 So thank you Victoria for the kind introduction So our body consists of about 30 trillion different cells Well, they're organized in audience. So like lungs the brain the gut Depending on their function the cells have different shapes. So this is a neuron So and it helps us to perceive the world as it is. So and there's lots of different cells in the brain, obviously When you go to other parts of your body cells look vastly different So the red blood cells are round and flexible and they transport the oxygen to every part of your body Then there are cells that form barriers So they keep the bad things out keep the good things in and in the case of our gut They take up nutrients So we want to talk about single-cell genomics today. I will go to talk to show and show you what is this about and I will use the example of the gut Well the gut it's not just a pipe that turns your food into feces While taking up the nutrients It's a high-performance organ and what you see here on the left-hand side as so-called V-Li and they Extend and increase the surface of your gut so you can take up even more nutrients When you're on high-fat diet eat a lot of burgers these V-Li are even larger so Taking up nutrients is really exhaustive so and the cells that take up the nutrients they die really quickly and So they have to be refilled and replenished every 45 days, which makes up like a 200 grams of cells every day So and the cells that Refill the gut and the surface of the gut are stem cells their tissue specific. They only form gut cells They reside in a small protected area, which is called a crypt and these are these crypts are located between the V-Li So this is our green cells their stem cells They produce all the different types of cells in the gut They support it by so-called pan of cells which also protect these cells And we have a couple of more cells that produce mucus or whose functions are even unknown to date so and I wanted to know How the stem cells actually formed the different cell types well for the gray cells that do all the nutrients take up job That's already quite known. That's okay But for all the other cells there is a lot of different competing models in the literature. I counted 12 last time I checked I would use this to two so one would be we have some kind of Not more stem cell like direct descendant of the stem cell that produces all different cell types Or we have this model of direct lineage allocation. It's called so the stem cells directly decide what they want to be in the future And then become this cell type all right So how can we check what a cell is and how they're going to do this decisions what they want to be? I give you a bit of a metaphor for this So imagine you have a doctor or you have a policeman obviously they use different tools for the daily life and The tools are different for the different professions But they also share a set of tools because they all have to do paperwork or look at our computer So once the tools broken you need a new one and you order it as an a catalog So you place an order and you get the delivery. It's as simple as that as long as you have money Well cells don't care about money All right, and in order to get the right item you place the correct catalog number Okay cells do pretty much the same thing They have DNA DNA is that catalog So and what a cell need for a day life? It orders with a molecule called mRNA and It's inverse that it gets a protein delivered and the proteins are the tools that the cells use in order to fulfill their function Well the mRNAs all have also catalog numbers which we call genes So and now to see how cells are working and which tools they use we now look at all the mRNAs all the orders a cell is placing and With this we can actually reveal what the cell is So and we can look at every cell one by one and see all the orders that they place at a certain time So we take our gut We single all the all the cells and we put this into this nice machine that we can only see through the microscope Because it's so tiny So it's a called a microfluidic system and all the tiny droplets that you see out passing through to the left hand side right hand for you These are nanoliter volumes. So what's a nanoliter? So imagine you take a teardrop you split it by a thousand and that's a nanoliter and we shoot the cells into these Small droplets and we can analyze this Using these droplets. So these are our reaction chambers where you can count the mRNA molecules Well, we use broken. Let's go to next All right. So once we counted all the mRNA molecules, we end up with such a Data table So and I'm a computer scientist. So this is where I actually start to work with So every say every dot and pixel in this Heat map is the number of mRNAs we counted per cell and per gene So it's actually yeah, we counted a lot. It's a huge data table. You don't want to see this an axle And now we want to make sense out of this. All right We and we use a process called dimensionality reduction to group the cells into a 2d space So and this grouping is happening by a so-called similarity replace cells that are similar to each other to have similar genes Replace close together and cells that are dissimilar replace on different edges of this map Okay, well the map is gray and we see their structure But we're ourselves Okay in order to find ourselves we use something called clustering where we group again the cells together and now we have more colorful plots here and And now having this grouping we start to annotate our cells using so-called market genes So biologists have been looking at the gut for quite some time already and they know already which genes are present in which cell type and this is what they use to Yeah find their Their favorite cell types again. All right. So and then this is Now how we can actually see okay. We have this map And we found our cells that we put in again. We can even characterize our cells further to see What's different between the cells which genes are characteristic for each cell type? and Which are more or less the same so Jeans are obviously so some cells So actually all the cells they need to have to do some kind of housekeeping So to keep the cell clean and healthy and fine So they need the same tools for that, but they have also characteristic tools they use for their function All right. Yay. We have ourselves but What was the initial question? We have to stem cells we want to know how the stem cells decide what they want to be So can we answer this with that kind of data analysis? I'll give you a bit of a different analogy for that. Yes, we can So imagine when you were a kid you had some kind of a flip book and When you flip over the pages you see that there's some incremental change and even though the first and the last page of your flip book are Fairly different. You saw a story developing. We can do the same thing with our cells So we have our stem cell and we have our mature specialized cell and we want to learn how these cells turn from one to the other So this is what we want to see But we don't have that really We rather have a lot of cells that were drawn from the process So now all we have to do is to define a starting point in our data define an end and Find the neighbors so that we can reconstruct that path through the cells This is the math part. That's difficult. I can talk about it in the break Or I tell you that works So here you see with the gray edges between all the cells which cells are close to each other and using now So now we can use our path drawing tool To connect the stem cells with all the respective cell types And what we can see and what we found mathematically is that the stem cells directly turn into the respective cell types and they have their personal direct descendant Sorry, it's just that the mic is just starting to Draw sorry for that. Alright, so what you can see is From our data, we can actually support This direct lineage allocation model. So the stem cells directly decide what they want to be and How they want to look like in the future So but you can do more we can even watch the cells grow up So starting from the stem cell here you see again a nice heat map and what's red is What's characteristic for these cells for the stem cells and what is in blue or even in gray? It's not expressed in the cells and now we can start to walk along our path and see okay, there is a cell that's intermediate state where the cell starts to Transition and we see that a couple of other genes are turned on that are characteristic for this transition state and Again as the cell is now Specializing we see that these stem cell genes are turned off in our blue and the characteristics Genes for that mature cell types have been turned on We can use these kind of processes to learn about the healthy state We learned a lot about the healthy state already and Once we go to a deceased state where we see another cell type popping up and being vastly overrepresented We can now learn losing using these tools What went wrong when it went wrong and how it went wrong? So I showed you a lot about the gut today how cells mature how they interact how they grow But there's more to a human than just the gut well more certainly and There's a couple of initiatives that want to learn now all about everything about all the other Organs, so we want to create a Parodic table of cell types of the human and filling in the blanks for all the other cells and all the other organs We then for Intel We concentrate on the brain on the different cell types of the brain How they interact how they work? One when things go wrong how they go wrong and once we've learned all these things we aim to Revolutionize medicine in the next 20 years. Thank you Thank you very much. I was very inspiring ending Let's see what kind of questions people have to your talk. There is one on the back Please Thank you for this wonderful talk with beautiful data And the idea by the periodic table, of course is that in atoms the atoms have a relationship to each other And there's also complete is that the same case with these these cells that the cells of a very clear relationship to each other And that this is somehow a complete map of all possible Cell cell types Sorry, the question was not clear. I guess Yeah, can you rephrase? I'll try. Yeah, so with Adams. There is The rows represents a sort of difference right and the columns represent a different difference. Yes of the you know I'm a nucleus. Is there something similar with cells. They have a very clear Functional relationship to each other So the question is that this this kind of periodic table of cell types actually relate to the actual Periodic table of elements I've been I've been being asked this question already again at once like all right Is that this is more like a conceptual figure we say some cells cell types are really related to each other And there's also a hierarchy of cells There's a bit of a discussion in the field to say what is a cell type the closer you look the less sure you are what it is We have also cells that gradually change from one cell type to the other and there's some kind of immediate intermediate states So we assured there's a lot going on on this And we haven't even discovered all the cell types in our body Yeah, I hope that answers your question At least it's very complex at what we definitely understood So maybe Karsten can talk to you more about this in the break if he's really curious to Let's see if there are more questions. I have one Thank you. Thank you for thank you for the presentation my question is when you say also sees stem cell transfers into an immediate or Another cell and send into the end stage. So what is the body of what we're doing with these intermediate cells? So what are they good for? So the question is what are the intermediate cells once we go from one state to the other Well, they're intermediates there They're not the one not the other it's like But what is our body doing with it? So it's it's So it's like school I would say You don't you don't stay in school forever unless you're a teacher No, nobody but not to be honest, so You basically at you get these cells are educated So they have to change and they change their shape and their function and in this transition state They basically, yeah, I have to turn into the other part Okay, so until they function fully send basically Yeah, exactly. So they have to establish their function. Thank you. Thanks. There was one question here in front It's a it's a related question. I'm just wondering how how you synchronize your cells because There's going like sorry. Oh, sorry Gene expression is a dynamic event and so how are your cells like of the different cell types actually synchronized How do you know they're all in the same place? Okay, so the question is how cells how the cells are genetically So, I mean genetically they're all the same and we take in vivo samples, but you're but the mRNA expression is Dynamic, right? Yes. So, how do you know that they're all like? Yeah, they're the same cell type, but How are they synchronized for gene expression? That's a very elaborate question. So There's one point gene expression is bursty so you have a bit of an expression and then it's often a bit of an expression then it's off again and We average over the all the single cells So we get signal for every single cell and then we group them together and look at these groups again to be sure you do it like in post Yes, it's not not before you Harvest or anything like you basically get the data and then do it by analysis Yes, we do that analysis That's the beauty of it because you can use organs and just patient samples for this You don't have to put them process them in the lab to synchronize them in order to get your signals You can just take patient samples. So hopefully we'll do this in the future. Just take a single cell sample Sequence it and get the result Immediately, I hope so, okay, so let's take all the other questions to the break and now thank Martin. Thank you very much