 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, no, no. Hold your applause, please. We don't have time. As said, I'm Lawrence. I'm coming to you from the Mahon Weizmann in Rechovot 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 race and ask the question, okay, what is the human microbiome? And in order to answer the question, I want to start with some very straightforward maths. With a figure, a number that you probably all know, I guess you know, it's three billion, but what's three billion? Any guesses? Three billion. If you hear three 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 blueprint of us as human beings. But the question is, is that all? Given this sequence information, is this all 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 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 assemble, 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, we are also complex. You know, we are not just one human cell. We have lung 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 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. They don't contain any of these genetic information because they are just red blood cells. They are just sacs of hemoglobin 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 sum. 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 sterile 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 stress the in, 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 and 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 adapted to 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. 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's 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. One micrometer is one meter divided by one million. So they are very small. Of course, some are just like half a micrometer, some are more like five. But on that scale, they all operate, no matter how they look. That's why they are microbes, why they make up the microbiome. They are living biome, okay, and they are microbes, rather small. But despite this common size, as I said, the morphology is very different. And then we can just look at the morphology and try to form groups among these microbes, okay? And then we say, yeah, 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 related than to the spiral-shaped one. And only then they are 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 in biology. So the spiral-shaped bacterium has a spiral shape for a certain purpose, okay? And so does the rot-shaped blue bacterium has. It's shaped for a certain purpose. So how do they functionally differ these bacteria? And to understand that, now you already managed like one third of my talk, let's altogether 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, 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 their metabolism and their life. What else do we have? How 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 differences. And also, there's people that like junk, and there is, no, well, never mind. So anyways, they have preferences in terms of dietary habits. So there is some bacteria that can process sugars where others cannot. And there is 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 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 a payoff of diversity as well. You have very different interaction partners that you can harness for your own benefits. 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 a rough understanding how bacteria interact, but for every specific pair of bacteria, it's quite tricky. So there's many question marks, many open questions here. But again, in general, we can derive 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 while 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 are depicted here as gears, okay? Because gears really fulfill 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 alive 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 as very technical devices, right, as 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 these 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 add it to the one unit of sushi that's 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 gear. And this is amazing because 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 gears. 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 for some of these input-output relations. It's not sushi, but it's some amino acids, rather simple. It's very well understood and I even published this in my bachelor's thesis when I simulated swarming behavior of these bacteria and in the journal of unsolved questions. 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 in 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 that 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 outgrows 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 cannot grow for a certain time because maybe another bacterium takes away all the sushi that it would like to consume. But then it keeps calm, takes some rest, takes a deep breath, and then it decides to regrow. It's also some sort of memory because it remembers where it was coming from. But it's this ability to persist even strong perturbations. Even if you're being pushed out of the sandbox, you just go to your daddy and cry, but then you go back, okay? 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 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, okay, 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, okay? So this also makes it hard to compare between different individuals, let's say, between me and you. So 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 feces, okay? We take feces either from mice or from humans and then we take bacteria out of these feces and put them into a petri dish. For instance, here we took the orange bacterium out of the feces 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 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 these 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 forth. So if you want, this is like the truth table of the human microbiome, okay? Because then if we put the feces 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's no oxygen but there's 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 get an idea, okay, so there must be an orange bacterium in this fissile sample. 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. Does this bacterium really do not grow in 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 these 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 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, okay, 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 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. But it's not just one piece of genetic information. We cannot only say it's this bacterium. We can also say, okay, we find many, many gears that are needed. So apart from the bacterium itself, we can also more look like four 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 does not just happen with the genetic information of a single bacterium. There is 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 metagenome, 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 sequenced, like every fissile sample, every stool sample, we mostly get NA, which is not available. There was nothing detected. Does it mean that this gear, 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 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 means that I just introduced to you. So we sequence these fissile samples and then we get an idea of which bacteria are inside there. Okay, and 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 stool samples and look at them as features. Okay, in an n-dimensional feature space, if you'd 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 detected, in this case, the orange one, on the other axis. And as you've 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're 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 correlations or you could also 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 cause? Well, maybe it gives us a hint what to try. And anyways, IT 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 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 that comes to me or that 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 while there's some contribution to our eating habits, fitness states, susceptibility for infections, aging cancer, et cetera, P.P. 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 a 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 their 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 we can do. 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 these 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 your good, you're a lean, 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? It just takes two samples from a healthy person and you consume them and the bacteria inside this poop will then also be inside you and do their job, will 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 the bacterium itself, not the living bacterium, but just some molecules on the surface of the bacterium that stimulate our body cells to do something healthy, that simulate our immune system or something. So you basically heat and activate 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 a 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 the options we have at hand. Now what to do with this in the future? Is it advisable to hack our human microbiome with 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 to 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 hear even now in the days of CRISPR-Cas where you can genetically engineer human cells. Bacteria, to engineer bacteria 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 the inside of us or other bacteria, it's becoming a genetically modified organism. We are becoming a genetically 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, the 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 Council 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 to 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 to gather, right? We have to talk to each other, to exchange information and only then make an educated decision how to handle this, whether and how to hack the human microbiome. And before I arrive at the final slide, I just would like to thank basically the foundation that allowed me to come here, 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. The Weizmann Institute is a beautiful place to do science. We are very open. So please feel warmly welcome whenever you are in the vicinity, just drop by. And then last and at 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 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 a huge variety of what has already been done so we just now understood that there's, 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 therefore, I mean, once the bacteria metabolize the cancer drug it will not be affected 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 U.S. 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 are small clinical trials in terms of research studies where this has been done but again, it's a very wide field and I think it's just yet to start. Thanks. Mike, number four, please. It's a simple question. Nowadays it is hard to get the proper information because there's a time of fake news, fake information. Where should I be educated about the 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, psychom there, science communication. Ask people who are doing it, they know their stuff. Sometimes they're good scientists, they're not the best people to communicate but that's something we as scientists have to learn. So don't be afraid and really approach them. 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. I think it is simple direct path. Thank you. Thank you. Number one, please. 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 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 I said, what is the relationship? And this has all been done and as I already indicated in the case of obesity, we're even one step further. So it's not only that we identified bacteria but we also identified molecules. These bacteria are producing that help 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 and we have very solid evidence on these bacteria and these molecule. However, I have to state, usually scientists report very modestly. They say, okay, we have a certain confidence here. We have 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 want 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 microbiome and polygenic scores? Polygenic scores? Yeah, like for instance, Robert Plum in recently published a book showing that obesity is mainly genetic, that the relationship is mainly caused by many genes and there is this concept of polygenic scores. Yes, I'm happy to elaborate on this. I'm afraid time will not allow, but you're happy to come here and then we can elaborate on this in a private chat. Thanks a lot. Fair enough. Perfect, thank our speaker again, please.