 Thank you Victoria, good evening so there's limited cure for neurologic disease and Part of this comes from the fact that We really need models to understand what really goes wrong in Neurologic disease So basically for many many years the mouse has been the most studied model Trying to understand what's going wrong, but as you can see here also There's major differences in size But also in the structure of for example the brain of a mouse Then the next step to get closer to humans would be to go for neuropathology and As you can see here, this is an Alzheimer's disease brain There's a clear difference, but this is the end stage of the disease and to really find cures you need to understand the temporal resolution of the disease and Since we are having troubles in asking a patient to give us a part of his brain we need to think about a very cellular models and One of them I will go to present today so the solution is don't take the brain take something else and the options are Broad but but for example blood or skin is much easier to reach than the brain obviously and the solution is to turn those cells into Cells of the brain for example neurons shown here and then to study the patient's disease in the dish by Looking at exactly the same cells that are affected So let's take a look a closer look and zoom in here so the major revolution was to learn how to turn any cell of the body for example the skin cell here into a neuron and The strategy for this is to do a gene switch to turn the skin cell Into a cell. That's pluripotent So basically to turn it back to an embryonic like state so that this cell can become anything when it's grown up and As as neuroscientists we are specifically interested in those cells that make the brain so we differentiate those cells via different steps and in the end we get a neuron and This is not my invention, but it's invention of Shinya Yamanaka who was awarded the Nobel Prize for this in 2012 so I decided to get you to have a look through the microscope and and this is kind of the Way from going here from pluripotent stem cells to neurons so the first step here the Pluripotent stem cells so they are clumped together Very round-ish cells and then we start to instruct them To do things that they would kind of do during embryonic development So first we ask them to free float and form balls And then we ask them to settle down to give them a chance that the neurons can start growing out of this ball And once we have those progenitor cells for neurons We then ask them to differentiate into fully mature neurons so this seems easy, but it's a process that takes six weeks or longer and a lot of my PhD students time at the moment and And this is how it looks at the end those beautiful green cells. Those are all Neurons and those were also the first neurons that we created in a long and at the time that we're from a human patient and One of the most important things about neurons is that they are able to communicate with each other and Neuronal communication is not chatting, but it's to be electrically active to transmit the signals and This is what we are going to use and Within the next couple of minutes, I'm going to show to you how we can apply those techniques to biomedical questions and the two major research fields that my lab is following up is to study disease mechanisms in specific diseases, but also to look at compound testing and Define drugs that potentially might turn into Medication Theoretically you can also transplant those cells back into the brain But it's a technique that in my expectation Will not become a valuable technique in Germany due to restrictions on the ethical and legal side and the two stories that I'm going to show within the next minutes is Is diseases that we are trying to understand by using this model? So one is a chronic pain and the other one is Parkinson's disease So let's start with a pain So this proof case is a patient with a chronic pain called small fiber neuropathy So to get you an imagination of what this all is about is that she has been in severe pain for more than 10 years And she has tried all the drugs that are usually given to treat pain and none of them work And when you ask her for the severeness of the pain Which is usually done on a scale from one to from zero to ten and Zero is no pain and ten is maximal pain and then with seven point five She's pretty pretty at the top of what somebody can be here over a time and we also have some Neurophysiology on the patient which is a technique called Microneography which my colleague Barbara Nama was performing on that patient And what she saw was that it's not only the pain in the patient but there's one measurement that kind of reflects this pain and it's this hyperactivity of very small nerves and so we went on to get a sample from the patient and To turn this into pluripotent stem cells and then turn it into peripheral neurons And since Activities seem to be so important in the patient. We also looked at activity first and so we put the cells on a multi electrode plate with electrodes measuring the activity and Here you can see the controls and activity would show up as one of those Blueish and then yellow dots which you rarely see in the controls But if you look at all the patient cells which around here, then you realize that there are many more of those blue Bright dots popping up over time So we started to measure this and this is what we found so in healthy Neurons we see rarely any activity But in the patient this activity as shown here again in those blue yellowish dots is significantly higher and the next step was to think about Compounds and potential ways of trying to reduce this hyperactivity back to a normal stage So we tried several compounds and I'm not showing this whole Testing right now. I just show you one drug because I think that was really important So that drug that I'm going to show is called lecosamide and it's a drug That's usually used to treat epilepsy and when we put on lecosamide Something very unexpected happened So we were able to turn this hyperactivity from in in the cells from the patient Back to normal levels here here in green So we were kind of really lucky since lecosamide is a is a drug that's that's approved by By the FDA so so people use it for other implications so we recommend it to the clinician of the patient to recommend it to the patient and So she took the medication and this is the untreated situation as seen before and This was really surprising So our prediction of what we saw in the electrophysiology on the cells Totally correlated with what we saw when she took it She said the pain is just gone and then for some other medical conditions She had to interrupt this treatment and the pain came back Which was not cool for her, but a proof that the compound worked and when she restarted it again it was back and Barbara now my colleague did microneuropathy on the patient again And what she could see is that this hyperactivity and the lecosamide normalized So basically we found a way here to take information from from the patient patient cells and Get those findings back to the patient So that was the pain But the next that I'm going to step into is a chronic and new degenerative disease it's called Parkinson's disease and Parkinson's disease motor symptoms mostly consists of shaking of slow movements and of stiffness of the muscles and right now There is symptomatic treatment, but there is no way to really halt the progression of the disease So this is what we see neuro pathologically There's this depth of dopaminergic neurons in in the midbrain so an area located around here and Since those dopaminergic neurons die there's less dopamine transmitted to the basal ganglia and that's what causes those symptoms and Still there are major differences between different patients. So some are very stable and some progress very fast and one of those Causes to module for this disease modulation is the immune system and so there is the hypothesis out there that not only the Immune system of the brain the microglia But also peripheral immune cells are able to infiltrate into the brain during Parkinson's disease and then Contact the neuron so we thought about technique to stimulate this this interaction in the dish and This is the work by PhD student in my lab Anika summer and Irina Prott's and Basically, they went the classical way to go for the neuron and then they took blood from the patient and with the help of Jürgen Winkler and Frank smart X writer in the outpatient clinic for Movement disorders and then isolated immune cells from this blood sample and activated them and then Created a co-culture of neurons and peripheral immune cells So what about Parkinson's disease if you take cells from Parkinson's disease patients They're controls what you see is that in PD? Those neurons disappear. So they're the neurons die when they interact with Immune cells and are we able to rescue this and Surprisingly enough we found an antibody based therapy where we were able to Block the immune cells and then the neurons would survive even in the Parkinson's disease patients And this is really important since this could define your therapies since one of the compounds that we tried here is Drug called sequo genie map which is used already in the clinic for the for psoriasis treatment and could be repurposed so those are ways to Look at neurons in the dish and enter and see what happens In disease modeling or compound testing on the neurons, but as already Mentioned there are many more cells in the brain that that need to be taken into account for this So there are astrocytes Oligodendrocytes, there is the immune cell of the brain, but also parasites and this led to the creation of a Bavarian consortium for human stem cells called for inter and as you can see the collaborators are located all over Bavaria and there is groups in Alangen who are mostly focusing on Cell-based assays. There is neuropathology involved There is a larger group of bioinformaticians and computational scientists and mathematicians involved but as humans themselves are also of Impact for for ethics and the law we also Got lawyers into our consortium and I'm happy to tell you that Tonight speakers are from different locations and from different aspects of this consortium and Will present their perspective on human stem cells So to sum up here I hope I could show you that human stem cells are a very important model for studying neurologic diseases and That those systems allow us to test for specific compounds and potential medication For neurologic diseases as shown for example for pain or Parkinson's disease But I think what's more important is that those are all very complex experiments that need that need clinicians that need people in molecular and cellular biology that Need a lot of computational biology, but also need to cover the ethical aspect and Consortial efforts are necessary for this. So thank you for your attention Thank you very much be a day Let's see if we have some questions. So we have two volunteers with microphones and there is one question in the middle Adela in the middle Please wait until Adela comes to you with a microphone Thank you. So I'm not sure I understood if the fact that neurons are killed by immune System cells in the Parkinson's disease is a is the cause of the Parkinson's disease or a consequence or you just don't know yet So I would say it's a it's an important modifier So so we are trying to find out whether or not it's a cause by taking a larger group into account But at the moment, I think we are sure enough to say it's an important modifier of the disease Thank you. Let's see if there are more Yes, there is also one more in the middle Adela a bit from front. Yeah Hey, thank you for the interesting lecture. I had I have a question because you mentioned that there were some ethical and legal concerns raised towards Like the subject of your research, could you elaborate on that? Like what what's the problem that people would be having? I'm not sure if I'm the expert elaborate since there will be a top on on on those aspects, but for our part of Of course, the most obvious part is we are working with material from patients that gave their cells to us to study But there are many more things that will be raised. I think after the break, right? Yes Yeah, yeah More biological side questions here, let's wait with the legal ones for later for hannes Not right now, okay. Well, yes, there is one more in the middle as well. Yes Hello, thank you very much for lecture. I have the question There was one slide where you showed that you turn the skin cells into the neurons and then in your words You said we first ask them to be like a ball or something and then we ask them. Could you elaborate? How do you ask like how does it work? I'm completely not from biology field. Yeah, so so the question was How exactly we perform the technique to turn the skin cell into a stem cell and into a neuron and basically this first step is is done by jump-starting Genes that are on during embryonic development So that can be done for example by adding a virus But that can also be done by adding protein So so there are various ways, but the important thing is to tell the pluripotency genes So to do this gene switch and turn them on again and then the cell can be anything it wants to be and then for the second step to go from the pluripotent cell to the Neuron, it's basically changing the environment and making the cell feel that this feels like in a brain and Adding adding kind of grow factors that that cell would also meet when it gets or when it's growing in the brain Thank you. Beate. So I encourage you all to come to Beate in the break ask more questions and now let's thank her