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From Wikipedia, the free encyclopedia

Robert Hinde
Born (1923-10-26)26 October 1923
Norwich, England
Died 23 December 2016(2016-12-23) (aged 93)
Citizenship British
Alma mater
Awards
Scientific career
Fields
Institutions University of Cambridge
Thesis A comparative behaviour study of the Paridae (1951)
Doctoral advisor David Lack
Doctoral students
Influences Niko Tinbergen

Robert Aubrey Hinde CBE FRS FBA /hnd/ (26 October 1923 – 23 December 2016) was a British zoologist, the Emeritus Royal Society Research Professor of Zoology at the University of Cambridge.[1]

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  • Anthropogeny and Medicine-Human-Specific Diseases; Heart Disease; Inflammation and Disease
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  • अल्बर्ट आइंस्टीन के गज़ब रोचक तथ्य Albert Einsteine Facts in Hindi

Transcription

- [Announcer] This UCSD-TV program is presented by University of California Television. Like what you learn? Visit our website, or follow us on Facebook and Twitter to keep up with the latest programs. (classical music) - [Narrator] We are the paradoxical ape, bipedal, naked, large-brained, long the master of fire, tools and language, but still trying to understand ourselves. Aware that death is inevitable, yet filled with optimism. We grow up slowly. We hand down knowledge. We empathize and deceive. We shape the future from our shared understanding of the past. Carta brings together experts from diverse disciplines to exchange insights on who we are and how we got here. An exploration made possible by the generosity of humans like you. (mellow piano music) - I'd like to begin by acknowledging and appreciating the talk that I just heard, which really emphasized this, that animals and humans can get the same diseases and yet physicians and veterinarians rarely consult with one another, and that human and non-human animal commonalities can be used to diagnose, threat, and heal patients of all species. And I also would like to acknowledge that this comes as Barbara pointed out from a long lineage that goes back to Oslo, and one of those steps along the way was one of our own here, Kurt Benirschke, unfortunately couldn't be here because of an illness, the founding director of CRESZS and professor of pathology here who really emphasized one medicine. I'd like to flip the coin around, and science has always two sides to every coin, and say, are there human-specific diseases? What we've been hearing about is the evolutionary biology and diseases of a large variety of animals, mostly warm-blooded social animals, vertebrates, and you can see an entire lineage here. Let's zoom in on the group that we belong to, primates, and zoom in further, and among these primates we have new-world monkeys, old-world monkeys, gibbons, various so-called great apes, and then us, humans. If we zoom in further here, we can see that we shared common ancestors with orangutans, gorillas, chimpanzees, bonobos just a very short time ago in evolutionary time. And here's another way to look at it. In millions of years before present, there's certainly some discussion about the time frame, but the very important point to make here is that while we classified all these species as great apes, the main difference between chimpanzees and bonobos is less than 1% of their amino acid sequence level. In fact, we are closer to bonobos and chimpanzees than they are to gorillas. In fact, we are closer to chimpanzees than mice and rats are to each other. So really, the classification should be like this, we are hominids, and then among the hominids, the lineage is leading to us, the hominins. So if you have a species that's 99% identical to us at the protein level, how could you possibly have anything that's different between them? And in fact, when I first got into this field, I found out at the veterinarians that the primates center I went to were using Harrison's textbook of internal medicine, same textbook I'd used. So that made sense. But if you wanna say there's such a thing as a human-specific disease, it's got to be very common in humans, rarely reported in closely-related species, now this is very important, I'm zooming in on this clip, not about things that happened at distant portions of evolution, even in captivity and could not be experimentally reproduced in such species, and I should warn you, I'm gonna talk about a few really horrible experiments that were done a long time ago that will never be done again. So there's a caveat: who do you compare with? In my opinion, reliable information is limited to data on a few thousand great apes in captivity which were cared for at NIH-funded facilities, with full veterinary care, probably better medical care than most Americans get, and full necropsies. Sp this is a reasonable data said to compare with humans. I think comparing with wild chimpanzees and self-domesticated humans isn't that useful in this question that we are trying to ask. So when I went to Yerkes Primate Center and other centers and asked, and said, "What's the commonest cause of death "in captive adult chimpanzees?" And they said, "Heart disease, "heart attacks, heart failures." So I said, "Oh, it's the same thing." But then my wife, Nissi Varki, who's a pathologist, went to see what is going on. She came back and said, "You fool, it's mostly a different disease!" And so we got together with various experts across, including Kurt, and wrote this article that says Heart Disease is Common in Humans and Chimpanzees, But is mostly Caused by Different Pathological Processes. So in comparing these two species, amazingly, it turns out that while we humans, essentially all of our heart attacks are due to what you heard about, atherosclerotic coronary blockade in the arteries, chimpanzees do get atherosclerosis, but it rarely ever leads to coronary thrombosis. Instead, they get this very peculiar kind of scarring in the myocardium, in the heart muscle, fibrosis, so-called interstitial myocardial fibrosis in great apes. This gives rise to abnormal rhythms, heart failure, and heart attacks, so it looks like humans but in autopsies, it's a different disease. In fact, since we wrote this article now put this out, it's become so well-recognized that interstitial myocardial fibrosis is such a major common in captive great apes in all the zoos that all the zoos led by Zoo Atlanta have gotten together and found a network to figure out what is this disease, and why is it killing all our great apes. And so there are two mysteries to be solved. One is, why do we humans not often get this fibrotic heart disease that's so common in our closest evolutionary cousins? Conversely, why do great apes not often get the kind of heart disease we get that's so common in humans? Since we're genetically so similar, there must be a very limited number of reasons. We'd immediately say, "Ah, it's just cholesterol." In fact, cholesterol is the leading thing that pushes atherosclerotic heart disease, but look at this figure here. Above is the black line, chimpanzee levels of cholesterol. Even at birth and soon after birth in the first decade, they're so high that they should be on statins. And they have similar HDL levels. They have APOE4 ancestral allele, higher Lp(a) levels, sedentary lifestyles, hypertension, and so on. Now, to be fair, there are some amino acid differences in those two very important proteins and that may be part of the story. So based on this kind of work, Nissi Varki and I went to several of these primate centers and tried to learn more about this biomedical differences. In this case, we're focusing on differences. I wanna be clear, there are many similarities, which I'm not gonna talk about. And so we, of course, worked on sialic acid biology. That's another story for another day, but this article also talks about those differences. So here's a list of candidates for human-specific diseases that I call definite, meaning the data so far suggest that long list. Obviously, I'm not going to go through the whole list. I'll give you a few examples. The big one, of course, that I mentioned is this remarkable difference in the rates of coronary thrombosis was this interstitial myocardial fibrosis. In fact, spontaneous coronary thrombosis due to atherosclerosis seems to be very rare in other animals, in the absence of experimental genetic or dietary manipulations. And the human-specific mechanics, undoubtedly as mentioned, have to do partly with behavioral and dietary changes, although I'm looking forward to the talk from Mike Gurvin on this hunter-gatherer heart disease, these amino acid changes in these two proteins, and something I'm not gonna go into, genetic change in sialic acid that seems to have made our immune cells much more prone to inflammation and also contributes to the effects of red meat and heart attacks, but that's, of course, a specialized case. Here's another disease, malignant malaria, the big killer malaria. Horrible, horrible studies done in the 1920s and 1940s in the Belgian Congo, two-way cross-transfusions between chimpanzees and humans infected or non-infected with malaria. No evidence of across infection. It turned out the parasites look the same but are different. Fast forward almost a century and work by CARTA member Francisco Ayala and others showed that all the falciparum in the world, this killer malaria belongs to a very small plate in the midst of many, many, many other ape malarias. In fact, Barbara Han later showed that Plasmodium falciparum probably arose by a single transfer from one gorilla to a human, sometime we don't know exactly when, a few tens of thousands of years ago. So Pascal Gagneuxa summarized it like this. Ape malarias are very common, and because of the sialic acid change, I'm not going to go into, we escaped the target and we had a free ride for a million years or so, but the parasites always win in the end. And finally the parasite in that one transfer switched to bind the human kind of sialic acid and then, of course, we spread to mosquitoes in our environment, and the rest is history. Here's another one, typhoid fever, big killer throughout human history until very recently. And it turns out there's been a host adaptation to humans. Again, most horrible studies done in the 1960s, large doses of Salmonella type fever given to chimpanzees. Survival was much better, and they were much less sensitive. It turns out we can find an explanation for this. There's a human kind of sialic acid shown on this side of the screen, and the other side of the screen, Gc is the chimpanzee type of sialic acid. And the typhoid toxin only binds to the human kind of sialic acid. And so using most models, we can sort of show that this is what's going on, that we have the sensitivity and resistance. Cholera, Robert Koch, the famous microbiologist said, "Although these experiments are constantly repeated "with material from fresh cholera cases, "our mice remained healthy. "We then made experiments on monkeys, cats, "poultry, dogs, and other animals, "and we were never able to arrive at anything "similar to a cholera process." So far, there's nothing except a baby rabbit model. Of course, there's explanation for this. Now I've been talking mostly about infectious disease from Jared Diamond and others, and if you look in the bottom of the screen, you can see that certain diseases like rabies can spread throughout many animals. And then eventually a disease makes its way into humans and by what's called the red queen effect, becomes highly specialized on one species. And so some of this is not so surprising, but the fact is that there are such diseases. There's one set of definite diseases that are kinda interesting. These are gonorrhea, various other organisms that infect newborns. But it appears that these bacteria have done is invent the human kind of sialic acid and coat themselves in what my colleague, Victor Nizet, calls molecular mimicry, basically wolves in sheep's clothing. And they're very successful pathogens. Okay, so that's some examples. I haven't gone through all of them human-specific diseases that seem to be human-specific. What about probable ones? Alzheimer's Disease. Another CARTA member, Doc Finch has written this. Commentary: is Alzheimer's disease uniquely human? "That Alzheimer's disease may be a human-specific disease "was hypothesized in 1989. "Apes accumulate considerable amyloid plaques after 40, "an age at which these are uncommon in humans. "Despite this early plaque buildup, ape brains "have not shown dystrophic neurites near plaques. "Aging great ape brains also have few tangles. "We cautiously support this hypothesis." And this is under further investigation. Carcinomas of epithelial origin. To date, of these few thousand apes cared for in captivity, not a single case of carcinoma of the esophagus, lung, stomach, pancreas, colon, uterus, ovary or prostate. And so Nissi and I looked into this and concluded that while relative carcinoma risk is a likely difference between humans and chimpanzees and other apes, a more systematic survey is needed. Of course, age is a factor, not just environment. And so you'd say, well, a lot of these diseases we're mentioning have to do with age. But in fact, chimpanzees in captivity can live up to the age of 45, 50, occasionally even up to 60. And so they are in the age range, if you're looking at the rates of human cancer here in human males and females, but you might expect to at least see a few carcinomas, a few heart attacks of the human kind and a few early cases of Alzheimer's-like disease, but none have been seen. Possible examples. Another long list. And here we have what is called absence of evidence, it's not evidence of absence. We really don't know. But it's kinda interesting that bronchial asthma, I've been looking for a case of bronchial asthma in a great ape, or for that matter, in a monkey, and there's no papers about this, except the papers like this. Here's a paper about the asthma-like syndrome in a single monkey that says "The present case is remarkable "in that there's a paucity of reports of naturally occurring "allergy airway disease in non-human primates." This could have to do with the hygiene hypothesis. Other issues remains to be seen. Anyway, to conclude, disease profiles of humans and chimpanzees are rather different, considering how genetically similar we are. Chimpanzees, contrary to the original idea of NIH and health sciences, are poor models of many human disease, and should not be used to model human diseases very often, if at all. Humans, conversely, are likely to be poor models of many chimpanzee diseases. So there are huge ethical issues here. Chimpanzees are sentient beings. I wouldn't do anything to a chimpanzee I wouldn't do it to a human, and with even greater care than with humans. And back in 2005, Jim More, Pascal Gagneuxa and I wrote this ethics paper. We suggested that we conduct research on great apes following principles generally similar to those accepted for human research, and even suggested that the researchers should volunteer to be subjects in the same studies. (audience laughing) Since I wrote this, I keep getting these letters saying, "Please sign this document "banning all future research on chimpanzees." And my answer is, "That's a terrible idea. "Would you ban all future research on humans?" But unfortunately, that's what's happened for other reasons, really good reasons of getting chimpanzees out of not-very-good facilities and avoiding invasive research. Then I just threw up its hand on this, stopped all chimpanzee research, practically speaking. And the question is, will the ban on chimpanzee research actually do more harm than good to both species? And add to that a final corollary, chimpanzees would benefit from more ethical studies of their own diseases, and I'm hoping that we can still keep this area of research open because I think it's important for both humans and chimpanzees and the diseases that we both get. Thank you. (mellow piano music) - One out of every four deaths basically in the US and the UK are from heart disease. So it's basically the number one killer, not just in the industrialized world, and a major source of cost burning our health care system, but also around the world, including in developing world, that heart disease and its more insidious form of it, atherosclerosis, is the source of say, every three out of 10 deaths around the world today. So it's so familiar to us that the obvious question is well, is atherosclerosis really a universal aspect of just human aging? It's sort of an inevitable aspect. By the time you're 20, you probably already have some of the fatty streaks that will later go on to become more complicated lesions and create problems for us. Or is that not the case? And so, maybe atherosclerosis, the process is universal but maybe it does or does not always present clinical manifestations that will affect our morbidity, and ultimately, mortality. So a standard kind of story is that if we could zoom back into the past and look at hunter-gatherers, that hunter-gatherers wouldn't have these types of heart disease, or other types of problems, and that it's modern features of our lifestyle that is making us ill, that there's a mismatch between our genetic adaptations and modern features of lifestyle. So changes in our nutrition, our diet, our physical activity, our bad habits as Barbara said, like cigarette smoking and alcohol consumption, that these are maybe what create the problem, and that hunter-gatherers would have little or no coronary heart disease. And the evidence for this is often focused on some risk factors, so cholesterol, Type II diabetes, low prevalence, that their risk factors seem to suggest a healthy heart. But there are some problems here is that we don't really know that in these types of populations that heart disease is fairly absent. First of all, the numbers are fairly small. And often, there'd be a medical team, like in the 1950s or 60s that would sweep through a village, but fairly quickly. And so, it could be that people who have heart disease died fairly quickly from it, and so unless you've spent a long time in an area, you might not actually see the real cases if the case fatality rate is quite high. And it could be that, you know, those people got weeded out of the population early. And so if you looked at people over the age of 60, no one has heart disease maybe because they died earlier on in life. But also, the assessment is fairly indirect as I mentioned, you know, it's easy to kind of take someone's blood pressure, to measure how much cholesterol they have, to measure their BMI, but it's much harder to get a direct assessment. And of course, if certain risk factors worked differently in different human populations, then it might not be a one-to-one relationship that the risk factors tell you about the actual underlying heart disease. And one good example from the 70s, was kind of became a established fact almost that the Inuit up near the arctic north, and in Alaska and Greenland in particular, that they don't have atherosclerosis, and they don't have heart disease, and particularly their marine-rich diet and particularly omega-3s was one good reason why despite a very meat-based diet, that they would not have heart disease. But it actually turns out there were some unreliable mortality statistics some of those earlier inferences were based on and further kind of x-ray and ultrasound studies actually show the opposite, that there is quite a decent amount of atherosclerosis and that heart disease didn't really look that different from near surrounding populations, and that stroke might even be higher. And also, more recent meta-analyses show no effect of omega-3 fish oils on heart-related deaths, heart attacks and strokes. So the standard story is actually a little bit different when you look into it in more detail. And also, the Horus group, which we'll see a little bit more further in the talk, looked at a unique sample of 137 mummies across four world regions, so ancient Egypt, ancient Peru, the southwest of the US, and the Aleutian Islands, and across 4,000 years of history, and he looked at different arterial beds for evidence of calcification. So a more direct measure using CT scans, whole body CT scans of these mummies. So for example, here you've got, these are both two Unangan women from the Aleutian Islands, up here, is woman about 50, here a woman about 30, and you can see some evidence of calcification in the aortic arch on top and in the carotid artery down here on the bottom. And what they found was evidence of calcification across all arterial beds, across all four populations. And so they argued that, their conclusion was that we found that heart disease is a serial killer that's been stalking mankind for thousands of years. The presence of atherosclerosis in pre-modern human beings suggests that the disease is an inherent component of human aging, and not characteristic of any specific diet or lifestyle. So now the paleo diet people hated this, right, because they were basically saying, "Look, it's all over, "it doesn't matter what you eat. "We find evidence of this everywhere." But of course, all the mummies have been long dead so it's hard to know what they actually died of and whether that atherosclerosis might have been relevant to their daily lives. Now also, if we're riding off of Adjit's talk, we now know that chimpanzees, while the number one cause of death in captives is heart attacks, it's not exactly coming from the same ideology as human heart attacks That chimpanzees do not seem to have the same kind of atherosclerosis, coronary artery disease is rare, but the heart failure instead is through this diffused interstitial myocardial fibrosis often triggered by arrythmias. You can see the diffused kind of fibrosis in the heart tissue in chimpanzees, the kind of sub-endothelial plaques in the human interior lumen, that this is very different. And in captive chimpanzees, despite the fact that they have higher cholesterol levels, they're homozygous for alleles in the ApoE4 that are higher risk of atherosclerosis in humans and less physical activity, so quite remarkable difference. Now the standard kind of evolutionary story brought to us by some evolutionary biologists in the critical foundational contributions Medawar as well as Holdane and Hamilton, that basically that the force of selection declines with age as fertility is dropping, so the relative contributions for future generations are declining, and so you can have mutations that exert effects late in life that might be somewhat blind to the effects of natural selection, especially if they have beneficial effects early in life. So what that means is that you've got deleterious effects that manifest, say, later in life, fall under the selection shadow. And it actually turns out when you actually look at the cases, this is from US data, the actual incidence of heart attacks and fail coronary heart disease, that those cases do fall into this selection shadow. So one kind of knee-jerk response is, well, maybe again, these things have always been with us, but in hunter-gatherers, if you're not gonna live to this kind of age range, then you're not gonna see these types of ailments. And so that might be the end of story, and that our longer lives in modern society is why we see so much more of it today. But that doesn't really seem to be the case. If we take some of the best demographic data out there on hunter-gatherers as kind of a key, obviously, living hunter-gatherers are not the same as our ancestors, but it's the closest thing we have to try to understand what life and mortality might be like without all the modern amenities. And so, in hunter-gatherers where the average life expectancy at birth is in the either high 20s or low 30s, compared to what we're used to in the US and other first-world countries is a dramatic difference. But if you notice, this is the ratio of the mortality in hunter-gatherers, say, the American mortality and it's quite high, the difference, but most of those differences are early in life. And that by the time you get to, say age 15, the mortality difference has dropped from, say 200, early in life to 14 times higher in hunter-gatherers, to about age 40, seven times higher in hunter-gatherers, and by age 60, that mortality difference is only three times higher. So if you live past this early period of high mortality and you survived to age 15, the mortal age of adult death is actually it ranges from 68 to 78 in this hunter-gatherer populations. So it's not probably the case that the absence of older people is why we don't see these types of problems presenting these kinds of populations. So I wanted to move beyond mortality and actually look at living bodies to see, well, okay, two people actually have some more direct evidence. And so since I mentioned since 1999, we've been working in central lowland Bolivia with the Tsimane, so again, horticulturist population that share many similarities with hunter-gatherers, their fertility is quite high, their fairly high pathogen load, most of their diet, not all their diet basically coming from the land, from fish, from their fields and also from wild game. Taking advantage of the French government donating a 16-slice CT scanner, just a mere 10 hours and several days in a canoe away, we brought people to the CT scanner to get a more direct measure of atherosclerosis through looking at coronary arterial calcification based on thoracic CT scans. So using the exact same methods for scoring as in US studies, what we compared Americans to the Tsimani, it actually turns out that well, the Tsimanis, these are here in red, there is evidence of atherosclerosis, of calcification, but the levels are much lower than what we see in the US. Now the mesa, this is the multi-ethnic study of atherosclerosis. These are asymptomatic people without heart disease or diabetes that are in the sample. So compared to those, the percentage of people with any calcification is much, much lower. And in fact, the Tsimani reached a level that the Americans have, that's a gap of over 20, 25 years. And so one easier way of thing about this and this kind of obscure calcification scoring is what's called the arterial age, and this is basically what age, based on the CAC score you have, was that at the equivalent of someone in the MACE study. And compared to what you would expect based on just the calcification score, that the Tsimanis show evidence that basically estimated arterial ages, that are about 20, 25 years younger than their chronological age. But the great thing about working with living people, if the story ended there, we might say, well, look, just like we found with the mummies, there's atherosclerosis in the Tsimani. But here at the clinical findings really suggest minimum manifestations of atherosclerosis. So over the past decade, we found minimal obesity, hypertension, cigarette smoking, moderate-high physical activity, low cholesterol levels, low your bad, your low density lipoprotein cholesterol, low blood glucose, so all the risk factors are fairly minimal. And then if we actually look based on EKGs, if we look for evidence of past infarcts, over 1,100 EKGs, we've looked at people 40 and up, maybe one case of an infarct looked at by our team of cardiologists. And even that, a couple of the cardiologists think it's dubious. And also based on other evidence with EKGs and also with ultrasound, evidence of preserved systolic and diastolic function. And it's not the case that the young people that have these conditions, then are dying at early ages, or that these people have high case fatality rates, so based on verbal autopsies, over the past 15 years, we don't see very much evidence at all, in fact, like maybe one case of someone who may have died of a heart attack. So there really doesn't seem like there's evidence of mortality selection that is explaining these differences away. Now this is in spite of the fact, you know they have some protective factors but they also have very high levels of inflammation. And you know, in the past 20 years or so, it's well-known that inflammation is a major risk factor. In fact, it is a fundamental to the process of what we know about atherosclerosis, and by a number of biomarkers, CE reactive protein is one many of you might be familiar with because you often get it done by your own clinician. They have very high levels and cumulative levels over their life course, levels that would basically associate with having heart disease amongst ourselves. And they also have low levels of the high-density lipoproteins or good cholesterol. So a few take-home messages for a larger biomedical field. First of all, it doesn't seem like the inflammation story is very complete, that the same kind of risk factor might not exert the same types of effects everywhere. I mean, probably would not have known that if we didn't look at populations that are I guess as Katie brought up, looking at non-weird populations, and particularly populations that experience lots of infection and have very different kind of lifestyle than we have. And in fact, not only do they have high levels of inflammation, but biomarkers of inflammation are either unrelated or in some ways oppositely associated with our measures of arterial calcification and other indicators of atherosclerosis. And it could be that inflammation that we experience from cigarette smoking, from obesity, the so-called sterile inflammation might have different effects than inflammation that is induced under the conditions more representative of the past which would be more from infection. But also, there are other types of infections, particularly helminths, these are intestinal worms, our old friends that we've carried with us for long, long periods of our evolutionary history, that they exert regulatory effects on the immune system and also anti-inflammatory effects that might perhaps protect against the otherwise destructive effects of inflammation. And the other take-home is that what we consider average might not be really normal. So James O'Keefe, a physician back in the early 2000s, argued the case based on randomized placebo-controlled studies with statins that if you look at the chronic LDL levels, and you looked at a whole bunch of things, this is just the decrease over time in the lumenal diameter, so the interior of the artery, but you gotta change the Y axis and make it heart attacks and other cardiac events, that when you actually looked at how the occurrence of these things in relation to the chronic LDL levels, it seemed to be a somewhat linear relationship to the point where if you draw the line, that you would expect to almost zero events. In this particular graph, it would mean basically a slowing of atherosclerosis to the point of stopping at a level of about 70 or just less than 70, and so they were arguing in a series of papers that the optimal LDL should be something between 50 to 70, whereas your typical recommendations, at least up until 2013 when the statin-based recommendations changed so that we're not reaching a target level. But it used to be that a hundred was a level. But it actually turns out there's a decent amount of heart attacks in the region between 70 to 100. And this is just from the Tsimane, but if we looked at other populations it would be a similar case. The distribution of the LDL here in the Tsimane compared to Americans, and it might be a little hard, sorry, to see the numbers, but the mode in the average there is about 70 for the Tsimane, whereas about 85% of Americans have LDL higher than that. And that what's yellow there is in that 70 to 100 region that basically many of Americans would fall into, even if they were taking statins. So less than 70 is a hunter-gatherer level of LDL that might be more extreme but probably very difficult for us as omnivores to reach, unless perhaps you're taking statins. So just to summarize and conclude, atherosclerosis is present just like we observed in the mummies, but it's less pervasive than we see in the West. So certain features of cardiovascular aging may be universal. So you might see some calcifications and stiffening of the arteries, there's some declines, they might be delayed in systolic and diastolic function, but they occur nonetheless. Yet the clinical manifestation, so whether it's heart attacks, hyper tension, peripheral arterial disease, strokes, that those themselves might not be universal, and were likely very rare throughout human evolutionary history, despite the fact that we can observe calcifications in these mummies. And also I think it behooves us to revisit common risk factors. That inflammation might be high in hunter-gatherer populations, but immune function might be better regulated in a very different environment, particularly in presence of a more diverse set of pathogens. And it also raises the question of what is normal, what are the target levels of different biomarkers like LDL that we should be reaching, what might they have been like over the course of evolutionary history. And to take advantage of the fact, if we hadn't looked at a population like the Tsimane, these non weird populations, so we can actually learn quite a bit about our own health in, say, the U.S., by focusing on people that are more likely to have certain types of infections that could be cardio-protective. Even a lot of our standard model organisms in the lab are infection-free, and so there might some limitations of what can be gained. And also taking advantage of the fact, and the horror of the fact, that all indigenous populations around the world are in different states of flux, so it's a kind of quasi-natural laboratory for looking at the changes in lifestyle and environment on how that shapes increases in Type II diabetes risk and in heart disease. And so it's sort of untapped territory that very, in fact I don't know any biomedically-oriented folks that are working in these populations to try to learn more about the underlying ideology. And so for the future, one thing that a take-home message is if the story was just that "Look, exercise more, eat well, don't smoke." We already knew. Those are your standard Framingham Study kinda risk factors. And I think those do make a big difference. But also, regulated immune function in the presence of certain parasites might also have some protective aspects on their heart. And that maybe in the future we might see that the hygiene hypothesis, this idea that we're not exposed to the same type of critters as we would have in the past, that not only helps explain auto-immune type diseases currently, but also may be extended to heart disease. Thank you very much for your time. (mellow piano music) - So I will discuss today the relation between inflammation and metabolism and metabolic homeostasis and diseases susceptibility. Inflammation is a protective response to a variety of challenges that we may experience, including infection and injury and various types of tissue stress and malfunctions and all the things that can go wrong. All of them can induce an inflammatory response that meant to be protective. And depending on the type of challenge that we experience, there's different physiological or intended purpose of the responses, such as host defense from infection, tissue repair response or restoration of a normal state of the tissues. And what is very interesting about inflammation and very clinically important is that all these different pathways to inflammation can result in a variety of pathological sequel, including auto-immune diseases, sepsis, fibrotic diseases, tumor growth, and a variety of diseases for homeostasis that are becoming more and more common in modern lifestyles. To give a very, very simplified summary of inflammation of inflammatory pathway. When inducers of inflammation such as pathogens or tissue damage are encountered, cells in our bodies, such as macrophages and epithelial cells and so on detect these inducers and produce various inflammatory mediators, including cytokines that some of them were mentioned already. And what these mediators do, they act on practically every tissue in the body and they change some functional characteristics that intend to either cause elimination of whatever caused inflammation, or adaptation to the presence of these conditions. And why inflammation is so broadly associated with diseases, very symbolically, it could be summarized here. So for every trait, including defense traits, there are benefits and costs for defenses. The cost are particularly pronounced. And the traits would be evolutionary stable if the benefits are higher than the costs. And anything in this green part of the triangle would be therefore potentially evolutionary stable and everything here would be unstable. And the problem is that, in the case of traits that can provide very high benefits such as survival, the acceptable cost can also be very high. And that leads to this type of picture where the part of this upper triangle that's on the right side where benefit can still outweigh the cost but in terms of the absolute value of the cost, this would be already, from the patient perspective at least, and the doctor's perspective, this would be already in the disease zone. This would be conditions that we would experience as something that is definitely not well being and doctors would diagnose as being various types of pathological or disease conditions even though they still provide more benefit than the cost. And what we're interested in is in the biology of this upper right corner, where the high benefits associated with very high cost and where we basically on the edge of the chaos or transition into the pathological states that can be potentially lethal. And this type of biology deals with not just common conditions, like mild infections or mild anomalies, but it has to do with, essentially biology of survival. What are the kinds of mechanisms that are employed by our system, by our organism in order to survive critical conditions? The ones the are just one step away from death. And this is just in a very schematic way summarized here, so if we consider this type of disease tree there're many conditions that we can one step away from health this various common mild illnesses, this has conditions that make you go to see a primary care physician. If there're complications of this conditions you get referred to some internal medicine specialist. These are more complex diseases, but you can still recover and go back to health. And in severe cases you can get into this critical illness state when you get into ICU. And you still can recover from here, and in this critical illness state, which is conditions like sepsis, pneumonia, heart attack, brain damage and so forth. In these conditions you are one step away from this tree proximal mechanisms that lead directly to death. And these are points of no return, which is respiratory failure, cardiovascular failure, or damage to the brain areas that control respiration and cardiovascular function. So we're interested in what happens here, what kind of mechanisms may be evolved to prevent this transition into this point of no return. The case I will discuss today has to do with this very enigmatic and very interesting and familiar to everyone, set of conditions known as sickness behaviors. This is something everybody in this room experience when you have flu or any other type of severe infection or other types of acute illness, we all experience this set of conditions such as loss of appetite, social withdrawal, fatigue, sleepiness and so on and so forth. So these are all stereotypic conditions that are associated with acute illness, most commonly with acute infections. So flue symptoms would all be in that category. And the biology of sickness behavior has not been really well-understood, although there were early studies that demonstrated that sickness behavior is not just a consequence of system being destroyed by a pathogen, but rather these are motivated behaviors, in other words they are intended by the organism for some reason. And there's been many speculations that whether there is aspects of sickness behavior, perhaps held the immune system to fight infection or maybe there's some other way that they may contribute to dealing with acute illness. So we were interested in investigating aspects of acute illness, including loss of appetite and change in sleeping patterns, and how they may contribute to survival of the acute illness. So there are two ways we can survive an infection or any other challenge for that matter. We can either resist it, so in the case of infection, normally where we would be in this state, where we're healthy and there's a low or a negligible pathogen load, and as we get infected and pathogen expand, we can become ill as indicated by this position, and from here, we can either go back to health by getting rid of pathogen, which is the role of the immune system, and this is referred to a resistance to disease, or we can adapt to the presence of the pathogen and go back to the healthy state despite microbial load. And this would be referred to as increased tolerance to infection or tolerance to damage. There are two ways that pathogens cause damage. One is directly through tissue destruction through toxins, viral infections and so forth. And the second more common way that pathogens infections call illness is due to damage by the inflammation caused by infection. And so we were interested in figuring out whether sickness behaviors provide benefit first of all, secondly whether they provide benefit because they promote immune function and resistance to infection, or whether they provide benefit by promoting tissue protection and tolerance to inflammatory damage or pathogen induced damage. Just like in humans and mice or in any animals that've been studied all the way back to insects, when they are ill with acute infection, they stop eating, this is food consumption in mice after they received a dose of listeria infection. This is common food poisoning type of infection. They stop eating and until they start clearing infection and they start recovering and then they start eating again. But there's a very profound anorexia associated with infection as you can see here. So some studies done over 40 years ago actually found that in the model of listeria infection, if mice are force-fed then mortality increases. And this is what we reproduce here. So this is showing survival of mice that are given LD 50 dose of listeria, those that kills half of mice, and this is what's shown here. And if they're force-fed then all of them die. And they were fed just 20% of daily caloric intake, so they're not really stuffed with food, they're just given a little bit of food and that kills them. And the food that we use is actually the same food that's used in ICU units. And then we ask what component of food kills. So we gave them separately proteins, fat, and sugar. And it turns out that sugar alone or glucose alone was sufficient to kill them, whether it was given orally or intravenously. So just giving them a small dose of sugar, only 2% of normal daily caloric intake of glucose, was sufficient to kill 100% of mice. Conversely, if we gave them glucose inhibitor called 2DG, 2-deoxyglucose, it's a modified form of glucose that cannot be metabolized so it blocks glucose utilization then 100% of mice would survive. And importantly, this was not because the immune system was affected in its ability to treat to get rid of the pathogen, and it's not because there was high dose of higher magnitude of inflammation, because there were not different between mice given glucose or not as you can see here. So this indicated that mice survived or died from this manipulation because of the affect on tissue protection, not on the immune function itself. So then ask what would happen in the most severe condition, like sepsis. Sepsis is the condition when infection becomes systemic, when it gets into blood. In this case it's a bacterial sepsis that's mimicked by giving mice this component and a toxin LPS. And as you can see here, if mice given LPS or septic mice, if they are given food, they die. Compared to a control, where they're just given saline solution. And importantly if they're just given sugar, then they all drop dead. But most excitingly they're just getting the simple drug that blocks glucose utilization, then 100% of them can be rescued from sepsis. And sepsis is a really terrible intractable condition that is still a very common cause of death in ICUs. So again, the mortality or protection from death in these manipulations was not dependent on the degree of inflammation as shown here, was example of a couple of inflammatory mediators. And again, indicating that it was due to increased tissue protection from damage caused by severe inflammation that is associated with sepsis. Then we asked what would happen in a different type of infection. So, so far I showed bacterial infection and bacterial sepsis, and now we ask what would happen in influenza virus infection. So when mice are infected with flu virus, again they undergo this period of anorexia when they stop eating until they start recovering. And if they're force-fed, to our great surprise, they actually survive better. So this is now giving almost lethal dose of flu infection, most mice die, but when they're given that food most of them survived. And also if they're given glucose that also provided partial protection, and if they're given 2DG glucose inhibitor then all of them dropped dead. So it was exact opposite to what happened in bacterial infection and bacterial sepsis. And again, the effect of glucose was not due to its impact on inflammatory response. So in viral infections it's a different type of inflammatory response, which is dominated by interference shown here, they're the same. And those of burden of the virus in the lungs was also the same, was not different. Again, suggesting the effects are due to impact on tolerance to tissue damage. And the data that I'm not gonna show, but I summarized here, what we found is that death from viral inflammation was associated with decline in vital functions, like respiration, blood pressure, so on, suggesting that there was a failure in autonomic control centers in the brain stem. And if mice are given food or glucose, then these declines in autonomic functions could be rescued, they're given 2DG, they're enhanced. In contrast, death from bacterial sepsis was associated with neuronal damage in the mid-brain area and the death was immediately proceeded by convulsions. And these were blocked by 2DG and they were enhanced by glucose. So we did PET scan analysis and found that glucose utilization under conditions of bacterial inflammation versus viral inflammation was very different, and it segregated exactly to this to this brain areas. Such that in viral inflammation it was primarily in brain stem, and in bacterial inflammation it was in mid-brain area. The increased delivery of glucose to this areas related to the impact of glucose or glucose inhibitors on the damage to these areas. And then we asked what does the mechanism of damage and what's happening there. So I will just summarize that part of the study. What we found was that in the case of viral inflammation, what happens with cells that are infected with a virus, one of the things that happens, there is particular type of cellular stress response, known as unfolded protein response, that has two branches. One branch tries to adapt to this stress condition and to resolve it, and if that fails, the second branch would kill the cells, as a second option. And this death from this response is mediated by this particular gene called CHOP, it's a transcription factor. And what is known is that glucose deprivation can exacerbate in unfolded protein response, this stress response pathway. And so we hypothesized that that brain stem area, the neurons in the brain stem, for reasons that remain mysterious, underwent this excessive unfold protein response stress that was ameliorated by glucose and exacerbated by 2DG. And then we asked whether this pathway of cell death or neuronal damage mediated by this gene is involved. And for that we asked whether mice that have a mutation in this gene, whether they would be rescued from the effect of such inflammatory manipulation. And indeed what we found, if we just look at this blue line, these are mice that have infection, that have viral inflammation, and they'd given 2DG they all die, and if they don't have that gene CHOP, then they all survive. And so the mechanism here is related to a blockade of this pathway for neuron dysfunction. And finally in the case of sepsis or bacterial inflammation, fasting metabolism that protected them from death was related to the switch from normal fat metabolism to a fasted metabolism, which there's a switch to fuels from glucose to ketones, and that which was necessary for mice to survive sepsis. And this is shown here, that giving glucose blocked transition to fasting metabolism and deletion of the gene that is responsible for keone production, made mice susceptible to sepsis. As I mentioned immediately before death, mice had convulsion in sepsis. So what we did in this final set of experiments, if we gave the mice anti-epileptic drug called valporic acid, then we could rescue them from death even when they're given glucose. And so that indicated that the reason that that worked is because valporic acid, unlike this other drug shown here, which is Keppra, which is also anti-convulsion drug, valporic acid, one of its mechanism is related to the effect through the same effect that ketones have on a particular class of enzymes in the cell. So I will summarize it here, that there are two different pathways to death, and fasting metabolism is protective in one case and detrimental in the other case. And the final, the implication for human treatment in ICU is that all clinical trials done so far, with nutrient manipulation in ICU units have been done on patients that have not been separated based on cause of sepsis, bacterial versus viral. And the results of the studies were mixed. And we think that it's because they were not separated and they basically cancelled each other out. So now we are planning to conduct a clinical trial where we'll separate them, based on causes of sepsis. So this is the summary and finally this work was done by three very talented scientist in the lab, Harding Luan, Sarah Huen, and Andrew Wang. And we had help from other colleagues at Yale, and thank you for your attention. (mellow piano music)

Contents

Biography

Born in Norwich, England, Hinde was the master of St. John's College, Cambridge in 1989-94.[2] He was the chair of British Pugwash. He studied "the application of biological and psychological data to understanding the bases of religion and ethics" and "eliminating the causes of war".[3]

Hinde was educated at St. John's College, Cambridge and at Balliol College, Oxford. He was a distinguished supporter of the British Humanist Association.

He died on 23 December 2016 at the age of 93.[4]

Publications

References

  1. ^ "Emeritus Royal Society Research Professor Robert Aubrey Hinde, CBE, FRS, FBA,FRCPsych — Department of Zoology". zoo.cam.ac.uk. Archived from the original on 25 September 2013. Retrieved 14 December 2014. 
  2. ^ "The Master and Fellows of St John's College | St John's College, Cambridge". joh.cam.ac.uk. Retrieved 2014-12-14. 
  3. ^ "Archived copy". Archived from the original on 28 December 2004. Retrieved 31 March 2006. 
  4. ^ HINDE
  5. ^ Hinde, R.A. (1974). Biological bases of human social behaviour. McGraw-Hill. ISBN 9780070289321. Retrieved 2014-12-14. 

External links

Academic offices
Preceded by
Francis Harry Hinsley
Master of St John's College, Cambridge
1989–1994
Succeeded by
Peter Goddard



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