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Welcome to UCL Brain Stories, the monthly podcast series from the UCL Neuroscience Domain presented by Caswell Barry (UCL Division of Biosciences), Steve Fleming (UCL Division of Psychology & Language Sciences) and Selina Wray (UCL Queen Square Institute of Neurology). UCL Brain Stories aims to showcase the best of UCL Neuroscience, highlighting the wide range of cutting-edge research going on within the Neuroscience Domain as well as bringing you the people behind the research to share their journey of how they ended up here. Each month we’ll be joined by a leading neuroscientist to offer their perspective on the big questions and challenges in Neuroscience research, to find out what stimulated their fascination with the brain and hear how they ended up becoming part of the UCL Neuroscience community.
For more information and to access the transcript: https://www.ucl.ac.uk/research/domains/neuroscience/brain-stories-podcast
Brain stories test
0:02
Hello and welcome to Brain Stories.
0:03
I'm Caswell Barry and I'm here with my Co-host Celina Ray on Brain Stories.
0:08
We aim to provide a behind the scenes profile of the latest and greatest work in neuroscience, highlighting the stories and the scientists who are making this field tick.
0:18
We don't just ask about the science, we ask about how the scientists got to where they are today and where they think their field is going in the future.
0:26
And we're really excited today to be joined by Professor Adrian Isaacs.
0:30
Adrian is a professor of neurodegenerative disease in the UK Dementia Research Institute and Department of Neurodegenerative Diseases at UCL Queen Square Institute of Neurology.
0:42
Adrian did his undergrad studies at the University of Manchester, which included time at the Mayo Clinic in Jacksonville, FL.
0:48
He did his PhD at Oxford and postdoctoral work at Harvard before coming to UCL, where he established his group.
0:56
His lab is focused on understanding the molecular mechanisms of motor neuron disease and frontotemporal dementia, and we're incredibly excited to hear more today about his work.
1:05
Welcome, Adrian, and thank you for joining us.
1:08
Thank you for having me.
1:10
Maybe we could start by just having hearing from you in your own words about what your research interests are, what your lab does.
1:19
Sure.
1:19
So my lab focuses on these two related diseases, frontotemporal dementia or FTD and amyotrophic lateral sclerosis or ALS, also known as motor neuron disease or I'll probably refer to it as ALS.
1:33
So people with frontotemporal dementia have loss of brain cells in the frontal and temporal lobes of the brain and that leads to, depending where the brain cell loss is, either language dysfunction or behavioural change.
1:50
Whereas people with motor neuron disease have loss of their upper motor neurons.
1:55
So those are the motor neurons in the brain and also their lower motor neurons.
1:59
So those are the ones that innervate their muscles and that leads to muscle weakness and progressive paralysis and ultimately usually death quite quickly.
2:09
So medium time to death is 30 months.
2:12
So the reason I talk about them together is that a proportion, about 15% of people with FTD go on to get ALS and about 15% of ALS people with ALS go on to get FTD.
2:24
So we know that they're Linked. In your lab.
2:26
You're particularly interested in some of the genetic causes that underlie these diseases.
2:34
I wonder if you could tell us a little bit about the genetics of FTD and ALS and the particular genes that you're interested in?
2:42
Well, the main gene that we focus on actually is one called C9ORF72.
2:49
And that was really a breakthrough in the field in 2011 when mutations in this gene called C9ORF72 were shown to be the most common cause of both FTD and ALS.
2:59
So they cause about 10% of all FTD cases and about 10% of all ALS cases.
3:05
So it's actually one of the most frequent single gene causes of neurodegeneration.
3:10
So my lab does a lot of work on C9ORF72.
3:13
We also work on some rarer causes of genetic causes of FTD, for instance, a gene called Gen 2B.
3:21
Can you tell us a little bit more about the C9ORF72 mutation?
3:26
Because as I understand, it's quite an unusual mutation that took a long time to from identifying the families.
3:32
It took a long time for the mutation to be discovered.
3:35
That's right.
3:36
It's an unusual mutation because it's a repeat expansion.
3:40
So it has a repeat of 6 letters, so four ‘G’s and two ‘C’s.
3:45
And in the general population there'll be two copies of that sequence, four ‘G’s and two ‘C’s and then another four ‘G’s and two ‘C’s.
3:52
Whereas in people with FTD and ALS, that sequence is repeated hundreds but often thousands of times.
3:58
So you have this huge extra piece of DNA.
4:01
And the other interesting thing is that it wasn't in what we would call the coding part of the gene.
4:06
It's actually in the something called an intronic part of the gene because it was so big and so repetitive, it wasn't observable by standard sequencing techniques, which is why it took so long to be discovered.
4:19
Just to add sort of question maybe for the less expert people of whom I'm counting myself very much in that.
4:25
So, so Selena said this.
4:27
So it sounds like is this is this sort of the standard way in which these genes are located.
4:32
You have a a family or a sort of a generation of families who are developing a particular variant of the disease and then your people go away and genotype them hoping to find genes that are responsible.
4:44
That's that's the sort of fairly standard way of investigating these sorts of neurodegenerative diseases.
4:50
Is that is that true?
4:51
Yeah, in this case.
4:53
So we're talking about what we've determined autosomal dominant disease.
4:58
So it's inherited in every generation of a family.
5:02
And if your parents, one of your parents has it, you have a 50% chance of getting the gene yourself, which of course you have.
5:08
You have one copy of the gene from your mum and one copy of the gene from your dad.
5:12
And then if you inherit the mutant copy, you'll end up getting the disease.
5:18
So that is how we've found a lot of these also indominant disease genes is through collecting families, narrowing down the region by comparing the region that's shared across all these families and ultimately finding the gene.
5:34
These intronic mutations are are really fascinating because it's not maybe immediately obvious how they would cause disease, unlike a coding mutation where you can kind of easily see that changing the amino acid sequence would disrupt the function of the protein.
5:51
So I wonder, and I know that your group was one of the first groups worldwide to develop models for C9 for the C9ORF72 mutation.
6:01
So I wonder if you could tell us a little bit about the models you created and how this intronic mutation might lead to neuronal dysfunction.
6:11
Yeah, absolutely.
6:12
So when the mutation was first discovered, it was a real challenge actually for the whole field because this repeat expansion was so big you couldn't use standard techniques to analyse it.
6:24
So normally in a cell biology lab or a medical biology lab, if you're interested in a gene these days, you can just order a gene synthesis and the company will synthesise that gene for you and then it will be made.
6:35
But because we have this huge repeat expansion, it wasn't amenable to gene synthesis.
6:40
It wasn't amenable to other techniques like plurimase chain reaction, PCR that we'd normally use.
6:45
So we had to come up with completely new ways to model a repeat.
6:49
So one of the breakthroughs in my lab was we came up with a way of taking a small number of these repeats and then using molecular biology techniques to stitch them together so we could then done building a very long repeat.
7:02
So we did that in the lab.
7:03
So we came up with a way of kind of doubling the repeats each time we did this type of cloning.
7:08
It was a really exciting moment in the lab because every time we did another experiment, we could see these repeats getting longer and longer.
7:13
And we knew after a while we'd built longer repeats than anywhere else in the world.
7:17
And then we were like, wow, what are we going to do with them?
7:20
And I think sort of the key moment, or one of the most important parts of that process was when we decided to make fruit fly models.
7:29
Of course, we didn't actually have expertise in fruit fly models, but one of the things I love about being at UCL is we have all of these experts and as a really brilliant fruit fly biologist called Linda Partridge, she works on ageing.
7:42
So she's actually Dame Professor Linda Partridge.
7:45
And when I had this, when we had built these repeats, you know, I was a very junior member of UCL.
7:52
So but I approached Professor Dame Linda and she was brilliant and said absolutely, this is a great project, let's work together.
7:57
So with Linda, we made fruit fly models.
8:01
Maybe should I tell you a little bit about why we love the fruit fly?
8:04
Yeah, Please do.
8:05
Yes, please.
8:05
Yeah.
8:07
So fruit flies are totally amazing.
8:09
So they've been used by geneticists since the early 1900s.
8:13
And because there's this accumulated wealth of experience of using fruit flies, the genetic tools in fruit flies are very advanced.
8:21
So you can basically turn genes on or off in any particular subset of cells or even neurons and subtypes of neurons that you would like.
8:30
So the other thing about fruit flies is 75% of their genes or 75% of genes that cause disease in humans are present in the fruit flies.
8:41
So there's been this brilliant work over the years, and several Nobel Prizes have been won actually by working pathways out in fruit flies.
8:48
And the most recent was circadian rhythm genes.
8:51
So all of these clock genes, they were discovered in flies.
8:55
And then it turned out the same genes do the same things in humans and, you know, they won the Nobel Prize.
8:59
So we know we can really derive insight by working with fruit flies.
9:05
So what we did in this case with Linda and our other long term fly collaborator Theresa Nikli at UCL is that we took these very long repeat regions and we turned them on only in the brain cells of the flies and only in the adult flies.
9:22
And what we saw when we did that is the flies had a dramatically reduced survival and they essentially became paralysed and then died.
9:31
So we've developed a fruit find model of neuron disease.
9:36
So these very long repeats, do you think this proved to be is, is it something that's sort of very specific to this particular disease or is this going to turn out to be something that is underlying a number of different diseases, sort of a more common mechanism?
9:51
Or do we not know the answer to that yet?
9:53
We asked a very permanent question, Caswell.
9:55
So we know there are certainly some repeat expansion diseases already.
10:00
So we learn a lot when we're modelling the diseases from myotonic dystrophy.
10:04
So that can also have very long expanded repeats also in non coding parts of the of the gene of the gene.
10:11
And then there's a whole host of repeat expansion diseases with repeats in the coding part of the gene.
10:17
So Huntington's disease is the most well known, but there are certainly spinal cervaritaxins as well.
10:22
But what we haven't managed yet is to try and understand whether these longer non coding repeats that maybe aren't inherited in ordinary autosomal dominant fashion, but may be causing a lot of what we might call sporadic cases of the disease.
10:40
And that is now a very kind of burgeoning area of interest.
10:43
Our regular listeners may remember our podcast with Professor Ed Wilde where we talked about the Huntington's repeat.
10:50
If you haven't heard that, it's well worth listen.
10:53
But Adrian, that brings us really nicely and talk about the mechanisms again by how C9ORF72 leads to disease.
11:02
So in Huntington's there is this is a coding mutation and it's in the coding sequence, sorry.
11:07
And it leads to this kind of long stretch of Poly Q.
11:12
But the C9 is slightly different in terms of what it does to the RNA, what it does to the protein.
11:18
So what are the different ways that C9 could be causing disease?
11:23
We have this extra piece of DNA and it's in the intron.
11:30
But for us molecular biologists, we know that that intronic DNA is transcribed into what we would call pre mRNA, but then those introns are normally spliced out and degraded.
11:42
But what we another one of our early findings was showing that this pre mRNA, these repeats of RNA aggregate mostly in the nucleus, so they persist in the cell.
11:54
So you have this persistence of repetitive RNA, but we also know that that repetitive RNA will then go on to be translated into repetitive proteins.
12:04
So you actually have the repeat RNA floating around in the cell and these repetitive proteins.
12:10
And our early work suggested that the repetitive proteins were really super toxic.
12:16
So when we looked at those in the flies, they really drove a very profound regeneration.
12:21
And we now wonder whether there may be a contribution of those proteins, but also the RNA in the cell as well.
12:29
So we think it's going to be the complex picture actually, I was going to say.
12:33
So do we know you, you said that you think some of these repeats might underlie sort of spontaneous occurrence of the disease.
12:39
Do we do we have any idea why, why you're getting sort of so much sort of duplication within and then what?
12:46
Right.
12:46
What I mean, maybe this is a very basic genetics question.
12:49
I just don't know the answer to what is causing the expansion of of these sequences.
12:53
Do we know it's just some sort of copy error that gets repeatedly rerun for some reason?
12:59
We don't know exactly the reason.
13:02
So some of it will be happening in your germ cells.
13:06
So I guess during mitosis, but there's increasing now interest in the idea of what it's a bit of a technical term we would call schematic mosaicism, where maybe in particular cells repeat is expanding more than in other cells.
13:24
And because neurons, you know, not dividing cells, so that couldn't happen during cell division.
13:30
That's more likely to be happening during transcription of a gene or during DNA repair mechanisms.
13:38
Coming back to the repeat proteins, Well, I think back to repeat proteins.
13:43
So your flying model was really one of the breakthroughs in in this field of showing that the repeat proteins are toxic.
13:51
But obviously the work in your lab expanded hugely on the basis of that finding.
13:56
And you've really been at the forefront of how we look for those repeats in patients.
14:02
And I wondered if you could tell us a little bit about the translational applications of what you've been doing in the lab in terms of maybe diagnosis and also clinical trials.
14:14
Yeah, our really fly work really suggested that those repetitive proteins that are made by the repeat are toxic and particularly toxic to neurons.
14:24
So we realised we had to be able to measure them if we were going to understand what they were doing.
14:29
We had to measure their levels not only in the fruit flies but also in our patient neuron models that we grow in the lab.
14:37
So we developed some sensitive techniques to measure those proteins and then we realised, well, if we're doing it in our model systems, why wouldn't we try doing it in patient material as well.
14:49
And we are very fortunate that I'm at the UK Dementia Research Institute and at the time I was sharing a lab with Henrik Zetterberg, who is really a leader in biomarker development and he had access to this really world leading platform that's very that can detect proteins in human body fluids extremely sensitively.
15:10
So we transferred our sort of lab assays onto this platform that we call the Simura platform.
15:18
And then working with another colleague at UCL who we've worked with for a long time, Professor John Rorer of the Dementia Research Centre.
15:25
And John Rorer has been collecting over many years sample where he works with familial FTD patients and he's been collecting biosamples.
15:35
So through working with John and Henrick, we were able to measure these dikeptide repeat proteins in the CSF of people with FTD and we could show that we only saw them in people who had C9orf72 FTD and they were completely, absolutely in control.
15:54
So it was one of those rare biomarkers that was completely specific and completely sensitive as well.
15:59
We picked everyone up and none of the none of the healthy samples.
16:05
So then having done that, we were approached by a biotech company who were running a clinical trial to test an anti sense or their nucleotide to target and reduce the C9ORF72 repeats.
16:19
And so we worked with them to validate the assay and show it was really reproducible across a number of different parameters.
16:26
And then that that biomarker assay was then used in their clinical trials.
16:31
So we've taken our work all the way from the bench all the way through to patients, which was, you know, very satisfying.
16:36
That's amazing.
16:37
I think it's what we all want to what we all aspire to as bench based scientists is that have something that really goes from the lab through to where it's having patient impact.
16:48
And what is the status of kind of treatment for these patients at the moment?
16:54
Have has there been any success in clinical trials?
16:56
Is there optimism around where the future is going there?
17:00
There's definitely optimism, but at the moment when a difficult position because those trials that there was a huge amount of hope for and two different companies did them where they took antisensitology nucleotides to target those repeats.
17:16
And using RSA we they could show that those proteins, those repetitive proteins were reduced after treatment, but yet there was no clinical benefit and those trials were actually halted.
17:29
And as I said, that was a real blow to the field.
17:33
So now we're starting to think, are there other things we need to be doing as well?
17:38
So there are lots of possible reasons for that failure.
17:41
So either we didn't treat early enough, maybe we didn't treat long enough, maybe we just didn't get enough into the brain.
17:49
But there's also other possibilities.
17:51
So this repeat is really weird because it's not only transcribed in the what we'd call the sense direction or conventional direction that a gene is transcribed in, it's also transcribed in the antisense direction.
18:04
So you also have antisense RNAs and antisense derived proteins lying around.
18:10
And that was another one of our early findings to show that.
18:12
So now we're very interested in whether the disease may be driven in part through these RNAs and proteins that are driven from the antisense strand.
18:23
And that's something now we're very interested in pursuing.
18:26
So this sort of strikes me about quite a few sort of neurodegenerative diseases is that by the time we're not very good at detecting them based on the behavioural symptoms.
18:36
So by the time, say, someone develops memory problems with Alzheimer's or presumably gait problems with motor neuron diseases, there's already quite a lot of damage been done to the the brain or specific sets of neurons within it.
18:53
Is.
18:54
What's your view on using these sorts of techniques and markers to identify people who are at risk early on and then trying to either halt the disease at that point or you know, is, is that, I don't know, is that a general concern?
19:10
Is that, or am I speaking from a position of not knowing very much?
19:13
We know that's true.
19:14
But generally people think, of course, the earlier you treat, the better effect you're going to have.
19:20
And there's a number of ways we can get to that.
19:23
So you know, our colleagues, like I mentioned, John Rohrer, are really working now on lots of different digital technologies to try and get information on, on early diagnosis for instance.
19:34
So I think that's really a burgeoning field.
19:35
And there's definitely also a lot of work going on in the fluid biomarker space, I guess we would call it, to look in the blood of people with these with these diseases and start getting more sensitive assays.
19:50
So I think both of those are going on in parallel and I think that would be very helpful for ultimately delivering earlier treatment.
19:58
Moving on to maybe your more recent papers there, I have two in mind that I thought it might be quite nice to to discuss as part of the podcast.
20:08
And you mentioned just now the complexity of trying to treat these diseases, particularly when there's sensors, antisense, there's multiple proteins.
20:19
And I know one of the developments from your lab has been what assays can we use to do drug screening.
20:27
So I wondered if you might tell us a little bit about the recent work you had about the drug screening assays that you developed.
20:37
We felt that it would be helpful if these repetitive proteins are contributing, can we work out ways to reduce them?
20:47
And we wanted to do that in AI would call an endogenous context.
20:52
So in this case, we were taking neurons that are derived from people with C9orf72 repeat expansions.
21:00
So this is this classic sort of stem cell technology where you can take a skin cell or a blood cell and you convert it into a stem cell and then you can take that stem cell and convert it into a neuron.
21:10
So you can have living neurons in the lab from people with these mutations.
21:14
So we did that, but then we did some molecular biology to add a little very sensitive sort of tag or sensor onto those repeat proteins.
21:28
So we put it into the DNA and then it will get ultimately turned into a protein.
21:33
And by adding a kind of very sensitive sensor of these proteins, we could then take these patient neurons, put them in a high throughput screening format and then do screens for.
21:50
Well, we did it genetically and we did it.
21:53
And so we knocked out a whole host of genes and we saw which ones would make these proteins come up or down.
21:58
And then we did it with small molecules as well.
22:01
And found, in fact, our most interesting one was one that actually make the repeat proteins go up.
22:07
And then we try to work out why it was doing that.
22:10
I think it'd be a phenomenal tool for the field for, for drug discovery.
22:15
And of course, the presence of, of the repeat within the cell leads to a whole stream of, of, of downstream effects.
22:23
And I really wanted to ask you about the work that you've been doing on on lipids and, and particularly, I mean, this this beautiful paper that you had had really a lot of kind of press coverage and I think very exciting with each translational potential.
22:40
So could you tell us a little bit about what you found and what role lipid dysregulation could potentially play in this disease?
22:49
Yeah, I was hoping you'd ask me about lipids doing.
22:51
And that is something that really I waited until the moment was right.
22:57
And again, that initially came from our flywear.
22:58
The flies have just been an incredible engine of discovery for us.
23:02
And So what we found initially in the flies was that we measured loads of different types of lipids or fats, so 1400 different types in the brains of the flies.
23:14
And this very specific class of fat called a polyunsaturated fatty acid was reduced.
23:20
And again, that immediately has interest because these polyunsaturated fatty acids often called omega-3 fatty acids or healthy fats.
23:28
So a lot of people have heard of them, but it turned out this reduction in these polyunsaturated fatty acids was there in our fruit fly models.
23:37
It was there in our patient neuron models that we wrote in the in the lab, and it was also there in the brains of people who died with frontotemporal dementia.
23:45
So there was this deficit in the in the specific polyunsaturated fatty acids.
23:50
But then to really work out what was going on, because that could have been helpful, that could have been harmful, it could have been neutral, we again turned to the flies into this really, I think, elegant set of experiments in the flies.
24:02
So the first thing we did was just feed them some of these polyunsaturated fatty acids because you generally get them from the diet.
24:10
And I've told you that our C9ORF72 repeat fruit flies have this dramatically shortened lifespan.
24:16
And we fed them these polyunsaturated fatty acids and they got a little bit, they lived a little bit longer.
24:22
But frankly, that was slightly disappointing.
24:24
It showed we were on the right direction, but it wasn't a huge finding.
24:27
So we wondered, is there a way of getting more directly to the brain?
24:32
And here we use this brilliant sort of quirk of evolution that these polyunsaturated fatty acids, some of them are called essential fatty acids, which means that we can't make them, we have to take them from our diet.
24:45
And that's true for us, that's true for food fries, but it's not true for worms.
24:49
So worms have an enzyme called a desaturated enzyme that makes these polyunsaturated fatty acids.
24:58
So we could take that worm gene, we could put it into our flies.
25:02
We could then turn it on only in the brain cells of those flies.
25:06
So we were delivering the polyunsaturated fatty acids only to the brain cells of the flies, and then we saw this dramatic extension of lifespan.
25:14
So this was telling us that they are protective, but actually you've got to get them to the brain to be protective.
25:20
So I think that was really the sort of most poignant experiment in that paper.
25:25
And then we showed that they're also protected in our stem cell models, our human stem cell models.
25:30
This is amazing.
25:31
I think, you know, listeners are learning that the fly and the worm are kind of humble but powerful for for neural degeneration research.
25:39
So this to me, well, I think to anyone has really exciting implications.
25:45
So do you think we should all be having more omega-3 in our diet to protect against neural degeneration?
25:52
Yeah, I'm going to be very careful about giving out clinical advice based on research in our fruit flies, but it's definitely made us think a lot more about that.
26:02
And so all of us in the team, when we got this data, suddenly realised we hadn't thought at all about omega-3 intake.
26:09
And so now I do think about that more as part of a healthy diet.
26:13
You know, the government guidelines say you should eat 1 portion of oily fish a week, and that's very rich in these omega-3.
26:20
So now I do that.
26:21
So I'm definitely not recommending supplements or anything like that by, you know, it's just a realisation.
26:27
It's worth following the government guidelines on these Omega threes.
26:32
And there's actually epidemiological evidence that a higher dietary intake of these omega-3 fatty acids reduces the risk of developing motor neurone disease.
26:43
So I'll work very well with that epidemiological evidence from this group at the Schools for Public Health.
26:50
So there is definitely evidence that it's worth having a healthy level of Omega threes in your diet.
26:57
But of course, the question we want to ask is specifically is that beneficial for people with ALS?
27:03
And to do that, we'll need to do a clinical trial.
27:06
And that's something we're actually having ongoing discussions with our colleagues here about.
27:10
So we're hoping we'll be able to initiate in a clinical trial really to test that specific question, presumably kind of supplementation or a trial in that way is something that we potentially already know is relatively safe.
27:25
So quite something that to me seems nothing is ever straightforward in clinical trials, but it's something that to me conceptually seems would be relatively low risk, high reward.
27:38
Yeah, no, definitely.
27:38
There's been a lot of work in the sort of cardiac space and you can't actually take too much of these things.
27:45
So they do have some side effects, which is why, you know, at this point, definitely don't be taking those as supplements.
27:51
But I think it's something that, yeah, can be relatively straightforward to investigate because we know the levels of which you can give them to people safely.
28:01
How?
28:01
What's the scope to go beyond that rather than just supplements?
28:04
I mean, I'm not suggesting we start splicing worm genes into people's heads, but it sounds like the supplement will only take you so far.
28:12
Is there any thoughts about that?
28:14
Yeah, definitely.
28:15
So again, dietary, if you take these things in through your diet, they saturate.
28:21
Absolutely.
28:22
So there's only a certain amount you can take and it saturates, and then only a certain amount when you get into your diet gets into the brain.
28:28
So the next question that we'd like to address, which is I think the most difficult one, is why are these polyunsaturated fatty acids being so beneficial?
28:39
And of course, if we could work that out, then we could potentially mimic their effects with a drug or potentially with the gene therapy and that might provide even more benefit.
28:50
But yeah, I agree, I don't think the worm gene is a way forward.
28:53
So we're not we're not pushing that as a gene therapy.
28:56
So maybe taking a step back from your your lab to kind of the field at large, what do you think are the most exciting areas in your field at the moment?
29:07
What does the future hold and what do you see as the, the biggest challenges in FTDALS research?
29:15
Well, I think we've already talked about it a little bit.
29:17
And I think the sort of future, at least the near future is gene therapy.
29:22
I'm super excited about the developments we're making in that area.
29:26
And of course, we're all inspired by really remarkable results, first in it's childhood disease, spinal muscular atrophy, where gene therapies are making a huge difference.
29:37
But now even in ALS, so there's all 1 gene therapy for a rare genetic cause of ALS caused by SOD 1 mutations that is actually proving very effective.
29:48
So that's telling us if we get the right gene in the right population and treat it at the right time, we can definitely make a difference.
29:54
So I'm super excited about the potential of gene therapies and we're going to see a lot the gene fairy P approaches coming through I think in the next few years.
30:05
So that's one area.
30:07
And actually, I say to my master's students when we're when I'm lecturing about this, like what an amazing time to be entering neurogenerative disease research.
30:16
Like, you know, we've all spent 20 years seeing really nothing being approved or is making a difference to patients.
30:23
And now here we are in a new era, truly a new era where we can start treating these diseases.
30:27
So it's a really exciting time, I think, to be in the field.
30:31
So, Adrian, thank you.
30:32
I mean, your research is utterly fascinating.
30:35
Is this, is this how you imagined where you imagined you'd be?
30:39
Was this always the plan to be working on, you know, the cutting edge of neurodegenerative disease or, you know, when you were an undergraduate before that, what did you what did you imagine you were going to be doing?
30:50
Yeah.
30:50
I had very little idea of what I was going to do.
30:53
And I kind of like biology.
30:56
So I thought I'd do an undergraduate degree in biology, but apart from that, I had very little idea.
31:02
So I actually went for a course called life sciences that allowed you to choose across the whole modules, across all aspects of biology.
31:11
Because, you know, I looked, you know, when I was looking for degrees and there were ones like biochemistry that kind of scared me.
31:16
It's like, how do I know?
31:17
How could I do three years when something so focused?
31:20
So by pricking a broad range of different modules, I sort of realised I was most interested in molecular biology and genetics.
31:27
So that started holing my interests.
31:30
But my degree was a four year degree and in the third year you got to do a year of research to really understand if you, you know, enjoyed science.
31:42
And that for me was like the most profoundly important year of my career, undoubtedly.
31:48
So in that year, I got the opportunity to go to the Mayo Clinic in Jacksonville in Florida and work with a guy called John Hardy.
31:58
And when I was there in the kind of what, mid late 90s, you know, he was really at the forefront of discovering new genes that caused neurodegenerative diseases.
32:09
So he'd identified the first gene that caused Alzheimer's disease.
32:13
So it was really at the forefront of his neurodegenerative disease genetics.
32:18
And when I got to the lab, I was very lucky to be mentored by one of his senior team called Mike Hutton, who really taught me how to do experiments, how to design experiments.
32:29
And you know, I loved it.
32:30
I loved being in a cutting edge environment, the camaraderie of the lab, the joy of discovery, just talking about all the different scientific experiments.
32:38
So that year was really influential in making me realise that I love being a scientist and that's something I wanted to carry on doing.
32:48
And actually the project I was working on led to the discovery that mutations in this gene called Tau cause FTD.
32:57
So, you know, that was the first gene known to cause FTD and it's still one of the most important genes in neurodegeneration.
33:04
So to be involved in that finding when I was 21, right the been in my career was really inspiring.
33:09
And that's kind of led to everything that I've done since.
33:13
And as you've heard, it sort of come full circle.
33:15
And now I work on other genes that cause FTD.
33:18
It's amazing.
33:19
And I think so important for some of our listeners about working out what they want to do and kind of take advantage of those opportunities.
33:27
Because one thing I always tell my students is doing science is quite different to learning about science.
33:32
And the only way to understand if you enjoy doing research is to get your teeth stuck in and do it.
33:38
And so did you carry on working on FTD kind of straight from that point, or did you kind of visit other areas of science and then return to to FTD?
33:48
Yeah.
33:48
So I went then went into other areas, but I made a very sort of clear decision after being part of that incredible finding.
33:56
I kind of thought to myself, that's brilliant.
33:58
We found the gene, but that's really just the end of the beginning.
34:01
And now we need to understand what that gene does if we're ultimately going to deliver patient benefit.
34:07
So then I made a very clear decision to kind of leave the gene hunting to people like John and try and develop skills to understand what those genes do.
34:16
So during my PHDI did a project really around modelling neurological diseases in mice.
34:24
And then for my postdoc, I did a similar idea, modelling Alzheimer's disease, but in neuronal cell cultures.
34:33
So I kind of wanted to build those cell and sort of in vivo model experience.
34:38
And then, so I say then in 2006 when that sort of post doc at Harvard was coming to an end, this sort of dream job advert arrived from UCL when I was looking through nature from John Collins and Lucy Fisher, who had just discovered a brand new gene that caused FTD and they wanted to bring someone in to work out what the gene did.
34:59
And that sort of perfectly aligned with all the skills I've been developing.
35:03
So, you know, the interview went well and I ended up getting up, getting the job and, you know, I loved being at UCL and sort of developed my lab through that.
35:12
So it started as really a postdoc and then I managed to get my own funding and and develop my own app.
35:18
We haven't really talked about the other genes that you work on.
35:22
So maybe now is a good a good point to to kind of just have a couple of minutes about what that gene was, what it does and kind of what you're work in that area has shown.
35:36
So the other gene, the original gene in my lab started working on is called Chimp 2B.
35:42
And this is the gene that has really many different roles in the cell.
35:47
So it's part of a cellular complex that's called the escort complex and that's really a membrane remodelling complex.
35:55
So it's involved in the function of endosomes.
35:59
This also can be hijacked by viruses to viruses use it to release their viral material from the cell.
36:08
So it does lots of different things.
36:09
It's involved in cell division.
36:11
And so we, you know, we made some mouse models, we made some cellular models.
36:16
And what we're most interested in at the moment is in work showing that this protein goes to sites of membrane damage.
36:25
So cellular membranes can be damaged.
36:29
And the way we do this with my collaborator Jazz Carlton at King's College London, is that you can use a microscope, SO2 photon laser to put a very, very precise hole in the membrane of a cell.
36:44
So one pixel by one pixel hole in the cell.
36:47
And then we take this T2B protein and we tag it with green, green fluorescent protein so we can see where it goes.
36:54
And if you put a little hole in the membrane of a cell, you see this cloud of Chimp 2B just immediately go to the site of damage.
37:04
It's totally amazing visually when you see it.
37:06
So we know that these proteins are involved in repairing damaged membranes.
37:12
And we wonder whether that's particularly important for neurons because neurons have these amazing, you know, dendritic arbours.
37:19
And, and so we wonder whether that's going to turn out to be an important role.
37:23
But that's still very much work in progress.
37:26
So we're almost out of time.
37:27
We're going to need to rash up.
37:29
But before we do, we like to ask each of our guests the same question, which we've warned you about.
37:34
And the question is this, what is your favourite fact about the brain?
37:40
So my favourite fact about the brain is actually a very simple one, and that is that our brain cells live as long as we do.
37:48
So our brain cells are our neurons, I should say, can live for 100 years.
37:53
So, you know, these other cell types in the body, they have to divide and replenish neurons.
37:58
They live as long as we do.
37:59
They have to make energy.
38:00
They have to clear waste.
38:01
They have to keep our brains working, and they can do it for 100 years.
38:04
I think that's amazing.
38:06
That's awesome.
38:07
That's a great.
38:08
Yeah, that's a great fact.
38:10
Thank you, That was a really fascinating discussion.
38:13
Thank you so much, Adrian for your time and for joining us on this episode of Brain Stories and for all our listeners, we look forward to seeing you next time.
38:22
We'd like to thank Patrick Robinson and UCL Digital Education for editing and mixing and UCLS Neuroscience Domain for funding the podcast.
38:30
Follow us on Blue Sky and LinkedIn, probably at UCL Brain Stories, depending on whether we've made and managed to register those things, for updates and information about forthcoming episodes available on all good social media platforms.