James (00:41): Today I had the honor of interviewing a brilliant man, one of the world’s top academics in the fields of oncology, immunotherapy and why our immune systems change as we age. He is a member of the scientific advisory board for Repair Biotechnologies inc. He is Co- Editor in Chief of cancer immunology immunotherapy and of immunity and aging, deputy editor of the journal of translational medicine, the associate editor of mechanisms of aging and development. And honestly, his resume goes on and on and on. It was a super interesting conversation and I feel like I really got a grasp of how important our immune system is going to be if we want to figure out this whole aging thing. If this was something that sounded interesting, something that sounds like you’d like to be a part of, I encourage you to reach out to Graham at tatty dash group dot D E that’s T a T I dash group dot D E. Graham, First of all, thank you, you so much for joining me today. How’s your day going so far?
Graham (01:52): Very welcome. I’m fine here. Despite the fact that there we were stuck at home with coronavirus, which is good because otherwise I, well, from this point view it’s good because otherwise I based a conference in London right now.
James (02:03): Yeah, it’s a scary time right now. I’m definitely worried about my family back home.
Graham (02:07): Yeah, it’s very serious and of course it’s directly relevant to the questions that I think you want to ask me about immunity in older people.
James (02:14): Yeah. It’s coincidentally a super relevant time to get you on the podcast. Let’s get right into things. You are an expert on immunity and cancer and more specifically how our immune systems change as we age. Yes, that is correct. All right, so here’s the big question then. Why do our immune systems seem to suffer as we grow older?
Graham (02:39): It’s one of those questions. James is easy to ask and complicated to answer, but very simply it’s due to evolution because having an immune system is very dangerous due to potential autoimmunity. The immune system always has to distinguish between your body and the invader and so have to have a system that’s complex, regulated, it can become dysregulated, it’s energetically expensive, etc, etc. So as is always the case, when you look at any physiological structures or any functions in mammals or vertebrates, at least what you see is the end result of a lot of compromises to keep the individuals alive for as long as they need to reproduce and bring up young. So in humans, as in other vertebrates, there has to be a defense system to stop bugs from killing everybody before they get a chance to have their children. As you know, in a pre antibiotic days, or let’s say before the beginning of the 19th 20th century when hygiene was not recognized as being so important. And indeed nowadays in, in people living in low and middle income countries, in some cases the infant mortality is very high because the immune system has not yet met the bugs that it needs to fight. And sometimes that battle is lost. And we are seeing this now with the newly emerged Corona virus where this has never been seen by anybody’s immune system before. So we do not have any training to recognize it. And that’s just one of the problems for the high level of difficulty that is experienced by some people that are infected. So to ask the question, like I said, it’s going to be around about and complicated answer, but essentially you need to have as a person, enough defense to keep you going until you’ve had your children, but you don’t need much more. So one part of the very important part of the immune system generates cellular components that are able to recognize and destroy invaders, but they need to be generated in large amounts when you’re young because that’s when you get exposed to all these new bugs normally in your tribe, for example. But you don’t necessarily need to have that when you’re already an adult because you will have already seen the bugs that are common in your tribe. You will have generated, if you’ve survived, you will have generated immune memory to those bugs to keep you protected against them if they ever come back. And it’s very unlikely that you’re going to be, or it’s less likely that you’re going to be exposed to many new bugs because in the past they’ve as long, so they didn’t have as long to be exposed. They didn’t travel probably, they didn’t travel quite so much. So mostly what you needed was a memory to keep the bugs that were already in your area and they at least until you were 20 or 30 or whatever, and you’d hide your children and they had grown up to reproductive age. So our immune system is so to say, programmed only to protect you under those circumstances for that length of time. And we’re all living way beyond ourselves. Date now up to 80 or 90 when the new capacity that you still have remaining and your immune system to recognize new bugs is very degraded. And I think that this is really the main problem with the perceived problems that elderly people have in immunity. It’s not that there’s a general decrease in immune function. Inflammation actually is exacerbated, which is a problem because it’s not regulated properly anymore. And memory is for most bugs, not really a problem. I think of measles, once you had measles or being vaccinated, you stay immune for 90 years or for your whole lifetime. So it’s not a general waning of immunity. It’s primarily the problem of not being able to defend yourself against new bugs as well as when you’re young. And that’s really very dramatically being illustrated at the moment with first the original SARS virus from 2003 or whenever it was. And now of course the saws version that has appeared right now and is causing worldwide economic and healthcare panic because older people are much, much more susceptible than younger people for the reasons that I’ve mentioned.
James (07:14): So it makes sense that children, young children in particular that haven’t had the chance to create any memory cells yet. This is why they can also be so susceptible to diseases and viruses like Corona virus.
Graham (07:30): Yes, very young children are highly susceptible. They are protected to some extent by antibodies that are coming across in the mother’s milk, which is why another reason why breastfeeding is good for you. But um, yeah, they have to take their chances. They are infected, they do become infected and it’s clear that it’s pretty clear that with this coronavirus again, young children do get infected for some reason they don’t get infected, but the, the consequences are for most of them not as bad because they do have a chance to generate an immune response. They have a pristine immune system that is able to see far more potential new antigens as they called the things that are recognized on bugs. For example antigens. They have a bigger repertoire as we call it, in the older person. The number of cells available with receptors to antigens that haven’t been seen before is numerically much, much lower than in children or in young adults.
Graham (08:28): So you have to think that the children, there’s the generation of a new immune system that is programmed to see a huge number of an infinite number of antigens. Whereas as you go through life, these naive cells as they are called both T-cells that directly kill infected cells. For example, if you have a Corona virus infected cell and you have a T-cell that is able to see it, it will lie as the, it will kill the infected cell before it has a chance to release new Corona virus so that you stop the virus in its tracks. And B cells are the ones that make the antibodies. So as a young person, you have a bigger repertoire of both the T cells and the B cells. And as you go through life, this is used up to generate memory cells against bugs that you’ve succeeded in protecting yourself against.
Graham (09:21): And the source of new naive cells is no longer there. It’s turned off at about the time of puberty, the T cells, this is where the thymus comes in. Famous is an organ that is required for processing precursors of T-cells that I made in the bone marrow, which then have to go to the thymus. This organ that sits above the heart is very large and children is very tiny after puberty because it’s more or less turnoff. You don’t need it anymore according to your evolutionary past at least. And so because it’s so energy intensive, generating lots of new cells that you don’t need, it’s turned off because of the danger of autoimmunity. It’s turned off in later life. So you don’t have a SNU, you’re under sources of new naive cells and older people have a very much smaller number of these cells than, than older people than younger people do.
Graham (10:17): Sorry. So what happens is that you might have what is called a hole in the repertoire. So in a young person, let’s say you have a million different possibilities of seeing a particular antigen in older people, this is diluted down to only say one and a hundred I’m just making up these figures as a, as an example, this is not actual, these are not actual numbers, but just to get the idea across that older people just simply have a reduced chance of being able to see a new antigen compared to younger people. And that is the major problem with immunity. In older people you might be unlucky and not have this particular repertoire possibility any longer. So there are ways that you can get around this theoretically and those are the interventions that many biotechs and academics are pursuing both at the level of the thymus, it stops working properly at puberty.
Graham (11:15): What happens if you could stop that stopping and rejuvenate it so that it’s continued to work for longer? Would that do any good? That’s one thing that’s being looked at. And otherwise you can also think of possibilities of genetic engineering which are beginning to take place already in cancer patients where you check which antigens are there. So in this case it would be which coronavirus antigens do you need to have cells, T-cells against the can recognize them, and then you can look using sophisticated molecular techniques. You can look in the blood for example, of the individual. They in fact have any cells with receptors that could see those antigens. If yes, then okay, it should work. All right because the way with all is there, if not, and this is missing hole in the repertoire as I called it earlier, then you might consider ways of engineering such receptors back into the cells and this is being done in some academic centers so far in cancer, you can do that. So theoretically, although it’d be very expensive, very high tech, very much individualized medicine that you wouldn’t be able to do in a Corona epidemic or pandemic like this. You’d be overwhelmed. But theoretically the technology exists to be able to approach these problems in that manner. And there are, as I said, several biotech companies or many biotech companies that are trying to leverage these new techniques to repair the deficits, let’s say, that are measurable in older people.
James (12:50): Well then that was one hell of an answer, Graham. You know, I watched your video on the undoing aging YouTube channel probably about five times to try and wrap my mind around this stuff and I feel like I’m finally, finally starting to understand what it is that you’re working on and the role of the immune system in healthy aging.
Graham (13:14): That sounds bad, James, if you had to listen five times to make sense of it,
James (13:18): Graham, you are presenting to an audience that likely has it just a slightly better grasp of the world of biotech than I do. So I wouldn’t feel too bad about that. But now that you explained things to me, uh, I’d like to give my own interpretation back to you and see how close I am to actually understanding things. So essentially when we’re young, we have a very active Dimus and this thymus, which is a, that little thing above your heart as you mentioned, is generating a ton of T cells, which are a huge part of our immune system. Essentially these T cells are immunity cells and so as we grew older, we are generating these T cells from the thymus generating T-cells from the thymus generating T-cells from the diamonds until we hit around puberty and by the time we’ve reached puberty, we will have run into a lot of different infections, a lot of different bacteria, a lot of different situations that would activate a memory cell response. And as we grow older, those reserve T cells or those memory cells or how does that all work together?
Graham (14:38): Well, yes, we are relying on our memory cells for bugs that are actually in our environment that we’ve seen in the past, which are there with the tribes say so. You know, you need to protect yourself against them. Whereas there’s any number of other bugs elsewhere in the world or newly roving which you’ve done it now you’ll ever see. And so it doesn’t make evolutionary and energetic sense to invest a lot of effort in maintaining immunity throughout decades of life to things that you might never ever encounter. This is the evolutionary argument. It’s not necessarily true. This is an interpretation of why we see Pharmakon volution as it’s called, starting in puberty, much reduced output of naive T cells throughout life. But there is still a trickle of new naive T cells probably until most people are in their forties or fifties so really towards the end of what we think would be the regular lifespan of humans, pre civilization, let’s say pre in the evolutionary past.
Graham (15:44): So it’s not that there’s absolutely none, there’s only a trickle. So it’s kind of almost turn not quiet and there is a difference. There are differences between different people, so some people retain more phonemic function for longer and it has never been shown whether those people actually do better when facing new infections costs. That would be an extremely difficult thing to be able to measure in humans. So often these things are actually very difficult to measure in humans because humans led so long, you can’t very easily follow people over a lifespan. Some studies are trying to do that. We were involved in several that started looking at humans when they’ve already old. So that you know, if you start with somebody who’s 80 then you don’t have to wait all that long in a cohort of people to see enough mortality to be able to check what’s important for dying and what is protective, things like that.
Graham (16:37): But you can use mice. These are of course the favorite experimental animal in biology and medical research. But the immune system in mice, although it bears many parallels and similarities to the immune system in human is remarkably different in some respects. For example, the thymus is fine. Making dilution and the maintenance in if naive T cells is different in mice and humans. So it’s not necessarily a very relevant model for humans. But in general what you are saying is correct. You are in later life, you rely on memory for things that are definitely in your environment and you don’t bother to spend a lot of time and effort and danger of autoimmunity to generate a lot of T cells that are specific for things that you might never encounter.
James (17:25): So as we grow older, as we get above 50 years old or so and we are not generating these immunity cells anymore, our stockpile of immunity has basically run out and that’s why older people tend to be much more susceptible to infectious disease like we’re seeing what the coronavirus
Graham (17:46): yes, James. I think that is correct. That’s part of reason. Of course. It’s never only one reason. A T cells are important naive T cells to see new antigens, new bugs, but it’s not only the T cells that change. So an immune response and these are the adaptive immune responses that we’re talking about. The ones with memory, right? There are two main arms of the immune response. The one we’ve been mostly talking about is the adaptive immune response that remembers seeing bugs in the past, but there’s also a more, it’s often referred to as a more primitive immune response, which is to do with inflammation. All animals have this arm of the immune response, the inflammatory arm of the immune response. So invertebrates like snails and squid and so on. They have this inflammatory immune system as we do, but they don’t have T-cells, obese cells, they manage completely without them.
Graham (18:39): It’s actually a puzzle as to why invertebrates don’t have these types of cells that all vertebrates do have. But that’s a different question that we’re not really concerned with. Now, what we are concerned with now is that people have an inflammatory response, which has changed with age as well as the adaptive T cell and B cell response. But the point of the inflammatory response is there first. So when a new bug attacks you, it takes perhaps a week or two or the adaptive immune response to get going. Whereas the innate immune response, as it’s called the inflammation happens immediately. You know that if you scratch your skin in a couple of seconds, you’re going to red rash. That’s the beginning of an inflammatory immune response. And this is something that is dysregulated in the elderly and it’s also a problem, but it’s also necessary to have an inflammatory response to kick off with the adaptive response because there’s a, a bridge between innate immunity and inflammation and the ability of T-cells to see the bugs.
Graham (19:43): The T cells cannot see bugs unless they’ve been processed. And antigens are presented by components of the innate inflammatory immune system. And that changes with age as well. So you have actually a whole series of things going differently and from this point of view, wrongly in all the people, so let me start right at the beginning of everything. That’s the bone marrow, right? So your immune system is coming out of your hematopoietic system that’s constantly generating red blood cells from the bone marrow that you need in billions and trillions every day, as well as white blood cells, which include these inflammatory cells as well as the B cell and T cell precursors. So we know that the hematopoietic system in older people, um, you know, in, in, in animals it’s, you know, clearly, obviously you can, you can examine these things in my sense to some extent and other animals more easily.
Graham (20:40): But in humans it’s also clear that the ability of the bone marrow to generate all the cells that you need, the red blood cells and the white blood cells, it’s different in older people and it’s generally worse in older people. You know, age associated anemia is a very well recognized and that’s a problem with him as paresis. But there’s also a problem with the generation of immune cells as well by the magic project system. So that’s the first problem that one has when considering what’s different and worse in older people. And of course that’s the major question. If you’re asking what can we do about it to reverse this? So there’s a problem right there, generating those cells in the bone marrow and then the ones that go into the thymus to be turned into proper maturity cells. As we discussed, the thymus is hardly there of the puberty.
Graham (21:26): So that doesn’t happen much. And because of the difficulties with um, the generation also of the innate immune cells, the ability to pick up bugs and present antigens as it’s called in the correct manner to T-cells to trigger an immune response is also compromised. So we don’t just have one problem, which of course you wouldn’t expect to be the case, but it does make trying to fix the problem difficult when you have a whole Dominos set of things that you’ve got to fix at the same time. That’s the thing, that’s the main challenge to fix these things, not just one thing, but a whole series of things. Each one dependent on the other down the road. I almost felt like when I finished the ink something
James (22:07): that’s definitely a Mike drop statement and it really gets me excited about the type of progress that we’re making in the world of biotech and especially just thinking about what the world will be like in 10 to 15 years. Which leads me to my next question. Maybe it’s an oversimplified question, but as an expert in oncology and cancer treatment, do you think that we will see a fairly consistent cure for cancer in the near future?
Graham (22:39): Okay. Yes, I do. Now five years ago would not have been possible to say the C word was the horrible C for cancer. Now it’s the C for cure and although we cannot say here is a patient, I’m guaranteed to cure this patient. That’s lamentably still not the case, but such great strides have been made in modulating the patient’s own immune system and helping to enhance responses against the patient’s own tumor with a whole range of different technologies that include genetic engineering of the type that I mentioned earlier where one can identify these holes in the repertoire, just not having the capacity to see a particular antigen. This can be an antigen on a virus, on a bacterium or on the cancer. Each Tuymans cancer expresses large ranges of these structures that are different on the cancer compared to the normal cells due to all the genetic mutations in the cancer that caused the cancer in the first place.
Graham (23:41): And some of them can be seen by the immune system or one of range things medically such that they can be seen by the immune system and a multipronged approach that modulates immunity and helps the immune system to recognize the correct antigens on the tumor cells and does a lot of other things in blocking the way the tumor cells protect themselves because they will try to escape from this commune attack. I think that we are seeing already in many different centers and many companies are of course extremely big and small pharma, extremely active in this area. Many, many clinical trials ongoing at the moment in all these different aspects that we have already seen, patients who are cured. The very, very, very earliest indication of this was in metastatic melanoma, the worst kind of skin cancer which when progressed to metastases in the visceral organs and particularly in the brain, was essentially up until 15 years ago, let’s say, or a decade ago, 2011 the FDA approved the first immunomodulatory antibody therapy.
Graham (24:48): In fact, so since 2011 that say it’s been possible really to cure some patients using antibodies that block the tumors defense against immune attack, let’s say, let’s put it that way and we’ve had patients in here, in our center in in tubing and in Germany that have been treated that long ago with as a experimental therapy. In those days it was impossible to treat these patients in any other way. Radiotherapy, chemotherapy, surgery and the brain of course metastases in the brain were not surgically excised. So these patients had a six month life expectancy on average and using this first-generation immunomodulatory treatment called checkpoint blockade. There are patients that were treated here in tubing and at that time that are still alive with no sign of disease after well over a decade. And I think one has to say, one is happy to say they are cured. That’s really exciting.
Graham (25:48): And has this been proven effective for all forms of cancer? It’s very exciting. It’s not just melanoma or either, it’s almost, it’s many solid tumors and some hematologic tumors as well. Not all the prostate cancer is, is resisting attacks so far in this way. But when is definitely moving towards answering the question, why do some tumors not respond very well to these treatments and why is it that some people with tumors that do respond and other people don’t? And this has been the focus of our own research actually in the lab here and in my lab in Canada for many years now to take a cancer patient and look for a test, a diagnostic test, which will predict whether or not they will respond to which treatment and then select the correct treatment individualized for that patient. This is the way that things are going and this is the way that if we managed retain the same kind of medical infrastructure and the research capacity, which as you so clearly pointed out, it requires lots of money and lots of faith in the scientific and the medical process.
Graham (26:58): Faith in scientific results rather than in wishful thinking and false hopes. Because cancer is a area where people have been so desperate for so long. Even though medical research has been delivering progress since at least the 1950s it hasn’t been sufficient to help the majority of cancer patients who turn to all kinds of scams and companies offering fake treatments and taking money from people who are desperate and so this is something which is not a scientific problem, but which is definitely a public health and social science problem too. It’s akin to the anti-vaxxers who ignore any evidence and simply believe what they wish to believe up until their dying breath.
James (27:47): Does this cancer immunotherapy work well for both adults and younger people? Does it kind of work the same? Is there a difference in how it works because obviously the immune systems will be different between an older and a young person?
Graham (28:01): I have to say, and it’s I guess very fortunate that with the albeit limited mechanisms and modes of cancer therapy that we have at the moment, there’s checkpoint blockade for example. It really looks as if older people who are at least all the people with melanoma do not only just as well as younger people, but possibly even better. And this is something we’ve looked at in our own cohorts of patients that even people over 80 just as likely to benefit from this treatment and importantly not to have West side effects compared to younger people. So they might actually even do better. So I guess you could sort of finish on an optimistic note that it’s not, as I say in some of my talks, is it all downhill? Is a, is it all downhill? Is aging all downhill? May. Maybe if you’re going to be a metastatic melanoma patient treated with checkpoint blockade, it’s better to be older.
James (28:54): Well that’s at least one thing to look forward to. It’s a really exciting time to be alive and be able to potentially witness all this stuff. A cure for cancer and not to mention the plethora of other things work being worked on in the longevity and biotech industry, the world. And more importantly, the human experience will be a very different one in the next 10 to 15 years. And if I can go back just to make sure that I understand how this immunotherapy works for cancer. Essentially these tumor cells or these tumors in general have kind of figured out a way to hide from our immune systems. And what you guys are working on is basically bringing these cancer or these tumor cells out hiding so that the immune systems can go to work and do what they do best, which is remove these cells. That’s correct. Awesome. So everything seems like it’s kind of coming together now. So if we’re looking at things not through just a humanitarian perspective but in a a doing the greater good perspective, but actually maybe a return on investment perspective, I would imagine that curing cancer would be very big business. If someone wanted to get involved with investing into this type of research, investing into companies that are working on this type of research, how would someone get involved?
Graham (30:21): Well, in cancer it’s a very, very wide open field, isn’t it? In aging research it’s much more limited. And I’m more dependent upon that kind of input. I would think that in cancer research, there’s so much interest at governmental charitable and big pharma level that, um, I dunno if there’s really a niche where people would want to put there to invest in a particular approach for, for that. But I think in the aging side though, that that’s a different kettle of fish.
James (30:49): Yeah. And there’s no doubt that we as humans, as we figure out to raise our immune system as we grow older, it’s going to have a pretty substantial impact on the average human lifespan.
Graham (31:00): Well, it might have because if one looks at the causes of death over the lifespan, you know, the frequency of cancer and cardiovascular disease is still increasing with age until you reach about 75 or so in the population after that, the incidents of cancer and cardiovascular disease in terms of its acceleration as a, as a cause of death in the whole surviving population decreases. And one believes, of course, simplistically, because people who were going to die already have, so what the ones that survive are going to get something else. Probably Alzheimer’s. It’d be the big problem in later life once we fix these other things. So neurodegeneration is something we’re also interested in because it certainly has an immune component, inflammatory and otherwise we believe so that their immune system is everywhere, obviously. So it has its finger in every pie. So to say. It’s interesting to see that in those cause of death statistics, which are not that brilliantly accurate actually in humans, you can see that the acceleration of the cause of death as infectious disease does not plateau. It continues to accelerate up until right up until 100 or the supercentenarians are 110 so almost everybody dies of infectious disease then if they were going to die of cancer or cardiovascular disease, they already would have beforehand,
James (32:20): right? So people that are above 100 or so, these centenarians, they would have already died from cancer if cancer was going to be an issue for them, but they still are extremely susceptible to infectious disease. So, so as we age above that, as we age, above 100 years old, our immune systems are going to become even more important to extending our lives to having a healthy lifespan
Graham (32:45): in the bigger scheme of things we would like to cancer is is being beaten back. I really believe that not there yet, but that would be a major accomplishment over the next 10 years or 15 years to move more in that direction. Cardiovascular disease is at this stage was at the stage maybe 10 or 15 years ago, so rates are still high in many countries, but much lower in, let’s call them Western developed countries now than they used to be for many reasons, not necessarily medical and then quitting smoking is a major impact of course on lung, lung cancer and heart disease. We’re going to see infectious disease remaining a big problem as we see with coronavirus now and neurodegenerative diseases, not just Alzheimer’s, but also the vascular dementia and Parkinson’s. They’re all climbing still and they all have an immune components. So for the bigger picture, yeah, that’s where one would need to focus one’s efforts.
Graham (33:43): Right now. If you were looking for investment opportunities for 10 years from now, that’s maybe where one would look. But of course those areas are also very, very well saturated. The Nia in the U S is spending vast sums of money so far to little avail in Alzheimer’s research. And so it’s not that these areas are our investment deserts or anything. You’ve got to find a niche within that area I suppose as always is the case. So for aging it’s easier to find kinds of things that have not been properly examined so far and to try to focus on them like finding rejuvenation for example, or trying to fix what’s going on in the bone marrow so that more of the kinds of cells you need are produced.
James (34:26): So in your opinion, if someone wanted to invest in these types of companies, companies that are working on increasing our immune systems, companies that are working on things like time and rejuvenation, which essentially is going to improve our production of T cells over time. T cells being very important for our immune systems or companies that are working on going in there and optimizing our bone marrow, which are also another production zone of immunity cells.
Graham (34:56): Yeah, I think so. I think that’s a good idea. I think that there are many things you can do. Like I said, you have to cause one individual or one group or one company. It doesn’t have to do everything, but you’d have to work together. To me, no good fixing one thing if downstream or upstream of that one thing. There are other problems that have not been fixed and so in fact, it’s kind of from logical and formal reasons. A truism that if aging individuals have many different problems including problems with immunity, if you fix them all, then there’s no problem anymore. So that doesn’t really help you though when you really have to get down to finding out exactly what those problems are and fixing them all at the same time. Or of course as doctors always say, prevention is better than QS, so clearly that would be something to focus on as well to prevent these problems happening in the first place. That’s easier said than done for sure.
James (35:51): Graham, this has been an incredibly educational and enjoyable discussion and to be honest, before this conversation, I didn’t really understand the role that our immune system is have in the bigger picture of longevity and life extension. Well, thank you so much again for joining me, Graham, and if you, the audience is listening and this was something that you found particularly interesting that you’d like to be a part of. I highly recommend reaching out to Graham at tatty dash group dot D E that’s T a T I dash group dot D E.
James (36:31): If you got this far, I just want to say thank you so much for listening. If this was all interesting to you, I’d love to connect on Instagram and hear your feedback. I’ll also be posting clips from the latest episodes as well as anything else I find interesting about the biotech industry. You can find me on Instagram at simple biotech, and if you’re interested in the companies that I’m looking at and the companies that I’m excited about, connect with me on angel list at angel.co/jamesrule. That’s James R. U. H. L. E. thank you so much and be safe out there.