Research Bytes podcast

Dr Katrina Champion's research looks at how early intervention on the 'big six' lifestyle risk factors could prevent chronic disease later in life. But her latest publication was not what they expected to find.

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Still to come

Dr Rachel Visontay looks at the long-term health effects of alcohol use. Her recent publication asks whether a little bit of alcohol might be good for depression.

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PROFESSOR ROBYN WARD

Hello, my name is Robyn Ward. I'm the Executive Dean of the Faculty of Medicine and Health at the University of Sydney. And this is a podcast called Research Bytes. And today I'm here with Rachel Visontay, who's working on a very important area of alcohol and depression. And I'm sure this is going to lead to a lot of interesting conversations. But first off, let me introduce Rachel and ask her to tell us a bit about herself.

DR RACHEL VISONTAY

Thanks so much for having me on. I finished my PhD last year. So I'm a fresh postdoc in the faculty here, I worked as a research assistant at the Matilda Centre, where we focus on mental health and substance use, I was working there for a few years really embedded in the research, and was looking for sort of a meaty topic that I could pursue for my PhD.

And I came across this area of alcohol and long term health. And the particular controversial issue, which was whether for some health outcomes, there might actually be a protective effect of a little bit of alcohol consumption, as opposed to just those harms that we know about heavy levels of drinking.

PROFESSOR ROBYN WARD

And just tell me what you describe as high risk alcohol consumption, because I think that's quite important for us to establish at the beginning, there are a continuum of alcohol consumption from abstinence right through to high risk.

DR RACHEL VISONTAY

Well, there's no consensus on that on unfortunately. So for the most part, I go off the Australian guidelines that are issued by the NHMRC. But in the research that we're going to be talking about today, I was actually using some American data.

And in that case, we were using the American guidelines, which are quite a bit higher and have different thresholds for men and women. So this is actually a bit of a problem with the research is that there is no consensus from country to country as to what constitutes moderate drinking. And what constitutes risky drinking

PROFESSOR ROBYN WARD

So you didn't distinguish between men and women in terms of alcohol consumption, so you don't subscribe to that idea, there's a difference between men and women?

DR RACHEL VISONTAY

There definitely is in terms of how men and women metabolise alcohol, and it's to do with the fat distribution in the body. So there are definitely physical differences there. But I suppose the health bodies that are making these guidelines on a national basis, they make different decisions based on what evidence they have before them. So the Americans have gone with different thresholds for men and women.

Although, again, what constitutes a standard drink differs between countries as well. So the Americans are a bit more tolerant there, they've got it a higher threshold, whereas in Australia, they decided to just make a uniform number of standard drinks per week between men and women. And I suppose that's in an effort to simplify the guidelines. And also around the more conservative side.

PROFESSOR ROBYN WARD

Now, we've established that it's very hard to define alcohol consumption, let's move on to the issue of what you described, and how you discovered this relationship between alcohol and depression, which was previously perhaps thought of in a different way.

DR RACHEL VISONTAY

I think a lot of us know that there's a strong link between very heavy and disordered alcohol consumption and higher rates of depression. But depression is one of these outcomes that keeps popping up, where there seems to be this J shaped relationship.

So you start off with people who totally abstain from alcohol, and their risk for depression. And then you go down to people who drink a little bit moderately, and their risk drops off a little bit. And then as people drink more and more, that risk steadily climb. So that that looks like a bit of a J shaped.

But the debate in the literature was, you know, does this relationship actually reflect cause and effect? Or is it simply an association, that sort of an artefact from the way that we've been limited in conducting studies thus far.

PROFESSOR ROBYN WARD

And it seems in your paper, which was published in the American Journal of Psychiatry, you used a new statistical methodology. And I think most of our audience are not sort of super statisticians. But perhaps you can explain in simple terms, what was really novel about using this new methodology.

DR RACHEL VISONTAY

So I think that the biggest problem with a lot of this kind of epidemiological research in the alcohol world is that we run into something called confounding.

So we know that people who drink occasionally or moderately tend to have a lot of other health protective factors, like being wealthier and being better educated. So it's really hard to know if it's the alcohol that's causing health protection, in this case, better mental health, or whether it's those other factors that are causing the health protection.

So obviously, we have statistical methods to try to control for those confounders. But the standard methods that we use can really only be applied in a simple case, for example, where we measure alcohol once we measure those confounding variables once and we measure the health outcome once at the end, and that doesn't really capture the complexity of the kind of longitudinal relationship that is of interest and also of public health relevance.

We know that people's drinking can change over time. So it's really important to capture those changes, something we call drinker drift, and also their values on those confounding variables. We talked about, like how much money they're earning, whether they're in employment, those things are changing over time as well.

So the statistical method that we were using something called a marginal structural model that allows us to look at the relationship in any kind of complex longitudinal way, while still controlling for those confounding variables.

PROFESSOR ROBYN WARD

And now tell me about the data you use, because you've already touched on this idea that you need to collect longitudinal data, meaning is a data point, say for someone at the age of 12. And then later on, and later on, and then you get to the 50 year age group, where did you get all that data from?

DR RACHEL VISONTAY

We used a data set called the National Longitudinal Survey of youth from the states, the people in this data set we interviewed from when they were quite young, 14 to 22, was when they were recruited.

That's really, really handy for us because we can have information about people's drinking, right back from when they kind of started drinking, we ended up using about three and a half 1000 People from this cohort, which is a pretty substantial number.

PROFESSOR ROBYN WARD

So is there any difference in Americans drinking and drinking in Europe or drinking in Australia, would you imagine that will be different or these signings broadly applicable?

DR RACHEL VISONTAY

Well, this one really comes down now to the mechanisms. So we found that indeed, occasional or moderate drinking did seem to have this protective effect against depression. But we weren't really able to tease apart whether that is purely because of alcohols effects on neurotransmitters like dopamine and GABA, or inflammation, or whether the effect is pub's mediated more through social interaction and social support, you know, that alcohol facilitates social interaction.

So if it's predominantly the former, you would hope that that would be consistent from country to country, obviously, the social context might differ a little bit in different countries, in terms of the differences between drinking in Australia and the USA, it's fairly similar.

We have higher rates of binge drinking. Unfortunately, that's not a good claim to fame for us. And the US also has higher rates of overall abstinence.

PROFESSOR ROBYN WARD

And I was also interested in how you define depression. So that's fascinating, you use the scoring system for depression. So can you tell us about how you define depression in this study, and then what that means, in real terms to the average person walking along the street.

DR RACHEL VISONTAY

So everybody in this study, and this is similar for other kinds of cohort studies like this, were administered a sort of validated scale assessing a range of different depressive symptoms. So they might ask you about how often you felt hopeless in the past couple of weeks.

And so we looked at two different outcome measurements. One is just the number of symptoms. So your average score on that scale. And the other one was using a cut off on that scale. A probable yes or no for depression.

PROFESSOR ROBYN WARD

So here's the million dollar question Should all those people who are abstinent from alcohol begin drinking moderately so that they're going to feel less depressed?

DR RACHEL VISONTAY

Absolutely not.

As I said, there are a couple of outcomes for which this sort of J shaped effect keeps popping up. So depression is one of them. diabetes, type two diabetes is another maybe dementia.

But for a lot of health conditions, we know that every single drink is going to increase your risk. And that includes cancers at many, many sites, in some in aggregate alcohol is not good for us.

The other problem is that we don't know who's going to be able to maintain drinking on an occasional or moderate level, keeping their drinking levels underneath those recommended guidelines, and who will actually go on to develop alcohol use disorder. So definitely not a recommendation.

PROFESSOR ROBYN WARD

So do you think one of the main sort of implications of your study then are really around looking for the mechanisms between depression and alcohol?

DR RACHEL VISONTAY

Absolutely, yeah. So if there is a benefit there, finding out what those mechanisms are means that we can identify potential targets for intervening on using some kind of intervention that's not alcohol, that doesn't also entail risk for things like cancer.

So for example, if social support is the main mechanism, then we know there are a host of other ways to improve people's level of social interaction and social support, and we can focus on those instead. I think it would be really fascinating to do some further research, where we try and tease apart whether it's the social interaction, or the more direct biological mediation that's causing these benefits for depression. We'll see how my NHMRC application goes on that one.

PROFESSOR ROBYN WARD

It's been great talking to you, Rachel, thank you for joining us on Research Bytes and we came to you on Gadigal land.

VOICEOVER

Thanks for listening. You can listen back, read the paper and find the transcript on https://soundcloud.com/fmh-news

Dr Caitlin Jones aimed to investigate the efficacy and safety of opioids for low back pain, and uncovered some interesting findings in her research.

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ROBYN WARD

Hello, everyone. My name is Robyn Ward. I'm the Executive Dean of the Faculty of Medicine and Health here at the University of Sydney. And welcome to Research Bytes. This is our second podcast. And the podcast is designed to profile some of the amazing work of our early and mid career researchers, and particularly those who are having impact on an international stage. And today, I'm joined by Caitlin Jones. And I'm going to first ask Caitlyn to tell us a little bit about herself. And then we're going to talk about her really important study about opioids and back pain. So Caitlin, where do you come from? And how long have you been at Sydney Uni?

CAITLIN JONES

So I come from a background of clinical work as an occupational therapist. I did that for a couple of years. And then I guess, just got curious about what else was out there. And I thought about doing some research. And I got some good advice early on that when you're thinking about doing research to go looking for the best supervisor, you could imagine, and to choose that person as the primary thing and let the exact topic be a secondary thing. So I went scouring through the internet to find someone that I thought would be an excellent supervisor and mentor. And I found Professor Christine Lin, and she was based at Sydney University. So I approached her and asked for a shot. And now here I still am years later

ROBYN WARD

Fantastic. And the paper you've got published is in the Lancet. And I think for people who don't know how important that journal is, perhaps they aren't working in this field, because it's extraordinarily important journal, particularly because it's influential with clinicians. And it's also very hard to get published in The Lancet. So congratulations, that's a major achievement. And the topic you've researched is back pain. And I don't think there'd be a single person out there who doesn't know someone or doesn't experience back pain themselves, acute back pain or chronic back pain. And I know personally from my own experience of having back pain, it's very painful and debilitating and can cause a lot of morbidity and mortality. And a lot of people use opioids for pain, despite the guidelines, because they think that that's going to help the pain and the pain is so severe that they feel there's nothing else to do but to take opioids. So your study was really very interesting, because you've made some different observations to what we have traditionally thought. So perhaps if you tell us about what you found, and why you think it is so important.

CAITLIN JONES

Yeah, sure. So like you said, Back pain is the most burdensome health condition in Australia and around the world from both the perspective of how much disability it causes people and what it costs the country to manage it as well. And you're right that a lot of people use opioid pain medicines for back pain. It's actually currently still in the guidelines to be considered as you know, a second or third line treatment when other things have failed. But that that recommendation wasn't based on any direct evidence before, it was sort of based on the assumption that an opioid pain medicine, being a strong painkiller would be suitable for severe pain like acute back and neck pain. But until the OPALtrial was done, we didn't actually have a good idea of how well it worked to compare that to the harms that opioids can cause which are serious and many. So yeah, the opioid trial was conceived by Professor Christine Lin and I got to join the trial as a PhD student. And we had a really surprising outcome. So we took about 350 people, and we randomly assigned them to either get a short course of an opioid pain medicine or a placebo, meaning nothing is a pill with it's made out of starch. And we followed them up for a full 12 months to see how they fared in terms of pain and function and quality of life and any short or long term side effects they had. And surprisingly, we found that in the short term, the people that took an opioid were no better off compared to the people that took a placebo. So there was no benefits in terms of pain, function or quality of life to taking an opioid. And perhaps even more interesting was the long term results, which was that the people in the opioid group actually fared worse over 12 months. And at the 12 month time point, they had worse pain on average than the people that took a placebo.

ROBYN WARD

And can you tell me what people on the placebo group actually had? Because they weren't just sort of decided that they had to go and grin and bear the pain did they? They had, they had some treatment, but what was the nature of that treatment that both groups got?

CAITLIN JONES

So everyone in the study got what we called guideline recommended treatments. So there were no restrictions on what doctors could prescribe for those patients. We just asked them to report what they did. So some people were sent off to physiotherapy. Some people were supplemented with other pain medicines like non steroidal anti inflammatories, like ibuprofen or paracetamol even. But we asked everyone to report what else they did. And there were no differences between groups. So on average, people went off and did about the same thing. It was really only the opioid that was the difference between those two groups.

ROBYN WARD

And based on your study and the rigor of that study, do you think that opioids should now be removed from any guidelines? Or are there still more work to be done before we remove the recommendations in some guidelines to continue to consider opioids for back pain,

CAITLIN JONES

I do think they should be removed for guidelines for acute back and neck pain, seeing as that was the population of the OPAL trial. And we got a really clear signal that there are just no benefits for that population. The OPAL trial looked at acute pain. So the recommendation is essentially to not start new users on opioids that have acute episodes of pain, but it's a whole different kettle of fish, people that have chronic pain, especially those that are already long term users of opioids. So the OPAL trial doesn't really give any answers to that population. And there are risks associated with abruptly stopping people on opioids. So we don't want the OPAL trial results to be misinterpreted to mean that clinicians should cease prescribing of opioids to people with chronic pain who have been on them for a long time. Because that can be dangerous when done suddenly.

ROBYN WARD

And in the study you you use the term back pain generically. And I noticed you have a larger group, who had low back pain and a relatively small number of people who had neck pain. And so I have a question around whether you think that these findings of not using opioids equally apply to people with low back pain, as well as people with neck pain.

CAITLIN JONES

It's true that our sample was majority back pain, I think it was maybe 80%, and only a small fraction of people had neck pain. So we were a bit underpowered to make really conclusive comments about neck pain. But the data we did see in the study that it wasn't any different. There doesn't seem to be any benefits for acute neck pain, either.

ROBYN WARD

And so why do you think Well, well, first off, what are the causes of low back pain, this acute low back pain? And why do you think opioids don't work?

CAITLIN JONES

Well, back pain is so complicated. Pain is so complicated. So you know, pain can be because of a physical injury, like some physical damage that leads to pain. But we also know you can experience pain when there's no identifiable physical damage there. You know, we know it's related to stress and lifestyle, as well as potentially physical damage. So it is really complicated. So when you think that there are so many different causes, and that the opioid only targets one kind of pain, which would be that, you know, pain related to physical damage, I guess it makes sense why it wasn't, you know, one simple treatment wasn't effective to treat such a complicated condition. And

ROBYN WARD

that's a that sort of leads me on to this next question, because there's so little in the way of diagnostic specificity in low back pain, how are we going to move the field forward so that we have better precision around the diagnosis and maybe there are subgroups of people within that, that opioids would work in or other treatments, but it's It's a sort of a big group of people who have different types of pain and different types of low back pain all get lumped together.

CAITLIN JONES

Yeah, that's such a good question. And it's a discussion that's happening in the field. Now, for a while we were moving away from trying to subgroup people. And we were sort of anyone who didn't have a obvious identifiable cause of back pain was given this label of nonspecific back pain. And they're the people we included in the opioid trial. So it's your garden variety, back pain, where there's no obvious cause, so people that perhaps had a fracture in runner, their vertebrae, or some sort of malignancy or infection, they weren't included in the opioid trial. So those serious pathological causes for back pain. And the findings of Opal don't necessarily apply to them. There is maybe more recently a bit of push back in the other direction that maybe we should be looking more closely at what subgroups exist. And seeing as most treatments we test don't work on average, across the board, maybe we do need to look at smaller, smaller groups of people and find things that work for smaller subgroups. And

ROBYN WARD

Do you have any views on their place of imaging in low back pain is, is that a bit beyond the remit of this study? But do you have any views yourself on whether people with low back pain should go along and have MRIs and CTS,

CAITLIN JONES

I'm not an expert what I do know in the literature is that while we don't really know how to subgroup people and treat them differently, there's no real benefit from going along and getting something like an x ray or an MRI, because you may find something a change that could be related to your pain, it could not be it could be a just a normal age related change, that then it sort of sets you on this pathway to get potentially unnecessary treatment, you might end up being referred for surgery to correct that structural damage they've seen. Whereas we don't know if that's actually causing your pain at all. And often it's not, because people go on to have them treated with surgeries and their back pain doesn't improve. So the way things are now, to go and get imaged is more likely to cause you harm than to actually help you solve your problem.

ROBYN WARD

Yeah, that's a great answer. And great advice as well, I think to people out there. So now, you're in this new world where you've done your study, and people will not be potentially using opioids anymore as a result of your important study. What are you going to advise? Or what should general practitioners and other people advise people who come into their rooms with low back pain? Take us through this sort of high level guidelines?

CAITLIN JONES

Yeah, sure. So people that first present with back pain, if it's acute, chances are, it's going to get better. So some reassurance to person to tell them that if they just do their best to maintain their normal activities, there's a very likely chance that they will feel better without any intervention. If that person does feel like they need some sort of intervention, non-steroidal anti-inflammatory drugs do seem to have the best benefit, harm balance they do have moderate benefits, and in most populations, only small harms. So that would be the go to medicine to turn to if you do feel like you need to turn to a medicine. For people with more chronic and complex back pain, there's recently been two really interesting studies called the resolve trial and the restore trial that have tested these complex multifaceted interventions with people and found really promising effects.

ROBYN WARD

And what are those interventions.

CAITLIN JONES
One is cognitive functional therapy. So it's, I guess, looking at the whole person and coming at it from a whole heap of different angles, which makes sense when you think that back pain has so many complicated causes. So yeah, those two trials have showed some effects where everyone in the back pain space was getting a bit depressed, because trial after trial, we just we keep finding things that don't work. But it's often the individual treatments don't work. But when you sort of help someone with this comprehensive program that helps them tackle all the different areas of their life that might be contributing to back pain. That's where we see the best effects. So I think that is where treatment for back pain is heading.

ROBYN WARD

And I was just curious, this study, it took quite a long time to recruit and finish. And I thought, well, the back pain is so common, you know, why would it take so long to recruit 300 odd patients? And I think ir was like four years or is that right?

CAITLIN JONES

Even longer!

ROBYN WARD 

Even longer? Okay, for more than four years. And so what does that tell us about the sorts of we the community engagement, we need to actually advance these fields because if it takes four or five years to recruit to just this study, then we're not going to advance the field of back pain if it's such a slow process.

CAITLIN JONES

We joke throughout the study that we've cured back pain, the best way to cure it is to go looking for people that have it and suddenly they all disappear. But it is so common and there's people with back pain all over the place but to find One who is willing to join a placebo-controlled study, it's quite a unique person because they have to agree to a 50/50 chance of getting either a strong and controversial pain medicine or a placebo, which they know is nothing. So often people had a strong preference, they'd say, Oh, I'll join as long as you can guarantee me an opioid. Or I'll join as long as you can guarantee me the placebo. But to find a person that would really be happy either way, is rare. So that's why it took so long. And I think that the answer going forward is for us to do an even better job at embedding clinical trials into regular practice, which is not so easy with placebos. But in other trials, where you're comparing two treatments to just be running trials in the natural healthcare system, so that no one has to go out of their way to join a study or a clinician doesn't have to go out of their way to recruit a patient to a study. And I think that will help us get important answers much faster.

ROBYN WARD

And I think that's often under appreciated. I know in the field that I work in, in cancer, clinical trials have become part of clinical practice, really, it's so embedded, it's sort of you can't separate the two. But in these other areas where you have huge morbidity, People are seemingly less engaged as a community in in understanding the importance of doing trials like this, because, you know, I imagine there's a lot of people whose take who have taken opioids, perhaps inadvisedly, now, over the last four years, if they had have had the opal trial results, their doctor or would not have prescribed an opioid. So that that's what those delays mean, in practice.

CAITLIN JONES

Yeah, I agree. I think it's also challenging when you're testing a treatment that's been around for a long time, it's not like we could offer a new exciting treatment. It was something that people could access easily outside the trial anyway. And so to convince them why they should take extra time and effort, you know, while while they're unwell with back pain to, to join a study to take a medicine that they could easily get outside the trial. It's a bit of a hard sell. So we really appreciate everyone that was that volunteered to join.

ROBYN WARD

It's been great talking to you today. Caitlin, congratulations on your study. Maybe you can just tell us what's next for you in your research career?

CAITLIN JONES

Well, so yeah, after looking at back pain, which is sort of, one of the biggest reasons for over prescription and inappropriate prescription of opioids, it seems like the next thing to look at is post surgical pain, because that's sort of the next biggest area where we think there's overuse and misuse of opioids. So our next plan is to tackle how effective opioids are used after surgery like hip and knee replacement.

ROBYN WARD

That is fantastic work. And I think everyone listening would be aware of the downsides of opioids. I don't think we need to provide any information on that. But I think it's very, very well-known abuse of opioids and their consequences to people, their families and how addictive they are

CAITLIN JONES

To whole communities as well.

ROBYN WARD
Exactly, it's been great talking to you, Caitlin, we really wish you all the best. And this is Research Bytes

CAITLIN JONES

Thanks for having me.

ROBYN WARD

So thank you for joining us on Research Bytes, and we came to you from Gadigal land

Dr Nick Hunt and his colleagues have been using nanotechnology to take us even closer to an oral insulin, negating the need for injections.

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PROFESSOR ROBYN WARD: 
So hi there, and welcome to Research Bytes, a podcast from the Faculty of Medicine and Health which explores the work of our early and mid-career researchers. I'm Executive Dean Professor Robyn Ward, and in this episode, I'm catching up with Dr. Nick Hunt from the School of Medical Sciences, who has done some pretty amazing work on oral insulin.

And I'm very keen to hear what he's got to say about his work. But before we get started, I thought it would be great just to hear a little bit about Nick. What have you done in your career? What's taken you to this point of working on diabetes and insulin?

DR NICK HUNT: 

A pleasure to be here and thank you very much for the invite to do this.

I've been a Sydney Uni person for a long time. So, I did my undergrad here, I did my PhD here, and aside from a brief stint over in NSW Health for about three months, I've been here for almost 10 years in research, so a good decade. So, the reason we have particularly focused on insulin and diabetes is when I finished my PhD, I jumped over from neuropathology and focused more on liver pharmacology.

And an amazing group at Anzac Research Institute as part of the Sydney Local Health District with Victoria Cogger. And the amazing team we've got together with Vic and David Le Couteur, who's the clinician of the hospital, is we started developing nanotechnology platforms for drug delivery. We were originally trying to target certain areas in the liver, called the liver sinusoidal endothelial cells, or the LSEC, and we're trying to look at how we can reverse age related changes with nanotechnology.

So, it was an incredibly fortunate time since when I finished my PhD, I got a one-year job with Vic, and then we were successful, well Vic was successful, getting an NHMRC grant. So that kind of then became the focus for us for the next three to four years, and then to kind of build on that.

So, we started off making nanotechnology platforms, and then we slowly branched into what else could we deliver with this technology. And one of the main problems facing clinicians in the hospital, as David pointed out, was the delivery of insulin if you've got a frail, older patient. One of the things that limited them from being able to go home from hospital, was that they'd have to have an initial management plan and would need someone to administer it.

So usually, it's either a nurse or you need a diabetic educator to come and instruct the family. So, we wanted something that's going to be safe and orally available. That's kind of how we morphed into the diabetes space because it's a question I do usually get, of ‘you work on nanotechnology, we have no experience in diabetes prior to 2018’, and that's how it slowly grew into it.

PROFESSOR ROBYN WARD: 
So, I mean, what I know about diabetes, what a lot of people know is that there's a lot of people in the world with diabetes, maybe close to 500 million, about say a hundred million of them are dependent on insulin. And for those people who are dependent on insulin, it's manageable when they're older.

As you say, but older people have trouble managing needles and insulin, but for a child with diabetes who is, who needs to take insulin from when they're very little, that exposes them to a lifelong exposure of insulin and and all the risks that are associated with taking insulin apart from injecting themselves forever.

So many, many decades, people have been talking about oral insulin and, and its promise and how amazing it would be. And we'll get onto the topic of hypoglycaemia soon, but, but why do you think your inventions are going to tackle this issue of oral availability, whereas many decades of work has failed to do so.

DR NICK HUNT: 

Yeah. So, it's been something that's been around for a good 60 years, the idea of oral insulin. I mean, insulin itself was discovered over 100 years ago. We had the anniversary last year.  It's an incredibly difficult area to go into and the main challenge is associated with its bioavailability and of course the costs associated with insulin.

So, insulin typically has a bioavailability of only 1 percent and we, with our technology have moved that up to 4%. So, a substantial increase but the main promise I think that we have from our technology is when we started looking at small pieces of tissue from human samples, we can get up to 40-fold more increase within the intestine of human patients, which is really exciting in an in vitro setting. We'll get to in vivo very soon. 

But that's part of the challenge associated with it.  As you were pointing out before, it's a combination of children that will be exposed and what we really tried to design with this technology is we pictured, if a clinician's sitting there in front of a child that's just been diagnosed, usually you do a titration series where you give them a tiny bit of insulin, see how they respond, then 15 20 minutes later, check their blood glucose, and then give them a tiny little bit more.

One of the challenges of oral insulins is they take over an hour in order to work.  So, what we designed is an insulin that would work within 15 minutes, so it could be at that first point of contact, so the patient would never actually need to go into injectable needles.  But it's not just on the child end, it's also on the type 2 diabetics, since that's the quite large and emerging market.

So, these are usually more elderly gentlemen, who really don't want to go on injectable insulin, so they will delay treatment for months, even a year, just to not have to do it. And if you can replace that with a tablet, it can be a lot easier, and it's also something we learned from the COVID pandemic.

People don't like taking injections at all, particularly around the vaccinations, but to be able to address that with an oral formulation can be a lot better and a better use for them.

PROFESSOR ROBYN WARD: 

And in your paper, which I read with great interest, there's a lot of complex terminology there. And part of this series is really trying to explain some of that in lay language, or at least in scientific language that your colleagues in the faculty and elsewhere can understand.

So, you talk a lot about quantum dots, and maybe you can explain what a quantum dot is and how do you get insulin onto a quantum dot?

DR NICK HUNT: 

Yeah, so quantum dots are an incredibly cool material, and they won the Nobel Prize for Chemistry earlier on in this year (2023).

So, quantum dots are a form of nanotechnologies. A nanotechnology is something that's between one to a hundred nanometres in size. And the usual way I get people to think about this is if you look at your finger, that's one centimetre across, you're talking about something that's a millionth the size of that.

And for another size comparison, think of the size of a soccer ball, and think of the size of the planet Earth. That's kind of the weird size dynamic that you've got.  The reason why we quite like quantum dots is they exist in the realm between what is something that can't pass between the gaps in cells.

So, they can't freely move throughout your entire body, but they are something that would be quite readily cleared by certain cells that would be in your liver. So, we've been exposed to nanomaterials for eons. Any grinding material, chewing food will create some level of nanomaterial. But quantum dots are a very small formulation of that which will be taken up by certain cell types in the body, and the body's developed that technique to clear those materials. So really, we're just cheating off something that's been developing for thousands of years of how our body would usually get rid of those materials, but we're using it to be able to transport something into the body that would then be rapidly cleared out, but they could release a payload or deliver a drug at that time point before they get cleared out of the body.

PROFESSOR ROBYN WARD: 

And how do you make one of these little quantum dots with a little insulin molecule sitting on it?

DR NICK HUNT: 

So, it's the challenge as we slowly start moving towards translation of this tech.

So right now, we're going through manufacturing of this to good manufacturing standards.  And the difficulty is, quantum dots are used quite a lot, but people would think about them, they're in their television sets. They're not something that's usually a pharmacological material. So how you do actually make them is the same process that you would for any other type of engineering material.

What we use is what is usually referred to as a hot injection method, where it really requires superheating of materials, till, effectively, if you think about a product that's been all clumped together, when you heat it a lot, it starts expanding quite quickly, and it starts, the term is nucleation, and you get separation of all these individual atoms.

And then as you slowly control how they're heated properly, they'll start forming quite complex shapes, and that's when you can start getting quantum dot formation. How you make those then, in a pharmacological setting and a biological setting, took a lot of work. But we slowly developed a process that can be implemented in a biological lab.

We did an R&D version of this, then moved on to a non GMP version, and then finally now moving to a, an accredited standard approach. So, it's required a lot of, so within the Australian context, CSIRO, who we partner for the non GMP work, was the first time they'd ever done anything like this. And it's the first-time quantum dots will be used in clinical trials for these particular purposes.

PROFESSOR ROBYN WARD: 

And what were the big scientific challenges around using quantum dots for this purpose? What, what sort of paradigms did you need to establish, and rules you needed to break.

DR NICK HUNT: 

Probably the chief rule is around the, the composition that we had. So, quantum dots, um, because they were designed, of course, for, for non-human purposes, uh, they've got really good versions that are not quite toxic to people.

We needed to develop a formulation that had a, a low level of toxicity associated with it. So, our ones are made up of silver and sulphur. But also start working around the idea of if you are going to be giving silver to patients, how much silver can they have? And the example I always love to give is if you're going to have our oral insulin formulation, there is more silver in a set of vegetables than there would be in that particular nanoparticle complex.

But it's a hard idea to kind of work around.  Aside from that, thinking about how we kind of grow with scale component of it. So, we're, of course, used to working in a small, tiny lab, but we needed to start making gram quantities of these materials. And it's a slow process. That's quite a lot of re-evaluations at each step.

But it's had an amazing team that's kind of brought together a lot of expertise in that space. And it's great to see that we now actually are ready. to make those kinds of quantities.

PROFESSOR ROBYN WARD: 

And one of the key advantages of, apart from being oral, is this avoidance of hypoglycaemia, which is a pretty terrible experience for any patient or a family member or a friend who's seen someone experience that, particularly in the evenings.

When I mean the evenings, I mean sleeping through the night and being hypoglycaemic is a real worry for mums and dads looking after kids with insulin dependent. So, what did you find in terms of hypoglycaemia? Is this a, an important finding for you? I mean, hypoglycaemia is the most important aspect of, of this particular technology.

DR NICK HUNT: 

So, within Australia, there's 64,000 hypoglycaemic events each year. For those patients or even their parents, half of them will call triple zero and then ten percent of them will need to go to hospital for treatment.  To be able to avoid that is incredibly important, but it's not just for the short-term complications, also for the long term.

So, the, the main energy that we're putting into a lot of diabetic management at the moment is trying to keep people in an optimal glycaemic range to try and limit the, the impact of, of nephropathy, so of retinopathy later on down in life. So, the way we went around designing this technology was to try and address that hypoglycaemic problem.

And what we aim to do is create a technology that only targets certain areas in the body. Uh, so that's where we started to target the liver. So traditionally of injectable insulin, you're giving very high non physiological dosages of insulin that will accumulate liver, muscle, and fat and almost take all the glucose out of the body instantaneously.

What we designed was technology that more closely replicated what happens physiologically of insulin. So, it's released from the pancreas, majority of it will work from the liver, and then a small amount will reach muscle and fat.  What we also did with this technology is we designed a polymer that would react to its environment to control how insulins released.

So, the polymer we have is designed to be degraded by enzymes that are released in response to high blood glucose levels. So, the net effect of that is when there's no glucose within the blood, or there's very low glucose environments, you don't get the release of the insulin payload. And this is actually something we discovered around COVID vaccines, since, um, 50 percent of it will just be excreted quite freely.

Nanomaterials are quite quickly cleared from the body. And if it doesn't have a release of its payload, it just gets taken out. So, it's not going to sit around and work. 24 hours, 48 hours later, you've got something where it's either the glucose is there, it's got the enzymes to release, to release that payload, or the material is cleared out.

So that's how we get that safety component. And one of my favourite lines from this tech is we've had in mice, rats, and baboons over a thousand data points, and we couldn't induce a single hypoglycaemic episode.  It's, it's great to see, uh, but you can just increase the safety profile of what insulin is. So, like, insulin typically, if you were to double the dosage, you can induce a hypoglycaemic episode.

With our technology, you need to have, uh, 20 times more. Uh, increase in the amount of insulin that you give in order to get that hypo. 2024 is the year of manufacturing and 2025 will be the year of clinical trials. Uh, so with this technology, of course, uh, we go through a traditional, um, what would it be, a commercial development process.

We've gone through and patented the technology; we then licensed it to a company and then that company is now leading it as it goes through to clinical trials.

PROFESSOR ROBYN WARD: 

Fantastic. And I know that everyone always thinks that a lot of research takes a lot of time, which is a very true statement. It does take a lot of time.

So how long did it take you from the day you begun on this project to where you are now? How many years has that been?

DR NICK HUNT: 

So, this has been a while. I think we originally got the grant to work on just kind of area in 2018. I've actually got a photo of the day when we actually discovered the, the polymer, because it really was a moment of, that doesn't actually look right, for how it was actually reacting in its environment.

And it turned out to be the formulation that went forward. So that was in mid 2019. What's crazy is when you go through and you're developing something for commercial translation, you can't talk about it for a long time. So, I had to sit there in conferences and people kind of go, Oh, okay, no, that's impossible.

It can't work. And I was sitting there going, we have data that already proves this. And you get there three years later and everyone's kind of going, awesome. But it's, it's a long time. So, this has taken up to, I suppose, five years for these steps. And I suppose getting it all the way through into patients and even to the phase two or phase three clinical trials, you're looking at another five years on top. Ten-year pipeline is usually how it works, and I like to think we're, we're nearing halfway.

PROFESSOR ROBYN WARD: 

So, this is, I think, such an exciting discovery that you've made. It was really a series of discoveries, very clinically applied, addressing a really big unmet need. And it's amazing that you've been able to do this here at the University of Sydney.

And it's been fantastic talking to you today about your discoveries. And I hope that people listening out there will really be inspired by what Nick and Victoria Cogger and David Le Couteur and many other people have done to bring this to fruition and are enjoying our very first episode of Research Bytes.

Thanks for listening.  You can listen back, read the paper and find the transcript on soundcloud.com/fmh-news.

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