Australian Life Scientist Mar/Apr 2014

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INDIGENOUS HEALTH | VIROLOGY | DIABETIC KIDNEY DISEASE

Vol 11 Issue 2 • March/April 2014

Cell BiologyUnderstanding cell mechanics and stopping metastasis

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Contents

REGULARS06 Movers and shakers12 GrantWatch29 New products33 Publish or perish34 Events

BIOTECH10 The life sciences boom

continuesThe latest Bioforum report from PricewaterhouseCoopers is cautiously optimistic about the current performance of the Australian life sciences sector. The positive results of 2013 are predicted to continue, although the challenges in sustaining this are noted.

FACE TO FACE14 Indigenous health expert

Professor Kerin O’Dea conducted pioneering research with Indigenous communities in the Kimberley region and showed adopting a traditional hunter-gatherer lifestyle could rapidly reverse diabetes and insulin resistance in these people. This work led to a lifelong career in adult nutrition and preventing chronic disease in Aboriginal people, along with the ongoing challenge of translating research results into practical interventions.

CELL BIOLOGY18 The mechanical forces of

metastasisStudying the proteins that bind cells together into organised communities has been a long-term focus of work by Professor Alpha Yap and his team. Unexpectedly, this research into the mechanics of cell-cell adhesion has led to a better understanding of the cell-ejection process that leads to

development of new treatments to reduce or restore the damage caused in this chronic disease. Professor Karin Jandeleit-Dahm and her team are working on blocking an enzyme that is an important mediator of kidney damage in diabetes. And Dr Phillip Kantharidis and his team are conducting research on microRNAs and developing a better understanding of complications associated with diabetes, such as diabetic nephropathy.

22metastasis. The team is now turning its attention to identifying treatments that will contain cancerous cells within primary tumours, halting the metastatic process at source.

VIROLOGY

22 The many faces of viral research Dr Fasséli Coulibaly is successfully deciphering how viruses assemble, interact with their hosts and manage to evade their hosts’ defence mechanisms. Using insect viruses and the crystalline polyhedra these viruses use as a means of protection, he is developing a platform for the delivery of vaccines with increased stability, extending vaccine applications for use in the developing world.

DIABETES

26 Diabetic kidney diseaseResearch into diabetic kidney disease at the Baker IDI in Melbourne is working towards the

IN THE NEXT ISSUE OF ALS• Microbiology• Clinical trials• Personalised medicine• Australian Society for

Microbiology meeting preview

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The diabetesepidemic

D iabetes is reportedly the fastest growing chronic condition in Australia.

The seriousness of this epidemic becomes clear when you look at the numbers. Almost 1.1 million Australians currently have diagnosed diabetes - 120,000 people have type 1 diabetes, 956,000 people have type 2 diabetes and 23,600 women have gestational diabetes.

On top of this, many people with type 2 diabetes remain undiagnosed.

A major concern is that type 2 diabetes is steadily increasing and people are getting it at a younger age. This sets up a perpetuating cycle because when women have diabetes in pregnancy, particularly type 2 diabetes, their babies have a greater risk of developing early onset obesity and type 2 diabetes.

Indigenous Australians are twice if not three times more likely to develop type 2 diabetes compared with non-Indigenous Australians.

When interviewing Professor Kerin O’Dea about her life’s work on chronic disease in Indigenous Australians (p14), she discussed some of the pioneering studies she conducted with Indigenous communities in the late 1970s and early 1980s. This work showed that Indigenous people with type 2 diabetes could significantly improve their health in the space of just seven weeks by adopting their traditional hunter gatherer lifestyle.

Diabetes can be reversed relatively quickly if people understand what makes up a healthy diet and lifestyle. And with an estimated 2 million Australians at high risk of developing type 2 diabetes, preventing this disease should be first and foremost on the agenda.

The quality of life costs are unquantifiable but the financial costs of diabetes are in the

billions due to healthcare costs, carers’ costs and losses in productivity. And when people start to get the complications associated with diabetes - such as kidney disease (p26), eye disease and heart disease - the healthcare costs escalate.

The amount of money spent on people when they get sick by far outweighs what

we spend on keeping people healthy. Yet maintaining a healthy lifestyle can significantly improve the complications associated with diabetes, so why not invest in keeping people healthy?

Providing subsidised healthy food for people living in remote areas and those who are disadvantaged is one way

to achieve this.France, Canada and Scandinavian countries

are listening to the economic arguments and subsidising food in this way. Canada has a program called Nutrition North Canada that delivers subsidised hampers of food to people living in remote areas.

Government public health campaigns educate people about health and nutrition, which is beneficial, but these campaigns expect people to change their behaviour and drive this themselves.

Integrating the messages of these campaigns into action by promoting fresh fruit and vegetables, lean meats and seafood, and providing ways for people to more easily access healthy foods rather than processed foods would be useful, especially given the food industry’s clever marketing campaigns around fast food.

Making healthy food cheaper, especially in remote areas, and subsidising meals given to children in day care, kindergarten and primary school are some of the things we could adopt to avert the growing diabetes epidemic.

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Seeing like a satelliteUnlike human eyes, which have three types of photoreceptors that send signals to the brain for comparison, the eyes of mantis shrimp (Haptosquilla trispinosa) use 12 different photoreceptors to create a pattern that is almost immediately recognised as a colour, without complex brain processing.

The discovery, by researchers at the Queensland Brain Institute (QBI), has shattered the illusion that more complex eyes with more colour channels generate better colour vision.

Researcher Ms Hanne Thoen and colleagues found that mantis shrimp with their 12-colour channel processing perform worse in differentiating between colours than humans with their three channels.

“Theoretically, mantis shrimp should be far better at distinguishing colours than we are,” Thoen said. “We tested their ability to discriminate between colours that differ a lot - such as red and blue, and then changed to colours that got closer and closer together along the spectrum - red-green, red-yellow, red-orange - and noted when they started to make mistakes,” Thoen said.

To account for these mistakes, the researchers suggest that mantis shrimp avoid the need for complex neural processing by scanning objects with their 12 photoreceptors - each one set to a different sensitivity.

Unlike human eyes, which have three types of photoreceptors that send signals to the brain for comparison, the eyes of mantis shrimp create a pattern that is almost immediately recognised as a colour, the researchers surmised.

Consequently, mantis shrimp lose some ability to discriminate between colours but can quickly recognise basic colours without comparing wavelengths of the visible spectrum in their brains.

The findings demonstrate how the design of the nervous system has evolved towards a simple arrangement, rather than trying to fully interpret all the information from a very complex colour vision at the retinal level.

“Modern cameras struggle with the amount of data they take in due to increased pixel numbers; maybe there is a more efficient way and the bio-inspiration provided by stomatopods could be the answer.” said Professor Justin Marshall, who runs the Sensory Neurobiology Group at QBI.

“In fact, mantis shrimp sample their world in a way more similar to a satellite than other animals.”

MOVERS & SHAKERS

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Australian medicalresearch measures upThe National Health & Medical Research Council’s bibliometric report, Measuring Up 2013, reveals the Australian health and medical research sector continues to produce high-quality research.

A five-year analysis of biomedical publications produced by NHMRC-funded research, the report measures the number of journal publications generated and the amount of times these were cited by other researchers.

“This report reinforces the strong international standing of Australia’s health and medical research sector,” said Professor Brendan Crabb, President of the Association of Australian Medical Research Institutes. “The majority of medical research institute funds come from the NHMRC, demonstrating that medical research institutes and the NHMRC are a highly effective combination."

From 2001 to 2010, Australia’s health and medical research sector ranked sixth internationally in terms of citations per publication.

This new report shows that between 2005-2009:•Australian health and medical publications had a relative

citation impact 17% above the world average, with NHMRC-funded publications, in particular, being 60% above the world average

•The number of Australian health and medical research publications increased by 44% between 2002-2006 and 2005-2009, with Australia contributing 3.1% of total world biomedical publications from just 1.1% of global health research dollars

•Australia’s medical research institutes outperformed other research sectors and world benchmarks, with a relative citation impact 65% above the world average and 40% above Australia overall

•International collaborations increased between 2005 and 2009, with 44% of medical research papers having an international author in 2009 - this is important, because papers with an international author had an average citation impact almost double that of publications without an international author.

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MOVERS & SHAKERS

Thousand-dollar genomeA big ambition for the genetics community for some years now has been to achieve the sequencing of a whole human genome for one thousand dollars. This goal has now been reached with the new high-throughput sequencer, HiSeq X Ten, able to sequence a complete human genome at a base cost below US$1000 - that’s roughly 6,000,000,000 base pairs.

Announced at the annual JP Morgan 32nd Annual Healthcare Conference in San Francisco, Illumina CEO Jay Flatley said that three of the sequencing platforms had already been sold - one system to Sydney’s Garvan Institute of Medical Research, another to South Korean genomics company Macrogen and a third to the Broad Institute of MIT and Harvard, which will use the platform in cancer genetics research.

The HiSeq X Ten sequencing system produces big data. Purposely built for use by institutions running large-scale sequencing projects, it is capable of sequencing around 350 genomes a week, or 18,000 a year.

Garvan’s acquisition will allow a massive increase in human genome sequencing capacity in Australia and possibly the region.

Professor John Mattick, executive director of Garvan, said they plan to use the system for large-scale research projects and problem-dependent diagnostics, such as the routine analysis of cancer biopsies and people with genetic disorders. They also plan to begin the analysis of genomes of people with conditions such as diabetes and Parkinson’s disease.

The increasing availability of unproven stem cell therapies is beginning to be addressed with the NHMRC releasing new documents to help people navigate this complex area.

Entitled Stem Cell Treatments - A Quick Guide for Medical Practitioners and Stem Cell Treatments: Frequently Asked Questions, the documents are designed to raise awareness in Australian medical practitioners and patients contemplating using stem cell-based treatment.

The regulation of cellular therapies in Australia by the Therapeutic Goods Association (TGA) is generally pretty good.

But a loophole exists that allows clinics to offer people treatment using their own cells - so-called autologous therapy.

Because autologous therapy is exempt from TGA regulation, clinics can offer people unproven and untested stem cell treatments - many of which are crude or poorly characterised tissue extracts that can cost thousands of dollars.

The new documents aim to help people make informed choices about treatment options as well as facilitate discussions between patients and their medical practitioner. They also raise awareness about doctors in Australia selling experimental treatments using a person’s own cells and encourage those who have concerns to report medical practitioners to the Australian Health Practitioners Regulatory Agency, Australian Competition and Consumer Commission or their relevant state or territory fair trading agencies.

Proven stem cell treatments that have undergone the rigorous approval process are currently limited to certain cancers, blood and autoimmune diseases, burns and repair of the cornea of the eye. All other treatments are experimental or entering clinical trials and yet to be demonstrated as safe and effective.

The International Society for Stem Cell Research released a statement last year supporting the need for regulatory oversight of this global issue.

Stem cell treatments on the agenda

“The initiative must be undertaken at a national level - and in collaboration with international partners, as it will need massive global databases to support interpretation of the data,” Mattick said, adding that they hope to develop a national alliance for delivering genomic medicine in Australia through partnerships with other research institutes as well as state and federal governments.

Associate Professor Marcel Dinger, head of clinical genomics at Garvan and leader of the bioinformatics team charged with interpreting and managing data, said: “Generating DNA sequences will be less of an issue than analysing them in a way that is meaningful to clinicians, so we are putting a lot of effort into transforming the primary data into clinical grade reports.

“It is an enormous task, one that can only be undertaken by a leading-edge research institute with a mission to bring research advances rapidly to patients. It will also enable us to partner with similar efforts internationally.”

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BIOTECH | LIFE SCIENCES SECTOR

The December quarter marked an underwhelming end to a very strong calendar year for the

Australian life sciences sector, according to PricewaterhouseCoopers’ latest Bioforum report.

The PwC Life Sciences Index declined 0.1% for the quarter, compared to a 2.6% increase for the All Ordinaries.

But the Life Sciences Index finished 2013 up 17.4%, compared to just 14.8% for the All Ordinaries. Smaller companies were the strongest performers, with the Life Science Ex Majors index growing an impressive 29.2% over the calendar year.

IPOs from Innate Therapeutics (ASX:IIL) - a company developing a drug candidate for the treatment of secondary progressive multiple sclerosis - as well as medical R&D company dorsaVi (ASX:DVL) helped ensure the quarter was

the busiest period for IPO activity in the sector since the third quarter of FY11.

In his introduction to the Bioforum report, PwC partner Manoj Santiago said the challenge for the life science sector will be to sustain its performance going forward.

“Some commentators are calling this a ‘renaissance’ for the Australian Life Sciences sector. If that is the case, what will make this resurgence different from previous periods of growth?” he asked. “History proves that it doesn’t take much for capital markets to lose faith in life sciences companies.”

He said government support for the sector has improved since the last life science boom, particularly with the new R&D tax incentive. “These are steps in the right direction, but we don’t think they’re enough to truly extract the maximum

value for the Australian economy that’s presented by the sector’s performance.”

During the fourth quarter, the government also confirmed it will exclude businesses with incomes exceeding $20 billion from claiming R&D tax concessions.

The top biotechnology performer on the ASX over the past four quarters has been Admedus (ASX:AHZ), which has delivered a return of 638% over this time. Oncosil Medical (ASX:OSL) was second with a 420% return, followed by iSonea (ASX:ISN) with a 379% return and Prana Biotechnology (ASX:PBT) with a 267% return.

The bottom performers were Pharmaxis (ASX:PXS) with a -92% return, Safety Medical Products (ASX:SFP) with a -75% return, Prima BioMed (ASX:PRR) with a -65% return and Advanced Surgical Design & Manufacture (ASX:AMT) with a -52% return. ALS

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MOVERS & SHAKERS

GrantWatchMillion-dollar grant to roll out HIV test

Funding for medical research

Burnet Institute in Melbourne has received US$1.6 million from global health organisation UNITAID to kickstart field evaluation studies in India and South Africa for their HIV diagnostic, VISITECT CD4.

VISITECT CD4 is a point-of-care test that determines CD4+ T cell counts in whole blood for assessing when an HIV-positive patient should begin antiretroviral drug treatment.

The grant is part of US$20 million of funding to four developers of easy-to-use HIV diagnostics designed for low-income countries. UNITAID has already committed over US$140 million to portable and easy-to-use HIV diagnostic technology.

The VISITECT CD4 test uses a small amount of blood from a finger prick with results available after 40 minutes at a cost of approximately $5 per test, which is significantly less than existing tests.

In the latest round of NHMRC funding, $133 million has been awarded to support research across a range of areas including influenza, childhood eczema and allergies, mental health, basic neuroscience and medical imaging.

Announced by Federal Minister for Health, Peter Dutton, the funding will support 153 grants across five NHMRC

schemes - Development Grants, Partnerships for Better Health - Partnership Projects, Program Grants, Postgraduate Scholarships and Targeted Call - Fetal Alcohol Spectrum Disorder.

This round of funding included:• 11 program grants worth $101.6

million awarded for multidisciplinary research in biomedical, clinical, public health and health services.

• 7 partnership projects totalling $4.4 million, given to researchers and policymakers working to identify changes in the delivery, organisation, funding and access to health services.

•24 development grants worth $14.7 million for early proof-of-concept for commercialisation research of new medical products, processes, procedures and services.

•3 targeted calls for research grants at a value of $2.8 million to improve understanding of fetal alcohol spectrum disorder.

•108 postgraduate scholarships totalling $9.5 million.While New South Wales received the highest ($38.8 million

for 47 grants) and Victoria a close second highest ($38.4 million for 58 grants), the University of Queensland received the greatest amount of funding ($26.3 million for 18 grants).

Cancer research was given $44.5 million, Indigenous health research $14.1 million and cardiovascular disease research $13.9 million.

“There are about 2.1 million people living with HIV in India and while patients attending many urban centres in India have excellent care, those living in rural areas lack access to affordable HIV monitoring tests,” said Burnet Institute Associate Director and VISITECT CD4 co-developer, Professor Suzanne Crowe.

“The low-cost, point-of-care VISITECT CD4 will greatly improve access to life-saving anti-HIV drugs for potentially hundreds of thousands of HIV-positive people in India. The test will be ready for field trials by July this year.”

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FACE TO FACE | INDIGENOUS HEALTH

Australian Life Scientist: What drew you into studying science?Kerin O’Dea: I wanted to study science from really quite a young age - when I was about 12. I was absolutely fascinated by reading about drug discovery and learning, for example, about curare, a powerful muscle relaxant used by the Indigenous people of South America in their ‘poison arrows’ to hunt and disable game - that that was then widely applied in surgery.

That got me interested in drugs and pharmacology and I ended up doing pharmacology at Melbourne University. I did the equivalent of an honours year in pharmacology but then switched fields to do a PhD in biochemistry.

ALS: How did you become involved in nutrition research?KO: I was working in a very specialised area of physical biochemistry and I couldn’t see the direct application of it and it wasn’t something I could discuss easily with people who weren’t experts in the field so I went back to pharmacology. I spent the first two years of my postdoc in the early 1970s working for Bayer in its research division.

That was in the days when the pharmaceutical industry was doing really good research. Bayer had very big research division and I ended up looking at alpha-glucosidase inhibitors. These were eventually turned into drugs and used not all that successfully in

diabetes treatment, but the principle was fascinating.

And that was what got me interested in nutrition generally. I was fascinated to see that you could greatly improve the metabolic profile of a rat that was insulin resistant by simply slowing down the digestion and absorption of complex carbohydrates. I realised it was like unrefining refined carbohydrate and felt it obviously had application in conditions like diabetes.

I did some of the early work on the glycaemic index - looking in particular at the rate of digestion and absorption of unprocessed foods, like brown rice, and then showing that if you ground it up you would get much faster digestion

Nutrition scientist and public health researcher Professor Kerin O’Dea discusses a career dedicated to researching diet and chronic disease in Indigenous Australians.

Indigenoushealth expert

Susan Williamson


INDIGENOUS HEALTH | FACE TO FACE

and absorption, and correspondingly higher glucose and insulin responses. So that’s really how I got interested in diet diabetes - and that remains a major research interest.ALS: Did working in Indigenous health bring you back to Australia?KO: I first got interested in diabetes in Germany. Then I was offered a job at the Cleveland Clinic in the US as a project scientist, and held that position for two years.

I was able to organise my own research program and I continued on with the work that I’d started at Bayer, looking at different feeding patterns in rats. Rats normally nibble on food throughout the night, but when you expose them to large amounts of food just twice a day they learn to gorge during those feeding periods. Even though they don’t eat more food, they actually put on more fat and develop insulin resistance. It was very interesting work.

This led to research on glucose and insulin metabolism in animal models of diabetes.

When I returned to Australia in 1977, I was working as a research scientist at the Royal Children’s Hospital in Melbourne. The Professor of Paediatrics at the time, Don Cheek, was working with Aboriginal communities looking at child health and undernutrition. I was interested in the opposite really - adult health and overnutrition.

Professor Cheek worked with clinicians in the Kimberley and Central Australia, and pointed out to me that Aboriginal people were starting to get type 2 diabetes. He also told me that groups of Aboriginal people in the Kimberley were going back to the bush

in the dry season and living off the land. I thought that would be a fascinating natural experiment - to see how their health changed as a result of going back to live off the land. And that was the first study in Indigenous health that I was involved with.ALS: You’ve conducted some pivotal studies in Indigenous health in Australia, can you discuss some of these?KO: I conducted several studies in the late 1970s and early 1980s where Aboriginal people actually did go out and live off the land completely. The most famous one was where we went out with a group of people with type 2 diabetes and showed a huge improvement in their health in the space of just seven weeks. All of the metabolic abnormalities of diabetes were reversed or greatly ameliorated.

The Aboriginal participants were not surprised - they knew their traditional lifestyle was very healthy. Clinicians were more surprised because they didn’t think you could reverse diabetes so quickly.

For me that was the most important study I’ve done because it put me on the path for the rest of my career. I was fascinated by the traditional hunter-gatherer diet and lifestyle and understanding the foods, looking at food quality and how different it is from our diet and lifestyle now. Agriculture has made food more palatable but it’s probably not nearly as healthy as the ‘wild’ foods that these people ate - wild animals are very high quality.

Aboriginal people - and hunter gatherers everywhere - ate everything from a carcass that was edible. They value things that are nutritionally

very healthy, which we value less. For example, they absolutely valued the brain, which is a fantastic source of long-chain omega-3 fatty acids, particularly DHA (docosahexaenoic acid), which we now know is probably very important for mental health - it’s certainly important for brain and nervous tissue development.

They also value the liver, which, interestingly, is a good source of vitamin C, and a wonderful source of folate, zinc, iron and numerous vitamins. You wouldn’t want to live on it, but the way Indigenous people ate it, which was small amounts shared among many people, was very healthy. They also valued bone marrow. Another highly valued food was honey.

While they got most of their energy most of the year from bulky foods with low energy density, their favourite and most highly valued foods were the fatty or sweet components of their diet. It is as if humans are programmed to know that these preferences were very important.ALS: Do these results translate to other populations?KO: Our genome has changed very little since we were all hunter gatherers.

There are a few differences. For example, most people in Western societies can drink milk and tolerate lactose well into older age, but that is not the case in many populations around the world where people develop lactose intolerance after infancy.

"We went out with a group of people with type 2 diabetes and showed a huge improvement in their health in the space of just seven weeks. All of the metabolic abnormalities of diabetes were reversed or greatly ameliorated."

Professor Kerin O'Dea.


FACE TO FACE | INDIGENOUS HEALTH

However, a hunter-gatherer diet is not practical for people living in big cities. We’re not hunting ourselves and we’re not eating the food really fresh.

I would never tell people to live entirely off animal food. The animals that we’ve bred for food, until recently, we’ve bred to be fat. From a hunter-gatherer perspective this was probably quite sensible, but for us, we are sedentary and consume too much.

I definitely use the hunter-gatherer diet as a model. The principles are excellent - minimally processed whole foods - lean meat, from wild animals ideally. I am also an advocate of eating offal - but not from intensively reared animals because you just don’t know what might be in them.ALS: In your work in the Kimberley region, was there a two-way exchange of knowledge in your work with Indigenous communities?KO: I did a lot of that work from a Melbourne base, but I’d go up to visit for a couple of months at a time.

The locals were fascinated with my interest in all this and were wonderful teachers. Their knowledge was extraordinary - of animal behaviour, animal life cycles, plants, the knowledge of their environment. These were people who were no longer living as hunter gatherers but they had spent time in their early life as hunter gatherers and their parents had been hunter gatherers. They

were very proud of that knowledge and it was most impressive.

I used to wonder how people could survive in the desert - and the people from the desert said they didn’t know how anybody survived anywhere else!

And all of a sudden I could see. Because there are grasses and grass seeds in the desert regions, emus and bush turkey as they are called - the Australian bustard - and goanna are actually quite fat because they have a good diet eating seeds. I was fascinated when people would go out and within half an hour they would have caught a few goanna, they might have ambushed (or in these days shot) a turkey, and they’d have a really good feed.

As Westerners we have a huge amount to learn from the study of the hunter-gatherer diet and lifestyle.

I really wanted to talk to Aboriginal people about how they could adapt the principles of the hunter-gatherer diet and lifestyle to their Western diet and lifestyle - to use the traditional diet and lifestyle as a benchmark. Even if they couldn’t go out hunting to choose store foods that are more like bush foods.ALS: You are one of the directors of Outback Stores, is this one of the possible solutions to people accessing better quality food in remote areas?KO: Working on the quality of the diet is certainly is one of the briefs of organisations like Outback Stores.

There’s another very good store organisation in the Northern Territory called ALPA. It was originally called the Arnhem Land Progress Association and is run by the elders of a number of Arnhem Land communities. They’ve had a healthy nutrition policy for years and try to minimise the cost of fresh fruit and vegetables. Outback Stores has the same goals.

Many people would say that the store in an outback community should be seen like the school and the clinic - that is as a service provider. But at the moment the store is a small business and so it has to make a profit.

I would love it if there could be links made with the major supermarket chains so that people could get the same sort of low prices that are available in cities. That’s the aim but we’re not there yet. ALS: Is the government providing support for this?KO: In principle they are, but I think there’s a real reluctance in Australia to provide food to people.

We give billions of dollars of support to industry in remote parts of Australia, such as providing the diesel fuel rebate, yet there’s a reluctance to provide food for children, for example.

I think in the long term we are going to have to make the economic arguments to set up some programs to improve the nutritional quality of food. Subsidising the whole food supply would be very expensive, but we could provide very cost effective healthy breakfasts and lunches for children and it would have huge beneficial outcomes.

Other countries are doing some interesting things. Canada has a program called Nutrition North where, as I understand it, communities can get subsidised hampers of food delivered in very remote areas. We spend so much on people once they get sick, yet we spend so little on keeping people healthy. The economic arguments will have to prevail eventually.

The health promotion approach we have assumes that if people have the knowledge they’ll change their behaviour. The campaigns about health barely

Kerin O'Dea, in the early 1980's, learning about a hunter-gatherer lifestyle with Indigenous people in the Kimberley.


I was Pro Vice-Chancellor of Research at Deakin for a couple of years as well. Through that work I became very familiar with the whole research management system in Australia. Those were two very good learning experiences that enabled me to then move in and be reasonably comfortable directing an institute like the Menzies School of Health Research. Also, it was an area I was passionate about. So becoming director of an independent health and medical research institute focusing on Indigenous and international health in northern and central Australia fitted with that passion.

The Sansom Institute for Health Research is a different kind of model. It is more of a vehicle with which to build the research culture in a university. The University of South Australia had patches of very strong health research but there were areas that weren’t strong as they could be.ALS: And finally, what are your plans for the future?KO: I stepped down [from being director of Sansom] because I have an NHMRC Program Grant - I say it will be the last big grant that I get - and I really needed more time to devote to that. I’m halfway through it now.

The project is looking at preventable chronic disease in Indigenous populations and really looking at the food supply, people with diabetes, how to get early interventions, that type of thing, what’s practical.

My longer term plan is to mentor younger people coming through because that is the future. It’s very important that they become advocates and lead research that is focused on solutions rather than just problem definition. ALS

make a dint in the very clever marketing campaigns for unhealthy food. The most heavily advertised foods and drinks are mostly the ones we should avoid.

I’m not against government health promotion programs but they need to be integrated into action.

One of the issues with the food supply is that the processed food and beverage industry is very powerful and these transnational companies have huge influence over government.ALS: What about taxing junk food?KO: Yes, there is a good argument for that and using the money raised to promote healthy food or using it in a way to make healthy food cheaper - for example, to support meals for children in day care, kindergarten and primary school.

It will take a courageous government to do it.

The real issue that we have to face is that obesity and type 2 diabetes are increasing at an alarming rate. People are getting type 2 diabetes at a younger age and this actually starts a terrible intergenerational cycle. When women have diabetes in pregnancy, particularly type 2 diabetes in pregnancy, which used to be very rare, their offspring are at much greater risk of developing early onset obesity and type 2 diabetes.

We need to break that cycle because we are all paying for it. So, although we are reluctant to tax some of the causes of obesity, we all carry the costs. And the healthcare costs are just getting higher and higher. I think these are some of the important discussions we are going to have to have. ALS: What do you think is the main challenge to overcome to turn this around and start reducing the rates of these diseases?KO: Translating the results of research is a big challenge. It will require major changes in the food supply and in the way we live. Physical activity needs to be built into daily routines. Urban planning to encourage walking and cycling, and an excellent public transport system are important components of a healthy society of the future.

People who are poorly educated and socially and economically disadvantaged are much more likely to be overweight, obese, have diabetes, etcetera. How do we minimise the impact of social disadvantage?

Education is fundamental to this and a lot of Aboriginal leaders have recognised that and are really pushing that children get the opportunities so that they can lead full lives in the future.

We used to be a society that was much more egalitarian in the middle of the 20th century. But we’ve become less equal over time and I think the health problems we are seeing are, in part, a consequence of this.

Working on interventions that can improve diet quality and lifestyle should be seen as an investment in our future, rather than seen as welfare. I think any country has to be judged on how it treats its most disadvantaged people, and I don’t think Australia is doing very well at the moment.ALS: You were director of the Menzies School of Health Research in Darwin and the Sansom Institute of Health Research at the University of South Australia. How did your career path come to this?KO: I have to say probably I wouldn’t have thought of doing anything like that until after I’d been at Deakin University. I had been a professor and head of a research institute there, and then I became the first Dean of Health and Behavioural Sciences in the newly merged larger institution.

That was a terrific experience and where I was supported to build a research culture in an organisation that previously didn’t have a very strong one.

INDIGENOUS HEALTH | FACE TO FACE

"Although we are reluctant to tax some of the causes of obesity, we all carry the costs. And the healthcare costs are just getting higher and higher. I think these are some of the important discussions we are going to have to have."

CELL BIOLOGY | CELL-CELL ADHESION

Graeme O'Neill

Professor Alpha Yap’s research team has identified a key player in the process that causes epithelial tumours to extrude cancerous cells that can go on to proliferate or invade. Their discovery offers a potential target for new drug therapies to prevent metastasis.

The mechanical forces of

metastasis


CELL-CELL ADHESION | CELL BIOLOGY

During the metastatic phase of epithelial cancers, mutated cells detach from a primary tumour and migrate in the surrounding tissue until they travel through the walls

of blood vessels or the lymphatic system to roam the body. Sooner or later, a liberated rogue cell that evades the body’s immunosurveillance systems anchors to the wall of a blood vessel, emerges and proliferates into an aggressive secondary tumour.

Professor Alpha Yap’s team in the Molecular Cell Biology Division of the University of Queensland’s Institute for Molecular Bioscience in Brisbane have specialised in studying cadherins - the transmembrane proteins that bind cells together in organised communities.

Recently, their work took them in an unexpected direction, where they found themselves in possession of a handle on the ejector mechanism that appears to be involved in liberating rogue cells from primary cancers of epithelial tissues - a necessary prelude to metastasis.

ONCOGENIC EXTRUSION

Often, cancer patients survive surgery, chemotherapy or radiotherapy to remove or ablate a primary tumour, only to succumb to aggressive, drug-resistant secondary tumours in other organs like the brain, liver or bones.

Understanding the cell-ejection mechanism, known as oncogenic extrusion, could lead to drugs that would corral cancerous cells within primary tumours, halting the metastatic process at source.

“Oncogenic extrusion is an interesting process that occurs when minorities of cancer cells are surrounded by normal or less abnormal cells,” Yap said. “Then, the surrounding cells actively expel the cancer cells from the tissue.

“This may have developed as a mechanism to clear tissues of damaged cells. But there is increasing evidence that extrusion contributes to important stages in cancer development - both early proliferation and in the earliest steps of invasion when they exit their tumour of origin.

“We didn’t start by being interested in oncogenic extrusion for its own sake; instead, this all began several years ago when we became interested in how cells regulate the mechanical processes that underpin their form and functions.”

DIFFERING TENSIONS WITHIN CELL-CELL JUNCTIONS

Yap says the field of cell-to-cell adhesion is beginning to be revolutionised.

“Adhesion prevents cells becoming detached from their host tissues in response to external forces,” he explained. “But over the past five years, we’ve realised that many forces that cells experience are actually generated within the cells themselves - they are constantly pulling on the cells around them.“We found, though, that there is a pattern of pulling forces even within the junctions between cells. In many epithelial cells, E-cadherin concentrates in a chicken mesh-like pattern at the apical poles of the cells (called the zonula adherens). This is a prominent feature, but there is also a lot of E-cadherin in the

junctions below the zonula adherens (which we call the lateral junctions).

“Despite this, we found that the contractile tensions generated by cells at their apical junctions were much greater than those in the lateral junctions below the zonula adherens, so even in the same cell-cell junction there are zones of differing contractile tension.”

The molecular mechanism underlying the differing tensions between apical and lateral junctions was a puzzle.

“Contractility was due to the acto-myosin cytoskeletal system, and we wondered if it was something to do with the actin,” Yap said.

Indeed, his team found that actin at the zonula adherens was more stable than actin at the lateral junctions, while stabilisation of actin filaments increased tension at the lateral junctions. This raised the issue of how actin was stabilised in the apical, but not the lateral, junctions.

A MOLECULAR HANDLE

Coincidentally, another project in the lab had focused on a protein called N-WASP, which is related to the protein that is mutated in Wiskott-Aldrich syndrome, a rare inherited disorder involving immunodeficiency and impaired blood clotting.

N-WASP is found in almost all cells of the body and regulates the assembly of actin. Earlier, though, the Yap lab had also discovered that N-WASP stabilises actin filaments, exactly the kind of action that they were now looking for to explain tension at the zonula adherens.

“Indeed, we found that N-WASP localises very much to the zonula adherens and if you knock it down, then apical tension is reduced. Selwin Wu in my group developed a very clever strategy to target N-WASP to all parts of the junctions and found that this increased tension in the lateral junctions. This was the molecular handle that we needed,” explained Yap.

“We set out to explore the purpose of the mechanism - why would cells bother to put an actin stabiliser in one region to support higher tension in the filaments?

“Selwin then did another clever experiment, trying to change the pattern of tension in cells. He wanted to convert cells from having high apical/low lateral tension to a situation where apical tension was lower and lateral tension increased. He did this by targeting N-WASP to the lateral junctions and depleting it from the apical junctions,” Yap continued.

“When you do these kind of experiments you often have small numbers of manipulated cells that are surrounded by normal cells. We were astonished to discover that when this happened the manipulated cells became extruded from the epithelium!”

GETTING THE LOCATION RIGHT

Yap’s team then developed a more realistic, pathological model of oncogenic extrusion, in which they mosaically expressed the oncogene H-RAS, surrounded by normal cells. They found that N-WASP became redistributed from the apical to the lateral junctions when transformed cells contacted normal cells - exactly where extrusion occurred.


“If you then knock down N-WASP in the cell expressing the oncogene, it blocks oncogenic extrusion,” Yap said.

Yap and his colleagues published their findings in a paper in Nature Cell Biology in January this year, titled ‘Cortical F-actin stabilisation generates apical lateral patterns of junctional contractility that integrate cells into epithelia’.

“The way we believe it works is that N-WASP is normally regulated to locate within a specific region of the contact junction, generating forces that keep the cells in place among their neighbours.

“Conversely, if N-WASP is aberrantly distributed, it increases tension in places distant from the apical region, which promotes extrusion. Like real estate, if N-WASP is normally positioned, it’s good. If it’s located incorrectly, it’s bad.”

Yap said they speculated that N-WASP mislocalisation may be involved in tumour progression, which may help oncogenic extrusion expel cells to allow them to proliferate or invade. Inhibiting this process might provide the basis for a useful therapy to prevent metastasis.

“Interestingly, we already have a drug that inhibits N-WASP, one that was designed in Mike Rosen’s lab as an exercise in rational drug design. So far, it has been used only in tissue culture, for research purposes, so it’s not known whether it could become a useful, deliverable therapeutic drug to inhibit dysregulation of N-WASP.”

GETTING BACK TO CELL MECHANICS

Yap says it is interesting that oncogenic extrusion is only one of a number of examples of cell extrusion. Most occur when minorities of cells are surrounded and then expelled by relatively normal cells.

When it was originally observed in the fruit fly, Drosophila, it was described as ‘delamination’. In mammalian systems, it was identified as a mechanism associated with apoptosis - a means of clearing dead or dying cells from healthy tissues.

A couple of years ago, it was identified as a mechanism for reducing cell overcrowding in growing tissues.

“It’s not clear whether the same processes operate in all of these different forms of extrusion, because we haven’t gone very deep to identify the specific mechanisms that apply in each case,” reflected Yap.

In most cases, though, the cells to be extruded must somehow be recognised by their neighbours, which then respond.

The question, says Yap, is: what is it that the responding cells are recognising? And, in the particular case of their work, what do the neighbouring cells experience when N-WASP becomes relocalised in a transformed cell?

“Possibly it involves stiffening of the cell cortex, or mechanosensory receptors in neighbouring cells detect something happening,” he proposed.

“It’s an interesting and important question, because it highlights the importance of understanding how mechanical forces influence cell behaviour, including cell behaviour within tissues.

“Researchers originally became interested in the mechanics of cell movement and shape way back in the 1920s and 1930s, but their work largely fell out of favour with the advent of the molecular biology revolution, because we could learn so much, and much faster.

“Now, we’re going back to cell mechanics and realising that they’re more than just epiphenomena of biochemical processes within the cell,” Yap said.

“Neuroscientists have known about this for many years, through the phenomenon of mechanosensitive ion channels. But many other types of proteins, including structural elements of the cytoskeleton and motor proteins, are mechanosensitive.

“Potentially, mechanical events can be sensed by surrounding cells and tissues, via diverse mechanosensors, and trigger a response.”

Asked if the Wnt signalling system, which establishes cell polarity, might be involved in some way with regulating asymmetries in the internal tensions of cells, Yap said it was not an area in which his team worked.

But he said Emmanuel Farge’s lab at the Curie Institute had published a paper in Nature Communications last year, reporting that if Zebrafish or Drosophila embryos were physically stimulated, it activated localised morphogenetic signalling that impinged on the Wnt signalling pathway.

“Thus, mechanical elements impinge on many levels of biology - from molecules, through tissues, to organisms,” Yap concluded.

Professor Alpha Yap heads the Molecular Cell Biology Division of the Institute for Molecular Bioscience at the University of Queensland. He obtained a Bachelor of Medicine/Bachelor of Surgery degree at the University of Queensland, before going on to complete a PhD in epithelial biology at UQ’s Department of Physiology and Pharmacology in 1994. He is a Principal Research Fellow of the NHMRC, former president of the Australia and New Zealand Society for Cell & Developmental Biology, was chair of the 2011 Gordon Research Conference on Cell Contact & Adhesion and a member of several editorial boards, including Molecular Biology of the Cell, Developmental Cell and Current Biology.

Professor Alpha Yap and colleagues (from left to right: Carol Au, Alpha Yap, Rashmi Priya, Selwin Wu and Guillermo Gomez). Image by Gemma Ward (IMB).

CELL BIOLOGY | CELL-CELL ADHESION

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VIROLOGY | VACCINES

ARC Future Fellow, Dr Fasséli Coulibaly heads the Structural Virology Laboratory at Monash

University’s School of Biomedical Sciences in Melbourne. After arriving in Australia (from France via New Zealand) as a one-man band in 2007, he now runs a diverse research program centred on viruses, particularly the protein structures that make these little pathogenic packages so efficient, and so elusive. The systems he studies range from fascinating insect viruses that encage themselves in Zen-like crystals for surviving the lean times, to human pathogens such as the poxvirus

family that includes the notorious smallpox virus.

“We study these different systems for various reasons. One of the drivers is to work out, at the protein structure level, exactly how viruses assemble and interact with their cellular hosts and then use that knowledge to better fight these viruses.”

But probably the major driver of Coulibaly’s career-long fascination with viruses lies in the enormous diversity and extraordinary functional efficiency of viruses.

“Knowing more about these aspects of viruses can tell us lots about how proteins

in general work across the biological spectrum. Primarily we are looking at every step of the viral infection - assembly, replication, virulence - across a variety of projects.”

Two current thrusts in the lab are Coulibaly’s poxvirus work and their venture into the world of vaccine delivery using viral microcrystals … with both poised to have far-reaching benefits.

CONTRIBUTING TO A LONG HISTORY

Poxviruses have long been used as model systems in viral research because of their complex infectious cycle and

It is sometimes said that the best ideas are those already thought of, and that is exactly what structural biologist Dr Fasséli Coulibaly in Melbourne is banking on with his research on viruses. By deciphering viral protein structures that have evolved over thousands of years, he hopes to stop viral infections in their tracks and improve delivery of vaccines against a variety of diseases to the developing world.

viral research

The many faces of

Fiona Wylie


VACCINES | VIROLOGY

their remarkable ability to hijack and neutralise cellular defence mechanisms.

Indeed, the eradication of smallpox by the end of the 1970s was the culmination of a worldwide vaccine effort against poxvirus infections.

As Coulibaly emphasised, “Pox is an ‘old’ disease in humans that has had a huge impact on history. Smallpox reportedly claimed the life of Egyptian pharaoh Ramses V around 1150 BC and 3000 years later was blamed for the fall of the mighty Aztec civilisation when the newly introduced smallpox virus wiped out over 3 million people.

“Even today, this family of viruses is still considered a threat to health through existing diseases such as the skin disease Molluscum contagiosum, smallpox-like diseases such as monkeypox that can jump from monkeys to humans … and of course there is always the bioterrorism potential of deliberate smallpox release - a very small risk but the impact would be massively devastating.

“Poxviruses are also fascinating because they are the largest and most complex viruses that infect humans, and they are still teaching us a lot about the cells that they infect and the many systems that viruses use to circumvent the host defences.”

In recent work on the prototype mammalian poxvirus Vaccinia (famous as the active constituent of the smallpox vaccine), Coulibaly and Alok Mitra, from the University of Auckland, used a combination of X-ray crystallography and electron microscopy to solve the structure of a Vaccinia scaffolding protein called D13 and confirm its role in assembling the immature poxvirus particles necessary for infection.

Coulibaly is hoping they have found the Achilles heel of the virus.

“At this early stage, the virus has to modify the membranes of the host cells to make its own particles, and it turns out that if we delete or neutralise this single protein, the virus dies before any infectious particle can be formed and infection is therefore blocked. D13 is also a target of the antibiotic rifampicin, and so we are now looking

to make small-molecule inhibitors of poxvirus assembly.”

GOOD THINGS DO GO INTO SMALL

PACKAGES

Another major part of Coulibaly’s work at Monash is a vaccine delivery project, which is based on a single protein produced, in this case, by insect viruses.

This exciting research venture is funded by the Bill & Melinda Gates Foundation and is a collaboration with Rosemary French at the Burnet Institute and Lorena Brown at University of Melbourne.

“Insect viruses are very special compared to all mammalian viruses, because they don’t infect as free virus particles,” explained Coulibaly. “Instead, they actually embed themselves into stable, crystalline matrices inside the infected cells, called polyhedra, that the virus itself makes by overexpressing one of its proteins, appropriately named polyhedrin.”

These relatively massive structures (up to several microns across), sometimes containing up to 1000 virus particles, have evolved to protect the free viruses from dehydration (and almost anything else) once the infected insect dies and the cells rupture.

Then, when another insect larva comes along and eats the crystal, the matrix dissolves in the alkaline pH of the gut, freeing all the virus particles to go on their merry infecting way, make more crystals and so on. A very nifty process indeed, and one that sparked Coulibaly’s interest as a potential microparticle carrier system for all sorts of stuff including fluorescent probes, growth factors, immunogenic proteins and drugs.

THE POWER OF CRYSTALS

The polyhedra and micropackages idea had been rattling around in Coulibaly’s head long before he successfully secured the initial Phase I Gates funding in 2009. In fact, it started a few years before at the University of Auckland where Coulibaly was doing postdoctoral studies on poxvirus

assembly, and fellow structural biologist Peter Metcalf threw him a tantalising protein crystallography challenge to think about in his spare time.

“Peter was trying to determine the structure of one of these infectious viral crystals from a cypovirus that infects silkworm,” said Coulibaly.

Although first viewed by electron microscopy in the late 1940s, virus polyhedra have remained largely uncharacterised in terms of atomic structure because of their extremely small size and the technical limits of X-ray crystallography.

Clearly one not to back away from such a challenge, Coulibaly went to work with Metcalf and, in 2007, determined the first atomic structure of polyhedra purified directly from infected insects. The work was published in Nature and represented the smallest crystals used for solving a new protein structure by X-ray crystallography.

“Importantly, our results also suggested molecular bases for the outstanding stability of polyhedra against most chemical treatments (SDS, urea, acids) and their rapid dissolution at the alkaline pH encountered in the mid-guts of insect larvae.”

Artistic representation of immature poxvirus particles based on X-ray crystallography and cryoEM data. The D13 protein forms a honeycomb scaffold on the surface of immature virions.


Two years later at Monash University, Coulibaly published the second structure of a polyhedra determined by X-ray crystallography from microcrystals produced in vivo, this time from the Baculovirus family of insect viruses. This study revealed interesting and unexpected differences in the polyhedra building blocks from the two viral species that suggested novel information about viral evolution - also a subject of intense interest for Coulibaly.

HOW THEY DID IT - THE TECHIE BITS

“There were several reasons at that time for Nature accepting this work, but in part it was because of the major technical

achievement needed to solve crystals that small by X-ray crystallography. And that approach is still used now to try and solve these sorts of structures more efficiently,” Coulibaly said.

The natural stability and abundant availability of the microcrystals helped, but basically the team had to develop a number of strategies from scratch along the way, even just to handle them for analysis. They used specifically fabricated micromatrices as holders for the crystals to enable separation and alignment of the crystals for data collection in the diffractometer.

“There were also other hardware developments in X-ray diffraction

just becoming available at that time, and specifically the third-generation synchrotron microfocus beamlines that are especially designed to transmit X-rays through these tiny crystals,” explained Coulibaly.

“So, doing all of this and using the X06SA beamline at the Swiss Light Source Synchrotron near Zurich (and later at the Australian Synchrotron), we were able to observe single-crystal diffraction. From there it was just lots of time and hard work to analyse several thousand of these microcrystals harvested from insect cells - and about 2 years later we had our first atomic structure of the cypovirus polyhedra to a resolution of 2 angstrom.”

MORE THAN JUST PRETTY FACES

Subsequent studies showed that the polyhedra could also be engineered using well-established insect-cell-expression systems to express other small molecules such as drugs or fluorescent probes, without losing their robust nature. And, unlike existing virus-like nanoparticles, the fine-crystal packages custom made by viruses are easy to manipulate because of their size and strength, and can accommodate a wide range of cargoes including growth factors and full-length protein antigens.

Indeed, it seems that size really doesn’t matter when it comes to packing the polyhedra with useful molecules such as HIV antigens.

Cartoon representation of the cypovirus polyhedrin which forms infectious crystals called polyhedra (shown as a scanning EM picture in the background, courtesy of Elaine Chiu). The polyhedrin molecule can be described as a left hand (top) and assembles into trimers (bottom) forming the building blocks of polyhedra. The extended ‘finger’ of polyhedrin was used to direct incorporation of antigens into the crystal in place of the virus particles to engineer tough microparticles for vaccination.

VIROLOGY | VACCINES

Fasséli Coulibaly discovered his passion for viruses and their protein structures in his PhD studies in 1999 with Dr Felix Rey at the Pasteur Institute in Paris. His successful X-ray crystallography of an infectious birnavirus particle changed current thinking of viral evolution and appeared on the cover of Cell. In 2004, he took up a postdoctoral position at the University of Auckland, New Zealand, with Professor Ted Baker to pursue his structural exploration of viral functions, where he also started a successful collaboration with Associate Professors Peter Metcalf and Alok Mitra. Four years later, Coulibaly moved across the Tasman to establish an independent structural virology research group at Monash University. He subsequently won an NHMRC Career Development Fellowship (2009-2012), and together with project funding from the NHMRC, ARC and the Gates Foundation, steadily expanded his research group over the next 4 years. In 2013, Coulibaly was awarded an ARC Future Fellowship (2013-16) and secured next-stage, Phase II funding from the Gates Foundation. He is co-inventor on three patents protecting the applications of his findings on flaviviruses, cypovirus polyhedra and microcrystalline vaccines.


MICROCUBES AS VACCINES FOR THE DEVELOPING WORLD

The Bill and Melinda Gates Grand Challenges Explorations (GCE) funding scheme invests in the early stages of bold ideas with real potential to solve the problems people in the developing world face every day.

The Phase I funding awarded to Coulibaly’s team in 2009 enabled proof-of-concept studies to establish MicroCubes as a promising platform to deliver new and more potent vaccines with increased stability, obviating the need for refrigeration and extending the vaccine applications for use in the developing world. These virus polyhedra-based microcarriers were successfully engineered to accommodate various antigens, including an HIV protein, and to elicit strong T-cell responses. Their unique crystalline organisation results in slow release of the antigen and stimulates both arms of the immune system in mice.

The highly competitive Phase II GCE grants recognise ideas that have made significant progress towards implementation, and Coulibaly’s project is one of only four awardees announced last year.

“In the Phase II work, we will assess the suitability of MicroCubes as a generic vaccine platform, while working on a candidate flu vaccine. The fantastic tools available for research on influenza virus should facilitate translating the preclinical studies to humans,” Coulibaly said.

“We’re hoping to establish … that MicroCubes have unique properties that also warrant their development as a vaccine vector targeting infectious diseases with the highest burden in developing countries - malaria, TB and HIV.”

“One of the key features that we immediately saw in these structures when thinking about them as a carrier platform for vaccines was their size - they can hold a huge amount of protein inside them, so something like an entire antigen should not be a problem. And so far we haven’t reached a limit in terms of size. We can use native full-length antigens and they are released exactly as the immune cells would normally see them in vivo,” Coulibaly said.

And best of all, the polyhedral carriers are all produced in vivo, in insect cell culture, where good quality control can be maintained over the production process. Plus, the isolation process from the cells has no need for complex protein purification or formulation, avoiding problems such as the expressed protein becoming insoluble or damaged during purification.

CAPITALISING ON THE GRAND

CHALLENGE

Coulibaly is keen to emphasise that the vaccine project is a separate focus in his lab and was only made possible due to the Gates Foundation funding.

“When I first came to Monash, I focused solely on the structural biology of viruses, which is my area of expertise. But I always had this plan, and so Rosemary Ffrench and I applied for Phase I Grand Challenges Exploration funding from the Bill & Melinda Gates Foundation to design ultrastable

microcapsules for HIV and flu vaccination based on viral polyhedra.”

The team’s success in gaining that funding allowed Coulibaly to take this new direction, which is exactly the aim of the Gates scheme - to attract and support translational aspects of basic research from people across different fields.

“And, now we have been very lucky to secure Phase II funding to continue the vaccine work (see box), which was quite unexpected but very welcome.

Extensions are rare and the larger grants are highly competitive. That started about 10 months ago and is very exciting for us.”

So, besides being a great tale of good science, brains, hard work, innovation and, of course, some luck, Fasséli Coulibaly’s research story highlights yet again the importance of funding basic science as the best way to generate novel discoveries with potentially far-reaching health consequences.

VACCINES | VIROLOGY

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DIABETES | KIDNEY DISEASE

Diabetes is the fastest growing non-communicable disease in Australia and all types of diabetes are increasing in prevalence throughout the world.

One in 10 adults in Australia currently have the disease - that’s 1.7 million people, and by 2035 this is predicted to increase to 2.3 million.

Diabetes is associated with micro- and macrovascular complications. Microvascular complications include retinopathy, nephropathy and neuropathy, and macrovascular complications include ischemic heart disease, peripheral vascular disease and cerebrovascular disease. These complications can result in serious organ and tissue damage, which current treatment options fail to protect patients against.

Nephropathy, or diabetic kidney disease, is the focus of some leading research happening in Melbourne that aims to develop new treatments to prevent or halt the progression of this serious and sometimes fatal complication.

TRIALLING A NEW ENZYME INHIBITOR

A potential new treatment for diabetic kidney disease is about to go into an international Phase II clinical trial and Australian patients will make up some of the participants.

Discovered through research conducted by Professor Karin Jandeleit-Dahm, Head of the Diabetes Complications Division at the Baker IDI Heart and Diabetes Institute, in collaboration with Prof Harald Schmidt from the University of Maastricht in Holland, the treatment inhibits a specific enzyme known to cause kidney injury in diabetes - NADH oxidase enzyme 4 (NOX4).

DIABETIC NEPHROPATHY

Diabetic-related kidney disease or diabetic nephropathy is the major cause of end-stage renal disease in the Western world. Diabetes also increases the risk of cardiovascular disease, which

is amplified if kidney disease is present, and diabetic retinopathy is another consequence of this condition.

The standard treatment option for kidney nephropathy (ACE inhibitors) targets the renin-angiotensin system and aims to reduce blood pressure by blocking angiotensin. This treatment halts the disease to some degree, but it is not a cure.

“Some people progress to requiring dialysis or kidney transplantation more quickly than others,” said Jandeleit-Dahm, “although it is not understood why.”

REDUCED DISEASE IN KNOCK-OUT MICE

Jandeleit-Dahm's research builds on earlier work in which the team identified a related enzyme, NOX1, to be an important target in preventing cardiovascular and eye disease in diabetes, as demonstrated in a collaboration with Professor Jennifer Wilkindon-Berka from Monash University.

“The NOX family of enzymes play a role in various complications,” Jandeleit-Dahm explained. “They are very important in the kidney and vascular systems. We have previously identified NOX1 in the aorta and demonstrated its importance in plaque formation and atherosclerosis, which leads to heart attacks and stroke.

“The NOX enzymes are important in generating oxidative stress in the kidney,” she said. “We used knock-out mice for NOX1 and NOX4, which were developed by our collaborator at the University of Maastricht, Professor Harald Schmidt, and showed that when these mice were made diabetic they underwent a reduction in albuminuria, kidney fibrosis and inflammation.”

INHIBITING OXIDATIVE STRESS

Albuminuria, or an increased level of albumin in the urine, is a hallmark of developing and ongoing kidney disease.

Susan Williamson

The persistently high blood glucose levels associated with diabetes can, over time, cause damage to blood vessels that result in so-called diabetes-related complications. Preventing or reducing diabetes-related complications in the kidney is the focus of some of the work currently underway at the Baker IDI.

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KIDNEY DISEASE | DIABETES

“We have also been looking at the expression or upregulation of the NOX genes and, using our Canadian colleagues’ state-of-the-art HPLC technology, we measured the amount of reactive oxygen species being produced in the NOX4 knock-out mice,” Jandeleit-Dahm said.

This work demonstrated that the NOX4 gene is important in mediating kidney disease in diabetes, whereas NOX1 is pivotal in mediating blood vessels and eye disease in diabetes.

“We have been collaborating with Genkyotex, a Swiss biotech company who have developed an inhibitor that blocks NOX1 and NOX4,” Jandeleit-Dahm continued. “When we treated mice with the inhibitor the results paralleled the studies in the knock-out mice for NOX4 with respect to kidney disease.”

The research, which Jandeleit-Dahm’s team presented at the 22nd World Diabetes Congress held in Melbourne at the end of 2013, has been published online in the Journal of the American Society of Nephrology.

ENTERING A CLINICAL TRIAL

The compound has entered an international Phase II clinical study for patients with type 2 diabetes-related kidney disease who have high levels of albuminuria. The Baker IDI is participating in the trial, which will initially assess safety and efficacy of the inhibitor on top of maximal treatment with the current standard treatment, ACE inhibitors or angiotensin receptor blockade.

“We want to investigate if there is a decrease in the level of albumin in the urine of trial participants,” said Jandeleit-Dahm. “A reduction in albuminuria also translates to a reduction in the risk of further progression of kidney disease and in cardiovascular disease risk.”

THE MICRORNA PERSPECTIVE

Better understanding the mechanisms underlying diabetic nephropathy and developing new treatments to reduce or restore the damage present in chronic kidney disease is also the focus of work by Dr Phillip Kantharidis, who heads the Genomics of Diabetes Complications Unit at the Baker Institute in Melbourne.

A key player for Kantharidis in this quest is microRNA (miRNA), a member of the small noncoding RNA family of molecules formerly known as ‘junk RNA’.

MicroRNAs are about 20-25 nucleotides long and make up about 3-10% of all the small noncoding RNAs found in cells.

“This is a relatively new area,” said Kantharidis. “MicroRNAs were first identified about 20 years ago and were thought to be peculiar to worms and yeast. Over the last decade not only have they been found in most living cells, but their huge influence on biological processes and in human disease has been recognised.”

A PROMISCUOUS MOLECULE

MicroRNAs are important in the normal functioning of cells and regulate numerous biological functions, such as basic cell signalling and tissue architecture.

“MicroRNAs act as fine regulators of gene expression by binding to the 3' end of messengerRNA (mRNA) molecules resulting in decreased protein translation,” explained Kantharidis.

They are also implicated in many cell pathologies and contribute to the development and progression of nephropathy by altering the expression of target genes which are important to normal kidney function.

In diabetic kidney disease the kidney undergoes an increase in collagen production, causing its structure to become fibrotic and decreasing its ability to conduct its filtration function. The high-glucose environment, along with factors such as transforming growth factor-β (TGF-β), drive this increase in collagen and matrix protein production.

Directly targeting of TGF-β as an anti-fibrotic treatment is problematic because of its critical role in immune surveillance. Thus, one tactic Kantharidis’s team is pursuing is to identify new treatment targets, such as miRNAs.

A number of miRNAs are now known to play a role in nephropathy and several of these are regulated by TGF-β.

“We were initially interested in whether miRNAs were altered in diabetic nephropathy and therefore changing the translation of important genes in the kidney,” said Kantharidis. “We found the level of a number miRNAs were significantly reduced. Importantly, these microRNAs targeted collagen and matrix proteins, leading to the increased expression of these genes.”

But this is not a simple task. As Kantharidis says, miRNAs are promiscuous molecules - one miRNA can bind up to one thousand genes.

“One transcription factor or a single RNA can be targeted by many different miRNAs,” he said. “And one miRNA can bind multiple RNAs, at a single or multiple sites, leading to a very complex regulatory circuit.”

SMALL MOLECULE INHIBITORS

Kantharidis’s team has identified five or six primary miRNAs that are altered in kidney disease. One of these is increased while the others are decreased in the diabetic kidney. It is early days, but these are potential candidates for developing a potential treatment.

“One of the miRNAs we recently identified is an amplifier of profibrotic signals in the kidney,” Kantharidis said. “We believe that by knocking down this miRNA we may be able to slow the progression of the kidney disease.”

The ‘Nox team’ – (L to R) Miss Elyse DiMarco, Professor Karin Jandeleit-Dahm, Dr Stephen Gray and Mr Jay Chandra Jha.


He expects the side effects will be minimal because miRNA molecules are fine regulators of expression and do not act as master switches to turn genes on and off.

“Drugs that inhibit certain microRNAs are being used in cancer research. We are interested in using some of these as they appear to target microRNAs relevant to kidney disease as well,” he said, adding that a number of companies are developing microRNA therapeutic products for the treatment of hepatitis C and heart disease.

They will start by looking at how to restore the expression of miRNAs by using these small molecule inhibitors in animal models of diabetes to assess their effect on kidney function.

“Our interest is in how miRNAs are dysregulated, up or down, in diabetic kidney disease and whether their expression can be restored to reduce or reverse kidney disease,” he added.

POTENTIAL BIOMARKERS

Kantharidis says miRNAs appear to be fairly stable in biological fluids. They have conducted next-generation sequencing on miRNAs released from cells that have been given various treatments, as well as miRNAs released into blood and urine.

“There are a lot of microRNAs in serum and urine, and they are found bound to RNA binding proteins or in small vesicles,” added Kantharidis. “They are transported in the plasma and in some cases have been shown to act at distal sites in the body, influencing gene expression in other organs, but how this works is not well understood.”

The presence of miRNAs in biofluids means they represent a potential source of readily available biomarkers for many diseases, including diabetic nephropathy.

Kantharidis’s team is also looking at identifying miRNAs in urine as potential biomarkers of diabetic kidney disease.

A NETWORK INFLUENCE

The concept of linear signalling goes out the window when miRNAs are around. Multiple miRNAs can target a single RNA, a single miRNA can target multiple RNAs and a single dysregulated miRNA can influence an entire signalling network. Understanding how they regulate and are regulated by factors that contribute to kidney disease is certainly a challenge.

“In one kidney cell that we studied, 50% of the total population of miRNAs were made up of one single miRNA,” he said. “The thinking is that abundant microRNAs maintain the cell phenotype, but once a cell is pushed past phenotypic boundaries, a resetting of the miRNAs expression profile occurs to adapt to the new phenotype.”

Kantharidis also presented this work at the 22nd World Diabetes Congress, and has a publication in the pipeline.

From left to right: Dr Phillip Kantharidis with colleagues Shinji Hagiwara and Aaron McLelland at the Baker IDI.

DIABETES | KIDNEY DISEASE

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PUBLISH OR PERISHPUBLISH OR PERISH

Tell the world about your event: email [email protected]

The return of our regular round-up of some of the best Australian research published each month in leading peer-reviewed journals.

Afshar-Sterle S, Zotos D, Bernard NJ, Scherger AK, Rödling L, Alsop AE, Walker J, Masson F, Belz GT, Corcoran LM, O’Reilly LA, Strasser A, Smyth MJ, Johnstone R, Tarlinton DM, Nutt SL, Kallies A. WEHI, Univ of Melb and Peter Mac, Vic, QIMR Berghofer Med Res Inst and UQFas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas. Nat Med. 2014 Feb 2.

Altin JA, Daley SR, Howitt J, Rickards HJ, Batkin AK, Horikawa K, Prasad SJ, Nelms KA, Kumar S, Wu LC, Tan SS, Cook MC, Goodnow CC. JCSMR, ANU, CanberraNdfip1 mediates peripheral tolerance to self and exogenous antigen by inducing cell cycle exit in responding CD4+ T cells.Proc Natl Acad Sci USA. 2014 Feb 11;111(6):2067-74.

Bonham KS, Orzalli MH, Hayashi K, Wolf AI, Glanemann C, Weninger W, Iwasaki A, Knipe DM, Kagan C.Centen Inst, SydA promiscuous lipid-binding protein diversifies the subcellular sites of toll-like receptor signal transduction. Cell 2014 Feb 13;156(4):705-16.

Bonning BC, Pal N, Liu S, Wang Z, Sivakumar S, Dixon PM, King GF, Miller WA. UQToxin delivery by the coat protein of an aphid-vectored plant virus provides plant resistance to aphids.Nat Biotechnol. 2014 Jan;32(1):102-5.

Bromfield JJ, Schjenken JE, Chin PY, Care AS, Jasper MJ, Robertson SA. Univ of AdelaideMaternal tract factors contribute to paternal seminal fluid impact on metabolic phenotype in offspring.Proc Natl Acad Sci USA. 2014 Feb 11;111(6):2200-5.

Callaghan BL, Li S, Richardson R. UNSWThe elusive engram: what can infantile amnesia tell us about memory?Trends Neurosci. 2014 Jan;37(1):47-53.

Eyre NS, Fiches GN, Aloia AL, Helbig KJ, McCartney EM, McErlean CS, Li K, Aggarwal A, Turville SG, Beard MR. Univ of AdelDynamic imaging of the hepatitis C virus NS5A protein during a productive infection.J Virol. 2014 Jan 15.

Feeney WE, Medina I, Somveille M, Heinsohn R, Hall ML, Mulder RA, Stein JA, Kilner RM, Langmore NE. ANU, CanberraBrood parasitism and the evolution of cooperative breeding in birds.Science 2013 Dec 20;342(6165):1506-8.

Funnell AP, Crossley M. UNSWHemophilia B Leyden and once mysterious cis-regulatory mutations.Trends Genet. 2014 Jan;30(1):18-23.

Haque A, Engwerda C. IMR Berghofer Med Res Inst, QldHepatocytes break the silence during liver-stage malaria.Nat Med. 2014 Jan;20(1):17-9.

Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, van den Ende J, Schuurs-Hoeijmakers JH, Marcelis CL, Willemsen MH, Vissers LE, Yntema HG, Bakshi M, Wilson M, Witherspoon KT, Malmgren H, Nordgren A, Annerén G, Fichera M, Bosco P, Romano C, de Vries BB, Kleefstra T, Kooy RF, Eichler EE, Van der Aa N. Westmd Hosp, Children’s Hosp Westmd, Syd A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat Genet. 2014 Feb 16.

Hussain M, Asgari S. UQ MicroRNA-like viral small RNA from Dengue virus 2 autoregulates its replication in mosquito cells.Proc Natl Acad Sci USA 2014 Feb 18;111(7):2746-51.

Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H. Univ WA and OS colleaguesPathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis.Nat Med. 2014 Jan;20(1):62-8.

Lisowski L, Dane AP, Chu K, Zhang Y, Cunningham SC, Wilson EM, Nygaard S, Grompe M, Alexander IE, Kay MA. Child’s Hosp Westmd and Child’s Med Res Inst, Univ Syd and OS colleaguesSelection and evaluation of clinically relevant AAV variants in a xenograft liver model. Nature 2014 Feb 20;506(7488):382-6.

Markmiller S, Cloonan N, Lardelli RM, Doggett K, Keightley MC, Boglev Y, Trotter AJ, Ng AY, Wilkins SJ, Verkade H, Ober EA, Field HA, Grimmond SM, Lieschke GJ, Stainier DY, Heath JK. Ludwig Inst Canc Res, VicMinor class splicing shapes the zebrafish transcriptome during development.Proc Natl Acad Sci USA 2014 Feb 10.

Necsulea A, Soumillon M, Warnefors M, Liechti A, Daish T, Zeller U, Baker JC, Grützner F, Kaessmann H. Univ of Adel, SA and OS colleaguesThe evolution of lncRNA repertoires and expression patterns in tetrapods.Nature 2014 Jan 30;505(7485):635-40.

Paolino M, Choidas A, Wallner S, Pranjic B, Uribesalgo I, Loeser S, Jamieson AM, Langdon WY, Ikeda F, Fededa JP, Cronin SJ, Nitsch R, Schultz-Fademrecht C, Eickhoff J, Menninger S, Unger A, Torka R, Gruber T, Hinterleitner R, Baier G, Wolf D, Ullrich A, Klebl BM, Penninger JM. Univ WAThe E3 ligase Cbl-b and TAM receptors regulate cancer metastasis via natural killer cells. Nature 2014 Feb 19.

Rios AC, Fu NY, Lindeman GJ, Visvader JE. WEHI, Univ of Melb, Royal Melb HospIn situ identification of bipotent stem cells in the mammary gland. Nature 2014 Feb 20;506(7488):322-7.

Rouet R, Christ D. Garvan and UNSW, SydBispecific antibodies with native chain structure.Nat Biotechnol. 2014 Feb 7;32(2):136-7.

Ryan PJ, Kastman HE, Krstew EV, Rosengren KJ, Hossain MA, Churilov L, Wade JD, Gundlach AL, Lawrence AJ. Univ MelbRelaxin-3/RXFP3 system regulates alcohol-seeking.Proc Natl Acad Sci USA 2013 Dec 17;110(51):20789-94.

Schlub TE, Grimm AJ, Smyth RP, Cromer D, Chopra A, Mallal S, Venturi V, Waugh C, Mak J, Davenport MP. Sydney Univ15-20% of HIV substitution mutations are associated with recombination.J Virol. 2014 Jan 22.

Sherwood S, Fu Q. UNSWClimate change. A drier future?Science 2014 Feb 14;343(6172):737-9.

Smith SM. University WAPlant biology: Witchcraft and destruction.Nature 2013 Dec 19;504(7480):384-5

Stirzaker C, Taberlay PC, Statham AL, Clark SJ. Garvan, Kinghorn Canc Cntr, and St Vin’s Clin Schl, UNSW, SydMining cancer methylomes: prospects and challenges.Trends Genet. 2014 Feb;30(2):75-84.

Tang YT, Gao X, Rosa BA, Abubucker S, Hallsworth-Pepin K, Martin J, Tyagi R, Heizer E, Zhang X, Bhonagiri-Palsikar V, Minx P, Warren WC, Wang Q, Zhan B, Hotez PJ, Sternberg PW, Dougall A, Gaze ST, Mulvenna J, Sotillo J, Ranganathan S, Rabelo EM, Wilson RK, Felgner PL, Bethony J, Hawdon JM, Gasser RB, Loukas A, Mitreva M. JCU, QIMR, Qld; Mac Univ, NSW; Univ Melb, Vic; and OS colleaguesGenome of the human hookworm Necator americanus. Nat Genet. 2014 Jan 19.



DATES FOR THE LIFE SCIENCES CALENDARThe coming year is packed with exciting local and international events. Here’s a taste.


EVENTS

11th Annual Conference of the Society for Brain Mapping and TherapeuticsMarch 17-19, Sydneywww.worldbrainmapping.org/11th-annual-congress/welcome-message

5th New Directions in Leukaemia Research (NDLR) meetingMarch 30- April 2, Noosa, Queenslandhttp://sapmea.asn.au/conventions/ndlr2014

AusMedtech 2014April 1-2, Melbournewww.ausmedtech.com.au

Big Data 2014April 3-4, Melbournewww.hisa.org.au/page/bigdata2014

Practice-Based Education Summit 2014, The promises of university education: Blending, including and integrating for future practiceApril 9-10, Sydneyhttp://csusap.csu.edu.au/~areport/pbe_summit_2014.htm

Deeble Institute short course: translating research findings into policy and practiceApril 14-16, Canberrahttps://ahha.asn.au/content/deeble-institute-short-course

The World Congress of Cardiology 2014 (WCC 2014) May 4-7, Melbournewww.worldcardiocongress.org/

Genemappers 2014May 11-14, Barossa Valley, South Australiawww.genemappers.org/

Innovating with Asia 2014 May 20-21, Perthhttp://conference.crca.asn.au/

The Fifth International Conference on the Development of Biomedical Engineering June 16-18, Ho Chi Minh City, Vietnamhttp://csc.hcmiu.edu.vn/BME2014

5th Congress of the International Society for Applied Phycology 2014June 22-27, Sydneywww.isap2014.com

Australian Society for Microbiology Annual Scientific MeetingJuly 6-9, Melbournehttp://asmmeeting.theasm.org.au

International Union for the Study of Social Insects international CongressJuly 13-18, Cairnswww.iussi2014.com

AIDS 2014 - 20th International AIDS ConferenceJuly 20-25, Melbournewww.aids2014.org/

12th International Conference on Cognitive Neuroscience 2014 (ICON 2014)July 27-31, Brisbanewww.icon2014.org/

2014 International Biophysics Congress August 3-7, Brisbanewww.iupab2014.org

10th Australasian Mutation Detection MeetingSeptember 1-4, Daydream Island, Whitsundayshttp://wired.ivvy.com/event/MD2014/

Joint International Symposium on the Nutrition of Herbivores/International Symposium on Ruminant Physiology International ConferenceSeptember 8-12, Canberrahttp://www.herbivores2014.com/

15th International Conference on Systems Biology September 13-19, Melbournewww.emblaustralia.org

ComBio2014September 28-October 2, Canberrawww.asbmb.org.au

Australian Genomic Technologies Association (AGTA) ConferenceOctober 12-15, Melbournewww.agtaconference.org

TRX14 - Translational Research ExcellenceOctober 24, Brisbanewww.trx14.com.au

Australasian Association of Clinical Biochemists 52nd Annual Scientific ConferenceOctober 27-29, Adelaidewww.aacb.asn.au/events/event/aacb-52nd-annual-scientific-conference

AusBiotech 2014October 28-31, Gold Coastwww.ausbiotech.org

Lab Management Conference 2014November 10-12, SydneyTBC

Australian Health and Medical Research CongressNovember 16-19, Melbournewww.ahmrcongress.org.au/

Science meets Parliament 2014March 17-18, CanberraScience meets Parliament will bring about 200 of Australia’s top scientists face to face with the decision-makers in Canberra. Funded by the Department of Industry, Capital Hill will live and breathe science at this annual event - that began in 1999 - as scientists keep parliamentarians informed on the big issues. This annual forum aims to give scientists unique personal development opportunities; help scientists understand the competing rationalities of science, politics, public policy and the media; stimulate and inform parliament’s discussion of scientific issues that underpin Australia’s economic, social and environmental wellbeing; improve the understanding of science through the wider community; build links between scientists, politicians and policymakers that open up avenues for information and idea exchanges into the future; and give scientists an outlook for opportunities that may require the input of scientific knowledge to further the interests of the nation.http://scienceandtechnologyaustralia.org.au/news-and-events/science-meets-parliament-2014/

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Australian Life Scientist Mar/Apr 2014

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