This issue has several stories focusing on diabetes, both type 1 and type 2. SVI arguably has the largest group of type 1 diabetes researchers in Australia and a very significant group doing research on type 2 diabetes.
The work occurring in the labs at SVI is based on our strong belief that improved treatment and new preventative strategies will only follow a greater understanding of disease processes. Mechanisms under investigation include interaction between the cells that produce insulin and the immune system, and understanding how different cells in the body and the molecular pathways within them work together to control blood glucose – when these pathways are faulty, diabetes can develop.
Both type 1 and type 2 diabetes represent serious challenges. Despite the fact that major advances have been made in understanding how type 1 diabetes develops, it is still treated by replacing insulin and not yet by treatments based on these advances in knowledge. Type 1 diabetes places a significant burden on people with it and their families whereas the rapid rise in type 2 diabetes means it is a challenge for society as a whole. As type 2 diabetes researchers Zane Andrews and Sandra Galic explained at our recent ‘Food Matters’ event, losing excess weight can be tremendously difficult; evolution has dictated the advantages of holding on to that weight. We all need to develop healthy living strategies that are more sustainable than diets that last a few weeks – and also pass on these healthy lifestyles to prevent the next generation putting on excess weight. Researchers in our Protein Chemistry and Metabolism Unit are working to better understand the metabolic pathways in our liver, muscles, fat cells and our brain and how these pathways interact with each other to govern energy usage and thereby, weight gain and loss.
The path to achieving our goals is by no means well mapped out: it relies on a detailed and rigorous scientific approach and working with collaborators to put different pieces of the puzzle together, incorporating the diverse skills needed to take projects towards clinical application.
The collaborators we seek out to develop our research include clinicians at St. Vincent’s and other nearby hospitals who have a tremendous understanding of the current challenges that face people with diabetes. We also collaborate with industry experts, who have the skills to establish clinical trials of new treatments and accelerate their progress to clinical use. One really great part of research is the international links and friendships that develop to advance our work.
Another important group of partners is people with diabetes – who not only provide a crucial consumer perspective but also participate in the research itself. You will read about several families who have toured SVI recently. Tours provide a first-hand opportunity to meet our scientists and hear about the most recent research advances. They also provide an occasion for our researchers to understand what questions are top of mind for those dealing with diabetes on a day-to-day basis. Of course there are many immediate concerns, but there is always the underlying hope that treatments will improve and new means of prevention will become available. We know that many advances will happen during the lifetimes of people we meet today – and researchers at SVI are focused on making those advances happen faster.
Inspiring future scientists
Dr Jess Holien captures the attention of Year 10 science students from Genazzano FCJ College, with her presentation on three-dimensional protein structure and drug design. August proved to be a busy month for SVI outreach, as we also hosted tours for Year 11 students from FCJ College Benalla and Year 10 students from St Columba’s College Essendon.
Deputy Director awarded NHMRC Fellowship
Associate Professor Natalie Sims has been awarded a Research Fellowship in the most recent round of NHMRC funding, announced in August.
Natalie’s work is focused on understanding the signaling pathways that control bone development and growth, with the aim of using these pathways to influence the outcome of bone disease such as osteoporosis.
Natalie says that the design of the Eiffel Tower was based on the structure of bone. This isn’t just the obsession of a single-minded scientist who sees her work reflected in the world around her. Apparently, Gustav Eiffel, when designing his now famous tower, was influenced by the work of anatomist Hermann von Meyer, who published some of the first detailed studies on the internal structure of the human thighbone.
Natalie says, “The pattern of struts and spars in the Eiffel Tower distributes weight and stress in the same way that the internal structure of bone – called trabecular bone – does. This means that our bones are light, but are still able to absorb the forces that occur when we jump a puddle or run for the tram.”
Natalie says that while we need our bones to be hard, this feature poses some unique difficulties for researchers like her. First, the nature of the tissue itself. “Because bone is so hard, we can’t easily see what is happening inside it – it is particularly complicated to cut through bone without destroying its internal structure unless you use specialised methods. For obvious reasons, we also can’t easily get samples from patients. In addition, bone structure is different in every part of the body - you can’t take a sample from the base of the Eiffel Tower and use that to understand what a bit at the top might be like. In the same way, what is happening inside say, the ankle, is often different to what is happening in another part of the skeleton.”
As a PhD student, Natalie spent a lot of time looking at bone slices down a microscope.
“Right about that time, people were starting to develop genetically modified mice and there was a real need for expertise in bone structure to help understand the influence of specific genes on that structure.”
Thanks to the skills that she has developed since then, Natalie has been highly sought after as an expert on bone structure . Much of her own career has been focused on studying the cells and signaling pathways that are responsible for the way that bone is composed. In 2018, she took on new responsibilities when she was appointed Deputy Director of SVI, an acknowledgement of her leadership role at the Institute, and of the high esteem in which she is held in the scientific community.
Recent studies from Natalie’s team have used genetically modified mice and the power of the Australian Synchrotron to examine bone structure in unprecedented detail – detail which Hermann Von Meyer himself could not possibly have imagined.
Sharing expertise in type 1 diabetes
Since its inception in 2007, SVI’s Islet Transplant Program has allowed 40 people with type 1 diabetes to be transplanted with insulin-producing islets to treat the severe hypoglycemic episodes that affected them.
In addition to this success, the Program has also provided an opportunity to train clinicians from around the world, who have visited SVI to learn the steps required to establish a successful procedure.
Most recently, Dr Pereyra Bonnet Federico, of the Instituto Universitario del Hospital Italiano de Buenos Aires, visited SVI for 3 months. During that time, he received training in the Susan Alberti Islet Transplant Facility, from Facility Manager, Dr Tom Loudovaris.
In order to transplant human islets from deceased organ donors, islets must be isolated in a “cleanroom facility”, following good manufacture practice (GMP) guidelines issued by government regulatory authorities. Dr Federico was trained in isolating islets following GMP policy guidelines with the aim of establishing the procedure in Argentina.
Upon his return home, in addition to establishing the program, Dr Federico plans to create a biobank of pancreatic islets to provide biological material for diagnostic and medical research groups in the region, and potentially provide access to rare material for Australian researchers. He also hopes to establish his Institute as a reference institution in Latin America for the training of medical professionals, and to provide a site for staff and student exchange and training with SVI.
What is the difference? Type 1 and type 2 diabetes
Despite the similarities in their names, type 1 and type 2 diabetes are different diseases, with diverse origins. What they have in common is that they are both chronic conditions that affect the way the body regulates blood glucose levels.
Glucose provides the energy that fuels the body’s cells. In order for glucose to be accessible to the cell, the hormone insulin is required. In a way, insulin is like a key that allows glucose to enter the cell.
People with type 1 diabetes have lost the ability to produce insulin – they simply don’t have a key. People with type 2 diabetes don’t respond to insulin as they should and some don’t make enough insulin. This is analogous to having a broken lock.
In people with type 1 diabetes, the body’s immune system mistakes its own healthy insulin-producing cells as foreign invaders. Subsequent destruction of these cells means that the pancreas can no longer produce insulin. People with the disease need to inject supplemental insulin from the time of diagnosis. The causes of the disease are unknown, but are likely to involve a combination of genetic and environmental factors. The disease can strike at any age, but is most commonly diagnosed in childhood. There is no cure and insulin is the only treatment.
In people with type 2 diabetes, the body’s cells become resistant to the effects of insulin. The pancreas tries to compensate by producing more insulin and eventually the insulin-producing cells become exhausted and stop making the hormone. Because the body’s cells are insulin resistant, they cannot take up glucose, and glucose builds up in the blood.
Type 2 diabetes is the more common condition – about 90% of the people affected by diabetes have type 2. Treatment involves lifestyle modification, including weight loss and exercise, as well as medication to reduce the risk of complications and slow the disease. Type 2 is most commonly diagnosed in adulthood.
There are two large groups of researchers at SVI who are focused on finding ways to treat type 1 and type 2 diabetes. Research in the Immunology and Diabetes Unit covers fundamental to clinical studies, working on understanding why the insulin-producing cells are killed in the first place, how to stop the disease from progressing and improving treatment options.
In the Protein Chemistry and Metabolism Unit, scientists are working to understand how the body regulates its use of energy, focusing on the role of a protein called AMP-activated protein kinase (AMPK). Through their work, they hope to better understand AMPK’s broad role in the body, including in heart disease, cancer and rebound weight gain. By finding ways to control AMPK’s functions, they hope to provide new ways to treat diseases like type 2 diabetes.
Dr Satoru Akazawa is a postdoctoral researcher in SVI’s Islet Biology Laboratory. His research focuses on type 1 diabetes, particularly on the early events that trigger development of the disease.
I ended up working in the area of islet biology because… I took part in the Immunology of Diabetes Society Congress in 2013 in Melbourne and shook hands with Tom (Kay, SVI Director). After that meeting I decided I wanted to work at the Institute.
If I could give young researchers advice… I would tell them to have fun, and to engage in what they have an interest in.
What I like most about working at SVI… is being surrounded by friendly colleagues. I also love the location; we’re located near the Carlton Gardens where I sometimes have lunch on sunny days.
If I wasn’t doing research…I would be spearfishing, which I enjoyed when I was a college student in Japan.
Satoru is currently the recipient of a Juvenile Diabetes Research Foundation (JDRF) Fellowship.
Accelerating treatments for type 2 diabetes
SVI’s Associate Professor Jon Oakhill was recently awarded funding from the 2018 round of the Victorian Medical Research Acceleration Fund (VMRAF).
Jon’s research is focused on finding new ways to treat type 2 diabetes. His project revolves around a molecule called SC4, which is a promising type 2 diabetes treatment.
A long-term metabolic disorder, type 2 diabetes is characterised by high blood sugar, insulin resistance, and relative lack of insulin. It can lead to life-threatening conditions and long-term complications associated with damage to kidneys, eyes, nerves and blood vessels. Recent work from Jon’s lab represents a significant advance in the effort to design a type 2 diabetes drug which one day could be used to treat the more than 500 million people affected by the condition.
One of the proven ways to lower blood glucose is via exercise. Exercise’s effect is mediated by an enzyme called AMP-activated protein kinase (AMPK). AMPK is sometimes called the body’s fuel gauge – when it recognises that fuel levels are low, as in the case of a muscle after exercise, it switches on, prompting the cell to find ways to replenish its reserves, for example, by absorbing the glucose found in the bloodstream.
AMPK has long been pursued as a drug target for type 2 diabetes. A drug which could specifically activate the enzyme in muscle would artificially mimic the effect of exercise and reduce blood sugar levels. However, Jon says that the work has been complicated by the fact that there are many different forms of the enzyme present in different tissues at different levels throughout the body.
“Our breakthrough came when we found SC4, after sifting through hundreds of existing activators of AMPK, and could show that it was able to specifically activate the type of AMPK present in skeletal muscle. It was a bit like finding a needle in a haystack,” says Jon.
After identifying SC4 as a promising candidate, the team made another breakthrough, thanks to the expertise of resident crystallographer, Dr Chris Langendorf. Chris used a technique called X-ray crystallography to determine the three-dimensional structure of the SC4 compound physically bound to AMPK.
“Without the three-dimensional structure you’re driving blind,” says Jon. “The structure gives you a map – you’re able to see how your compound structure fits into the protein and understand how you can increase its potency or specificity. It’s an essential part of refinement in the drug development cycle.”
The VMRAF scheme was established to fast-track innovative projects from research to reality – leading to better treatment for patients in Victoria and across the world. Jon’s project, in collaboration with Monash University’s Professor Jonathan Baell, was one of 30 projects funded.
The next step for the team, and the goal of the project funded by the VMRAF, is to improve the compound to make it a better drug candidate. The group will then test the resulting compounds in animal models of type 2 diabetes. They already have promising results showing that the presence of SC4 helps skeletal muscle absorb more glucose, thus lowering blood glucose more effectively.
“In the long run this has the potential to lead to an alternative to insulin injection for people with type 2 diabetes and could be particularly useful for people who have difficulty exercising. It’s not at clinical trial stage yet, but we’re on the right track.”
Image: Different subunits of the AMPK enzyme shown in yellow and pink, showing the binding site of the SC4 compound
David shares his story
David was 13 when he was diagnosed with type 1 diabetes.
“I was with my Aunt Kate one night, and while I wasn’t feeling unwell, she noticed I was drinking and weeing a lot. She has type 1 diabetes, so she told my Mum. The next day we went to the doctor.
After a urine test, the doctor sent us straight to the Royal Children’s Hospital where they confirmed the diagnosis after a few blood tests. While above the normal range, they initially weren’t sure if I had type 1 diabetes. Looking at my family’s health history we found that, in addition to Aunt Kate, there were multiple occurrences back in the 1920s.”
David’s mother Jeni says that for the first 6 months, she thought life would never be the same again. “Initially we felt unprepared, out of our depth and shattered. But our life has returned to normal.
I recall my sister Kate saying, ‘Nobody understands my condition’, and now I know what she means. Most people have very little knowledge of type 1 diabetes, and when they do, it is often confused with type 2.
While David’s diagnosis came as a shock, type 1 diabetes hasn’t stopped him from leading an active life. A year after his diagnosis, he’s ridden 300km in 5 days, sailed in a state championship, rowed in the Head of the River competition, and participated in a week-long surf camp.
He constantly uses his blood monitor that transmits to our phones and, when he is on camp, his teachers’ phones. An alarm sounds when his blood glucose level is too low or high. It doesn’t replace finger pricks, but gives greater peace of mind.
It is wonderful to know of the research that is going into prevention for people predisposed to type 1, and I hope the knowledge continues improving at the current rapid rate to help those living with the condition.”
Image: David (right) with his mother and brother
A special type of supporter
While SVI has Australia’s largest complement of type 1 diabetes researchers, we’re also starting to build one of Victoria’s largest communities of type 1 diabetes research supporters.
In the last 6 months alone, these people have advocated, cajoled, begged, pleaded, organised and executed their way to over $50,000 worth of type 1 diabetes research dollars for SVI.
So, what drives these people to give up their weekends and evenings, why do they choose to support SVI and what are their hopes for the future?
Julie Merrett, Walkers of Merrett
“When the first of our children, Christian was diagnosed with type 1 diabetes, he was 3 years old. His twin brother, Noah, was diagnosed 2 years later. We were contacted by the Juvenile Diabetes Research Foundation to become ambassadors for them and during this time we met other families fundraising for research. After a while, a friend and I started up Walkers of Merrett and found ourselves hosting Gala balls and other smaller events.
No one has to fundraise to the extent we have, but if everyone living with this disease does just a little bit, our researchers will have all opportunities possible to find a proven prevention to stop this hideous disease and a cure for it, and our future will look brighter.
Despite government funding, I feel more funds are needed to give all research bodies the funding they need to put every resource they can towards each and every project.
Sadly, for a time I had lost hope for a cure. Technical treatments are on the rise and we will always be so grateful for that. I was desperate for a cure though - and a prevention, so that my eldest child didn’t develop this disease. Two children in one household was already too hard, it is heartbreaking and inconceivable to consider a third.
While deciding if we would hold one more, and maybe last, fundraising event, we approached SVI, asking what research projects were currently active and in need of funding. We were invited to the labs to see for ourselves what they were working on and meet the researchers. As we left the building after an enlightening and emotional couple of hours, we decided we would host another event, our 6th Gala Ball, and we would call it HOPE.
Associate Professor Stuart Mannering, who we had met during our visit, attended the event and spoke about his research.
Our hopes for medical research for the future? Simple. A prevention for Joshua and millions of other people around the world, and the biggie... a cure for Christian and Noah and the many thousands of other type 1 diabetes sufferers. We have faith this will happen.”
Danielle Romanes, Type One Melbourne
“Type 1 diabetes treatments have come a long way since insulin was first discovered in 1923, and type 1 diabetes is a more manageable condition as a result.
This wouldn’t be the case without the efforts of researchers like those at St Vincent’s Institute, whose work couldn’t happen without community philanthropy and support.
In our lifetimes, we hope to see new treatments to better control, prevent, and eventually cure type 1 diabetes, and will be doing all we can to help SVI get there.”
Type One Melbourne held a Type One Trivia Night, where Associate Professor Helen Thomas spoke about her research and led one of the trivia rounds.
Other SVI type 1 diabetes fundraising activities included T1 Troopers’ Race Day in May (led by Amanda Lenehan); Walkers of Merrett supporter Debra McCormick raised funds for SVI at a HealthExpo; and Erica Marriott raised $2000 in lieu of presents for her thirteenth birthday – pretty amazing!
The funds raised support research in the laboratories of Helen Thomas and Stuart Mannering. Stuart is trying to gain a better understanding of why T cells attack the body’s insulin producing cells. Helen and her team are working on preventative therapies to both protect the beta cell and calm the immune system. With promising recent results, she is hoping to test her approach soon in a clinical trial.
Image: Julie Merrett’s twins Christian and Noah
Investing in young talent keeps memories alive
Tony Reeves, Chair of the SVI Board, and his wife, Margaret, a long-time member of SVI’s Support Group, are supporting Top-up Scholarships for students Vanessa Tsui and James Beddoes, from SVI’s Genome Stability Unit. Tony and Margaret previously donated to the SVI Top-Up Scholarship Program in honour of Margaret’s mother Margaret Mocatta, in 2012, supporting then-PhD student Alannah Green.
“It is the memory of my parents that continues to inspire us to keep their values alive, while supporting the bright young minds of science. My parents passionately dedicated their lives to improve the health of others, so we think it’s fitting that we support students who are committed to alleviate the pain and suffering that disease can cause,” says Margaret.
Margaret Reeves’ father Lawrence joined the Flying Doctors Service after serving in the war and gaining his medical qualification on his return. He was based in Katherine when he met Margaret, who had gone to the Northern Territory as a nurse to ‘have a bit of an adventure’.
The devoted couple had four children together; Lawrence eventually specialized in dermatology and set up a practice in Darwin. Tragedy struck when Lawrence, an avid sailor, was lost at sea in bad weather while sailing from Brisbane to Darwin with friends.
Margaret, who was only 36 at the time, had to become both mother and father to their four children. She wrapped up Lawrence’s practice and settled in Lismore NSW, where she returned to nursing. She worked for 22 more years at Lismore Base Hospital, and eventually became Deputy Director of Nursing, while continuing to be a devoted mother and grand-mother. Margaret sadly passed away from lung cancer in 2001.
The Reeves hope that Vanessa and James’ work will help future cancer sufferers. Vanessa studies the genetics of a rare disease, Fanconi Anaemia. “What we learn from this disease will help us to develop new treatments for common cancers. Thanks to Tony and Margaret’s generous support, I am able to continue my aspiration of becoming a researcher who improves human health. The financial support of $5,000pa during my PhD will allow me to devote all of my attention and effort to my work,“ she says.
“For my Honours project I am investigating an exciting new approach to kill cancer cells, such as those found in breast and ovarian tumours. The precise nature of this method targets only cancer cells and leaves healthy cells unaffected,” says James. “I am extremely grateful to be a recipient of a Top-up Scholarship. The support allows me to focus on my studies, without the added stress of part-time work.”
“Having met Vanessa and James, we know the future of medical research is in good hands,” says Tony.
Named PhD scholarships require a 3.5 year commitment of $5,000 per year. If you would like to create a named Scholarship in honour of a loved one, please contact SVI Foundation CEO, Kate Barnett on (03) 9231 2480.
Image: (l-r) James Beddoes, Margaret Reeves, Tony Reeves, Vanessa Tsui