Investigating the brain’s insulation

CHRIS HATZIS
Eavesdrop on Experts, a podcast about stories of inspiration and insights. It’s where expert types obsess, confess and profess. I’m Chris Hatzis, let’s eavesdrop on experts changing the world - one lecture, one experiment, one interview at a time.

Dr David Gonsalvez is a research scientist at the Department of Anatomy and Neuroscience, University of Melbourne, and could very well be a poster boy for careers in STEM.

Dr Gonsalvez has always had a curious mind and been intrigued by science, beginning with the first time he looked down an old Zeiss microscope. However, it was a personal experience via a family member that really catalysed and fuelled his passion to pursue a career in science, and specifically his work in multiple sclerosis.

Whether creating knowledge resulting in the better understanding of biological processes of the disease, identifying novel therapeutic targets, or developing practical applications, Dr Gonsalvez admits he finds it very easy to be motivated and passionate about what he does.

Dr David Gonsalves sat down with our reporter Dr Andi Horvath to talk about that passion for his work.

DR DAVID GONSALVEZ
I'm a research scientist and I work at the University of Melbourne but I also do some teaching. I do a little bit of teaching in the medical course, as a tutor, as a CSL tutor where we cover pretty much all of the subjects that undergraduate medical students do.

DR ANDI HORVATH
What's CSL?

DR DAVID GONSALVEZ
It's called Case Supported Learning. The students get all their lectures and they don't have lots of tutes like you would have in undergraduate courses, but you have this one big case and you work through all of your lectures and all of the biological pathways and I guess, understanding that underpins disease that they're trying to understand at the time.

So, that's one thing I do. I lecture in the third year of the undergraduate science and biomedical courses. This is a topic that I'm really interested in, which is the refinement of connections in the brain. So, when you're developing, your brain is this growing mess.

It's almost like you could think of it as a chaotic forest that's just got as much stuff as possible to grow but everything collides in with each other and there's not enough space. Eventually things have to sort themselves out and it develops this nice kind of balance and equilibrium, but any different forest I guess, would be very different.

You might go to one in the outback and it will look really different to one in Northern Cairns. How that equilibrium is reached is what a developing brain is like and we lecture on the processes by which cells interact with each other and refine how they're connected to each other and how they might grow, how quickly some cells might grow at one point and other points and what factors change those things and what happens if those things go wrong.

DR ANDI HORVATH
So, my brain could be an Amazon forest and someone else's brain could be the Australian bush?

DR DAVID GONSALVEZ
Yeah. Maybe parts of your brain could be the Amazon forest and other parts will be also a tropical rainforest but different. So, you might be the Amazon and I might be, I don't know, I'd hope to be Port Douglas or something like that; somewhere inland, just inland of Port Douglas. Yeah, something like that. So, conditions can be similar but when you go in and you're really looking at all of the connections between cells, strikingly different; can be, it can be strikingly different.

DR ANDI HORVATH
Is that because there are a gazillion gazillion connections?

DR DAVID GONSALVEZ
Yeah, that's right. So, there are lots and lots of different connections. There are also lots and lots of different types of cells and we're learning more and more that one type of cell which we might have thought all was the same, when we drill down and start looking at them more closely, we're starting to realise that they're really different. So, the cells that I study are the ones that make the insulating material that covers all of the wires in the brain.

Just like the wires in your house, they're not bare, because if they're bare, the electrical signal gets disrupted. They're insulated. They're wrapped with this specialised - in a house usually it's plastic or some sort of inert substance; in the brain it's membranes. It's the stuff that cells that make that form the outer casing and they wrap around the wires and keep them insulated. That's to protect the electrical signal but at the same time, those cells feed the cable because the cable's living. So, I'm interested in those cells.

It was once thought that those cells are just filling space and then we worked out, no, we need them to make the electrical signal go really well. Then we thought, they're all one thing, they're all one type of cell. Then only a couple of years ago it was figured out that there's a huge amount of heterogeneity, which means differences, amongst these cells.

So, it's like saying, I've got a football team and every player in that football team is exactly the same. That's what we used to think but now we know everyone in the football team is dramatically different. Each player might have slightly different roles because one might be able to jump really high, so they are the centre. Another one might run real fast, so they play a different position. That's sort of what is going on with this particular lineage of cells called the oligodendrocytes.

DR ANDI HORVATH
So, it's really the champion team, not a team of champions that we need to play together…

DR DAVID GONSALVEZ
That's right. Yeah.

DR ANDI HORVATH
…and get that nerve cell well fed and insulated. Dr David Gonsalves, tell me about the researcher in you? What are you famous for?

DR DAVID GONSALVEZ
I guess I would be known for studying - I'm really interested in how the rates of tissues grow. I, during my PhD, developed a method to study how fast cells can divide in vivo. So, that means in tissue, and I've applied that method to study how fast nerve cells in one part of the peripheral nervous system grow, but now I've turned to looking at the brain and looking at these non‑nerve cells, these non‑neuronal cells.

What I'm really interested in is characterising how fast they grow and how many cells are made per day, how many are lost and whether or not if you say, are put in an enriched condition or if you're stressed out, whether or not that impacts those rates of growth; because we know that you have a limited window to generate these cells and we want to really know, one, how do they become - how do they generate and what are the mechanisms the cells are using. Are they dividing fast, are they dividing slow, are there lost of them dividing, are there not many dividing. These are the sorts of things I'm interested in.

Secondarily, I'm starting to get really interested in whether or not those features of growth are impacted by your environment and your conditions and also how, how has it changed.

DR ANDI HORVATH
No doubt funding bodies and taxpayers will be asking you, why do we need to know this?

DR DAVID GONSALVEZ
Right. One of the topical issues at the moment is we have all around the world, young people that might be put in conditions say, like on a camp, somewhere where we wouldn't ideally want to house a young person, a person that you or I might know, and we really don't know how lasting the effects of something like that are on the brain. We know it's bad. So, putting someone in isolation, taking someone out of an environment that's social, basically incarcerating somebody or holding…

DR ANDI HORVATH
So, loneliness or prisoners?

DR DAVID GONSALVEZ
Loneliness or prison, or even just knowingfully being in detention or something like that. We don't really know what those negative social environments, how that may impact the brain, but what we do know is that the process of myelination is permanent. So, that's recent.

We've recently found out that once you lay the insulation down on the cable that's it. It's there for good. So, it's not - at this stage there's very little evidence that it's remodelled. The connections between your brain, they can be remodelled and then there's a period where they can be remodelled quite a bit. As you get older it's harder to remodel.

DR ANDI HORVATH
That's plasticity.

DR DAVID GONSALVEZ
That's plasticity, right?

DR ANDI HORVATH
Yep.

DR DAVID GONSALVEZ
That's neural plasticity.

DR ANDI HORVATH
Got it.

DR DAVID GONSALVEZ
This is another form of neural plasticity but all the evidence we have at the moment is once a myelinating cell wraps around an axon, it's there for your lifetime.

DR ANDI HORVATH
So, the insulation is there at the beginning and it's there forever?

DR DAVID GONSALVEZ
Well, once it's laid down - you're being insulated - what we now know is that in a mammal you're being insulated throughout life but the rate at which it's being insulated, we're not very, very - we haven't fully characterised, but what we do know, is you're adaptable early and what you get early, you're left with later.

So, we're really interested in knowing how that process works and whether or not putting someone in an isolated condition might alter that and whether or not that then is permanently altered.

DR ANDI HORVATH
So, if I'm living by myself for too long that's going to alter my brain?

DR DAVID GONSALVEZ
Well, it will alter your brain. It may not be bad, it may be really good. Any situation that you're put in, any interaction you're having with the environment and any interaction you have with other people and anybody, will have an impact on your brain. If you think about your brain, your brain is constantly changing its structure, all the time. It's not a static thing.

If I was to say to a person in the street, if you're thinking about a brain, you can't think about this, like, bit of porridge that's between your ears that doesn't change. Inside of that is this intricate network that's constantly modifying. Now, some things can be modified more than others and why I'm really interested in the insulating material called myelin is that we think that that, once it's laid down, has less of an ability to be removed and replaced later.

DR ANDI HORVATH
Is that a problem?

DR DAVID GONSALVEZ
It could be a problem if it contributes to say, a negative type of circuit, whatever we might define as negative, earlier on in life. It may be then more difficult to adapt that circuit because we may not be able to make as much new myelin and we may not be able to get rid of the stuff that's already been integrated into circuits.

DR ANDI HORVATH
What disease states are related to your research, or interested in your research rather?

DR DAVID GONSALVEZ
Well, pretty much every neuropsychological disorder that we've characterised has some kind of white matter pathology, or not - I wouldn't say pathology. Maybe differences. We see differences on scans where we try to look at this stuff and we identify changes in white matter but the real big disease that people - it's well known by the general public, is the disease called multiple sclerosis; but that's kind of different to development.

Multiple sclerosis is where, as an adult for some reason your immune system just decides to start attacking this myelin. Now, this stresses how important this substance is, because when the immune system attacks it, basically the information that goes between neurons gets stopped because the insulation around the cable goes away. Then, unlike a house, the brain's cables need to be fed. So, the metabolic support to the cable is then lost and you get what we call a conduction block. So, the electrical activity can't get from A to B and when electrical activity in the brain can't get from A to B that can be devastating.

A perfect example is if your brain is trying to move your legs and the information can't get from your brain to your legs it means your legs don't move. That's why sometimes people who have - well, often people who have multiple sclerosis end up in a wheelchair.

DR ANDI HORVATH
So, it's not just your grey matter that's important, your nerves, it's your white matter, your myelin, your insulation?

DR DAVID GONSALVEZ
Oh, yeah. Super important. It's integral to brain function. You can't take the white matter away from your brain. You can't take the myelin away from your brain and have a functioning brain.

DR ANDI HORVATH
All right.

DR DAVID GONSALVEZ
Yeah.

DR ANDI HORVATH
Let's to back to early David. How did you get inspired to enter this whole field of science? Was it luck, what it inspiration? What turned your attention to the brain?

DR DAVID GONSALVEZ
Initially, when I finished school, I kind of had very little idea about where I would end up, in terms of a long‑term career. I knew I was interested in science because it interested me. I did well in maths. So, I did a science degree and the first go at my science degree wasn't the best go. I ended up leaving uni for a little while and I went and worked in all sorts of different jobs.

DR ANDI HORVATH
Like what?

DR DAVID GONSALVEZ
I've done everything from being in a call centre - I actually was a door‑to‑door vacuum cleaner salesman at one point. Didn't last very long. I thought I'd try it out but I don't think that sort of thing was for me really. Yeah, I worked in bars, I worked as a DJ casually. I've done a whole bunch of stuff.

DR ANDI HORVATH
What was the turning point for you?

DR DAVID GONSALVEZ
Well, I ended up moving in with - I have an uncle who - he's a surgeon, or he was. He's still qualified as a surgeon, doesn't practice, but he had a car accident and after the car accident was quadriplegic. I ended up moving in with him and it was more he was doing me a favour that I was doing him a favour. He lived closer to the city and I was thinking about going back to uni. So, it worked out that I could be a bit of a carer and then live with him and get back into study; because I was getting over doing different types of work.

When his accident happened and when he was coming out of rehabilitation we were just spending a lot of time together and chatting a lot about the brain. It fascinated me that the brain just has very little capacity for repair in that condition. It was also very interesting to me in terms of how much impact a very small - if you're thinking about an injury, relative to total body size, it's a very small injury but it can have such a dramatic impact on function, on human function, whole body function.

He was a general surgeon so he had a bit of scientific background. We got interested in talking about how the brain works and then I got really interested in the brain. When I got back into uni I majored in neuroscience and went from there.

DR ANDI HORVATH
You took it further. You did a PhD.

DR DAVID GONSALVEZ
Yeah.

DR ANDI HORVATH
You're now a researcher and a lecturer. Tell me, what have you seen that's changed in the field of neuroscience? Have you already seen some changes? Is it moving fast?

DR DAVID GONSALVEZ
Even just the field of myelin biology, five to10 years ago, we had no idea it played any role in neuroplasticity. None. We had ideas. We had pieces of information that the activity in nerve cells can change the behaviour of these myelinating cells but we didn't know that if you block that behaviour by myelinating cells you can stop certain types of learning.

So, that's a completely opened up field that we just didn't know about. I doubt that most people walking around understand that a major component of neuroplasticity lies in these cells being able to adapt to the changing behaviour of neurons and other cells. So, that's one thing that's been quite a huge change, I think.

When I was doing my undergraduate studies, which was not that long ago, we were not taught any of that. It was not in our course. Now it's great. I'm working on this stuff so in our third year lectures I don't actually use anything in a textbook anymore. We go to all of - we go to conferences and get all this published work and get all this new information.

What we do is we give the students a bit of a status quo on what we know, but then we also give them a taste of all of this new stuff that you can't get in a book because the book was published six years ago and by that time the field has changed.

In some ways, it's a really privileged position to be in, to be able to communicate that information to people and see that, wow, you see it on people's faces when you tell them, if you stop - if you block new myelin being added then certain motor learning can't be done. That changes people's thinking.

DR ANDI HORVATH
Tell me about some surprises you've encountered that's absolutely delighted you in your area or knocked you for a sixer?

DR DAVID GONSALVEZ
Okay. One of the things recently, we've just submitted a paper on it actually. One of the things that has revolutionised our field is the ability to look at the system. Science, as long as we've gone back in terms of biology and neuroscience, a lot has depended on how much we can actually see. In order for us to study the brain we need to be able to see what's happening in the brain, look at connections.

Myelin is something that's really hard to actually see. In the past, the only way to really look at the structure of myelin was to go to an electron microscope. A few years ago a lab in Yale, they published this method that myelin itself, the structure of it, because it's wrapped around so tight - it's like, if you imagine you've got a bit of gladwrap, actually gladwrap on a roll, if you got a bit of gladwrap and wrapped it, wrapped it, wrapped it, wrapped it, wrapped it, wrapped it, wrapped it round a mushy cube of jelly or something, the gladwrap becomes hard but the other thing that happens with this particular gladwrap that's in the brain is it becomes optically reflective. It's like a mirror. It's weird.

DR ANDI HORVATH
So, if you shine a light on it, it kind of bounces back?

DR DAVID GONSALVEZ
Yeah. Light bounces off this particular stuff. So, this group published a paper saying, well, if you shine laser light on brain tissue and you have the equipment to capture the reflection of that light, you can actually see this stuff, this myelin. I thought that was fantastic. I got the paper, we had a look at it and we worked out that the Uni had just bought these really nice microscopes and they had the capacity to do this.

So, we - well, we - one day I went in the lab and just set it all up and took some sections in to look at it and thought, this is not going to work. Shone this laser light down at the tissue and then lo and behold, coming back was this beautiful picture of where all of the myelin was in the sample. We didn't have to do anything to the sample, didn't have to process it, didn't have to put any labels on it, nothing. It's just literally the reflection of the tissue. The only thing in brain tissue that has this reflective property is myelin.

We've now been able to use this particular technique to start studying debris in the context of multiple sclerosis. We know when the immune system comes in and it attacks the myelin, it breaks up and it forms these clumps that are reflective. We know these clumps are not good for repair but we weren't able to quantify them. We weren't able to see them.

So, using this technique, we can now actually see these clumps and we can also see them inside the cells that are eating them. We can monitor how fast they're getting cleared. These are all things that we weren't able to do in the past and now we can do them, so we can look at whether or not a new drug improves the process of clearing the debris, or something like that. So, that's really, really exciting. That was a really - I almost fell off my chair.

Normally with science, when you try an experiment, it's likely it's not going to work the first time round but this was one of those situations where, yeah, it just came good.

DR ANDI HORVATH
Now, I have to ask, whose brains do you look at? Are they animal brains, are they human donations?

DR DAVID GONSALVEZ
At the moment I'm looking at everything from mouse to human brains. This reflective technology, the reflective property of myelin doesn't change if you're a mouse or you're a man or you're a zebra fish or whatever. Yeah, if it's compacted and wrapped around tight it reflects light. One of the projects I'm interested at the moment is we don't actually know how myelin changes in ageing but we do have quite a good collection of people who have donated their bodies to science for the purpose of studying - teaching either anatomy to medical students or doing research.

We're able to now use this technique to study how myelin is integrated into the cortex during human ageing; and that's really exciting because at the moment we're not sure whether or not this stuff is added right through to being very old. We know in a mouse, myelin is added into the cortex until the mouse is the equivalent of an 80 or a 90-year-old human.

The other day I had a look at a 92-year-old bit of brain. I know that might sound strange, but there's quite a lot of cortical myelin, and I was quite surprised by that. So, we're really excited by this project because we can track the trajectory of myelination. Whether or not that's good for preventing against certain types of age related decline, we're not sure.

DR ANDI HORVATH
When you chat with the public and they find out you're a neuroscientist and work with the brain, do you find that some people have misconceptions about the brain, or even your students, when they come to class; what are some of the common misconceptions they have?

DR DAVID GONSALVEZ
I think one of the biggest things about neuroscience is that the public - people are usually not comfortable with the fact that maybe what we know today isn't what's going to be what we know now or tomorrow. Some of the stuff that I was taught during my undergraduate is no longer legitimate. One of the things that we notice a lot is, that I notice a lot, is that that for some reason is difficult for people to come to terms with when it comes to the brain. I don't know why, why the brain is something any different.

For a long time people thought that there was no immune cell service surveying the brain. Now we know that that's just not true. Immune cells go in, they look at the brain, they do it like they do it with other tissues in the body and then they leave. There's a pathway for them to get in and get out and we know all of this but sometimes people will say, it's a privileged site; and it is privileged, it is different.

Immune cells can't go into the brain the same way that they can go into, I don't know, a bit of muscle or liver or something, but they can get there. Things like that are really odd. We find that even in - even when I talk to my uncle, he's a clinician, and they're one of the group of people that find it the most difficult because they need to know that what they know is spot on and it's difficult when you have to be confronted by the fact that this tissue, this bit of thing, we don’t really get, that means when we find new information it could change our existing position. I find that that's one of the things that people find difficult coming to terms with.

DR ANDI HORVATH
Give us a good take home message. Next time we see a picture of a friend's MRI or a cartoon of a brain what would you like us to think about?

DR DAVID GONSALVEZ
I think I'd like people to think - well, I've got little kids and I think - maybe to overlay two things. One, it's not a static thing. Two, I don’t think it's a lot like the way we analogise a brain to a computer. A brain is not a yes and no operating machine. The way a neuron fires is a yes and a no but to get to that point it's a mess of an analogue signal that's sitting beneath it.

The other thing is, is that it's super‑dynamic. Things are changing all the time and the uniqueness in each brain is that structural difference and that structural difference then means that there's differences in the way things move around, things connect, things are talking to each other. So, when you're looking at an MRI of someone's brain and you look at an MRI of someone else's brain, it can look really similar but to me, what I would hope someone thinks, is that those things are extremely different. Behind that MRI is two completely different things.

The second thing is behind the MRI of a little person and an old person is also a completely different thing. Even though all the structures might look the same, you've got the same gross bits, within those structures I think it's almost like a universe of difference. So, not just a wee bit of difference, a massive difference.

I think if people can think that this is a structure that's just constantly moving and changing and adapting to what's going on around you, and also that constant ebb and flow is completely different in you to me, and that's what makes us who we are, I think that would be absolutely fantastic.

DR ANDI HORVATH
Dr David Gonsalvez, thank you.

DR DAVID GONSALVEZ
Cheers. Thanks.

CHRIS HATZIS
Thank you to Dr David Gonsalvez, research scientist at the Department of Anatomy and Neuroscience, University of Melbourne. And thanks to our reporter Dr Andi Horvath. Now, Andi and David aren’t done, they have something more to tell you.

DR ANDI HORVATH
You have also appeared on one of our sister podcasts. It's called Secret Life of STEM - surprising stories behind STEM careers. It's a new podcast made by the University of Melbourne and it explores the fears and hopes and misconceptions about studying and working in STEM. You can relate to that.

DR DAVID GONSALVEZ
Absolutely. I guess I didn't take a traditional path. Actually, I know quite a lot of scientists that didn't maybe take the traditional path. So, I actually was kicked out of uni. So, I got in, got out and then got back in again somehow, so it's a completely atypical way to get to where I am now, but I think if you're interested in those sorts of background stories then go for it.

DR ANDI HORVATH
I think it's good to get the whole range of stories. So, if you're in high school or a secondary school student anywhere around the world this podcast is for you. It's the Secret Life of STEM. Chris Hatzis will give you all the details.

CHRIS HATZIS
Thank you, Andi. Yes, The Secret Life of STEM, it’s a new podcast from the University of Melbourne and is available on iTunes or wherever you get your podcasts. Do check it out.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on June 19, 2019. You’ll find a full transcript on the Pursuit website. Audio engineering by me, Chris Hatzis. Co-production - Silvi Vann-Wall and Dr Andi Horvath. Eavesdrop on Experts is licensed under Creative Commons, Copyright 2019, The University of Melbourne. If you enjoyed this episode, drop us a review on Apple Podcasts and check out the rest of the Eavesdrop episodes in our archive. I’m Chris Hatzis, producer and editor. Join us again next time for another Eavesdrop on Experts.