, because the way we collate ethnicity, age, you know, the geographical units in which we collect that data are different in England, and different in Italy. So it was two independent and separate studies. However, they all showed same thing. So the more UV where you live, the less the risk of death from COVID. So we, we sent this into an american journal PNAS, and I have to stop fuming here, but now that he's fantastic, we love it really interesting. And they sat on it for six months and then changed. It changed our minds. And the fancy is fine, but it's not very interesting. Having sat in it for six months, that guy was pissed. We were comfortable anyway. An American group, by the way, from Harvard did a similar will did an a similar analysis. A lovely analysis, which they did published in PNAS they submitted at the same time is us. So they looked at growth in cases of COVID around the world, and they looked at Northern and Southern Hemisphere countries. And they looked at growth and rates of COVID. And they looked at UV and humidity and temperature. And what was great there was the southern hemisphere is turning to winter, as the northern hemisphere is turning to summer. So you know, it was rather nice sort of. And what they showed was, the more you V there was, the lower the growth in COVID cases, but that temperature and humidity had no effect. So this American group, and we showed less growth in COVID, and less deaths from COVID.
Nick Jikomes 40:33
That temperature and humidity did not having effect. That's interesting, because I was about to ask, you know, how much of this do we think could be light exposure per se, versus you know, how much of this is just an artifact of of people spending more time outside and lower density environments when there's more sunlight around? Yeah. But the fact that that temperature doesn't correlate with suggests that might not be the case?
Richard Weller 40:55
Yeah, I mean, really good question. And of course, always the fallback to epidemiology studies is confounders you know, what are the independent factors, you know, a confounder, a factor which is independently associated with the exposure and the outcome, it is a behavioral due to temperature. So absolutely right, which you need to think about? Well, so what you need to do to remove it to confirm it is to then do an interventional study. And there's a super an American company called cytokines, who then ran a super pilot study down in New Orleans, last year, year before last. And they took patients being admitted to New Orleans, the university hospital there with COVID. And they ran a randomized placebo controlled double blinded clinical trials say, you know, the kind of gold standard proper trial, giving up phototherapy to half the patients who came in and giving a sham control to the other. Now, to be admitted into the trial, you had to have proven COVID You had to be sick, as in your oxygen levels had to be below 94%. So that's, you know, kind of sick, but not on intensive care. So you had to be sick, but not moribund. And, you know, by the time you've you know, 300 patients come in, you'll save it by the time you're going to shift down inclusion criteria exclusion criteria consent, given the ended up with 30 patients, so 15, gotten up phototherapy and 15 got control. And those that were in the active group had the standard American Academy of Dermatology because of course, dermatologists use UV phototherapy all the time to treat our patients. We're either telling our patients don't go in the sun, or we're saying can I give you some sun to cure your psoriasis and eczema? We're funny people. And anyway, so we so we have the standard protocols for giving you v this evil stuff to patients to make them better. So they gave 15 of them the other 15 that were given up phototherapy, two of the 15 died of the 15 who got the sham, five of the 15 died. Now, it's not big enough to be significant, but it's moving where you expect him to move in was that UVA only was at UVA and UVB no interesting it was UV B. And you know, we've said a lot of my research, my cardiovascular research in particular, we've used UVA because it doesn't make vitamin D and I've been keen to show vitamin D independent mechanisms of benefit of sunlight. Because dermatologists have grudgingly accepted that sunlight might have some small benefits. And paraphrasing the the sort of dermatology advice has been live in a cave take vitamin D supplements I'm that those aren't the exact words but that's that's the kind of broad the feeling behind it. Because we know that vitamin D Well, you know, 100 years ago again, dramatically when rickets osteomalacia caused by vitamin D deficiency caused by either poor diet or lack of sunlight led to rickets, a huge problem 100 years ago, and that was dramatically cured. When first of all cod liver oil contains lots of vitamin D came along and then vitamin D tablets. So this kind of wow, this amazing one of the first one to drugs. And the problem is we haven't really moved beyond where we were 100 years ago saying UV causes skin cancer. Thank you Jocelyn leaf, and vitamin D Staats. rickets, vitamin D made by Sun terribly good for you. And we've kind of got we could have got stuck there for 100 years. Well, so moving
Nick Jikomes 44:49
on. I want to dig into vitamin D and skin for sure. Let's let's let's put a bow on the COVID stuff. So So what sort of where do we stand with respect to sunlight UV and COVID, what would you say the overall summary is? And
Richard Weller 45:03
I think it's, yeah. So I think the overall summary is the EPA, there is epidemiology that in areas with more sunlight, there is less COVID death that tells you nothing about the mechanism. Is this an action of UV on airborne COVID virus, I think, probably important part of him, or is it an effect on UV on us, you know, an effect on arming our innate immune system. For instance, we know that UV activates the innate immune system. And that's part of our defense against viruses. We also know which we'll move on to that UV mobilizes nitric oxide from stores in the skin into the systemic circulation. Now, no Nobel Prize for Medicine back in 1998. Is this very important chemical messenger. It's a gas. It's a chemical messenger. It's responsible for lots of the cardiovascular benefits of sunshine. But we also have fairly good evidence that no prevents prevent SARS cov, the virus that causes COVID southgobi to it prevents its action. So the first bit of evidence is when the first SARS cov virus came along, I want to call it SARS cov. One, but it was called SARS cov because they didn't know there was a bigger and badder brother coming along later. So when SARS cov arrived five years ago, there was some really nice work showing that nitric oxide binds to it, it prevents the post translational modifications that are acquired for the virus to bind to the ACE two receptor. So if you expose SARS cov to No, the myristoylation, which is needed, stops it binding that ace two receptor, it has since been shown that no also prevent SARS cov. Two, it's a spike the spike protein that sticks at a SARS cov is what it binds to the receptor with and it shows the no prevents the manipulation taking place, allowing SARS cov to to bind to the ACE two receptor. And there are several clinical trials underway of using nitric oxide to treat COVID. And some of the early data is coming back showing promise for no. And sunlight releases no from the circulation. So there's a number of mechanisms by which sunlight might be reducing these cases and deaths from COVID.
Nick Jikomes 47:39
as well. Yeah, there's plausible mechanisms there that are there candidates for how this could be sunlight per se, rather than some indirect effect.
Richard Weller 47:48
Yes, yes. As a matter, of course, at the moment, what we website kind of working on is getting the the sort of backing to do a bigger trial on photo therapy to treat COVID. Because the thing about photo therapy, we use photos that this is a treatment, which has been around since the 60s, um, you know, we've had we've had photo op for 60 years. It's it's it's safe, inexpensive, easy to administer, almost, you know, whatever the mechanisms, we have the treatment. So, you know, we can work on the mechanism, of course, important to know, but but we have the treatment available now. It's just a matter of really of amplifying up this small pilot study into a into a larger trial of the use of code of UB for that. So I suppose you were asking me about infection. And this is really taking us full circle to here we have an example of an infectious disease, which so the data is good for, you know, for sunlight helping us Oh, and I should quickly come back to vitamin D, lots and lots of observational studies showing that people with higher vitamin D levels are less likely to die of COVID two big clinical trials, both published in the British Medical Journal. In the last two months, one study was using cod liver oil to treat patients with COVID. The other large study and these are randomized, double blind, placebo controlled clinical trials, you know, the kind of gold standard was giving vitamin D supplements and neither study showed benefits from oral vitamin D, in preventing COVID. And yet, we have the observational stuff that people with high vitamin D levels measured are less likely to die. And of course, a measured vitamin D level is a marker of sunlight exposure.
Nick Jikomes 49:53
I see So so the correlation there could be sunlight exposure. Vitamin D is just a marker of that even though vitamin D doesn't have Have anything itself potentially to do with this trend? Well, the other question I was eventually going to ask you is, is there a difference between vitamin D supplementation or from the diet exogenous vitamin D, and the endogenously produced vitamin D in the skin?
Richard Weller 50:15
Um, so yes, so vitamin d three, so the, the the Dartry, Vitamin T, we have plant derived vitamin D ergosterol, D two, and we have animal derived vitamin D and vitamin D, we produce vitamin d3, always the importance when considering vitamin D studies, there's endless headlines, vitamin D stop says vitamin D stops that you have to pick apart the observational studies from the interventional studies. So if you do observation, if you measure people's vitamin D levels, um, and look at Associated Diseases with those. So we know that people with high measured vitamin D levels are less apt at heart disease, less likely to have strokes less likely to have diabetes, less likely to break, it's less likely. And so this
Nick Jikomes 51:11
was the d3 measured and
Richard Weller 51:13
measured in say your, your d3 measured in you. The problem is so all of these observational studies, correlating high measured vitamin d3 with less disease are not proof of causation. You know, correlation does not equal causation rule 101 of epidemiology. And there have been a mass of studies of vitamin D supplementation on health outcomes. And the biggest one is the vital study run in America. And this really wrapped up about two years ago. So 25,000, middle aged Americans were given oral vitamin D sub, were randomized into this trial, half were given vitamin D supplements for five years, and half were given a sham placebo control. And the results are coming out. And if you've got cancer, vitamin D supplementation seems to prevent it progressing. But in terms of heart disease, strokes, blood pressure, diabetes, no effect whatsoever. And is the New England Yeah,
Nick Jikomes 52:20
this is d3 that they're giving or D to exactly what is it?
Richard Weller 52:24
I cannot remember. It's I think it was I'd have to look at the papers, D three, open access papers, New England Journal, but a new income Journal editorial, about three July of last year. So 30% of Americans over the age of 60. take vitamin D supplements, and the New England Journal editorial, rounded off Stop it. You know, it's we have no proven benefits for a multiplicity of these diseases. Obviously, it's important in certain cases, in osteoporosis rickets, we know it does prevent progression of cancer. But a lot of those associations, it's not the vitamin D, driving the reduction in disease. So we need to look again.
Nick Jikomes 53:12
So how much you know on the subject of vitamin D, animals produce D three plants produce D two, there's this connection between UV and vitamin D and the skin that pretty much everyone has heard about how much is being produced? Is it? Do we get most of it from the diet? Most of it from skin production? Like how does that break down?
Richard Weller 53:30
Well, a lot of it most, I suppose it depends where you live. So if you live in if you live in Scotland in winter, none of its coming from sun. If you live in Florida, Mr. Fitz coming from the sun,
Nick Jikomes 53:43
I see. So it can go in either direction, depending on environment.
Richard Weller 53:47
And the other thing that matters is skin color. So what we know is that if you have darker skin, you need more UV, say no for a given a given amount of UV, there is a lower rise in UV driven vitamin D in people with darker skin. And this may well have been one of the drivers to pale skin as humans move to high latitude. Because one of the benefits of pale skin is in a low light environments. You make more vitamin D, you make vitamin more vitamin D, despite the low light. So that is one of the benefits. And also just using vitamin D as a kind of biological marker of response to UV. It shows that biological processes driven by UV those we know about like vitamin D and nitric oxide release occur better in low light environments. And that I'm sure the same applies to the mechanisms we haven't yet discovered. UV driven mechanisms pails In favor stays in a low light environment. And presumably that is what has driven this repeated evolution of pale skin and environments. There's probably
Nick Jikomes 55:08
there's probably, I guess the idea would be there's probably multiple physiological effects of UV, which the body can use for good healthy functioning. And vitamin D is one of them but you know, the lighter your skin is maybe the more generally sensitive to these physical stimulators you are,
Richard Weller 55:25
yeah, and the send some really good epidemiology confirming that so I'm a friend and colleague of mine pedaling fist over at the Karolinska in Sweden has done analyze the data from a wonderful study called the melanoma in southern Sweden study. So this is a study that was started in 1990. And they recruited 30,000, middle aged Swedish, and they took it was actually a quarter of the population of middle aged Swedish women and in 90 and they wanted to find out how much UV leads to melanoma. And and how does that kill people. So they recruited those 30,000 people and they asked them four key questions about sunlight exposure. So do they sunbathe in summer? Do this sunbathing winter bizarre in Sweden, but they're bizarre people and some of them do. Do they go on foreign holidays and do they use sunbeds? Now clearly, there are lots of confounders associated but if you use fig on foreign holidays, you're richer so you're probably better educated, you're less likely to smoke etcetera, etcetera, etcetera. But they went in in great detail and corrected for all those confounders so they asked about, you know, education level income in Sweden, everyone's tax return is published openly on the same day, every year. If you want to find out what your neighbor earns, you can look it up every year or the Prime Minister. It's an open publication. So they checked in a health records, did they have diabetes, health problems, marital status, alcohol, tobacco, you know, they went in and corrected for all these confounders. And they then went back 25 years later to find out who got melanoma and who died. And so you had a score broadly of nought to four, depending on your sunlight exposure habits. And what they found after correcting for all of these confounders was that those people that got the most sunlight? First of all, they got more melanoma, on average, that there was more melanoma in the group that got more sunlight. However, the group that got more sunlight were half as likely to be dead. As those delicate all cause mortality, all all cause mortality, they were half as likely to be dead all cause mortality, as these dermatological, goody two shoes avoided the sons altogether.
Nick Jikomes 57:54
So what So I think that I think this is a related question that I wanted to ask anyway, is, what is the difference between? So there's a correlation audit, we know that we know that UV is carcinogenic. So there's obviously going to be related to skin to skin to the skin. So we know there's going to be relationship between things like melanoma, and sunlight exposure, how much of that is UV exposure, per se, as like one continuous variable? versus how much of that is? Can you separate out those who get skin burns versus sunlight exposure without getting burned? And is that relevant here?
Richard Weller 58:26
Yeah, it's a really important question, because not all methods of not all types of UV exposure are the risk. So my classic question to medical students here is, where is melanoma common white Australians or white Britons? The answer is white Australians, by the way, just not to put you on the spot here, Nick. My next question is who has the more melanoma outdoor workers or indoor workers? The answer was okay, Nick, I'm going to put you on the spot. I see where
Nick Jikomes 59:01
you're going. I think, well, the the the natural intuitive answer most people would give is outdoor, but I suspect you're about to tell us it's indoor.
Richard Weller 59:09
Correct? Correct. I am going to have to try harder on time. So quite right. So what appears to be the risk factor? So when of course that as a question as a epidemiological thing is is really dirty and it do do self selected people who don't have red hair and tend to tan well, because it was always all in from observational studies, all the problems. However, the epidemiology really is that intermittent sunlight exposure and in particular, sunburn is the risk factor for melanoma. So that is the and in fact, the World Health Organization now has classified melanomas into various types based on the epidemiology of sunlight that leads to them. So the melanomas that are so common now, you know, this rise in melanoma was diagnosed, predominantly what we call soup Official spreading ones are no are now classified by the WHO has low cumulative sun exposure melanomas, because when you look at that skin around the melanoma, there are not the marks of long term sun exposure. There's no wrinkling, there's no antigen news. There's none of those marks. Now, some types of melanoma are caused by chronic sun exposure, this classic one that old people, they've had enough time to get lots of sun exposure, get on their cheeks, a site that is always exposed to the sun, called the lentigo maligna melanoma, but the melanomas which occur in young ish and middle aged people, which are the main focus of our concern, tend to care on the on the back, for instance, on the torso on intermittently exposed sites. So the the real epidemic of melanoma we have now is intermittent sun exposure and sun burning. And is there a chronic sun exposure?
Nick Jikomes 1:01:01
Yeah, it occurs to me that I want to potentially connect this to something that we discussed at the beginning, we talked about sweat and the fact that your skin is plastic, it can be trained to adapt to a local environment to produce more sweat if case you need it to dissipate more heat, because you're in that warmer environment. Is something similar true with your body's ability to naturally defend against UV? And is there a difference between you know, you know, if I go to Mexico next month for vacation, and I just get out of the plane, and I'm there, versus I sort of slowly ramp up my UV sun exposure over over a longer period? Is that Is that important here?
Richard Weller 1:01:37
Yeah. But of course, you see, we have an entirely different pattern of UV exposure now to what our historical one is. So until 150 years ago, the industrial revolution, our entire evolutionary history was lived outdoors. You know, we were hunter gatherers, then we were farmers. But we weren't sitting inside playing on our mobile phones or doing podcasts from an office somewhere, you know, we were, so where it's now, whether it's going to Cancun on holiday, brief and very intense for two weeks, or whether it's being in an office for most of the day, and stepping outside. We are so actually, in here my thing, sunlight is good. Some protection is also really important to us sunscreen, because our pattern of UV exposure now is intermittent sun exposure, weather abroad, or whether domestically outside our offices in the daylight to which we are not, which isn't the ideal pattern. It's this intermittent burning exposure. So you know, I see where some protection to to prevent that.
Nick Jikomes 1:02:39
And just so just to be clear, is is it intermittent sun exposure, or is it intermittent sunburn? That is the key here.
Richard Weller 1:02:48
A bit of uncertainty we're getting my son is coming into it. Can I just quickly put you on mute? One second? Yes. Yeah. Yeah.
Nick Jikomes 1:03:01
One second everyone.
I think we're about to return you're still on mute. Richard.
Richard Weller 1:03:15
My My apologies. This is the battle over screen having just discussed people playing on their phones. This is the screen time battle with my, my son, the which I think, has he done its homework. So yeah. So yeah, so what so is it burned? Or is it intermittent? And it's hard to pick apart? You know, we all we have is epidemiology. We don't really have good animal models for melanoma.
Nick Jikomes 1:03:44
So it could be either or both. It could be either,
Richard Weller 1:03:46
and I might say that there is good trial data showing that from Australia, where they have done good clinical trials of sunscreen, and we know that sunscreen prevents melanoma developments. Now, whether it's doing it by preventing that intermittent high sun or the intermittent burning, I don't know. But what we know is that sunscreen prevents melanoma.
Nick Jikomes 1:04:08
Okay, so there's so many things to talk about here. Here's where I want to take this, based on what you've said, based on what I think you might be telling us. I'm wondering if this would be a good progression? Let's talk so intermittent sun exposure, is what we just discussed, and that can be bad. What is your view on sunscreen, I suspect what you might say is, you should definitely use it if you're going to highlight environment for intermittent exposure. But can you can you explain that to us and then how that compares to the standard advice I get from a dermatologist which is I should always be in 30 Plus SPF sunscreen on every skin surface every single time I'm ever going outside for the rest of my life.
Richard Weller 1:04:52
Well, I this is a complex question. And I think we can do better with sunscreens than than we do now. So So I've been talking about melanoma and the concern with melanoma is that is the, that's the cancer, you know, most 80% of patients with melanoma are cured of it, but 20% aren't and that is for me as a dermatologist that bad news. And we know that sunscreen prevents melanoma. So that matters. Now the studies showing that sunscreen prevents melanoma, we're done in Australia, which is a sunny place. But but you know, that's this robust data we've got, I might say. The other thing is that I think that information also applies to America. What one forgets is how much closer to the equator, equator America is, than the UK. So if you if you are living in New Orleans, for instance, for Louisiana, you are at the same latitude as North Africa as as Morocco or run Algeria. If you live in New England, you're the same latitude as as the Mediterranean coast of France of the COTE desert, you know, so you guys are living in a very sunny, sunny environment. And we know from the Australian data that daily daily sunscreen use prevents melanoma development by whatever mechanism. The other so melanoma is the most important cancer because it's the one that kills most people. The second most important cancer is squamous cell skin cancer. The mortality is not as high as melanoma, but it's still there. So we'll go back to my Australian questions. Is SCC common in Australia or Britain? It's common in Australia. Is SCC common in outdoor workers or indoor workers? Over to you, Nick?
Nick Jikomes 1:06:45
Well, we said earlier that it was indoor even though most people suffer
Richard Weller 1:06:49
from melanoma, whereas for squamous cell skin cancer, the second most common type it outdoor work, I see. And long term sun exposure is a risk factor for squamous cell skin cancers. So those cancers are absolutely prevented by sunscreens.
Nick Jikomes 1:07:12
And do not mutations that cause cancer? Are they coming from UVA and UVB? Or
Richard Weller 1:07:18
no they are, so the direct mutations are coming from UVB. Um, but UVA will drive certain free radical generation that can cause different types of mutations to DNA. So these two types of skin cancers, different patterns of UV lead to them. But both, but both the drive skin cancer and of course, the other thing about skin and sunscreen is is some that is aging. So my comment about those Sun avoiding sweets is, you know, who are twice as likely to be dead. They were beautiful corpses, you know, they had not a wrinkle on them. But you know, we know that so sunscreen will prevent your skin aging, it will prevent your risk of sameness, health skin cancers, and it prevents your risk of melanomas. The problem is, is it also blocking the benefits of sunshine on other systems? And that I think is, you know, and that's what I've been what, that's one of the areas I've been working on, can we get sunscreens that will give you the benefits of sunlight, whilst also preventing the harms of sunlight?
Nick Jikomes 1:08:32
Yeah, so can you start talking a little bit about some of these benefits? Obviously, everyone sort of just knows intuitively from experience, suddenly, it feels good. It can, it can boost your mood. And, you know, the, you know, we evolved from hunter gatherers who spent a lot of time outside it makes sense that, you know, the cancer causing effects of UV radiation aren't going to be the whole story. So what are some of the beneficial effects and what's going on there? Physiologically,
Richard Weller 1:08:59
let me quickly close this door so the dog is not barking in the background. Hold on.
Nick Jikomes 1:09:05
Sorry, folks, one more short break here. This is part of being a podcaster
Richard Weller 1:09:11
right here we come. So that will so I Yun I think the big benefits of sunlight now I think the ones that are most important to us are run cardiovascular disease. So um, I spoke about Peles work looking at all cause mortality in the Swedes that guesstimate sunlight. And it turns out that the biggest cause of this fall in all cause mortality was the reduction in cardiovascular mortality. So the epidemiology suggests cardiovascular benefits. And a lot of my work over the last 20 years has been working on these cardiovascular benefits of sunshine. So I'm the mechanism which I and my colleagues in Germany have disc Ovid is that the skin. So we so we know that people's blood pressure is lower in summer than winter. So seasonal blood pressure in Britain is about six millimeters of mercury systolic lower in summer than winter. And we also know that people living closer if you look at population blood pressure looking at whole countries, the closer a country is to the equator, the lower the population blood pressure is. So we have, and from Peles work, we showed that more sunlight, less heart disease. So there's all this observational data suggesting that people in sunny places, or at sunny at times of year, or with behaviors that lead to more sunlight exposure, have reduced heart disease. So and we also know that it's not vitamin D, because although people with measured high vitamin D levels are less likely to have high blood pressure, strokes, heart attacks, giving them vitamin D supplements does absolutely nothing. And doing what are called Mendelian randomization studies, people that don't make so much Vitamin D has no effects on heart disease. So, with my work, we showed that the skin contains large stores of nitrogen oxides, oxidized versions of this substance, nitric oxide, so it turns out, you've got huge stores, in your skin in your dermis in your epidermis. Now, nitric oxide was initially called endothelial derived relaxing factor discovered by Bob ferch got an American Nobel laureate from NYU. And he showed how the end so that the the endothelial cells lining your blood vessels release nitric oxide, which relaxes your smooth muscles that line your arteries. And nitric oxide is essential for keeping your arteries relaxed, and thus your blood pressure healthfully low. And he showed this occurs via this an enzyme called nitric oxide synthase axon arginine releases no Nobel Prize, boom you no wonder fantastic stuff. The way that nitric oxide and of course what was exciting about that was this was a chemical messenger, which wasn't a complex protein, which you know, lock and key hypothesis fitted into exactly matched receptor and turned on pathways. This was a simple gas, a nitrogen and an oxygen, that kind of just dilated things. So an entirely new way of thinking about signal transmission in the body. And the question then was, well, how do you turn it off? And it turns out, Eno's got a half life of a few seconds. And it's oxidized first of all, to no to nitrite. And it's then further oxidized to further from nitrate and Oh, three, and nitrates. incredibly stable, thought to be inert. The idea was the nitrates, the end product, and you pee it out. And that's it. Well, that's where the science for a long time was. No, that's fantastic stuff, oxidized nitrate up it out. And that's it all over? Well, we then found big stores of nitrates and nitrites and nitrates are files, snda groups in the skin. And we're really wondering what they could do. But a couple of other researchers came up with some important work. So the first I says the main one was Martin fish down in Southampton. And he showed that ultraviolet radiation spalling on nitrate, and oh three in the presence of filegroups sh groups will photochemically reduce that nitrate to No. So actually, although we have thought of that nitrate as an inert end product, it can be turned down actually be taken back. And that came along. Just after I had, I had found these big stores of nitrate in the skin and I was thinking was that doing and I managed to publish it but I really, and you know, when I submitted the paper, I wrote the usual cover letter. It's important you must take this work in your journal that's billions and important. And I was thinking I don't know what this means. I don't know what this means. Anyway. JD barber Gilchrist God bless the J I D ed of the JD accepted it's and it was published a very highly cited paper now, because we then some years later, Martin discovered this photochemical and of course as then hit by thought that hang on in the skin, you've got all these nitrate stores. There's lots of files in the proteins that make up the epidermis, and UV. These three ingredients are brought together. And I could also remember from my internal medicine days, and about the seasonal changes in blood pressure, and I also remembered from my time working in Australia, um, About the fact they've got far less heart disease than we had in Britain. And of course, the Australians always said, You really pawns you sit around and you're fat backsides doing nothing. And we're athletic super folk. And I discovered the the Aussies are as lazy and bone idle as the Brits, they are no better or morally superior. It's sunny. And they live three years longer than us. And it's nothing to do with their athleticism or prowess in that way. So all of those sorts came together. And we set about to do the experiments to show that sunlight can indeed release nitric oxide from the stores in the skin, and lower blood pressure. And I mean, short story, and I did a TED talk on this, which has had a fair number of hits. We showed that actually sunlight falling with skin does indeed mobilize no it moves into the circulation, it dilates your arteries. That accounts I think, the seasonal variations in blood pressure,
Nick Jikomes 1:15:59
is that coming just from seasonal variation and sun intensity, or does it have specificity in terms of UVA, UVB? Or is it both? Yeah,
Richard Weller 1:16:07
yeah, these are really good questions. Or you could help write my next grant application. Yeah. So when I did the experiments, I used UVA because it doesn't make vitamin D. And I wanted to say, because, you know, for 100 years, we've said vitamin D, causing a move away from the body vitamin D thing. So we use UVA, to show it was a vitamin D independent effect. However, I did some observation. So first of all, the sun, the actual absorption spectrum of UV by the species is highest in the UVB range. So there's physical or chemical reasons thinking UVB might be important. The other thing, I was working with a supergroup based in New York, the renal Research Institute, so Fresenius run most of the dialysis units in America. And they've got a fantastic research arm renal Research Institute. And they have got 2000 Plus dialysis units all over America. And again, the size of America, you guys are lucky to have that large chunk of geography. They collect data on all of these centers, and dialysis patients have their blood pressure measured three times a week, week in, week out. So they have a shedload of data. They've got 340,000 patients on dialysis. So we were able this was pre COVID. This kind of the methods here sparked off my later COVID research. So working with them, we were able to look at the blood pressure in 340,000 Americans on dialysis, taken throughout the year, three times a week for three years at 2000 centers. So out of those 2000 centers, we could go back to the good old NOAA and use their UV data. And we could cross reference UV at each of those centers. With blood pressure, we could account for temperature, because it's always been assumed in the past, our blood pressure is lower in summer because it's warmer. Well actually, we showed that about half the variation in blood pressure with season is caused by temperature. And about half of it is due to UV independently of temperature. But the point of that I'm coming to is we showed the fall in blood pressure for a rise in UVB was much greater than the fall in blood pressure for a rise in UVA. So it appears that UVB is more important in driving a reduction in blood pressure. The other important finding was we had 340,000 patients, of whom just over 100,000 were were African black American, and 200,000 were white American. And we've found that if you had dark skin, you had less of a fall in blood pressure with a rise in UV than white skin. Again, it's this story coming back that skin color isn't is an adaptation to ambient UV. And if you've got paler skin, you are more sensitive, good and bad. Good blood pressure vitamin D bad skin cancer, if you've got paler skin, you are more sensitive to UV than if you've got darker skin.
Nick Jikomes 1:19:28
So how do you think about skin sunscreen? What What are your sunscreen use patterns and what type of sunscreen how like how do you think about all these trade offs? And I guess that that is part of the point that we will probably make the people I suppose is it there are trade offs here.
Richard Weller 1:19:47
Yeah, well, so it does my dermatologist side come first. All my physicians that come first and I think you've the skin health or am I thinking of the general health? Well, what I'll say here is actually we I think we can make sunscreen. better. Um, actually, what I have done is we have developed an additive you can put into sunscreen. So we talked about this nitric oxide release in your skin being being really important for the cardiovascular benefits of sunshine. And what we show is that sunscreen blocks that from happening. So we've done work, and we show that if you put sunscreen on the skin, and shine up, we've been used ex vivo bits of skin, we show that a an SPF 50 blocks that release of No, which is a good thing when the when sunlight hits the skin. So what we have done is we have developed an additive that you can put into sunscreen, that does that nitric oxide release when you V hits the skin. So I think sunscreen, as it exists is good and bad. I think it it prevents those skin cancers. It prevents that skin aging. My concern is it it also blocks the good stuff. But I think you can work around that. And I think the solution is to improve our sunscreens as put in something that will reproduce the annual release. That's what I wear.
Nick Jikomes 1:21:21
Okay, so I guess a good a good bullet point for people is traditional sunscreen is going to block the effects of the sun sort of period, it's gonna block the bad stuff, aging and mutations that will cause skin cancer. And it's also going to block the good stuff like nitric oxide. Having beneficial
Richard Weller 1:21:39
effects. Yeah, yeah. Then vitamin D. Yeah, yep.
Nick Jikomes 1:21:43
So so like, what? Like so, you know, there's no, there's no universal answer here for people. But like, how would you advise someone to put on sunscreen most of the time, if they're in a sunny place, but get a little bit of exposure without sunscreen? Like, how should someone start to think about that?
Richard Weller 1:22:04
With the existing technologies, I think it's important to protect yourself from Intamin intermittent sun and sun burning, and sunscreen is good for that. And I should declare a conflict of interest at that I'm actually working with an American sunscreen manufacturer. And we are working on, you know, building on my research to actually release what I think the next generation of sunscreens, which will allow this nitric oxide release from the sunscreen, as if you had not been wearing sunscreen at all
Nick Jikomes 1:22:38
in the society. So it would still block the UV in other respects.
Richard Weller 1:22:42
So you're not getting that UV damaged your keratinocytes you're not getting DNA damage, you're not getting the UV trip and free radical damage. So all of those bad things are stopped. But it's allowing the nitric oxide release, which certainly accounts for many of the benefits of sunlight.
Nick Jikomes 1:22:59
So can you talk about how traditional sunscreen works in terms of like, you know, physically, how is it absorbing or reflecting or whatever the UV radiation, then what is the difference between, you know, the so called chemical versus physical sunblocks? Yeah,
Richard Weller 1:23:13
so that so there's two means there's two, those are the two broad types of sunscreen. So the sort of chemical ones were the first one to get the very first sunscreen I think back in the 90s. And I think, developed I think around the time of the Second World War was this Vaseline red, you know, red Vaseline that was smeared over gi Stan in the Pacific. So it I think it was about an SPF of two or three, it wasn't much but better than nothing. And of course, now we've got this amazing array of very beautifully designed filters that prevent sunlight. And broadly the chemical ones, they use a photochemical different chemicals, chemicals absorb UV. In fact, one of the ways that chemists can tell can differentiate different chemicals is that UV absorption pattern. So the chemical sunscreens absorb UV and different chemicals in different ways. And there are a range of very cleverly designed chemicals which will absorb those particular particularly UVB wavelengths that are problematic are absorbed by chemical sunscreens, the different filters, absorb different things. So that's the chemical ones lovely, lovely bits of chemistry. The physical sunscreens tend to be zinc and titanium, and they just reflect it, you know, those are kind of crushed up, and they just they just bounce that light back. So there's two different approaches. The the industry is in a fair bit of flux at the moment in terms of, I suppose, the industry in America is in certain amount of flux and that will feed through to us in Europe ultimately, in terms of the regulatory things you know, are the chemicals sunscreens absorbed if they are doesn't make any difference. I mean, they've been used for 50 years without people going to heads using sunscreen. So I, you know, I my own feeling is that people are too concerned about it because we've used these things for half a century without problems. So those are concerns which are floating around at the moment. So there's a lot of thought going into, can one develop better sunscreen filters without problems?
Nick Jikomes 1:25:32
Interesting. So is there any concern about the chemical versus the physical, having side effects that you know, any of the like chemical compounds can get into your skin or anything like that?
Richard Weller 1:25:47
Yeah, there's concerns about it. How realistic there are, they are? I don't know. So the there was a paper published, I think, in JAMA showing that a lot of these sunscreens, the traditional filters are absorbed, if you measure in people systemically. My feeling is we wouldn't know if we hadn't been told. And that we have No, we've never picked up a signal of sunscreen users developing. I don't know, cancers, or heart disease or anything else. So after 50 years, yeah, I mean, smokers die yawns and people that drink we've picked out exactly right. And the other concern is, reef is damages to coral reefs, about whether these so when I was working in Australia, I lived in Cannes on the on the Great Barrier Reef I was done, I spent a lot of time scuba diving out there and really conscious of these wonderful ecosystems. The My own view is that the data showing that some filters kill certain types of coral polyps is that that is done at very high concentrations in the lab. And that, given the vastness of the ocean, and the fact that people are clustered in a few small areas, in small seasons, and that the concentrations will be nothing like as big, I mean, orders of magnitude lower than these tests are done. I see.
Nick Jikomes 1:27:21
So it's actually never been formally demonstrated that reef loss in the actual ocean is clearly related to that it's just a hypothesis because in the lab, you see this stuff
Richard Weller 1:27:31
and nobody does it. And of course, the great risk to reefs is not that it's global heating, you know, the fact that the temperature of the world is going up, the temperature of the Seas is going up. And coral polyps are adapted to a very narrow temperature range, which is being exceeded. So, you know, jumping on your jet to jet off to wherever, with your reef safe sunscreen, you know, the damage done by a sunscreen, compared to the damage done by that flight is, you know, streets apart.
Nick Jikomes 1:28:03
I see. So, so this new sunscreen that you're working on, can you talk about how it works? Is it filtering UVA versus B differently? Yeah, what
Richard Weller 1:28:10
so so you you have a sunscreen, which is exactly works exactly as a sunscreen does. But it then has I'm kind of constrained by the patent arm into what I can talk about. But but then it basically reproduces that healthy chemistry, you know, nitrogen oxides and styles and UV meeting together skin. So some that is reproduced the same ingredients, our eyes are in your skin,
Nick Jikomes 1:28:39
because I was struggling to wrap my head around it. I was like, how does it allow the UV to do the nitric oxide thing but all this other stuff. But there's there's something else in there that is chemically liberating that nitric oxide.
Richard Weller 1:28:50
Exactly right. And it's basically it's the it's the the substances, which are in the skin are then in the sunscreens. So you're moving that chemistry into the sunscreen. So the sunscreen carries on being that protective barrier. But but that is also where the chemistry and that chemistry moves into the skin.
Nick Jikomes 1:29:07
And is that still in development? Is that something that's available?
Richard Weller 1:29:11
I am we are in negotiations, and we are hoping it'll be available in 2020. Force spring of next year.
Nick Jikomes 1:29:21
Interesting. So we talked about COVID stuff earlier. And I want to kind of circle back to the immune system in general, can you just give people a broad picture? Because I know that there's a lot of interesting stuff going on with sunlight and the immune system. What are the the basics there in terms of how sunlight exposure affects the human immune system?
Richard Weller 1:29:44
Well, again, we aren't we're starting off I mean, there's almost a kind of line in research between observational studies which set questions you know, this is the kind of big mechanistic what's actually happening, an intervention can you do a trial can you give something can you do something? So we started with the open elevational studies. So some a wonderful paper published by a chap called Doppler co in Nature Communications about five years ago, one of these fantastic research projects where you don't do any of the actual data collecting yourself. But like what's in a creek, you actually harvest other people's data. I won't call him lazy, because there was a lot of work involved. But it's, you know, open access data is amazing. So they went along, and they looked at the healthy control subjects in a number of studies that have been done around the world. And all of these studies had looked at gene transcription that looked at whole blood, or adipose tissue, but mostly whole blood, and what genes were that every single gene which is turned on or off. And whereas the studies had been looking at, you know, various things diet or behavior or something or other, and this was in the control group analysis, they went, and they analyzed the healthy control samples by the month of the year in which they were collected. So they were looking at these individuals that had the whole transcriptome measured at different times of year, and a number of studies in Britain, and studies in Australia, and studies in Iceland and studies in Ghana. And what they showed, so we all know about the circadian rhythm, your 24 hour rhythms in your kind of sleep wake cycles, and this is turned on and this is turned off and have you have these 24 circadian cycles. But what Dapo and colleagues showed was that 30% of your entire transcriptome, all the genes, you would have had 30% of them have a seasonal variation in expression. So a third of your genes pretty well have seasonal variation and expression, it is a huge effect. And they looked in Australia and Britain because what was lovely is the British, you know, Britain, June had to be swapped for, you know, it was the same as Australian, as Australian August. And they broadly what was found was that anti inflammatory genes are upregulated in summer, and pro inflammatory genes are upregulated, with big kind of broad picture stuff. And the idea was that, you know, in winter, lots of infectious diseases flying around, so your turn up the immune system ready to jump on infections, and that if somebody wants to turn off the, the inflammation, because inflammation is bad for you. So in the in the Gambia, it was the inflammatory genes were turned on in the just just before the wet season, when you need to get ready. And Iceland was all over the place actually scrambled we shouldn't be there. sleep wake cycles, daylight hours, 24 hours of like, humans should not be in Iceland. So but broadly, we have this kind of picture. And, and then Antony young Tanner, excuse dermatology in London has given you v two people actively gone and given and again, he has shown that UV drives a number of systemic gene effects. And we currently here are looking at the effects of UV on systemic, immune and inflammatory markers, because dermatologists use UV to treat inflammatory skin disease, psoriasis, and eczema. My suspicion is it it's not just skin inflammation, but systemic inflammation, which may well be modified by UV. So that's what we're really looking at now.
Nick Jikomes 1:33:36
So you like so well, let me ask you this. This just occurred to me. If someone lives in a high latitude environment, you know, I live here in Seattle, you're in England, we're not getting a lot of UVI for a good chunk of the year. What would your what would your recommendation be if someone is interested in going tanning in a tanning booth? Is there a safe semi safe level of that if you if you're considering the trade offs, or is that just something you would advise against completely? Yeah,
Richard Weller 1:34:09
so we know that tanning salons are a big risk for melanoma. You know, they it's this intense, very intense sunlight, they are a definite risk factor for melanoma that we know for sure that that data is pretty robust. But what about all cause mortality, because that's what we're coming down to. And in fact, we are working on a manuscript at the moment, I'm going to give a trailer for a paper which we're about to submit. So we've looked at the UK Biobank. So the UK Biobank is this prospective study where 500,000 people were recruited over about a five year period end of the last century, you know, 25 years ago, started 12 years ago, and a massive data were collected and massive behavioral information was collected by was one of the subjects you know, there was three via interviews, and those half million people have been followed since then. And as more and more of them die, the data gets better and better. You know, the data of my epidemiologist friends get excited each year that passes because the numbers get better. One of the questions they were asked was, hold on a sec.
Nick Jikomes 1:35:26
One second, folks.
Richard Weller 1:35:29
If you're ever negotiating as an 11 year old, believe me having your dad on our podcast is a strong, strong position. And so we um, so one of the questions asked about was, was use of some beds. Now, some bed users, you know, they they're not representative, the entire population, you have to pick apart what are the confounders that go with it? We've pretty exhaustively looked at all of the corrected for all of the confounders that go with them, you know, age behavioral things. It sounds fun. And we have some unexpected and exciting data, which we're about to submit, and I probably can't let you know, on a pod of four, I presented it at a meeting, although this does seem a very good audience. But
Nick Jikomes 1:36:22
I'll let you decide. I can already tell I can already tell the answer. Yeah, I
Richard Weller 1:36:24
can tell. Okay, so and that we don't know whether it's the sun beds that exert the effect we found, or it's a fact we think that sunbed users up somebody's waiting is probably a marker for some seeking behavior, because we've looked at the sunbed users in every way. And the effect we found is not linearly it's not dose response associated with some as in miles and bad users are not getting less than perfect and heavier. Some bed users are living in small rooms and each. So we're not getting a dose response suggesting it's a some beds themselves. We think the sun beds are a marker for Sun seeking behavior. And I'll let you guess what Sun seeking behavior does to all cause mortality? Yeah,
Nick Jikomes 1:37:06
it goes down. Well, so let me ask you this. So I mean, there's no right or wrong answer. Everyone has to make their own personal decision at the end of the day after weighing the benefits and the risks. Well, let me ask you this. So like I am a light skinned person living at a fairly northern latitude. And I also have psoriasis on my on my elbows mainly. I burn very easily. But what like would it be insane for me to go into a tanning bed for like five minutes, like one day a week or something like that? Would that likely produce benefits for me, in addition to increasing my risk for melanoma, melanoma?
Richard Weller 1:37:43
I think at the moment the answer is we don't have enough data. But look for psoriasis. We know that narrowband UVB is a fantastic treatment, it's safe, it's effective. It's inexpensive. You know, we know that that's a highly effective treatment. I suppose the truth is we don't have enough evidence for what interventional u v, giving you v is going to do this or this. And I think that's a huge hole in our knowledge. Because the epidemiology is so strong for sunlight having health benefits, particularly on cardiovascular health, the mechanistic studies, you know, we're showing this nitric oxide pathway really important. But me and Edinburgh, you and Seattle's, you know, it's just gray and rainy outside, you know, all the knowledge in the world. What can we do to get around that? And I think I think we need to be, I think we need to be moving beyond thinking about sunlight, skin cancer to sunlight health. And what is that risk, overall risk benefit ratio? And of course, the other thing I would say about Finley, he was looking at white skinned Europeans who had gone to Australia and India and Texas. He wasn't thinking about the reverse migrations. He was talking about people who had made an evolutionarily inappropriate move to somewhere very sunny. What about people who've made the opposite move for which we have no research, no considerations? And who in fact, the given pretty similar sound advice to those of us with pale skin?
Nick Jikomes 1:39:23
Interesting. So, I mean, is there anything that you want to reiterate or just say, again, in terms of what we talked about, especially in terms of things that you feel are maybe like misconceptions about sunlight and UV with respect to skin health?
Richard Weller 1:39:38
Well, I think sunlight has has risks and benefits. And as a physician risk analysis of risk benefit ratios is what I do every day, you whenever I press I was doing my excellent clinic this morning, all excellent patients. Whenever I prescribe a drug, I think the benefits why I'm giving you this drug to make you better and I think the risks the side effect profile. I mean, all new staff you is the core skill of physicians. That's what we do. And we've completely forgotten that with sunlight because when we talk about sunlight, all we talk about is risks. We, we forget our physician only, I'm addressing my physician colleague theorizes, we forget our core physician new skill, which is to balance risks and benefits. And all of the research and all of the thoughts of the last 100 years has been on the risks of sunlight without stepping back to consider the benefits. And that's a very, that's poor medicines. And I think we should be rebalancing things to look at it in the whole.
Nick Jikomes 1:40:45
Interesting. Well, this is fascinating stuff. Thank you for your time. Dr. Richard Weller. I definitely, before I started reading about some of this, I didn't know I was going to be this interested in skin. But there's I mean, there's lots of exciting, exciting stuff out there. It sounds like there's probably a lot of stuff that we're going to discover that that we don't know about, and we didn't even think we didn't even know that we didn't know about until fairly recently. Well, thanks.
Richard Weller 1:41:09
Great podcast. Super questions. Nick. Thanks so much. I really enjoyed it.