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AMRF recently held its 2022 Research Awards Event. This was a moment to recognise the excellent young and emerging researchers receiving AMRF funding over the year. It was also a chance for their family, friends, colleagues, whānau and AMRF stakeholders and donors to see what their donations can achieve to move research forward. One story in particular stood out at the recent event. Elaijah Tuivaiti and Hemi Young are both budding 21 year old med students, having just finished their second year of study towards their MBChB degrees at the University of Auckland. Hemi and Elai both received a scholarship to Dilworth School, and have remained in the same class for almost the past decade. Originally, Hemi is from Pukenui, a small place north of Kaitaia, in the far North and Elai is from Ōtāhuhu, the isthmus defined as the entrance to South Auckland. Hemi and Elai are passionate about addressing inequalities and inequities, having grown up being surrounded by them. They were fortunate enough to have the opportunity to do a summer studentship after their pre-medicine year with the Kidz First Team supervised under Prof Shanthi Ameratunga and Dr Braden Te Ao. Their research on the project of "Achieving Pae Ora for Children Surviving Injury: A Call To Action" investigates injury hospital presentation of tamariki, and their access to services, rehabilitation, and recovery post-hospitalisation. Currently, ACC figures show inequities in post-hospitalisation funding for injury, as certain populations have lower funding despite higher rates of presentation. "This begs the question, are we treating our tamariki equally or equitably?" "Our review shows the lack of research surrounding this topic. This neglect on this topic allows for the neglect of these tamariki. A classic saying is "No stats, no problem", and it seems to be the issue here, where there can be no perceived problem if there are no statistics to show for it." Hemi and Elai were awarded the 2022 AMRF Best Oral Presentation in Population Health Research at the recent Te Whatu Ora Counties Manukau 2022 Research Week. They say, "This award means a lot to us and will significantly aid us in our careers. Being young students in med school, we know that this funding will unlock opportunities that would not have otherwise been possible. By increasing and unlocking accessibility to conferences for us, we can learn, connect, and flourish in this area of medicine and health that we enjoy so much." Congratulations to all the AMRF award recipients in 2022, listed here with photos of the event below.

Q: How can a 1951 MG help drive improvements in health? A: When the proceeds from its sale are donated to fund medical research. At Auckland Medical Research Foundation, we thought all our Christmases had come at once when Noel and Heather Davies told us they were donating half of the monies received from the sale of their treasured 1951 MG car. When we looked back through the 1950s, the decade of origin of this gleaming blue beauty, it was an incredibly important era. Auckland Medical Research Foundation was founded in 1955 and it was a decade of medical innovations. To name just a few: New Zealand’s very own cardiothoracic surgeon, Sir Brian Barratt-Boyes, pioneered the development of the cardiopulmonary bypass Cliff Hart created New Zealand’s first portable X-ray service The first kidney dialysis machine was trialed and first kidney transplant performed A “stopped heart” operation executed successfully The polio vaccine was developed It is so heartening to see how far we have travelled from the medical discoveries made in that era and the continued improvements to our health and quality of life we now enjoy because of medical research begun decades ago. This wonderful act of generosity from Noel and Heather will help to support our researchers’ ongoing journeys and we would be immensely grateful if you could share the auction details with all of your family, friends and networks. Help us drive future medical breakthroughs.

This Science and the Healthier Heart presentation by Professor Julian Paton PhD FRSCNZ, Manaaki Manawa, Centre for Heart Research, Medical and Health Sciences, The University of Auckland addresses the latest research into understanding and treatments for heart disease. Watch the video and read the transcript of Prof Paton below and keep watching for more heart health research from Dr Nikki Earle. First of all I'd like to start by thanking the Auckland Medical Research Foundation for this fantastic opportunity to talk about my research. It gives me a great pleasure to share what we're doing in terms of heart research. The title of my presentation “At the Heart of Research: From giraffe and metronomes to 3D printers” and that title will become obvious as we go through the presentation. I want to start off by telling you a little bit about cardiovascular disease in New Zealand. I think most of us know of somebody with cardiovascular disease and the consequences of that particular disease. In New Zealand we have about one death every 90 minutes from cardiovascular disease and that means one in three deaths in our country is caused by cardiovascular disease. The mortality in our Māori population is at least twice that of our non-Māori population and that presents an unacceptable inequity and that's something we'd really like to resolve. Currently there is no treatment for heart failure which of course is a major goal and aspiration of what we're trying to do here at the University of Auckland. So how do we go about doing that? To resolve that we have set up a new Heart Research Centre established in July 2019 called Manaaki Manawa. This is the Centre for Heart Research located and hosted at the Faculty of Medical and Health Sciences at The University of Auckland. I want to give a big shout out to our fantastic Research Operations Manager Lisa Wong, who together with myself directs Manaaki Manawa, and has played a vital role for mobilising this new Heart Research Centre. I'm just going to spend a little bit of time telling you about the centre before I explain some of the exciting research that's going on. The mission for Manaaki Manawa is “in partnership with Māori and Pacific People, create a vibrant world-class centre for heart research underpinned by evidenced based and multi-disciplinary research that delivers clinical benefits and equity to all in Aotearoa New Zealand”. One aspect of that mission statement is the multidisciplinarity and that's quite unique because for the first time under our centre we've been able to bring together researchers from different avenues. Classically these researchers have always worked in silos and so we've gone around breaking down the silos and throwing everyone into the same mix. We have clinical scientists, biomedical scientists, epidemiologists, analytical scientists, bioengineering scientists, biomarker scientists and genomics scientists all working under the same roof together with our Māori and Pacific cardiovascular researchers. We are fully integrated into a multi-disciplinary approach to resolving some of the issues around cardiovascular disease inequity in New Zealand. This gives us an enormous strength. Manaaki Manawa actually stands for “preserving the life force of the heart” and that name was gifted to us by Dame Naida Glavish. I'm going to tell you a little bit now about some of the exciting research that we're doing and I'm going to block this into three compartments. I'm going to talk to you about a silent killer, then listening to nature, and growing your heart valve. These are three examples of some of the research that we're currently doing. I'm going to start with high blood pressure which is a leading risk factor for death and disability in New Zealand. Around 20 percent of the population in New Zealand have high blood pressure which is similar in other countries globally. As you may know it's asymptomatic - it has no symptoms. Unfortunately it's 32 percent higher in our Māori population and remarkably 50% of the hypertension in our communities can be prevented. It is indeed a modifiable risk factor. Let me talk a little bit about risk factors. I think the first thing to say and, as you can see below from this plot of blood pressure against age, is that blood pressure rises as you become older. As blood pressure rises it does indeed contribute to increasing the risk of a cardiovascular event such as stroke, a heart attack or heart failure, renal failure and can worsen diabetes. Now this risk obviously increases with age because blood pressure has increased and high blood pressure is a risk factor for these comorbidities. However, if you also smoke or drink excessive alcohol, are overweight, you lead a sedentary lifestyle, you have a high cholesterol or have a high salt intake, and/or have a family history this further increases your risk of a cardiovascular event. That's the epidemiological evidence for cardiovascular events and it's really now a matter of trying to understand what we can do about this. Firstly, I want to tell you something that's come from some very recent data published this year about a disease called heart failure with preserved ejection fraction, which is a disease that's caused by high blood pressure. As you can see in the top left hand panel (next slide) we have a schematic of the heart. What high blood pressure can do to the heart is thicken the walls of the main chambers of the heart - these are the so-called ventricles. Not only do they become thicker but they also become stiffer which means when the heart tries to fill properly it can't fully dilate to allow new blood to come into the heart before it then contracts. Now it may well be that under resting conditions, where you're not exerting yourself you're okay, but it's when you start to exercise - when you need your heart to start pumping more blood - that the heart really struggles because it cannot fill to accept more blood, to pump more blood, because it's become stiff as a result of the high blood pressure. Now we know this stiffening is caused by something called fibrosis, and it's an increase in fibrosis, and you have underneath the heart a picture of the heart at very high magnification (showing in red the muscle cells and in blue the fibrosis). You can see in somebody with heart failure with preserved ejection fraction there is a lot more blue - a lot more fibrosis. Now I'll tell you in a moment what that fibrosis is. First of all I just want to let you know that if we look at a single heart muscle cell as depicted in the slide below (top right), every heart cell has little tubules that project into the inside of the heart cell. This is important to allow the heart cells to contract properly. What we've detected, and this is work from David Crossman's group, is that in these tubules there is a lot of fibrosis and that fibrosis is due to something called Collagen 6. Collagen 6 is a peptide - it's an important protein that helps hold things together. In the healthy condition you can see in green the tubules running in to the heart cell and you can see there's a little bit of red and that's the Collagen 6; but in heart failure with preserved ejection fraction you can see that the amount of collagen here is greatly enhanced which is causing it to become stiff. The new finding is that we've detected a new biomarker for heart failure with a preserved ejection fraction and this is really exciting and important because, if we can catch it early, we can do something about it before it's too late. During the formation of Collagen 6 it releases a protein into the blood called endotrophin and we can now detect endotrophin in the blood. This recent study shows very nicely that if we look at survival of patients with heart failure with preserved ejection fraction against time over about four or five years, you can see those with high amounts of endotrophin don't survive too well, those with lower endotrophins survive much, much better. So the early detection of heart failure with preserved ejection fraction is now possible by measuring endotrophin in the blood. This will help preventing worsening of this condition but clearly further research is needed to assess what we can do to actually lower Collagen 6 in the first place and prevent stiffening of the heart. I’m going to move on and ask a question now. What was the greatest invention to lower blood pressure? Surprisingly it was refrigeration and the reason it was refrigeration is because the development of cooling food prevented its preservation by addition of salt. This tells you something about a major cause of high blood pressure which is high salt. The other thing that helps to reduce high blood pressure is exercise and I just show this 24-hour fitness centre here in the United States with a bit of a tongue-in-cheek because you will notice that there is an escalator up to the fitness centre - both up and indeed back down again too. I think only in America would you have a fitness centre with escalators. Now regarding the salt and high blood pressure - most of our drugs that are given to control high blood pressure are acting on the body to try and help remove salt and reduce the amount of blood volume by excreting water from our body. So if we look at treatment which is typically a, b, c, d standing for ACE inhibitors or angiotensin receptor blockers, beta blockers, calcium channel blockers and diuretics. You can see below how these drugs relate to different parts of the body and the main organs that are affected are the kidneys, the arteries, the adrenal glands and the heart. A, b and d will all help reduce the salt and water in the body and they will counteract a hormone called Angiotensin II which I want to come back to in a moment. Angiotensin II is a hormone. It's been in animals for many many years. It originally evolved when animals moved from an aquatic environment out into land. Because when you move from water dwelling to land dwelling you need to preserve water and salt because you don't want to lose water through dehydration. However Angiotensin II is a major culprit for cardiovascular disease. Unfortunately, both in New Zealand and many other countries around the world, blood pressure is poorly controlled and there are a number of reasons for this. First of all we noticed that 50% of those that are treated for their blood pressure, so they're taking their drugs, still remain with hypertension, although blood pressure may be lowered they remain hypertensive. Those that are treated and controlled, that have normal blood pressure, remain at elevated risk for disease and that is quite an alarming fact. This would suggest that our current drug armoury is not preventing causes of high blood pressure but rather treating symptoms. So the question then becomes so what are possible causes of the high blood pressure? And, if we were able to treat those causes, we ought to be able to have a more effective way of lowering blood pressure in patients. So I want to return to the idea that the nervous system, the so-called autonomic or automatic nervous system within our body, is contributing to high blood pressure. Indeed the heart as you can see on the slide below is covered in nerves. The nerves are in red. This doesn't matter if it's a human heart or an animal heart, there are nerves. These nerves are part of the parasympathetic nervous system because there are two types of nerves that innervate the cardiovascular system. Those that are parasympathetic and those that are sympathetic. We see clearly here a very rich innovation by the parasympathetic nerves carried in the vagal nerve that goes to the heart and originates from the brain. Now I'd like to demonstrate with a short video the connection between the brain and the heart and the way I'm going to do this is, I'm going to activate the vagus nerve to the heart and the vagus nerve causes a slowing of the heart. The way that we can activate that vagus nerve is to stimulate cold receptors around your face - around your nose and your lips. These cold sensors are connected to a different part of the brain which eventually connects to the vagus nerve and activates it to slow the heart and this is called the diving response. So when you put your face into water your heart rate will slow down and the reason it slows down is to preserve oxygen usage because the body realises that you can't breathe underwater. This is a video of a participant that's going to put the head into a bucket of cold water while we record heart rate using an oximeter that's connected to the index finger of her right hand and what I want you to do is I want you to listen to the beeps that this machine makes which indicate her heart rate. Continue listening despite the fact that she will lift her head out of the water after about 20 seconds because her heart rate continues to fall. What happened was her heart rate fell from a heart rate of 115 down to 54. That's a reduction of 61 beats per minute and that is due by activation of this vagus nerve. Now the other nerves I want to talk about that connect the brain to the cardiovascular system are the sympathetic nerves and in the slide below, what we've got is a blood vessel. Every blood vessel in the body is connected to the brain via these sympathetic nerves and they are the green wiggly lines. What do those nerves do? Well those nerves if activated as you can see in the schematic below, cause your blood vessels to constrict, to become narrower, and as you constrict those blood vessels that increases blood pressure. The analogy I would give is like putting your finger over the end of a hose pipe - you do that and you increase the pressure in that hose pipe which means now you can squirt the water further from the end of the hose. You also know that the pressure is increased in the hose pipe because if your hose pipe is like mine the other end of the hose connected to the tap normally blows off. If we could find a way of reducing that activity in those sympathetic nerves that should dilate vessels and lower blood pressure. What we've discovered is an organ called the carotid body and the carotid body drives up sympathetic activity in those nerves to cause hypertension. We demonstrated this for the very first time some years ago, by selecting patients with drug resistant hypertension, that means they were not responding to drug treatment and had huge pressures of around 180 to 200 millimetres of mercury. We remove one carotid body for the very first time. Here it is seen below and we reduced blood pressure in those patients by around 20 millimetres of mercury which is quite a substantial lowering. The exciting news that I bring today is that we have unearthed a natural way to temper the activity of this carotid body that means we do not advocate going around and removing carotid bodies. So we sought to try and find a natural occurrent compound to block those receptors and have found one, but I can't tell you exactly what it is because it's under patent. The giraffe has also been a fascination of ours for quite some time because it has high blood pressure but this is natural for it. It has blood pressure that's twice that of humans - typically at the level of the heart our pressure would be around 95 millimetres of mercury - but it needs that high pressure in order to push blood up its neck into its brain. We've wondered for many years what it is about the giraffe that allows it to be able to adapt to high blood pressure because it never dies of cardiovascular disease. Normally, unfortunately, giraffes die from being caught by lions. So what is it that we can learn? Well the first thing we know is that the neck artery is wide and open as you would expect, but those arteries in its leg are very very narrow and this is how it generates its high blood pressure - through a narrowing of the arteries in the leg. Those that are supplying the brain such as the neck arteries are nice and wide and open and in fact, if you remember, if you increase the resistance to flow you will get higher blood pressure as we saw in the hose pipe. Very recently the genome of the giraffe has been fully sequenced and what's come out of that is something called fibroblast growth factor receptor like 1 or FGFRL1. This is a novel gene that's been identified and is related to high blood pressure. What's recently been published in science is that that gene has a number of mutations and those mutations, relative to the human FGFRL1, are of unknown function. In order to determine what the function of those mutations in that gene might be, the giraffe FGFRL1 Gene has been snipped out of the giraffe genome and has been replaced in the mouse genome as indicated by the schematic above. Now we are going to look at what happens in a mouse that now has the giraffe FGFRL1. Here you see the mouse in the lower panel (slide below) relative to a mouse containing its own FGFRL1. Interestingly enough you don't see a long neck. In fact you don't see too much difference. If anything the mouse is a little bit shorter at the same age. What we do know is that the bone density is massively increased which you would expect in a giraffe that's bearing all that weight but there's something very important that's been discovered and that is this. Remember I told you that Angiotensin II is a major culprit for raising blood pressure and indeed if you look at the mouse with its own FGFRL1 and you give that mouse Angiotensin II you can see you can raise its blood pressure relative to giving vehicle control. If you then take the mouse that has the FGFRL1, surprisingly Angiotensin II is completely ineffective. That was something that had not been predicted but what that tells us is that the giraffe is desensitized to Angiotensin II probably to protect itself from generating further high blood pressure. This opens up huge avenues for us now to exploit and to try and understand how we might be able to modulate FGFRL1 in humans. The next thing I want to briefly mention about blood pressure is renal denervation and this is a one-time procedure to lower blood pressure that may help to combat issues around accessing clinical treatment for blood pressure. It may also address a compliance of drug taking (people don't like taking pills) and also tolerance issues around drugs that gives nasty side effects. What you can see on the left of the slide below is the catheter that's placed into the renal artery - it's an ablation catheter. It's a two or three hour procedure and it ablates all the nerves going to the kidney. Now when you do that, as you can see here, very recent data. After three years you can see quite a nice fall in blood pressure approaching 20 millimetres of mercury. We are currently hoping to set up a trial in New Zealand very shortly to be able to form renal denervation. I want to move now to listening to nature which is a new pacemaker that we're developing. Most pacemakers are situated as a device just under the skin on the chest and have a lead that goes down into the heart as you can see in the slide. That's very standard. The other thing that's very standard is that the pacing is typically metronomic. The heart never beats metronomically and so we've raised the question very early on so why are we pacing hearts metronomically? I want to demonstrate that hearts don't beat metronomically by looking at this participant and the way he breathes and how his breathing is affecting his heart rate. What he's going to do is he's connected up to the same device used in the first video so you will hear beeping again. Every beep is a heart rate and I want you to listen to how his heart rate increases as he raises his hand that's because he will inhale, he's indicating breathing in through raising his hand, and then as he breathes out he will lower his hand and he's going to take three breaths and those three breaths are going to be related to changes in heart rate (decreasing) as you will hear. So we have developed a pacemaker that allows us to modulate heart rate every breath and we found some spectacular results in a large animal model of heart failure. This is a sheep model of heart failure. We fitted our novel pacemaker such that every time the animal breathes its heart rate increases and every time it breathes out its heart rate decreases just as we saw in the video. If we do that for a number of weeks, four weeks in total, you can see how the pumping, which is rather reduced because of the heart failure, dramatically increases by about 25 percent. That increase in heart pumping efficiency is three times that of current pacemakers which really is a very exciting and novel observation. The question is how is it doing that? What we've seen when we look at the heart tissue and these are pictures of the heart tissue (below) that have been labelled with antibodies connected to fluorescent markers. One is red indicating the T tubules - those are those tubes that I was talking about earlier on - they're in red - and associated with them is something called Ryanodine receptors in green. These Ryanodine receptors are really important for contractility of heart muscle, they give it the power to contract. You can see in a healthy situation the green and the red are beautifully aligned tubules with the Ryanodine receptors. In heart failure the tubules become fragmented and the Ryanodine receptors lose their location with those t-tubules but after our pacing you can see this beautiful realignment of the t-tubules and the Ryanodine receptors. Which means to us that we're actually beginning to see a way of reversing heart failure, reversing the damage to heart muscle cells. I'm delighted to say that we're able to start a trial in the first quarter of next year which will be performed by Dr Martin Styles in Waikato Hospital. We will be using this new pacemaker and connect it to an external pacemaker device which they use in the hospitals already. This will connect it to patients after they have had coronary artery bypass grafting. The reason for selecting those patients is that they have exteriorised pacemaker leads which allows us to connect our pacemaker device directly to the patient without having to implant it. Hopefully this time next year we'll have some positive data on this new form of pacing but what this does mean is that New Zealand has an opportunity here, if this works, to demonstrate to the world a completely new revolution of cardiac pacemakers. I want to end with rheumatic heart disease and rheumatic heart disease is something that this country, as a developed country, really should not have. You may know that rheumatic heart disease is due to repeated streptococcal or sore throat infections. After replication of these infections an autoimmune disease is triggered which means that one's own immune system now begins to attack the body. The part of the body that it attacks unfortunately are the valves within the heart. Now a valve in the heart plays an essential role because it allows the correct direction of blood to flow through the heart. Rheumatic heart disease basically destroys these valves which no longer operate and therefore there is poor directional movement of blood. It doesn't know whether to come forward or back and as a result the heart becomes a really very weakened pump. Currently to address this patients undergo operations to either fit a titanium valve - a metal valve - or a valve from an animal such as a pig or cow. This is a real world problem. Matt Johnson who's a retired Blues midfielder was diagnosed with rheumatic heart disease not so long ago. He no longer is able to play rugby because he has now been fitted with a titanium valve and indeed I met Matt not so long ago after his operation and you could hear this valve click opening and closed with every heartbeat. The other thing that Matt unfortunately has to do is take a blood thinning drug called Warfarin, because with a valve such as this it can cause blood to clot. Being on a blood thinner means he cannot play contact sport because he's very prone to bruising and large bleeds under the skin so this is hugely problematic for people clearly throughout their life. Rheumatic heart disease if caught early typically can be found in young children and here we have a young man who has just had his rheumatic heart disease valve repaired and this is six weeks since surgery. Unfortunately for this young man he's going to have a lifetime of operations to replace his heart valve. The reason for this is that there are a number of problems. The first is the current valves don't grow. I showed you a metal valve and a porcine valve - they simply don't grow but his heart will grow and as his heart grows so the valve will begin to leak because it will remain the same size. Very often animal valves are rejected eventually by the body or simply wear out after a period of time. So repeated heart surgeries are needed and every time this child comes back in for a heart surgery the surgeons are faced with technically more challenging operations. What can we do to address this? I think this is a nice example now of how Manaaki Manawa with its interdisciplinary approach to cardiovascular disease really demonstrates its power. Recently a colleague in engineering, Olaf Diegel, has received a 3D printer which allows us to print growth matrices and scaffolds that will support human tissue growth. This will be ideal for making personalised body parts and as I said interfaces engineering with medicine very beautifully. Here's what we're planning on doing. We're trying to grow your own heart valve. Let's imagine we have a young child that has been diagnosed here with rheumatic heart disease. We take a skin biopsy from that child and we reprogramme the cells to produce from their skin cells pluripotent stem cells. We can then take those stem cells and drive them into heart valve cells. At the same time, the child's heart can be scanned using a high-powered magnetic resonance imaging so that we can get an exact copy of the size and shape of the heart valve needed for that particular individual - so-called personalised medicine. Once we've got an image, a 3D image of the valve, we can then set up the 3D printer to print an exact replica of a heart valve. Printed in this growth matrix gel scaffold and now that gel will be impregnated with all the right growth factors that are needed to stimulate the stem cells to grow into heart valve cells. Those heart valves will then be implanted back into the heart of that recipient and the beautiful thing here is that those heart valves will not only fit perfectly, because they've been personalised, but because they have been grown from cells that originated from the patient there will be no rejection of those valves. That is an aspiration, that is something that we would love to be able to progress to do with funding that could come from the Auckland Medical Research Foundation. Thank you very much for listening. It's been a great pleasure to be able to update you with some of the fantastic research that's going on in Manaaki Manawa. Thank you.

Women are more likely to have a heart attack, yet they are the minority in heart research. Māori women even more so. That is something Auckland researcher Dr Nikki Earle wants to address. Jump to the end of this page to watch Nikki's recent lecture on her cardiovascular research. The Auckland Medical Research Foundation postdoctoral fellow is conducting a longitudinal study of more than 2000 New Zealanders who have survived their first heart attack. The aim is to develop ways to identify people at highest risk of death or re-hospitalisation and intervene with more personalised treatments. The majority of those who have been recruited on to the study so far are males, so Nikki, the recipient of the AMRF Douglas Goodfellow Postdoctoral Fellowship, wants to expand the cohort to be more representative of the population. “Historically, heart research studies have included more men than women, meaning that heart disease in women has not been as well investigated,” Nikki explains. “We have 2015 people enrolled, and our work will now focus on filling equity gaps. This will help us to better understand how heart attacks manifest differently in women compared with men, and to identify risk markers for subsequent events that are specific to women. Women made up one fifth of the initial cohort, with the risk of death from any cause or cardiovascular readmission higher in women than men—26.7 percent vs 19.6 percent—and highest overall for Māori women at 31.1 percent. Our work may lead to more personalised and better targeted treatments, and more equitable health outcomes for women with heart disease in New Zealand. As treatments improve over time, more people are surviving events such as heart attacks. Currently more than 186,000 people in New Zealand have some form of heart condition, and are then at high risk of further events. The Multi Ethnic New Zealand study of Acute Coronary Syndromes (MENZACS) is an ongoing multi-centre, longitudinal cohort study aiming to explore how environmental and genetic factors contribute to acute coronary syndromes in New Zealand’s ethnically-diverse population. Extensive clinical and research data is collected from patients at 11 hospital coronary care units across the country during their first admission, along with a blood sample. Those blood results will measure biomarkers including genetic markers of heart disease risk, as well as known clinical and environmental cardiovascular risk factors such as nutrition, stress, and physical activity. “Women have been so understudied. Things like premature menopause, having gestational diabetes when pregnant, or having any sort of high blood pressure problems when you're pregnant can increase your risk of cardiovascular disease, but so few women have been in any of these studies,” she explains. “We're trying to double the number of women we have enrolled, so we end up with 800 women and we’re aiming to enrol another 250 Māori. Because we're looking at people when they've had their first event it can take a number of years for these subsequent things to happen, so it really is a long term game.” Patients remain anonymous and do not need to participate other than provide their medical history along with any family history of heart disease and lifestyle behaviours (nutrition and exercise details, work stress etc) and allow on-going access to their medical records, stored under their National Health Identifier number. “We can look at things like how you respond to different medications based on your genetics, whether people are receiving the best medication for them while they've been in hospital and afterwards. With time, the data set becomes more valuable.” Nikki has been funded by AMRF on several occasions: in addition to supporting her PhD from 2012 to 2015 with a doctoral scholarship, Nikki has been awarded two AMRF project grants as well as the postdoctoral fellowship. The quality of her work and the promise of her career meant she was also awarded an Emerging Researcher Start-Up Award from AMRF's partnership with the Kelliher Charitable Trust. I don't know what I would be doing if I didn't get this fellowship “This funding gives me peace of mind that I can continue this valuable work.” Hear Dr Nikki Earle and Prof Julian Paton describe their cardiovascular research from the laboratory bench to the cardio clinic . Watch it now!

Read more now in the latest AMRF newsletter. You can read about the progress of research and the researchers supported by donors like you including: Using artificial intelligence to help asthma patients breathe easier. Breakthroughs in tinnitus research, finally finding relief for some suffering from this traumatic hearing impairment. Healthy hearts research will be presented by Dr Nikki Earle and Prof Julian Paton in a free, online video event on October 19. Register now to get the details to hear from these researchers with us live! Thanking AMRF's long-standing treasurer, Mr Paul Keeling, for his years of dedicated service on his retirement from our Board of Trustees. Click below to read and download the PDF newsletter

A/Prof Michael Hay presents an overview of cancer research happening right here in Auckland. From the laboratory bench through to clinical trials, hear directly from a leader in the field. Watch the video above or read the transcript here. Advances in Cancer Therapy: Targeting the tumour microenvironment Thank you very much everybody for coming my name is Michael Hay. I’d like to talk to you about some work that has been ongoing in the Auckland Cancer Society Research Centre and which has been generously supported by Auckland Medical Research Foundation as well so I just would like to start with a brief overview of cancer. 10-year cancer survival rates (1972-2011) Here is a representation of cancer survival in New Zealand and the rates of cancer survival and you can see that across the many diseases there are very very different circumstances and outcomes. The point I’d like to make today is that across all cancers from of over a 40-year period from around 1972-ish through the current day the rates of long-term cancer survival over ten years have improved from around one in four to well over fifty percent. That's a remarkable and steady gain that can be attributable to multiple causes not least of all improved screening and detection, improved treatments, improved follow-up and a wide variety of impacts. I think that's a very positive thing but obviously there's still a lot to do across the whole range of improvements that can be made for patients and for people who are diagnosed with cancer. Hallmarks of cancer Our area of expertise is drug development and we are looking at cancer as a disease and across all of those multiple diseases and you can think about almost up to 200 separate diseases which we can identify some commonalities. If I look at this chart and sort of try and break it down for you cancers are typified by a loss of control and that control is around how they receive messages to grow, how they evade the mechanisms that normal cells use to control growth, that they become active and engage in invasion through surrounding tissues and can also move out of the site of origin and metastasize to distant sites. They become essentially immortal and they have certainly can resist all the signals that would normally tell a cell to die in an appropriate context and they also recruit their own blood supply to create an environment that they can survive in. There are some more recently defined features that are also typical of many cancers: they deregulate their cellular metabolism to cope with the environment in which they find themselves so often they're finding that because of their rapid growth and because of the poor blood supply they often are short of nutrients. Cancer is a moving target They can adapt their metabolism so they're essentially invisible to the immune surveillance that is constantly on in action in our bodies. They are often inflamed and that promotes further malignancy and one of the underlying features is in fact the genomic instability that leads to more mutation and the evolution of cancers. It's a moving target and here is a cartoon that just demonstrates that from a single mutation there will be an evolution that might be as many as 30 generations before a cancer is detectable. So over this period of time the cancer is growing in a stressful environment adapting to that and changing and it's going to eventually be detected somewhere in this region in the meantime or thereafter it has metastasized and has gone on and will keep growing unless treated in some way. You can think about this in terms of an evolutionary pressure. The environment drives evolution and that also encourages diversity that can respond to that environment. If we look at this diagram which is just following the time of starting from a single cell with a chromosomal problem or mutation you can see that it acquires more drivers if you like of this cancer. Some of these die out, some of these clades or clones don't survive, and others will survive. So whilst most of the cancer is represented here from a common ancestor there are other evolutionary groups of cancer cells. so they're not all the same so you have heterogeneous genius genetic background and I think it's best example exemplified if you look at say -- I’m sure many of you have looked into ancestry and tried to do some family tree tracking. if you were to say well do Zara and Prince Harry represent their distant ancestor Queen Victoria you might go well there's a connection but they're quite different people, and they will respond quite differently to their circumstances. I think that's a convenient metaphor to consider the heterogeneity that you'll see within a tumour. The tumour microenvironment Also there's this micro environment. cancer cell cancer tumours are not simply groups of cells of all the same evolution. there's cancer cells, there's the normal cells that support this, so endothelial cells, fibroblasts, all sorts of other cells immune cells that are all mixed intimately in this relationship. we try and capture that in this cartoon: it's an environment, it's genetically flexible, it's very disorganized and it's invisible to the immune system. You can see that because of the poor blood supply and the strong demand for oxygen and nutrients, there will be gradients of these nutrients and there is a term called hypoxia which really just means lack of oxygen. so these cells are under stress and they respond they will respond to that stress and also in terms of drug delivery this is not a particularly well served environment for drugs to move into from the bloodstream. Understanding Tumours: Cancers as Weeds I’m sure many of you are gardeners and if you just think about your garden which you've tended carefully and you have all your plants growing appropriately and you've got the irrigation system going. well your tumour microenvironment looks more like this: the irrigation system is broken the weeds are invading and they're growing. you can still see there's somewhere in there there's some roses and there's some other various plants but they're being strangled and lost. Complex ecology of many types of cells Carcinoma cells + endothelial cells, fibroblasts, immune cells, + extracellular matrix molecules Creates environment for tumour growth Genetically flexible and adaptable A highly disorganised architecture Invisible to the immune system Tumour hypoxia So that is kind of the a good metaphor for what might be happening in the tumour micro environment so this lack of oxygen the tumour hypoxia is a consequence of trying to grow the tumour, and trying to recruit and attract blood vessels to supply it with nutrients. Whereas a normal bloodstream has a distinct architecture that allows for diffusion of oxygen and nutrients the chaotic architecture you can see here and also over here leads to these hypoxic cells. They're all usually at some distance from the blood vessel because sometimes these blood vessels just constrict because of pressure within the tumour or they leak and therefore the flows of oxygen are not particularly good. You can see here compared to normal tissue where you have this nice architecture where you have an artery leading down through an arterial into a capillary and out to a vein. here we've got all this very lots of dead ends lots of loops lots of short processes that really go nowhere. you can see how inefficient that might be so that is one of the problems of the tumour micro environment that we have spent probably three decades trying to understand and trying to work out what its impact is. The four pillars of cancer treatment Certainly when we come and look at the pillars of cancer treatment surgery chemotherapy radiation and now more laterally immunotherapy you can see that in fact the micro-environmental factors the heterogeneity of those tumour cells. the fact that you're in a hypoxic environment which is stressful and it's acting as an evolutionary stress can defeat each of these modalities. If we think about in terms of which of these are used most often, surgery is in fact the most successful treatment for cancers and it often is because they are discrete they are often very easily accessible. this is followed by radiotherapy again is used very often and chemotherapy less often. more often than not these are all combined into a schedule of treatment but it just gives you some sense of the distribution of therapy with intent to cure. The data I have here is a little old and it hasn't really taken account of the tremendous impact that immunotherapy is currently making on cancer treatment. Just thinking about some of the various modalities of treatment the new generation of targeted cancer therapies are in fact incredibly precise and they can have some dramatic effects. You can see here this is a patient who's metastatic melanoma with advanced disease. the cancer is driven predominantly by a mutation in one of one of those oncogenic mutations that drive the cancer growth. You can see treatment with a targeted treatment that stops that particular pathway of growth leads to this remarkable remission and you can see what a tremendous benefit that has achieved in that period of time. Unfortunately it's the tumour heterogeneity will actually defeat many of these agents. unfortunately and this patient obviously relapses because some elements of that tumour are not responsive to this incredibly precise therapy. You can see that occurring although the treatment does provide an advantage in blue over the standard of care and green most patients are not seeing long-term benefit. Game changer: Immunotherapy and dramatic recent improvements There is a subset for whom this treatment is working but again you can see the challenge with just applying that particular targeted therapy immunotherapy is changing the game dramatically. This cartoon here is just meant to represent the idea that tumour cells do present antigens which could be recognized by the immune surveillance system and detected as foreign and that they then can go on and prime the soldiers if you like who go around and sort out the problems in your body. These T cells can be activated but there is a very well defined handshake system that stops the T cells running out of control, running amok. So many T-cells find themselves inactivated the use of some of these immune checkpoint blockade inhibitors such as ipilimumab can bind and disrupt that particular handshake and allow another handshake that activates the T cell, allows it to go out throughout the body and identify these particular tumour cells and get rid of them. Indeed you can see here that in we're looking at again metastatic melanoma and you can see that for patients with advanced disease who are treated with alone there is a proportion of patients that will achieve long-term survival, essentially long-term disease control without symptoms, When we look at another one of these immune checkpoint inhibitors called Nivolumab which affects a different handshake you can see that there is again significant benefit. And when we combine the two you can see that approximately four in ten patients will achieve a long-term survival That is a dramatic effect that is a tremendously different effect from five years ago when these there were very few options for these patients. Immunotherapy is a tremendous game changer. Radiotherapy: a cost-effective treatment Radiotherapy is also used very widely. More than half the patients who have cancer will receive radiotherapy and of those the majority will be treated with curative intent either alone or in combination with other modalities of treatment. Increase in precision drive increases in survival It has the advantage it can be used across many different tumour types and there are a variety of different technologies that can deliver this. It's also pretty economical in terms of its fraction of the cancer budget it's relatively low so it is a good therapy. It has particular application and indeed much of the advances in the last 20 odd years have been driven by improved technology has given improved treatment responses. We can see here in 2003 this is for patient data probably from last century but just radiotherapy alone is achieving local region control in head and neck cancer patients. whereas if you add in chemotherapy either afterwards or concurrently you can achieve increasing control and that very much maps to survival as well. So that is quite effective with 75 odd percent of patients responding positively to the treatment and over the last 20 years the technology has increased the ability to deliver that radiation to the tumour sparing normal tissue which is very important, whether the pancreas, lung, neuroendocrine or other tissue. In head and neck cancer it has improved dramatically and the survival rates have actually increased as well just incrementally but steadily going upwards so that again is a very positive trend looking forward. Combination therapy: targeting mechanisms of resistance Further advances in cancer treatment are going to be driven by combinations of these therapy modalities. You can see in this cartoon the various sorts of classical chemotherapy and genomically targeted or therapies all provide improvement or can or some degree of protection from cancer but are not necessarily long-term solutions. The real game changer is seen in immune checkpoint therapy. It really will be a positive outcome for a certain proportion of patients but not all patients and again how do we move the green line up to the red line. We will need to focus on the mechanisms of resistance such as hypoxia and genetic heterogeneity and also the DNA repair mechanisms that lead to these highly mutated diseases that have lost control Hypoxia as a therapeutic target So I’d like to now focus on some work that we've been doing over literally three decades in our laboratories trying to use hypoxia as a therapeutic target. It is pretty unique to tumours most other locations in your body are reasonably well oxygenated. We can see here in thin green, these are areas of hypoxia that we've stained, imaged and they've sort of formed these circles around what are you probably can't see blood vessels in the centre and well oxygenated tissue surrounding them. then as you go out along the periphery you can see this tissue many tumour types have hypoxia but it's very variable . You can see from these this is a degree of hypoxia across a whole range of different diseases and you can just see the huge variation there but it is a therapeutic target. we can see here some data from Denmark where looking back at patients who received radiotherapy alone and who for whom the tumours could be stratified into being more or less hypoxic. You can see that the least hypoxic tumours or the patients with those less hypoxic tumours fare better than those with hypoxic tumours and that was a consequence of the failure to control the tumour within the radiotherapy field most often times. And again the hypoxia tumours were less controllable and that could be manipulated therapeutically. You can see here when you separate the two groups of patients and you can treat them with a relatively simple agent nimorazole which works against anaerobic bacteria but like metronidazole you can see that for patients that don't have hypoxic tumours it has no benefit but for those patients for whom their tumours they have a significant hypoxic fraction the nimorazole acts to redeem or to make that radiotherapy more effective. That has a dramatic effect. Unfortunately this drug is only licensed for use in Denmark and has been so for the last 15 or so years it is under review in Europe to be included with radiotherapy regimens. Tumour Selective Drug Delivery Our take on this is to look at that and go yes we and we have developed drugs that can be used in the same manner and targeting and killing hypoxic cells but is also to look at those hypoxic cells which are treatment resistant is a very specific location, a postal address, to which you can send a drug. This is deactivated, a thing we call a pro drug/prodrug. It's non-toxic, non-effective when it diffuses into the tumour where it's activated by enzymes in the absence of oxygen and releases an active metabolite which could be something like a cytotoxin which goes and kills the cells and surrounding cells. Tumour Selective Drugs: Hypoxia activated prodrugs Or it could be one of these exquisitely targeted molecular agents that have been developed more recently and this cartoon just shows you what we're trying to achieve. Over here the blood vessel surrounded by tumour cells and the pro drug diffuses out through into this hypoxic zone, it's activated and then returns back and can kill or inhibit the growth of the surrounding cells. Tarloxotinib I just want to showcase some work from two very talented investigators in our laboratories, Associate Professors Adam Patterson and Jeff Smale who've taken a very targeted agent that targets one of those growth signals which is driven through the epidermal growth factor receptor. This is a receptor that sits on the cell wall and has a site outside which then can recognize proteins that can come and stimulate that and set off a signal in cascade. It has this intracellular domain where it has an active site which the drug has been designed to just fit in there. Here's a better example of how that signalling pathway works so the receptor out here can be bound by a molecule that stimulates this growth pathway and whether through an oversupply of the stimulation or an over-expression of the receptor or a mutation that leaves it permanently on. This drives growth through this signal pathway. If you inhibit that intracellular domain, you inhibit the function, and you have the signal and the cell which is essentially addicted to the signalling pathway will then certainly stop growing and most probably die. Here's another cartoon just demonstrating how that might work. You can see that the drug diffuses out of the blood system to these hypoxic cells where it's activated and then it can then start to drag the tumour with the released molecularly targeted inhibitor. it can then diffuse from this zone so we've killed that treatment resistant portion of the tumour. it can also diffuse and start to target more of the cells with it throughout the whole tumour. You can see here a picture of this again just showing areas of hypoxia that we have been staining within a tumour and you can see that it's not through the whole tissue and here Adam and Jeff have mapped the activation of the drug from the pro drug with the red being the highest concentration. You can see that there it has diffused through much of the tumour from those areas of high concentration now. Tarloxotinib as it's called has been taken into phase one clinical trial firstly in the USA and also in two sites in Auckland and that's been led in New Zealand by two of the researchers from the Auckland Cancer Society Research Centre, Associate Professor Mike Jameson down in Hamilton and Professor Mark Mckeage in Auckland. It's also gone on to phase two clinical trials. we're still currently in trial looking at its ability to work with a particular subset of non-small cell lung cancers that are driven by these mutations in that signalling pathway and also in recurrent or metastatic squamous cell carcinomas of the head and neck or of the skin. These studies are currently limited to these types of cancer, but future work may look at cervical, pancreatic or bowel cancers at different stages. Whilst those are ongoing, what Adam and Jeff have been able to do is to bring it back home to New Zealand and with Dr Andrew McCann from Auckland City Hospital they are hoping next year to start what we call a window of opportunity study to look at the combination of this drug with a form of radiation in head and neck patients prior to them receiving the surgery they would normally receive. So this gives us the researchers an opportunity to see how the drug works in combination with radiotherapy. It is an active drug and the preliminary analysis of the phase two trials are showing at least some partial responses in patients. This is when it's just given alone and so it is certainly working on mechanism within these patients. You can see the sorts of effects that are being achieved with this patient who has this pleural effusion and tumour mass. After approximately 12 or 12 doses of the drug that has been cleared so this is ongoing research and there's no definitive answers as to the efficacy of the drug at this stage but it is a very positive signal. Drugs from the ACSRC I’d just like to – having looked closely at a little bit of research from the centre – step back a little bit and just talk about our centre overall and what we're trying to achieve. One of the big things that we are trying to do is to impact patients with new cancer therapies. We've had a measure of success over many years and we can go back to Bruce Kane who developed amsacrine in the 1970s and it was finally approved in 1983. That also spun out a series of other DNA binding drugs if we go back far enough of course the structure of DNA had just been described, cancer was really only known of as a disease that was constantly replicating, and DNA was part of that so targeting DNA was the target to choose. So a flurry of clinical activity from the Centre lead to one approval We're also looking at immune stimulants and a drug here called DMXAA was worked all the way through to phase three clinical trial in Europe and New Zealand with Novartis but was ultimately unsuccessful. Further work with the DNA binding drug has actually led to a rather novel application where it's used to sterilize blood cells and remove viruses. There's been a big body of work around these targeted agents--we call them kinase inhibitors that target those signalling pathways I mentioned. And indeed work with Pfizer over several decades has led finally to the registration of one of these agents. It's available in the us but not currently in New Zealand and another agent has been segued sideways into companion animal therapy We have a very strong TB program which has led to clinical activity; another program with immune stimulants has also been licensed into clinical trial and again we have this strong area where we're targeting hypoxia as a therapy. Commercialisation of research I’ve mentioned the progress with tarloxotinib but there is another agent and there is another whole program of work following in behind this with the next generation of agents have we done this and again I’m just trying to sort of point to the fact that it is very challenging to go from preclinical research into clinical research. We've been able to utilise the university’s commercialization arm but we've had to be agile and quick thinking. We've worked with international charities we've worked with big pharmaceutical companies where we've partnered with them and that's been very much a learning curve. We've taken advantage of their wealth and knowledge and been able to advance our ideas very successfully. We've licensed it out to a range of commercial companies from big pharma such as Novartis to tiny small companies that had been set up around the world and again that has led to successful access to clinical trials. We've even set up our own start-up companies in New Zealand and then let them head off to overseas taking the drugs with them in an effort to try and raise the money to conduct these trials and I hope today just to convince you that in fact academic laboratories have a very important role to play. The important role of academic laboratories Our mission statement is to improve outcomes for cancer patients in New Zealand and globally and we do this by understanding the mechanisms of disease and resistance to treatment. Our job is to try and translate these new ideas into drugs into the clinic and also train the workforce while we're at it and so there's some opportunities that an academic lab has we often have longer time frames. We don't try and compete head to head with the big boys, if you will. There are niches we need to occupy and these ideas aren't necessarily the main thing in front of you. We've been very productive and perhaps the one thing that's missing is how are we developing drugs in New Zealand for New Zealanders. Inevitably taking our drugs offshore means we lose some of the development approach some of the local flavour and context and also the ability to actually move these into use in New Zealand and that's a big challenge for us. I’d just like to finish by taking this opportunity to thank the AMRF and to thank you the donors and supporters of the AMRF over I think it's 25 or 26 years. The AMRF has very generously funded a lot of research in our laboratories particularly early career researchers and I think if I add this up and convert it to today's dollars it's over three million dollars’ worth of research has been funded in our centre so we're extremely grateful I think that we've done a reasonable job in trying to convert that into great things. It's often it's not necessarily the quantum of money: it's the fact that small portions of money can be very effective as glue that holds together bigger programs that we can leverage and take forward to develop drugs which will cost tens of millions of dollars to develop but it is in fact very important glue so thank you very much. I’d like to thank you for your patience and attendance but also for your generosity and support. Thank you. Give now to support cancer researchers like A/Prof Mike Hay. Learn more about cancer research supported by donations from people like you.

The collective efforts of many has led to a a break-through in the personalised treatment of tinnitus. Listen to this recent radio interview on a digital polytherapeutic treatment for tinnitus from Associate Professor Grant Searchfield on 95bFM. "Tinnitus research is not easy. The field of tinnitus is littered by false hopes of miracle cures and treatments that overpromise but underdeliver" Read more about tinnitus research funded by the Auckland Medical Research Foundation.

Mr Conor Nelson and Associate Professor Debbie Young work to create new cures for memory loss, such as those seen in Alzheimer's disease and other dementia related illnesses. Enjoy this video interview of Mr Conor Nelson and A/Prof Debbie Young here or read the transcript to learn more about their research into Alzheimer's disease treatment. Transcript of interview with Mr Conor Nelson (CN) and Associate Professor Debbie Young (DY) by Hayley McLarin (HM) DY: Hi, I'm Associate Professor Debbie Young and I am located in the Department of Pharmacology and also the Centre for Brain Research at the University of Auckland. I have a long standing interest in the development of therapies for neurodegenerative diseases and these include gene therapy strategies as well as antibody based strategies. CN: Hi, I'm Conor Nelson. I'm a second year PhD student in Debbie’s lab. My current project is using an antibody therapy to treat diseases of ageing, specifically, dementia and other dementia associated illnesses. HM: Debbie and Conor thank you so much. What do you hope to achieve with the research? DY: What we are trying to achieve with our research is to develop a therapy that may have applicability for people who suffer from conditions associated with learning. This is important because we've shown that in preclinical models we can actually improve learning and memory function. HM: And Debbie, Conor is working with you on this project? DY: Conor is taking one step towards this goal by now examining whether this treatment could actually be effective against a neurodegenerative disease like Alzheimer's or Huntington's disease. The project of interest that Conor’s working on is based on the development of an antibody-based therapy that we think might have applicability for improving learning and memory problems for people with dementia and also age related cognitive impairment. HM: So tell me Debbie, how long has Auckland Medical Research Foundation been funding you? DY: The Auckland Medical Research Foundation has been funding me for around 10 to 15 years for a number of different projects. Back in 2013, the AMRF funded a piece of work that made some pivotal findings in defining how these antibodies actually work to cause improvement of learning memory in preclinical models. HM: What are the potential outcomes for you? What are the next steps from here? DY: Conor is going to work on a specific part of this research programme, and he's going to talk more about how his work will contribute to an understanding of how this therapy might actually work in the context of neurodegenerative disease. HM: So first off Conor, can you please tell me, what is antibody therapy? CN: To understand antibody therapy, the first thing you need to know is what an antibody is. So basically it is a collection of proteins that your body produces to bind to foreign proteins and normally this would be binding to something like bacterial viruses, but we can actually design these antibodies in our lab to target specific things. Some people use them to target proteins that cause disease, or in our case, we are targeting a receptor that acts like an on-off switch. So the binding of these antibodies to a receptor can change the way the cells act and hopefully encourage them to survive. HM: And tell me, what are the symptoms and effects of Alzheimer’s disease for a person? CN: General estimates tend to be at that about 11% of the population, or one in nine people above the age of 65, will suffer from some dementia associated illness. In these illnesses you tend to see general cognitive decline, you see losses in spatial learning and memory, you see a whole lot of issues that can make it really hard to just live your life. It's really important that, especially as our population continues to get older, we manage to make it so these people can live their life to the best of their ability and improve their quality of life. Prophylactic therapies that come before the onset of symptoms would be amazing. Our therapy that we've developed will hopefully offer some therapeutic benefit in both cases. Our current belief is that this therapy should be more beneficial if it's given before disease onset, but our data does suggest that it can potentially halt the progression so to stop any further deterioration from occurring. HM: And Conor, what is a prophylactic therapy? CN: A prophylactic therapy is a therapy that is given to prevent something. Normally whenever you think of a medication, you think of something like an antibiotic where you end up going ‘okay, I'm sick, I'm taking this drug and this will help clear the illness’. With the prophylactic, it's something more like what you would think of with vaccines where you go, ‘okay I'll give you this medicine before you get sick and this will prevent the disease from ever happening’, hopefully! HM: Are you looking to treat Alzheimer’s disease or are you hoping to be able to prevent it altogether? CN: One thing that's quite tricky with a lot of these age related illnesses is quite often you don't know who's going to get them before they actually start. So in some cases, you can look at genetic or environmental factors, for example, people who've had multiple traumatic brain injuries like concussions are more likely to develop Alzheimer's disease. You also see that with a range of other factors, but as a general rule, with this sort of therapy, what you need to be looking at is the early stages of the disease. So once people start to have mild cognitive impairment or just some level of cognitive decline that's when you want to target this therapy. Hopefully, if you target it early enough, you may be able to actually recover a little bit of that functionality, but even just being able to stop any further progression would be absolutely amazing and miles beyond what we currently can do. HM: Conor, what prompted you to focus on this area for your research career? CN: I'm sure that everyone has known someone who has some form of dementia, and they've seen the sort of deterioration they experience. For me, so much of what I think of myself comes down to my experiences, my memories, the things that I associate as being part of me and how much that's just purely cognitive. The idea of having some sort of constant decline is honestly kind of terrifying. It would be amazing to be able to stop some people from having to experience that. There are some therapies available which do help alleviate symptoms for people but being able to offer something that will actually change the course of someone's life would be absolutely amazing. HM: And how do you go about doing this research? CN: Basically, what we ended up developing is a designer antibody and this antibody will bind to one protein and one protein only, this is one subunit of the MDA receptor. These receptors are heavily implicated in the processes of learning and memory. They act like switches which control a whole bunch of different pathways within the cell. These pathways can either encourage cell survival or cell death. A little bit of cell death is perfectly normal within the brain, and that's actually quite healthy, but where you end up with a problem is when you have the cell death signalling massively outcompeting the cell survival signalling and that leads to neurodegeneration. One thing our antibodies are able to do is they are able to preferentially inhibit this cell death signalling and allow the cell survival signalling to take over. As a result you end up getting more cells surviving and that should hopefully allow us to halt this process of degeneration. Once we end up refining this therapy and we find it does actually work in various preclinical models with either reversal or prevention of this disease process; then we modify it to ensure it's 100% safe for human use. That is when we would then move forward, see if we can take it into a clinical trial and give it to patients with the disease to see if we can modify their disease progression. HM: Conor, I understand you were awarded the Helen Goodwin doctoral scholarship. Congratulations. That must be a huge relief for you to know that you are being funded to carry out this work. CN: This work wouldn't be possible if it wasn't for Helen Goodwin and the Gooduck Charitable trust. They have ended up funding this entire PhD scholarship for me. As a result, this means I can focus on this work without having to worry about my finances in the meantime, because I know some PhD students are constantly trying to work part time jobs to try to facilitate their study. For me, I can just focus on my research, which means that hopefully this will result in a much better outcome for the project. DY: Donors play a pivotal role in this work because essentially developing a drug, from a concept in a lab right through to something that is used in people, is actually a long drawn out process, and every single piece of research counts towards achieving that goal. Just having a small project that might take a couple of years is really important to building that picture so that when we actually get to the stage of being able to test this treatment in people, we're going to be very certain that we have an idea of how this treatment is going to work and whether it's actually going to work in humans as well. HM: What keeps you motivated? What keeps you wanting to work in this area? DY: It’s that next discovery. It's the unexpected discovery. So you have an idea when you do this research, what you predict you might find, but then you might get something totally the opposite. It's that sort of contradictory result that basically gets my brain almost in hyperdrive, thinking, well this is not how I think it should be working and maybe there's some other explanation. I've always liked things like puzzles, doing Sudoku and things like that, so doing research is right up my alley because it's always finding the unexpected, and then trying to figure out how come I got this unexpected result - maybe there's something in this result that's leading me down a different pathway. So this research programme that started as quite a simple research programme developing a therapy and has now grown from two arms of different lines of investigation, to almost like an octopus. Different lines we're trying to chase and looking at things in our preclinical models that determine some of those factors that potentially can change an aged brain back into a young brain. So, those are other projects that I'm keen to get off the ground with other students. HM: Debbie and Conor thank you so much. I have really enjoyed talking to you. I felt that I’ve learned so much today and I am sure that everyone else who is watching will have to. I really appreciate your time.

Dr Brigid Ryan has dedicated her scientific research career to helping those diagnosed with early-onset dementia. With the blessing of a local family suffering from the disease, Dr Ryan works with them to learn how to prevent the progressive loss of personality and independence in this devastating disease. By identifying early signs of dementia years or decades before clinical diagnosis, she gives us hope that early intervention is possible. Enjoy this video interview of Dr Brigid Ryan here or read the transcript to learn more about her and the very special family she works with. Transcript of interview of Dr Brigid Ryan (BR) by Hayley McLarin (HM) HM: Hi Brigid, thank you so much for joining us. I'm really excited to catch up with you today because I'm really fascinated by your research. Can you tell me a little bit about what you're doing? BR: Thanks, Hayley. It's really nice to be here. My research is based on the premise that the key to combating dementia is early detection. What we're trying to do is identify the early signs of dementia before symptoms appear, so that it can be prevented. This is because we know that the brain changes that underlie dementia start many years before people notice symptoms and we also know that trying to treat dementia once symptoms exist, has been unsuccessful so far. So I think that we need to intervene early, and to do this, we need two things. We need treatments that work at this early stage and we also need a way to identify people who are in this early stage. My research is working on the second part - identifying people before they have symptoms. HM: And how do you go about doing that? BR: The way we are doing this is we're working with a family who have a type of dementia called genetic frontotemporal dementia. So genetic testing on healthy members of this family tells us whether they'll develop dementia in the future or not. By studying these people many years before they get symptoms, when they're still healthy, we hope to develop a test - like a blood test for example - that we can then use in the general population to identify this really early dementia. Ultimately, our hope is that this will lead to successful intervention at this early stage to prevent these symptoms from developing in the first place. HM: How did you find this family and when you do the tests do they then know that they are likely to get dementia later? BR: That’s a really good question. It’s actually a really interesting part of the study and it started in quite an unusual way. The family that is involved, they actually heard about our research and they had previously had someone in their family who had donated their brain to the Neurological Foundation Human Brain Bank at the University of Auckland. Through that donation, the family became interested in research and they approached researchers at the Centre for Brain Research to ask if they could be involved in any studies and that is why it is quite an unusual way for a study to start. We are identifying people in this family who carry genetic mutations that will eventually lead to dementia. Because we're doing this in a research capacity rather than a clinical capacity, we don't give this information to our participants. But if they want to find out this information, we do support them to go through the clinical process so that they can find that information out. Some people in the family do want to know if they're carrying this mutation, so they can plan for the future. Some people don't want to know. HM: So are you looking at just one particular generation, one age group? Or does this traverse quite a few generations? BR: So our participants age range starts from 25 and that is the youngest person in the study. That's because that's when we think it is the earliest time point we might be able to see these changes starting, so that equates to around about 30 years before we would expect to see symptoms in this family. We know from previous research that it is likely we will see changes happening at that early stage. Really interestingly, this is a common feature of lots of types of dementia that we do get these changes in the brain happening a long time before symptoms are apparent in a person. What this means is we've got this really amazing opportunity to intervene during this window of change, where there are some things starting to happen in the brain, but it hasn't got to the point yet where it's causing symptoms. BR: As you can see from this diagram, this is the family tree of the family that's involved in our study. The black indicates people who have been affected by frontotemporal dementia. The line through the symbols indicates people who have passed away. So as you can see, people have been affected by Frontotemporal dementia through generations of this family. And one of the people in this family, who has passed away, is the woman who first donated her brain to the Neurological Foundation Human Brain Bank and started off this whole project. We have around two thirds of family members who could be involved or who were invited to be involved, that have agreed to be in the study. This means the study is really unique internationally because we have a very large group of people from a single family taking part in the research, and that's a really difficult thing to do, to find a family like this who are generous enough to be involved in research and especially involved in research over the long term. HM: So how often do you see these family members? What do you look for? What do you do with them? BR: We're conducting a longitudinal observational study of the family involved in this research. What that means is we're studying them over time with each participant coming into the research clinic once a year and we take lots and lots of measurements of things like thinking ability and sense of smell. We also take a blood sample, which allows us to measure changes in molecules that we can measure in the blood, and we also take images of the brain using MRI. This study is observational, because we're not testing the family in any way, we're just observing what's happening to them over the course of their lives. What we're looking for are changes between the two groups in the family. One group is people in the family who will go on to develop dementia and the second group is people in the family who won't go on to develop dementia. Ultimately, we're hoping the changes we identify will be able to be used to develop a test that can then be used in the general population and we would use this test to identify people who are at risk of getting dementia sometime in the future. That would allow us to intervene before those people develop symptoms. HM: And have you had any initial findings? Have you seen anything come up that would suggest you can see those changes earlier? BR: This is a long term project and we started in 2016. So far we've collected data for all of our participants on at least three occasions and for some of them we've collected data five times now. We're currently in the process of analysing our first three years of data and the preliminary results of this are really exciting. They've shown that we can detect very early changes, for example, in thinking ability, so things like language ability, and also some memory changes we're finding those happening really early on in this family. So we're talking 30 years before symptoms are expected to develop and we can also detect a decline in sense of smell. These early findings are really exciting because they prove that we can see differences many years, and even decades, before people are expected to develop symptoms. They're also really exciting for us because they align with what similar studies are finding overseas. It's demonstrated that even with a single family, in a relatively small group of people, we are able to detect these early changes, which is really encouraging to us. I think the important thing is that this kind of work does take a long time, and so the support we've had from AMRF has been really critical to continuing this project. It's not the sort of thing you can complete in three years or even five years. We want to study this family for as long as possible to learn as much as we can about the really early stages of dementia because we have a really unique opportunity to work with this family. HM: Tell me are there other studies around the world that you can compare yourself to, or is New Zealand really doing something that the world is watching? BR: One of the great things that's happened recently is that we've had the opportunity to work really closely with similar studies around the world. There are other studies in Europe, America, South America and also studies are emerging in Asia as well that are doing similar work to what we're doing. This is really valuable because for the type of work that we're doing, the more data that we can combine the stronger our findings are going to be. For a relatively rare condition like frontotemporal dementia it really requires an international effort. It requires researchers from across the world to be involved in this effort. What this study has done is really put New Zealand on the map in terms of frontotemporal dementia research. It's allowed us to be involved in that international effort. What's really unique about our study, compared to these international studies, is the size of our single family. These international studies have a lot more people involved but they have people from many different families, with lots of different mutations. It is quite unusual to have a single, large multi-generational family like we have and it's also unusual to have people who are so generous with their time and able to keep coming back year after year to collect that long term data, which is really important. HM: Where would you hope to take this research? Is it limited to the dementia that you're working in? BR: I suppose my greatest hope for the research we're doing and research in this field in general, is we will be able to use this work to identify people very early and intervene at that point to prevent dementia symptoms from occurring. Initially, this work is relevant to a particular type of dementia, so frontotemporal dementia, and that in itself would be hugely significant if we were able to contribute to that area of research. The really interesting thing about this particular family, the particular type of frontotemporal dementia that they have, is that it involves a protein called tau which is the same protein that's involved in Alzheimer's disease. So we also hope that the findings from this study may inform research into Alzheimer's disease as well. HM: What made you want to work in this area? What led you to where you are now? BR: We know that four out of five New Zealanders know someone with dementia and for me that person was my grandma. She developed dementia when I was younger, and she passed away in 2019. So that experience of seeing her gradually lose her vitality gave me a small insight into what it was like to live with dementia. That was the first thing that got me interested in this as a research field. After finishing my PhD, I had the opportunity to work with Professor Maurice Curtis at the University of Auckland to establish a project centred around this particular family and working closely with people who are actually affected by dementia really appealed to me. It was a great opportunity for me to branch out and study a type of dementia that I don't think has had enough research attention previously. HM: Brigid, you must spend so much time with these people and form a real relationship with them - does that help give you the motivation to keep striving to get to the end? BR: Absolutely, and that's the thing that I love the most about this project, is being able to get to know this family and develop relationships with them. It's helpful in two ways. I think in the first step, as you've said, is this motivation to really want to work towards treatments for people in their situation in the future and, secondly, it's also given me a real insight to what it's like to experience a condition like frontotemporal dementia. It's so valuable for us as scientists, I think it's quite common to be working on a health condition that you don't actually know a lot about. So having the opportunity to talk to this family and spend time with them over the years has been hugely valuable for my understanding of frontotemporal dementia, dementia in general, and I find it really, really motivating and rewarding. It's also really important to point out that I'm not the only researcher involved in this project. It's a huge team effort. We're taking measurements of many, many different areas and that involves expertise from a large group of researchers and clinicians. Another important aspect of the study as well is that these researchers and clinicians come from different institutions so we have people from both the University of Auckland and the University of Otago working together on this project, which is really valuable. HM: So you're doing this work and you're able to identify someone who may show signs earlier, but we don't know what those signs are. What treatments, what interventions are available now? BR: That’s a really great question. There are no treatments or interventions that are available at this point. That's why the research we're doing is really one half of two parts of the wider research that's important in this area. We're working on identifying people really early so we can intervene and a whole lot of other researchers around the world are working on interventions that can be used at that point. I believe that because we are giving these other researchers the opportunity to deliver interventions really early, this is our best chance at preventing or treating dementia. The treatments that have been developed to date have all been used once people are already symptomatic and, unfortunately, those treatments haven't worked to cure or stop the progression of dementia at that point. I believe our greatest hope with preventing dementia is to intervene at this really early point and it might even be the case that some treatments that have been tried when people already have symptoms may actually work if we deliver them earlier. So, it might not be a case of developing new interventions, it might just be a case of repurposing those interventions that have failed at a later time point and trying to use them at a much earlier time. HM: Wow, that's an amazing thing to think that we might, you and your team might be able to get us to a point of. How phenomenal. Tell me how has AMRF helped in all of this? BR: The support I've had from AMRF has been really critical to both my career and also to this project. So because this project is longitudinal and it takes place over the long term, it is a difficult project to get funding for because we don't have results within a two or three or even five year timeframe. The support we've had from AMRF has been really valuable and from my point of view as a mid-career researcher, the AMRF Fellowship has been hugely important to my work. I would also like to acknowledge the Kelliher Charitable Trust for their support which has been in the form of additional funding via an emerging researcher award and also an extension to my fellowship. Personally, if it wasn't for the AMRF Fellowship, I would have had to seriously think about other career options either outside of science or outside of New Zealand.

With an elevated heart rate, hydraulic shock to vessels is increased, leading to higher impedance from the brain, negatively affecting imaging. The ability to separate the contributions from the cardiac cycle will enable two things: (1) better discernment at different physiological states and (2) improved diagnosis of different diseases and disorders. This movie shows the optical flow (vector arrows showing magnitude and direction of the relative movement of the brain) of a male volunteer baseline amplified MRI (aMRI). Through the AMRF's Sir Douglas Robb Memorial fund, Dr Eryn Kwon and collaborators were able to acquire and compare amplified MRI scans at resting and elevated heart rates for proof-of-concept testing of this technique. They found they were able to compensate for the additional brain motion seen in MRI caused by increased heart rate. From this preliminary funding, they can now expand their studies to further refine the technique and make the sequence viable as a routine clinical scan. As this is a post-processing technique, it is easily accessible for the general public and will improve diagnosis of neurological diseases, which is a significant health concern not just in New Zealand but worldwide. Read more about heart health, blood pressure, MRI and more medical research in our 2021 annual report.

The AMRF is pleased to have awarded Dr Arezoo Malihi a 2021 Postdoctoral Fellowship award to support her research and career. Here, Dr Malihi describes her important health research. My fellowship addresses a national priority for New Zealand but also a significant gap that has been identified by advocates and stakeholders who work directly with refugee communities. I aim to provide strong evidence-based foundations to improve the quality of the mental health services available to refugees in NZ. I will be using administrative data to develop a proxy measure of well-being across a range of health, education, employment and social factors such as neighborhood deprivation index. The findings of this research will provide, for the first time, critical insights at a population level into the mental well-being and service access rate of refugees. "Receiving an AMRF postdoctoral fellowship means opening an ideal opportunity to grow as an emerging scholar and contribute to the diverse fabric of New Zealand society." My work will help to better plan service reach in the NZ health system with culturally appropriate services to ensure an equitable service provision for this diverse group. In addition, the proposed measure that incorporates societal, community and individual factors could be potentially used for other important population groups, including Māori and Pacifica people provided that a subjective component of wellbeing is considered alongside the knowledge learnt from this administrative dataset analysis. My research will inform further data analyses for other health and non-health related outcomes for vulnerable groups which in turn informs policies that can improve their wellbeing. Collaboratively, my work will help the health system to plan strategies to improve mental wellbeing of all New Zealanders. Read more about all the health and medical research we fund in the Awarded Grants section of our website.

Read more now in the latest AMRF newsletter. You can read about the progress of research and the researchers supported by donors like you including: Medical researchers benefitting from a special Covid-19 relief fund for projects affected by lockdowns Professor Jennifer Weller and her team use their preliminary AMRF-funded studies to create real-to-life surgical simulations, significantly reducing patient risk in operating theatres throughout New Zealand. Dr Brigid Ryan, Mr Conor Nelson and A/Prof Debbie Young will present a free, online video event on July 6, discussing The Ageing Brain. Click here to watch the presentations from these neuroscientists. Early career researchers are at an exciting stage in their scientific development. Read more about them, including the international work of cancer researcher and AMRF doctoral scholarship, Dr Stacey D'mello. Click below to read and download the PDF newsletter