This is a live recording of the fourth session of Discovery days from 2023 featuring talks from Professor Ian Ganley on ‘Understanding the role of mitochondria in Parkinson’s disease’, Dr Sucharita Nanjappa on ‘Low-tech solutions leading to engaged learning’ and Professor Peter Hoskins on ‘Quantification in diagnostic ultrasound’.
Discovery Days offer a fascinating exploration of a wide range of important topics, from health and wellbeing, human rights, and our ground-breaking scientific research and arts practice. All our speakers are helping us to transform lives locally and around the world.
Press release: https://www.dundee.ac.uk/stories/discovery-days-2023
Please welcome the chair for this session. Professor Blair Grubb, our Vice Principal of Education. Over to you, Blair. Thank you very much, John, and welcome everybody to today’s session or this afternoon’s session. This is session four of our Discovery Days which are a showcase for the excellence
In research and education that we carry out here at the University. Delighted, we’ve got three fantastic speakers for this afternoon’s session and the format will be: each of them will give a 15 minute talk one after another, and then I’ll invite them at the end to take their seats on the floor here
And you’ll be invited as guests to ask questions, either in person or if you’re online and listening; welcome to you as well. You’ll be able to ask questions via the chat and Emma and John will relay these to me so I can ask your questions to the speakers here live.
So everyone has a chance. Okay, you want to hear as little as possible from me today, that’s certainly true. So let me just put the other windows on. So, I’m really delighted to welcome Professor Ian Ganley, who’s our chair of Cellular Homeostasis at the University. Ian obtained his undergraduate and master’s
Degree from the University of Oxford, his Ph.D. from the University of Cambridge. He’s worked at Stanford University, he’s worked at the Memorial Sloan Kettering Cancer Centre in New York, one of the top research centres in the world. I think that research pedigree tells you we’re in for a treat today. That’s absolutely fantastic.
Ian’s interest is in mitochondria, which are the little power stations in every cell which generate energy to allow our cells to do work. And disorders of mitochondria lead to a lot of metabolic disorders which result in abnormalities and can result in disease and disablement for individuals.
Ian has worked closely on mitochondria and their role in Parkinson’s disease and has developed new techniques to look at how we can study this and also some work to develop a new pre-clinical drug in this area. And I think that is what he’s going to tell us today.
“Understanding the role of mitochondria in Parkinson’s Disease”. Welcome, Ian. Great. Well, thank you very much for the very kind introduction. And yeah, it’s a great pleasure to be here today and an honour to kind of tell you a little bit about the work that’s going on in my lab.
So by trade, I’m a cell biologist and I actually I really love this image. And it’s actually from a group in Australia. And what it is, it’s a little bit a little section of brain tissue and it’s been placed under the electron microscope, which is a really high powered microscope.
And this really allows us to look into the details of what’s inside the cell. And what they’ve done is that they’ve cured in just one cell that you can see here. What you realize is, the cell is packed full of all these weird and wonderful structures, and these are membrane compartments
Or organelles, and they allow the cell to do, perform specific functions. And I want to draw your attention to these structures here, these circular structures. These small structures, they’re about between one-, and two-millionth of a meter in diameter. So they’re very small and they’re called mitochondria.
And this is what my lab is interested in. So this is a bit of the basic schematic. And as you heard from Blair, they’re often known as the energy generating powerhouses of the cell. So what they do is, they take molecules that are derived from the food we eat;
They take oxygen derived from the air that we breathe, and they convert it into this molecule, ATP, which is kind of like the energy currency of the cell. So all these metabolic reactions that go on in our cells, they use ATP as the energy source.
But part of the problem of making ATP is, is that they also produce free radicals or reactive oxygen species. And these potentially can be quite damaging to various cellular components. And we also have another problem with mitochondria in that they can release this compound called cytochrome C and if mitochondria release this,
What happens is it’s kind of a suicide molecule and the cell dies. So normally this is not a problem. So how can you make ATP? There’s very little ROS produced and there’s no cytochrome C released. However, if mitochondria become damaged, which they do over time or under very stressful conditions,
There’s a risk of increased ROS production and increased cytochrome C release. And this can be very bad news for the cell because in the cell, if the cell doesn’t deal with it, this can lead to a kind of reactor meltdown. And if this persists over time, it leads to diseases, in particular, cancer.
And as I’ll talk about later, neurodegeneration and Parkinson’s disease. So this raises an interesting question. Well, you know, what does the cell do when mitochondria become damaged? It can do two main things. One, it can try and repair the mitochondria. Or two, it can either recycle it, it can degrade it,
Get rid of it, and make new ones or other things. And it’s this recycling pathway that my lab works on, and it’s called Mitophagy. And this is how I like to think of Mitophagy occurring in the cells: a little Pac-Man going around inside our cells, eating the mitochondria.
And as you see, actually this isn’t that far from the truth. So here’s a kind of basic diagram of our understanding of Mitophagy. So what happens is so, so damaged mitochondria, they release these signals and this leads to the formation of this cup-shaped membrane structure
Inside the cell and it grows and surrounds the mitochondria. So this is like the Pac-Man, so it engulfs the mitochondria and it surrounds it. And this structure is called an autophagosome. The autophagosome then fuses with another membrane compartment inside the cell, and this is the lysosome
And the llysosome is the equivalent of the stomach of the cell. It’s very acidic and it’s packed full of digestive enzymes. So when this happens, you know, the mitochondria get degraded. So because it’s known to get rid of these damaged mitochondria, it’s thought to be a cell protective mechanism.
And of course, if this protective mechanism fails, we think it can lead to disease. And in particular, we think that mitophagy might be important in Parkinson’s disease. Okay, so what’s Parkinson’s disease? I’m sure everybody’s heard about Parkinson’s disease. Well, actually, it’s the second most common neurodegenerative condition worldwide.
I mean, in Scotland alone at the moment, there are over 12,000 people living with Parkinson’s disease, so very important disease. And it has its classical symptoms, these kind of so-called motor symptoms, this rigidity and these tremors. But there’s also other symptoms such as depression, fatigue and indeed neurodegeneration and dementia.
So we don’t really understand the disease fully at all. But one major characteristic of the disease is that in the brain, a very specific population of cells die, and these are neurons that transmit these electric signals in the brain. And it’s a very individual population of cells, these so called dopaminergic neurons
That are involved in this movement and are located in the substantia nigra pars compacta. In simple terms, this is right in the middle of our brain. And these cells are very unusual in that each individual cell it in originates here in the middle and it sends out a structure called an axon.
And these cells, each individual cell with its axons, it can contact hundreds of thousands of other cells at the same time. So they’re thought to be amazingly complex cells and obviously require a lot of energy and ATP to function normally. So it’s an incurable disease.
And in fact, by the time these motor symptoms arise, 60 to 80% of these dopaminergic neurons are already gone. So we really need to understand this disease before this happens, because once these cells are gone, as far as we know, they don’t get replaced. And in fact, the last therapy,
The most successful therapy for Parkinson’s disease is levodopa. And this is made in 1967. And this only treats some of the symptoms, not the cause. So you still get your degeneration. So we don’t know what causes it, really, the both environmental and genetic factors. But we know that dysfunctional mitochondria,
A characteristic of this disease. I mean, early on in the eighties, it was found that this molecule can cause Parkinson’s disease. It’s actually quite a sad story. There was a chemist, I will say, who was trying to make synthetic heroin, and he actually sampled his own (…)
That he made and he developed Parkinson’s disease. And it turns out after an investigation, it was found that his prep of heroin was contaminated by this compound. And later on it was found that this compound goes very specifically to those dopaminergic neurons in the cells in the brain and kills the mitochondria.
But also recently, more recently, especially in the US, a lot of pesticides are used by these massive farms and one in particular paraquat – we know it inhibits mitochondrial function. And unfortunately a lot of the farmers that were using this pesticide, they develop Parkinson’s disease.
So there’s a lot of big lawsuits now going on in the US over this. So these are the kind of more environmental factors as I mentioned, a small percentage are genetic. And these are some of the genes that have been found mutated in various families.
And when these are mutated, it leads to Parkinson’s disease. But because, you know, we’ve identified these genes, we don’t really know what they do. And because we know that dysfunctional mitochondria are important in this disease, we think maybe that we know mitophagy, which recycling pathway that we work on.
If that fails, it leads to accumulation of dysfunctional mitochondria. So we have this idea that, well, maybe some of these Parkinson’s related genes are important in regulating mitophagy. So you know, when we started looking at this, we didn’t really know: Is Mitophagy going on physiologically?
Because in the past, by only being able to look at cells in isolation under very non physiological conditions, we can’t grow brains in a dish. We can’t really grow these specialized neurons in a dish. So it isn’t going on in these kinds of cells.
And if it is, how do we look at it? You know, this is an important question and if it is going on, is it disrupted in Parkinson’s disease and can we target it therapeutically? So to look at this first question, what we had to do
Is we had to devise a way to look at this under physiological conditions. And we decided to make a mouse model because this really is the only way at the moment we can do this. So what we did was we engineered a fluorescent mouse model that we’ve called mito-QC,
And what we did was we took these two proteins and mCherry and GFP and under the microscope, they glow, these proteins. So they glow red and they glow green. And what we did was we attached them to mitochondria. So when you look down the microscope,
They both fluoresce red and green, which overlaps to a yellow-y colour. But if you think of this mitophagy, this recycling pathway, it takes mitochondria to the lysosome, this acidic stomach of the cell and the acidity in the lysosome is actually quenches the green fluorescence, but not the red.
So what happens is when you get mitochondria that are being recycled, they switch to this red colour and is exactly what you see here. So this is actually in cell lines. Here’s the mitochondria. These are the ones that are being cycled. So the mice, they’re healthy and normal.
But this then allowed us to ask the question, is mitophagy going on in these clinically important cells? So what we did is we took samples of brain from these mice, from this midbrain, the substantia nigra pars compacta, and we can identify these neurons using a special stain.
So here you can see here is one such neuron here. And if you look, this is the axon that comes out and contacts all those hundreds of thousands of other cells. So what about the mitochondria? What about our fluorescent staining? So there’s actually a lot going on in this slide.
These are all different cell types that surround this neuron. But if you look at this neuron in isolation, what you can see is that, yes, indeed there is this recycling pathway mitophagy occurring in these neurons. So this is really exciting. The first time we’ve ever seen
This happening in these really important, clinically relevant cells. So, yes, Mitophagy is going on in these brain cells. Now we found a way that we can look at it – so is it disrupted in Parkinson’s disease? So we went back to the genetics and we started to look at these genes
That had been mutated in Parkinson’s disease. And we took one gene in particular this LRRK2 gene or ‘lerk two’ gene and we have a mouse model that has this gene mutated, the same mutation that causes Parkinson’s disease in humans. So what we did was we looked at Mitophagy now in this mouse model.
So you can see here, we looked in these dopaminergic neurons you can see here and these are healthy, we call them ‘wild type’ mice. These are healthy mice and these are the mutant mice that have this Parkinson’s disease causing mutation. And we simply counted the number of red dots in these neurons,
These mitochondria being recycled. And what you can see in the mutant Parkinson’s disease, mutant has actually less mitophagy. There are less mitochondria being recycled. So this fits with our idea that a failure to recycle mitochondria leads to the accumulation of damaged mitochondria and eventually Parkinson’s disease.
But we’re lucky in that we were able to collaborate with a pharmaceutical company, GlaxoSmithKline, and they’ve been developing medicines that we can specifically target LRRK2. And so what we did is, we collaborated and we got hold of that medicine, that small molecule drug
And we gave it to the mice and asked, can this rescue this mitophagy effect? And indeed it can. I mean, particularly if you look at the mutant mice, when there is less mitophagy going on, when we add this drug in Inhb, we see it rescues the mitophagy level back to the level
Of the healthy mice. So this, you know, we were really excited about this. So we can say that mitophagy or mitochondrial cycle is disrupted in brains related to Parkinson’s disease and we can target it therapeutically with a small molecule drug. So you know what we found
Is that it’s actually the most common mutation found in Parkinson’s disease. It disrupts this mitophagy, this mitochondrial recycling pathway in these really clinically relevant cells, but we can rescue it with a small molecule drug. So this is exciting. It suggests that these LRRK2 inhibitors, they really could be a good therapeutic
Approach to enhance mitophagy and treat Parkinson’s disease. And indeed there are now drugs targeting LRRK2 on the clinical trials. So we actually published this paper recently and it’s open access. So if anybody’s interested, they can go and access this online and read it. But of course now
You know, we’re interested: What about these are the genes? Excitingly, there are other groups that have found related genes also appear to affect this mitochondrial recycling. So we’re very much interested now in, well, one of the nuts and bolts of this reactions, how do they occur molecularly?
Are there any the other targets we could use our drugs against? But I think what’s kind of building up now is a picture that maybe this recycling mitophagy pathway, it might be a common pathway perturbed in Parkinson’s disease, but it also might be a common pathway we can take advantage of therapeutically.
And with that, I would like to finish. I think I’m still on time and I’d just like to acknowledge my fantastic lab who without with, I wouldn’t have been able to get this work. They really have made everything possible. And of course, you know, the collaborators here,
And the people from the research and GlaxoSmithKline. And with that, thank you very much for listening. [The introduction of Dr Sucharita Kanjappa was unfortunately not recorded due to technical difficulties. We apologise for the inconvenience] Thank you, Blair, and thank you all for being here today.
So the reason I chose the “Slightly Low Tech solutions” is almost in reaction to the award I got for innovation in teaching, because in my mind, innovation is all about technology and advances in technology. And unfortunately I’m a bit of a slow adopter of new technologies.
But it was very reassuring for me to see that my students appreciated this and put me forward for this particular award. So what I want to do today is actually share some of the techniques that we use in the dental school. So learning happens as the result of this interaction between
The learner, the learning environment and the learning activities. So I have a few examples to just show you what we do in the dental school to help our learners get the best of out of what we’d like them to do. So the very first one is about creation of a safe environment.
And for me this really underpins everything else -because a safe environment, we require a safe environment in order for students to really engage with the activity. And I’m talking not about the physical safe environment, and that’s really important, but the psychological safe space that the students need.
So this makes them feel safe to engage, to express their thoughts or to ask questions, make mistakes if they have to and learn from those mistakes. So all of these things. But what I also found that it doesn’t take much to do this. So just listening to our students and then feeding back
Or responding in a way that’s nonjudgmental is basically what it is. So I just have some slides from during lockdown when we did teaching online to see how powerful this is with students. So this was our first year dental students and by the end of the session I had hearts
And seeing that they loved the session, I don’t think I’ll see that ever again. But this was this was lovely. So the next thing I want to share is a learning activity. And this one’s based on a theatre technique. So we use this to teach complex communication skills
Like breaking bad news and handling the aggressive patient. So this is based on a technique called Forum Theatre, and we involve the students right from the start. So we get our student reps to make these posters, almost like going to the theatre kind of posters and put them up in areas that students
Frequent, build up a little bit of excitement and curiosity about what the session is going to be – also ensures that the students then attend the session, they want to know what’s going to happen there. So what the session is that is we have two professional actors,
The ones that you see on the stage there in that picture, and we give them a scenario based on one of these topics and it plays out that the person playing the dentist handles the situation really badly. So the scenario goes really downhill, really quickly and ends badly. So we run this through.
The students watch this, they have an opportunity to make their notes and then the facilitators have a discussion with the students. What did they see? What went wrong? What might they do differently? And then we run through this the second time. But this time the students are almost directors of this interaction,
So they are told that they can stop this interaction the minute they see something’s going wrong and then they can see what they think should happen to make this go better. That worked really, really well and also, the students realized there is not one
Right answer for these things – because lots of times they’re looking at us for us to provide this one solution to everything. But now they realize there’s lots of different ways with dealing with the same situation, and most times they have the answer. So the facilitators were there just to help them realise,
You know, what the thing is. But it’s the students that do all the hard work here. And we did a formal evaluation of this, and not surprisingly, students like this better than a standard lecture. But they also really learned a lot from this. They really they felt that it made them think.
They also appreciated hearing from the other students. Like one of my students said: she felt like she almost had an arsenal of communication skills handy that she could pick out in different situations and use when needed. It also suited different learning styles so students could sit back and observe
And see what was happening and what it looked like there. And we concluded that this has actually really contributed to their confidence and skills. So if you want a little bit more, we’ve published this in the journal European Journal of Dental Education. So the next example is around..
– So I teach communication skills and although extremely important, a lot of times it’s just, you know, common , certain things that we already know. And sometimes for the students when it’s simple, it’s almost unimportant. So we like to get the students to realize for themselves how important these things are.
So both communication skills and things like dental public health. So what we do in year one is get our students in groups and go out and speak to members of the wider community. So it’s not any kind of story, but actually just to chat with people and they talk about things like what
People think about their own oral health, what are their attitudes towards it, what do they expect from the dentist when they visit, what what’s the importance of communication with the dentist? They had experiences around this and also their journey to the dentist. What’s the experience been around
Accessing an actual experience while being at the dentist? So they come away with really, really lots of good insights and lots of things that then they carry forward right through the journey. So like some of the quotes I have here is that thinking about,
You know, the different experiences that people might have, different perspectives, different expectations when they come to the dentist. And also, you know, they realize the importance of things like communication skills and teamworking. What the students do is then share their experiences with the wider group.
So there’s this element of peer to peer learning that goes on. And in my final example, this is something that we do with our fourth year dental students. So it’s a five year course and in the fourth year we engage or we send them out to engage with some community groups.
So various organisations such as Wellbeing Works or the Scottish Prisons Service, even so, it’s people with experiencing mental health challenges or learning difficulties or experiencing homelessness. Young mothers, pregnant teenagers, international women, you know, migrant women. So lots of different organizations, communities or groups that the students may not encounter in the student clinics.
But it’s really important for them to realize that lots of dental or oral health inequalities exist in the community and how they can they can help as professionals. So students go and speak to these different people and find out from them what their challenges are around oral health, you know, challenges to obtaining
Good oral health or maintaining good oral health or anything around this. And then they’re tasked with coming up with some kind of a solution tailored to a specific group and a specific problem. So here’s kind of – I’m not doing real justice to the brilliant ideas
That my students have come up with but here are just some of them. So, for example, this particular one here was targeted at people who were anxious about going to the dentist, but their anxiety was more about the anxiety of the unknown.
So it was they don’t know what they’re going into and what it entails. So they came up with this little comic book like strip talking about exactly what happens and talking them through this process. I also had students that made posters and leaflets and things like that
To increase awareness about things like maybe brushing techniques. We also had videos on how to brush your teeth properly. We also had – luckily students are more fluent in technologies like I am – so we had things like an interactive smartphone app to help pregnant mothers look after their teeth during their pregnancy.
So lots of really, really good ideas from the students. Well, we also prepare the students before they go in to speak to these groups because they going in again to unknown situations. And we used tools taken from service design and these are called empathy maps and journey maps.
So the empathy map is about putting yourself in that person’s shoes and thinking about things that what does that person feel? What did they see? What did they hear? What are their worries? What are their aspirations? Someone was building this this picture up. We also use the journey maps for students to start
Thinking about what does the journey to the dentist look like. So from identifying the dentist, maybe making that appointment and then landing in that dental chair. So thinking about the various obstacles that they might face on the way and they all come up with lots of different, different variations.
And this is just one of the examples. We also try and get the students to do this before and after. So there’s again, you know, there’s preconceptions that they have about the group they’re going to meet, and then once they go chat with the people, come back, they have some different ideas.
So again, this seems to have worked really well. The students enjoy this activity and get a lot from it. And like I said, it also addresses a lot of the preconceptions or like this person has said, they were surprised to discover that many homeless people, despite the challenges
They encounter in day to day life, could greatly about their oral health and are keen to find out what they can do to improve it. So they make this effort to make sure that every person that comes to them
After that for care that they able to help them and go out of their way to do this. But it was also good that the organizations also got something from this. So the organizations are happy to have the students there and they feel their participants feel appreciated.
They like that their opinions and what they see is taken into consideration. And these students are actually going to address this. Again, they encourage that we continue with this kind of activity. So this actually has got quite a lot of press. And we’ve also have the Oral Health Foundation, which is a charity
In England, to sponsors a prize to the students that come up with the most kind of innovative ideas. So adds a little bit of extra excitement towards the students. So this is it. So I think the result is really engaged students to have this environment that develops learning and they’re able
To critically analyze situations, able to take the initiative, be reflective, I think. So just before I finish, just to say a big thank you to all my colleagues in the dental school who support this teaching and also to the late Professor Freeman, whose ideas got us into all the different ways of teaching.
So thank you. Thank you very much. Thank you, Suchi for such fantastic talk. And it’s great to see the way in which you’ve managed to take your dental public health message out to marginalized communities, but also engage your students so impressively with those communities and get great feedback from both in the process.
So well done. And it’s absolutely no surprise that you won the award. You did fantastic work. So I’m pleased now to invite our final speaker of this session, Professor Pete Hoskins, who’s our chair Biomedical Engineering, to give a talk. Pete’s in the School of Science and Engineering and has worked
In either the NHS or in universities for the last 40 years. He’s a medical physicist with an interest in ultrasound and he’s going to give us a talk today on that. I mean, reading through your bio, Pete, it’s pretty impressive. He’s got four degrees. Who has got four degrees?
That’s just what, at least two too many. He’s published an impressive number of papers and has published major textbooks in his field, making sure that the dissemination of this knowledge out into the community, into the health community, is done. And he’s published a major textbook in diagnostic ultrasound in cardiovascular biomechanics,
Because ultrasound in the cardiovascular system is really Perte’s specialty. He’s going to talk to us today on his specialty, and he’s got 15 minutes to talk to us about quantification and diagnostic ultrasound. Welcome, Pete. Thank you Blair and good afternoon everybody, including those online.
So what I’m going to do is I’m going to run through some highlights of my research over the last 20 years, and we’re going to talk about the opportunities that there are in the University. So this is an ultrasound system just here, as you can see.
And this is Karen, and she’s undertaken an ultrasound examination of this patient. And you’ll see the transducer that she’s holding. It’s been pressed against the skin, the transducer is generating ultrasound waves which pass into the patient, and then an image is formed, which you can see on the screen at the top there.
So what you’re looking at the screen is this patient’s artery. And he’s obviously got a problem with circulation in his legs. And so this is an ultrasound examination of the arteries in the leg. So let’s talk a little bit about one of the diseases of arteries – this is atherosclerosis.
Everybody here has got some version of atherosclerosis, hopefully relatively minor. It’s a worldwide condition and it’s associated with fair enough of the arteries, which you can see just here. And this is a kind of microscopic examination of a carotid plaque. This is the disease in the carotid artery.
And if that plaque ruptures, then the contents will spill downstream, which leads to the clinical events such as heart attack, if it’s in the coronary arteries or stroke, if it’s an effect in the brain. So a lot of attention is paid both in clinical diagnosis, clinical therapy and in research in this area.
So this is a typical ultrasound examination of the carotid artery. And what’s happening now is that the transducer has been pressed against the neck. The carotid arteries supply the brain. And what we have here in grayscale is the B mode image, which is looking at the tissue structure.
The disease is around about here somewhere. The color is a color flow image. Where we are looking at blood flow in the carotid artery here and then you will see at the top – the operator has got this line coming down and he’s taken these blood velocity waveforms
From this particular location within the carotid artery. So here the blood velocity waveforms and outlined in blue is the maximum velocity. So as a result of this examination, what the operators try to get is a measurement of the peak systolic velocity, the peak blood velocity within the carotid artery.
So that’s this number which are round in red. So the peak systolic velocity in this case it reads here 184 centilitres a second. So now going across to this table, we’ve got velocity on the left hand side and the percent stenosis. So this is the degree of
The diameter of the vessel which is being occluded by the disease. And we can read across here. So this this patient has got a stenosis of 50 to 69% Had this patient had is notice of more than 70, that would have been considered the carotid surgery,
Not just this number of other forms of clinical evidence as well. But the point I’d like you to gather from this is that as a result of this examination, that numbers are being generated and this is in this case, this is a physical measurement of blood velocity.
And these numbers are being used to inform decisions on treatment. So I’m a physicist, but physicists care a lot about errors. And so the next slide is concerned with looking at errors in the measurement of blood velocity using an ultrasound system. So on the left here we’ve got a string phantom,
And this is exactly what it sounds like. There’s a piece of string being driven around the loop here at a known constant velocity. And then in the middle we’ve got the ultrasound examination of this string. Here’s the string just here so we can make measurements of the velocity of the string
And then compare that against the true velocity to get this data. So the true velocity is 0.61 meters per second. And this is the measured velocity. You might be surprised that this velocity is in error, often by quite a lot. 20, 30, 40%.
Just bear that in mind and we’ll come back to that and I’ll round up the kind of whys of all of this in a couple of slides time. Right. So the next thing we need to know is that the blood flow patterns in arteries are generally complex.
If you read the textbooks, especially the relatively simple textbooks, they’ll describe blood traveling in straight lines parallel to the vessel wall. That does happen a bit, here you can see in the carotid artery, the flow is highly complex. So this is a region of
This is the internal carotid artery where you get a lot of disease and this flow going all over the place just here. So for a true characterization of blood flow, we need three spatial components: X, Y, and Z, three velocity components: the X, the Y, and Z,
And one time that’s seven components in our 7D flow. That’s what we ideally need to describe complex blood flow. Let’s have a look at how ultrasound does in this regard. So having a blood velocity white forms on the left hand side just here.
So these come from a relatively small area within the artery. So that’s zero components. There is only one velocity component actually being measured in the line of the beam. And I’ll talk about that in more detail in a minute; and time. So we got two components for spectral Doppler. Looking at color flow.
We’ve now got a 2D map of flow. So that’s two spatial components, one velocity component and time. So we’ve gone up from 2 to 4 D and it’s not seven D, So let’s just stop for a second and have a look at what the drivers and opportunities are.
So first of all, we need better diagnosis of disease. One of my vascular surgery colleagues told me many years ago that ten operations are performed to prevent one stroke. So anything that can improve those numbers is going to be helpful. So concerning diagnosis and the use of ultrasound,
Physical measurements are being made, but velocity is one. Others could be made, such as volume flow and especially wall shear stress. And wall shear stress is a very, very important quantity. It’s concerned with the way that the blood creates a viscous force on the arterial wall.
And this viscous force is known to be associated with initiation of the disease, progression of disease and rupture of the plaque. So if you can find good, efficient ways of measuring this quantity, then that hopefully will help. And finally, accuracy. We need methods to validate measurements which are called phantoms
And we need improved technology and ultimately we need to measure 7D flow. So for the last 20 or so years, my research has been divided into three areas associated with that type of approach. First of all, the development of testing devices called phantoms. Secondly, use of those phantoms to look at error measurements
And then new and improved measurement methods – all around the idea of underpinning the science for clinical applications and improving those clinical applications. So let’s have a look at some of the improvements in technology. On the left hand side, we have conventional Doppler ultrasound.
This is the transducer just here and the transducer operates in a transmit mode. It transmits a beam and then a receiver motor receives a beam, and in this case the transmit and the receive is along the same beam direction, measuring just one velocity component that along the beam direction.
So here is a typical conventional Doppler ultrasound just using a single beam with a single spectral doppler trace. On the other side, we have our vector Doppler system where we’ve now got a single transmit that was split in the aperture into two to receive two beams.
So we’ve now got two velocity components and with a very simple little bit of maths, these can be combined so that the velocity magnitude and the direction are estimated automatically. And this is some of the data using a prototype vector Doppler system,
Which we got from one of the manufacturers and we’re using a phantom here. So this is I’ll talk about phantoms in a second. This is a, a phantom, which is a mockup of a disease. You can see the narrowed segment just here with some waveforms.
We’re going to measure the velocity of these waveforms. And in the middle, we’ve got the conventional single beam Doppler system and the true velocities are shown as a line. And in all cases, the Doppler system is overestimating these velocities, as you can see, often by large amounts.
So the same experimental setup using our dual vector Doppler system. This time the measurements are quite tightly contained and they’re all around about the right value. So use of this two beam system is vastly increasing the accuracy of the measurement. So that certainly helps moving on a few years.
This is data from Yang, who’s currently based in Shanghai, writing up his PhD, and he’s making measurements of wall shear stress, as we can see. So this is using a vector Doppler system. Again, we’ve got phantoms here then used to undertake the validation. Velocity measurements in the middle with the little arrows
Showing the velocity direction and the wall shear stress values being shown here, showing that this type of technology can make these measurements and hopefully will go on to make these measurements in patients. So this is wall shear stress, which I said was associated with the initiation development of disease and plaque rupture.
So I’ve talked about the need to measure 7D flow and computation of fluid dynamics is a fantastically powerful tool for measuring 7D flow. And the way this works is that you need 3D data set, you need 3D geometries of the arteries, and in this case
We’re going to collect this data using ultrasound and what we’ve got is our ultrasound scanner. We’ve got a transducer just here. And you can see with attached this little thing here to the transducer and this has got light emitting diodes on which have been trapped in space by this camera.
And so as the transducer is moved along the artery, so the camera knows exactly where the transducer is and can build up a 3D dataset consisting of lots of 2D slices. So this is exactly what you’re looking at here. You can have a 3D data set as the transducer is being gradually
Moved along the carotid artery, going from the common carotid artery through into the bifurcation where the disease is, can see the disease just here and then into the internal and external carotid arteries. So we get our 3D dataset. This goes through an image processing technique to segment the data and mesh the data.
And then this is passed to a computational fluid dynamics solver in a computer which will calculate these velocity streamlines, the velocity profiles and the wall shear stress. So this is that 7D data that we need. So now moving on to phantoms, the Phantom is used for validation of ultrasound measurements.
And this is a typical phantom as it’s used in the lab. We’ve got this kind of gray agar-based tissue mimic just here with a channel running through it, the transducer is held in a retort standing clamp just here. And we’ve got this picture up here, which I’ve already shown,
And this is a phantom of a diseased vessel with white foams just here. So the Phantom typically consists of three different components: a tissue mimic, a blood mimic and a vessel mimic. And these need to have very similar properties to the acoustic properties of tissues in humans.
So these specific properties that need to be mimicked were specified by an organization called the International Electrotechnical Commission some time ago, and this is the density, the speed of sound, the attenuation coefficient and the viscosity. So my lab has spent a lot of effort making tissue mimics, blood
Mimics and vessel mimics which have got the correct physical properties. So it started on the left hand side, the original agar-based tissue, and because you can see it’s relatively weak and it splits very, very easily. Now this is a problem if the vessel is quite close to the surface
Or if the anatomy is complex, the fountain will rupture. So we spent some time developing a much stronger material based on conjac carrageenan. And these are chemicals used in the food industry. And as you can see, it’s not splitting in the middle. We’ve got blood mimic and this is the White blood mimic
That we developed based upon nylon particles as used in the paint industry. And this has become the international standard blood mimic used all over the world. And on the right hand side, we’ve got a vessel mimic just here. This is this grey material in this grey pipe which is embedded
In this yellow tissue in just here. And we’re interested in the motion of the tissue. As you can see, the vessel mimic is here just pulsating nicely as an artery would do in the living body. So Phantom design, the easiest phantoms to make flow phantoms is to make straight tube phantoms.
But as we’ve seen flow in arteries can be very complex. So what we’d ideally like to do is to make phantoms, which have got complex geometries, and this comes from a collaboration we had with Liverpool University and they used what was then called rapid prototyping.
The phrase 3D printing now has become to encompass a lot of that. It was known as rapid prototyping at that time. So we start off with a solid model, an idealized CAD file on the left hand side which have been taken using MRI and then idealized.
This goes through a stereolithography process to make this solid model at the top. This then gets incorporated into a silicon mould to make the mould, to make the silicone mould. Once the silicone mould is made, you need to pour a low melting point
Alloy into the mould, let that set, take it out, polish it up, put it in the box, pour in the tissue mimic, let the tissue mimic set, melt out the low melting point alloy. You’re left with a channel through the tissue mimic, which has got the proper carotid geometry.
And as you can see here, just wait for it to go round. So going from the common carotid through into the internal and external, and if you look closely, you can see this is pulsating, This is being driven by pulsatile flow. And this is typical. This pulsatile motion is typical.
Typically what you get in carotid artery generally. Even though this was published 15 years ago, this remains the best work to date in the area. So what the next step would be to take a 3D printer and to directly 3D print all of this. But this still remains my main of research, really.
So quick summary of my research with the opportunities for Dundee. This is Colin Murdoch. Colin Murdoch has just got a big grant 390,000 awarded from the MRC to purchase a Vivo 2 ultrasound scanner for pre-clinical use. And this is for scanning in mice and rats.
And the technical co-investigators are myself and George Corner upon this. And what we want to do is we want to develop an engineering team to run in parallel to the application team, to develop some of the technologies that I’ve talked about and more. I’ve only got 15 minutes today.
And in order to do that, we asked Colin if he would include within that grant application £35,000 for this research package called VADA. And this allows for programming of the ultrasound system so we can program the beam from inside and processing of the received data. So this is incredibly powerful.
It allows us to do things that an average ultrasound machine just cannot do. So there’s a fantastic opportunity for Dundee University there and over the next few years, Charles and I hope to set up and run the engineering team. So that concludes my talk.
I’d like to acknowledge Professor Zehong Huang for continuing support and as Blair said, I also wrote books, so thank you very much. So can I ask our three speakers now to have a seat at the front. They can encourage everyone to think up their questions, particularly the people online.
If you ask those questions, they will come to us hopefully via the chat. And if you’ve got a question, please put your hand up. One, either Shabnam or Rachael will come up and will hand you a microphone. Please don’t speak until you’ve got the microphone, because then otherwise people online can’t hear you.
So questions, please. Yes. At the back there, thank you very much. Question for Ian. Fantastic talk by the way. Have you got any ideas how you can deliver these drugs to the centre of the brain? Well, at the moment the drugs for example, these, these look LRRK2 inhibitors, they’re actually taken orally,
But you can use the tablets and they just diffuse into the blood and they pass the brain barrier and go in and affect those cells. So we think they may affect every cell in our body, but because it’s really disrupted in the dopaminergic neurons, we think that they’ll get the most benefit.
And in general, we think it’s a good thing to enhance this recycling process in our body because we know over time and age, the recycling tends to go down. So we think it’s probably a good way anyway to live a healthy life.
But yet we’re quite lucky in this sense in that we don’t need, we don’t think we need to specifically target it into the brain, just by taking the drug, it will get to those cells that need it. Thank you. If I could ask Peter question, I’ve got a question about the measurement
Of blood flow, particularly around the bifurcation of the carotid artery. You spoke a lot about the fact that blood flow is not, as you’d say, governed by precise law, laminar flow through perfect tubes. It’s actually quite disturbed and disrupted. What is it about the flow around
That bifurcation that actually causes the plaques to form in the first place? Is that known? Is it disrupted blood flow? Well, concerning the carotid artery, the carotid artery has got this whole area where the pressure sensors are. There’s what’s called a carotid bulb. So it’s unusual in terms of human anatomy.
And what that creates is a region where the wall shear stress is low. So you can often get a bit of recirculating flow in that region. And it’s the low wall shear stress which drives the disease, which is why if you get atherosclerosis,
You often get it in the carotid artery in that region. So the carotid artery is very unusual in that, but. It’s really down to the little anatomy that causes that. In that particular area, combined with poor lifestyle choices. Lots of other things. Yeah, absolutely. Other questions, yes, at the front here. Hi.
Thanks for the really interesting talks. I have a question for Ian. So there are three branches where the mitophagy like the mitochondrial disease contributes to. And there’s one branch that you didn’t talk about as much, which is aging. So I just wondered if Mitophagy would be a solution to delay aging.
And because Parkinson’s is also a disease of aging of some sorts. And also the second question is, is that something that you were researching in your lab? So yeah, I mean, that’s a great question. And definitely , we think it is associated with increased, you know, if you can’t do this process,
We think this accelerates this aging phenotype. I mean and one thing so a lot of experiments have been done in in fruit flies or Drosophila and C. elegans, which is experimental worms. And these are kind of quite easy to knock out this recycling pathway or enhance it.
And so for a long time and even now, when you think about dieting and all the rage, this caloric restriction, you know, if you limit your dieting, you live longer and they’ve shown this in these flies. If they kind of starved and give them a very meager diet,
What happens is this recycling pathways, they get enhanced. And if you block this recycling pathway, then the animals, they die sooner. And there’s some evidence that this actually may be happening in humans as well. So we think this recycling pathway, it basically gets rid of all the junk,
You know, the junk mitochondria that accumulate. It helps clear them because when they’re around these ones that aren’t functioning properly, they’re releasing these free radicals and things which slowly damage other components of the cell. So everything starts to kind of not work as well as it did; generally increases this aging phenotype.
So we think it is very important. I mean, we’re very much interested in the basic mechanisms, you know, about it, and it will have relevance for aging. And Shabnam, before I bring Mike in, who wants to ask the next question, maybe you can give him the mic.
I just ask Ian, is anything known about the effectiveness of or the rate of mitophagy as, for example, mice age from zero to an old mice, which would be around two and a half or three; in people seem to slow down. And it’s that slowing down of mitophagy,
You know, linked to the genes that you’ve identified here. And are there mutations that accelerate it, decrease the rate of mitophagy? So this is this is a kind of common hypothesis that we have that. Overall this process, it slows down as we age. You know, things don’t start to work as efficiently.
But because we’ve actually developed these mouse models now, we can actually look at it experimentally. And it’s strange actually in some tissues in cell types, it does go down as in age, but in others, it goes up. We don’t fully understand that, is it because there’s more damage as we age
And therefore this process increases? I mean, it’s much more complicated, I think, and we don’t fully understand it yet. But the overall idea is that these processes do slow down with age. And this leads to the accumulation of these dysfunctional mitochondria. Thank you very much. Mike?
You know, I think just to firr off the last two questions, because Ian and I have been exchanging emails over the New Year period, I think we have a fantastic opportunity here at the University of Dundee to take your beautiful Mitophagy assay, which is outstanding
And using our own chemical libraries and our drug discovery. Find our own start points, find the targets which are different from LRRK2 and get some really original intellectual property on mitophagy enhancers, which create a fantastic spin out company. So I’m really keen. Exactly.
You know, I mean, you know, as Mike said, the molecular and nuts and bolts of these pathways, we don’t fully understand it yet, you know. So I think there’s a lot of kind of space here to identify new therapeutic targets. You know,
I think it’s going to be important not just for Parkinson’s disease, but also potentially cancer and other neurodegenerative disorders. So I think there’s a lot of scope here for making… …a route to immortality, as well … Yes, question there. Hi, I really liked your talk, Suchi, it’s really, really interesting.
Have you shared these kind of techniques with the medical school? Are you collaborating and sharing it more widely across the sector too? let’s say see with education and social work as well, because it can be really, as you say, simple methods to have really, really big impacts. Yeah.
As now we haven’t really done anything with the other schools, but I’d be open for collaborating with if you feel interested, or with any of the other schools because yes, it is really quite straightforward techniques but they are really effective. We’d be happy to collaborate. Thank you.
Yes. Question here, Rachael, we’ll just give you the microphone, if that’s okay. Yes, thank you. I was very impressed with you of the tech used to engage learning and I thought this has application for the training of many professionals, including politicians and those engaged in international relations or in pastoral ministries too,
And counsellors. And there’s so much there that could be of use. And I wondered if Dundee University could carry this forward to these some of these methods. Thank you for that. Yeah, we’re very happy to collaborate with anyone who wants and use these techniques for lots of different teaching.
I think it would be applicable. Very happy to chat further if you want to discuss how we might actually do this. What we want to do in the next year is develop an education academy within the University where we will have a focus on sharing best practice across the University.
Exactly the sort of thing that Suchi has spoken about today so that we have a showcase for people to see what we do in different parts of the University. Because there is a tendency, as we were working our schools, to sometimes be a little bit siloed,
Although we have heard very good examples of cross collaboration from Mike MacDonald in the previous session between Science and Engineering, Life Sciences and Medicine, it does happen, but it can sometimes become a little bit siloed. So the point you make of
Sharing good practice is a good one and we need to do that more. Thank you very much. Any other questions? Any online? None so far. Anyone else? Yes. Please, here. Hi, I got a question for Professor Ganley. Is there any relationship in the aging process between a degradation in mitochondrial recycling
And the shortening of telomeres in cells? So yeah, that. If you want to explain what the shortening of telomeres mean and when it occurs? So so telomeres, these are the ends of chromosomes. So in the way, you know, when a cell divides, you know, it needs to replicate its chromosomes.
But it has a problem because when it gets to the end of the chromosomes, it can’t easily at the replication machinery can’t easily come off and recycle. So what happens is, as you age, as the cells divide the chromosomes, they get smaller. And so we have these telomeres at the end
Which are designed to buffer this, you know, the chromosomes getting smaller because obviously if they get too small, then you lose genetic information. So I think with Parkinson’s disease, it occurs in cells that no longer divide. So they’re not really replicating that chromosomal DNA anymore kind of thing. They keep it there.
So it’s probably, in this instance, it’s probably less of a problem, but it may have been affected because there are certain defects that affect telomere length. And I don’t think there’s any evidence to suggest that those are predisposed to neurodegeneration those conditions. But it’s possible. It’s possible. Any other questions from the audience?
No. Okay. Well, it remains for me to thank our three speakers today Ian, Suchi and Pete for three absolutely fantastic talks to thank you, our audience, for listening diligently and for asking excellent questions. I think – have we tea and coffee now?
We’ve tea and coffee outside and we return for the next session at 3.15pm. So thank you, everybody.