Januari 03, 2017
- [announcer] this ucsd-tv program ispresented by university of california television. like what you learn? visit ourwebsite, or follow us on facebook and twitter to keep up with the latestprograms. ♪ [music] ♪ - [narrator] we are the paradoxical ape;bipedal, naked large-brained. lone the master of fire, tools and language, butstill trying to understand ourselves. aware that death is inevitable, yet filledwith 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 bringstogether experts from diverse disciplines
to exchange insights on who we are and howwe got here. an exploration made possible by the generosity of humans like you. - [christina] thank you so much. it's sucha pleasure to be here. i'm going to be talking about some other genomes thatcontribute to what makes us human. this may look like a photograph of outer space,but these pinpoints of light are not stars. they're in fact the glowing genomesof millions of bacterial cells on the surface of human teeth. this is dentalplaque. the human body contains an estimated 30 trillion human cells and bythe latest estimate, 40 trillion bacterial cells. and so, if you add these twonumbers up together you will find that we
are more than 50% bacterial. 40 trillionbacterial cells is an incredible number and at an average length of just over onemicron, if you were to line them up, just the ones in your own body alone, end toend, they would actually wrap around the entire earth and span more than 20,000miles. 40 trillion bacterial cells is truly an astronomical number and even thisfails to capture the immensity of this number because there are only about 300billion stars in the milky way galaxy. and so, the number of bacteria in and on yourbody actually exceed the number of stars in more than 100 galaxies. at this pointyou may be wondering how you appear human at all and the answer is that, althoughnumerous, these bacteria are also very
small; on average they're 1,000 timessmaller than a human cell. when you add them all up together, they make up about2% of your body weight or roughly 1.5 kilograms. that's a really interestingnumber because that's about the same weight as your brain and your liver. somehave argued that we should start to think of the microbiome as an additional organsystem. most of these bacteria are concentrated in the gut and specificallyin the distal colon. and in feces, they're actually concentrated to an extraordinarydegree. there are over a 100 billion viable bacterial cells per gram of feces.and so, if you follow math through that means with each trip to the toilet youactually lose 20% of your total body
cells. but don't worry, you regeneratethem very quickly after your next meal. in addition to the gut, a smaller but alsovery important fraction of your microbiome lives within your oral cavity and therethey inhabit the buccal mucosa, the surface of the tongue, and the surfaces ofyour teeth where they're called dental plaque. now, the oral microbiome actuallyplays a very important role in the history of microbiology because the firstundisputed description of bacteria comes from a letter written by antony vanleeuwenhoek to the royal society of london, approximately 300 years ago, inwhich he described, "very many small animals which moved themselves veryextravagantly within his dental plaque."
he drew many of these organisms and hetried to count them but he eventually gave up and he wrote, "the number of theseanimals in the scurf of man's teeth are so numerous that i believe they exceed thenumber of men in a kingdom." now, if anything, this is a gross understatementbecause we now know that there are nearly as many bacteria on the surface of yourteeth as there are humans on earth and each day you swallow an average of 80billion bacteria in your saliva. so in addition to being numerous, these bacteriaalso contain an immense diversity of genes. on average, there are about a 150times more genes in your microbiome than in your human genome. this bacterialgenome is so large that it's often
referred to as your accessory genome andin fact, you require these genes in order to perform some of your most basic humanlife functions. this has led some to describe the relationship between humansand their microbes as that of a super organism like a colony of bees, manyindependent organisms contributing together, or more recently, as aholobiont, an ecosystem so tightly interdependent that it behaves as a singleorganism like coral. rather than just being a leaf on the great tree of life, insome ways humans are actually more like a tree house; a home woven from manypermanent and transient microbial inhabitants. yet, we have only veryrecently come to even notice this large
number of under explored, and mostlynameless, microorganisms that inhabit the human body. in fact, it was only in 2001that joshua lederberg coined the term "microbiome" in order to "...signify theecological community of commensal, symbiotic, and pathogenic microorganismsthat literally share our body space and have been all but ignored as determinantsof health and disease." this is rather remarkable because these microbialcommunities perform essential major functions within their host bodies thatinclude various aspects of digestion; vitamin production and drug metabolism;education of the immune system; and defense against pathogens. but themicrobiome can also be a source of
infectious agents for example, the oralmicrobiome is the natural reservoir for numerous respiratory opportunisticpathogens that are responsible for infections ranging from pneumonia tomeningitis. the oral and gut microbiomes have been implicated in several chronicinflammatory diseases including cardiovascular disease where in a recentstudy it was found that more than 80% of diseased valve and arterial tissuescontain oral bacteria. so the microbiome clearly plays a pivotal role in humanbiology, and therefore, it is critical to understand its evolution and changingecology through time. one way we can do this is we can investigate the ancestralhuman microbiome by directly measuring and
analyzing it from archaeological material.now ancient dna studies have long focused on the analysis of the bones and teeth.and we've made major advancements studying these tissues. and we've been able to, forexample, recover host and pathogen dna and reconstruct the entire genomes of extinctanimals, archaic humans, and even ancient pathogens. but studying the microbiome hasbeen very challenging. the human body decays rapidly after death. in some cases,mummification can occur but in the vast majority of instances, we are left withonly a skeleton. but there is one microbiome that routinely persists afterdeath and that is something called dental calculus. this is a...what it essentiallyis is dental plaque that has spontaneously
calcified during life, you know this bythe name tartar which is what your dentist calls it. it calcifies during life...in away it actually is the only part of your body that fossilizes while you're stillalive and therefore, persists, like your skeleton, long after death. this is just aclose-up image of dental calculus; you can kind of see what it is. if you'rewondering what this looks like in a living person, here's an image here. this iscalcified microbial matrix on the surface of teeth. this particular example is froma woman who died approximately 1,000 years ago. we can take a...we can zoom in onthis particular tooth here, and here i've just shown that same tooth now incross-section using scanning electron
microscopy. we can zoom in on thiscalculus deposit that you can see on the surface of the enamel; there it is rightthere. we're going to zoom in, again, on this part right here and one of the thingsthat's very clear immediately is that it has structure, it has a layered structure.that is because dental calculus forms incrementally. dental plaque undergoesspontaneous calcification which kills the microorganisms inside but also entombsthem. then, another layer of dental plaque forms and this process repeats and, overtime, it builds up layers like tree rings or layers of an onion. what's reallysignificant about this is what it means is that we have an ordered record of thisperson's life history from the earliest
period, closest to the surface of theteeth, to the latest period of their life just before they died. this structurenever remodels and therefore, is a remarkable record of this person's lifehistory. we can zoom in even further and actually see the individual microbialcells that have been calcified in situ. we can also decalcify it and use stains likegram stain to visualize these bacteria. remarkably, when you remove the mineral,the bacteria do not disintegrate. and in fact, you can see individual microbialcells here. so, these are individual gram positive bacteria, for example, here stillwith cell wall intact. what to me was most remarkable is we tried, kind of on a larkwe didn't think it would work, we decided
to use another stain, in this case hooke'sdye which is very similar to dot b [sp] if you've ever used that, it's a dna dye, itbinds to double-stranded dna. this is the image we got after that which you saw inthe beginning. this is the only archeological material that i know toexist that has so much dna inside that you can actually see it under a microscope.this property turns out to be pretty remarkable for calculus. if we're going touse by comparison, let's just sort of talk a little about bone and dentin, those arethe tissues that are most commonly studied. they actually have very littledna inside, even when a person is alive. so, bone, for example, has fewer than1,000 cells per milligram, it's almost
acellular. we have, typically inarcheological context, we recover very little dna; typically, less than ananogram of dna per milligram that we study. even that is mostly environmentalbacteria that have invaded postmortem. here's just some data we've generated inmy own lab. we looked at four teeth from different parts of the world, differenttime periods, and we looked to see what the endogenous content was of dentin. whatwe find is that only a tiny fraction of that dna is actually human, most of it,the vast majority, is postmortem environmental bacteria that aredecomposing the teeth. on average, we get something like 0.1 to 8% human dna; so,very very low amounts of endogenous dna.
calculus is completely different. firstoff, it starts off with far more cells. on average, it has more than 200 millioncells per milligram. in our lab we've isolated in excess of 500 nanograms of dnaper milligram we've studied. what's also really remarkable is we have very lowcontamination from environmental sources. these are the same teeth, but now we'veanalyzed the calculus from them and what you can see is the endogenous content, theoral microbiome per portion is much much higher, it's on the order of 60 to 80%. wecan look then at pairs, again, of calculus and dentin and we can see the amount ofdna that we can recover, this is a logarithmic scale, is on average about twoorders of magnitude higher; nearly 100
times more dna in calculus than in dentin,in some cases, 1,000 times higher. we thought in the beginning this might bejust because it starts off with more dna so we decided to test this. we took atooth that was very diseased, it had a massive carious lesion and also a giantabscess, this would have had tons of bacterial dna, tons of bacteria at thetime this person died and we expected we might see elevated levels of dna fromthese samples. in fact, we don't. we find they're almost the same as what we see forhealthy dentin. that seems to imply that there's something special about calculusthat facilitates dna preservation. we can then actually go in and say, "what do wefind in calculus? this is an amazing
structure, it's full of dna, what sorts ofinformation can we learn from it?" we can break it down into different categoriesand we can say "well, about 99% of it is bacterial." that makes sense. we know thisis made of dental plaque. dental plaque is primarily a microbial matrix, but about 1%is quite interesting. we have a little bit more than a half a percent which iseukaryotic, that's mostly host and dietary. we also find a tiny bit archaeaand a little bit of virus. the virus is actually bacteriophage which are virusesthat infect bacteria. we can also extract proteins from dental calculus. we can alsoclassify them. what we find is about 80% of the proteins are bacterial in originand about 20% are human. i'll come back to
that in just a few minutes. let's focus onthe bacteria first. we've identified more than 1,000 species, but the vast majority,more than 85% of the sequences, bacterial sequences, that we find actually belong to100 highly abundant taxa and some of them are very interesting. here's just aselection of some of the bacteria that we've identified in dental calculus,ancient dental calculus. i mentioned earlier that the oral microbiome is amajor reservoir for opportunistic infections. we find many of these bacteriapreserved in dental calculus. i want to caution here that finding them does notindicate this person had this disease while they were alive. carriage of theseorganisms is quite widespread, even
asymptomatic carriage, but these bacteriahave the capacity to cause disease under the right circumstances, for example, ifthe host is immunocompromised. what's really significant about this is it givesus the opportunity to study the evolution of these opportunistic pathogens becausethey do not preserve in any other context and some of them are very interesting. so,for example, streptococcus pneumoniae is a causative agent of pneumonia.streptococcus pyogenes that's one of the causes of strep throat. haemophilusinfluenzae causes respiratory infections and neisseria meningitides is a leadingcause of bacterial meningitis. now, we have a reliable source to study theevolution of these opportunistic
pathogens. a couple others that we foundextremely interesting are these three, a little bit lesser known. we have hereporphyromonas gingivalis, tannerella forsythia, and treponema denticola. wehave them at really high abundance and this is potentially clinically significantbecause these are the major causative agents of periodontal disease today. weinvestigated this a little further, we wanted to know did our ancient sampleshave unusually high abundances of these three taxa. what we did is we compared itto a reference set of healthy individuals from the human microbiome project. wefound that the frequency of these organisms within healthy individuals arevanishingly small. very very few copies of
these bacteria are present in healthypeople, but our ancient individuals had much higher frequencies of these bacteria.this did make sense, however, because we'd actually selected these individuals forstudy because they showed osteological evidence for periodontal disease. what wasinteresting about this is we were able to show that despite a century of intensiveefforts to prophylactically treat periodontal disease and prevent it, westill see the same organisms that are causing it over a span of more than 1,000years. now, one of these organisms, tannerella forsythia, we actually found atsuch high abundance that we were able to reconstruct a full draft genome. we're nowinvestigating it to try to understand the
evolution of this pathogen through time.in addition to the bacteria that are present, i mentioned before that we dofind some really interesting other material there. tt turns out dentalcalculus, like dental plaque, acts as a kind of sink for all the other things thatyou put into your mouth; including, host biomolecules, as well as food. talk reallyquickly about the host. early on we noticed that we were seeing human dnawithin dental calculus, this was really interesting to us. we just published astudy last month where using a capture based approach, we were able to enrich forhuman dna and reconstruct full mitochondrial genomes, in this case, froma cemetery, native american cemetery from
illinois. this is potentially, actually,quite impactful especially in north america there are many tribes who do notallow genetic analysis of skeletal remains because it is a destructive process. ifdental calculus can serve as a surrogate, it may be a way of conducting ancientgenetic analysis without disturbing the actual skeletal remains themselves. wealso find a huge abundance of human proteins within dental calculus; this iswhere it gets extremely interesting. most of these proteins, i've color-coded themby sort of what their function is, most of these proteins are colored red and that'sbecause they are part of the innate immune system. what's interesting about this isthat by having proteins we get an
additional level of information. we arenot only identifying that we have human proteins, but many of these proteins arespecifically expressed in different cell types. in this case, many of them arespecific to neutrophils. so we can identify the source of these proteins as aspecific immune cell that's reacting to dental calculus. so what we're actuallyvisualizing here is evidence of an active infection at the time of death. in termsof diet, it's long been known that microfossils, plant microfossils andanimals microfossil, preserve within dental calculus. so, all that little bitsof food that get stuck between your teeth, they actually stick around for a reallylong time and we can see them under the
microscope. what you're looking at here,this is a little bit of connective tissue from some sort of animal tissue thisperson ate. this is a phyta life, it's a little piece of plant glass. these twohere are actually intact starch granules. this one, the morphology is consistentwith the plant tribe tricaceae which includes things like wheat and barley.this one has characteristic structures of the plant family fabaceae which includesthings like peas and beans. we can also extract dna from this and get even higherspecies level resolution. this particular tooth came from a man who lived in germanyabout 1,000 years ago when in his teeth we found evidence of sheep, pigs, cabbage,and wheat. therefore, conclusively
demonstrated the german diet has notchanged much in more than 900 years. we can also isolate proteins from dentalcalculus to investigate diet. one of the most interesting ones that we have foundso far is one called beta-lactoglobulin. beta-lactoglobulin is specific to milk andas a result, we've now been able to test more than 100 individuals and identify thepresence of dairy throughout europe dating back to at least the bronze age. wepublished these results last year. we're building on them now. our goal in the nextphase of this project is to try to understand the origins and spread of dairyin the middle east and europe. what's also amazing about proteins and using thisapproach is that because it's sequence
based, there are sequence variants thatare species specific. we can actually distinguish cattle milk, sheep milk, andgoat milk and have a very fine scale resolution of how these dietary practiceschanged. if you'll pardon my pun, i think we've only scratched the surface of wherewe can go with dental calculus analysis. one of the most exciting things that ifind about it is that, is it's ubiquity. so, dental calculus is found in allliving, in all known living populations today and we find it ubiquitously inskeletal assemblages from the past. it's also found on neandertal teeth and theteeth of ostropreozines, it's actually quite abundant on chimpanzee teeth aswell. and i think by studying it, it can
provide a unique window, a lens throughwhich we can better begin to understand the evolution of our ancient microbialself. thank you very much. i'd like to thank these people.
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