 Good morning. Well trained. So the idea that Inuit peoples who ate almost nothing but meat for most of the year in the most plant-generous of interpretations has sparked a hot fire of debate in the paleo and ketogenic world. There seems to be a lot at stake. People have argued on the one hand that the diet isn't really ketogenic, maybe the levels of protein in the diet are too high for ketosis or the plant intake was much higher than we recognize or even that muscle glycogen has somehow escaped its normal biological fate of turning into lactate and thereby made the diet high in carbs. But a potentially more fatal blow is the fact that a recently discovered genetic variant that affects arctic peoples worldwide, including Inuit, seems to show that they can't get into ketosis at all even when fasting. This has been discovered tragically because there's a high rate of hospitalization in Alaska of infants and young children who are homozygous for the gene and who happen to maybe get a viral illness so they have no appetite or they can't keep food down and what happens is their glucose goes down, but the ketones don't go up to compensate and so it becomes an emergency. Researchers who have studied children with two copies of the gene have confirmed this fasting intolerance and if you look at studies in the last century on Inuit, it seems to also confirm this idea, although not all of them and so I'm going to examine some of that literature. The heat in this discussion though comes from downstream questions. If the Inuit mostly ate a diet that would be ketogenic in others and Inuit on their traditional diets were usually in ketosis, then sustained ketosis in humans has a definite precedent and so it would stand to reason that long-term ketosis is a natural and safe state for humans. If on the other hand, even the Inuit weren't in ketosis, either because some aspect of their diet prevented it or more strongly they developed a genetic mutation specifically to avoid it, then long-term ketosis seems like a modern hack that might be harmful. These potential consequences have then thrown the actual question out of proportion and bias us to interpret observations one way or the other out of commitment to one of these bottom lines. So in this talk, I'll examine the question of whether Inuit really were in ketosis and the effect of that gene and I'll try to do it in as unbiased way as possible given that I do have a preference among these interpretations. So let's look at some studies. The earliest study that I could find on diet was this Krogan-Krogue study. They were looking at Greenlanders. In the first row there, they had also collected some data that a previous researcher had reported on just a whole annual amount of food intake and so they did calculations to divide it up per year and came out with about a kilogram of meat per day per person plus another half kilogram of fish. Note that already at that time in 1857 they were already eating 36 grams of bread a day on average and there was a berry component but that 50 grams of berries again is amortized over the whole year and that was probably compressed into maybe three weeks and the amount of carbohydrate may have come out to 50 grams a day per day if it was in just three weeks, so not a large component. They didn't do any ketosis experiments in this paper but they did discuss many cultural and dietary things. The paper is fascinating and it's available on the Internet Archive for you to read. The dietary components that they emphasized were seal, reindeer, walrus, whale, birds and fish that there were negligible plants but the time of that writing they compared it to Rinks study and said that they estimate that people were already in the early 1900s when they were there eating 200 grams of bread a day. So we're already not going to be able to get the kind of data we would hope for about traditional diets from this population. The first experiments that measured ketosis that I could find were both from Heinbecker. He did the experiment twice once in 1928 and then he went back to confirm in 1931. This was in Baffin Island. He also, the way he described the diet was the Eskimo in his natural state eats practically only flesh. It is impossible for him to do otherwise as plant life of a type yielding edible material does not exist. Very occasionally a bit of kelp or a few blueberries are eaten, but they cannot be considered articles of diet. He measured, in both cases, he measured ketosis starting from non-fasting and for a period of four days of fasting and the way he measured it was breath acetone and urine beta-hydroxybutyrate, which is not what we usually measure in urine or not how we usually measure beta-hydroxybutyrate and he did find that on day zero of the fasting they were not detectably in ketosis, but as the days went on they certainly did develop ketosis. So that's one data point. He did say that the levels were milder than expected, except for in both cases there was one subject who was in one case nursing in one case pregnant and nursing and those levels went up to the expected in fasting. Sinclair did an extensive review of North America, so it included Baffin Island, Greenland, Northwest Canada and Alaska in 1953. His comments about the diet were similar to what comments we've already seen, but he also added this extraordinary claim that Inuit were eating four kilograms of meat a day in a single meal and there were also some anecdotes where people had asked natives to eat as much as they could and eight, maybe eight kilograms a day, but I don't think that was a normal occurrence. And so in his conclusions, he said this diet is obviously too much protein for ketosis, but he himself didn't make any measurements in this study. He did cite a previous study that he was involved in, which I was unable to find, but he said that there were four Eskimos eating Pemmican only for six days and then fasted. They tested urine acetoacetate and there was no ketoneuria on the Pemmican days, but definitely ketoneuria in the fasted days. And then finally, fast forward to 1972, where ketosis was again measured, these two papers turn out to be the same study, which is obvious if you look at it. It's mostly the same characters involved and it's in Alaska. In the first study, they emphasized that they had measured the people that they were measuring, measured their diet and they were already at 15 to 20 percent of carbohydrate. In the second study, they talked about the surrounding population and they said that the adult population was eating 28 percent carbohydrate at the time and the adolescents were eating 40 percent, a third of which was coming from candy. So already by 1972, we can't really say much about the effect of a traditional diet. They did measure blood acetoacetate, also not something we normally do today and it was a little bit fasted, 16 to 26 hours fasted and it came out negative, which they said wasn't surprising because it wasn't long enough to detect. So most of these tests that were used in these studies have been developed to detect fasting levels of ketosis or clinical or ketoacidosis levels. And so I want to go over these tests just briefly and talk about what they can detect and the influence of mild levels of ketosis or ketoacidosis on these tests. So if you look at a classical ketogenic diet, you can see that acetoacetate levels and beta hydroxybutyrate levels are approximately the same before the diet, maybe up to twice as much beta hydroxybutyrate, but very quickly the ratio climbs in favor of beta hydroxybutyrate and here even with the beta hydroxybutyrate up to over four, the acetoacetate levels have leveled off at about 1.2. These two graphics are from fasting and it shows the same pattern, but the thing to notice about this, if you are hanging out in the lower end of nutritional ketosis range and your levels of beta hydroxybutyrate are say between 0.5 and 1.5, your blood acetoacetate levels are going to be fairly low, maybe around 0.3. And 0.3 is well below the detection limits of some of the tests that were used in those studies, the blood acetoacetate test in particular. Now the relationship between blood levels and urine levels isn't straightforward. I think this is actually taken just in fasting. Well with acetoacetate it is kind of straightforward. Urine output is directly related to the blood, but beta hydroxybutyrate, which we don't normally measure in urine, has a very different pattern. It really doesn't start to show up in urine until you've passed a certain threshold after which it goes up very steeply. So again, if you're in mild nutritional ketosis, urine measurements of acetoacetate are going to be hard to pick up and beta hydroxybutyrate is also going to be hard to pick up, which is especially important if you're accustomed to looking for the levels that you would find in fasting. To make matters worse, the nitropreside test, which is what is used for both urine and blood, even at the current state of the art has a very high false negative rate. This chart shows an experiment with given levels of urine acetoacetate and the range of beta hydroxybutyrate in the blood. And again, if you think about the person with beta hydroxybutyrate levels between 0.5 and 1.5, there's a significant chance that your urine acetoacetate is going to be negative. This problem is exacerbated by ketoadaptation. This study isn't about the relevant population and I only bring it up to point out a couple of things that they brought up in their introduction. It was already known at that time in 1954 that ketoadaptation reduces ketoneuria. So the notes about ketoadaptation are in the red here. In one point they say that it was known from a previous study that ketoneuria reaches a peak at three to five days during fasting and then it drops off. And the second part in the red is saying that after months on a carbohydrate-free diet ketoneuria diminishes. And then the part in blue is just to highlight that in this paper they had in their company an Eskimo soldier who had been eating the normal army rations and when they put him on a ketogenic diet he showed ketones immediately the way that would be expected. So all of these points point out that ketoadaptation may be having a real effect on our ability to detect ketosis in these cases. So where are we? I think that these studies do show that the traditional diet was low enough in carbohydrate. Maybe it was high in protein that's a little unclear but there was already a growing intake of flour that's in the diet by the early 1900s. As for ketosis it was not detected during fasting and during or sorry not well not fasted but during fasting it was definitely present though in some cases there is evidence that the level is not at what we would expect. So as to hypotheses that we can make at this point we can either think that there wasn't really ketosis or it was really really low and that could have been because of a diet being too high in protein or maybe some carb cream or we can it's still the data is still compatible with believing that there was ketosis but it was too mild and ketoadaptation was making it too hard to detect. But there's more information so as I've already alluded to there is a genetic variant of CPT1a that's coming into play in this population. CPT1a is an enzyme that is used to transport long chain fatty acids into mitochondria for fatty acid oxidation which you need to be able to get energy or ketone bodies. A is the form in the liver so this isn't affecting all the other tissues if you're on a very high fat diet and CPT1a is compromised you're still going to be able to get energy into your muscles for example but the ketone glucose sparing effect is what's going to be compromised. And this genetic variant is found across the world in Arctic populations it's not just Inuit. What does that variant do? Well it's been shown in certain experiments to actually reduce the activity of CPT1a. Various measurements have shown anywhere between 2 and 54 percent of activity and so it's called a deficiency and as we saw earlier can be very dangerous because it will diminish your ability to fast and this has shown up in increased infant mortality rates in the Alaskan population so it's very serious. But this is astonishing. Given a gene that increases infant mortality rate I can hardly imagine a genetic variant that would be more subject to selective pressure against it so I think this means that there must have been a very strong selective advantage to offset this or there's more going on to the story than we're seeing. It's not a rare one-off mutation like an inborn error of metabolism it's extremely prevalent in the Arctic populations. So for example here are the Inupia and Yupik people in Alaska. The red dots are for being homozygous and the green ones are for being heterozygous. I think the average of that population is about 0.7 and a similar story happens in north of Canada particularly in Nunavut. These columns show no copies, one copy and both copies of the gene. The northwest territories it only showed up in the Inuit and Inuvia loop populations in much less than the first nations which is interesting and the Yukon it showed up barely at all but we can't tell from this data whether that's because non-native people or lineage or in the data pool or if there's a difference, a drastic difference when you start going inland. All of these in the previous ones were data taken from infant screening which is now a practice because of that problem but there's also data showing that the gene is prevalent across the world in Arctic populations. So the first idea that I heard about why this gene might be selected is that the diet is low in carbohydrate and the gene was selected to avoid chronic ketosis from this naturally low carb diet. Now note that this hypothesis only makes sense if you're going to concede that the diet was ketogenic in the first place. If you don't believe the diet was ketogenic you can't then say that the gene selected against it that makes no sense so you have to choose one of those at most. What was special about the environment that this gene is prevalent in? Well we know the diet was low in carbohydrate it was also potentially high in animal protein but it's also very high in cold water fish and sea mammals and it's cold and coastal. Well what would be so special about a diet of cold water fish, seal, walrus and polar bear that would make it different from caribou or reindeer in the inland populations. What those kinds of foods have in common is very high levels of polyunsaturated fatty acids. This study is from 1980 and so the Eskimo population are already eating a large amount of biscuits and sugar but the meat that they were eating was at least the same kind of meat that they had been eating previously and if you look at it compared to the Danish control population you can see that the percent of saturated fatty acids is much less and polyunsaturated fat is much higher in these greenlanders and when you compound this with the previous fact of 135 grams of fat per day as estimated in that first study I showed you that's going to be some 25 or 30 grams a day of just polyunsaturated fatty acid which is mostly omega-3. Well we know that polyunsaturated fat upregulates CPT1A. This study was done in rats and they were looking at the enzyme activity in various ways and showed that if you were using fatty acids that were high in saturated fat and low in polyunsaturated fat and vice versa it had a big effect on the activity of the enzyme. Specifically, polyunsaturated fat is much more activating even omega-6 but more so omega-3 and this translates directly into ketosis levels. This study compared ketogenic humans on either a very high saturated fat diet or a very high polyunsaturated fat diet and the difference is really striking. They said beta hydroxybutyrate increased 8.4 milligrams per deciliter in the polyunsaturated group compared with 3.1 in the saturated group. Of course, I think normally most of our fat is mono-unsaturated but just to compare those directly. So there is a reason to believe that without this gene arctic peoples would have had much higher levels of ketosis than people with similarly low carbohydrate meat-based diets inland. And there are other ways that the polyunsaturated fat could compensate just other than just the way that it's being oxidized. For example, there's a reason to believe it will increase the P-PAR alpha transcription factor. It could increase the expression of the actual gene for the enzyme itself. If you're in a low glucose situation, you probably have increased mitochondrial biogenesis. And so, you know, if you had twice as much gene expression, that's nearly going to compensate or at least do a go a long way to compensate for a deficit that takes it to 22%. And none of these compensations would show up in any of the data that we have because we're looking at children who are on high carb diets or we're looking at fibroblasts that are grown in glucose. So we don't have the data that would show what would happen if we were under the right context. This allows us to amend our first hypothesis and say maybe the gene was selected to reduce ketosis but it wasn't to eliminate ketosis. It was just to reduce high levels of ketosis that it exceeded some safe threshold. Of course, that makes us wonder what that threshold would be and what it means to be in ketosis at various levels. But if this were the case of the gene, then we would still have mild ketosis being perfectly sustainable. But the Arctic variant has another effect that hasn't been acknowledged very widely. The second effect of the gene is that it reduces the sensitivity of CPT1A to malonyl-CoA and I'll explain what that means if I can. Malonyl-CoA is a result of the carb metabolism pathway on the path to generating fat. And since CPT1 is burning fat, it's very sensitive to detecting when fat is being actually generated. You don't want to have the gas and the break on at the same time. And so in the presence of malonyl-CoA, CPT1 activity goes way, way down. The study that this graphic is from is showing that if you desensitize CPT1A to malonyl-CoA, you can increase fat oxidation even more than you can by overexpressing the CPT1A gene and enzyme itself. So if you look, this study was, I've messed with this slide because the study was on different mutations of fatty acid oxidation. The only one that is the relevant gene mutation is patient 6. You can see that there is a big drop in baseline activity, but that it's much less affected by the presence of malonyl-CoA. You might think that this is irrelevant, giving that the levels are already so low, but you remember that the baseline levels are in the wrong dietary context. So it's an empirical question and I think a reasonable hypothesis that with high exposure to polyunsaturated fatty acids, those baseline levels would be significantly higher in the first place. So at this point, it seems like we may be at a bit of a theoretical impasse. We have the high polyunsaturated fatty acids in the diet, which are offsetting the deficiency, and then we have potentially high levels of protein, which could be addressed by the low malonyl-CoA sensitivity because a higher protein diet, of course, results in more glucose oxidation. So this suggests a different hypothesis. This hypothesis was first published in Greenberg 2009. He said that instead of the selective advantage being to reduce ketosis, the selective advantage is actually to maintain ketosis in lean times. And that this is only made possible. We only see this in the Arctic because only there are the levels of polyunsaturated fats so high that ketosis is so high that we can afford to bring it back without losing it entirely. And so if this hypothesis is correct, then it's quite possible that high polyunsaturated fatty acid diets would give a higher baseline of CPT1 activity, and maybe those children who have too fast for illness would not have the same symptoms. And that question is right now under investigation by David Kohler at the Oregon Health and Science University. When I spoke to Dr. Kohler, he also suggested that there may be a mixed copy effect. So in this case, the people who are heterozygous for the gene may have the best of both worlds because it turns out that the reduction in fatty acid oxidation behaves more recessively. It's not nearly as big a blow if you only have one copy of the gene as if you have two. Whereas the benefit from the reduction in sensitivity to malinal CoA behaves more dominantly and you only need one copy of the gene to get a benefit. So in this case, the homozygous people would be the worst off because they have reduced fatty acid oxidation. And not only does that limit ketosis, but if you remember in the earlier slide, two of the five homozygous children that were in that study not only were not generating enough ketones, but were having dangerous levels of hypoglycemia. And so if this gene is actually causing a limitation in gluconeogenesis, then it's much more serious and it's not necessarily easy to understand how it could be successful in a population that relies on both gluconeogenesis and ketosis. So what can we conclude? Was the Inuit diet ketogenic in the sense of it would be ketogenic, at least without the context of that gene? I think that the evidence is pretty strong that it would be. There is some question about higher protein levels, but it seems to be offset by the amount of carbohydrate and the amount of fat, especially in light of the nature of the fat. And of course, notice that both of these competing hypotheses, whether it's mitigating or maintaining ketosis, rely on the fact that ketosis would have been higher or they make no sense. But were the Inuit on a traditional diet in ketosis? Here is where we need more empirical data because there are conflicting sources of information. We know there is reduced CPT1A activity, at least in the modern context. The diet may have compensated. We also have to talk about the degree because maybe we're arguing about different things if one person is saying, of course they weren't at level 4 beta hydroxybutyrate all the time and maybe we're only talking about level 1, then it's not as much of a contentious issue. So if the Inuit genes were actually selecting against ketosis, that was their function. We don't know if that was the advantage itself or if it was just a tolerable side effect for some other greater advantage, but the problem with that hypothesis is that it doesn't account for the in tandem hypoglycemia that sometimes occurs and it doesn't really address what would happen with possible compensations from the diet and from the other effect of the gene that we've seen. But even if we grant that, can we conclude from this that long-term ketosis is harmful? I'm not sure we can. It's not automatic, at least, because we have to remember that this is a very specific population with a very specific diet. If we look at, for example, the Mongolians who were nomadic people and had a very low carbohydrate and high animal intake as well before they were introduced to flour and sugar, I don't see that there are any medical issues or genetic issues so far as yet that I've heard that have come up. Of course, also, people argue that during the ice ages, which did affect the climates of Africa and Asia where we would have been induced a similar kind of dietary constraints, but we can't know that for sure. Certainly though, if there really was no human precedent for long-term ketosis, it does make the basis for recommending long-term ketogenic diets a little bit less of a, gives it less of a foundation. On the other hand, if we can establish that they probably were in ketosis, then we would definitely have a precedent of sustained ketosis in human history, and although I can see that it could have been merely tolerated for in exchange for some other advantage, we know it's not a deal-breaker, right? We know that there would, we would know at that point that there was a healthy population that was not adversely affected by that. What we really need, the bottom line, is that we can't tell what the selective advantage was at this point, and maybe never because that's speculation, but there are competing theories that are very different that can't be ruled out. We need to look at the genes acting in the environment that they adapted to, not in people eating high-carb diets or in fibroblasts that have been grown in glucose. We need better experiments to be able to resolve this question regardless of what the consequences are for us. Thank you. All right, just a couple of minutes for questions, and please stay up here so people can ask you questions. And the microphone is over there, please line up with the microphone. Thank you. Hi, Amber, an interesting talk. And the one thing that comes to my mind when you're talking about this, the homozygous case of this gene variant, is that human infants are in ketosis, especially strongly when they're first born. Look at the picture on your end slide here. Unlike great apes and other primates, humans are born with a really high amount of white adipose tissue, and that's to maintain ketosis. Do these children have a problem early in infancy? I am not sure about early, and I think that if their breastfed, especially the adipose tissue of infants, is also higher in those polyunsaturated fatty acids, and that might help. I don't know, and that it's a bit of a mystery to me. I think that early cessation of breastfeeding might be part of the problem in the population as well. What time do they, do you know when they traditionally wean? No. But I know that they were often just strapped along and carried, and I don't think that they would naturally be fasting, unless I suppose if they were really ill. I just had a question. I didn't actually catch the date in the first slide. Oh, sure. This was three and four year olds who were homozygous and were put under fasting conditions, and so the gray area is the 90th and 10th percentile of the non with the wild type variant, what ketosis level you would expect there, and that was the results they got. And then on the right hand side there is the glucose levels where two of the subjects have fallen below the normal glucose level. The other question would be if you assume that you're trying to prevent effects of ketosis, what kind of effects would be harmful? That I can't really speak. I don't know what would be harmful. I think people have suggested that it's inefficient or that it's stressful to the body somehow. I don't really buy those arguments. That doesn't sound good. No, I mean I think it's a bad principle to assume harm when there is no. I think the idea is it's got to be growing out of the idea that a high carbohydrate diet is the default diet, and to deviate from that would be messing with our evolutionary adaptations. That does sound like a good principle. So we hear stories from the laboratory about new discoveries, and then you ask the researcher, well, are you taking this product? And that kind of is the witness test, how good is that product? So ma'am, what diet are you on and why or why not? Thank you. I am on a carnivorous diet. I probably don't get the level of polyunsaturated fatty acids that they do in the north, but I don't eat any plants, and I do that because it's made me the healthiest that I've been in my adult life. And in particular, it's completely eliminated my mood disorder that I had in my life. So sure, I eat animal-based foods, many of them mostly ruminants like beef and lamb, but I also eat pork and chicken and fish and eggs. Very occasionally I eat dairy, sometimes more than others. Yeah, and I was drinking coffee for many, many years, but I have stopped drinking coffee, at least for a little while, too, to see what that would do. Thank you. Thanks, Amber. This was great, as always. Thank you. I've been asked to ask you a question about uncoupling. So you're obviously, I won't butcher his surname, but you'll obviously be familiar with Peter from hyperlipids hypothesis of high free fatty acids outside the mitochondria, driving greater mitochondrial uncoupling for heat generation in these populations. And if you look at mitochondrial haplotypes, the further away you get away from the equator, the more likely you are to have uncoupled mitochondria probably for heat generation. So do you have any thoughts on that in this context? I do, and I'm so glad you asked that because I didn't have time to talk about that. One idea that I came up with, and I'm sure it's not just my own, is that when you're in that cold Arctic environment, that the heat generation is really important. In fact, if you remember that study where I was looking at just the points about keto adaptation, that study was actually done in non-native explorers. They had heard that ketosis is happening to their explorers on their rations, and they thought maybe they should try to prevent it because it might be dangerous. So they studied, they gave them all carbohydrate rations and all meat rations in a mix. And they concluded that while the meat rations did result in more ketosis, it actually made such a difference in their heat generation that they thought it was preferable. Further to that, I'm not sure it makes biochemical sense. I'll have to get a biochemist to tell me if this is crazy, but I think if your rate limit of entry into the mitochondria of fatty acids goes, is limited, and you still have fatty acids left over, even if they're long chain fatty acids, they'll begin to be burned in the peroxisome instead of in the mitochondria. And if I understand correctly, that results in even more uncoupling than ketosis. And so that could be a great selective advantage that wouldn't have any bearing on ketosis. And ketosis lowering would be just a side effect. One other thing from what you said, though, is obviously the thermic effect of protein is much higher than, so if you're comparing meat versus carbohydrate, that does kind of bring in another confounder. That's true. That's true. It was more deeply ketogenic too, but that's a really good point. Yeah. I just wanted to remark that chronic ketosis has to be defined because a population that eats a lot of protein will get out of ketosis and inco-ketosis, especially if they are fat adapted and also depending on how much protein there is in the animal that they hunt. So I think it's better to talk about chronic ketosis, but not 100% of the time in ketosis. I don't know if it makes any difference from a health point of view, but this is, in my opinion, what was prevalent throughout the Paleolithic, throughout the world, not just by... So it's in and out of ketosis on a daily basis. On a daily basis. On a daily basis. Yes. I can attest from my personal experience. If I eat a lot of protein, I get out of ketosis. In the morning, I'm ketosis. I think that's an excellent distinction to make. If you're eating a low-carb diet that's high in protein, right after you eat, you may well go out of ketosis, but the amount of time it takes to get back to that level that would take many days in a person on a high-carb diet of fasting, you and I, on our diets, would be back in that level after the post-absorptive phase within a day easily. And so maybe we're looking at percentage of time in ketosis and the level of ketosis all come into play when you're evaluating whether or not they're in ketosis, which really is a qualitative word. My questions were going to be also about the high protein, the context of a low-carb diet, but this has me thinking about when were they testing ketones on these populations? Was it immediately after they'd eaten? Was it, I know some of what was fast and so on, but, and then also bringing in Ben Bickman's research that he's most recently presented this year, right? In the context of a low-carb diet that high protein does not suppress ketosis, I know that several of us have been experimenting with that, me being one of those, and I can eat up to 180 grams of even lean protein like from fish and seafood and maintain my state of ketosis, even increasing that. So how that all fits into this picture is yet to be seen, right? That's a good point. Yes, the effective protein I think our understanding of it has been overly affected by high-carb or people with high blood glucose levels in the first place, and the glucagon to insulin ratio is going to be affected much to a much worse way if you have high blood glucose in the first place in a way that it wouldn't on a low-carb diet. Moreover, if you're looking at a diet that has taken all carbohydrate out instead of say, suppose you have a diet that has 25 grams of carbohydrate, because you know you can stay in ketosis that way, you can add less protein in that situation. If you take out those 25 grams, suddenly you have a lot more leeway before the insulin level is going to be reactive. Thank you for the talk. Last question. I was really looking forward to this talk and it's just sparked so many questions in my mind because I'm a First Nations ancestry from the west coast of British Columbia mixed with some European. And some of the data points that you had on one of the slides was showing some spots in an area called Metla Katla in the south end of Alaska. And my nation is a little way south from there, not very far. And along that coastal pathway all down the west coast, our diet traditionally has always been seafood, water-based, whatever we could get out of the ocean. But there was also more opportunity for plant gathering because as you go further and further south, the climate gets warmer and warmer and there's more plants. So I'm super curious if these variants, how far south they persist, where the seafood diet is still there, but then you start adding more carbohydrate-rich foods, especially in the summertime there's a lot of berries and stuff available. The other thing is a little bit of a tragic feeling from what you presented in terms of how the introduced foods have already clouded the picture very, very early when studies were being done like flour and bread in the 1800s. It was already starting. And we see, I belong to a chair, actually a committee called the Indigenous Women's Health Initiatives Committee for the Society of Obstetricians and Gynecologies of Canada. And we look at health outcomes and issues in Indigenous populations across Canada. In the Inuit, we still see of all of the Indigenous peoples who have and we all have higher infant mortality rates than mainstream Canadians, but in the Inuit they have the highest rate of infant mortality to this day. But one of the issues, like there's so many confounding issues because they also have the highest rate of maternal smoking and many other factors like that that might totally override whatever this variant might have. If this is at play somehow still, it's confounded by other things. But anyway, thank you so much for your talk. I found it fascinating. Thank you very much.