 Good morning everyone. Thank you for showing up so early in the morning. You have to of course You are halfway almost through the school and I've really enjoyed myself It's the second year. I'm invited to come here and be part of the full program and and it's really an honor To do so so before I jump into there Just want to tell you about myself. Yeah, my name is Peter as you heard I studied physics here in Italy Milan and then I went to do my PhD in Cambridge in 2000 and And I stayed in in Cambridge ever since fact. I was very lucky with my career I'll talk about my career. I think on Monday a bit more, but I was very lucky and I always had job opportunities and my group grew and grew and grew and Now I have a group of about 20 people and we work on four topics, which this one is the fourth So I'll just spend two seconds telling me about the other ones So the biggest topic we have in the group is understanding how Systems of mortal Silia that we humans and all the mammals have in the airways and in the brains and in fallopian tubes Covering tissues and and beating and moving liquid how how these Silia synchronized together in order to make the nice Mexican wave Kind of motion that you saw on in Eva's talk yesterday Like people at the stadium and that that that delivers fluids to to where we need this So this is a big project these these fantastic structures are shared all the way from humans down to Eucharotic algae and the the molecular structures the same and also how they interact It's quite a universal property. So there's a lot of physics as well as biology and that kind of problem then we also have a big project on looking at Lipid membranes these are kind of important constituents of cells and of life So very thin membranes floppy They have a lot of physics that comes from from soft matter physics and and we're looking at when you make a mixture of lipids there are situations where face separation happens and here here it's very interesting to me because there's this important biological questions About how this face separation affects proteins on the membrane But there's also a lot of physics that comes from the whole body of critical phenomena So you can actually get the physics of two-dimensional phase transitions imaged in the microscope very easily and The third big project that we have funded is is actually probably the most biological one We we look at bacteria like E. Coli These are organisms that are models in biology a huge amount of information is known On the genetics and on the proteins and on the processes that go on here but but again the biologists don't know physics and so there's an opportunity for Physicists to go and see whether there's anything that they know that can be applied in biology and the particular question We have here is whether the the chromosome which is the DNA that carries the genetic sequence Being a polymer a double strand of DNA Whether any of the polymer Properties that we know from polymer physics have any influence on the biological processes and Just to cut a long story short if that polymer is very condensed and stuck together Then it's more difficult for for the machinery that has to make the proteins to read out the sequence Turn it into RNA and then from RNA into proteins So so we're asking polymer physics questions about the confirmation of the polymer inside bacteria that involves experiments and Polymer models So these are three projects on which I will say nothing more but but from looking at your posters a few of you are working on chromosome confirmation some of you are soft matter People and a lot of you are non-linear dynamics people in fact This is what I met Harry a few years ago at a workshop and how I ended up being here because of this problem in my lab But the project today on which I'll spend the rest of my time is project number four So it's the baby project on which I have no money But I like it a lot and I would talk about this So what does it mean host pathogen interactions it means looking at a system where there's a parasite infecting a cell and the particular example I will talk about today is Is involving the disease malaria To be more specific that there's many species of malaria one of them is the deadly one for humans It's called a plasmodium falciparum, and it's a fantastic organism in a way because It has a very complicated life cycle I'll tell you a little bit about that and and there's a stage in which it infects our red blood cells of humans And that's the stage that carries the symptoms and often the mortality So it's also a stage that we can look at in the lab A lot of what I'll tell you is the work of Alex Crick who finished his PhD with me last year and And there's a second PhD who took on from him Yan Chun But I'll just tell you what she's doing at the very end. There's no data from her yet And I should also mention Yuri Kota who's been for many years a postdoc with me And has built a lot of the fantastic instruments that allow Across across all the products in my group that allow people to do good experiments We have collaborations with biologists. So even though we're not actually funded to do this thing We're networked with people who are and that's really essential. There's a This group is a cell biology group looking at malaria and this group at the welcome trust Sanger, which is a Fantastic campus outside Cambridge where a lot of the human genome was sequenced. This is a more genetics group with expertise in In that side of the biological question So I have two take-home messages from my talk. I want to tell you about a bit of the science but also I will have a second theme that I will try to carry along which is How how why I'm actually working on this question and perhaps this can challenge you to think about How you choose your search questions in your various stages of career? You actually have to choose who you work with and what you do Okay, back to malaria. It's it's a it's a huge Problem worldwide. It's a disease that is present in all of these shaded countries The color of this shading is actually representing drug resistance emergence of drug resistance strains So the dark brown are areas where there is a drug resistance drug resistance malaria So a huge number of people die from the disease and and these are actually mostly children If you if you survive through childhood and in a malaria Um Infested region then then you probably live forever, but still many of you will know much better than me Uh, it will still give you very kind of strong flu-like symptoms. Uh, perhaps perhaps annually So even though an adult will probably not die that there's still a huge economic burden And people have estimated how much this disease costs to the economy of countries where where malaria is endemic in in regions Uh These are things that some of you do come from these countries and and you will actually know first hand what's going on um It was a disease that was also present in uh in the southern united states and in places like italy until Just a generation of say my grandparents And it was eradicated mostly by using ddt with with other consequences Okay, so In terms of kind of having a vaccine or a drug. Um, it's a disease that has escaped Escaped efforts so far to to a large extent and I'll try to explain why as we go along um If you just kind of forget about all the problems it causes and just look at it in terms of biology It's actually you can think of it as a quite fantastic organism um It's a bit like a frog that has a a tadpole stage and then becomes a frog frog And and the two don't look anything like each other This this organism actually has three stages that don't look at all like each other So so somehow the information in the genome codes for three very different forms of life Uh for for the same organism So you're familiar with the fact that uh mosquitoes have to bite you uh in order to to get malaria And so there's a there's a stage of the disease which uh, which is in inside the mosquito So that that's this stage that stage is sexual. So there's a male and a female Parasite and and they live in the mosquito gut then the mosquito bites a human And uh and introduces uh one form of the organism into um into the blood and that parasite goes into the liver Where where it survives as a liver stage and it's actually a motile parasite at that stage in the liver From the liver it's expelled into the blood in a different form called morosulite And this is the form that we can study in the lab most easily And and it's uh in the blood it inserts itself into red blood cells where it digests hemoglobin And just amplifies its number. So from one parasite entering one blood cell After 48 hours, there are about 20 parasites They're all clones identical clones and there's no male and female at that stage And then that cell bursts and releases 20 parasites into the blood And the cycle starts again for each one of those with quite a high probability Becomes 20 after another 48 hours. This goes on uh repeatedly until there are millions and millions of parasites in the blood And a large fraction of the red blood cells are infected and this is the cause of anemia So so uh people have that stage of the disease um Suffer from the symptoms of of not carrying enough oxygen and carbon dioxide in the blood And also these infected cells are stiff and they can clog capillaries And that's one of the major sources of mortality is is the fact that people get hemorrhages In the brain or elsewhere where where capillaries have become blocked So the the the parasite itself is of course not trying on purpose to kill people For from the parasites evolution and um and livelihoods would be much better not to kill anyone But there's a balance and and and some people do die um So we want to understand this cycle because if you if you're thinking of giving people a vaccine or Stimulating the immune system to do something or giving a drug once the parasite is already there Targeting the blood stage is uh is the most obvious place. It's more difficult to target liver You can't target the mosquito and there's also programs actually addressed in the mosquito. Um Either by really eradicating it with with anti pesticides or Or putting fish in ponds where the mosquito lay eggs Or or even very simple things like mosquito nets and in fact big funders like gates foundation are now Have switched completely from from trying to target and understand the biology to very practical programs of mosquito nets This is a problem for us trying to understand the biology um Okay, um Why is the blood stage still so poorly understood despite this disease being known to doctors uh for I think over 100 years Well, the problem with the blood stage is that nobody really has good data on on how this uh this amplification process goes on Even though if you take red blood cells from a person you put them Under the microscope you keep them at the right temperature and and uh and ph etc The and you put some parasites that the the thing will actually happen under your eyes But it will happen so slowly so the cycle for each cell is 48 hours And yet so fast because the important part is when the when the parasites come out and infect here And this part is less than a minute that the combination is is quite quite dramatic and and um and until This a paper this year and one paper a few years ago and our own paper last year These three three papers are the only ones with uh some video collections of of what's actually going on here and uh Until you have sufficient data you you can't really tell precisely the sequence of events How these parasites make their way through the membrane out And perhaps even more importantly how they make their way in uh a new cell How they stick and how how they get in and with what probability each of these things is happening And how uh each drug that you might want to test uh affects the various uh the various aspects I should probably say the traditional drugs um Like kinene and uh and things related to that Targets the the digestion of hemoglobin by by the parasite but parasites The drug resistant ones have become capable of uh of not being blocked by by that whole family of drugs So so it's not sufficient anymore to try to stop the the growth inside the cell And and we hope there's there's some scope to either target aggress So the the chance of getting out or invasion chance of getting in uh a new cell here Okay, so our first uh idea was um was well there's a challenge of image analysis There are there are all these cells in cell culture and uh and the biggest problem is that you don't want to keep a student For 48 hours to see a single event And then another 48 hours to see another event because their their phd will be over before enough events have been measured Uh and the phd might student might not be happy anyway during that time so So you've heard a lot about image analysis at this hands-on meeting So we did some very simple image analysis basically the cells uh once they're infected they are They're about eight microns in diameter. So they're they're not terribly small and they look quite round So so we you can do things like uh hop transforms or very simple filtering to actually find the infected cells You can even distinguish the infected from the non-infected because the non-infected I'll have other images later, but they're they're not as Circular as these things and they are a little bit bigger. So these become They they projected they look a bit smaller because they're a bit more spherical Essentially you can find these ones. They also uh once they're mature. They have this uh black spot Which is a crystal of the digested hemoglobin. So which is another thing that you can target by image analysis So so you can run uh kind of the microscope and you can scan around and you can record Where the positions of these cells? Because they're quite big eight microns. They don't actually move about Not very much. So you can you can also Look at various fields of view go back and uh, there's a good chance that you will find Yeah, you're a favorite cell again. So you can actually monitor quite a few And you can and you can definitely from the image tell when the cell bursts because it completely changes its size So so we had some we we wrote some very simple filters to to Get the microscope to reliably Understands when aggress was taking place And that gave us a collection of about a hundred movies in in not a very long time About about about the grass So so these two are just two sequences over over time. So this is the cell. This is one cell just I've called it time zero, which is just the moment of Where first parasites is about to come out and then we took with a in bright field. So it's not very difficult to take frames Hundreds 100 times per second You can see first parasite popping out After 200 seconds, it's gone a little bit further away Then a second parasite Is ejected after the first one and a third and then after a few are ejected as single events That the membrane curls back And the whole bunch it is out And and there's a paper by a french group in montpellier on on the mechanics of the membrane turning back And and how that actually contributes to pushing out parasites So that says this this aggress is quite quite an interesting phenomenon from from the physics and mechanics As well biologically it involves digesting various membranes. So there's a sequence of Of events where the parasites release specific proteins, which biology are called enzymes if they have a function So specific enzymes that digest The two membranes there's a membrane that holds the parasites and then There's a cytoskeleton of the red blood cell and then there's this phospholipid Layer of the red blood cells. So those three have to be taken care of in order to get a parasite out This is another aggress that is more kind of So this this is the kind of phenotype. So phenotype in biology just means The appearance when when you when you make a good description, you call it. This is a phenotype This is the phenotype described by the french group a few years ago It's not universal sometimes you get An aggression phenotype that looks very different with just the clumps And never and not the kind of the single guys shot out You can particle track these these morosalites. They are about one micron in size They in with our resolution that you see them as Essentially little spheres, but they are more like pairs. They have a head an apical point and that apical point Is important because to invade it has to touch the red blood cell It's not enough for say the bottom of the pair to touch the cell. It's actually got to turn around and So we've we've been doing some some tracking to understand how that process of turning happens and whether it's purely purely random Or or if it's driven and We didn't really manage to conclude anything from our videos, but in the meantime a german team did simulations of of a pair like objects touching soft membranes And and they they decided that the fact that it's a pair is important So the so the shape is important And also that they think there's a there's a gradient of stickiness From the nose from the top of the pair to the bottom And so so that when when this object is doing its random motion on a membrane It's actually driven towards turning with a the pointy side towards the membrane So so that exists as a as a result from simulations and We're trying to do experiments where we can Resolve the tip of the parasite and work out if it's really true But these are experiments where In a preliminary fashion. We have the red blood cell. We're tracking this parasite Exploring the trajectories and trying to see what type of Mean square displacement versus time curve we would get for the parasites The one result we could get from from this sort of kind of automated video So by this time we'd grown to having a few hundreds Kind of a grass and invasion videos We were called invasion phenotypes and this excited at least our biological collaborators who Who didn't know about these numbers? Well, nobody had these numbers before before anybody measured them So we could we could basically by analyzing videos of Egress and and what happens to to all the parasites Which ones invade and how long they take? We could work out these sort of histograms. So this one Is the number of invasion events That we see as a function of the time between when the parasite has come out and when it's invades So what's interesting here is that there's a there's a peak and it happens between one one and two minutes So 120 seconds here and and this tails off So it doesn't tail off because all the parasites invade invade the red blood cells nearby There are still parasites that are doing Brownian motion and haven't Haven't found a cell yet The the reason why it tails off is more interesting It's due to the fact that a parasite that has been outside the red blood cell for more than two minutes becomes Less sticky and and much less able once stuck to to go in and this is a more sophisticated Indication that the the proteins that are required for invasion are being passivated So probably molecules from from the from the blood are sticking to them Or or those proteins are not expressed by them the little parasites anymore And we don't really know which one of these two, but but the the clear result is that Kind of an old parasites more than two minutes old is not able to to invade the red blood cell This other graph shows the number of the the invasive events from Measuring the time from when the parasite first touches the red blood cell to when it goes in So this is a shorter time peak that 30 seconds So this is the typical time that a parasite spends touching the red blood cell membrane and And doing kind of random motions trying to get the the point towards the membrane And and then you can imagine if you have a drug or some sort of Change in the in the blood conditions changing osmotic pressure or something like that you can actually Do these measurements and see which parameter is affected and that that might give you a good indication of what's going on on the cell So in our various projects one thing we developed Uh over 10 years ago now is uh is optical tweezers and we we've used that also now in malaria So tweezers some of you actually work with them because I've met you already this week um our um a focus laser beam and very often one uses uh infrared because The lasers are cheap and uh and the light doesn't damage cells And uh the focus laser beam will will then cause objects with a higher effective index to to fall into the focus of the laser beam and um And very often the potential With which you're holding the object i've drawn drawn here this blue sphere Resembles very much uh spring so a harmonic trap but this trap is made of light And the infrared light travels through cells and and through liquids so This uh technology has been around As a mainstream technology for maybe 25 years There's a community who is using it to To pull single molecules and that's quite a kind of a specialist application There's uh there's another community who is using it to to move objects about and that's More kind of what i'm doing with that The it's possible to to position a laser beam in many ways you can steer a mirror That's the most kind of low-tech way of moving a laser beam um, but there are also Little gadgets called um acousto optical deflectors, which are crystals Where you set up a uh a grating by putting a uh a compression wave and that grating you can update really fast So basically you can change the grating spacing uh at a tens or hundreds of kilohertz frequency Which which relates to moving the beam So with the grating deflects the beam and if you're in the right focal plane that deflection becomes a movement So so you can actually hold objects and move them about By positioning the beam where you want it and you can do that very fast if you want to So the first thing we've done a few years ago with these uh optical tweezers was to grab grab hold of red blood cells This here in the middle is a healthy red blood cell. There are no parasites here and we we grabbed it by Getting two uh well-defined five micron diameter Colloids and making them sticky with with some some protein and then and then that would stick to the red blood cell The reason for we can also grab the cell directly with a beam if you want to and actually I have some videos Where we do that in a second But the reason to do this properly through spheres is because it's possible to calibrate The laser force on the sphere really well and that's quite easy And once you do that then when you pull the cell What you see is this red cross here slightly displaced from the center Of of the green bead and here we've put a stronger trap. So there's less displacement and from this Difference here of where the laser is and where the bead is we know how much force We're putting on in this axis So so we've calibrated on the bead we can then stretch the cell And and we know how strong the cell is from from doing that experiment So that was interesting because we we actually then used this information on how strong a red blood Red blood cell is to to get to Information on how strongly malaria parasites attaches to a cell so Before I show you that we did experiments to show that we weren't killing The the malaria parasites by by having these optical beams in the system So so this is just images where we grabbed a parasite took it to a cell weighted a bit a little bit more than a minute and This parasite you can see here is sticking to the cell It's even causing it causing the cell to do quite large deformations And then it's gone in and the cell is very deformed for a bit Which is something that happens almost all the time when parasites parasites invade cells And this is a video of those same Same frames Not sure it's gonna start it should start So this is this we've trapped with the beam and we're we're gonna move it there And then Then the video speeds up right has less pure frames And the parasite has got has gone in Yeah, so the star shape is called a kinocytic shape Um, you can even get to it if you drink enough beers so if you if you You go to the bar and drink a lot of your blood cells will actually look like that quite dramatic uh spiky shape Yeah, we can but but also I then need to get some blood from each of you and um take it to the microscope Okay, so the shape of our blood cell is a delicate balance of the Phospholipids and how they bend and the cytoskeleton just inside that has some tension And uh, and you can upset it by alcohol or or temperature in many ways And uh, the when the when these parasites invade they unbalance the calcium levels and they unbalance this This balance of the bending of the phospholipids and the tension from the cytoskeleton And the the cells go that shape for a little bit and then the pumps that balance all these ions Regulate it again and after a few minutes that shape goes back to normal, but the parasite is inside but No, the blobs are I mean no there are no Those blobs don't correspond to clumps of molecules. It's really It's really a mechanics problem. It's like the structure has a resistance to bending But a tension inside and it has an instability between being the biconcave shape and being this kind of starry shape and Has to be true because it's been reproduced in numerical simulations as well by just simple balance of tension and bending okay, so So we can use the the elasticity of a cell almost as a calibrated calibrated spring And so because if we if we pull the cell we get force versus pulling and it's quite linear so I could spend a lot of time on this because uh Because we wrote entire papers on this and and in fact it's it's much less trivial than just being Being a linear spring. So if you start changing the rate at which you pull, this is a material which is non-linear and And has a very complicated rheology But if you fix the pulling rates and you go slowly then it does behave like a Like like apparently like a linear thing and provided you don't change the rates you can trust this This line to give you a stiffness And and you can use it as a you can use the elongation of the cell to report on the force that you're actually measuring on a system so What we did here then was to use the elongation of cell to tell us about forces And we created So we couldn't really bring colloids here. So so that's why we had to rely on the This calibration of the red blood cell. So we've got a laser beam pulling the cell from here This cell is attached to the glass and here in the middle is a parasite. So now you can see it again So the parasite is sticking to both cells. We're we're pulling this one And then at some point it detaches So this we did on on many Similar situations. So again cell is stuck. There was a parasite in the middle So so we we actually assemble So So alex took a cell found the parasite got it to stick and then brought the cell with the stuck parasite to another cell And then pulled away And this this he could do On 10 10s of cells So then what he measured was the elongation Of the cell being pulled at the moment of of detachment So there are lots of problems on this. I mean and and if you're experts on On pulling molecules then you can complain. You can ask me kind of nasty questions because Because essentially what we're measuring is a first passage time problem So we should be really careful about The rates at which we're pulling and a lot of complications But but he should also realize this is the first time anybody has ever put any sort of number on on this Parasite sticking and also there are other obvious consequences of what you see here such as the fact that the parasite sticks on both ends And also these are these are old parasites because it does take us more than two minutes to go and get them So these are these parasites remain sticky After they're they're not invasive anymore Yeah Yeah, so if if it's still polarized after two minutes, which nobody knows then we'd be measuring the weak side My suspicion is that after two minutes is actually lost that clever gradient of adhesion. And so it will probably be more uniform So we're measuring a number which is 40 plus or minus eight pico nuisance So this number should be probably put in context of other numbers of Ligand receptor interactions The the biggest and strongest of everything is biotin stripped abidin at 160. This is kind of the super glue of biology This this won't be broken by thermal forces in any way And it's used also in in nanoscience a lot to to create constructs There are much much weaker illegal interaction Forces such as the binding between actin and myosin that takes place in mussels. That's at 1.7 pico newtons And so this 40 We don't really know if it's coming from many weak ones or a few more specific protein Protein interactions from the parasite to the cell. So this is kind of all still to be explored We could also start putting some drugs and seeing what happens and we tried three Three very kind of classical approaches This this heparin is a it's a blood thinner. It does it does stop All sorts of adhesions. It stops red blood cells from from clumping with each other But and it does stop the parasite from invading but it's not a good drug because it will kill people before Before it actually affects the parasites thinking Chemotrypsin is Is a molecule which is also used currently as a drug It stops some of the interactions between surface proteins and red blood cell proteins But it only it's not 100 effective and and it only affects some types of Phosphorum more than others. So it's not the it's not the final kind of Final good drug for everything This cytokinesine D is a molecule which is well known in molecular biology It stops the actin myosin motors from working So there's a stage in the invasion where this this parasite deploys a molecular motor to actually Exert forces and and tunnel into the into the red blood cell cytoskeleton And membrane that happens here So so this was interesting to see if things got stuck there so so we could measure The forces I told you there was a 40 in in the normal condition the wild type and Heparin reduces dramatically that 40 down to less than 10 So the the sticking really goes down the other two drugs reduce the sticking a tiny bit, but but not that much and there's an effect of especially cytokinesine on on the on the percentage of parasites that That are dear later times So if we look at fresh parasites before three minutes of regression and after three minutes of regression These three drugs The fresh parasites still stick, but the the older parasites don't stick here again. We don't know and our biology Collaboratives are excited, but they don't really know either why why this would happen this I think we we can stick. Well, I have a video on this. So which is more interesting This was interesting because we we spent some time looking at these older parasites and the fact that they still were sticking What was interesting and also the fact that they don't just stick, but they're able to to make big deformations on On the red blood cells that they that they target. So I think this is more obvious in the video So at the moment we're holding this parasite with the tweezers So it says on and then at some point we we let go it will say off Yeah off and this parasite Sticks and it causes kind of these big waves and the cell is even kind of folding on on itself a bit So those are movements that a cell by itself will never do it will never kind of fold up on itself Like that's from from just a random fluctuations so so we're quite keen to explore this because to actually For a parasite to cause those deformations either It's the fact that it's a pair a very sticky pair that that causes Adhesion and and the cell folds up a bit that could be one of the ways in which that's happening Or it could be even more active. It could be pumping calcium into the cytoskeleton of the cell That calcium could cause contractions of the of the Essentially acting of the cytoskeleton and those contractions could be folding the cell But whichever of these of these two ways it's very obvious that the parasite is is causing red blood cell deformations and those deformations Clearly increased the chance of the apical part of the parasites coming into contact with the membrane That's the part where I think the physics and the mechanics come together with What the biologists know about the specific proteins and and you actually have to come up with a unified description of the process Okay, my last slide is just to say that this I mean for me working with this host pathogen requires learning As much as possible about the the biology side But but the techniques were actually quite simple. We had the microscope We had the tweezers and we just tried to use them in a way that would Give some interesting information for the biologists Keeping in mind We also knew a bit about the membranes and the mechanics of the membranes And so in the back of my mind, I had the idea that I might even use some of the physics As well as just giving numbers to the biologists and turns out That this idea of looking at pathogens and hosts It's incredibly important in a lot of infectious disease work And so as soon as we started working on one problem We had a lot of biologists coming to us whether we could look at their favorite host and pathogen so So we did some work also with Salmonella, which is one of the biggest food Food pathogens worldwide It's a bacterium whereas a falciparum that I spoke about up to now is a eukaryote So a much more sophisticated organism bacterium is quite simple But but interesting in many ways and this bacterium interacts With cells of our immune system Macrophage cells that it finds Aligning the gut So so here we We again used our our microscopes and and quantified Addition times. This is a distribution of how long The the the contacts are between Bacteria and macrophage cells and it's kind of a Poisson distribution But then a long tail here That that those these are These long events Describes some difference interaction between the bacterium and the the cell which is not random And probably leads to some of these bacteria actually being able to enter the cell So these red ones Here are bacteria which are not stuck on the outside. They're actually inside cell which we can tell by scanning in z So this also essentially gave us a kind of phenotypes of of this host pathogen interaction and Perhaps interestingly for people looking at motile bacteria the the same bacterium But just with the mutations that affected how strongly it swims gave rise to two different invasion Uh Different distributions for contact times and also a different capacity for for invading cells So, okay, I think it's time to conclude I showed you some A bit of automation used on a on a biological problem I showed you How we use optical tweezers in a fairly simple way but to get a number that that nobody had measured before And I explained to you a little bit about why I'm excited to look at the malaria parasites Let me drink before I finish concluding We're hoping to To scale up the experiment I showed you so far is is partially automated But to to make kind of a generation jump and And really be able to screen drugs We will want to measure at least 10 times more cells Ideally hundreds more in the same kind of time And to do that we actually have to move to to microfluidics So the current phd student yan chun is is trying to scale down everything I showed you Into into channels so that we can mix parasites with With fresh cells and and we can have a piece of the piece of the lab on chip device Basically full of the infected cells and generating lots of parasites Which we can then downstream mix with the fresh cells If we if we crack that then we will really be able to to screen drugs in a systematic fashion And not just do the qualitative measurements. I'll show you up to here Because the red thing says it's important to to look at single cell observations That that's I think generally very true and A lot of kind of molecular and cell biology has reached A good understanding today by looking at populations But a huge amount of detail is is hidden in what each cell is doing So in biology, it's it's very often not true That's that the population is a is a good representative for everyone. There's a there's very often outliers And those outliers very often are doing a quite a critical job inside the population also Inside the population you will have young and old cells that that's a very basic fact But those young and old cells will behave differently to each other So to actually go from The type of measurements you can do in a population Which have a big error because they mix young and old to a better understanding You've you've actually got to follow individual cells and know What they are in their own cell cycle so So this really brings in a microscopy and very often ideas from microfluidics and structures They they don't need to be very expensive ideas. They you just need to um understand Which which problems might really benefit from from a closer look and then Gear up some sort of automated fashion to to still have enough data From from looking at single cells because that's what you lose when you move from a big beaker with millions of cells To a situation where you're trying to follow each one. You don't want you don't want to be looking at too few cells my second and last conclusion is um Goes back to why I chose this project so I spoke about it last year and I said I hadn't managed to fund it Well, we've had two more attempts since last year and it's still not funded But i'm still gonna stick with it Oh, there is one PhD students working on it. So I have to support her at least It's very difficult to to fund this In the uk and probably in any of the western countries Because even though there's a good network of biologists who like the project when it then goes to the funding agencies It competes with diseases that are killing people in that country And that that's where it then fails uh because it competes against cancer and uh and diabetes and uh and Alzheimer's disease um So that's a specific problem that that I have I guess it points to the fact that if if you were to be working on a problem of local interest Then it would be much easier to to find money for for for that problem But uh on the other hand there are there are positives which are the reason I want to keep trying with this It's really an area where I can see that um the things I know how to do when I say I I mean now kind of my group knows how to do are um Are things that we know but but the biologists that that work on this problem Don't know and and wouldn't be able to do even if we kind of gave them Templates that they would still need help and um And so so that really is a definition of an area where you can make progress that that hasn't been made before And that's important when you when you choose a problem The the techniques that we use are new that also often defines good areas So things you've heard this week from anything from an automated image analysis the power of computers power of image analysis Um cameras uh microphrytics all of those things are fairly new they've only Come into being affordable in the last few years and uh and they can really help It's a project that has an obvious importance and applications If if anything useful were to come with this it would actually directly affect people and that that's that's a good motivation for for choosing a problem and um and students who are very often very intentioned people Understand the things above and so so there's no problem actually attracting people to to work on this problem And um, I told you there's this specific problem of dollars or pounds But it's it's it's just a problem that the disease is not is not So relevant in in the rich countries Um, I'll come back to some of these points on one monday I've been asked to to have the discussion on career developments. And so some of these things I'll come back to And thank you very much for listening to me