#354      34 min 17 sec
Brain in a dish: The therapeutic potential of stem cells and organoids

Epilepsy researcher Steve Petrou and developmental neuroscientist Mirella Dottori discuss the potential of organoids -- miniature immature organs grown in dishes -- for future epilepsy and autism research. Presented by Dr Andi Horvath.

“Many epilepsy drugs are targeted at the symptoms and not the cause. We're going after the cause with our organoid research.” -- Assoc Prof Steve Petrou




Dr Mirella Dottori
Dr Mirella Dottori

Dr Mirella Dottori is an ARC Future Fellow and Group Leader of the Stem Cell Laboratory at the Centre for Neural Engineering, University of Melbourne. Since 2003, Dr Dottori’s research has been within the field of human pluripotent stem cell biology, which is one of the most rapidly advancing areas of medical research. The major focus of Dr Dottori’s research is studying human pluripotent stem cells and their differentiation to specific lineages of the central and peripheral nervous system. Her research objectives are to create human cellular models of neural development and neurodegenerative diseases and also to develop stem cell therapies to promote regeneration within the nervous system.   

Assoc Prof Steve Petrou
Assoc Prof Steve Petrou

Associate Professor Steve Petrou is a Deputy Director, Head of the Florey's Division of Epilepsy, and heads the Laboratory of Ion Channels and Human Disease, a multidisciplinary team of researchers with a focus on revealing fundamental mechanisms of disease genesis in the central nervous system. Current major areas of investigation centre on the development and characterisation of genetically engineered mice models for the study of human familial epilepsy. He works closely with industry and has several patents for his discoveries. In addition to his many roles within the Florey Institutes and the University of Melbourne, he serves on the editorial board of the Journal Neurobiology of Disease and the Investigators Workshop Committee for the American Epilepsy Society.

Credits

Host: Andi Horvath
Producers: Peter Clarke, Andi Horvath
Audio Engineer: Gavin Nebauer
Voiceover: Louise Bennet
Series Creators: Kelvin Param & Eric van Bemmel

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VOICEOVER 

This is Up Close, the research talk show from the University of Melbourne, Australia.

DR ANDI HORVATH

I'm Dr Andi Horvath.  Thanks for joining us.  Today we bring you up close to bio medical laboratories that study diseases by growing tiny immature clumps of cells that actually resemble organs.  They are known as the organoids.  In the last few years scientists have cracked the recipe on how to grow these miniscule organs in a dish.  They are lentil sized balls of cells and their life span is only months, but they resemble the features of our developing brains, our livers, out guts, kidneys, prostates and pancreas.  In fact, the list of organoids is rapidly expanding.  This laboratory technology means we can now study our biology in action outside a patient's body.  They are already being used to understand developmental diseases such as Alzheimer's, Parkinson's and cancers.

On Up Close today, we're going to be talking to Professor Steve Petrou from the Florey Institute of Neuroscience and Mental Health, as well as the Department of Medicine Melbourne.  Also joining us is University of Melbourne's, Dr Mirella Dottori from the Centre of Neural Engineering and the Department of Electrical and Electronic Engineering.  Steve uses organoids to model the condition of epilepsy and test the efficacy or toxicology of novel drugs.  Mirella is studying the basic dynamics of organoids also with a view to understand autism.  Welcome to Up Close Steve and welcome to Up Close Mirella.

PROFESSOR STEVE PETROU

Thanks Andi.

DR MIRELLA DOTTORI

Thanks Andi.

DR ANDI HORVATH

What exactly are organoids?  Now they're connected to stem cell technology aren't they?

DR MIRELLA DOTTORI

Stem cells are cells that can have the potential to become other cell types of the body.  You can classify them according to different classifications according to the potential that they can become.  Now organoids are basically aggregates of cells that very much resemble a tissue or an organ.  That's why they're called organoids.  But the difference is organoids usually are derived from stem cells that have become the cell types of that organ that they represent.  So an organoid very much is like a little piece of tissue in a dish that resembles the organ of what we're trying to mimic.

DR ANDI HORVATH

When was the first organoid created?

DR MIRELLA DOTTORI

Actually they've been around for several years but they've been working with cells that were derived from the organ itself like intestinal organoids where they used intestinal stem cells.  But more recently with the technology of embryonic stem cells and induced pluripotent stem cells, which have the potential to give rise to any cell type of the body, now it's brought the whole organoid technology to a whole new level.  Because with these stem cells we can make any cell type of the body, now they have the potential to make any organoid of the body.

DR ANDI HORVATH

I have this picture of organoids being little doll house versions of our brains and our kidneys.

DR MIRELLA DOTTORI

Organoids as opposed to thinking of them like doll houses, they're actually like the room of a particular doll house.  Because what they actually represent is one component of that organ in the way that they're created.  So it could be the kitchen or the bedroom.  Same with, for example, brain organoids.  Perhaps you can have some regions of the brain or some regions of the liver.

DR ANDI HORVATH

So you can have different types of organoids that represent different parts of the brain.  But are they made up of different types of cells?  Like, what's inside a particular organoid that's from a particular side of the brain?

DR MIRELLA DOTTORI

Yes, very much.  Even though there were derived from stem cells, so the same type of cell as that cell differentiated, that is that is started to become other cell types and they started forming complex structures, then they become various different cell types that's relevant to that part of the brain.  For example, in the cortex you would get different types of neurons that are assembled together that resemble the layers of the cortex.

DR ANDI HORVATH

These clumps of cells that are the size of breadcrumbs, why are they different to cell cultures?  Is it because the cells start to talk to each other?

DR MIRELLA DOTTORI

In cell cultures they're traditionally a mono-layer of cells.  An organoid is a three dimensional structure, hence an organoid.  They are assembled together very much in the way that a tissue is assembled together.  So the way the cells are interacting are similar to how cells within that organ interact.  Whereas in cell culture as a mono-layer you can't get that same complexity of interaction in a two dimensional system.

DR ANDI HORVATH

And this is now a standard laboratory tool.  These little versions of very immature organs.

DR MIRELLA DOTTORI

We have both.  We still have the 2D monolayer culture systems and we also complement that with the organoid studies.  Because remember, we haven't solved making the whole organ itself.  We can make components that mimic different regions, in my case the brain.  We basically need multiple models to study the one thing.

DR ANDI HORVATH

Okay, so these aren't adult cells.  These are very immature embryonic cells sort of like the developing embryo in early stages of first trimester.

DR MIRELLA DOTTORI

Yes.

DR ANDI HORVATH

But they don't live for very long outside the dish, is that right?

DR MIRELLA DOTTORI

Yes.  That's right.  The key word was development.  They very much mimic the development of that embryo so if they're mimicking organogenesis as it would occur in utero.  The length of these organoids depends on the culture system that you use.  The minimum can be one month but from the paper that was published by Lancaster, they claimed they could grow them for more than a year.  In our case we can grow them up to three months or so.  The length of time depends on the culture conditions, how many cells you start with, how big you want to grow it, and so forth.

DR ANDI HORVATH

Tell us about the history of the discovery of organoids to give us some insights into what these things are.

DR MIRELLA DOTTORI

I'll speak specifically about the brain organoids.  We've been culturing stem cells and driving them into neurons for several years now.  Pluripotent stem cells were first derived in 1998.  What we were able to do was culture these cells into aggregates and clumps which then became into neurons.  They somewhat resembled different regions of the brain.  Where Lancaster’s study had made a significant step further, hence we called it organoids, is that she was able to culture them for significantly longer periods.  So we used the similar technologies in we know the proteins and growth factors that we can drive these stem cells into brain cells types, or neuronal cell types and we can culture them in an aggregate.

But what she then did was use a bio-reactor and put them in a particular scaffold.  This bio-reactor was able to spin these organoids around, put them in a spinning motion and it's this spinning motion which basically push fluid through the cells so that the centre regions of the organoids were able to get the nutrients.  Hence, they were able to grow for significantly longer amounts of time.  This increase in time length meant that the organoids could be cultured for longer and hence we got more complex structures.

DR ANDI HORVATH

Some of these growth factors that actually induce cells to sort of express different proteins and develop in different ways.  That's kind of extraordinary that we can control a cell in a dish to either revert back to being a stem cell or from that stem cell to become a particular stem cell.  There must have been an enormous body of research that fed into these growth factors and cocktails of biological chemistry that makes things react.

DR MIRELLA DOTTORI

And it comes from all our studies of developmental biology.  So very similar processes happen in embryogenesis whether you're studying a frog, mouse, and in humans.  Very similar.  So from all our knowledge in all these other systems, we basically mimic very similar events in the culture dish.  Hence we can drive them into these different linages.

DR ANDI HORVATH

Steve, the growth factors that are involved in making cells do things we'd like them to do, like become a kidney or become part of the brain.  Tell us about that biochemistry.  That's fascinating.

PROFESSOR STEVE PETROU

I think that's where the magic happens in this organoid technology.  The actual sequence and the timing of the exposure to these different factors is what generates the organoid.  I think Lancaster saw that happen somewhat spontaneously.  Once the environment starts to form, that sort of cell fulfils itself.  The environment forms.  The growth factors become more localised and a new environment is formed that encourages further development.  This is a mirroring of what's happening biologically in the brain to a lesser extent but nonetheless hijacking the same basic chemical processes and this self-organisation that occurs.

DR ANDI HORVATH

I'm Andi Horvath and you're listening to Up Close.  In this episode we're talking about organoids as a research tool.  Next we've going to explore their use in epilepsy and autism research.  Steve tell us about organoids to study say epilepsy and how useful is it as a tool compared to other research technologies.

PROFESSOR STEVE PETROU

Epilepsy is a disorder of networks of brain activity.  In order to more completely model that, we need a system that can express that complexity.  There are models at the single cell level.  There are animal models that are used at higher organisational levels but many animal models don't have human pharmacology.  So the prediction from an animal study to a clinical study isn't very good in this field.  We can get a drug that works in an animal or doesn't work in an animal that doesn't always translate.  As we know the cost of developing drugs is extraordinarily high.  So getting models that more faithfully recapitulate what happens in a person is critical.  Organoids have that promise that we can put the genetic changes that we see in patients with these various forms of epilepsy.  We know we're going to have the same pharmacology and we hope that the emergent behaviour of the organoids mirrors the pathology that we see in the patients.

DR ANDI HORVATH

Give us some insight into the type of epilepsy you study.

PROFESSOR STEVE PETROU

Right now our focus is on so-called sporadic genetic epilepsy.  These are cases of epilepsy where the mutation appears in the embryo either as a result of a mutation in the egg or the sperm or even as a mutation that can occur after that somatically.  These are single gene epilepsies and they're very very devastating.  They're associated with cognitive impairment, motor impairment, multiple seizures per day and often early death.  They aren't treated well by current forms of drugs and there's an urgent clinical need to do something about it.  Because we've got such a strong handle on the genetics and because of the urgency, we think this is where we should focus our initial efforts.  We've chosen those for that reason.  The types of drugs you might give may not have to have the safety profile that you would for a drug like a common cold where it has to be exceedingly safe.  People are desperate and we want to try and put the drugs into the hands of patients as soon as possible.

DR ANDI HORVATH

Now some epilepsies are drug resident, is that right?

PROFESSOR STEVE PETROU

That's correct.  On average about 30 per cent of epilepsies aren't medically treatable with current medications.  It hasn't changed over the years.  We think that's due to the lack of a mechanism dependent drug.  By that we mean if you understand at the fundamental molecular level what is happening in epilepsy, you've got a greater chance of delivering a drug that's targeted at that disease mechanism.  Many epilepsy drugs are targeted at the symptoms and not the cause.  We're going after the cause with our organoid research.

DR ANDI HORVATH

Right.  If you go right back to the cellular mechanisms you're more likely to get back to the point of where the disease starts to happen is that right?

PROFESSOR STEVE PETROU

That's correct Andi.  And two things happen when you go back to that.  We know epilepsy, everyone associates that with seizures, the involuntary movements, and loss of consciousness that you might see.  But in addition to that there are these things that we call co-morbidities which are additional consequences of the disorder.  As I said before movement, intellectual disability, other changes to the patients.  But it can be to the parents and the patient as devastating or worse than the seizures themselves.  So by tracking the disorder back to its root cause we hope to tackle the epilepsy and the co-morbidities and not just one or the other.

DR ANDI HORVATH

Steve, your research has shown some interesting effects from drugs that we don't normally use on epilepsy.

PROFESSOR STEVE PETROU

That's right.  Repurposing we call that.  Where we take existing compounds and try to use them in new and imaginative ways.  It's quite remarkable what additional effects the current crop of drugs have.  They've been developed and used against a particular target we call.  But when you look more deeply often they target and they hit other molecules within the body.  We're trying to exploit that knowledge.  The reason we're trying to do that is because the drugs are already approved for human use.  If we can say take drug X for condition Y, but now we're saying take drug X for condition Z, that's something that can rapidly impact clinical care.

We've had a little bit of success with that with Quinidine.  Quinidine was originally an anti-malarial.  Is also used as a cardiac drug for arrhythmia.  We found that in a group of patients that had a particular genetic form of epilepsy that the Quinidine at the molecular level affected the mutant protein in a way that should restore normal function.  Clinical success has been mixed largely because of the properties of Quinidine as a drug.  We can't get it into the brain at the levels high enough that we need to get the effect on the brain without having the effect on the heart.  So what needs to happen is that we need to improve the chemical properties of these molecules to reduce now what was originally the original effect and enhance this unwanted effect.  That's possible with a process called medicinal chemistry.

DR ANDI HORVATH

This is quite extraordinary.  Using drugs that were meant for other conditions for epilepsy.  I know most drugs have side effects so it's kind of like you're making use of some of these side effects for the right type of disease.

PROFESSOR STEVE PETROU

Yes.  You may have heard of it in the medical literature as off-label use.  That's been happening for some time in the field.  It hasn't necessarily been backed by fundamental research that rationalises why we should use that drug in that way but it is the same sort of process with a scientific basis though.  Rather than often doctors say that well actually this epilepsy drug works great for mood stabilisation as well, let's try - that's not something that's sanctioned by the pharmaceutical industry because they can't do that for legal reasons and for good legal reasons.  But doctors can make that decision in the clinic.  We're sort of taking that to the next level we hope by providing a sound scientific basis as to why a physician might want to use this drug in this way.

DR ANDI HORVATH

How did you think to use Quinidine?

PROFESSOR STEVE PETROU

The protein of interest that we found in these patients with this form of epilepsy had been studied in the past just for science’s sake.  That really speaks to the advantage and the important of basic research.  This group led by Professor Len Kaczmarek in the States had been studying this protein for many years because it was just interesting.  After that we found the relationship to epilepsy.  In their course of studies they had shown studying in the rat that there was some block by Quinidine.  We've taken advantage of that finding and pushed it into a clinical direction.  That's just the way science works when you build on the discoveries and findings of your colleagues.

DR ANDI HORVATH

Let's now explore autism in a dish.  Mirella, how is organoid technology useful for the study of autism?  That's a behavioural disorder.  Does that have a genetic component too?

DR MIRELLA DOTTORI

Yes.  There are some known cases where there is genetic causes.  Studying autism you can imagine is incredibly complex because it's a spectrum disorder.  Symptoms are very varied.  The behaviours and very varied.  Sometimes they don't even know is it autism or is it something else.  So the way people mainly approach this is by obviously studying the behaviour but then looking at the underlying genetics of these patients and looking if these genes are mutated or disrupted in some ways.

What we can do with organoid technology is go the other way.  Because basically it's studying the development of the brain in a dish, we can sort of say, okay, perhaps there's some complexity going on.  If we can take some of using iPS technology, this is where we take the skin samples from the patients, reprogram or convert them back into stem cells.  Then from stem cells make them into brain organoids, we can basically wind back the clock and see how their brain developed in a dish.  A component of their brain.  Now we can start asking the questions.  What is going wrong and when?  That's the power of organoid technology for autism where we can take obviously the genetics approach, but we can also take the other approach where we're trying to recreate the brain a dish and see what goes wrong when.

DR ANDI HORVATH

You're using these actual patient cells.  So you harvest one of their skin cells and turn it into a stem cell.  Then organoids.

DR MIRELLA DOTTORI

Yes.  This is called induced pluripotent technology where Yamanaka group in Japan got a Nobel prize for in 2012.  We're using this technology in the lab as so do many other groups around the world now for modelling diseases.

DR ANDI HORVATH

When it comes to autism, does this mean you can target the moment at which the nerves are starting to act in a different way compared to say patient controls.

DR MIRELLA DOTTORI

That's right.  With the organoid because it's in a dish you can stop at any stage of development.  We can ask questions of did it start with when the cells were dividing to give the different types of neurons?  Or is it when they're actually starting to form connectivity and connections?  Or is it because of the neuro transmitters they're secreting?  So we can stop it at any point and look at different aspects and compare it to, we say controls or non-autistic patient samples, and look at differences.

DR ANDI HORVATH

Will this mean that at some point in the future we'll be able to decide whether or not autism is environmentally induced?

DR MIRELLA DOTTORI

It will definitely shed important light in that.  Like a lot of diseases it's probably both going on or in some cases genetics only.  In other cases environmental only.  In other cases a combination of both.  It's highly complex.  But at least we now have a way to start interrogating this part of it.  Not just the genetics.

DR ANDI HORVATH

So some autism patients may be at genetic risk.  In other words they're susceptible for it to go down that path after uterine development.

DR MIRELLA DOTTORI

Yes.  That's right.  But we didn't know that.  Like Steve was saying, sometimes it could be new mutation occurring in-utero or something from the eggs.  Not something that necessarily was carried by the parents.  And to identify that gene can be incredibly difficult because it's a minefield.  So we can go backwards.  Once we see what is going wrong, often we know the genes are involved in that process in the cells so we can start looking at those specific genes and go back and say, okay, is there a mutation in that specific gene.

PROFESSOR STEVE PETROU

Just to add to that, in October of 2015, Christopher Walsh's group just published a manuscript showing the extent of genetic variation in individual cells of the brain.  This was hitherto really unknown.  It is the history of that cell hundreds or thousands of mutations that have accumulated in these cells.  There might be hundreds or thousands or regions within the brain each with their own little clump of differentiation that adds enormous complexity to the analysis of these sorts of conditions.  It really does give another pathway that we really hadn't thought about for the disease genesis.

We'd think epigenetics which is how the genes are modified by other chemical factors.  We talk about genetics themselves where there are individual mutations.  Now we've got to think about well, you know different parts of the brain can start to have their own genetic environment.  How do we deal with that complexity?  And for developmental disorders that occur on a longer timescale you can see how this is completely new confound.  Potentially we can start to mirror some of that in this organoid cultures.  We'll think of inventive ways we can do that.  Comparing different organoids that each start from the same point and do they end up at the same position?  Can we see genetic change accumulating in those and how does that inform us of these disease processes.  I think it's a really important time now in neurogenetic disorders.  We're primed for some breakthroughs.

DR ANDI HORVATH

How do you actually measure electrical activity and nerve activity in organoids?  Because we've talked about looking at the organoids mimicking the activity of brains, but how do you tell?

PROFESSOR STEVE PETROU

There's two broad approaches you use to measuring electrical activity in a neuron or a nerve cell.  The same applies to doing it in an organoid.  It has additional challenges.  Basically you can use a little bit of wire and measure the electrical potential either outside or inside the neuron.

DR ANDI HORVATH

Okay.

PROFESSOR STEVE PETROU

The second method relies on optical measurements.  So using molecules that fluoresce.  I think many people have been under the black light at the disco and their white shirt glows.  We have the same sorts of molecules we can put into a cell and they change their intensity of glowing according to the electrical activity.  So therefore we can use microscopes to measure that.  With the wires we can push the wires into the culture or we can grow them on a substrate where the wires are already imbedded.  As the organoid grows it attaches and connects to these things.  We can start to get a three dimensional view of what's happening in the organoid.

As Mirella mentioned, cultures are normally single sheets.  Now we have a three dimensional structure.  We don't just look on the outside.  We can look on the inside.  So we need a method to do that.  With wires you can see how it might happen.  With optical measures, there are numerous optical approaches.  One method's called two photon microscopy that lets you get the light in deeper into a structure.  You can actually look inside the organoid with these optical dyes.  Those methods together can let you explore the basic physiology of these things and also the action of drugs.

DR ANDI HORVATH

Mirella, you actually grow some of your organoids on scaffolds.

DR MIRELLA DOTTORI

Yes.  Building on the idea of that it's really critical.  Especially for modelling brain function is to measure circuitry networks.  We're at the moment exploring different scaffold materials that are electrically conductive.  One in particular we're exploring is graphene because it is conductive.  So our idea is that if we can culture these neurons in these particular scaffolds and grow them into an organoid, we can potentially stimulate them and measure connectivity between the different neurons.

DR ANDI HORVATH

Wow, so you stimulate the actual scaffold that's connected to another nerve cell somewhere else and look at activity across that.

DR MIRELLA DOTTORI

Yes.  It's what we're exploring at the moment.  The first step is exploring the scaffolds which would be suitable for these nerves.  Do they adhere?  Do they survive?  Can they grow on them?  Can they form connections?  Then the next step is to actually, okay let's look at the conductive properties of this scaffold.  That's where working with the engineers is really powerful because that's really their expertise looking how to wire up the particular scaffolds so we can stimulate one part of it and record another.

DR ANDI HORVATH

Mapping epilepsy and autism.  In complex systems there are so many variables.  How do you guys keep a track of what's going on?

PROFESSOR STEVE PETROU

There are two approaches again.  One of them is the skill of observation.  Looking at what's happening to the system as a whole and making notes and observing that.  But there are so many things we can measure out of one of these organoids that we start to lean on our engineering colleagues again.  In this case engineers that are experts in classification and pattern matching. Collaborations with the same sorts of minds that can figure out what Google ad to deliver to you based on your demographics and your browsing habits, we can use that technology to understand what the patterns are in a diseased brain.  What the patterns are with the drug that causes toxicology.  What the patterns are with the drug that causes benefit.

For me, I think that's where the future of this is.  Because the brain is such a complex thing.  You can't look at the activity of a thousand electrodes and say, oh that's what's happening.  We don't understand why that pattern of electrical activity gives rise to a certain behaviour.  But statistically I think we can get a measure using these big data analytics.

DR MIRELLA DOTTORI

And also we can break it up.  You can just study the cells alone.  Or you can just study the way two cells interact, or three cells.  Then you build it up into more complex systems.  Because understanding at the cellular level gives you real important information about their function in a multi-cellular system.  If we see something's wrong at the cellular level most likely it will also go wrong when it interacts with other cells as well.

DR ANDI HORVATH

I'm Andi Horvath and you're listening to Professor Steve Petrou and Dr Mirella Dottori.  We're delving into the revolutionary technology of organoids and its capacity for understanding and treating human diseases.  Steve, where do we go from here?  What would you like to see happen in this research?

PROFESSOR STEVE PETROU

I think for me we'd like to see better control of the conditions that lead to a particular organoid type.  That's happening at the basic cell technology level with cell biologists, stem cell biologists.  We'd like that field to advance to the point where we know the sequence to induce organoids into a particular class.  We know for epilepsy some parts of the brain are more important than others for studying the disorder and we'd like to control that.  Right now we don't have terrific control over what the organoid will end up looking like.  What cell types will end up being in it?  To be able to control that better is critical for us.  Because in studying the effects of drugs and disease you need reproducibility.

If we don't fully understand the system, the random nature of things can produce a lot of variation in the results we see making it harder to unmask a signal.  That's key for us.  Lock steps with that is going to be advances in the technology in which to understand the stem cells both at the genetic level where we can look at the transcriptome which is the RNA that's made from the DNA.  There are a whole host of tools and bio-informatic approaches now that are used to understand what it looks like and then also the functional aspects.  Also the structural aspects.  So we need advances in different fields and inter-disciplinarity is the key here so that multiple brains of different types can be looking at this.  That's what I'm hoping will happen.

DR ANDI HORVATH

Tell us a little bit more about organoids as drug testing.  I mean in some ways drug testing is very expensive.  How can these help with drug toxicology or even possible new drugs working for conditions?

PROFESSOR STEVE PETROU

Our hope, and it hasn't been shown yet, but our hope is that as I mentioned earlier they'll be more predictable.  So what we want to do, and we're in the process or working up, is adding known drugs to organoids and seeing whether they reflect clinical reality as it is now.  If we could get a correspondence with a known collection of drugs, both those that work and don't work.  If we see correlation there then the hope is that future drugs that we apply with unknown effects, will likewise fall into the same categories.  That would save lots of money because we've improved the ability to translate from the bench into a patient.

DR ANDI HORVATH

Right.  They'll streamline those clinical studies.  They might say right we're not testing that drug because it didn't work on the organoids.

PROFESSOR STEVE PETROU

Right.  Hopefully we won't have to go to animal models.  Animal models are expensive.  There's certain ethical concerns around using a lot of animals and if we have better prediction from the stem cells we can forego that step.  I think it's going to be important.

DR ANDI HORVATH

Mirella, what are your hopes for this area of research?

DR MIRELLA DOTTORI

Our current limitations with the organoids are as Steve said, is that whilst we can control them somewhat, we can direct them into specific regions of the brain but not all regions of the brain.  They are organic actually.  They tend to do what they want at their own rate.  If we have better control over those steps we can much more model the specific regions of the brain that we're really relevant in.

The second biggest limitation is brain maturation.  Because really a lot of these brain disorders, even in a child, the brain is fairly mature.  You have myelinated neurons, you have the immune system there.  With organoids what we can model at the moment is really brains in-utero.  Really a lot of the problems happen later.  We need to think of ways how to push the system even further so we see that maturation step.  Then incorporating other cell types.  The immune system plays an enormous role in brain function.  Several steps away, but I think we'll get there, is how do we start incorporating putting blood vessels or immune cell types in the brain so we can see that specific interaction and how that plays a role in dysfunction.

DR ANDI HORVATH

Right.  The interaction between the other cell types that develop in the embryo.  Mirella, is there capacity to ever transplant these organoids into humans?  Is that something we might hope for in the future?

DR MIRELLA DOTTORI

Transplantation in the brain is highly complex because the brain is a complex system.  It's in the adult usually and these organoids are more embryonic-like.  It is happening for certain diseases like for Parkinson's disease where they're transplanting dopaminergic neurons in regions of the brain.  Where they're shown promising results that do form connections.

DR ANDI HORVATH

In the humans.

DR MIRELLA DOTTORI

In the humans.  And setting up clinical trials for doing this.  Nothing's impossible even though at the moment we can't do it yet.  Who knows?  At the moment we're a long way off putting an actual organoid into the brain.  But I think for specific types of diseases it may be a feasible option.  Maybe even certain cancers.  Maybe an organoid can be delivering a particular toxicity drug that's targeting to specific cell types.  There's a lot of different ways we can work with cells.

DR ANDI HORVATH

Steve, let's dare to speculate about the future.  As you think past your current research, what do you think might happen?

PROFESSOR STEVE PETROU

I think stem cells will be incorporated into the drug discovery cycle.  I think stem cells will be at the heart of delivering so-called precision medicine.  We talked about that concept of making drugs against targeted disease and mechanisms.  I think the stem cells and the organoids are going to be key to that.  In the future I see the ability to, at a patient level, to be able to use stem cells to really understand which of the available drugs are most efficacious.

There was an earlier concept of personalised medicine that promised to make drugs specifically for individual patients.  Now precision medicine is the next incarnation of that where we know it's not feasible.  It takes half a billion to one billion dollars to bring a drug to market.  But if stem cells and organoid technology let us supply the drugs we do have, and even some of the new ones we do make as a result of this in the best possible way, that's the dream for this method.  That we'll be able to treat disease intelligently.  In maybe a five to 10 year time window.

DR ANDI HORVATH

So Mirella, what do you see in the distant horizon?

DR MIRELLA DOTTORI

I think the power of stem cells is basically uncovering what we still don't know.  There's so much going on in brain development that we yet haven't been able to study.  Because understandably it's difficult to do especially in humans in-utero.  Hopefully using organoids and stem cells we'll be able to uncover novel mechanisms that may play fundamental roles in brain development.  Alongside of that they are extremely powerful for understanding brain function dysfunction but particularly for drug testing and so forth.  What we hope is that with this technology once we understand the underlying causes, whether it be the genetics or certain mechanisms perhaps we can cure particular diseases in-utero.  Go in there and correct certain mutations or replace certain cell types.  That is the ultimate power of this technology that would be the dream home run.

DR ANDI HORVATH

Steve and Mirella, thank you for being on Up Close today.  Good luck with your research.

DR MIRELLA DOTTORI

Thank you Andi.  It's a pleasure.  Thank you.

PROFESSOR STEVE PETROU

Thank you Andi.

DR ANDI HORVATH

We've been speaking about the use of organoids in providing insight to understanding and treating certain epilepsies and autism with researches Steve Petrou and Mirella Dottori based at the University of Melbourne.  You'll find a full transcript and more information on this and all of our episodes on the Up Close website.  Up Close is a production of the University of Melbourne Australia.  This episode was recorded on 19 October 2015.  Producer was Peter Clarke.  Audio engineering by Gavin Nebauer.  Up Close was created by Eric van Bemmel and Kelvin Param.  I'm Dr Andi Horvath.  Cheers.

VOICEOVER

You've been listening to Up Close.  For more information visit upclose.unimail.edu.au. You can also find us on Twitter and Facebook.  Copyright 2015.  The University of Melbourne.

 


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