Mae'r mawn i'r ddedw i'n wneud o'ch dwais deall gwyllgo mwy diwethaf. Yn mwyn fwy ymddir i糾od trwy ddechrau y bydd amser a'r bobl mewn ymwneud yw'r gweld yn ll場. Mae'r bobl yn drefnol yw'r newid. Mae'r newid ddioletheol i wyg Dfosig ym Nifer. Dw i'n cymorth yw Nicola. Mae'r cymorth o bachurau bwysig yn cyllidol Jameson. Mae'n mynd i'n ddulig i gael ystod trefn ymddiol ystafell, can inform evolutionary biology and vice versa. In doing so we've tried to show that Native American mortality after European contact need not have derived from so-called differing immunities in a virgin soil, as scholars once argued. Rather we join recent scholarship by Jones, Kelton and others in emphasizing that contingent aspects of colonization, particularly the rupturing of inherited nutritional frameworks, were more than enough to destroy Native American populations. In order to make these arguments therefore we've had to consider very closely the myriad nutritional frameworks enjoyed by indigenous peoples in North America, including in regions such as the Pacific Northwest and Alaska, before European arrivals. In the case of Alaska, Russians were the first to arrive en masse in the 18th century and the aftermath was catastrophic. Among other things, we'd assumed that we would find evidence that indigenous communities in the region would have been in ketosis, at least much of the time, given what we read in the popular ancestral literature. But as we look more closely and consider their nutritional heritage and ecology in light of modern genetic studies, we became, I'd say, more agnostic on this issue and realized just how complex indigenous arctic metabolic science and history can be and how problematic blanket statements regarding assumed metabolic profiles are in this population or maybe even in any human population. So to explain why I believe this is to be the case, I'm going to survey the interaction between ecology and nutrition in the region from 21,000 years ago to the present. Different theories for the migration of indigenous people into North America via Alaska 21,000 years ago and the evolution of nutritional needs during that period. Why reasserting the centrality of the mega-3 fatty acid DHA versus saturated fat is important to understand both the insulin sensitivity and the pre-contact immunological health of indigenous Alaskan populations and what that might tell us more generally. Why the presence of DHA might be used to support the notion that communities might have been likely to spend much time in ketosis but also support a counterargument. How growing evidence of genetic adaptations to extreme cold environments in global communities ought to force us to question the notion that indigenous Alaskan people burn ketones primarily, making us consider instead the potential to oxidise fatty acids efficiently without entering the metabolic state of ketosis or at least as it's popularly defined. How historical and non-genetic factors such as the potential to convert animal tissue into glycogen may unsettle the notion of permanent ketosis in these communities. How ketosis from fasting, for example on long hunts, would possibly or even probably have been more likely to produce the metabolic state than via exogenous consumption of fats. And why, if we have enough time, we ought to consider the indigenous Arctic microbiome as another overlooked factor in health, including as it might have developed in relation to overlooked sources of plants and even starch sources popularly known in the field as resistant starch. I'd like to offer a very quick statement on the word eskimo in the context. I've always found the word problematic, as I guess some of you have as well, as do some indigenous peoples in and out the region. Other indigenous peoples in Alaska and beyond however prefer the term. Others prefer Inuit and it gets very complicated. But in fact what I'd really prefer to use is simply the term indigenous peoples in the Alaskan region to avoid any problems. So until recently scholars suggested that immigration onto a so-called bearing land bridge that many of us will have heard of, the area between the present day far eastern Siberia and Alaska, now covered by the bearing in Chukchi Seas, likely took place more than 13,500 years ago. The movement responded to the area having become gradually available due to lowered sea levels which followed the ice fixation of global fresh water supplies. The newer Beringian standstill hypothesis suggests that the region was actually populated for far longer than once assumed. Perhaps more than 21,000 years ago people, some scholars even say longer before the eventual migration of its population into Alaska and other regions of North America. Genetic studies have suggested some support for this hypothesis, highlighting what's termed a northern Pacific Rim genetic cluster, claiming that movements, at least into the far western part of the region, took place as early as 34,000 years ago or at least that movements from Siberia began as early as then. Now during this period, and there's a map of the region that we're talking about at this point, for thousands of years a so-called shrub tundra refugium provided the setting for hunted land mammals and woody plants to facilitate the burning of bones for fuel. So here we can see the traditional images that we're often familiar with, the kind of the megafauna some now extinct that we think from archeological and other evidence was in this region. So this is an ice age and we even have a lot of paleoart, something that I've just recently discovered, artists using anthropological archeological evidence and then kind of filling in the blanks with their pencils and paint to give us a picture as to what Beringia might have looked like. So all these images suggest the consumption of large mammals and in the popular literature at least you would suggest or assume there would be a lot of saturated fat consumption therein. But I'd also like to point out that DHA was perhaps more important from 21,000 years ago up until more recent history of the region. And so I'd like to kind of modify what some of us have come to think about the use of megafauna and fats and particularly saturated fats in that context. Several scholars, as we all know, these are not merely a few outliers, have hypothesized that DHA had an important role in cognitive development and some even say more controversially increasing brain size compared to earlier hominids during an overlooked so-called marine coastal stage of human evolution from around 200,000 to even 100,000 years ago. So very recent in our history and much later than that first important step that we all know about associated with the expense of tissue hypothesis, big brain, small gut and all of that. The literature on omega-3s remains relatively controversial, as I've said, though I personally find it quite convincing. Maybe just that I don't know enough about the field that I can sort of move from one to the other and find something convincing after reading a few papers, I guess. But I find it quite convincing. But the literature on the brain and the guts requirement of DHA, we all know, that's far less contentious. And this is why I wish to highlight the overlooked role of DHA in indigenous Alaskan history given the tendency to focus, at least popularly, on the consumption of saturated fats. Just as scholars once focused on the expense of tissue hypothesis, I've often ignored much later marine coastal stages of human development, including potentially of human cognition and immunological development in association with greater consumption of DHA before early humans left Africa, scholars of native American and proto-native American history have overlooked what is now being called the kelp highway or the kelp super highway, which is really another theory as to how the progenitors of native American populations got to North America. So without discounting the land bridge in the Bering Strait, scholars such as Erlundson particularly have suggested that the original pre-native American communities would have hopped over on various islands all the way from what's now, I guess you would call, coastal Alaska, some of the Aleutian islands, and then all the way to North America eventually getting to coastal California and before that Alaska as early as 21,000 or more years ago. So I've become increasingly interested in and convinced by aspects of this hypothesis proposed by Erlundson and others. So here are a few more of the relatively recent studies that are looking at this alternative theory for the coastal migration via marine-rich, DHA-rich, I guess you could also say iodine-rich nutritional frameworks that developed as these communities moved along. So we've even got the National Park Service who talks about a paleoarctic era from 12,000 years ago but even as early as 21,000, depending on who you talk to, when marine consumption was more important than one's thought. Of course we don't need to discount either of these hypotheses when we consider the role of DHA in wild animals. We all know from the earliest paleo literature in the 70s and 80s which some now discount, I say maybe a little bit unfairly, looking at wild animals having a higher proportion of DHA in relation to saturated fat. And so therefore whether you're eating mammals or marine animals on this other alternative coastal way of getting to North America, your DHA consumption will be higher than perhaps we've once thought. It's even worth noting for example this recent study which suggests that Inuit in Greenland who are related to but of course not entirely the same as indigenous communities in Alaska may have genetic and physiological adaptations to consuming a high DHA diet developed over several tens of thousands of years, including and encouraging them to maintain good insulin sensitivity. At least that's the factor that the authors of the study suggest is important to note. Work carried out by the Alaska Siberia project and other studies have suggested that the high consumption of DHA is linked to low blood pressure in these communities which are closely genetically related to those indigenous communities in Alaska. And glucose tolerance of course measures how efficient individuals could clear glucose from the blood with enhanced efficiency due to DHA among other things. So the studies detect an inverse relationship between fasting plasma glucose levels and plasma omega-3. But why should we care that DHA may encourage greater glucose tolerance in human populations more generally and among indigenous Alaskan communities more specifically? After all, aren't there a population that is archetypally high fat, low, or even close to zero carb? Given the presumed lack of plasma glucose in the population prehistorically, historically, and even in the present day among those who follow an ancestral diet, greater insulin sensitivity due to DHA or any other factor might not be as relevant as we might think. Some suggest, as many of us know, that ketosis in an animal meat-dominated diet is a tricky state to achieve. We've all seen people carrying their knobs of butter and their bits of avocado and MCT oils and so on to try and maintain ketosis. We know what the Mayo Clinic, as it originally, creates its own ketogenic diet. It was about isolating fats above all else. So this is tricky to do. So I would suggest that historical communities likely consume protein alongside fat, which might sometimes produce excess glucose from gluconeogenesis to the point where insulin secretion may be necessary. The body is never completely accurate and may overproduce glucose rather than excreting excess protein or using it in other ways. So the presence of DHA alongside saturated fat and other fats, I guess, might have made a ketotic state more likely in those who might otherwise have been, quote, knocked out of ketosis as people use that phrase by excess protein consumption. Or perhaps not, as we will see, as we examine the period of animal consumption from the period around 13,500 years ago until the field period of proto-eskimo culture to around AD 1,000 and even later in history, where we'll see that evidence suggests a greater variety of animals than those large mammals that have traditionally dominated the narrative, those woolly mammoths and strange North American rhinos and camels and all of that. Some especially smaller mammals, of course, are higher in protein than fat. Others higher in DHA, particularly when we take into account marine consumption, than saturated fats than once thought. Was this ever all high enough, in fact, to maintain regular ketosis, as it was suggested in the popular literature? And more specifically is ketosis likely in diets with a higher ratio of omega-3 fatty acids to saturated fats. Does the mix of polyunsaturated and saturated make a difference to the overall propensity? I don't know the answer to that question or indeed even really whether it's a question that, in fact, makes sense, but I just would throw that out there and there's definitely people in this room who would know much more about that than I do. But before we can even answer that question, we've got to enter that other conceptual hornet's nest. The historical prevalence of ketosis in indigenous communities, even if we assume that they did consume a relatively or even high fat diet. Was it the norm? Well, we know that ketosis from the burgeoning literature in scientific nutritional science is potentially extremely beneficial for neurological disorders. We know it's beneficial more generally in terms of general health, autoimmunity, even human longevity, keeping insulin down and all of that. But was it ever a metabolic state that would have been likely in these particular communities that we're talking about? Would it have been likely, as a metabolic state from exogenously consumed fats or more likely from fasting, which we'll get onto in a moment? Firstly, we need to consider the possibility of specific genetic adaptations to try and get to answering these questions associated with cold adaptation. Over 21,000 years ago, but even as early as 13,500 years ago, if that is a period of time that is indeed a... Some might argue it's too recent to allow adaptations, some might not. But various studies for cold adaptation in cold climates, northern climates, have shown, for example, in Greenland, Inuit, northern Japanese and Siberian communities, the potential for genetic adaptations, such as greater vascularity, dense networks of blood levels, short stature. Recent genome studies have identified mutations that may affect the proportion of fatty acids in the cell membranes in these populations, which in turn may affect growth hormone signaling. Contemporary northern Japanese populations, for example, have been shown to be able to burn more fatty acids the cold of the individual gets. And this has been mimicked by rats who are cold adapted in controlled experiments. The question to ask is, if cold adaptation in genetic ways is possible in northern communities around the world, including in a relatively short time period of 20,000 to 30,000 or less years, in extreme context that make natural selection or genetic drift more likely, we might then ask, were other adaptations possible or likely in these and other related communities, such as those in Alaska, including adaptations that may relate to a greater ability to oxidise fat for energy use without necessarily entering what we might call ketosis. The genetic adaptations to allow fat consumption without ketosis are unlikely to be prevalent if populations are found to be in the metabolic state when consuming their ancestral high fat diet. But as described in a set of characteristically lively and actually quite rigorous commentaries from Richard Nicolai, a number of studies have suggested they were not in ketosis. So this is Eskimo communities who studied, I don't like that word, in the early 20th century up until the 1970s. They were not necessarily found to show evidence for what we would think of as ketosis, metabolically, while consuming ancestral foods. Others, of course, have doubled down on their assertion that these communities are ketogenic par excellence, so let's consider these studies for ourselves. All early 20th century studies noted that the historical diet of Eskimos has consisted of meat, fish, a few carbs, and a few carbohydrates, sometimes none, to a greater extent than other global populations. Four to eight pounds of land mammal meat every day diet that's very low in carbs. The big study that people often refer to is by Peter Heindbecker studies on the metabolism of Eskimos, one study in 28, another related one in 31 and 32. Some might suggest that these studies were not rigorous or efficient enough to measure ketones in the way that we might today. However, the controls and methods were actually very well advanced, in my opinion. Not nearly amusing a keto strip here or there, but rigorous attempts to characterize the metabolism, controls, respiratory tents, and many other measurements to explore the metabolism in detail. Acetone, diacetic, and beta-hydroxybutyric acid was measured in the urine, following consumption of what was assured to be an ancestral native diet. This wasn't just epidemiology, without any intervening Western sources of carbs. Glucose levels, ketone blood levels measured, acetone levels measured in the breath. Respiratory quotients were also measured in the Heindbecker study and several others, representing the ratio with a volume of CO2 relative to that of oxygen consumed by an organism, tissue, or cell in a given time. And it gives kind of a rough estimation of the proportion of fat and carbs being oxidized. Heindbecker's results and conclusions suggested that the metabolism may have differed from that of non Eskimos. The levels of urinary ketones were lower than expected, suggesting only a mild level of ketosis. Glucose tolerance was found to be very good, also supporting the conclusion that subjects were only in a mild state, given that glucose tolerance is expected to decrease in the deeper state of ketosis. Though, of course, it can come back very quickly, as we know. It was suggested that the high protein content of the diet prevented ketosis, whether historically or during a present era, or even that fats could be converted to glucose. I know Chris Masterjohn once wrote an interesting piece that I've learned a lot from on that matter while trying to make sense of some of this stuff myself. They detected the presence of ketones during fasting, but at a lower level than found in non Eskimos. As a further control, higher levels were found in a woman who was breastfeeding, and in subsequent experiments, higher levels were found in seven day fasts. In another control of sorts, higher levels were found in a subject who was nursing and at the later stage of pregnancy, on days three and four of a fast. I had to reread that several times. Subjects were found to have had a lower respiratory quotient, the ratio of CO2 to oxygen, again, which is associated with the greater metabolism of fat in proportion to carbs. On fasting, the respiratory quotient of two out of three subjects was below that expected for the metabolism of fat in no carbs. Again, Heinebecher explained the low quotient as due to the formation of carbs from ingested fat, as well as protein potentially, the conversion of triglycerides to fat. From our analytical perspective, good tolerance of glucose suggests that indigenous Arctic communities have historically utilized a low carb rather than necessarily a ketogenic diet. Though, of course, populations such as the Hadza can also demonstrate good insulin sensitivity with a relatively high carb diet, cure rolling eyes of some, that the Hadza are being trotted out again, but just that bears noting. Studies in 1972, this is a different study by Ho, measuring ketone levels in the urine of what we're referred to at the time as Eskimos, using the strip paper technique, and in the breath also found no evidence of ketosis. The study stated that carbohydrate accounted for 15 to 20% of calories, largely in the form of glycogen in their interpretation from starches in frozen or raw animal meat. Candidate with 15 to 20% carbs be ketogenic. Perhaps not the more research needed. We need to take into account how much exercise people were doing and all of that. But other studies have corroborated behind Becker and Ho conclusions. So let's explore a little bit more as to what this might mean. Consider two explanations in further detail. Potential genetic factors and that indigenous Arctic diet and food preparation. Recent genetic research suggests that Inuit in Canada may have adapted to high levels of nutritional fatty acids by a mutation that limits ketone body production while still allowing a high level of fatty acid oxidation. And so Alaskan indigenous peoples might enjoy similar mutations, just a hypothesis, thereby explaining how they could be eating a high fat diet without necessarily measuring high ketones, at least as shown by the studies detailed so far. So to repeat, this is defined as a mutation that stops individuals whose nutritional profile might otherwise be expected to push them into ketosis. And it's been suggested that some northern Japanese communities may have similar mutations. Other genome-wide scans of Siberians, Greenland Inuit and Canadian Inuit, again related to Arctic Ashkimo, Arctic indigenous peoples, show the potential for genes increasing the rate and efficiency of fatty acid oxidation as opposed to ketosis per se. Now the authors suggest a selective advantage may be the protection of Inuit against high ketone levels. However, more research is needed to test that hypothesis and of course such a claim might of course be biased by suppositions that ketosis itself might be somehow problematic going back to all those studies that conflate ketosis with ketoacidosis and so on. But still there ought to be much food for thought here. I know Sarah Ballentine has recently discussed some of these studies. So let us return to some, here's some of the more studies that mention this as well. But let's return to some non-genetic factors that may have prevented or at least reduced the level of ketosis. Ho and others have suggested a low level of atherosclerosis and a high total cholesterol in the 70s and 80s in another set of studies. At this point this was suggested to be a paradox but like many of these paradoxes like the French paradox it's possibly not a paradox at all but more akin to what we might call an anti-inflammatory, low-ish carb diet but not necessarily one in ketosis and thus one which might be good for heart health. Secondly, as Nicolae and others have pointed out in reference to a number of studies there's always that overlooked potential for a relatively high glycogen content from carbs often described in the early 20th century quite quaintly but I like it as animal starch in raw or frozen meat sources. Now some might say that these substances will quickly degrade to lactic acid but when raw or frozen this may be less likely to take place and so therefore glycogen in these forms may have been consumed to a greater extent than we've previously thought. There's also a relatively high glycogen content of whale blubber for those who are interested and this goes back to several studies going back to the early 20th century. So again whale blubber itself which is sometimes dominated the literature on high fat consumption may actually have had more glycogen than thought. Some historical accounts also suggest that blubber itself was consumed far less in Alaska going back several hundreds of years in even thousands of years some suggested based on ethnographic and other data it was consumed less because it was used as a fuel to make fire rather than eaten itself. Also we should think about the potential role of these things called glycans. Again many in the room will know a lot more about their exact biochemical makeup than I do but we can call them as something akin to a resistant starch that are in animal tissue and again which when consumed may tell us more about the consumption of what some would call resistant starch than solely the consumption of fatty acids. There's the slide on those marine blubber also consumed less than thought. So there are some takeaways so far I won't go into them because they're a bit push for time but I've just been thinking recently about some insights from Altafani one of his posts where he says ketosis possibly more likely in any global historical community from what you don't eat than what you do eat. That is possibly something that we should think about when thinking about indigenous arctic peoples or indeed any indigenous people in North America or anyone from what we know about histories, ethnographies, anthropologies. So not necessarily fixed time for meals, long hunts, people waiting while hunts are going on. So long periods of what we would call fasting or intermittent fasting rather than necessarily ketosis from exogenous consumption. Of course this is all very extremely difficult to measure historically anthropologically but it's just something that we should all try and is worth thinking about. In the last four or five minutes, moving beyond, I think it's important perhaps to move beyond animal protein, hit some more, I guess we call hot button issues, the way I describe them might be a bit crude, may irritate some people but there we are, there's some nice slides of some plants that we can find coming up for those who want something to look forward to. Resistance starch and what we might call the indigenous microbiome in Alaska. We need to think about that perhaps a bit more or even a lot more rather than necessarily being obsessed with whether or not these communities were or not in ketosis and rather than just being solely obsessed with their fat consumption above all else. We know from a substantial ethnobotanical literature, so it's a literature looking at what is consumed in indigenous Arctic communities and making sure to ascertain that that reflects that which they consumed before European contact using various other forms of evidence to try and show us that this goes back hundreds if not in many more years than that, there were plant sources that were consumed that we've often forgotten and that we've tended to forget, some of which, as we'll see, are a potentially good form of resistant starch, i.e. that which produces short chain fatty acids in the healthy microbiome might not necessarily only have been produced via glycans consumed from meat but also potentially via the consumption of these overlooked plants in Alaska alongside a very high fat, high protein diet. Here is some Indian celery in the interior Alaskan region. Here's some Indian celery, Arctic dark, Alaskan willow, alpine sweet veg. Some of these are leafy plants. Some of them have got tubers that contain inulin. We should also think about tree in a bark and the carbohydrate in lichens, partially digested in animal stomachs as well as seaweed that were eaten. There's quite a lot of ethnographic evidence for the prized consumption of lichens from within, say, a caribou stomach alongside seaweed and there's a longer statement on that for us all to read in our own time. Here's some more on the edible plants of the Arctic and more on a study on the vitamin content of lichens. We should also think about a preserved skeleton from around 600 years ago in the St. Elias Mountains in BC. Estimated to be up to 600 years old, thought to have moved from Alaska to the indigenous interior, the young man was found with preserved herbaceous items, mountain sweets, Sicily, these very poetic sounding plants that are thought to have eaten. Needles of mountain hemlock and a large proportion of channel pod pollen in stomach samples thought to be the edible perennial glasswort alongside evidence of crab and salmon also traced to the bodies as 600 years ago. So here we have plants and alongside animal products, particularly those high in DHA. Historical traveller accounts have also talked about fat and protein combined with plant materials and these are accounts that precede the arrival of Russians and others in the mid to later part of the 18th century which is often thought to be the quote contact period for European indigenous peoples, even a kind of pemican made from dried caribou meat with several berries and herbs. I know a lot of people often complain that pemican, as it's made for the public market, is always combined with berries and high fructose fruity things but it's a lot more indigenous than some might actually say. And so just in the last minute, should that resistant starch debate come to Alaska, maybe particularly when we think about wood fern, rice root, sweet veg, all of these, many of these I should say, contain Inuit and oligofructose, so non-fermentable carbs that could be acting as a prebiotic and there's some general stuff on the potentially positive effects of Inuit. Some more stuff here that we don't have time to get into on the Pacific Northwest, corn and tuber consumption, wild potatoes and how it was particularly used in a way that we would define as resistant starch. We know that these substances can help the microbiome potentially. And we also know that Native American communities elsewhere in North America were often founded on what are called big acorn complexes, so ground up acorn powders. You can now find that at HMAR and other Asian food stores for those who wish to consume ground acorn powder as a kind of resistant starch. The question that we need to ask ourselves is were similar forms of resistant starch consumed in a way that we've completely overlooked in the Alaskan interior? We know they were in the Pacific Northwest but does the evidence that we have for the consumption of these plants which include corn, tubers and so forth, rhizomes, did this complement the consumption of fats and proteins, make those more digestible, I guess you could say, as well as enhancing indigenous immunity so that when the Europeans arrive with all their diseases and as your nutritional framework is threatened, it is going to be a double whammy. You're going to have all your good proteins, a good DHA, your relatively high consumption of saturated fats, that's all going to be destroyed but also might be, what also might be destroyed is your ability and availability of sources of RS. Put it all together and you have a kind of an ancestral diet that itself will be destroyed, thus lowering your immunity even before you talk about differing immunities and so on. So some conclusions, DHA more important than thought nutritionally including an insulin sensitivity, communities not necessarily historically in ketosis, we need to think about genetic differences, glycogen in frozen raw meat, if keto perhaps more likely from fasting then exogenously and the need to think about potential RS and carb sources in the region but whatever we say, European disruption destroys these ancestral nutritional frameworks, reduces immunity and can be an important factor to account for extensive loss of lice and this is just something I found a couple of weeks ago. It's indigenous peoples in Alaska are now at the forefront of a new fight I guess against farmed salmon but I won't get into that but DHA important. Thank you for listening to all of this. Sorry I had to breathe through it so quickly. We have about five minutes for questions. If anybody does have a question you can move over to that microphone if you're on that side and if you're on this side I can bring the microphone to you. Hello Gideon, thank you for your talk and for bringing up many of these controversial points that I think are important to discuss. I take issue with some of them but I think the crux of my, what I think is important to distinguish is the level of ketosis that we're talking about. Does mild ketosis count as ketosis when you're talking about somebody who is in a weight stable position? I feel we're to go by the levels of ketosis that I reach at a weight stable zero carbohydrate diet. I would never reach the levels where the kind of detection methods that they were using in the papers back then would have been able to detect particularly if it's just acetoacetate which is about one quarter, one fifth of the amount that beta hydroxybutyrate would reach. And so I guess what I would ask is how are we defining ketosis and if we were to define it as a lower keto adapted state would your conclusions be different? Yes I guess they would be and your question and greater knowledge of this top on this issue goes to show that we need a large scale I guess you could say meta-analysis taking into account history and evolutionary biology taking indigenous Arctic communities into account because they've been used and misused in so many respects. As far as differentiating between I guess what you could call mild and deep ketosis I only go by that Heimbecker study and the others and the way that they use controls. I guess the problem with what you might say with some of their controls is is the metabolic state different from that which is induced by not eating stuff as opposed to that which is induced from eating stuff that's a question that I'm sure opens up a whole can of worms many which I wouldn't possibly myself be able to comment much on but I would say yeah I go by those controls that Heimbecker used which is to say they did detect ketones in the way that they detect them from fasting or in other states and they also use controls in other populations who ate a higher fat diet but they just didn't find it among those who were in ketosis. I guess another thing to add to that might be of course I would also suggest that the ability to measure ketones might be contingent upon the metabolic state so far as to say that the ketones might have been used already before they've even been measured I know that's something that many nutritionists and scientists are looking at right now as we speak as to whether or not when you have a very high fat diet would that mean that your metabolism is such that those ketones are going to be burned basically too quick for you to detect in a way that you would detect it in other ways but yeah it needs to be more of a wide scale analysis taking into account all these contingent factors of measurement and so on and so forth. We have time for just one more question. Thank you for your very interesting talk. I had trouble following your argument around CPT-1 so my understanding of biochemistry is CPT-1 allows fatty acids to get into the mitochondria whereas which is where they undergo beta-oxidation which is what leads to ketogenesis. So I was confused first of all about whether the mutation decreases CPT-1 or increases it. If it decreases it, it should allow more beta-oxidation more ketogenesis. If it decreases it, it should allow less beta-oxidation and less ketogenesis. How would the mutation either way lead to less ketogenesis and more efficient beta-oxidation? Yeah with my head spinning I would say that consult my research partner on this who is much more familiar with the scientific terminology and the various what you might even call counterintuitive ways that you can understand how these mutations work. Going back to this, going back to the study from the way that I read it, the enzyme is quote the major rate limiting enzyme for long chain fatty acid oxidation. It's the transporter that allows fatty acids into the mitochondria through the inner mitochondrial membrane. What I took it, the authors see it as a defect in fatty acid oxidation. Oh well so where I first read about this was in my textbook on inborn errors of metabolism where it's regarded as something that stops you from oxidizing fatty acids at all and as far as I know from that textbook this is the only example of an inborn error of metabolism that is ever fully penetrated into a population. So I haven't studied it directly. My impression was that it was a fatty acid oxidation disorder like the authors of the paper you just cited said it was. But you're saying differently. From how I interpreted it, the fatty acid oxidation disorder somehow reduces, goes hand in hand with the potential reduction of the measured ketones at the same time. Well right, because if you can oxidize fatty acids you can't make ketones. Yeah, that's the point. Nobody's really been able to answer that. I mean you cited other data saying they're doing other things with fat like turning it into glucose and stuff like that. I don't know, I mean that kind of makes sense to me.  I guess with the earlier 20th century studies would say they're going to possibly be getting even glycogen from fat going back some of the stuff that you've written about. That part of it does make sense. Thank you for your time, I appreciate it. Thank you Dr Gideon-Mailer.


Everyone, welcome back to theCUBE's Unstoppable Domains Partner Showcase. I'm John Furrier, host of theCUBE. This segment and this session is about expansion into Asia Pacific and Europe for Unstoppable Domains. It's a hot startup in the Web3 area. Really creating a new innovation around NFTs, crypto, single sign-on, and digital identity, giving users the power like they should. We've got two great guests, Ajad Rahman, head of Europe, and Neal Kanth, owner's Neal, I.R. head of Asia. So, Ajad Neal, welcome to this Cube and let's talk about the expansion. It's not really expansion, the global economy is a global, but showcase here about Unstoppable is going to Europe. Thanks for coming on. Thanks, John, for inviting us. So, we're living in a global world, obviously crypto, blockchain, decentralized applications. You're starting to see mainstream adoption, which means the shift is happening. There are more apps coming and it means more infrastructure and things got to get easier, right? So, reduce the steps it takes to do stuff, make the wallets better, give people more secure access and control of the day. This is what Unstoppable is all about.  What is the potential of Web 3 with Unstoppable and in general in Asia and in Europe? I can go first. So, let's look at the Asia market. I mean, typically we see the US market, the Europe markets for typical Web 2.0 software and infrastructure is definitely the larger markets with US typically accounting for about 60% and Europe about 20 to 30% and Asia has always been small. But we see in this whole world of blockchain, crypto, Web 3.0, Asia already has about 160 million users. They have more than 35 local exchanges. And if you really look at the number of countries in terms of the rate of adoption, many of the Asian countries which probably you would have never even heard of like Vietnam actually topping the list, right? One of the reasons that this is happening again, if you go through the Asian Development Bank's latest report, you have these Gen Zs and millennials, that's 50% of the Asian population. And if you really look at 50% of the Asian population, that's 1.1 billion people out of the total 1.8 billion Gen Z and millennials that you have in the world. And these folks are digital native. Their people, in fact, the Gen Zs are mobile first and millennials, many of us like myself at least are people who are digital. And 20% of the world's economy is currently digital. And the rest, 40 to 50% which is going to happen, it's going to happen in the Web 3.0 world. And that's going to be driven by millennials and Gen Zs. I think that's why this whole space is so exciting because it's being driven by the users, by the new generation. I mean, that's my broad part on this whole thing. Before we get to the side, I want to just comment on Asia also and the other areas where mobile first came, you had to end the younger demographics, absolutely driving the change because they're like, well, I don't want the old way. They go right from scratch at the beginning, they're using the technologies. That has propelled the crypto world. I mean, that is absolutely true. Everyone's kind of seeing that. And that's now influencing some of these developer nations like say in Europe, for instance, and even North America, I think Europe's more advanced than North America, in my opinion, but we'll get to that. So potential in Europe. Sajad, can you take us through your thoughts on as head of Europe for a while? Absolutely. So news right, I think Asia's way ahead in terms of Gen Z user adopting crypto. Europe is actually a distant second, but it's surprising to note that Europe actually has the highest transaction activity in crypto over the last year and a half. And if you dig a bit deeper, I'd say arguably for Europe, I think the opportunity in web-free is perhaps the largest and perhaps it can mean the most for Europe. Europe for the last decade has been trailing behind Asia and North America when it comes to birthing unicorns. And I think web-free can provide a step-change opportunity. This belief for me stems from the fact that Europe's policy, right? Like for example, GDPR is focused on enabling user data ownership. And I think I recently read a very good paper out of Stanford by Patrick Henson. They speak for web-free being the best pathway for Europe enabling traditional sovereignty. So what that means is users control the data, they bring to the internet and they harness the value from it. And on one hand, while Europe is enabling that regulation, that could bring that forth, web-free actually brings it into action. So I think with more enablement, better regulation and we'll see more hubs like the crypto valley in Switzerland pop-up that will bring, I think, and I became able to say not over-regulation, the right regulation, we can expect more influence of capital, more builder talent that then drives more adoption. So I think the prospects for Europe in terms of usage, as well as builders are quite right. Yeah, and I think also you guys are in areas where the cultural shift is so dramatic. You mentioned Asia, the demographics. Even the entrepreneurial culture in Europe right now is booming. You look at all the venture-backed startups and the young generation building companies, again, cloud computing is a big part of that, as obviously, but compared to the United States, you go back 15 years ago, Europe was way behind on the startup scene. Now it's booming and pumping on all cylinders and kind of points at this cultural shift. It's almost like a generational, it's like the digital hippies changing the world. They're web three, I don't want to be web two. Web two is so old, I don't want to do that. And then it's all because it's changing, right? And there are things inadequate with web two on the naming system. Also the arbitrage around fake information, bots, users being manipulated, and also, you know, merchandise and monetize through these portals. That's kind of ending. So talk about the dynamic of web two, three at those areas. You've got users and you've got companies who build applications, they're going to shift and be forced, in our opinion, and you want to get your reaction to that. Do you think applications are going to have to be web three or users will reject them? Yeah, I think I'll jump in and I'm not to hear a news port. I think the web three is built on few principles, right? There's decentralization, worship, and composability. And I think these are not binary. So, you know, if I look further on the future, I don't see a future where you have just web three. I think there's going to be a coexistence of cooperation between web two companies, web three and the deep bridges. I think there's going to be, there's a sliding scale to decentralization versus centralization, similarly, you know, ownership. And I think users will find what works best for them in different contexts. I think what unstoppable is doing is essentially providing the identity system for web three. And that's way more powerful when it comes being built on the options than the naming system we had for web three, right? The identity system can serve the purpose of taking a user's personal identifier as your blockchain domain name and attaching all kinds of attributes that define who you are both in the physical and digital world and filling out information that you can transact on the basis of. And I think the users would, as we go to a no-port and no-port future, right? Where, you know, in web two, more of the users were essentially consumers or readers of the internet. And in web three, with more low-port and no-port technology platforms taking shape and getting proliferation, you would see more users being actually writers, publishers, and developers on the internet. And they would value owning their data and to harness the most amount of value from them. So I think that's the powerful concept. And I think that's the future I see that web three, where web three will dominate. Neil, what do you think? Well, I think you put it very, very nicely. I think you covered most of the points. But I'm seeing a lot of different things that are happening in the ground. I think a lot of the governments, a lot of the web two dot zero players, the traditional banks, these guys are not sitting quiet on the blockchain space. There are a lot of pilots happening in the blockchain space, right?  I mean, one of the biggest example is in my home state of Maharashtra in Mumbai is, they actually partnered with Polygon Matic, right? They actually built a private blockchain-based capability to kind of deliver your COVID vaccination certificates with the QR code, right? And that's the only way they could deliver that kind of volumes in that short of time with the kind of user control, the user control the user has on the data, that could only be possible because of blockchain. Of course, it's still private because it's healthcare data. They still want to keep it something that's not fully on a blockchain. That is something. Similarly, there is a consortium of about nine banks who have actually been trying to work on making things like remittances or, you know, trade finance much, much easier. I mean, remittances through a traditional web two dot zero world is very, very costly. And especially in the Asian countries, but a lot of people from Southeast Asia work across the world and send back money home. It's a very costly and a time-taking affair. So they have actually partnered and built a blockchain based capability. Again, in a pilot stage to kind of reduce the transaction costs. Like for example, if you just look at the trade finance space where there are 40 million traders who do 2.45 trillion dollars of transaction, they were able to actually reduce the time that it takes from eight to nine days to about two to three days. So to add on to what you're saying, I think these two worlds are going to meet and meet very soon. And when they meet, what they need is a single digital identity, a human readable way of being able to send and receive and do commerce. I think that's where I see unstoppable domains, very nicely positioned to be able to integrate these two worlds. So that's, that's my thought on that. That was a great point. I was going to get into which industries and kind of what areas to see in your, in geographies, but that's a good point about saving time. I like how you brought that up because in these new waves, you either got to reduce the steps that takes to do something or save time, make it easy. And these are the, this is the success for formula in anything, whether it's an app or UI or whatever. But what specifically are they doing in your areas? And what about unstoppable, how they attract it to? Is it because of the identity? Is it because of the, the apps? Is it because of the single sign-on? What is that? What is the reason that they're leaning in and unpacking this further into their pilots? Sajat, do you want to take that? Yeah. I have a piece out there. So I think, and let me clarify the question, John, you're talking about where two companies looking to partner and solve potential partnerships, right? Yeah, what are they seeing? And what are they seeing as the value that the pilots we heard from Neil Kanath around the financial industry? I think obviously gaming is one that's obvious, huge. Financial, healthcare. I mean, these are obviously verticals that are going to be heavily impacted in a positive way. What are they seeing as the value? What's getting them motivated to do these pilots? Why are they jumping in with both feet, if you will, on these projects? Is it because it's saving money? Is it time or both? Is it ease of use? Is it the users' expectations? Trying to tease out how you guys see that evolving. Yeah. I think the space as the movement is going very fast, but I think the space is still young. And right now, a lot of these companies are seeking the potential that Web3 offers. And I think the key dimensions, like possibility, decentralization, ownership. So I think the key thing I'm seeing in EU is these Web2 companies seeing the momentum and looking to harness that by enabling bridges to Web3. One of the key friends in Europe has been fintech. I think over the last five to six years we'll have the Revolute N26 eToro, creating platforms, new banks and super finance, super apps rising to the forefront. And they are all enabling or so connected and bridge with Web3 in some shape and form. Either any of them creating a crypto, some are launching their own native wallets. And these are essentially ways that they can want to track users. So the Gen Z who are looking for more frictional finance to get them on board, but also to look to enable more adoption by their own users who are not using these services that potentially create new revenue streams and create allocation of capital that they could not have access to otherwise. So I think that's one friend I'm seeing over here. I think the other key trend in Europe at least has been games and again, that links to a dimension of Web3 that is called the metaverse. So a lot of game companies are looking to step into game file, which is a game completely different business model to what traditional game companies use to use. Similarly, metaverse is where game ownership creates a different business model. And they see that users and gamers of the future would want to engage with that versus just being monetized on the basis of friction or ads. And I think that's something that they're becoming aware of and will quickly in the space of launching your metaverses or game by applications or creating in probability with these employees applications. You know, I wanted to get into this point, but I was going to ask about the community empowerment piece of this equation, because digital identity is about the user's identity, which implies they're part of a community. Web3 is very community centric, but you mentioned gaming. I mean, people who have been watching the gaming world like ourselves know that communities and marketplaces have been very active for years, many years, over 15 years, community games, currency, in-game activity has been out there, right? But siloed within the games themselves. So now it seems that that paradigm is coming in and empowering all communities. Is this something that you guys see and agree with? And if so, what's different about that? How are our communities being empowered? I guess that's the question. Yeah, I can maybe take that to that. So, I mean, I was so hard of actually infinity. 40% of their user base is in Vietnam and the average earning that a person makes in a month out of playing this game is more than the national daily or minimum wage that is there, right? So that's the kind of potential. Actually, going back as a combination of actually answering your earlier question and I think over and above what Sajat said, what's very unique in Asia is we still have a lot of unbanked people, right? So if you really look at the total unbanked population of the world, it's 1.6 billion and 24% of that is in Asia. So almost 375 million people are in Asia. So these are people who do not have access to finance or credit. So the whole idea is how do we get these people onto a banking system, onto peer-to-peer lending or peer-to-peer finance kind of capabilities? I think, again, unstoppable domains kind of helps in that. If you just look at the pure Web 3.0 world and the complex technical way in which money or other crypto is transferred from one wallet to the other, it's very difficult for an unbanked person who probably cannot even do basic communication, cannot read and write to actually be able to do it. But something that's very human-readable, something that's very easy for him to understand, something that's visual, something that he can see on his mobile with a 2G network. We are not talking of, the world is talking about 5G, but there are parts of Asia which are still using 2G and 2.5G kind of network, right? So I think that's one key use case. I think the banks are trying to solve because for them, this is a whole new customer segment and sorry, I actually went back a little bit to your earlier question, but coming back to this whole community building, right? So on March 8th, we're launching something called as Women of Web 3.0, that is Wow 3. This is basically to again empower. So if you again look at Asia, women need a lot of training, they need a lot of enablement for them to be able to leverage the power of Web 3.0. I know I can talk about India because being from India, a lot of the women do not, they do all the small businesses, but the money is taken by middlemen or taken by their husbands. With Web 3.0, fundamentally the money comes to them because that's what they use to educate their children. And it's the same thing in a lot of other Southeast Asian countries as well. I think it's very important to build those communities or communities of women entrepreneurs. I think this is a big opportunity to really get the section of society which probably will take 10 more years if we go through the normal Web 1 to Web 2.0 progression where the power is with corporations and not with the individuals. And that's a great announcement by the way you mentioned the $10 million where the domains being issued out for, this is democratization is what it's all about. Again, this is a new revolution. I mean, this is a new thing.  So they need the wallets. So let's get to the real meat here. You guys are in the territory of Europe and Asia where there's a lot of wallets, there's a lot of changes because they're not in the United States, there's a few of them there, but most of them outside the United States and you got a lot of de-apps developing, decentralized applications. So you've got all this coming together in your territory. What's the strategy? How are you going to attack that? You got the wallets, you got the exchanges and you got de-applications, de-apps. Yeah, I'm having a different day of worst passing. So I think, just quickly there, I think one point is, and Neil really expressed beautifully, is the financial inclusion. That is something that has inspired me how Web3 can make Internet more inclusive. That inspired my move here. Yeah, I think for us, I think when we're at the very start, when it comes to Europe, right? And the key focus in terms of our approach in Europe would be that we want to do two things. One, we want to increase the utility of these domain games. And the second thing is we want to write collaboration with our partners. So when I speak about utility, I think utility is when you have a universal identifier, which is a domain name, and then you have these attributes around it, right? What that defines your identity. So in the context in Europe, you would look to find partners who help us enrich that identity around the domain name and that adds value for users in terms of acquiring these domains in new places. And on the other end when it comes to proliferation, I think it's about working with all those crypto and crypto and Web3 participants as well as Web3 adjacent companies, brands, services, who can help us educate current and future and upcoming Web3 users about the utility of domain names and help us onboard them to the decent like Internet. So I think that's going to be a general focus. I think the key is that as hopefully we have one overarching regulation in the EU that allows us to do this at a regional level, but at the outset, I think it's going to be tackling it country by country, identifying countries where there's deeper penetration for Web3 and then making sure that we are partnering with local trusted partners that are already venting for local communities there. So yeah, that's my view. I think please do that once in court. I think, yeah. So again, in Asia, one is you have a significant part of humanity living in Asia, right? So obviously, all the other challenges and the opportunities that we talk about, I think the first area of focus would be educating the people on the massive opportunity that they have. And if you're able to get them in early, I think it's great for them as well, right? Because by the time governments, regulations, large banking financial companies move, but if you can get the larger population into this whole space, it's good for them. So they are first movers in that space. I think we're doing a lot of things on this worldwide. I think we've done more than a hundred podcasts, just educating people on what is Web3.0, what are NFT domains, what is DeFi and so on and so forth. I think it would need some bit of localization, customization in Asia, given that, you know, India itself has about 22 languages and then there are the other countries, each of them with their own local languages and syntax semantics and all those things, right? So I think that that is very important to be able to disseminate the knowledge, although it's global, but I think to get the grassroots people to understand the opportunity, I think it would need some amount of work there. I think also building communities, I think John, you talked about communities, so did Sajat talk about communities. I think it's very important to build communities because communities create ideation. It talks about people share their challenges so that people don't repeat the same mistakes. So I think it's very important to build communities based on interest. I think we all know in the technology world, you can build communities around Telegram, Telegram, Discord, Twitter spaces and all those things. But again, when we're talking of financial inclusion, we're talking of a different kind of community building. I think that that would be important. And then of course I will kind of primarily from a company perspective, I think getting the 35 odd exchanges in Asia, the wallets to partner with us, just as an example, MATIC, they had till September of last year about 3,500 apps. In just one quarter, it doubled to 7,000 dApps on their platform. But that is the pace or the speed of innovation that we are seeing on this whole 3.0 space. I think it's very important to get those key partners who are developing those dApps, see the power of single sign-on, having a human readable digital identity, being able to seamlessly transfer your assets, digital assets across multiple cryptos, across multiple NFT marketplaces and so on and so forth. And I think the whole community thing too is also you see the communities being part of, certainly in the entertainment area and the artistry creator world, the users are part of the community, they own it too. So it goes both ways, but this brings up the marketplace too as well, because you guys have the opportunity to have trust built into the software layer. So now you can keep the reputation data. You can be anonymous, but it's trustworthy versus bots, which we all know bots can be killed and then started again with, and no one knows the time long it's been around. So the whole inadequacy of Web 2, which is just growing pains, right? This is what evolution looks like, next abstraction layer. So I love that vibe. How advanced do you think that thinking is where people are saying, hey, we need this abstraction layer, we need this digital identity, we need to start expanding our application so that the users can move across these and break down those silos where the data is. Because this is like the nerd problem, right? It's the data silos that are holding it back. What's your guys reaction to that? The killing the silos and making it horizontally scalable? I think it's a nerd problem. It is a problem of people who understand technology. It's a problem of a lot of the people in the business who want to compete effectively against those giants which are holding all the data. So I think those are the people who will innovate and move. Again, coming back to financial inclusion, coming back to the unbanked, those guys just want to do their business. They want to live their daily life. I think that's not where you will see, you will see innovation in a different form, but they're not going to disrupt the disruptors. I think that would be the people, you know, fintechs. I think they would be the first to move on to something like that. I mean, that's my humble opinion. Suggest. Yeah, I think... Go ahead. Absolutely. I mean, I touch on creators, right? So, and like I said earlier, right? We are heading for a future where more people will be creators on the internet, whether you're publishing, writing something, you're creating video content. And that means that the data they own, because that's their data, they bring it to the internet, that's more powerful, more useful, and they should be able to transact on that basis. So I think people are recognizing that and they will increasingly look to do so. And as they do that, they would want these systems that enable them to hold permissions with data. They would want to be able to control what the permission and what they want to provide for that. And at the end of the day, these applications have to work backwards from customers and keep the customers looking for that and that's where they would build. The users want freedom. They want to be able to be connected and not be restricted. They want to freely move around the global internet and do whatever they want with the friends and apps that they want to consume and not feel arbitraged. They don't want to feel like they're kind of nailed into a walled garden and stuck there and having to come back. It's the new normal. They don't want to be the product. They don't want to be the product. Gentlemen, great to have you on. Great conversation. We're going to continue this later. Certainly want to keep the updates coming. You guys are in a very hot area in Europe and Asia-Pacific. That's where a lot of the action is happening. We see the entrepreneurial activity, the business transformation, certainly with the new paradigm shift and this big wave that's coming. It's here, it's mainstream. Thanks for coming on and sharing your insights. Appreciate it. Thanks John, thanks for the opportunity. Have a good day. Great conversation. All the action is moving and happening real fast. This is theCUBE, Unstoppable Domains, partner showcase with, I'm John Furrier, your host. Thanks for watching.


What's going on everybody my name is John Hammond and this weekend Saturday and Sunday June 22nd 23rd Google CTF is happening and to hype up for the competition I participated in a race to solve reverse engineering challenge with live overflow, Xanad, Mermis CTF and myself. I don't know who won the race but you can go check out the video or it's all playing side-by-side it's super cool it's on the reverse IT YouTube channel there's a link in the description and on the video right here so if you'd like to go check it out please do you can hang out with all those cool people in my discord server link in the description and play with us Google CTF this kind of weekend June 27 23rd it's gonna be awesome let's get ready to play