Formed in 2010, Snowdome seeks to improve outcomes for Australians with blood cancers (myeloma, lymphoma, leukaemia). The charity’s aim is to ‘unlock new treatments’ by channelling government and philanthropic investment into early phase human clinical trials of next-generation drugs and therapies.

So how is pathology involved?

Molecular pathology techniques are used to diagnose all blood cancers including myeloma, leukaemia and lymphoma.

Pathology testing also shows how a person is responding to a novel treatment during clinical trials, and for patients who may have exhausted other options, access to these treatments can be lifesaving.

Snowdome funds projects based at several different institutions including the Peter MacCallum Cancer Centre and Epworth HealthCare.

Nicole Brooks, Research Program Manager, Molecular Oncology and Cancer Immunology Department (MOCI) Epworth HealthCare said;

“As researchers, we want to ask more questions and as a result of the efforts of the Snowdome Foundation, Epworth Medical Foundation and other philanthropic organisations we are in a fortunate position to continue our research efforts.

“Our research is not just tinkering in the lab in the way many people might think. Rather, a group effort to provide desperate patients an alternative option and when we can prove that something is actually working, we can then make a case to get access to new drugs for more patients.”

As cancer therapy is increasingly delivered as precision treatment, this requires precision diagnostics.

Dr Piers Blombery is a Consultant Haematologist and medical lead of Peter Mac’s Molecular Haematology Laboratory. This lab runs an Australia-wide genomic testing service which from a blood sample can identify genes or genetic irregularities known to drive cancer.

“For the patient it’s no more difficult than a standard blood test, and the information we get is very powerful in guiding and personalising their treatment,” says Dr Blombery.

“It often means we can rule out approaches that won’t work, or will have a very poor response, and instead go down treatment pathways that should get the best results.”

For example, every year about 1000 Australians are diagnosed with chronic lymphocytic leukaemia (CLL). Genomic testing can reveal whether these patients have either an IGHV or TP53 gene irregularity.

Both are clinically important. CLL patients with an IGHV irregularity respond well to standard chemo-immunotherapy, and this treatment can give them long-term remissions.

“Alternatively, we also know CLL patients with a TP53 irregularity will likely have a very poor response to standard chemo-immunotherapy,” Dr Blombery says.

“These patients do better on novel agents such as BTK inhibitors or BH3-mimetic agents which are currently accessible through clinical trials or compassionate access programs.”

“It is genomic testing that allows us to find these irregularities and ensure patients get the treatments most likely to work for them.”

Dr Blombery also said when performing genomic testing, new clinically important gene irregularities can be discovered. These are passed to researchers who are looking to better understand the fundamental drivers of cancer.

“The more of these gene irregularities we know of, the more we can develop potential new anti-cancer drugs and also personalise treatments so patients have better outcomes.”

Miriam Dexter, CEO of Snowdome Foundation, said;

“Based on international evidence, we know that patients have better outcomes on clinical trials, but many people will be unaware that due to our small population, Australian patients are rarely included in blood cancer trials”.

“That is the mission of Snowdome, to ensure more early phase clinical trials are initiated here in Australia.”

The type of research we fund is not confined to the laboratory, but relies on pathology testing to monitor success and manage patient welfare, as well as the development of companion diagnostic tests that are the gateway to novel therapies.”

To learn more about Snowdome Foundation visit snowdome.org.au

IMAGE: Supplied by Snowdome Foundation, taken at Cartherics Lab (MHTP).

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Dementia refers to a group of neurodegenerative diseases including Alzheimer’s disease, frontotemporal dementia, and vascular dementia. Neurodegeneration is the progressive loss of structure or function of neurons – the building blocks of the nervous system. The most common form of dementia, responsible for 60% – 80% of cases, is Alzheimer’s disease.

Alzheimer’s disease occurs when a protein called beta-amyloid accumulates in the brain.  When this protein reacts with copper and iron, which are found in high levels in the brain, a chemical reaction similar to rusting occurs and this damages brain cells so that they can no longer effectively transmit information.

Diagnosis and the role of research

A 100% accurate diagnosis of Alzheimer’s can only be made after death when brain tissue can be analysed under a microscope by a pathologist. There are tests that can diagnose early and fully-developed Alzheimer’s, including PET scans or a lumbar puncture, when a sample of spinal fluid is taken from a patient and measured for the beta-amyloid protein. But these are expensive and invasive procedures, so usually a diagnosis will be made without them, relying on a full medical and psychological assessment by a doctor.

Despite the increase in deaths we still don’t know enough about Alzheimer’s, and great effort is being taken around the world to research what contributes to the condition, possible preventative measures we could take, and potential new treatments.

For example, several studies have emerged recently about the positive effects of exercise in staving off Alzheimer’s. Ongoing research known as ‘the nun study’ is using the brains of a group of nuns to determine factors that may predict, contribute to, or protect against the development of the disease. This research is unique in having access to a group of people with almost identical lifestyles, diets and sleeping habits, providing near perfect control measures.

However, accurate, non-invasive, early detection of Alzheimer’s remains a vital area of research and Australia is leading the way.

A study published in Nature journal earlier this month by a team of Australian and Japanese researchers looked into a potential new blood test to diagnose the disease.

Although beta-amyloid protein build-up is one of the first signs of Alzheimer’s it only appears in the blood in very small amounts, so testing for it has historically proved difficult. The latest researchers used a process involving mass spectrometry which allowed them to more accurately measure very small fragments of the protein in blood samples. They found that the blood test results correlated well with the traditional methods of lumbar puncture and PET scan.

How does this finding help patients?

Initially the blood test will be most significant in recruiting patients for clinical trials. The ability to test volunteers with a blood test rather than an invasive procedure will make it easier to recruit more people, which is vital in the hunt for treatments.

Many major media outlets have been heralding the test as a new option for screening, but this is still a long way off. Firstly, it needs to be trialled over many years to see if it is accurate as a predictor. And secondly, given there is no cure for Alzheimer’s there is an ethical concern over telling a person they will develop a disease that they can do nothing about.

Laureate Professor Colin Masters of the Florey Institute of Neuroscience and Mental Health, and The University of Melbourne, co-led the research into the blood test. He said;

“Progress in developing new therapeutic strategies for Alzheimer’s disease has been disappointingly slow. New drugs are urgently required, and the only way to do that is to speed up the whole process.

Once you can diagnose the condition accurately and specifically, then it makes it so much easier to work on developing a specific therapy.”

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• CRISPR is a gene editing technology with enormous potential to cure disease

• CRISPR technology has prompted international debate due to its ability to alter DNA in human embryos

• Genome correction of embryos is illegal in Australia but scientists want the laws to be changed

Science is experiencing a golden age in gene editing thanks to a new technology called CRISPR, credited with potential applications in everything from gene therapy and drug research to diagnosing viruses.

CRISPR works as a type of molecular scissors by combining a DNA-cutting enzyme with a molecular guide that can selectively trim away unwanted parts of the genome and replace it with new stretches of DNA.

In 2015, CRISPR was named breakthrough of the year however its application in medicine is subject to much debate.

In August 2017, CRISPR technology attracted global media attention after scientists in the US and Korea successfully freed embryos of a piece of faulty DNA that causes deadly heart disease to run in families. This discovery could potentially open the door to preventing 10,000 disorders that are passed down the generations.

In the study, the genetic repair happened during conception. Sperm from a man with hypertrophic cardiomyopathy was injected into healthy donated eggs alongside CRISPR technology to correct the defect. Although it did not work all the time, 72% of embryos were free from disease-causing mutations.^[1]

Dr Shoukhrat Mitalipov, a key figure in the research team, said: “Every generation on would carry this repair because we’ve removed the disease-causing gene variant from that family’s lineage. By using this technique, it’s possible to reduce the burden of this heritable disease on the family and eventually the human population.”

Ethical concerns

While the UK, Sweden and North America press forward on research involving human embryos, genome correction of human embryos is currently illegal in Australia. Scientists have pushed for a relaxation of these laws but opinion is divided.

Dr Sara Howden, Senior Research Officer and Gene Editing Core Facility Director at Murdoch Childrens Research Institute says the technology raises concerns about the creation of unintended DNA changes that are inherited by future generations:

“CRISPR/Cas9 is still a very new technology and most experts in the field would agree that we must be very cautious about using this technology to create lasting changes that are passed on to subsequent generations as this could have undesirable and unpredictable consequences. Further studies are needed, even those using human embryos that would otherwise be discarded, to fully evaluate its safety and address its potential risks.”

Professor John Rasko, Head of the Gene and Stem Cell Therapy Program, Centenary Institute, believes the law should be changed to allow embryonic editing in research settings:

“Extensive research from the UK indicates that CRISPR is a safe and effective tool for genomic editing. The technology is advanced enough to be used in Australian research settings and I think the law should reflect this. While I support embryonic editing, it’s important to note that very few diseases can be cured through this method. Most hereditary illnesses can be detected and managed using pathology tests such as pre-natal blood tests and IVF screening.”

NSW Stem Cell Network regularly holds events for the scientific community to discuss the risks and benefits of genomic editing.  In March, the organisation publicly called on regulators to consider changing Australian laws to permit some gene editing of embryos for therapeutic purposes.

Embryonic editing is an increasingly pertinent issue for Australian scientists and more discussion is needed to evaluate its ethical, legal and social implications. With further campaigning from universities and scientific institutes, it is likely that genomic editing could be available by 2020.

^[1] BBC News – Human embryos edited to stop disease

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We’ve spoken a lot about the potential uses of CRISPR – the gene-editing technology that has been a constant of health research headlines recently.

The technique, which allows scientists to make specific changes in DNA without killing cells, has now been harnessed in what is being labelled a ‘breakthrough’ in the diagnosis and treatment of Parkinson’s disease.

A team of researchers at the University of Central Florida has used the technology to “light up” and monitor a brain protein called alpha-synuclein that has been associated with Parkinson’s.

Everyone has alpha-synuclein present in their brain but a person with Parkinson’s will develop abnormal levels of the protein. The researchers’ hope is that by monitoring the protein in the cell they will be able to measure what causes it to go up and what treatments can make it go down. This could be beneficial in the identification of new drug therapies for Parkinson’s disease.

Parkinson’s disease is a debilitating degenerative disorder involving the malfunction and death of vital nerve cells in the brain, called neurons. The disorder affects around 80,000 Australians. There is currently no single test to diagnose it and no cure.

The team used CRISPR to edit the alpha-synuclein gene and inserted a luminescent tag made from proteins that light up. This meant that every time a cell created the alpha-synuclein protein, the tag would give off a light, making it much easier to monitor if too much alpha-synuclein was being produced.

Associate Professor Yoon-Seong Kim, one of the study’s lead researchers said;

“CRISPR is the most powerful and widely used gene-editing technique in use because it allows us to change the DNA in living cells.

The innovation of this method is that it enables us to monitor this gene in real-time without killing the cell. Without the CRISPR Cas-9 method, you would have to extract all the proteins from the cell to measure them, which kills the cell.”

With the new technology, the scientists hope to identify ways to reduce alpha-synuclein production that can possibly prevent Parkinson’s or its progression in patients diagnosed with the disease.

“If we take one of these modified cells and treat it with a particular drug, if it doesn’t produce light anymore, then this means the drug is a potential treatment for this disease,” Sambuddha Basu, another researcher on the team, said.

With the engineered cells, the researchers will screen new and existing drugs and hope to also focus on what aspects of the alpha- synuclein protein kill neurons during Parkinson’s disease.

The team published its findings in the Scientific Reports journal.

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All eating disorders can have serious consequences, and because of the typical symptoms of fear of weight gain and severely restricted eating, untreated anorexia is associated with devastating physical consequences and has a high mortality rate. The condition can affect people of any age but the most severe illness commonly occurs in the 20-45 year age group, and the disease is more common in women.²

Anorexia is often viewed as a condition based largely on external factors such as media and advertising featuring unrealistic images of the body. However in many cases the role of these external factors including trauma, abuse or societal pressure is to trigger the disease in a person who may be predisposed to anorexia because of their genetics.

It has long been known that family history is a risk factor for anorexia but a large global study has now been able to better pinpoint contributing factors.

Researchers at the University of North Carolina (pictured above) collaborated with institutions across the US and Europe bringing together 220 scientists to analyse genomic data from 3,495 people with anorexia nervosa and 10,982 unaffected people.

The researchers found genetic variations on chromosome 12 that were common to the participants with anorexia – this region of chromosome 12 is also associated with Type 1 diabetes and autoimmune disorders.²

Investigators also found genetic correlations with certain metabolic factors including a person’s Body Mass Index (BMI) and their insulin-glucose metabolism.

There are currently no drug treatments specifically for anorexia. Greater understanding of factors that contribute to a person’s risk of developing anorexia is important in developing effective treatments; either new therapies or existing drugs used for other conditions.

Lead Investigator Professor Cynthia Bulik from University of North Carolina said:

“Anorexia is a devastating illness and is not well understood in the community. This research is a big step in pinpointing where predisposition to the disease begins and encourages us to look more deeply at how metabolic factors increase the risk for anorexia. We want to find ways to target treatment and data like this is a key part of that process.”

Prof Bulik leads the Anorexia Nervosa Genetics Initiative (ANGI) which has joined with a project called AN25K, collecting 25,000 blood samples from people across the globe who have been diagnosed with anorexia nervosa.

Large sample sizes are critical when looking at the genetics of psychiatric illnesses as many genes may be involved in disease risk.

More research is needed but these latest findings mean that genetic testing could one day be part of guiding effective treatment for people with anorexia.

¹ https://www.eatingdisorders.org.au/key-research-a-statistics

² https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2017.16121402?journalCode=ajp

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Australian infectious disease researchers at the Illawarra Health and Medical Research Institute have found that people with the blood type O (the most common blood type among Australian patients) could be at higher risk of developing streptococcal infections than those with other blood types.

There are various types of Streptococcal infection, ranging from mild sore throats to deadly infections of the blood or organs. Repeated infections can lead to chronic conditions, such as rheumatic heart disease.

Post-Doctoral Researcher Dr David De Oliveira studied Group A Streptococcus (GAS) and found that the sugar molecules on type O blood may create a ‘bridge’ for colonisation – leaving type O carriers more susceptible to a particularly virulent clone of GAS (M1T1 GAS) present in many invasive infections.

Senior Research Fellow Dr Martina Sanderson-Smith, who co-published the study with Dr De Oliveria, said;

 “We know that some people are more susceptible to streptococcal infections. We wanted to see if there are other biological reasons that increase the risks, and understand why some people suffer repeated infections.”

The next step for the researchers will be a new project studying saliva samples taken from people colonised with GAS, in collaboration with researchers at the Murdoch Children’s Research Institute.

Their hope is that one day they will be able to develop a non-antibiotic treatment for children with sore throats;

“A sore throat is one of the most common reasons children are prescribed antibiotics, but we are becoming more aware that antibiotic overuse can be a problem, so developing non-antibiotic treatments for bacterial infections is important”, said Dr Sanderson-Smith.

Read more about the research here.

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The purpose of a clinical trial is to establish evidence to inform clinical practice. Much emphasis is placed on trials that bring new drugs or devices to the clinic, but a large body of research also assesses which existing practices work best; these are known as comparative effectiveness trials.

All trials can be broken down into a series of steps:

1. Hypothesis generation and design

A clinical question is identified based on addressing an identified problem. For instance, there may be a suspected greater risk of infection in people with an increased BMI (Body Mass Index) who are undergoing large abdominal surgery. Researchers would first check their theory by cross checking medical records and pathology notes. As a possible solution, investigators might suggest using an antibiotic pre-emptively to prevent infection. To test this intervention, researchers would measure the number and types of any infections after surgery, as well as the overall health of patients. Pathology would be used in analysis of infections and ensuring patient safety in the trial.

2. Recruitment

Pathology is used to make sure a person meets the inclusion criteria to take part in a trial, for example that they have a cancer with specific characteristics such as HER2 positive breast cancer. There are also exclusion criteria that may prevent someone from participating, for example levels of immune system, liver and kidney function. These are confirmed by pathology testing.

3. Ongoing analysis of drug response:

In clinical trials involving drugs, pathology testing is used to check that patients are receiving the dose of drugs as administered because drugs can metabolise differently in different people. Tests also ensure patient safety by monitoring critical blood and organ function that may be affected by drugs. Drug interactions must also be monitored, including interactions with substances inside the body such as foods and other medications, as well as external factors such as sun exposure.

4. Analysis of data

Pathology results can be used to help prove an intervention has worked. In the example above of using pre-emptive antibiotics, pathology results could show significantly fewer infections in patients receiving the intervention. Other biomarkers could be measured and recorded as secondary outcomes, for example if patients receiving the intervention also had lower rates of inflammation post-surgery.

5. Correlative studies and future work

In drug trials, pharmacogenomic analysis can be used – this testing looks at a person’s genetic make-up for markers that might affect how their body responds to the drug. This could enable researchers to discover or confirm genetic markers that influence the drug action. Discoveries could also point to new areas to research.

6. Introduction to clinical practice

Following a successful trial of a new drug, pathology results will be used in an application to the Therapeutic Goods Administration (TGA) to have the drug approved for medical use in Australia. Not only can pathology prove effectiveness, test results may also inform clinical guidelines, for example when a drug could be toxic to patients with liver conditions or will only work for those who have a specific genetic mutation.

7. Ongoing surveillance

Once a drug is approved it must be monitored for ongoing safety. Pathology tests can be used to look at the risk of long term side effects.

PAA Ambassador, Prof Nik Zeps said:

“Pathology really is integral to clinical trials. It is often involved throughout the process from deciding upon a theory and how to test it, to guiding future research and getting the right drug to the right patient. With the explosion in genomics and our growing knowledge of how genetics influence disease risk and response to treatment, pathology testing in clinical trials will become even more important to guide research.”

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