Hacking the Human Microbiome

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Video in TIB AV-Portal: Hacking the Human Microbiome

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Hacking the Human Microbiome
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2018
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The human microbiome is a diverse community of bacteria that lives inside us. Their contribution towards our personal well-being or sickness is controversially discussed within the scientific world and, likewise, in our society. First attempts to rationally (reverse-)engineer the human microbiome are hyped in medicine and within the DIY biohacking scene. The implications of these endeavours potentially concern several aspects of our life: eating habits, fitness state, susceptibility for infections, aging, and cancer. But what about ethical aspects of hacking the human microbiome? How can biosafety be maintained? Are there any data security issues? I will seriously discuss the state-of-the-art and future directions of the research to show whether actual hacking of the human microbiome is rather science or fiction.
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[Music] let's start by refreshing memories in reminiscence of a time when we were
striving to build computation devices from technical modules with defined functions to perform complex operations in reminiscence of a time after that when we were seeking to create self-replicating sustainable systems from biological bricks to understand life in reminiscence of a time after that when we were aiming at the optimization of our own life based on trillions of foreign cells bacteria inside us that time is now and with this
a warm welcome to all of you thanks for coming I'm really thrilled to be here
I'm excited to be here it's my first Congress unfortunately I have been sick I brought you some of the bacteria we're going to talk about but now I'm here I'm happy to be here no audio applause please we don't have time I said I'm Lawrence I'm coming to you from the Mahone Weitzman in revolt in beautiful Israel I'm happy to be here in this wonderful city leipzig and i want to talk to you about hacking the human
microbiome and i want to do this by answering four very essential questions
the first is of course what is the human
microbiome second of all after I introduced some general concepts of the human microbiome I want to tell you how we study the human microbiome what technologies we apply here and why this is all relevant to all of us then I want to answer the question whether there is a hype in public media about the human microbiome and whether this at all is justified lastly I want to also look into this glass ball into the future and want to ask okay what's next what's next in hacking the human microbiome again very relevant to all of us but let's go right into media's of this and ask the question okay what is the human microbiome and in order to answer that question I want to start with some very straightforward maps with a figure a number that you probably all
know I guess you know it's three billion but what's free billion any guesses three billion if you here free billion what comes to your mind it's not your
income unfortunately no it's the size of the human genome it's the length of the sequence of the genetic code of a human being these letters some of you I've given you here define this human being here this chubby guy and you see it's in blue so it serves as a blue blueprint of us as human beings but the question is is that all given this sequence information is this all that makes us us that makes us human or is there more to that more than this sequence well in fact there is more because we're not just human we are also bacteria here's one one bacterium and also this bacterium contains genetic information you see it looks a bit different now it's green not blue apparently and it's also less complex so instead of three billion letters it only contains around about five million and now you may say
okay so these three billion letters that define us as human beings it's just three billion letters for one single human being right but within us there's
not a single kind of bacterium there's many hundreds some estimates even say thousands so this complex letter a Samba we have to even multiply by hundreds or thousands to get the complexity of all bacteria that live inside us that make us now you may say okay but we as human beings were also complex you know we are not just one human cell
we have line cells heart cells some people even have brain cells so if you sum them all up we get a number of around 40 trillion okay we have 40
trillion cells on the other hand we have to admit that there's also not just a thousand different kinds of bacteria but
there are many in terms of numbers that even outnumber Adly or at least level the numbers of human cells so we also have 40 trillion bacteria inside us which is all published and you can look up if you don't trust me and if we want
to play this numbers game here we should be further more precise because from these 40 trillion human cells that we contain 80% of them we should not consider because they don't contain any DNA anymore and they don't contain any of these genetic information because they are just red blood cells they they are just sacks of ephemeral globin
without any genetic information okay so the human cells are much less complex in terms of genetic information and maybe one last math trick here to understand the complexity of these bacteria we have to take the Sun we have to take all of them all that live inside us with all their genetic complexity sum up to what we call the human microbiome now no matter how you do this number crunching one thing is for sure this is really complex and to understand it requires a lot of thinking so putting all this math aside again in a nutshell
the human microbiome is all bacteria that live inside us well at least if we consider ourselves human beings but even if you more think you know I'm more like a robot or something bacteria also grow on very sterilized surfaces like metal surfaces of very sophisticated and supposed to be sterile engines so even robots do have a microbiome but let's stick to the human microbiome okay I'm saying the human microbiome are all bacteria that live inside us and I stray
the inn but that's actually not true because they are also living on us if we look where we can find bacteria living together with human beings making us human beings we find them on the skin we
find them in our mouth in the airwaves we might even find them in our spinal cords can you imagine that bacteria in our nerves maybe in our brain dictating what we think how we behave is that even possible well I put a question mark there and we will come back to this later on most of the bacteria as a matter of fact do reside in our gastrointestinal tract so in our stomach and in the intestine in the colon and so forth and this is very fortunate because they are easily accessible usually we can access them in a very frequent
manner if we go to the toilet we sort of flush most of them out but no matter if you look in the toilet or on other sites these bacteria that you find that
compose the human microbiome as a matter of fact are a very complex community they are very diverse and I don't know what you think but for us as scientists diversity is something very positive it's very intriguing it's very valuable because it's inspiring something new we are not afraid of something new we can learn something from something new and
we are open-minded and looking for diversity and that's what we can find in the human microbiome and these bacteria are so diverse because they are highly adapted so in evolution they adapt to do very specific niches and became very different from each other and to depict this diversity of the human microbiome I show here four examples of these
bacteria okay they are very different for instance you have a blue one which has some flagella some sort of tails that it can propel to swim then you have
the purple one which has like a spiral shape you have an elliptic one which is rather reddish and you have an orange one that has like a spirit shape so just in terms of their morphology how they look from the outside they seem to be very different however there is one characteristic that they all share remember they are microbes so what they share is their common size in size they're around about I mean in terms of orders of magnitude they are one micrometer in length 1 micrometer is one meter divided by 1 million so they are very small of course some are just like half a micrometer some are more
like 5 but on that scale they all operate no matter how they look that's why there are microbes why they make up the microbiome they are living biome ok and their microbes so small rather small and but despite this common size as I said the morphology is very different and then we can just look at morphology
and try to form groups among these microbes ok and then we say yeah the the red one and the orange one they look rather similar so they are more evolutionarily related and then this group of bacteria is more later than 2 the spiral-shaped one and only then they are like related or ancestors share common ancestors with the blue one and all of them of course go back to one common origin the common ancestor of all these bacteria the bacterium that was there at first and this origin of course is the source of this entire diversity that nowadays lives inside us but here's the concept in biology that you need to know form follows function so every structure that we find is intimately related to a function biology so this spiral shape bacterium has a spiral shape for a certain purpose ok and so does the rod shape blue bacterium has its shape for a certain purpose so how do they functionally differ this bacteria and to understand that now you already managed like one third of my talk let's all together just take a deep breath okay there's even a phone buzzing this is also a function that could discriminate but in this case the ability to breathe air to live from air a differs between these bacteria okay so only two out of four can basically live with oxygen how come well some of these bacteria are somewhere hidden in our stomach so they are never exposed to oxygen they can live without it for them oxygen is even toxic but some of them are exposed to oxygen so they evolve towards using the oxygen for day for their metabolism and their life
what else do we have what else are we as humans for instance different from each other well when it comes to nutrition are there any vegans in the audience now you may argue that they are not yet an
entire different species but with eating habits comes a lot of you know differences and also you know there's people that like choke and there is no well never mind so anyways they have their preferences in terms of dietary habits so there is some bacteria that can process sugars
while others cannot and there are some bacteria that can process fatty acids short chain fatty acids long chain fatty acids unsaturated fatty acids and so forth and some others cannot and based on this if we look at these properties we could again assign some sort of
similarity matrix and then say okay we have like one group of bacteria and another group of bacteria and they are all very different from each other but with these differences also come interdependencies potential modes of interactions how these bacteria also depend on one another right they have to interact with each other that's like the payoff of diversity as well you have very different interaction partners that you can harness for your own benefit so let's look at the interdependencies of these bacteria if we have them here we
could in general hypothesize that they
all interact now in general we have like rough understanding how bacteria interact but for every specific peer power of bacteria it's quite tricky so there's many question marks many open questions here but again in general we can derive some some overarching principles how these interactions and interdependencies work for instance there is one set of bacteria that can process the ice cream that we are eating okay on the other extreme there's another subset of bacteria again living inside us the human microbiome that can process the sushi we are eating whereas the others cannot and why processing sushi now the blue bacterium generates small molecules that the other bacteria need to fuel their engines or even to build up their engines and these output molecules that it creates after processing sushi I depicted here as gears okay because gears really fulfilled this concept that they can fuel an engine itself or they can build up another machinery that can drive metabolic processes and make these bacteria life inside us and this sort of input-output relation a bacterium that consumes sushi and produces a gear can also on a conceptual level help us to better understand some phenomena we see in these bacteria now it's very technical devices right as some some sort of processing units so if we have now one processing unit one of these bacteria that processes one unit of sushi it generates one unit of gear okay and now comes an amazing property if we wait just a short while and expose this one unit of bacteria with another single unit of sushi it produces two units of gear okay so this bacteria this bacteria just as this Congress has the ability of refreshing memories it remembers okay I was exposed to one unit of sushi and it can edit to the one unit of sushi this exposed right now and produce two as a sum of one and one however this property this memory function does not last infinitely long so if we wait long enough and we now expose this bacterium to three units of sushi it produces three units of Eire and this is amazing because it this means that it was reset to zero and is still sensitive to large amounts of sushi just imagine you would expose your bacteria your gut microbiome to three units of sushi but as an output you would only get two units of years this would not be healthy in the long run so fortunately these bacteria can adapt which means that they are still sensitive even to large excessive numbers of input without again losing their ability to respond properly and this is even on a molecular level it for some of these input output relations it's not sushi but it's an onliner acid so rather simple it's very well understood and I even published this in my bachelors thesis when I simulated
swarming behavior of these bacteria and in the Journal of unsolved questions okay so we can even make very small contributions to the field now these features of refreshing memory adaptation and so forth translate now to a dynamic
behavior of these bacteria so they change with time right they grow they die they change the numbers inside us right while we are breathing here while we are listening to this talk and this dynamic behavior we can also from this dynamic behavior we can also derive common principles so if we look now at
the amount of these four bacteria over time first of all let's look at the extremes okay so there's always some bacteria they just die for instance the orange one it just gets extinct with time the other extreme there's one
bacterium that is not really there in the beginning but then it outperforms in terms of growth all the other bacteria and it dominates the culture or our human microbiome with time it just out grows all the others so it just increases the amount with time that's the purple one but then there's also some let's say intermediate phenomena for instance the red bacterium it just fluctuates with time but among these fluctuations which could in fact be very low maybe we cannot even detect them we cannot even measure them it's rather stable it always stays around the same level okay so this is some sort of
stability feature so even if we now try to perturb this bacterium we would not succeed because it's very robust in a sense and then there's the feature that you may know if you already encountered let's say the kids corners around here it's a phenomenon called resilience and this means basically one bacterium is
basically pushed away it's it cannot grow for for a certain time because maybe another bacterium takes away all the sushi that it would like would it that it would like to consume but then it you know takes keeps calm take some rest takes a deep breath and then it
decides to regrow it's also some sort of because it remembers where it was coming from but it's this ability to persist even strong perturbations you know even if you're being pushed out of the sandbox you just go to your daddy and cry but then you go back ok that's resilience and also bacteria do this however what is important here if we now look at the end of our experiment to
identify what kind of bacteria and what am i would like to which amounts we have them inside us usually it's just a relative measure so we cannot really measure absolute number of bacteria counting them individually but we can only say ok we have a lot of for sure at the end we have a lot of purple ones and we have very few of the orange ones but it's only in relation to each other ok so this also makes it hard to compare between different individuals let's say between me and and you so what what kind of technologies do we have to first of all identify these bacteria and then also tell more about like how many of these we have what techniques do we have to study the human microbiome this is
our next question and I've already outlined to you where we have a good source of the human microbiome in the toilet
so what we are doing all day in essence is we are extracting faeces ok we take faeces either from mice or from humans and then we take bacteria out of these faeces and put them into a petri dish for instance here we took the orange bacterium out of the faeces and put them into a petri dish where it has some growth media like all the nutrients it likes the sushi or whatever to grow but to know whether this is the orange
bacterium or the purple one or any other we have to test certain growth conditions let's assume we know about this bacterium whether it grows on in the presence of certain substances or not then we can just expose it to these conditions to see whether it's indeed the bacterium we think it is and that's exactly what has been done so we take this bacteria out of the fissile samples and then put them on plates under different conditions for instance there's one plate where there's no oxygen and also no sugar but then there's a plate where we do have oxygen but no sugar and so far so if you want this is like a the truth table of the of the human microbiome okay because then if we put the faeces on these plates we see okay if we don't have neither oxygen nor sugar in the top-left corner we have just a few bacteria but if there is no exit oxygen but they are sugar we have
many of these bacteria so now we can check okay which bacteria are known to grow in absence of oxygen but in presence of sugar and then we can boil it down and we can idea okay so there must be in an orange bacterium in this faeces and there's two problems with that first it's not as simple because
usually it's not sufficient to just test two conditions usually we do test 128 conditions and of course this matrix is much more complex then but even this matrix is not enough because there is no unique assignment of these conditions to individual bacterial strains individual bacterial species and also this is not a black-and-white picture
thus this bacterium really do not grow an absence of sugar I mean we have some of these bacteria there right so maybe we need some more sophisticated means and more sophisticated means we go back to the genetic information we crack open these bacteria and look at the genetic
code of this bacteria and we apply a technology that is called shotgun sequencing and by shotgun sequencing we
mean that we fragment this genetic information into small pieces just as the bullets of a shotgun are scattered when shooting I didn't invent this terminology and then we have to then we basically read these small fragments and have to put them back together in like a jigsaw puzzle okay and once we have the entire sequence back in one piece we have to check ok does this now look like one bacterium or the other bacterium so we have to find a good match just in any dating app that doesn't work this is also a non-trivial task because you can argue about the reference sequence that we have but you know with a certain probability we can now say okay that's the green bacterium here we
can infer we can predict what we sequenced here in this fissile sample must be the green bacterium it's not just one piece of genetic information we cannot only say it's this bacterium we can also say okay we find your many many gears that are needed so apart from the bacterium itself we can also more look like for functions that are carried out and can even put them together to more complex assembly lines for instance the sushi processing pathway now another note in terms of complexity of course this is does not just happen with the genetic information of a single bacterium there are hundreds of bacteria as I already told you so here we are not looking at a simple genome but the higher assembly of genomes which we call meta-genome okay which requires sophisticated means of computation also to denoise the signal and so forth because if we look at the data that is generated by this sequencing approach it basically looks
like this it's a very sparse matrix so here we have like for every gear that we can detect based on the genetic information and every sample that we
sequence like every fissile sample every stool sample we mostly get na which is not available there was nothing detected does it mean that this year that this bacterium this genetic information was not there or was it just too low to be recognized so this very sparse matrix is
very hard to interpret we need very good models to discern the true positives from the false positives and the true negatives from the false negatives and this brings us back to one of our initial questions bacteria in the brain if we now find a certain signal a certain sequence of a bacterium in fluid from the spinal cord does it really mean the bacterium is there no it's an indication but it can be a false positive and therefore this is still being discussed in the scientific community largely whether this is really true so in order to be certain whether some bacteria are really there of course we can do this in a huge cohort and look for something very easy to relate to for instance obesity okay so we take
stool samples from lean and obese patients and then we analyze them by me that I just introduced to you so we sequence these fissile samples and then we get an idea of which bacteria inside there okay now from looking at this kind of data it seems like okay the orange bacterium is more abundant in the lean human and purple bacterium is more abundant in the obese bacterium but again this is just relative maybe one is just pushing out the other is it the absence of one or the presence of the other that really makes us lean or obese well first what you can do you can take all these bacteria that we identified by sequencing in these two samples and look at them as features okay in an N dimensional feature space if you sequenced n different bacterial species you identified n different bacterial species you have an N dimensional feature space and then you can reduce dimensions and ask the question well can
i really separate the obese ones from the lean ones and I mean it looks like we have some decent separation okay so you can ask okay what are the features that discriminate the lean from the
obese which bacteria make us lean or obese and then if you find some bacteria that contribute to this you can basically look how they correlate so you put all the body weights of your
participants in this clinical trial on one axis and the amount of the bacterium that you detect it in this case the orange one on the other axis and as you have already learned most of the entries are zero because you cannot detect it but for the others you see some sort of trend so it seems like there's a negative correlation between the presence of this bacterium and your body weight meaning if you have more of this bacterium you are a leaner okay so this is maybe some bacterium that you want but of course you can also do like more sophisticated approaches here this is just some rank based correlation so you could also you know train like a
decision tree and some classifier do some machine learning stuff that you probably know better than I do but in the end does the patient care about whether this is correlation or really cost well maybe it gives us a hint what to try and anyways idea is what it is so what we want is we want to find bacteria that we can use for rational intervention that we can use to really now help these obese patients to become leaner or the lean persons to stay lean okay and what what can we do about this at the moment if you look at the media
there is quite a hype and there's one central question it comes to me or it should come to all of us when we see something that is being hyped in public media why I mean why is this relevant to
us well if we have bacteria that make us
leaner faster smarter we tend towards like self optimization and it's something very easy to try right to optimize ourselves so if we look at the media we can read well
there's some contribution to our eating habits Fitness State susceptibility for infections aging cancer etc PP you can do the search for your own if you just type microbiome in your favorite search engine you will find it there is one quote I brought you from an Israeli journalist who said he said in Hebrew but I brought you translation yesterday I interviewed the respected scientist of the computational biology field who told me that the best diet for obese people is eating poop of lean people and let the gut microbiome work okay so this is a straightforward suggestion if you type in your favorite search engine how to eat poop you will find what to do like microwave it filter it but let's take a step back okay let's see what what we can do they the funny thing is you can do all kind of mathematical operations with your microbiome you can subtract so
you have your set of bacteria in your gut okay that you want to optimize you
can take antibiotics they just eradicate some of the bacteria probably most of them but some will survive and you pretty much know a priori which are resistant to this bacteria and which not you can also do something more targeted which is like swallowing viruses for bacteria that are very specific that may just eradicate it like a single bacterium and all the others will survive but you can also multiply bacteria for instance assume you already have bacteria that do you good you're Alena and you just want to get a boost so you can just take what is known as prebiotics which are basically metabolites for instance like the sushi that some bacteria need to grow so you swallow that and your bacteria will multiply and you will have plenty of them another option is like a simple addition this is now the option of eating poop okay right you just takes two samples from from a healthy person and you consume them and the bacteria inside will inside this poop will then also be inside you and do their job we'll keep you lean or whatever you can also take certain yogurts or mixtures which are known as probiotics to just get some of these bacteria like very defined species that are supposed to be healthy in whatever sense or there's also some sort of vaccination where assume it's not a bacterium itself not the living bacterium but just some molecules on the surface of the bacterium that stimulate our body cells to do something healthier that stimulate our immune system or something so you basically heat inactivate the poop or maybe you add these specific parts that you already know that do good some of the gears right from the sushi and then you just inject them with the vaccination which will also I mean kill most of the bacteria in due to the heat but will probably give you these one specific pieces that you need to stay healthy the last mathematical operation missing is the division which is some sort of fasting so by just drinking water you basically wash out all the substances that the bacteria need to grow and they will be diluted themselves and you will be remaining with just a few bacteria and maybe all the bad ones are just gone okay so this is two options we have a tent now what to do with this in the future is it advisable to hack our human microbiome at this state-of-the-art in science I only want to provide you with
a single slide on that and just give a few advices here because it's on you it's on all of us too decide right it's on the Society we can just provide some guidance so here's
some guidance from my point of view
do-it-yourself biology is very tempting we really like it in Germany we have some legal constraints here but genetic engineering of bacteria is much much more simple than you here even now in the days of CRISPR cars where you can genetically engineer human cells bacteria to engineer bacterial says the
technology is 40 years old everybody knows it it's very straightforward however there are safety concerns whenever we engineer bacteria be it bacteria inside us from in from the inside of us or other bacteria it's becoming a genetically modified organism we are becoming genetically or modified organism I'm not saying it's a bad thing I'm just saying we have to consider biosafety first okay
then we've mentioned the human genetic information about human the human genome this is some very personal data right it is according to German laws very neatly protected but what about our meta genome is this not also part of our identity I'm raising this question here because the German ethics counsel is not discussing this even though again all
the technology has been there for decades we have to have this debate how to store this data how to encrypt it this has never been discussed and the time for this is really now what about
patenting genetic sequences we cannot patent our own genome but what about the genome of the bacteria inside us it's a legal gray zone - all that I know we have to think about this what if I only know the sequence of some bacteria that live inside me but other people don't we have to share these sequences - to learn something from this so in a nutshell and to cut a long story short what we can learn from this the human microbiome has
a lot of potential but there are also some threats and the only way to deal with them is together right we have to talk to each other to exchange information and only then make an educated decision how to handle this we and how to hack the human microbiome and before I arrived at the final slide I just would like to thank basically the
foundation that allowed me to come here to it that covers my travel expenses but of course all the organizers here I think it's again it's my first but it's the best Congress right I ever attended divides mine institute is a beautiful place to do science we are very open so please feel warmly a welcome whenever you are like in the vicinity just drop
by and then last not least let's end by
refreshing memories the human microbiome
is a complex ensemble of bacteria with non-intuitive interactions and interdependencies we are exploring mechanisms of regulation through hacking by rational interference under controlled conditions individuals single people companies try to monopolize technology knowledge and data constraining free and open research rendering the potential of hacking the human microbiome a threat through uneducated trials friends that time is over now thank you very much
thanks for the excellent talk we now
have about five minutes for questions you know the drill line up at the microphones and please keep it short because we are a bit short on time microphone number two please thank you for your talk I just wanted to
ask you if you can give us some examples of therapies that are used already with the bacteria maybe some examples yeah there's there's a youtube variety of what has already been done so we just now under sorted this for instance some bacteria that metabolize cancer drugs so they're basically what has been done now in addition to the cancer treatment is like there is antibiotics being given to eradicate basically the bacteria that could metabolize the cancer drug and and therefore I mean once the bacteria metabolize the cancer drug it will not be effective anymore so this is where like the eradication of some bacterial species benefits the cancer treatment then there is the treatment of crohn's disease which is done with bacterial supplements especially in the US this is already more conventional in Germany the legal situation is a bit more constrained let's say so all these things are just in the beginning we are starting to understand and I think there's many to come in the years following but again there's just a few examples where this has already been done in the clinics apart from this there is small clinical trials in terms of research studies where this has been done but again it's a very right field and I think it's just yet to start thanks Mike number four
please it's a simple question nowadays there is
hard to get the proper information because there's time of fake news fakes information where should I be educated about the you know microbiome nowadays proper research yes so good question I think the best source of information is actually the origin where it's generated so talk to the scientists that's why I put this hashtag psych on there science communication asked people who are doing it they know their stuff sometimes they are you know they're good scientists they are not the best people to communicate but that's something we as scientists have to learn right so don't be afraid and really approach them that's I think it's our obligation and our duty to share this information so go right to these people and approach them and they should provide you with all the information you need thank you thank you
number one place yeah you made a link
between obesity and your microbiome and your stomach and so on how do you know you're looking at the right point here and that you're not mixing cause and effect yeah that's a very valid point in fact there's many mechanistic studies as we put it so there is there were some bacteria which were associated with weight gain for instance and targeted depletion of these bacteria showed that basically the weight gain is reduced and then you can basically also turn it around and say okay if I now for instance you to food restriction in man or in mice if I lose weight does this bacterium also go away like is there what is the relationship and this has all been done and as I already indicated in the case of obesity where even one step further so it's not only that we identified bacteria but we also identified molecules these bacteria are producing that helped us to for instance keep our weight or stop regaining weight after weight loss and stuff like this so here we have very detailed information that very we have very solid evidence on this bacteria and this molecule however I have to state usually scientists report very modestly they say okay we have a certain confidence here we have a certain uncertainty and then this goes to public media and there's of course a huge headline like we only need to swallow poop to get lean but again I wanted to tell you it's more complex than that but again in this particular case we have a very solid understanding I feel thanks right thank you okay one
last hopefully short question from number three please hi it's a bit on the
same topic as the question before but what is the relation between micro biome and polygenic scores polygenic scores yeah like for instance Robert Plumbing recently published a book on like showing that obesity is mainly genetic at the the relationship yeah is mainly caused by like many genes yes and there is this concept of polygenic scores mm-hmm yes I'm happy to elaborate on this I'm afraid that with time we're not allowed but you're happy to come here and then we can elaborate on this in a private jet thanks a lot urn of perfect thank our speaker again
please [Applause]
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