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today we have associate professor Brad Turner and here's a National Health and Medical Research Council dementia Reese research and leader fellowship fellow and the NHMRC as we call it is national government funding body so very important to Brad and the Florie he is also the head of the MND laboratory at the Florrie Institute he obtained his PhD in biochemistry at the University of Melbourne in 2005 he undertook his postdoctoral training in mouth functional genetics at the University of Oxford for three years before returning to the Florey and he has established here his independent research group associate professor Turner is an MD expert that Y is here to talk to you today and he leads a large team of researchers and graduate students investigating the molecular basis of MND using patient stem cell derived and animal models to develop drug gene and immune based therapeutic approaches which he'll talk to about today his team has recently embarked on a world first drug screening program for MND which he will talk about in today's lecture so without further ado Tina thank you great Thank You Jane for the introduction and what a great week to deliver this lecture in the lead-up to the big freeze at the MCG so this is the vitamin D Neil Diamond whose foundation and what I'll talk about today is how how their support of our laboratory and Institute has really transformed the way we're were addressing treatments of motor neuron disease so it shows you how support can have an impact so before I begin I just wanted to show you this slide this is a slide generated from the laboratory and what you can see here are these red cells and these are these are the motor neurons so these are the nerve cells affected by the disease we have about 6000 on each side of our brain and you can see that quite pretty looking and they've got these long connections here and so these are the cells that are lost and disrupted in the disease so just an overview of today's lecture I thought I'd give you a brief history of MND motor neuron disease it's also known as ALS amyotrophic lateral sclerosis and I thought today I would give a different perspective I'd give you the Australian version of of motor neuron disease and what impact Australia has had on this disease I'll talk about the causes of MND what we understand to be the genetic and environmental factors that are involved in the disease it's quite a complicated disease I'll mention briefly clinical trials what's happening in the clinical trial space see motor neuron disease and then of course I'll talk about our establishment of a high throughput drug screening facility at the flora Institute so let's begin with this history of MND ALS and I guess for Australia it all started with this chap yes this is Alfred walter campbell and he's actually a very distinguished neurologist he's actually considered the first clinical neurologist in australia and he was trained in edinburgh and he practiced in the UK and he returned to australia in about 1905 and he he published a very famous monograph which is called histological studies on the localization of the cerebral function say and this is a document that was published in 1905 and what it contained was he essentially was able to map the architecture of the brain so he did some very detailed structure and functional studies and in collaboration with another prophet Arrington they were able to determine the region of the brain that controls motor function and we refer to this as the motor cortex and this is a strip of the brain which contains those motor neurons affected in MND and this part of the brain is involved in sensory input and converting that into a voluntary movement but he did some more studies and what we can see here this is a slice of brain tissue and this is under the microscope everything's drawn by hand and he was able to sketch out these different nerve cells and you can see that they vary in size and shape as you get deep into the brain tissue but he was particularly interested in these enormous cells in this layer layer five and six and these cells he actually sketched out and these are actually the motor neurons that result in the brain and they're also also called bet cells so these are some of these very early diagrams of these cells but he went one step further and that is he he characterized a couple of cases of patients with motor neuron disease and in this particular case he did work in the salem at the time this male patient who was about 35 years of age at the time of diagnosis complained of symptoms and these symptoms involved muscular pain or spasm and also signs of weakness and these are the two features of motor neuron disease in its onset and he recognized that this was als or motor neuron disease but he went a bit further and he he noticed that the the wasting had spread to the muscles of the body so this is another characteristic feature of motor neuron disease is progressive spread of weakness and paralysis but what was clever about Campbell study was he examined this patient at autopsy under the Pisco and he focused on these large bed cells in the in the motor cortex and he noted he counted them and he noted that about eighty-five percent of the cells had been completely swept away so he had actually defined the pathological hallmark of motor neuron disease which is that the loss of these giant cells but furthermore he noticed that the loss of these cells was unique in that cells occurring other regions of the brain were intact and preserved so this speaks to the selectivity of motor neuron disease for motor neurons so what happened next was I guess the first clinical description of MND in Australia following Tom Campbell's original reports from the UK whereby two neurologists someone was housing so he reported a case of what he called muscular atrophy in 1918 and this was followed by Murphy who reported a case of money earned Azizi in 1924 so this was the beginning of the emergence of money neuron disease diagnosis in Australia and it was published in this famous journal which is the Medical Journal of Australia so the next step in this Odyssey was I guess in the 1960s there was an appearance of a disease there was an endemic disease affecting the the Aboriginal population of an island called Group Tollan in East Arnhem Land as shown here and these aboriginals were coming down with a syndrome which resembled motor neuron disease and in fact they called this fruit Island MND originally and it was characterized by muscle weakness and wasting but also stiffness of the body and in fact the aboriginals referred to people affected by this disease as the so called bird people because they were they resembled our water birds such as the heron and this is an example of a wooden carving and the disease was quite prevalent so in every 1000 people on this island during this region six people were impacted by this disease so this so this was the first beginning of clusters of mo'ne neuron disease like syndromes in Australia so I guess the next step was there was this worldwide hunt going to solve the genes responsible for brain diseases and Australia joined that front in the 1980s about 1984 in which we when we knew of the existence of these large families affected by motor neuron disease so we can see that the disease in this case is clearly inherited so the individuals in black are affected by the disease and it was actually the Australians who contributed families to this worldwide effort and clinical material in DNA and you can clearly see the pattern of inheritance in his family so we call this dominance so it's the MND is appearing in every generation of this family tree and it was through this worldwide consortium and effort that the first MND gene was solved in 1993 and this is the original paper and I've noted the two prominent geneticists and neurologists on this paper so this was Australia's contribution and this this gene is called sod one or sod1 and it was the first MMD gene discovered and this is a quick this is a picture of the crystal structure if you like of the proteins this is how it folds in nature and it's actually dotted with mutations and so this was the first gene discovered about 25 odd years ago so this was a major milestone so then something happened the following a year and that was there was a drug which was approved for money on disease so this is the first clinically approved drug and it's called real assault and this this is it's also known as real attacks that's taken in oral form and this is the effect that it has on patients with motor neuron disease so if you track these patients over time looking at survival we can see that real Zoll patients taking real azole are afforded a rather small effect protective effects in fact they survived look in the increased or maybe increased by 2 to 3 months now the sad state of affairs is actually this is still the state of play in motor neuron disease this is the only approved therapeutic and has a very marginal effect and we have not seen anything emerged in the last 25 years or so so that will bring me to the Russian hour but the drug screen program that we've established at the Florida Institute so I guess not much happened in the motor neuron disease space for about twenty years until we had me the MND ice bucket challenge and I always like to mention this so you might remember this craze that swept the globe in which people from everyday people to celebrities were dunking themselves with ice buckets and here we have some famous faces so this is Bill Gates for those of you that can recognize him this is Mark Zuckerberg and even to trump got into the action there although he got doused by some supermodels so he had conditions so um this is actually a shot of the lab back in 2014 undertaking the challenge it was quite a brave challenge at the time because it was the dead of winter equivalent in the southern hemisphere and this was a serious feat because it actually elevated the awareness of the disease and raised some serious funds so globally it raised about two hundred million dollars and in Australia about three million and then I always like to remark in that same year we had more exposure for motor neuron disease so we had the film called the theory of everything and for those of you who haven't seen this movie this is this is the story or the biography of the light professor Stephen Hawking and it was Eddie redmayne's portrayal of Stephen Hawking there earned him the Best Actor Oscar and he in any speech he he dedicated his Oscar to everyone living with motor neuron disease and here's a picture of professor Hawking he passed away recently but then we had our own hero emerge our own celebrity in 2014 and that this of course was Neil Danaher so most of you will be aware he's leading the fight MND foundation he's leading a very public awareness campaign and we've got the big fruit for which is occurring next week on queen's birthday and he's brought a lot of exposure and awareness and funding to the institute and here we have premier andrews visiting the lab with neil and we've had many many events so we're close allies of the of neil danaher's for him in the association so now this brings me to the facts what are the what are the facts of not in your on disease so what I can tell you is that this is a disease which impacts about 2500 Australians and we know that two people are diagnosed every day and two people are lost every day to money your on disease and it's this disease is different to other degenerative brain diseases you can think of such as Alzheimer's and Parkinson's and Huntington's which can linger on for decades this disease is rapidly progressive and lethal and the average survival of most patients is around 27 months from diagnosis the lifetime risk of developing marine neuron disease is not trivial so it's thought to be one in 300 so if you think of if you go to the cinema that's one person in every cinema and we know that the incidence of motor neuron disease is on the rise so the it's thought that in the last 10 years the incidence of MND has doubled in Australia this is a very costly disease to manage and it was estimated that this is a disease which cost the Australian economy about 2.4 billion dollars and that works out to be about 1.1 million dollars per patient and there are many factors behind this but the main one is this disease requires intense multidisciplinary care so you need you need a neurologist a physiotherapist speech pathologist dietician occupational therapists and so on so you need a a cast of people managing these patients so now I'm going to move on to the causes of motor neuron disease so what do we understand to be some of the causes implicated and I always like to start off with this pie chart and what we do know is in that 10 percent of cases there is a inheritance and we call this familial motor neuron disease and what this means is that there is a positive history of motor neuron disease in the family so it has to be present in at least two of the generations of the family tree but this is only true for about ten percent of cases so the vast majority of cases of motor neuron disease are of the sporadic four and what this means is simply out of the blue so if you considered kneel down Oh her he has three brothers they all played professional football but only he is affected by the disease so that the mystery here is what what is the cause of sporadic motor neuron disease which is out of the blue another way that we can illustrate this is if we use a pedigree or a family tree as shown here so here we have a family affected by familial or inherited motor neuron disease and you can see that the affected individuals are colored in black and this individual was passed on the journey to two of his children and subsequently the three of the grandchildren we're on the right side of the screen we can see sporadic MND so here we have ten individuals who are not related seemingly not related yet three of them have developed the disease so there's no clear reason as to why this has happened so let's start by talking about what are some of the possible risk factors implicated in the sporadic motor neuron disease and I could probably reel off a hundred of them I've heard very different stories from patients and and their families as to what they think that what their theories are behind their the disease but some of them are mentioned today so we do know that cigarette smoking has been associated with the twofold increasing motor neuron disease we know that professional sports and athleticism is associated with an increased burden of motor neuron disease in some populations military service are a lot of Gulf War veterans give up going to develop motor neuron disease and the Department of Defense in the States is very interested in and why this is occurring this is an illustration of a virus so there's some ideas that maybe viruses could be lurking within the brain and could be responsible for this disease and then lastly this little critter here is actually blue-green algae which I'll talk about since as a micro organism so let's just go through some of these so let's start with sports so we're talking here about a leaf elite professional athleticism and sports and one of the most famous examples of someone who contracted motor neuron disease in their professional time was Lou Gehrig so Lou Gehrig was a professional baseball er and he was struck down with the disease after 17 seasons of playing baseball and he had to retire and he have a very formidable speech so Lou Gehrig is a good example Neal downer heroes another and I recall there was this study published about ten years ago in which a group of people had followed a soccer team of Italian players over a decade and what they had established what these these players have actually had about a six and a half fold increased risk of developing motor neuron disease compared to the normal population however when you're really drilling to this study you find that it's not as convincing so they did look at they analyzed about seven and a half thousand players over ten years and they expected about 0.7 cases of motor neuron disease and what they found was about five so in the end it was only five cases discovered and there are many other studies which dispute the link between professional sports and their political system and money you're on disease so it remains controversial so let's move on to viruses and when I talk about viruses I'm referring to a particular virus which is called a retrovirus so what he's a retrovirus they look cool and this this has been a really enduring idea in the field and for the last ten years and it was really this publication in a scientific journal a few years ago which suggested some evidence for a viral infection that could be linked to motor neuron disease and what this group did was they were able to take autopsy material off spinal cord from patients who have died from motor neuron disease and they detected the presence of viral particles inside these nerve cells yet the control patients were completely clear and this led them to propose that perhaps there could be a viral agent looking within motor neuron disease and the idea behind this is that about 9% of all your genes are actually viral so throughout evolution viruses have inserted themselves into our genes and they lay dormant and it's thought that the idea behind this is perhaps on disease these viral genes are activated and they assemble viral particles and these viruses can then infect motor neurons and spread through the nervous system causing damage and this theory would certainly be consistent with the spreading nature of motor neuron disease throughout the body and what's fantastic is at the moment the best way to address this hypothesis is to test an antiviral agent in motor neuron disease patients and this is a trial which is being conducted through neuroscience trials Australia embedded within the Florrie Institute and it's called the lighthouse trial and what they're doing in this trial is they're taking a drug called Troya mech which is a cocktail of antiviral drugs used for HIV patients of which there must be hundreds of thousands of people on this drug and they're testing the effect of this drug in motor neuron disease patients as we speak so I think this is a really exciting direction so now we're going to move on to blue-green algae so this was the picture that I showed you before so what is the link between blue-green algae and motor neuron disease and I always like to tell this tale because it's a it's a great tale of Epidemiology and murder neuron disease and this is a story which really started in the 1950s in the island of Guam which I guess is always under threat by North Korea and what was occurring on this island was there was a group of people called the Tomorrow People and they were suffering from a disease which looked very similar to moaning you're on disease and they referred to it as little go buddy and this translates into paralysis and in tremor and here we can see a victim of this disease so this man is holding his wife and she has very pronounced wasting and paralysis she can no longer walk so this got medical scientists interested in what was causing this disease and I'll just point out that this disease this form of motor neuron disease was a hundred times more common than anywhere else in the world in the 1950s and people began to suspect an environmental agent or a toxin and they looked to this particular plant and this plant is called a cycad tree and it produces these edible seeds and the locals have been earning these seeds for decades and it was knowing that the seeds contained a toxin and the locals were very aware of this and what they would do is they would cover up these seeds and they would wash them repeatedly to rinse out the toxin and then they would grind up the seeds to make their tortillas so this got the medical researchers were quite confused by this I thought well if though cleansing out the toxin how was it actually entering these people and then they noticed that the island was occupied by these fruit bats and these fruit bats were voracious eaters consumers of these cycad seeds yet the fruit bats were immune to the effects of the toxin and then it was discovered that the Tomorrow People love to dine on fruit bats this is where the plot begins to thicken they love for it bad faith and for breakfast lunch and dinner and this was part of their diet and so it was beginning it was theorized that perhaps the fruit bats were the point of entry of this toxin into the Tomorrow People and with a bit of a bit more investigation and study it was found that within the roots of this particular plan there exists blue-green algae and this makes this toxin this poison which then concentrates into the seed and so then we have this theory that the blue-green algae are producing a toxin which is concentrated in the sea it's consumed by the fruit bats and consequently eaten by the humans and this was the theory of the the mystery of the they call it the body hypothesis and this has been a really enduring idea for the last few decades once they put a band to the consumption of fruit bats the incidence of motor neuron disease dropped so it's virtually zero in Guam so there's a that this clearly implicates this source of entry for this toxin now how is this relevant to modern days well it turns out that blue-green algae is ubiquitous so this is actually a picture of the the murray river and earlier this year and we can see a blue marine an algal bloom and the the river area area which some of you may have had the pleasure of visit is rife with blue-green algae at the moment and that blue-green algae makes this toxin so there's potential entry into the waterways and through this and particularly if we look here at the moment at northern Victoria this also hotspots of nineteen year on disease so in some regions of the Riverina the instance of MND is increased by six times so this raises the the question of whether or not there's an association with exposure to blue green algae derived poison okay so there's some of the ideas about sporadic MND so now I return to the inherited form of the disease what do we know quite a lot so this is a graph showing you the number of genes identified him owning your own disease over time and I've told you before that the Australian were involved in the discovery of sod one and since then we've actually seen this explosion this exponential increase in the number of genes involved so what I can tell you right now is there are dozens of genes responsible for murdering your own disease and we're at this point here now where I can tell you that we have solved about 70% of them in DJ's and I always say that within the next five years or so we should crack the other 30% and what this means is you that you can give a definitive genetic diagnosis to families with motor neuron disease but the problem with this is it doesn't help us with sporadic motor neuron disease and remember that was the form that was out of the blue so this now brings me to clinical trials running your own disease so what's happening in the clinical trial space and again this is a very crowded space we can see a lot of activity if we just focus on the right side of this graph what we what we do know is that there clinical trials are divided into four stages and the aim is to get your drug into this central area here so if you see that there there's a lot of activity in this space these are all experimental investigational drugs many of them have actually failed they've dropped out of the pipeline and there's new contenders and there's constant activity in this area but to reiterate there's been not known drug approval in Australia for motor neuron disease it's real azole now Australia is very active in the clinical trial space in moaning your own disease and we have these four major sites so first in Victoria we have the Bethlehem Recovery Hospital which is engaged in clinical trials such as the antiviral medication I spoke about so this brings me to the exciting part of the talk so I've given you all the background on the history of MND and the causes and and told you how miserable that the clinical trial space is so we did we devised a plan and that was to establish a high throughput drug discovery program at the flooring Institute why did we do this well we identified that there were some key issues in motor neuron disease which were impacting clinical trials and the first problem I'll identify is that MMD is not one disease it's not a singular disease it's highly variable from patient to patient so when a patient arrives a clinic and they're diagnosed with MND ALS it can then go in different directions and what I mean by this is that there are different forms of money on disease there are forms that affect primarily the brain and the spinal cord and these have different names we then have different forms of the disease which can affect the facial muscles MND is shown to overlap with a form of dementia called frontotemporal dementia as illustrated here so that 15 percent of MND patients will go on to develop from frank frontotemporal dementia yet some patients are cognitively intact so why is that we have different variants they involve the extremities such as the arm and leg flower variants there are different forms of motor neuron disease we have early onset we have light onset we have a rapidly progressive disease but we also see cases that are slowly progressive and I don't know of a case that is lingered for 35 years and then Stephen Hawking is a great example of slowly progressive disease and then bulbar onset refers to the muscles involved in speech and swallowing so some patients present first in this area but the majority of patients presenting the spine so they'll present in the arm and the leg so we have this immense diversity in the form of money on disease this is another way that we can illustrate this so what I'm showing you here as a plot of patients over time and this is a clinical function score so all patients start off at about 50 and then they drop over time so we can see that these individuals have classic mode in your own disease they succumb to their disease within the first twenty seven months or so yet remarkably there are patients that can survive with this disease at four years so you'll notice that you get different trajectories and we call this a spaghetti plot and you can appreciate from this plot that there's a lot of noise in this system and it's no surprise that clinical trials will be deemed to all doomed to fail op fail at this rate because these patients are not correctly subtype we need we need to accurately subtype the fast progresses from the slow progresses and enroll them in different trials the second problem that we identified is that for the last 25 years or so the whole scientific in research community have been focusing on this part of the pie chart so there's 10% of genetic familial motor neuron disease and surprisingly any drug success you find in this area will not work for the majority of patients with sporadic MND so we have we have a real lack of laboratory models sporadic money on disease and this is a major problem for clinical trials the third problem and I'm going to show your mouse researcher but I do appreciate this is that we have seen perhaps in over reliance on mouse models or animal models of motor neuron disease in the last 25 years so what works in a mouse does not work in a human from learning neuron disease so there's questions raised about the usefulness of mice and rats so we embarked upon a new program which will address all of these key issues and it's a really it's a world first program dedicated to motor neuron disease and I'm pleased to say it was funded last April last year and it was a five million dollar program and it was co-funded by some key players so we had the Victorian state government vitamin D and also the Vulcan Group proprietary limited and the mission of this program is very simple what we are seeking to do is to rapidly screen clinically approved drugs so these are prescription medication using sporadic mnd patient cells so we're working primarily with the sporadic disease and we're aiming to identify priority agents that we can then advance to clinical trials and we call this drug repurposing so we're taking existing prescription medications that you may have at home and try to repurpose them see if they've got any activity or potential for motor neuron disease so this is an overview of the vitamin D drug screening program and it begins with collecting cells from the MND patients and these cells are then reprogrammed into stem cells and I can take you through that these cells are then intensely in rigorously studied and categorized and what we do is we identify a subset of lines that we can use for drug screening and then we can engage in high-throughput drug screening so we have a primary panel of patient cells that we use for our drug screening and any hits any potential drugs that we get out of this screen we can then extend to the entire patient cohort and then we bring this back so this is the circular nature of this program we bring this back to clinical trials so how does this program work I'm just going to take you through two stages of the program so we're quite ambitious so we're aiming to recruit about 200 MND patients through this program and also 50 controls and this is done in collaboration with our clinical neurologist at calvary health care Bethlehem and barwon health and also through the i near hospital and this is how this program works what we do is we can take a superficial skin biopsy from the forearm of an mnd patient and we're able to then grow those skin cells in cold and this is a picture of these cells under the microscope this is a process which takes about two weeks and then using molecular tricks so using some Nobel prize-winning technology we're then able to convert those cells back into stem cells and this is a process which takes about three months and again these are the stem cells are going under the microscope so we're able to turn these skin cells back in time to their stem cell state and then that gives us the power to then turn them into motor neurons so we can turn them into any cell top we desire but in this case approaches from the motor neurons and this is a process that can take at least a month around here are some images of these cells and what we're trying to achieve here is M&D in a dish and it's personalized M&D in a dish if you think about to 200 patients that we're recruiting so stage 2 is where we get into our drug screens so let's imagine that we generated we now have an infinite resource of motor neurons the affected cell type from patients living with motor neuron disease what were able to do is then drop them into these SA plates about 10,000 cells per well and imagine that we have 20 or so of these plates and we can then subject them to what we call high throughput drug screening and this is facilitated by robots I'm going to talk here a little bit about some of the robots that we've installed in the Institute so what you're looking at here is a 1 million dollar machine or I thought that was installed and it's capable of taking these so-called drug libraries which contain thousands of tens of thousands of drugs and then treating these motor neurons the second phase of this is that we have a this is the Australian first version of this microscope this is a high power at high resolution microscope which can then track the health and survival of these motor neurons in response to drug treatment and the ideal hope of this program is that we're able to generate drug hits that we can then take forward for further validation I just wanted to point out that using conventional manual techniques we've estimated that we can increase the efficiency of drug screening by about 150 times using this approach I wanted to show you a video that we've generated so now you're looking down into one of these wells in these assay plates and what we've done is we've labeled the motor neurons in green so we can make them glow green so we can identify them and what you can see here is movement over time if you track this motor neuron here you can see that these cells are quite mobile they put out these connections and they're sensing their environment and this is the key parameter all the readout that we're looking for so here we have a motor neuron colored in green and if we track this cell over time you can see that that green is eventually extinguished and that cell dies and that's the that's the key measure that we're looking for we're looking for survival of these cells under the microscope so here's another way that we can picture this where we're modeling running your own disease in the dish and we're looking for a loss of that green signal over time as this cell converts into a a sick diseased motor neuron and what we do is we can score living cells versus dead cells and we can generate these plots so this is not too dissimilar from that survival graph that I showed you before for real assault trade many many on disease patients and what we have here is each little increment on this graph represents the loss of them loading urine at a time and this is a theoretical plot and we're looking here at the health of a controlled motor neuron and we would estimate that they can survive up to a week but a motor neuron that's affected by MND has a reduced survival and that's measurable by this method so we can now see shift towards the left of this graph what we now do is we intervene so once we establish a drug hit so to say drug X we're looking here to bring that money you're on and back to life to promote its survival so now we're talking here about clinical trial in a dish so here we have a motor neuron analysis this is a Marine you're unaffected by MND and using drug X were able to bring back the survival but the real power of this heart put system as we can now consider combinations of drugs targeting different aspects of the disease and here we have now we have an additive effect so we're looking now at drug combinations and again this is a nice coral of a clinical trial so think of this as a clinical trial in the dish but much more efficient so here we have a yum a local who dropped in to donate his skin cells so this is Neel danaher's he was the first patient to donate to our program they look very lucky to have him in our program and here are some action shots from the lab collected so this is an Chris and we also have Catherine over here who who are running the program and you can see that there are at different stages of the program see here we have the the robot which plays out the drugs and we've got some motor neurons got some analysis here and eventually a lot of microscope use so I just wanted to give you an update on progress on this program and I'm very pleased to tell you that we started patient recruitment last December and we're aiming to recruit twenty patients per month and we're on track so I need to get ideally to 200 patients but right now I can tell you that we've steadily increased our patient number to about 150 so we're certainly on track to hit our aim of 200 patients and now I just wanted to break down those 150 patients so what I can tell you is that this is primarily a Victorian initiative so we've enrolled 120 patients from Victoria that we have taken an some interstate patients with even have had patients flying from Perth or how about to be exist so candidly part of this proper initiative and then these are just some of the characteristics of the patients so who have currently enrolled predominantly male patients so this diseases is actually 50% more common emails in men than women so this fits and then age of onset so the majority of the patients M&D is a usually a late onset disease that spikes usually in the 50s to 70s so we're capturing that patient cohort but it's not unusual to capture patients with young onset learning your own disease and this is precisely what we want to do we want to capture the entire clinical spectrum of disease so we can model this and then I told you before that MND diagnostically there are different forms and different variants so majority of the patients were capturing a classical ALS but we we are seeing we are enrolling other forms of the disease the slowly progressive form the brain form the spinal form and then sort of onset so these patients present in different parts of their Anatomy so the majority of our patients have spinal onset where they present in the leg or the arm but we do have patients presenting in these muscles of speech and swallowing and also generalize so again capturing that whole clinical picture and then progression rate we're just estimated here we've got the slow progresses the rapid progresses and in the classic or also capturing some of the genetic forms of marine Joran disease so that these are a good solid positive controls to have and we do have you may recall that first gene that was identified 25 years ago so we have those patients represented within our cohort amongst other different forms so it's a very exciting program recruitment is certainly well underway drug screening will be underway in the second half of this year we have our first drug libraries we're very excited to start generating hits but I just wanted to end my talk by telling you that I think there is much more scope and potential to this program so we think of this as a unique resource for Australia it's certainly the largest collection of stem cells from owning your own disease patients and there are so many other questions that you can address and there are different directions that we're taking this program in so one of our interests at the moment is to really profile these motor neurons and really get into the genes and the molecules behind the disease and we and what we would like to do is actually subtype or subgroup patients at the genetic and molecular level using profiling technology and this is called precision medicine so this is a this is a term which is widely a worldwide it's actually widely practicing in oncology and haematology but it's in its infancy in neurology and what it means is it's really about bringing the the drug back to the cause of that individuals moaning your own disease so this is one particular area that we're hoping to branch off to we also want to build more complex models so there's the so called brain in addition systems where you can build in complexity and you can start to model those those brain structures that I showed you from the Campbell drew over 100 years ago in a dish and also brain on the chip is also another way another approach where you can interface these cells with technology in order to deliver a blood supply and you can grow them on a chip so I just wanted to end by saying this is the lab we've donned our beanies for the the big freeze which is next next week so I just wanted to point out how can you help our research continue well there's obviously two ways one is you can buy a beanie so they're available at reception I've got a bag behind me to support fight MND but also donate to the flooring Institute so we can keep this program going we can continue our recruitment of patients and keep the drug screening alive so thanks very much [Applause] you