MND Queensland’s Jason Russo Interviews Dr Shyuan Ngo – Winner of the Betty Laidlaw MND Research Prize 2020 – Monday 11 November 2019
JR: Hi Shyuan. Congratulations on winning the 2020 Betty Laidlaw MND Research Prize. Could you please explain to our readers what your research project involves, maybe using plain language? SN: Ok, so the 2020 Betty Laidlaw Research Prize is going to support a research project that is really focusing on how motor neurons might die in MND. So we know that motor neurons die, we just don’t know how that happens. One of the things that you see in almost all cases of MND patients after they’ve deceased is you see these protein clumps inside the neurons and they’re in an area of the neuron that they’re not meant to be. So usually this protein is in the nucleus of the cell, where all of the DNA is packaged, but what you see in MND is it moves out of the nucleus and into the cytoplasm which is essentially the environment inside the cell, but outside the nucleus. What happens to the protein there is it starts to form clumps, and we don’t know why the protein clumps, we know that it’s probably got to do with how it’s processed overall, but we get these clumps and essentially they become a bit toxic to the neuron, and then they close the cell and die. Usually these protein clumps are sort of managed by an internal garbage disposal system in the cell. So you can think of it as you’ve got garbage trucks going around the city picking up rubbish, and that’s what’s clearing the rubbish in the cells, but if the truck drivers go on strike, you get a buildup of the rubbish and the city gets a bit… yeah (laughs). So that’s what’s happening inside the neurons, you get these protein clumps. JR: But we don’t know why the truck drivers are going on strike?! SN: The system, that truck driver system is dysfunctional in MND as well, so you get the buildup of these clumps. So there’s research into targeting that pathway, but the current Betty Laidlaw project that we’ll be working on is really looking at the interaction of these protein clumps with a specific little structure in the cell called the mitochondria, which is the powerhouse of the cell. This little organelle, it generates all of the energy that the cell needs to function and survive. We think that these protein clumps are interacting with these powerhouses and causing for them to be dysfunctional. It changes the way the network is established or formed in the cell, or how the network is maintained and then it causes for these powerhouses to become dysfunctional which means they don’t generate energy as efficiently and so the cell can’t function at its optimum and over time it’s going to work harder and harder and harder to do its job, it’s going to burnout and then it’s going to die. So that’s the interaction that we’re looking at, to see whether or not this happens in all cells that we generate from patients with MND and whether or not it’s something we can target. JR: Including familial? SN: Yes, so what we’re doing is we’re growing neurons that we’ve generated from stem cells which we’ve generated from skin cells from people with MND and the cells that are going to be a part of this study have been generated from people who have familial MND but also people who have that sporadic MND. JR: How many years have you been researching MND? SN: This is my 10th year as an MND researcher. I started in 2009, almost immediately after I finished my PhD. For my PhD I trained in a wet lab, sort of a basic scientist, I was a neuroscientist, and once I finished my PhD I wanted to work in something that was more translational, because I was stuck in the lab, and there’s nothing wrong with being in the lab because there’s a lot of discovery science that goes on in the lab, I wanted to see how the research that I was doing in the lab would be more applicable in the real world, so I went for a position with the two researchers at the Royal Brisbane
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Women’s Hospital who oversee the MND research clinic there and neurologists are interesting people, but Pam (Prof. Pamela McCombe) and Rob (Dr. Robert Henderson) were just so dedicated to helping the patients that they were looking after, and not only in supporting their care and managing their symptoms throughout the disease, but also, conducting research to look for that cure and they just had this whole package thing and they were just so dedicated to the people so I thought ‘so if I’m going to move into something that’s a bit more challenging, then this is where I want to be, because obviously Pam and Rob know where they want to go, and I want to be a part of that.’ JR: So they were inspiring for you? SN: They were very inspirational. JR: So I guess you’ve answered the next question already which was ‘What drew you to specialize so much in MND research?’ SN: Yeah, Pam and Rob! JR: How did you come across them to begin with? SN: When I was submitting my PhD thesis my PhD supervisor had mentioned that Pam had just received a research grant and she was looking for someone to work on the project, which was essentially looking at something they’d developed in the clinic for tracking disease progression, to see whether or not it was really accurate enough. So what I had to do – which is an interesting way to do things – is I had to take what was developed in the clinic and put it into a mouse. ‘Cause usually you go from mouse to human, so I went from human to mouse to show that the method was actually not too bad at tracking the loss of motor neurons in the mouse at least and so you could sort of extend that to think that maybe you could use that to track loss of motor neurons in patients with MND. They did warn me ‘it’s going to be a boring project cause you’re just going to be counting.’ (laughs) I can count! (laughs) But a lot of people get swayed by research projects where you have to count things ‘cause they think ‘well, it’s tedious’ and ‘it’s boring sitting at a microscope counting’. I think that it might be tedious, but it’s the most important thing. Because when we look at motor neurons and when we look at the connections between the nerve and the muscle, we’re counting connections, we’re counting neurons… So you have to count them, you have to know how many is left to know if any treatment that you’re doing is working. So I don’t shy away from the tedious stuff because it’s absolutely critical. If you do any treatment in a mouse, they’re going to say ‘well, does it save motor neurons?’ so you’ve got to count them. JR: So obviously it was their work then, that was not tedious to you, but inspirational. SN: Yeah! I think overall their drive to want to improve outcomes for patients, not just right now, but also in the future. JR: And obviously the holistic view of the person as well. SN: Yeah! And I’ve sort of taken that on and I’ve just run with it so over the last 10 years, everything that we’ve built, and I say ‘we’ because it’s a team, so myself, and Derik and all the researchers here and then Pam and Rob and the nurses, we’ve just built something that is very holistic, it’s helping people now, doing research in the clinic with patients which then informs what we do in the lab. So there used to be a time when we did research in the lab because the research question was interesting, but now a lot of these research questions in the lab are informed a lot by the conversations that we have in the clinic. We’ve had a lot of patients talk about fatigue and so in the lab now we’re developing projects where we’re testing compounds to see if we can improve fatigue in our mouse models. So it’s a difficult research question, but you know, it’s a huge problem for people too, so we’re developing research projects to answer those questions as well as our own questions of interest. We need to make sure that we’re covering all bases. JR: And I guess one finding might lead to another question as well at times.
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SN: Yeah. So we’ve found that a lot with our research, bringing what we’ve learnt from the clinic into the lab. We’re asking a new set of research questions now and this Betty Laidlaw project is one of these research questions. Because it’s all about energy use in patients, that’s what we’ve been studying, and now it’s like ‘what’s causing that energy use to be defective?’ JR: You just mentioned your partner, Derik. Now he also won a Fat Rabbit MND Research Grant in the latest MNDRIA funding round. How is it working together and living together? Are you both always thinking about work and research and coming up with theories and ideas over dinner? SN: (laughs) We do! (laughs) And it’s not just at dinner, it’s lunch, everything! But I think it’s a really good place for us to be. I think a lot of people find it interesting, that we can work well together. I think we work well together because we’re on the same page, in life and research, and so we’re very open to heavy criticism from each other and that helps us develop our research ideas. But I think what’s also really good about it is work is work, and life is life for us, so when I when I do criticize him, or he criticizes me about our research ideas, it’s not personal. We don’t take it personally. It’s just about the science because we both work in the clinic as well with patients and we understand that what we’re trying to achieve is essentially better outcomes for patients, so we put our egos on the backseat and it might hurt my feelings every now and then but you know, we step away from it and in the grander scheme of things it’s all geared towards what we want to achieve. So we do talk a lot about research and I think that it’s not really taxing for us to do that because we both love it, so it just comes naturally and I think there are times when ideas just pop up in our head and it’s easier just to talk to someone just then and there to get some clarity around it rather than saying ‘well, I’ll write that down later’ and then you forget about it. I think the other thing is that we do a lot of work in the community and so our life and work is quite intertwined. Just this weekend we were at some fundraisers, raising research funding for MND. So we do a lot of that and our team, the researchers also do a lot of that. So we like to live that lifestyle of – do the research – but it’s more than just science. We need to contribute to the community as well. And all of the students and post-docs are of that same mentality. JR: That’s fantastic! Do you get competitive with each other around seeking grants to further your work? SN: Yes and no. (laughs) We get competitive in our ideas as to whose idea we think is better. (laughs) Because there’s always a bit of healthy competition. Healthy competition is what drives innovation, but we understand that funding is difficult to come by and it’s very limited, so what we do in the context of competition, we try to push ourselves to get the best ideas and then we support each other in the grant-writing. ‘Cause we actually did develop the ideas together and we pick holes in each other’s research grants to improve them. So essentially it’s always a collaborative effort when it comes to seeking funding. JR: So you’re always both winning!? SN: Yeah, I’d like to think that we’re always both winning and if there’s ever a case where one person gets funding and the other doesn’t it’s really no hard feelings because for us the goal is really for one of us, either of us to get the funding to do the research. JR: And then it’s all about MND. SN: Yeah! It’s not about who gets it, as long as one of us gets it. We have our independent research ideas, so if Derik gets funded then his idea was better than mine and that’s OK. It makes me work harder for next time. (laughs) So no, I think it’s good. JR: It’s wonderful you can bounce off each other that way because it’s for the benefit of the cause really isn’t it?
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SN: Yeah! And in the end it’s very much about what we want to achieve, which is, to help people with MND. We do a lot of clinic work and we’re at that stage now where we need to move back into the basic science and work on the next ideas. And we both are tied to patients living with MND, but Derik… he’s just got this huge heart! (laughs) Like huge! His mother passed away from a neurodegenerative disease and so it’s very close to him to make sure that patients are always involved. He comes up with so many ideas and they just keep coming at me and I’m like ‘Oh wow! Just slow down. We have to just take one step at a time’ because there are so many things we can do but we have to focus on the first step before moving forward. JR: And I guess like with any grant it’s about focusing on what you’ve promised to deliver as well. SN: Yeah. But our grants span the basic lab, which is like the Betty Laidlaw, and actually the Fat Rabbit grant is also a more fundamental research drug repurposing/drug development type of grant. We have other grants that are funded independently that are all about working in the clinic and improving biomarkers for MND and for improving management of diet and stuff for people with MND. It’s a huge spread. JR: You must keep an eye on things that are happening around the world in terms of MND research, I noticed you’ve been involved in conversations around research topics on our Facebook page. Other than your own research and that of your colleagues here at UQ, what do you consider to be the most exciting or promising research projects out there at the moment? SN: There’s something that’s come out in the news recently by a research group in the US, Northwestern, they’ve coined a new term called ‘mitoautophagy’ and it interests me because it’s about mitochondria - the powerhouse of the cell – and it’s something that they’ve noticed in the neurons in the brain very early on and they’ve noticed it in mice. The idea is that there’s two processes of cell death and cells being reabsorbed and one’s autophagy and one’s mitophagy, but they’ve noticed that these mitochondria seem to self-destruct before you get any symptoms, well, any pathology in the upper motor neurons in the brains of these mice. So they think that this mitoautophagy might be one of the initiating sequences of events. So if we could stop it there… I predict, and I think the Betty Laidlaw Research Prize sets the scene, I think in the next few years we’re going to see a big explosion of people concentrating on the mitochondria again. Because there was a clinical trial a few years ago that was targeting mitochondria and that clinical trial did end up not progressing further because the overall data showed that it didn’t really help people, but when they went back and looked at the data and did some sub-group analysis, it looked like a small cohort of people that this drug was working for, so I think with MND being so complex, it’s going to be very targeted trials that are going to be helping people. That sort of brings me to the next big exciting thing that’s going around the world and that’s that people are really beginning to accept the fact that MND is so complex, there’s a lot of work that needs to be done on identifying sub-groups of disease. Do you have ALS? Do you have PLS? Do you have something else? And so of course if you have ALS versus PLS the treatment is going to be different. So how do we design clinical trials that are going to be more cost-efficient for patients who are enrolling into the trials and then the outcomes that we are measuring. Because obviously someone with ALS will progress very differently to someone who doesn’t have that classical ALS and if you group them into the same trial, the effects might cancel each other out. So there’s a lot of talk in the clinical trial space of how do we better stratify clients and design trials specifically for ALS patients, or MND. In the US they’re starting to do the platform trials where they’re running multiple drugs in parallel with the one placebo. So that’s actually saving costs for clinical trials as well. I think those are the two exciting things for me. JR: In your opinion, how long do you think it will be until we see a breakthrough in finding the
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cause of MND and hopefully a cure, or at least more effective treatments that prolong lives and improve peoples’ quality of life? SN: Hmm, I think that’s a hard one to answer because you don’t really want to put a yardstick on anything, but I would certainly say that in the last five years for example there’s just been such an explosion in technologies that support research, innovation, discoveries and this understanding of how trials should be run, that I think that in the next 5-10 years, we’re going to see a lot of advancements in how MND is managed and whether that’s discovery of new compounds that will work for sub-groups of people and people will know that now there are so many clinical trials being run compared to what we were seeing five years ago that there’s bound to be something that will work for a sub-group of people. It’s for us to understand that this will work for a sub-group of people for managing certain symptoms and signs or slowing the disease versus another group of people where we might have to come up with a different approach. So I think in the next five to ten years there will certainly be many more discoveries that are going to tell us more about MND - we can’t treat MND if we don’t know MND - and then that’s going to direct the different treatments and how the clinical trials are run. There is a huge focus on drug repurposing, so I think that there will be old drugs coming back that can be used for MND that have previously been shelved. JR: Other than being a research super-hero, tell us a little about yourself… What do you enjoy doing in your free time? When was the last time you took a holiday and where did you go? Any pets? SN: (laughs) Let’s start with pets, because that’s an easy one! We do have pets. We have cats. We have many cats. We have three cats and we’re going to get another two cats. (laughs) We both like animals, but because we work such long hours, they can look after themselves. We have wanted to get dogs but we’re just not home enough and it’s not fair. So we do do cats and the next two cats are going to be huge cats, the Main Coon. We thought if we can’t have a dog, then we can have three small cats and two big cats and make up one dog. (laughs) JR: Well, you can still train cats to go on a walk with you. SN: I’m doing that at the moment. (laughs) With one of them. So that’s the pets. JR: What do you enjoy doing in your free time? SN: We do volunteer a lot. Raising funds or speaking at events. People hold events where they’re fundraising and basically they want their local community to know about MND research, so Derik and I do a lot of that. I do like baking ‘cause I like to feed people, (laughs) and make people happy. Because I grew up in a restaurant so food is very important to me and my culture, the Chinese culture, food is very central, so I like to bake, and feed people. I do collect indoor plants, but they’re getting a bit heavy in the work at the moment. I have a lot of plants, over 100, but I’m going to start paring back on that because that’s a lot of work. JR: And the cats don’t tear them to pieces? SN: No they don’t. Because I take them for a walk out in the backyard. And then what was the other question? JR: Do you ever get time for holidays? SN: Yes, so our last holiday was in March this year we went to Japan, but it was only a few days holiday because we went there because the MND and Me Foundation were running the Tokyo Marathon, so we went to support the runners in the Tokyo Marathon and we thought we’d tack a few days on the end for my birthday. So that was our last holiday. We did go to Fraser for a week. We never used to take many holidays, but we’ve sort of stepped back now and realized that the work that we do, particularly with the patients, can be very… emotionally, I wouldn’t say draining, but there’s a burden there that doesn’t naturally come, because the patients and the caregivers don’t want to put
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that onto you, but because we work with patients almost every day, it’s just something that naturally happens in the background and so we understand that that’s a big thing and we do talk to our staff about making sure that they’re aware of when they’re getting to that point, and so we are trying to take little breaks, even if it’s a day or two here and there, just to recuperate and sort of reset the mind because it’s a burden that can be emotional, but also psychological and physiological because when we work with people, our attention is all on them. It’s all about them. I have so much respect for doctors and caregivers, nurses, palliative care, allied health services, people like yourself working with MND Queensland, it’s just so much! And you do need to recognize that you do need time to yourself now and then. Derik and I do attend a lot of funerals of research participants as well and it makes a big difference for their families when we’re there because then they know that the person is not just there for research. It’s a real connection. So there are times where we just have to take a day and say sit in the office and write our next grant or something rather than have an interaction with someone. JR: I know that sometimes researchers are looking for people with MND with particular attributes as candidates for research projects and trials and this sometimes frustrates people who don’t fit those attributes but want to get involved in research projects. What do you recommend to our readers with MND who want to get involved in research projects? SN: At the Royal Brisbane, we have quite a number of projects that people can get involved with. It’s a very different story when it comes to clinical trials because if they’re sponsored by a pharmaceutical company, the pharmaceutical company wants to see very specific outcomes. So they design their criteria to meet their outcomes. So essentially it’s out of the hands of the neurologists, they can’t control what people are wanting to see their drug impact. If someone, for example, some of the recent trials looking at a drug that might improve breathing function, then of course your breathing needs to be affected somewhat to get into the trial because they want to show that it’s improving. And not everyone meets that criteria. So it’s good in a sense that you don’t meet that criteria because your breathing is still excellent but on the other side of the coin it’s terrible that you can’t be involved in the trial and to contribute. So it’s a bit of a double-edged sword and the neurologists are really just stuck in the middle when it comes to how the criteria is set. Clinical trials aside, there are a lot of research projects that people can get involved in. At the Royal Brisbane, people can give a blood sample, there is essentially no criteria for that. You can just come in and give your consent and you can give a blood sample and we use the blood to look for proteins in the blood that might be different between people with MND and people without MND. So if a carer feels inclined, they can be involved in the research as a non-MND-affected-person and contribute a blood sample as well. Then there are other research projects that we are looking at; metabolism, how the body uses energy. Essentially we capture most people in that research, the only thing that really impacts it is if you have diabetes because we’re looking at energy use and diabetes does affect energy use. But we capture most people who come through the Royal Brisbane who want to be involved in research. But then there are times, for example, there are a lot of people who have a slower progressing disease and so come that median of the 27 months, they’re still here and some of the research projects will, particularly ALICE for example, it’s a two-year project, so once you go past two years or the eight visits you don’t qualify to be in that research anymore. And Derik and I don’t really like that at all. So we’re in the process of developing a new research project that will capture those people. JR: For as long as they want to participate? SN: For as long as they want to participate. So the people who have gone past the two years in our project, when we have that last research visit and we say ‘well, this is their last one.’ It’s very hard for everyone and so we’ve sort of felt that they’re a unique group of people and there’s something very unique about them, there’s something that we can certainly learn from them, because there could be something in that disease that could give us clues about how we could stop more rapid progressing diseases, so we’re in the process of setting up all the foundations for starting a new research project for people that might have a more slower progressing disease that affects primarily the neurons in the brain. People who experience a lot of stiffness and spasticity. And so we’re working with exercise physiologists, and trying to look at new ways that we can try and improve stiffness. And that’s quality
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of life for people who have a slow progressing disease, but are still very debilitated because of the stiffness. It still affects their mobility and how they can get out and about, so we’re looking at things like that. We don’t want to leave anyone out. (laughs) JR: Thanks for your time today and for all that you do for trying to find the cause, and a cure for MND. Are there any final words you’d like to share with our readers? SN: (pauses) As an MND researcher, I feel very honored and privileged to be able to do the research that I do and I wouldn’t be able to do this research if it wasn’t for the MND community and people living with MND and the carers and the families and everyone pushing for the research, pushing for learning the cause, pushing for a cure. So I want to thank the community for everything that they do to support everything that the researchers can do because we wouldn’t be here doing what we do without them.
Pictured: (seated) Dr. Shyuan Ngo winner of the Betty Laidlaw MND Research Prize 2020 with her partner Dr. Frederik Steyn (aka Derik) winner of the Fat Rabbit MND Research Grant in their lab at AIBN, University of Queensland.
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