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THE PERFECT STORM behind

Welcome

Dear Garvan family,

It is a huge pleasure to welcome you to this first issue of Breakthrough in 2025.

Garvan is built on a foundation of more than 60 years of breakthrough discoveries. Thanks to you, we’re now working even harder to translate them into impact in patient lives.

Genomics, in all its many forms, is one of Garvan’s critical research strengths. In this issue, you will see how it helped solve a mystery in how viral infections can cause autoimmune disease, lighting a path to new treatments. You’ll read about Associate Professor Jodie Ingles’ work to identify the underlying genetic causes of sudden cardiac arrest, which may ultimately guide the development of new treatments. And finally, you will see an update from Stella, a remarkable girl whose life was transformed by Garvan’s genomics research.

When I was recently interviewed on the Garvan podcast Medical Minds, I had the opportunity to reflect on what makes up the kind of thriving research environment that gives rise to the next breakthroughs in science and medicine. Whether it’s researchers sharing reagents and ideas, our dedicated Garvan support staff enabling our work or the vision of our community of supporters – medical research is a team sport, and no discovery happens in isolation.

So I wholeheartedly thank you, our Garvan family, for your help in making extraordinary science happen.

Yours,

A mind for mysteries

From a mathematics and physics student in Siberia to a leading researcher in Sydney, Dr Ksenia Skvortsova’s scientific path spans more than a decade of discovery across developmental biology, evolution and cancer. Now appointed to Garvan Faculty, she brings her expertise to a fascinating question: why do women experience certain immune disorders more frequently than men?

Inside every cell in a woman’s body, a remarkable balancing act takes place. With two X chromosomes instead of one, female cells must silence one to function properly. “It’s like having two copies of an instruction manual, but only being allowed to read one,” Dr Skvortsova explains. “We’re discovering that sometimes the silenced copy gets partially read, which may trigger unexpected immune responses.”

Professor Benjamin Kile Executive Director

Leading the Developmental and Disease Epigenomics Lab, part of Garvan’s Precision Immunology Program, Dr Skvortsova aims to understand this intricate epigenetic process, potentially opening new pathways for treating conditions like lupus and rheumatoid arthritis.

Cover image: A 3D illustration of B cell activation

Dr Ksenia Skvortsova

Listen to the Medical Minds podcast featuring Professor Benjamin Kile

Discoveries in Focus

A cancer cell’s chaotic choreography

At first glance, this striking image above might remind you of a distant nebula or an exotic celestial body, with its ethereal core and cyan flares reaching outward against a dark background. But what you’re actually seeing is something much closer to home – yet equally fascinating: a cancer cell caught in an abnormal division process.

Captured by PhD student Cerys McCool in the Cancer Cell Plasticity

Lab at Garvan, this microscopic image reveals a cancer cell with four ‘spindle poles’ instead of the normal two. In healthy cell division, two poles orchestrate an elegant dance of chromosome separation. Here, we see chaos in action – the cell has developed multiple spindle poles (shown in white), while its DNA (in blue) and ZEB1 protein (in magenta) – a key player in cancer progression – create an almost cosmic display.

When I first saw this cell, it stopped me in my tracks.

PhD student Cerys McCool

“These aberrant divisions are relatively rare to catch in action, and the visual impact was stunning. It looked like something from a sci-fi movie, but it’s actually showing us how cancer cells go rogue.”

This image was captured using confocal microscopy, with special dyes that highlight different cellular components. It’s part of research led by Associate Professor Christine Chaffer, whose team is investigating how cancer cells can change their characteristics – a feature that makes them more aggressive and resistant to treatment.

By studying how and why cancer cells divide abnormally, McCool and her colleagues are working toward their ultimate goal: finding ways to prevent cancer cells from developing these aggressive characteristics and improving outcomes for cancer patients.

Cerys McCool

Medical research saved Karen’s life

On a bright morning in early 2020, Karen received a delivery she nearly dismissed.

It came from Australia’s National Bowel Cancer Screening Program, the sort of correspondence that often ends up relegated to a pile of unopened junk mail in a drawer. Less than a year earlier, Karen had undergone a routine colonoscopy that returned clear results, leaving her with no immediate concerns about her health. So, putting the test kit aside seemed harmless. Still, one day, something made her think, “What the heck, I may as well do it.”

That simple decision saved her life.

Five days after mailing her sample, Karen’s test came back positive for faecal occult blood. A followup colonoscopy then revealed the worst: she had rectal cancer.

Over the next two years, she underwent five weeks of tablet chemotherapy and radiotherapy, followed by major surgery to remove part of her large intestine.

Karen spent months with a stoma bag and endured much of her treatment alone, as COVID-19 lockdowns kept her family away.

Then came an even harsher blow. Nearly a year after her diagnosis, a routine CT scan revealed the cancer had spread to her liver. If the proposed treatment didn’t work, her oncologist said she might have just 12 months to live.

The gruelling regime involved undergoing 12 rounds of infusion chemotherapy and surgery to remove her gallbladder and half of her liver. Fortunately, it proved a success.

Though she never lost her sense of humour, her experience profoundly changed her. Now cancer-free, she advocates for early bowel screening and supports medical research at Garvan.

“I started by donating small amounts and reading Garvan’s newsletters,” she says.

I became a Partner for the Future by including Garvan in my Will. It’s my way of honouring what I went through and supporting the researchers whose work saved my life.

Instead of Christmas gifts, she asks her family to donate to Garvan’s research, which has led to significant breakthroughs in diseases like cancer. “We’re not all billionaires, but lots of small contributions add up. If every Australian gave $50, imagine what we could achieve.”

Now, five years after that fateful test, Karen’s story stands as a powerful testament to early detection and cutting-edge research. A single test saved her life, but she believes the next breakthrough will save many more.

For more information or for a no obligation conversation, please contact Rachael Arrott on (02) 9295 8559 or futuregiving@garvan.org.au or visit garvan.org.au/gift-in-will

Karen’s story is a testament to the power of early detection.

Karen, Partner for the Future

Transforming the future of cancer care

With global cancer diagnoses set to reach 30 million annually by 2040, the race to develop effective treatments has never been more critical. In our Translational Oncology Program, researchers are taking an innovative approach to this challenge.

“The traditional path from laboratory discovery to patient treatment can take decades,” explains Professor Marina Pajic, who co-leads the Program with Professor Anthony Joshua. “We’re working to change that by creating direct pathways between research and clinical implementation.”

The Program brings together laboratory scientists, clinicians, biostatisticians and patients to tackle some of the most aggressive forms of cancer.

It’s about creating an ecosystem where discoveries can move quickly but safely into clinical testing.

They’ve also identified two new potential drug targets – molecules (K11 and K12) – that show promise in preventing the spread of triple-negative breast cancer.

But discoveries like these are only the first step. Translating them into clinical impact involves collaboration across disciplines, cutting-edge tech, and a streamlined preclinical-to-clinical pipeline. Trials like PORCUPINE-02 – a study exploring combination therapies to target tumour microenvironments – are already underway, with others in development to tackle cancers with few effective treatments including those that develop resistance to current treatments.

“Understanding treatment resistance is crucial,” Professor Pajic says. “We need to understand why therapies stop working in some patients, as it helps us design more effective treatment combinations.”

Through partnerships with institutions from Melbourne and Adelaide to Toronto, the Program combines international expertise with local clinical innovation. As new molecular targets are identified, these findings feed directly into the next wave of clinical trials – creating a continuous cycle of discovery and testing.

We

have

active clinical trials in:

• Pancreatic cancer

• Triple-negative breast cancer

• Ocular melanoma

• High-risk neuroblastoma

• Prostate cancer

At the heart of the Program’s work is precision medicine, an approach that uses the molecular makeup of a tumour to guide treatment. Researchers are uncovering dynamic mechanisms of cancer resistance – the co-operative interactions between genetic signals, tumour microenvironment factors, including immune system – and new ways to target them.

This precision approach has opened several promising directions. Using cellular barcoding and single-cell analysis, researchers are tracking how cancers evolve and spread, particularly in pancreatic cancer.

• HPV-negative oral squamous cell carcinoma

• Ovarian cancer

• Appendiceal cancer

Professor Marina Pajic and Professor Anthony Joshua

The Translational Oncology Program is supported by The Patricia Guest Foundation and Joseph Palmer Foundation.

Professor Anthony Joshua

How do viral infections trigger autoimmune disease?

The three genetic changes that make defender cells turn rogue

Research Program is

The HOPE

supported by Mr Ken Allen AO and Mrs Jill Allen, John Brown Cook Foundation, Croall Foundation, The Bill and Patricia Ritchie Foundation, Niki Scevak and Sarah Davin, and Miss Lyn Unsworth.

Image: A 3D illustration of B cell activation

In a study that challenges long-held scientific beliefs, Garvan researchers recently uncovered a ‘perfect storm’ of mutations by which viral infections can lead to devastating autoimmune conditions. The discovery, focusing on hepatitis C virus (HCV), provides new hope for millions affected by autoimmune diseases worldwide.

The research team, led by Professor Chris Goodnow, investigated how HCV triggers cryoglobulinemic vasculitis – a serious autoimmune condition that occurs in up to 15% of HCV cases. This condition causes antibodies to attack blood vessels, potentially damaging organs throughout the body.

Contrary to the previous theory that viral proteins merely confused the immune system by mimicking the body’s own proteins, the team discovered that the real cause is a complex series of mutations in immune cells called B cells.

This discovery fundamentally changes our understanding of how infections can cause autoimmune conditions.

While two of these mutations occur normally in B cells, the third mutation – typically associated with blood cancers – happens by chance over time. When these three mutations combine, they allow harmful ‘rogue clone’ B cells to multiply dramatically, triggering the autoimmune response.

Dr Dan Suan, Clinical Director of the Hope Research Program at Garvan, says: “While we’ve focused on HCV, these findings have broader implications for predicting and preventing autoimmune complications.” The insights could prove valuable for understanding other infection-associated autoimmune conditions, including Guillain-Barré syndrome and multiple sclerosis.

The research opens exciting new pathways for treatment. Rather than simply managing symptoms, future therapies could target the root cause of autoimmune diseases by preventing the formation of these harmful antibody clusters or intercepting the mutation process before it leads to autoimmune complications.

“Understanding how mutations can drive autoimmunity is a significant step forward in our mission to eliminate the root cause of autoimmune disease rather than just managing symptoms,” says Dr Suan.

“By pinpointing these rogue clones, we can better understand how to target them, which is a potentially transformative approach to treating autoimmune disease in patients.”

Using sophisticated single-cell analysis and whole genome sequencing, the researchers identified a ‘perfect storm’ of three distinct mutations that must occur for the autoimmune disease to develop. Dr Clara Young, the study’s lead author, explains: “During a chronic hepatitis C infection, antibodies on the virus surface form an antibody cluster that persistently stimulates the B cells to mutate.”

This ongoing stimulation creates the perfect environment for these mutations to accumulate.

Do you know?

• Up to 15% of people with hepatitis C develop a serious autoimmune complication

• This is the first time scientists have mapped how distinct mutations caused by infection lead to autoimmune disease

• The research could help develop treatment for numerous autoimmune conditions

• The findings challenge 30+ years of scientific understanding

Dr Clara Young

Dr Daniel Suan

Professor Chris Goodnow

A metabolism switch that could help stop pancreatic cancer

How blocking a molecule that regulates metabolism could slow pancreatic cancer spread.

Garvan researchers have uncovered how pancreatic cancer hijacks a crucial metabolism ‘switch’ to help it spread, revealing a potential new treatment strategy for this highly aggressive disease.

The research, published in Science Advances, identifies the molecule Neuropeptide Y (NPY) as a key driver of pancreatic cancer metastasis – the process by which cancer spreads to other organs. This discovery offers new hope for pancreatic cancer patients, who currently face one of the most aggressive forms of cancer, with only a 13% five-year survival rate.

“NPY is a signalling molecule best known for its role in regulating metabolism, appetite and satiety. By blocking its function in preclinical models, we found we could substantially reduce the spread of pancreatic cancer to the liver, the most common site of metastasis in patients,” says Dr David Herrmann, senior author of the study and Group Leader at Garvan.

The study is the first time the role of NPY has been investigated in pancreatic cancer metastasis, building on previous research that linked the molecule to cancer progression in breast, prostate and neuroblastoma cancers.

We found the signalling molecule NPY to be significantly higher in pancreatic cancer cells compared to normal tissue. Our preliminary findings reveal this molecule as a promising target to investigate further for pancreatic cancer.

The team has already developed an antibody designed to neutralise NPY’s effect safely in the human immune system and is testing it in preclinical models. The next phase involves optimising this approach alongside existing treatments.

“One of our next steps is to refine how we use this approach in combination with chemotherapy,” says Dr Herrmann. “There’s growing evidence that timing is critical – thus determining whether NPY inhibition is most effective when introduced before or after chemotherapy is important. Understanding this will be key to translating our findings into clinical trials, and ultimately to improve the outcomes of this disease.”

This research was supported by Suttons Motors Management, Tour de Cure, Sydney Catalyst, Ainsworth 4 Foundation, Mr Len Ainsworth AM, The Ronald Geoffrey Arnott Foundation, In Memory of Dr and Mrs Wing Kan Fok, Girgensohn Foundation, The Late Mr Philip Hemstritch, The Kinghorn Foundation, Snow Medical Research Foundation and the Baxter Charitable Foundation. The project was made possible by grants from PanKind, The Australian Pancreatic Cancer Foundation.

Dr David Herrmann

Pancreatic cancer cells (green) colonising a secondary site in the liver (purple)

Photo credit: Dr Kendelle Murphy

Championing heart research

A community rallies to honour Josh’s legacy and advance research into sudden

cardiac arrest.

Each year, around 3,000 Australians under the age of 50 experience sudden cardiac arrest, a life-threatening event caused by an abnormal heart rhythm that prevents the heart from pumping blood effectively. Typically, those affected have no prior health conditions, and only one in ten survive to reach the hospital. With no warning signs often present, the loss can be devastating.

This was tragically the case for Josh Avvenevole, a beloved son, brother and friend, who passed away from sudden cardiac death at just 26. In his memory, Josh’s family and friends, driven by his passion for sports and science, organised the Heart of the Green charity golf event last October.

Go4Garvan at City2Surf

Support from our community is essential to accelerate our medical discoveries. You can help us make a difference by joining this year’s City2Surf on 10 August, either individually or as part of a team, and fundraising for our lifechanging research.

To contact us, please call (02) 9295 8110 or email community@garvan.org.au

Their efforts raised an incredible $85,577 to support research led by Associate Professor Jodie Ingles and her team at Garvan. Their work focuses on cardiac genomics and genetic counselling to improve outcomes for those with inherited cardiovascular diseases.

“The unimaginably sudden and unexpected cardiac death of a young person is something that a family will always live with,” says Associate Professor Ingles, Head of the Clinical Genomics Lab and Co-Director of the Genomic and Inherited Diseases Program at Garvan. “We need to identify the risk factors so that we can better identify, monitor and treat those at risk.”

A key part of this research is the NSW Sudden Cardiac Arrest Registry, which collects valuable data to understand the causes of sudden cardiac arrest in young people. This registry helps predict risk and improve care for affected individuals and families. To date, 61 participants have joined the registry, contributing to the growing effort to tackle the issue.

The IMPROVE-SCA initiative, another project spearheaded by Associate Professor Ingles, is expanding nationwide. It aims to improve access to care for families affected by sudden cardiac arrest. By connecting healthcare professionals, using online platforms and focusing on genetic factors, the initiative’s goal is to improve risk identification and provide better support for those affected.

Left to right: Archie Cullen, Sarah Cullen, Associate Professor Jodie Ingles, Jenny Avvenevole, Anthony Avvenevole, Ben Avvenevole, Jo Cullen

Garvan team at City2Surf 2024.

Stella’s story

At three weeks old, Stella developed a life-threatening condition that left doctors puzzled. Then genetic testing provided an answer that saved her life.

Stella is like any other nine-year-old – she loves gymnastics, hockey and her friends, and dreams of one day becoming a teacher. But her journey has been far from ordinary. Shortly after she was born, Stella developed a rare immune disorder that left her with a 50/50 chance of surviving past the age of 20.

At three weeks old, blisters began to form on Stella’s skin, shedding so severely that her mother, Collien, had to vacuum the bed each morning. Initially thought to be baby acne, her condition worsened, and she was diagnosed with ‘failure to thrive’, along with severe allergies and eczema. A feeding tube was inserted in her nose to help her gain weight, and her parents took turns watching over her to prevent her from scratching her raw, bleeding skin.

Desperate for answers, the family visited numerous specialists without success. Finally, they were referred to the Clinical Immunogenomics Research Consortium Australia (CIRCA), a network focused on challenging immune diseases. Genetic testing revealed that Stella was one of only five people in Australia with DOCK8 immunodeficiency syndrome, a condition that devastates the immune system.

“DOCK8 is important for maintaining the shape and integrity of immune cells,” explains Professor Stuart Tangye, who leads CIRCA with immunologists and clinicians from Garvan and other organisations across Australia and New Zealand. “Without it, these cells can’t move through the body properly and are too fragile to protect against viruses, bacteria and fungal infections. Without treatment, life expectancy drops significantly.”

The only treatment for DOCK8 deficiency is a bone marrow transplant, a risky procedure involving chemotherapy to destroy malfunctioning bone marrow. At just two years old, Stella underwent the life-saving transplant at Sydney Children’s Hospital, receiving a 100% bone marrow match.

Recovery was challenging, and there was a real fear she wouldn’t survive. But Stella fought through. “She was, and still is, incredibly resilient,” says her father, Nico.

Stella’s diagnosis transformed her life. Despite ongoing battles with the effects of DOCK8, and regular visits to specialists, her family is reminded of her progress.

If Garvan hadn’t done the genetic testing, she wouldn’t have survived. Her quality of life was so poor, and her life expectancy so short, she would not have made it to age 10. We would have lost a child.

Stella will need lifelong medical monitoring, but her diagnosis has given her a chance to be like any other nine-year-old – enjoying school, spending time with family, and dreaming of a future now filled with possibilities.

CIRCA is supported by John Brown Cook Foundation and The Corio Foundation.

Stella’s mother, Collien

Stella with CIRCA members Professor Stuart Tangye (left) and Associate Professor Paul Gray (right)

Stella and her mother, Collien

Supporting those affected by rare disease

In recognition of World Rare Disease Day on 28 February, we launched Garvan’s Genomics of Rare Disease Registry, a national initiative designed to better understand rare inherited diseases and connect families with valuable research opportunities. With over 7,000 known rare diseases affecting around two million Australians, many of these conditions have unknown causes but are suspected to be genetic in nature.

The Genomics of Rare Disease Registry is part of a nationwide study focused on uncovering the genetic causes of these diseases. The goal is to improve our understanding, identification and management of rare inherited diseases. By joining the registry, families impacted by these conditions can gain access to cutting-edge research and studies aimed at finding genetic diagnoses and advancing treatment options.

We are inviting people who meet the following criteria to participate:

• Those with a rare disease that has a known genetic cause.

• Those with a rare disease suspected to have a genetic origin, such as a family history of the condition.

• Family members of individuals living with an inherited rare disease.

How to participate:

• To get involved, please complete the Expression of Interest form on our website using the link below.

What does participation involve?

• Providing informed consent to access your medical records.

• Completing a brief 15-minute survey at the beginning of the study.

• Agreeing to be contacted about future research opportunities. The study has been approved by the Royal Children’s Hospital Human Research Ethics Committee (reference number 95179).

For more information, or if you have any questions, please visit garvan.org.au/rare-disease-registry