Matt Burgess (00:08):
Hello, my name's Matt Burgess and I am a genetic counselor based in Melbourne, Australia. And this is a podcast called Demystifying Genetics. And today my guest is Professor Martin Delatycki. Martin graduated from the University of Melbourne with a medical degree in 1988 and with a PhD in 1999. And today our conversation focuses on ataxia and in particular Frederick's ataxia. There's some interesting research that we spoke about with a particular chemical or drug called resveratrol. And we also talk about spinal cerebellar ataxia type three. Hello Martin.
Martin Delatycki (00:53):
Hello, Matthew. Thank you for having me.
Matt Burgess (00:55):
Now I'm going to start with a story which or start with something that I thought I would never do on this podcast, but it's to talk about football. I don't know if you remember the first day that we started working together and, and what happened, or if you know what I'm going to,
Martin Delatycki (01:14):
It's kind of coming back, but yeah, go on.
Matt Burgess (01:16):
So for those of you who dunno I was living in Sydney, Australia, and I was lucky enough to get a job in Melbourne and Melbourne is the home of Australian football or Aussie rules or afl. And as I was moving, I thought, oh, okay, I'm moving to Melbourne. I need to pick a football team. I, I wonder who I'm going to pick. And then I kind of thought, oh, you know, the interview the, the universe will show me the way I will find a, a team somehow. And then when I turned up on my first day I remember you pointed me towards a picture on your wall of the Carlton football team, and you said, this will be the team you will go for. And I thought, okay. But now
Martin Delatycki (02:07):
I what terrible advice that was.
Matt Burgess (02:09):
I dunno how good that was because yeah, we're sort of coming last on the ladder at the moment.
Martin Delatycki (02:15):
Yeah, I know. But it's good to start low and then when good things happen, you'll have been through the hard times. So I, it was a lesson in life that I'm teaching you, Matthew,
Matt Burgess (02:23):
Something about resilience or resilience.
Martin Delatycki (02:25):
Yes, exactly.
Matt Burgess (02:27):
<Laugh>. Excellent. But changing a little bit I'd really like to talk to you today about ataxia. So I know that's sort of like a, a broad, very broad introduction, but can you tell me about ataxia and how your interest in this area sort of came about?
Martin Delatycki (02:49):
Yes. So ataxia is the medical term for incoordination or unsteadiness. So we have all seen ataxic people at three in the morning outside nightclubs, et cetera, because the most common cause is acute injury to the brain, such as by alcohol. But there are many genetic causes of ataxia that don't improve with a good night's sleep. And I got into the field in the mid nineties when my then boss at Murdoch Institute, Bob Williamson, who'd come from London. I said, what should I do my PhD? And he said, you should do it in Friedrich's ataxia. And being an obedient young man, I ab obeyed him. And I've worked in Friedrich ataxia for the last 20 years, and it's been an incredibly exciting time. But there are many genetic causes of ataxia other than Friedrich's ataxia. And some of these are recessive like Friedrich's ataxia, meaning you need two faulty genes to have it, whereas others are dominant, meaning you only need one faulty gene. And so the dominant ataxias tend to affect multiple generations, whereas the recessive ones like Friedrich's ataxia tends to affect one generation.
Matt Burgess (04:03):
And so had you worked with many families with Friedrich's ataxia before you started your PhD?
Martin Delatycki (04:11):
If I had, I don't remember it. I certainly remember it being on various lists when I was studying to be a physician. And so in Friedrich's ataxia, it has the rare combination of brisk knee jerks in some people and absent ankle jerks and up going planter responses with absent ankle jerks. And so I remember it being on lifts like that. But
Matt Burgess (04:35):
So I might just stop you there because I think I know what you mean, but so when you're doing a neurological consult or exam, you have a, a little plastic hammer that you sort of test people's reflexes, is that what you mean when
Martin Delatycki (04:51):
You That's absolutely correct. So, so you bang the front of the knee and the leg could, should give a little jump. But in some people with Friedrichs, it gives a very big jump. And in others it doesn't give a jump at all. And when you tickle the bottom of the foot, the big toe should bend downwards. But in people with ics, it often bends upwards. So these are the obscure tests that particularly neurologists do. So I knew about the existence of Friedrich ataxia, but I can't remember definitely seeing anyone before I started working on in the mid nineties.
Matt Burgess (05:27):
Okay. And, and what was the, the, the question that you were looking at in your study with your PhD?
Martin Delatycki (05:35):
So it initially started that I was gonna develop genetic therapies for Frederick ataxia. And I had big aims. And the way we were gonna do it was using the non-toxic fragment of tetanus tox. And I started working on that. But then I went to a conference in Montreal and there was this big discovery. So the gene had just been discovered a year before, and there was a big discovery that there was too much iron in mitochondria. So mitochondria, the little batteries in cells. And it's a really an interesting story that a very young man who was not even a graduate of university, he was doing a summer job during his university degree was working in a lab in Utah that were interested in iron. And they were just knocking out random genes in yeast. And they knocked out this gene and there was enormously increased mitochondrial iron, and they looked at which gene it was, and lo and behold, it was the yeast friedrich ataxia gene. Mm. And so this completely changed the course of my PhD and I started looking at iron levels in cells from people with friedrich ataxia. And we found that the same thing that was true in yeast was true in people with Friedrich. And so this led to various lines of investigation. I guess the great example of how science, you can start looking at one thing, but change direction when your nose takes you in a new direction, <laugh>. So that was exciting times.
Matt Burgess (07:10):
Excellent. so one of the things I love about you is that you are involved with so many different things like you have like this broad interest. So you are a medical doctor, a a clinical geneticist, and so you see people and help people with genetic conditions. But you also are involved with management and directing a, a, a large clinical genetic service in Melbourne. But you're also really interested in different areas of research. And I was just wondering if you can sort of tell me what areas of research that you're working on at the moment?
Martin Delatycki (07:49):
Yeah, well, yeah, I've probably got far too many interests and spread myself far too thin. But anyway, as I say, I've always gone where my nose takes me. So we just finished a study in a condition called hemochromatosis. So hemochromatosis is the most common genetic condition amongst individuals of European descent. And in hemochromatosis there's too much iron in the body. And this can get deposited in the brain, sorry, in the heart, in the liver in joints and can cause anywhere between no symptoms through to cirrhosis, the liver, liver cancer, diabetes, and many other symptoms. And you might think that I'm obsessed with iron, but in fact I got into Friedrichs without an interest in iron and I got into hemochromatosis cuz of my interest in genetic screening. But coincidentally both of them have iron involved. And so if people have very high iron levels, no one would argue that they should be treated.
(08:52):
And the treatment's really quite simple. It's a matter of giving blood because the red cells in blood have very high iron levels. So if you give a unit of blood, you remove a significant amount of iron from the body. And so if someone has very high iron levels where they're at high risk of liver cirrhosis, everyone would agree to treat them. But what was less clear is where the people who have iron levels that are a bit high, but not very high need to be treated. And so we worked out a way of doing a blinded study that means that the people having the treatment didn't know if we were removing iron or not. And we had half the people reduced, we reduced their iron in the body and the other half we didn't mm-hmm. <Affirmative>. And we did all sorts of measures before and after to see if there was benefits.
(09:40):
And we found that indeed those who did have iron removed had a number of benefits, including symptoms that they reported on a scale called the modified fatigue impact scale, as well as various blood tests that we did. And so this study now has shown that yes, if you have mildly increased iron from hemochromatosis, you should be treated. And so we are now on the path to doing a larger study that we've applied for funding to do, to screen a very large number of people to see how we can go about doing screening in the community. Now that we know there are, we estimate about 85,000 Australians who would benefit from such treatment and about a million people in the US and a million in Europe.
Matt Burgess (10:29):
Wow, that's fantastic. And you know, like that's research, but it, it sounds like, you know, it has the potential to to really sort of cross over into you know, into the real world and sort of have implications for, for people out there in the community.
Martin Delatycki (10:48):
That's Yeah, that's exactly right. So the, the buzzword is translational research that research that can go from being a, a research study to offering new treatments in the clinic. And so that's certainly what my team is, is all about, is finding new ways to treat things and then to, to put that in the clinic. Other studies that we've got going we are doing a trial of a medication called resveratrol for Friedrichs ataxia. So resveratrol is a very famous naturally occurring medication and it's famous because it's in red wine. And so there are theories that it's resveratrol in red wine that mean that French people who have a very high fat diet have, but have a very, a relatively low level of heart disease. People have wondered if this is due to resveratrol. And so we trialed resveratrol in Friedrichs ataxia and had a hint of benefit. And now we're gonna do a placebo controlled trial. But I always warn people not to try to get the dose of resveratrol. We're going to use <laugh> through drinking wine cuz you would need to drink a thousand bottles of red wine a day to get the dose. So,
Matt Burgess (12:04):
Ok. So
Martin Delatycki (12:05):
We think the tablet is a safer way of going
Matt Burgess (12:07):
That. That's interesting. Cause I, I, I knew that we would be talking about this today and I was googling resveratrol the other day and sort of looking at different bits and pieces sort of out there and there are a few blogs that we're talking about benefit of drinking red wine when you've got a cold. And I don't know if you can tell or if you can hear, but I'm sort of just getting over a, a cold and I thought I'm a man of science <laugh> <laugh>, I feel sick, you know, I I've stuffed up and I I I've got a cold, but I'm gonna see if, you know, this works cuz you know, the last thing I wanna do is have a glass of red wine, but you know, I'll see what ha what happens and all
Martin Delatycki (12:53):
In the name of sight,
Matt Burgess (12:54):
All in the name of sight. And the article says, you know, not only does it, it help because of the resveratrol in the red wine, but you'll also get a buzz and yeah, I don't think I'll be trying that again. <Laugh>
Martin Delatycki (13:06):
It didn't, didn't work well when we get our, our spectacular formulation of resveratrol that has very good ability to get into the bloodstream, I, I'll see if I can get you some for your next Yeah.
Matt Burgess (13:19):
<Laugh>, is that an association you'd heard before about the link between resveratrol and colds?
Martin Delatycki (13:28):
No, I haven't heard about that one, but there's an enormous literature about trying resveratrol in numerous different situations including Alzheimer's disease, Huntington's disease. So it's really being tried broadly, but also people have tried to find the bit of resveratrol that does the most good and, and make new medications that are much more powerful. So there's a lot of excitement around resveratrol and, and its sisters and brothers that will hopefully get to the clinic and improve people's lives. And it's probably most famous for being found to increase the lifespan of, of a number of species. So for, they started with yeast and then they went bacteria and finally they showed that mice have a longer lifespan if treated with rol. And that work was led by an Australian guy called David Sinclair, who's really a remarkable scientist who's now based at Harvard. And he's done really amazing work with resveratrol and other similar medications.
Matt Burgess (14:34):
Mm-Hmm. Interesting. Yeah. But I think I will sort of maybe just have my red wine when I'm feeling a okay. And not sick with a, a cold.
Martin Delatycki (14:46):
Sounds a good plan.
Matt Burgess (14:47):
Now are you involved with rehab of studies looking at how to physically help people with ataxia?
Martin Delatycki (14:57):
Yeah, so I've got a wonderful colleague called Sarah Mill, who's a physiotherapist, and Sarah did her PhD with me. And Sarah did a study where she did intense physiotherapy for six weeks with people with Friedrichs. And half the people started straight away and half the people waited six weeks so she could compare the waiting period to the active period. And she showed some benefit from her physiotherapy that was done at a rehab center in Melbourne where people spent some of the time in the water and some on the land. And so then we applied to do a much bigger study not just of Friedrich ataxia, but other genetic ataxias. And we were fortunate to get funding from the government to do that study. So we're about to embark on that study and that will be done in Melbourne, Sydney, Perth.
(15:53):
And then we are gonna be working with a group of indigenous Australians. So there's a form of genetic ataxia called Mercado Joseph Disease, sometimes called spino cerebella ataxia type three. And this is present in many populations, but one group who have this are a group of indigenous Australians, mainly in the very north of Australia. Mm-Hmm. <affirmative> in Darwin and Gru Island. And so we are going to be working with that group as well to look at rehabilitation for, for those individuals. So on Gru Island, one in 53 people have ataxia. So that's probably the highest incidence of ataxia in the world.
Matt Burgess (16:35):
Mm-Hmm. <affirmative>. Yeah. And so you work with a, a great genetic counselor who is involved with working up in Darwin and sort of in the Northern Territory. And is it, it's Lindsay, isn't it
Martin Delatycki (16:49):
Lindsay Tour? Yep. Yes. She's a fantastic genetic counselor and has really become integrated into that community and does some amazing work with predictive testing in those communities. So I'm not sure if you've talked to your audience about predictive testing, but No,
Matt Burgess (17:08):
Not, not a lot actually. We have, yeah, like I've covered sort of different areas of, of testing, but I haven't actually defined what predictive testing is, and it hasn't really come up yet. So yeah, let's talk about that.
Martin Delatycki (17:23):
Well, predictive testing is the ability to have someone who's at risk of a genetic condition to know if they're gonna develop it so they don't have symptoms at the time. So the best example is Huntington disease, or the most common example where each child of a person with the condition has a 50% chance of having the condition and a 50% chance not to. And so we know that most people at risk of these conditions choose not to have predictive testing. So we did a study 10 or more years ago where we found only about 15% of people at risk of these conditions where there's no treatment to prevent or delay the onset, choose to have treatment. And so normally when you and I do predictive testing together, we'll see people in clinic and talk through the issues, maybe see them a couple of times and then provide the result. But when Lindsey does it in in some very remote communities in the north of Australia these sitting in a, in a clinic, in a capital city is, is out of the question. And she's got some wonderful photos of doing predictive testing on beaches in, in Northern territory and, you know, really meeting the needs of that community. And she's really doing an incredible job up there.
Matt Burgess (18:43):
It's amazing cuz you know, like in genetic counseling we talk about sort of being patient centered or, you know, patient focused genetic counseling, but yeah, working in Melbourne or you know, in a large city like logistically, we try and be as patient focused as we can, but we are saying, you need to come to us, you need to come to us on this day between this time and, you know, this is what, this is how we'll make it work. But you know, what she's doing up in you know, in North Northern Australia is, it looks amazing. Like I've heard Lindsay talk a a couple of times about sort of some of the, the challenges and the different ways of working and it's just, you know, that was not covered when I did predictive testing at uni. You know, like we did not talk about that sort of thing. It is just amazing.
Martin Delatycki (19:36):
It is amazing and I, I'm fortunate to spend a week a year where we go and do clinics in Darwin and Alice Springs. And it is I think my favorite week of the year in terms of my work. It's just a completely different set of conditions. It's completely different way of working and it's, it's absolutely fabulous to do. So it's as you say, it's, it's doing things to meet the needs of people, not not our own, our set ways and our own methods. You know, I think it's really important in, in all medicine to, to be able to do that.
Matt Burgess (20:11):
And I think you know, an interesting thing that sort of ties onto that was you know, when people think of professor Mantic, I think they think Friedrich's ataxia and hemochromatosis, but they also think about screening in the community. And that's something that you've been involved with for a long time. But since we've been working together, the screening program has sort of changed from you know, screening children or, or people in the Jewish community when they're at school to changing that model because of how the genetic testing technology has changed.
Martin Delatycki (20:51):
Yeah, I mean, when we started screening, we started screening in the late nineties for, for a condition called Tacs disease. So it's a recessive condition where both parents need to be carriers and if a child has tacs disease, it's a devastating condition where death usually occurs in the first few years of life. And we were able to start screening by measuring blood levels of an enzyme. Then we moved to a genetic test, then we started testing for a number of other conditions. Now we can test for many, many hundreds of conditions in one test. And so screening is completely changing how it's being done, the breadth of it, the ability for couples to have choice about whether or not they want to have screening. If they have screening whether or not they want to have testing of an established pregnancy, or now of course using ivf it's possible to test embryos and only implant embryos that don't have the genetic predisposition. So the choices people have now are incredible compared to as recently as 20 years ago. And of course it's only 30 years ago that the first genetic testing became possible. So it's been a remarkable period in, in humanity in terms of genetics and what it can offer.
Matt Burgess (22:17):
Mm. And what about clinical trials? Are, are you doing research or are you involved with sort of clinical trials and research as well?
Martin Delatycki (22:28):
Yeah, so we're involved in quite a few different clinical trials. So the, the rehabilitation study we'll be doing is a randomized trial, so some people will get intense rehabilitation therapy and others won't. We're involved in two medication trials in Friedrich ataxia, so I mentioned resveratrol, and we're working with a US company called RHA on a particular medication that they've developed in Friedrich ataxia. The hemochromatosis trial that we've finished was a randomized trial. So I think clinical trials is, you know, really the next phase of genetic research. And we're now discovering when I say we much clever people than me are discovering treatments based on understanding the genetics of a particular condition. And the only way to know if they work is to, to design proper randomized blinded clinical trials. So double blinded means the person in the trial doesn't know whether they're getting the medication or placebo and the person administering the treatment doesn't know either. And, you know, doing very rigorous trials is critical to to know where the treatments work and get them into the clinic as quickly as possible.
Matt Burgess (23:44):
Mm-Hmm. Mm-hmm. And I just think it's fascinating the, the different research that's out there about clinical genetics and I think that it's important as, as a genetic counselor, I think that, you know, it is important that we get really good robust genetic counseling research published and sort of get it out there in the, the literature. And you know, with a previous guest we spoke about you know, evidence-based genetic counseling, and a lot of the time we have a feeling or you know, intuition that we're doing the right thing. But, you know, if we can back it up with the evidence from the literature, I think that that's really important.
Martin Delatycki (24:27):
Yeah, I agree. And I think, you know, we were both involved in a study a few years ago where there was a randomized trial of communication in, in genetic counseling and did extra contact with families assist in family communication and, and you know, the trial showed that yes those who had extra communication with a clinical geneticist were able to communicate with the family in a better way and in a, a broader way than people who didn't have that extra input. And I think, you know, those sort of studies are really important, as you say evidence-based. And we're all biased in how we think we should do things and we think we're doing a good job. But, but I think any research that can be done to confirm the best way to do things is, is absolutely critical. And I think genetic counseling is an area, you know, it's a new profession relatively to many other areas in health. But I think there are a lot of fantastic fantastic academic genetic counselors both here and overseas who are doing fantastic work to assist us in knowing the best way to do our work.
Matt Burgess (25:40):
So you're a medical doctor, you're a, a clinical geneticist, but you provide genetic counseling and there are other professions that also provide genetic counseling, but there are also genetic counselors that do genetic counseling. And just wondering what you think makes a good genetic counselor and what, what you like about working with genetic counselors?
Martin Delatycki (26:08):
Well, I think, you know, what makes a good genetic counselor is a person who's a good person. I think that's what makes a good clinical geneticist, what makes, what's a good dermatologist, a good neurologist, et cetera. I think, you know, having that ability to connect with people and have empathy and be a good communicator is very important. And, you know, we work very closely clinical geneticists and genetic counselors to provide a, a holistic approach to managing individuals and families. I think as a profession, we're very much family focused, so not just the person sitting in front of us, but what's the impact of what we're doing on another person. So, you know, in genetics you can do a test on one person that can reveal information about another person, and, and we have to be very mindful of that.
(27:06):
So I think, you know, there's a fantastic group of genetic counselors in Melbourne who I've had the absolute privilege to work with over many years. Some of them call Matthew and they it's just a great team to work with. And I think as I say, to provide the, the, the holistic approach, the, the really thorough approach to families and following up families and individuals to, to help them through what is often very difficult decisions and difficult diagnoses and difficult times to, to deal with news about genetic conditions in individuals and families.
Matt Burgess (27:48):
Mm-Hmm. <affirmative>. And I'm just wondering if you could, like, like I'm sure other people ask you this as well, but you know, working in clinical genetics, do you have a case or a family that kind of you know, sticks in your mind of getting a really good outcome for people?
Martin Delatycki (28:09):
Wow, that's a big question. <Laugh>. I mean, they've been, you know, my hair is very gray because I'm old, and so I've seen many, many families in my career. But you know, I think there's just so many times when it's not only when you can tell people that they don't have the gene for Huntington disease or Alzheimer's disease or breast cancer, that, that, that, that you feel like you've done a good job, but helping people through when you tell them you do have the gene for these devastating conditions. And that's, you know, I think a very important part of all of our, our work giving people hope. You know, so working in Friedrich ataxia, you know, when I started the gene wasn't discovered. We didn't know really anything, and now we're doing so many trials around the world which gives just such incredible hope.
(29:01):
And, you know, we're hopeful that in the next 18 to, to months to two years that we'll be doing gene therapy trials in free Friedrich ataxia which is something that, you know, as I said, I started my PhD thinking about it now. We'll be hopefully doing those trials. And there's some absolutely amazing therapies coming through. So spinal muscular atrophy, you know, devastating condition with children dying before two years of age with a new medication called Nuer, which is a genetic therapy injected into the spinal fluid. And, you know, these children are are doing incredibly well at 2, 3, 4 years of age now. So, you know, I think it's an amazing time and incredible things are happening, and it's exciting to be working in this year and no doubt about it.
Matt Burgess (29:53):
Mm-Hmm. No, I completely agree. I think that it is exciting that we are able to say that we can be involved with providing people with hope and optimism and, you know, I, I think there's still you know, some people out there that are saying, oh, you know, what's the, the point or of having a genetic test or, you know, you can't do anything. But I think I can challenge that and say, you know, if we can provide people with that hope and optimism, you know, that that's a really important thing and it's a lovely thing for people to have.
Martin Delatycki (30:26):
Absolutely.
Matt Burgess (30:27):
Excellent. Well, I think what a great place to, to finish up. So I'd like to say thank you very much for joining me on the podcast today. And yeah, it's been a pleasure having the first guest that hasn't been a genetic counselor on here.
Martin Delatycki (30:45):
I'm deeply honored. And I thank you so much for having me on your podcast, Matthew.
Matt Burgess (30:50):
Excellent. Thanks Martin. Bye-Bye.
Martin Delatycki (30:52):
All the best,
Matt Burgess (30:53):
As usual the information that you've heard today, if you'd like any more questions answered or if you'd like to ask me a question I will have a fact sheet online and you can access that fact sheet and more information about what we spoke about@insightgenomiccard.com au.