Reversing irreversible blindness

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.

The eye is often touted as the most amazing and complex organ we possess. But around the world, about 40 million people are blind and roughly six times that many have some kind of vision impairment. Furthermore, 80 per cent of vision problems worldwide are often avoidable or even curable.

KEITH MARTIN
Well, I'm Keith Martin. I'm the Ringland Anderson Professor of Ophthalmology in the University of Melbourne and also the Managing Director of the Centre for Eye Research Australia.

CHRIS HATZIS
Professor Keith Martin isn’t just any internationally-renowned clinician-scientist, he’s on the Ophthalmologist Power List for 2019. Yes, they have a Power List. Keith’s passion is to develop innovative and creative approaches to prevent vision loss, restore sight and reduce the burden of blinding eye disease around the world. It’s been a busy few months for Keith, his time occupied by World Glaucoma Week and the World Glaucoma Congress 2019 just held here in Melbourne. He took some time out to sit and chat with our reporter, Dr Andi Horvath.

ANDI HORVATH
Keith, you made it to the Ophthalmologist Power List for 2019. What is an Ophthalmologist Power List?

KEITH MARTIN

I wouldn't read too much into that. I mean this is something that is just done by one of the major magazines that publicises what's going on in ophthalmology and they do this I think for a bit of fun each year. They identify people who have been nominated by their peers as being influential within the field of ophthalmology. I just happened to make it onto that list this year as someone - as emerging leader in ophthalmology. I guess that means I haven't emerged yet but I'm emerging.

ANDI HORVATH
You're currently the president of the World Glaucoma Association. What exactly is glaucoma?

KEITH MARTIN
Okay, so glaucoma is a condition which causes gradual loss of vision over time. The common perception is that it's just related to high pressure in the eye and that's what it is, it's just high pressure in the eye, but really this is a condition which can occur irrespective of what the pressure is in the eye. The most important thing about diagnosing the condition is people often in the early stages don't know they've got it. Now if we can pick up the condition early then we can treat it effectively in most cases.

So what we're always trying to do is encourage people to be tested for glaucoma and this is a simple eye check that can be done by any optometrist in the community. It involves checking the peripheral vision because that's what gets affected first in glaucoma, looking carefully at the optic nerve which we can see within the eye with special instruments and also measuring the pressure in the eye. A very simple check, very important particularly if you have a family member affected with glaucoma because this remains the leading cause of irreversible blindness worldwide and yet if we get it early, we can usually treat it.

ANDI HORVATH
How prevalent is it? Is it mainly an elderly person's disease?

KEITH MARTIN
You're absolutely right that it's more common as we get older. By the time we reach the age of 80 about 15 per cent of us or more will have glaucoma. So it gets more common after the age of 40 but I treat children who are born with forms of congenital glaucoma as well. That's very rare but it can occur at any age, but yes as we get older it gets more common.

ANDI HORVATH
Give us the stats. What is it worldwide?

KEITH MARTIN
Well, I think the estimate in 2010 was around 60 million people affected with glaucoma and that's due to rise to over 80 million by 2020 and that's because we're living longer. As this is a condition which gets more common with age, the longer we live the more likely we are to develop it. So it's becoming more prevalent in the population and more than 4.5 million people are bilaterally blind, in other words blind in both eyes due to the condition so it is a big problem.

ANDI HORVATH
That would cause the loss of independence, your wellbeing will plummet…

KEITH MARTIN
This is it and it's a quality of life issue. Early in the disease you may not know there's anything going on. As the disease comes on, the first thing you might notice is tripping over things, elderly people having more falls - that might be what brings it to the attention that the vision isn't quite so good and then it's the loss of the driving licence. We know that elderly people with glaucoma get out less. They have less social contact, they take less steps. Believe it or not that's been measured with fitness bands and all the rest of it. They just become more isolated over time so anything we can do to avoid that sort of quality of life effect of visual loss is really important.

ANDI HORVATH

Keith, you're known for your passion to prevent vision loss, restore sight and reduce the burden of blinding eye diseases around the world. Now you're clearly passionate about this because you've been heard to say that essentially in the next 10 years you want to ensure there are treatments that not only stop the decline of vision but also restore sight. Wow, that's a goal if I've ever heard of one.

KEITH MARTIN
Well, it is but it's becoming very realistic and we're already doing this. If you look at what's happening in eye research, even locally within Melbourne - if you look at the bionic eye project for example - that might have sounded like science fiction 10 years ago where we put a chip into the eye that restores vision in people who were previously blind. This is already happening and the next generation of these devices are going into patients now and this technology is only going to improve.

If you look at what's happening in other fields as well, again my particular interest is in gene therapy. We're developing a gene therapy for glaucoma but gene therapy is already being applied to other eye diseases in other studies around the world and has been shown to restore vision in previously untreatable conditions. So I think we're moving beyond the era where all we could do for this chronic degenerative diseases was slow things down and we're now really talking about restoring function in a realistic way.

ANDI HORVATH
Is glaucoma genetic? Is there a genetic component?

KEITH MARTIN
Yes, there is but only a few people - a small number of people with glaucoma have a single gene problem, in other words just an inherited familial type of glaucoma. But if you look at the risk within people with an affected family member - if you have a first degree relative affected by glaucoma, in other words your parent or a sibling was affected - your risk can be as high as one in four of developing the disease so there is certainly a strong inherited component to it.

ANDI HORVATH
When you talk about gene therapy, what exactly do you mean?

KEITH MARTIN
Gene therapy is a way of changing what cells do. If you think about how we actually deliver gene therapy, we use viruses to do that and that's because viruses are very good at pushing their genes into ourselves. Every time we get a cold or the flu what's happening is a virus is sticking to the outside of the cell and it's being taken up into the cell and changing what the cell does. You think of it a little bit about like a text message. So the virus contains some information and that information is taken up by the cell and the cell reads that message and does what it's told to do. What we do with gene therapy is we take that virus and we take out the bits that cause disease and we replace them with something that helps in a disease process. That can either be replacing a missing gene or putting in a protective gene that is nourishing to the cell in some other way that helps it to survive injury.

ANDI HORVATH
You’re talking about the nerve cells, the optic nerve?

KEITH MARTIN
That's exactly right. The cells I'm most interested in glaucoma are called retinal ganglion cells and these are the cells that connect the eye to the brain. When light hits the eye, photoreceptors pick up that light and they signal through to these retinal ganglion cells that send the messages back to our brain. If we lose that cable that connects the eye to the brain, the picture quality degrades. It's a bit like the cable that connects a camera to your computer, if that cable gets damaged over time the picture quality gets worse.

ANDI HORVATH
Now you also talk about stem cell therapy. Is that the same thing or is that different?

KEITH MARTIN

So that's different. What we mean by stem cell therapy is actually using cells that we isolate either from embryos or more commonly these days from the patient's own tissue - so we can do this from a skin sample. We can grow cells that don't just become new skin cells but become all sorts of other different types of cell. We can push these cells down a particular route of differentiation to make the cells that we want to replace. If we have a condition where we've lost photoreceptors within the eye, potentially we can make new photoreceptors and replace those and we've been looking at whether we can do this with retinal ganglion cells to replace them.

ANDI HORVATH

So this is why you're thinking in 10 years time we could restore vision because we're putting back that function that we lost.

KEITH MARTIN
Yes, this is one of the ways that I think we can potentially restore vision. Again, this is not science fiction anymore, this is already being done in human clinical trials. There are trials ongoing that replace what are called retinal pigment epithelium cells. These are support cells that help the photoreceptors and the eye to do what they do. There are multiple clinical trials going on replacing these as a treatment for age-related macular degeneration, another very common cause of central vision loss in elderly people. This is already being done and there is potential to replace photoreceptors, other cell types within the eye.

ANDI HORVATH

Now you're a bit of an innovator. You started this work in Cambridge and you even set up a company so not only are you embracing the R, you're doing the R and the D. Tell us about that.

KEITH MARTIN

Well, that's been a bit of a roller coaster ride as well because this was not something I ever planned to do. But we realised if we were going to get this gene therapy through to the clinic, we were going to need a bigger investment that we can with standard research grants. The University of Cambridge helped us to establish a spinout company from the lab and that was supported by the Wellcome Trust in the UK and Innovate UK and a variety of other funding sources with the idea that we would develop something which could then be partnered by a big pharmaceutical company with the resources to actually take this through to the clinical trial stage. So that's what we did and we set up a company called Quethera.

To cut a long story short, over the last three years we've developed what we think is a pretty good candidate for a gene therapy for glaucoma and that was acquired last year by a large Japanese pharmaceutical company. We're working in partnership with them now to plan the clinical trials that will hopefully get this treatment through to the clinic.

ANDI HORVATH
So you've got a multi-pronged approach. You're doing gene therapy, you're doing stem cell therapy but I've also heard you're kind of interested in treatments before those therapies hit because what is the current treatment for glaucoma - that's problematic too, isn't it?

KEITH MARTIN
The current treatment for glaucoma - there are multiple different treatments for glaucoma but they all have one thing in common, they all reduce the pressure in the eye. So be it using eye drops - very common in glaucoma patients or using a laser or using surgery, all of the treatments that we currently have reduce pressure and that's very effective for many of our patients. The problem is that about 10 to 15 percent of patients continue to deteriorate and lose vision to blindness in at least one eye even with pressure reduction. So I guess the focus of what I do is dealing with that 10 to 15 percent in how we develop new treatments for them.

ANDI HORVATH
Because it's quite fiddly, isn't it, doing the drops, people don't do them and it's just - it's too hard.

KEITH MARTIN

It's too hard and that's a real problem when you have a disease which in its early phases, asymptomatic. If you have lost your central vision and you can see every day that your central vision is getting worse, you're pretty motivated to come and get treatment. So these patients with macular degeneration will rock up and have injections in their eye every month and they do it. They turn up and they don't miss their appointments. Glaucoma patients where you don't actually realise there's a problem and somebody tells you you have to take drops for the rest of your life, you may do it for a bit then you may get out of the habit of doing it because you're not aware that you're actually losing anything. That's a real problem because part of the reason I think people get worse is because they're not using the treatments effectively. We know at least half of the patients that we prescribe eye drops to don’t use them.

ANDI HORVATH

Yeah, it's a sinister disease because it's sort of like you can't see losing your sight - pun intended.

KEITH MARTIN

Exactly and there's also a misconception about what the visual loss that people experience is like. Sometimes you see - and even online if you look up glaucoma, you look at the pictures of what people experience, you'll often see this sort of tunnel vision with a black surround and people are only able to see a little patch in the middle and then everything around is black and that's not at all what glaucoma patients experience. What happens is that it's like the picture gradually becomes lower resolution so rather than having a high-density definition megapixel image, as the retinal ganglion cells drop out you lose pixels in the picture. But your brain is quite clever and what it does is it tries to fill in the gaps and so your brain is processing - trying to make up for what is missing in the image. It's making guesses and fooling you that everything is fine and that's one of the problems when it comes to people knowing that there's a problem because they aren't aware of it because the computer does such a good job. Often when they're tired and things fall apart a bit more then they're more likely to trip over and fall and miss things.

ANDI HORVATH

The eye isn't an isolated sort of ball in our head. It's connected to our brain and the signals that go through the optic nerve of course is the critical pathway but what's the other side of the eye?

KEITH MARTIN
Well, the eye is part of the brain and so the eye is the one part of the brain where we can actually watch what's happening in real time. We can see pathology in action. We can't do that with any other part of the brain so it's an amazing way to study some of the processes that occur in neurodegeneration for example. One example of this is one of the projects that we have ongoing at the University of Melbourne and the Centre of Eye Research Australia. We are looking at signs that we can see within the eye that are predictors of someone who will later develop Alzheimer's disease.

Now that's work that Peter van Wijngaarden is doing and by using a very special camera - there are only a few of these cameras in the world and it's been pioneered at CERA in University of Melbourne - by using this camera that is very sensitive to very subtle differences in colour, we can see changes within the retina that are predictive of Alzheimer's disease. This is really important because if we can get in early with our treatments that modify this risk potentially, we can reduce the risk of patients developing Alzheimer's disease in the future. So this is an example of how observing the eye - and the eye is really the window on the brain if you like - observing through the eye we can predict something which is happening in the rest of the brain and do something about it.

ANDI HORVATH
Often when I have visual disturbances because I've been working too hard because I love my job - but sometimes I work too hard and I get that zebra thing happening in front of me which I know is stress but that's a brain thing not an eye thing.

KEITH MARTIN
Usually that's the case and that's the brain playing tricks on you. The brain is constantly interpreting the information that's coming in from the eye and sometimes it gets it wrong and there are many different ways it can get it wrong. If you think of hallucinations that you see in the desert when you see an oasis, that's a case of the eye playing tricks on you and there are all sorts of other tricks that it can play.

ANDI HORVATH
What are some of the surprises you've encountered in your research that you didn't expect?

KEITH MARTIN

I'm constantly surprised. You talk about multi-pronged approach and that's really because I don't feel we're smart enough to actually know what's going to work and what isn't. You need to actually try multiple approaches because you never really know with science what's going to happen. All you can do with science is ask the questions and nature interprets those questions literally and gives you an answer and sometimes that answer helps you in terms of developing a new treatment and sometimes it just raises more questions and you end up following a different line that you initially intended to do. So I guess the multi-pronged sort of strategy falls from never really being sure what is going to be the most successful strategy.

ANDI HORVATH
Because it's quite a risk to spread your energy in different directions.

KEITH MARTIN
I think that is one of the things in science that you have to make that calculation between putting all of your eggs in one basket and actually - but I view it in more as spreading the risk and we always have in the lab a variety of different projects with a range of different risks. We have some projects that we know will deliver data and no matter what the data is, it will be potentially of interest. Then we've got high risk projects that maybe - it may work or it may fail and if they fail we don't get very much from them at all so it's a case of balancing that risk across the research portfolio.

ANDI HORVATH
Sure. In some ways we've got to go down some garden paths and go ‘okay, not that way.’

KEITH MARTIN

Yeah, that's absolutely right but I think one thing that you bring as a clinician scientist is to try and ask the questions that are relevant to the disease. So in some branches of science, you maybe particularly interested in a particular molecule or a pathway and the focus of your research will be to follow that to its natural conclusion. As a clinical scientist we come at it the other way and we are only interested in a particular approach to the extent that it makes a difference in the disease that we're interested in.

For example, when we started the stem cell work there are two different ways you could have gone about that work. You could have tried to learn absolutely everything about a particular type of stem cell and exactly what it does and then think about applying that far down the line to a model of disease.

We came about it completely the other way around. We put some cells in the eye and see what happens and then we take it from there. If it has a beneficial effect, then we're interested and then we may want to learn more about the mechanism of how it's acting and what it's doing. If it doesn't do anything at all then we move on. So the clinician scientist type experimental medicine approach does things the other way around sometimes to traditional science.

ANDI HORVATH
You've got a certain goal at the end as opposed to sort of curiosity-driven stuff but you're also paying attention to odd results.

KEITH MARTIN
That's right and the odd results are usually the ones that tell you most and it's the things that don't work out the way you expect when you try to unpick why that's happened you often learn far more. Those are the results that are the most fun and those are the ones that frustrate our students and the rest of it because it didn't quite work out and we're always saying actually this could be far more interesting than the answer you were hoping for.

ANDI HORVATH
I hope we're sitting here in 10 years' time Keith - come back for a cup of tea - in the studio here and let's celebrate what happened in the last 10 years because I get a feeling we're getting there.

KEITH MARTIN
I think we really are and the eye is a fantastic organ to work on. We have better ways to assess the structure and the function of the eye than pretty much any other part of the body. So I can go into the clinic, not even into the research lab, into the clinic and I can see individual photoreceptors within the living human eye of patients at cellular resolution with instruments that are in the clinic already. We can pick up responses to just a handful of photons of light in terms of the effect that it has on the eye so we have an amazing ability to look at real biology in action.

When it comes to gene therapy approaches, in contrast to larger organs, we can hit with a single injection the large majority of the cells that we're interested in treating and so we have a huge advantage working on the eye compared to some other branches of medicine.

ANDI HORVATH
So Keith what got you into the eye? What made you think as a medicine student I want to do eye stuff - ophthalmology, that's where I'm headed?

KEITH MARTIN
My path into ophthalmology was slightly unconventional. I was interested in neuroscience at university and I always thought I wanted to be a neurologist because I thought neurology had something to do with neuroscience. It was with crushing disappointment that I realised it had very little to do with neuroscience back in those days. It was about classifying funny walks and scratching people's feet with sticks and watching which way their toes went as a predictor. It didn't feel very related to the sort of neuroscience, it wasn't very quantitative. Now things have moved on to a degree but I also missed the aspect of fixing stuff. There weren't really so many treatments available and I liked the precision that I saw in ophthalmology. I came to realise that ophthalmology was a very nice mix of medicine and surgery and microsurgery at that.

Having fallen into medicine in the way that you do in the UK at far too early a stage, I came to realise that I didn't actually particularly enjoy dealing with sick people all the time. I actually quite enjoyed dealing with people who were well so that sort of limited my options slightly in medicine so I fell into ophthalmology being a bit miserable doing neurology. I went to stay with a friend who was doing ophthalmology who seemed to be having a very much better time than I was and so I thought I'll give this a go for six months and here we are quite a few years down the line.

ANDI HORVATH
And so what set you off on that path in science? There must have been something that inspired you or triggered you to go, do you know what, I want to know how the world works.

KEITH MARTIN

I think that's a - I call it the curse of curiosity. You can have a much more straightforward simple life if you just accept the treatments that are out there and apply them and get on with doing a good job in that regard. I think there's a real place for doing that but I've always been curious about how stuff works. I've always been a tinkerer and enjoyed taking stuff to pieces and that’s what we do with biology really.

We're taking things apart, we're sort of reverse engineering - trying to work out what's going on. Again it makes your life more complicated and trying to juggle that with being a practising clinician and being a scientist and trying to organise other scientists as well is a lot to juggle but I think it makes for a more interesting career path if you're cursed with that sort of curiosity to wonder how things work.

ANDI HORVATH
What sort of misconceptions do the public have about ophthalmology and eye health? Is there something that you often encounter that you think needs correcting?

KEITH MARTIN
I think when it comes to eye health one of the things that we find is that many people will go and see their optometrist if they have a problem. If they can't see what they want to be able to see or they notice their vision getting worse they will go and see their optometrist. One of the messages we try to get across is actually it's really important to pick up some types of disease in the eye early that you have a regular check.

ANDI HORVATH

What are some of those diseases?

KEITH MARTIN
Well there are tell-tale signs in the eye of many different diseases. Clearly, we've talked about glaucoma and I'm particularly interested in that but there are other signs - there are early signs for example of macular degeneration that you can see before the manifestation of the disease. At the early stage of the disease it might just be a case of saying to people look, you may have a more of a tendency to develop this and if you notice things it's important you get back to us quickly because we may be able to treat it.

Some of the work that is going on locally in that situation using lasers to treat some forms of early macular degeneration may give us the opportunity in the future to actually intervene earlier in the course of the disease and actually prevent people getting something that they were inevitably going to get down the line. So my message is that it's important to get tested regularly and as we get older, most people should be getting a check, at least by an optometrist, annually.

ANDI HORVATH

Professor Keith Martin, what's the best advice you've ever been given?

KEITH MARTIN

Oh, that's a difficult one. I've been given lots of advice, some of it welcome, some of it not but I guess the best advice really is to follow what your passion is and don't try to game - particularly if you're talking to medical students - don't try to game it in terms of what's going to be the job openings or whatever, just do what you're interested in.

You're more likely to be successful if you're doing something that you really love compared to trying to force yourself down a route where you see there may be more openings and I think that's the piece of advice that I've stuck to.

ANDI HORVATH

Also give out by the sounds of it.

KEITH MARTIN
Well, I think so yeah, pass it along.

ANDI HORVATH
Profess, Professor! What would you like us to think about the next time we walk past an optometrist?

KEITH MARTIN
Well, I think that they are… they're not just there to sell glasses and that's the first thing.

Optometrists are well-trained to pick up other eye diseases. They can spot signs of diabetes in the eye, for example, or there are even signs of untreated high blood pressure which can be manifest in the eye. They can pick up glaucoma, they can pick up early signs of macular degeneration, they can pick up a cataract - all these other things that can affect your vision and your quality of life so I think that's the important thing.

Also in terms of a plug for vision research, if you ask people what they are most scared of in life, and this has been in done in multiple different studies - there are two things that come out repeatedly, cancer and going blind and they're usually quite close together actually. People are very scared of losing their vision and yet when you look at the research spend - we analysed this in the UK, the amount of research money spent on vision research compared to cancer is 0.9 percent in the UK. And so I think one of the things that we are constantly facing is that vision research is well-funded and there are many charities out there that support that - actually that's really not the case.

We have a real track record in vision research of delivering real progress on limited resources. One of the things that I am emphasising is how much more we could do if we had more resources, more people working on these problems. Blinding eye disease is still a major problem worldwide. We haven’t sold this by any stretch of the imagination. We've made real progress but there's a huge amount more that we could do with additional resources.

ANDI HORVATH
Thanks for passing by. Thank you, Professor Keith Martin.

KEITH MARTIN
Thank you so much, I've enjoyed it.

CHRIS HATZIS
Thank you to Professor Keith Martin, Ringland Anderson Chair of Ophthalmology and Managing Director of the Centre for Eye Research Australia, University of Melbourne. And thanks to our reporter Dr Andi Horvath.

Eavesdrop on Experts - stories of inspiration and insights - was made possible by the University of Melbourne. This episode was recorded on April 10, 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 iTunes 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.