How to treat a swollen prostate

- [announcer] this ucsd-tvprogram is presented by university of california television. like what you learn? visit our website, or followus 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 expertsfrom 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, whichreally emphasized this, that animals and humanscan get the same diseases

and yet physicians and veterinarians rarely consult with one another, and that human and non-humananimal 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 lineagethat goes back to oslo, and one of those steps along the way

was one of our own here, kurt benirschke, unfortunately couldn't behere 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 alwaystwo sides to every coin, and say, are therehuman-specific diseases? what we've been hearingabout is the evolutionary

biology and diseases of alarge variety of animals, mostly warm-blooded socialanimals, vertebrates, and you can see an entire lineage here. let's zoom in on thegroup that we belong to, primates, and zoom in further, and among these primateswe 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 timeago in evolutionary time. and here's another way to look at it. in millions of years before present, there's certainly somediscussion about the time frame, but the very importantpoint to make here is that while we classified allthese species as great apes, the main difference betweenchimpanzees and bonobos

is less than 1% of theiramino acid sequence level. in fact, we are closer tobonobos 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 classificationshould be like this, we are hominids, andthen among the hominids, the lineage is leadingto 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 firstgot 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 inclosely-related species, now this is very important, i'm zooming in on thisclip, not about things that happened at distantportions of evolution, even in captivity and could notbe experimentally reproduced in such species, and i should warn you,

i'm gonna talk about a fewreally 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, reliableinformation is limited to data on a few thousandgreat apes in captivity which were cared for atnih-funded facilities, with full veterinary care,probably better medical care than most americans get,and full necropsies.

sp this is a reasonable datasaid to compare with humans. i think comparing with wild chimpanzees and self-domesticatedhumans isn't that useful in this question thatwe 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, nissivarki, who's a pathologist, went to see what is going on. she came back and said, "you fool, it's mostlya different disease!" and so we got together withvarious experts across, including kurt, and wrotethis article that says heart disease is commonin humans and chimpanzees,

but is mostly caused bydifferent pathological processes. so in comparing these two species, amazingly, it turns outthat while we humans, essentially all of our heart attacks are due to what you heard about, atherosclerotic coronaryblockade in the arteries, chimpanzees do get atherosclerosis, but it rarely ever leadsto coronary thrombosis. instead, they get thisvery peculiar kind of

scarring in the myocardium,in the heart muscle, fibrosis, so-called interstitial myocardialfibrosis in great apes. this gives rise to abnormalrhythms, heart failure, and heart attacks, so it looks like humans but in autopsies, it'sa different disease. in fact, since we wrote this article now put this out, it'sbecome so well-recognized that interstitial myocardialfibrosis is such a major common in captivegreat apes in all the zoos

that all the zoos led by zooatlanta have gotten together and found a network to figureout what is this disease, and why is it killing all our great apes. and so there are twomysteries to be solved. one is, why do we humans not often get this fibrotic heartdisease that's so common in our closest evolutionary cousins? conversely, why dogreat 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 verylimited 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 afterbirth in the first decade, they're so high that theyshould be on statins. and they have similar hdl levels. they have apoe4 ancestralallele, higher lp(a) levels, sedentary lifestyles,hypertension, and so on. now, to be fair, there aresome amino acid differences in those two very important proteins and that may be part of the story. so based on this kind ofwork, nissi varki and i

went to several of these primate centers and tried to learn more aboutthis biomedical differences. in this case, we'refocusing on differences. i wanna be clear, thereare many similarities, which i'm not gonna talk about. and so we, of course, workedon sialic acid biology. that's another story for another day, but this article also talksabout those differences. so here's a list of candidates

for human-specific diseasesthat i call definite, meaning the data so farsuggest that long list. obviously, i'm not going togo through the whole list. i'll give you a few examples. the big one, of course,that i mentioned is this remarkable difference in therates of coronary thrombosis was this interstitial myocardial fibrosis. in fact, spontaneous coronary thrombosis due to atherosclerosisseems to be very rare

in other animals, in theabsence of experimental genetic or dietary manipulations. and the human-specific mechanics,undoubtedly as mentioned, have to do partly withbehavioral and dietary changes, although i'm looking forwardto the talk from mike gurvin on this hunter-gatherer heart disease, these amino acid changesin these two proteins, and something i'm not gonna go into, genetic change in sialicacid that seems to have

made our immune cells muchmore 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, horriblestudies done in the 1920s and 1940s in the belgian congo, two-way cross-transfusionsbetween chimpanzees

and humans infected ornon-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 franciscoayala and others showed that all the falciparum inthe world, this killer malaria belongs to a very smallplate 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 fromone gorilla to a human, sometime we don't know exactly when, a few tens of thousands of years ago. so pascal gagneuxasummarized 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 targetand we had a free ride for a million years or so, but the parasites always win in the end. and finally the parasitein that one transfer switched to bind thehuman kind of sialic acid and then, of course,we spread to mosquitoes in our environment, andthe rest is history. here's another one,typhoid fever, big killer throughout human historyuntil very recently.

and it turns out there's beena host adaptation to humans. again, most horriblestudies done in the 1960s, large doses of salmonella typefever given to chimpanzees. survival was much better, andthey were much less sensitive. it turns out we can findan 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 thesensitivity and resistance. cholera, robert koch, thefamous microbiologist said, "although these experimentsare constantly repeated "with material from fresh cholera cases, "our mice remained healthy.

"we then made experimentson monkeys, cats, "poultry, dogs, and other animals, "and we were never ableto arrive at anything "similar to a cholera process." so far, there's nothingexcept a baby rabbit model. of course, there's explanation for this. now i've been talking mostlyabout infectious disease from jared diamond and others, and if you look in thebottom of the screen,

you can see that certaindiseases like rabies can spread throughout many animals. and then eventually a diseasemakes 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 thatthere 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 thesebacteria have done is invent the human kind ofsialic acid and coat themselves in what my colleague, victornizet, 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 ofthem human-specific diseases

that seem to be human-specific. what about probable ones? alzheimer's disease. another carta member, docfinch has written this. commentary: is alzheimer'sdisease uniquely human? "that alzheimer's disease maybe a human-specific disease "was hypothesized in 1989. "apes accumulate considerableamyloid plaques after 40, "an age at which theseare uncommon in humans.

"despite this earlyplaque buildup, ape brains "have not shown dystrophicneurites near plaques. "aging great ape brainsalso have few tangles. "we cautiously support this hypothesis." and this is under further investigation. carcinomas of epithelial origin. to date, of these few thousandapes cared for in captivity, not a single case ofcarcinoma of the esophagus, lung, stomach, pancreas, colon,uterus, ovary or prostate.

and so nissi and i lookedinto this and concluded that while relative carcinomarisk is a likely difference between humans andchimpanzees 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, chimpanzeesin 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 therates 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 ofalzheimer's-like disease, but none have been seen. possible examples. another long list.

and here we have what iscalled absence of evidence, it's not evidence of absence. we really don't know. but it's kinda interestingthat bronchial asthma, i've been looking for acase of bronchial asthma in a great ape, or forthat matter, in a monkey, and there's no papers about this, except the papers like this. here's a paper aboutthe asthma-like syndrome

in a single monkey that says "the present case is remarkable "in that there's a paucity ofreports of naturally occurring "allergy airway diseasein non-human primates." this could have to do withthe hygiene hypothesis. other issues remains to be seen. anyway, to conclude,disease profiles of humans and chimpanzees are rather different, considering howgenetically similar we are.

chimpanzees, contrary to the original idea of nih and healthsciences, are poor models of many human disease,and should not be used to model human diseasesvery often, if at all. humans, conversely, arelikely 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 greatercare than with humans. and back in 2005, jimmore, pascal gagneuxa and i wrote this ethics paper. we suggested that we conductresearch on great apes following principles generally similar to those accepted for human research, and even suggested that the researchers should volunteer to besubjects in the same studies.

(audience laughing) since i wrote this, i keep getting these letters saying, "please sign this document "banning all futureresearch on chimpanzees." and my answer is, "that's a terrible idea. "would you ban all futureresearch on humans?" but unfortunately, that's what's happened for other reasons, really good reasons of getting chimpanzees out ofnot-very-good facilities

and avoiding invasive research. then i just threw up its hand on this, stopped all chimpanzeeresearch, practically speaking. and the question is, will theban on chimpanzee research actually do more harmthan good to both species? and add to that a final corollary,chimpanzees would benefit from more ethical studiesof their own diseases, and i'm hoping that we can still keep this area of research open because

i think it's important forboth humans and chimpanzees and the diseases that we both get. thank you. - 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 itsmore insidious form of it, atherosclerosis, is the source of say, every three out of 10 deathsaround the world today. so it's so familiar to usthat the obvious question is well, is atherosclerosisreally 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 streaksthat 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 ordoes not always present clinical manifestations thatwill affect our morbidity,

and ultimately, mortality. so a standard kind ofstory is that if we could zoom back into the past andlook at hunter-gatherers, that hunter-gathererswouldn't have these types of heart disease, orother types of problems, and that it's modernfeatures 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, ourbad habits as barbara said, like cigarette smokingand alcohol consumption, that these are maybewhat create the problem, and that hunter-gathererswould have little or no coronary heart disease. and the evidence for this is often focused on some risk factors, so cholesterol, type iidiabetes, low prevalence,

that their risk factors seemto 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, thenumbers are fairly small. and often, there'd be amedical team, like in the 1950s or 60s that would sweep through a village, but fairly quickly.

and so, it could be thatpeople who have heart disease died fairly quickly from it, and so unless you've spenta 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 atpeople over the age of 60, no one has heart disease maybe because

they died earlier on in life. but also, the assessmentis 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 indifferent human populations,

then it might not be aone-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 aestablished 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-3swas 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 earlierinferences were based on and further kind of x-rayand ultrasound studies actually show the opposite,

that there is quite a decentamount of atherosclerosis and that heart disease didn'treally 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 fishoils on heart-related deaths, heart attacks and strokes. so the standard story isactually 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 unanganwomen from the aleutian islands, up here, is woman about50, here a woman about 30, and you can see someevidence of calcification in the aortic arch on topand in the carotid artery down here on the bottom. and what they found wasevidence of calcification

across all arterial beds, across all four populations. and so they argued that, their conclusion was thatwe found that heart disease is a serial killer that'sbeen stalking mankind for thousands of years. the presence of atherosclerosisin pre-modern human beings suggests that the diseaseis an inherent component of human aging, and not characteristic

of any specific diet or lifestyle. so now the paleo dietpeople hated this, right, because they were basicallysaying, "look, it's all over, "it doesn't matter what you eat. "we find evidence of this everywhere." but of course, all themummies have been long dead so it's hard to know whatthey actually died of and whether that atherosclerosis might have been relevantto their daily lives.

now also, if we're ridingoff of adjit's talk, we now know that chimpanzees, while the number onecause of death in captives is heart attacks, it's not exactly coming from the same ideologyas human heart attacks that chimpanzees do not seem to have the same kind of atherosclerosis, coronary artery disease is rare, but the heart failureinstead is through this

diffused interstitial myocardial fibrosis often triggered by arrythmias. you can see the diffused kind of fibrosis in the hearttissue 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 foralleles in the apoe4 that are higher risk ofatherosclerosis in humans and less physical activity, so quite remarkable difference. now the standard kindof evolutionary story brought to us by someevolutionary biologists in the critical foundational contributions medawar as well as holdane and hamilton, that basically that the force of selection

declines with age asfertility is dropping, so the relative contributionsfor future generations are declining, and soyou can have mutations that exert effects latein life that might be somewhat blind to theeffects of natural selection, especially if they havebeneficial effects early in life. so what that means is thatyou'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 failcoronary heart disease, that those cases do fallinto this selection shadow. so one kind of knee-jerkresponse is, well, maybe again, these things havealways been with us, but in hunter-gatherers, if you're not gonna live to this kind of age range,

then you're not gonna seethese types of ailments. and so that might be the end of story, and that our longerlives in modern society is why we see so much more of it today. but that doesn't reallyseem to be the case. if we take some of thebest demographic data out there on hunter-gatherersas kind of a key, obviously, livinghunter-gatherers are not the same as our ancestors, but it'sthe closest thing we have

to try to understandwhat life and mortality might be like withoutall the modern amenities. and so, in hunter-gathererswhere the average life expectancy at birthis 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 mortalityand it's quite high, the difference, but mostof those differences are early in life. and that by the timeyou get to, say age 15, the mortality differencehas dropped from, say 200, early in life to 14 timeshigher in hunter-gatherers, to about age 40, seven timeshigher in hunter-gatherers, and by age 60, that mortality difference is only three times higher.

so if you live past thisearly period of high mortality and you survived to age 15, the mortal age of adult death is actuallyit 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 seethese 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, twopeople actually have some more direct evidence. and so since i mentioned since 1999, we've been working incentral lowland bolivia with the tsimane, so again,horticulturist population that share many similaritieswith 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 andseveral days in a canoe away, we brought people to the ct scanner to get a more directmeasure of atherosclerosis through looking at coronaryarterial calcification

based on thoracic ct scans. so using the exact samemethods for scoring as in us studies, whatwe compared americans to the tsimani, it actually turns out that well, the tsimanis, these are here in red, there is evidence ofatherosclerosis, of calcification, but the levels are much lowerthan what we see in the us. now the mesa, this isthe multi-ethnic study of atherosclerosis.

these are asymptomaticpeople without heart disease or diabetes that are in the sample. so compared to those,the percentage of people with any calcificationis much, much lower. and in fact, the tsimani reached a level that the americans have, that'sa gap of over 20, 25 years. and so one easier way of thing about this and this kind of obscurecalcification 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 equivalentof someone in the mace study. and compared to what you would expect based on just the calcification score, that the tsimanis showevidence that basically estimated arterial ages, that are about 20, 25 years younger thantheir chronological age. but the great thing aboutworking with living people,

if the story ended there, we might say, well, look, just like wefound with the mummies, there's atherosclerosis in the tsimani. but here at the clinicalfindings 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 densitylipoprotein cholesterol, low blood glucose, so all the risk factors are fairly minimal. and then if we actuallylook based on ekgs, if we look for evidence of past infarcts, over 1,100 ekgs, we'velooked at people 40 and up, maybe one case of an infarct looked at by our team of cardiologists. and even that, a coupleof the cardiologists

think it's dubious. and also based on other evidence with ekgs and also with ultrasound, evidence of preserved systolicand diastolic function. and it's not the casethat the young people that have these conditions, then are dying at early ages, or that these people havehigh 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'tseem 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 veryhigh levels of inflammation.

and you know, in the past 20 years or so, it's well-known that inflammationis a major risk factor. in fact, it is afundamental 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 doneby your own clinician. they have very high levelsand cumulative levels over their life course, levels that would

basically associate withhaving heart disease amongst ourselves. and they also have low levels of the high-density lipoproteinsor good cholesterol. so a few take-home messagesfor a larger biomedical field. first of all, it doesn't seemlike the inflammation story is very complete, that thesame kind of risk factor might not exert the sametypes 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 particularlypopulations 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 inflammationare either unrelated

or in some ways oppositelyassociated with our measures of arterial calcificationand other indicators and it could be thatinflammation that we experience from cigarette smoking, from obesity, the so-called sterile inflammation might have differenteffects than inflammation that is induced under the conditions more representative of the past which would be more from infection.

but also, there are othertypes of infections, particularly helminths,these are intestinal worms, our old friends that we've carried with us for long, long periods ofour evolutionary history, that they exert regulatoryeffects on the immune system and also anti-inflammatoryeffects that might perhaps protect against theotherwise destructive effects of inflammation. and the other take-home is that

what we consider averagemight not be really normal. so james o'keefe, a physicianback in the early 2000s, argued the case based on randomized placebo-controlled studies with statins that if you look atthe chronic ldl levels, and you looked at a whole bunch of things, this is just the decrease over time in the lumenal diameter, sothe interior of the artery, but you gotta changethe 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 somewhatlinear relationship to the point where if you draw the line, that you would expectto almost zero events. in this particular graph,it would mean basically a slowing of atherosclerosisto the point of stopping

at a level of about 70or just less than 70, and so they were arguingin a series of papers that the optimal ldl shouldbe something between 50 to 70, whereas your typical recommendations,at least up until 2013 when the statin-basedrecommendations changed so that we're not reaching a target level. but it used to be thata hundred was a level. but it actually turns outthere's a decent amount of heart attacks in theregion 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 theldl here in the tsimane compared to americans, andit might be a little hard, sorry, to see the numbers, butthe mode in the average there is about 70 for the tsimane, whereas about 85% of americanshave ldl higher than that. and that what's yellow thereis in that 70 to 100 region

that basically many ofamericans would fall into, even if they were taking statins. so less than 70 is ahunter-gatherer level of ldl that might be more extremebut 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 pervasivethan we see in the west. so certain features ofcardiovascular aging may be universal. so you might see some calcifications and stiffening of the arteries,there's some declines, they might be delayed insystolic and diastolic function, but they occur nonetheless. yet the clinical manifestation, so whether it's heartattacks, hyper tension,

peripheral arterial disease, strokes, that those themselvesmight not be universal, and were likely very rare throughout human evolutionaryhistory, despite the fact that we can observecalcifications 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 ina very different environment, particularly in presence of amore diverse set of pathogens. and it also raises thequestion of what is normal, what are the target levelsof 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 apopulation 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 thatare more likely to have certain types of infectionsthat could be cardio-protective. even a lot of our standardmodel organisms in the lab are infection-free, and sothere might some limitations of what can be gained. and also taking advantage of the fact,

and the horror of the fact, that all indigenouspopulations around the world are in different states of flux, so it's a kind of quasi-natural laboratory for looking at the changesin lifestyle and environment on how that shapes increasesin type ii diabetes risk and in heart disease. and so it's sort of untappedterritory that very, in fact i don't know anybiomedically-oriented folks

that are working in thesepopulations 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 framinghamstudy kinda risk factors. and i think those domake a big difference.

but also, regulated immune function in the presence of certain parasites might also have some protectiveaspects 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 crittersas we would have in the past, that not only helps explainauto-immune type diseases currently, but also may beextended to heart disease.

thank you very much for your time. - so i will discuss todaythe relation between inflammation and metabolismand metabolic homeostasis and diseases susceptibility. inflammation is a protective response to a variety of challengesthat we may experience, including infection and injury and various types of tissuestress and malfunctions and all the things that can go wrong.

all of them can inducean inflammatory response that meant to be protective. and depending on the type ofchallenge that we experience, there's different physiologicalor intended purpose of the responses, such ashost defense from infection, tissue repair response or restoration of a normal state of the tissues. and what is very interestingabout inflammation and very clinically important is that

all these differentpathways to inflammation can result in a varietyof 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 simplifiedsummary of inflammation of inflammatory pathway.

when inducers of inflammation such as pathogens or tissuedamage 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 practicallyevery tissue in the body

and they change somefunctional characteristics that intend to either cause elimination of whatever caused inflammation, or adaptation to thepresence of these conditions. and why inflammation is sobroadly associated with diseases, very symbolically, itcould 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 wouldbe evolutionary stable if the benefits are higher than the costs. and anything in thisgreen part of the triangle would be therefore potentiallyevolutionary stable and everything here would be unstable. and the problem is that,in the case of traits that can provide very highbenefits 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 theabsolute value of the cost, this would be already, fromthe patient perspective at least, and the doctor's perspective, this would be already in the disease zone. this would be conditionsthat we would experience as something that isdefinitely not well being

and doctors would diagnoseas being various types of pathological or diseaseconditions even though they still provide morebenefit than the cost. and what we're interestedin is in the biology of this upper right corner,where the high benefits associated with very highcost and where we basically on the edge of the chaos or transition into the pathological statesthat 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 ofmechanisms that are employed by our system, by ourorganism in order to survive critical conditions? the ones the are justone step away from death. and this is just in a very schematic way summarized here, so if weconsider 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 complicationsof this conditions you get referred to someinternal medicine specialist. these are more complex diseases, but you can still recoverand go back to health.

and in severe cases you can get into this critical illness statewhen you get into icu. and you still can recover from here, and in this critical illness state, which is conditions likesepsis, pneumonia, heart attack, brain damage and so forth. in these conditions you areone step away from this tree proximal mechanisms thatlead directly to death. and these are points of no return,

which is respiratory failure,cardiovascular failure, or damage to the brain areasthat control respiration and cardiovascular function. so we're interested in what happens here, what kind of mechanisms may be evolved to prevent this transitioninto this point of no return. the case i will discuss today has to do with this very enigmaticand very interesting and familiar to everyone,

set of conditions knownas sickness behaviors. this is something everybodyin this room experience when you have flu or anyother type of severe infection or other types of acuteillness, we all experience this set of conditionssuch 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 wouldall be in that category. and the biology of sickness behavior has not been really well-understood, although there were earlystudies that demonstrated that sickness behavioris not just a consequence of system being destroyed by a pathogen, but rather these are motivated behaviors, in other words they areintended by the organism

for some reason. and there's been many speculations that whether there isaspects of sickness behavior, perhaps held the immunesystem to fight infection or maybe there's some otherway 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 wecan survive an infection or any other challenge for that matter. we can either resist it, soin 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 infectedand pathogen expand, we can become ill asindicated by this position,

and from here, we caneither go back to health by getting rid ofpathogen, which is the role of the immune system,and this is referred to a resistance to disease, or we can adapt to thepresence of the pathogen and go back to the healthystate despite microbial load. and this would be referredto as increased tolerance to infection or tolerance to damage. there are two ways thatpathogens cause damage.

one is directly through tissuedestruction through toxins, viral infections and so forth. and the second more commonway that pathogens infections call illness is due todamage by the inflammation caused by infection. and so we were interested in figuring out whether sickness behaviorsprovide benefit first of all, secondly whether they providebenefit because they promote immune function andresistance to infection,

or whether they providebenefit by promoting tissue protection and toleranceto inflammatory damage or pathogen induced damage. just like in humans andmice or in any animals that've been studied allthe way back to insects, when they are ill with acuteinfection, they stop eating, this is food consumptionin mice after they received a dose of listeria infection. this is common foodpoisoning type of infection.

they stop eating and untilthey start clearing infection and they start recovering andthen they start eating again. but there's a very profound anorexia associated with infectionas you can see here. so some studies done over40 years ago actually found that in the model of listeria infection, if mice are force-fedthen mortality increases. and this is what we reproduce here. so this is showing survivalof mice that are given

ld 50 dose of listeria, thosethat kills half of mice, and this is what's shown here. and if they're force-fedthen 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 whatcomponent of food kills. so we gave them separately proteins, fat, and sugar. and it turns out that sugaralone 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 dailycaloric intake of glucose, was sufficient to kill 100% of mice.

conversely, if we gave themglucose inhibitor called 2dg, 2-deoxyglucose, it's amodified form of glucose that cannot be metabolized soit blocks glucose utilization then 100% of mice would survive. and importantly, this was notbecause the immune system was affected in its ability to treatto get rid of the pathogen, and it's not becausethere was high dose of higher magnitude of inflammation, because there were not different between

mice given glucose ornot as you can see here. so this indicated thatmice survived or died from this manipulation because of the affecton 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 wheninfection becomes systemic, when it gets into blood.

in this case it's a bacterialsepsis that's mimicked by giving mice thiscomponent and a toxin lps. and as you can see here, ifmice 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 ifthey're just given sugar, then they all drop dead. but most excitingly they'rejust getting the simple drug

that blocks glucose utilization, then 100% of them canbe rescued from sepsis. and sepsis is a reallyterrible intractable condition that is still a very commoncause of death in icus. so again, the mortalityor protection from death in these manipulations was not dependent on the degree ofinflammation as shown here, was example of a coupleof 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, andnow we ask what would happen in influenza virus infection. so when mice are infected withflu virus, again they undergo

this period of anorexiawhen 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 almostlethal dose of flu infection, most mice die, but whenthey'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 infectionand bacterial sepsis. and again, the effect of glucosewas not due to its impact on inflammatory response. so in viral infectionsit's a different type of inflammatory response,which is dominated by interference shownhere, they're the same.

and those of burden ofthe virus in the lungs was also the same, was not different. again, suggesting theeffects are due to impact on tolerance to tissue damage. and the data that i'm not gonnashow, but i summarized here, what we found is that deathfrom viral inflammation was associated withdecline in vital functions, like respiration, blood pressure, so on, suggesting that there was a failure

in autonomic controlcenters in the brain stem. and if mice are given food or glucose, then these declines in autonomicfunctions could be rescued, they're given 2dg, they're enhanced. in contrast, death frombacterial sepsis was associated with neuronal damage in the mid-brain area and the death was immediatelyproceeded 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 inflammationversus viral inflammation was very different, and it segregated exactlyto this to this brain areas. such that in viral inflammation it was primarily in brain stem, and in bacterial inflammationit was in mid-brain area. the increased deliveryof glucose to this areas

related to the impact ofglucose or glucose inhibitors on the damage to these areas. and then we asked what doesthe mechanism of damage and what's happening there. so i will just summarizethat part of the study. what we found was that in thecase of viral inflammation, what happens with cells thatare infected with a virus, one of the things that happens, there is particular type ofcellular stress response,

known as unfolded proteinresponse, that has two branches. one branch tries to adaptto this stress condition and to resolve it, and if that fails, the second branch would killthe cells, as a second option. and this death from thisresponse is mediated by this particular gene called chop, it's a transcription factor. and what is known is that glucosedeprivation can exacerbate in unfolded protein response,this stress response pathway.

and so we hypothesizedthat that brain stem area, the neurons in the brain stem, for reasons that remain mysterious, underwent this excessiveunfold protein response stress that was ameliorated byglucose and exacerbated by 2dg. and then we asked whetherthis pathway of cell death or neuronal damage mediatedby this gene is involved. and for that we asked whethermice that have a mutation in this gene, whetherthey would be rescued

from the effect of suchinflammatory manipulation. and indeed what we found, ifwe 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 hereis related to a blockade of this pathway for neuron dysfunction.

and finally in the case ofsepsis or bacterial inflammation, fasting metabolism thatprotected them from death was related to the switchfrom normal fat metabolism to a fasted metabolism,which there's a switch to fuels from glucose toketones, and that which was necessary for mice to survive sepsis. and this is shown here,that giving glucose blocked transition to fasting metabolismand 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 thisfinal set of experiments, if we gave the mice anti-epileptic drug called valporic acid,then we could rescue them from death even whenthey're given glucose. and so that indicated thatthe reason that that worked is because valporic acid, unlikethis other drug shown here,

which is keppra, which isalso anti-convulsion drug, valporic acid, one of itsmechanism is related to the effect through the sameeffect that ketones have on a particular classof enzymes in the cell. so i will summarize it here, that there are twodifferent pathways to death, and fasting metabolismis protective in one case and detrimental in the other case. and the final, the implicationfor human treatment in icu

is that all clinical trials done so far, with nutrient manipulationin 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 becausethey were not separated and they basicallycancelled each other out. so now we are planning toconduct a clinical trial where we'll separate them,based on causes of sepsis.

so this is the summary andfinally this work was done by three very talentedscientist in the lab, harding luan, sarah huen, and andrew wang. and we had help fromother colleagues at yale, and thank you for your attention.