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THE PROMISE OF STEM CELLS | NEXT GEN SEQUENCING | IMMUNOLOGY

Vol 10 Issue 6 • November/December 2013

Putting the

brain into brain research back

http://www.lonza.com

www.lifescientist.com.au NOVEMBER / DECEMBER 2013 3AUSTRALIAN LIFE SCIENTIST

Contents

IN THE NEXT ISSUE OF ALS• Lorne conference previews: – Proteomics/Protein structure and function – Cancer – Genome• Neuroscience

REGULARS06 Movers and shakers10 GrantWatch12 AusBiotech35 New products41 Publish or perish42 Events

FACE TO FACE

14 Immortal scienceStem cell scientist Professor Martin Pera reflects on his involvement in research that led to the successful development of human embryonic stem cells and where this research field is at today.

NEXT GENERATION SEQUENCING

18 Anatomy of an HCV infectionThe hepatitis C virus is an adept mutator. Next-generation sequencing is helping to reveal the behaviour of this RNA virus that generates a diversity of quasi species during initial infection in humans.

22 Melanoma Genome Project on trackThe multimillion-dollar initiative that is unravelling the secrets of malignant melanoma is on track to deliver sequencing data early next year.

AUSTRALASIAN SOCIETY FOR IMMUNOLOGY PREVIEW

24 Hooked on immunologyProfessor Alan Baxter will deliver the annual Australasian Society for Immunology’s Postgraduate Lecture at this year’s meeting to inspire a new crop of immunologists to take up a career in science.

27 A new lymphoid cellA new type of lymphoid cell that appears to play a role in defence against cutaneous infection has been described and visualised for the first time in the skin by Professor Wolfgang Weninger’s Sydney-based research group.

AUSTRALASIAN NEUROSCIENCE SOCIETY MEETING PREVIEW

30 Perceptual distortions of the body in pain

People who experience chronic pain often have altered physical self-awareness or a distorted perception of their painful body part. This changed neuroperception forms the basis of Dr Tasha Stanton’s research into how the brain perceives pain and what differs in the brain when pain persists.

32 Putting the brain back into brain research

Brain banks remain an incredibly important and valuable resource for many studies in neuroscience. Professor James Vickers, whose research on dementia spans 20 years, is keen to explain why at this year’s meeting.

Cover image: © iStockphoto.com/video-doctor

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Editorial deadline: 04/12/13Advertising deadline: 04/12/13

www.lifescientist.com.au4 NOVEMBER / DECEMBER 2013 AUSTRALIAN LIFE SCIENTIST

Australia has a competent research workforce that is said to punch above its weight in terms of research

performance. At least in medical research, earth sciences, engineering and astronomy, citation records shows that we produce more quality research than would be expected from our small population.

Whether we can hold this position remains to be seen with the good work being conducted in Asian countries increasingly being recognised and research partners in Europe and the US forging ahead.

Investing in our research capacity is key to growing and maintaining the sector.

The Prime Minister’s presence at the NHMRC grant announcements at the end of October indicates that Tony Abbott is interested in the health sector - after all he did hold the health portfolio for four years under the Howard government.

Abbott reiterated his pre-election promise not to cut funding of health and medical research at the grant announcements. This was backed up in the announcement of a Commission of Audit into government finances, which the government has promised will involve no reductions to the health or education portfolios.

Encouragingly, basic science was fairly well represented overall in the 2013 NHMRC grant outcomes; however, the success rates dropped. From over 5000 applications, 19% were funded and only 17% of program grants received funding. Applications for three-year research project funding used to have a 23% success rate - but that was a couple of years ago.

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ARC-funded discovery research projects had a 22% success rate for 2013.

This low success rate provides little incentive for those contemplating a career in science. Yet supporting people who choose to take up careers as researchers, whether

in clinical or basic research, is essential to growing our research capacity.

This lack of incentives for taking on a research career may provide some explanation for the drop in students choosing to take on science at school and university.

Finding a common message across the sciences and promoting

the value of science and technology to the future of Australia to government and the community will help turn this around.

Another option is to generate teamwork and collaborations that cut across the traditional boundaries of academic departments and colleges.

The predicted convergence of physics, biology and engineering is being cited as one way the decline in graduates in the maths and physical sciences can be reversed. This convergence or blurring of boundaries will translate to advances in medicine, energy production, agriculture, manufacturing and sustainable environments.

Health and education, basic research and the public service sector in general are usually an easy target for new governments to makes things meet with their budget promises.

Let’s hope the government’s Commission of Audit, where ‘nothing is off the table’, does not target research and higher education to allow them to tighten their purse strings.

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creative mindsNurturing

Susan Williamson

creative minds

Access the free white paper at lifetechnologies.com/parkinsonsFor Research Use Only. Not for use in diagnostic procedures. © 2013 Life Technologies Corporation. All rights reserved. The trademarks mentioned herein are the property of Life Technologies Corporation and/or its affiliate(s) or their respective owners. CO115286 1013

Modeling neurodegenerative diseaseStem cells help develop cellular models for understanding Parkinson’s diseaseFrom modeling diseases to discovering therapies, stem cells have the potential to change the way we think about medicine. Researchers at The Parkinson’s Institute and Life Technologies have partnered to build a path to more physiologically relevant cellular models for Parkinson’s disease using donor cells to generate induced pluripotent stem cells.

Read about the journey the researchers have started, the novel tools they have utilized, and the models they are producing to help advance Parkinson’s disease research.

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MOVERS & SHAKERS

Sydney professor appointed UNESCO chairProfessor Elaine Baker, from the School of Geosciences at the University of Sydney, has received the prestigious appointment of a United Nations Educational, Scientific and Cultural Organisation (UNESCO) chair in ocean governance.

Starting in mid-September 2013, Professor Baker’s position is for four years with the option of renewal at the end of this period.

“Being made a UNESCO chair is a great honour,” said Baker, who hopes to use this position to develop a more visible presence for the science that supports the sustainable use of the oceans.

UNESCO chair positions aim to improve the capacity of institutions to work globally and form partnerships with each other to deal with issues at a global level.

Baker leads the partnership between the 28 organisations involved in University of the Sea - a program that allows senior researchers from the Asia-Pacific region to work with young local scholars on marine issues in the region.

“The UNESCO chair position came about as the result of the collaborative project that is University of the Sea, but this is only one of many collaborative projects and capacity-building activities that I am involved in,” said Baker.

“Most recently the United Nations has launched a program - the World Ocean Assessment - to make regular reports on the state of the marine environment including socioeconomic aspects. I have been very much involved in this process,” explained Baker.

Marine spatial planning and The Economics of Ecosystems and Biodiversity (TEEB) for oceans project will be Baker’s major research focuses in this new position.

New President for the Australian Academy of ScienceIn its four-yearly swing to the physical sciences, the Australian Academy of Science has elected a pioneer of research in organic electronics, Professor Andrew Holmes, as its next President.

The presidency alternates between the physical and biological sciences and the term lasts for 4 years.

Holmes, a Laureate Professor of Chemistry at the University of Melbourne’s Bio21 Institute, a CSIRO Fellow and Distinguished Research Fellow in the Department of Chemistry at the Imperial College London, will take up the role after the Academy’s next Annual General Meeting in May 2014.

The current President, immunologist Professor Suzanne Cory, said, “Professor Holmes will lead our Academy with great distinction, energy and integrity.

“As Foreign Secretary, he has worked tirelessly on behalf of the Academy and its programs, with the deep conviction that Australia’s future prosperity depends on strong research and education in science and mathematics and in further developing international science linkages.”

Holmes graduated in chemistry from the University of Melbourne and completed a PhD at University College, London. He then moved to Cambridge University, where he became Professor of Organic and Polymer Chemistry and Director of the Melville Laboratory for Polymer Synthesis.

In the 1990s, Holmes achieved international

prominence when the team he was working with developed a new class of light-emitting polymers. These polymers transformed technology for televisions and computers with lightweight, super-thin, flexible video screens bright enough to be viewed even in direct sunlight.

Holmes returned to Melbourne in 2004 as a Federation Fellow to establish a laboratory at the then newly established Bio21 Institute. He was instrumental in forming the Victorian Organic Solar Cell Consortium.

In 2000, Holmes was elected a Fellow of the Royal Society and awarded its prestigious Royal Medal in 2012. He was elected as Fellow of the Australian Academy of Science in 2006 and appointed a Member of the Order of Australia in the 2004 Australia Day Honours list.

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MOVERS & SHAKERS

A life’s work rewardedThis year’s winner of the 2013 CSL Florey Medal, a $50,000 biennial award made by the Australian Institute of Policy and Science, is Melbourne researcher Professor Ruth Bishop.The medal honours the significant achievements Bishop has made through her life’s work in discovering, understanding and working out how to treat rotavirus.

Back in 1973 Bishop, Brian Ruck, Geoffrey Davidson and Dr Ian Holmes at the Royal Children’s Hospital and the University of Melbourne’s microbiology department found the rotavirus.

Looking initially for a bacterium, they found a virus, called rotavirus for its distinctive wheel-like shape.

Rotavirus is the main cause of severe gastroenteritis in infants and young children - by their third birthday, just about every child in the world has had a rotavirus infection. About half a million children die from it each year.

Until the middle of the last decade, rotavirus caused about 10,000 Australian children to be hospitalised each year with acute gastroenteritis.

As a result of Bishop and colleagues’ research, vaccination against ‘gastro’ has been part of the National Immunisation Program for all Australian infants since mid 2007. And the number of hospital admissions has dropped by more than 70%.

Fifty million children in the poorest countries will be vaccinated by 2015 by GAVI, the Global Alliance for Vaccines

and Immunisation, and their partners, supported by the Bill and Melinda Gates Foundation.

Countries that have introduced rotavirus vaccines have seen a dramatic improvement in child health. GAVI is currently working with its partners to reach the world’s poorest 30 nations by 2015.

Bishop, now in her eighties, won’t be fully satisfied until a new vaccine she helped develop becomes available. It’s intended for newborns, “the only time children in many developing countries are likely to be near a hospital,” she said. The vaccine is currently being trialled in Indonesia and New Zealand.

2013 Victoria Prize rewards malaria researcher

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Malaria researcher Professor Alan Cowman from the Walter and Eliza Hall Institute has been awarded the 2013 Victoria Prize for Science and Innovation in recognition of his outstanding contributions in the quest to eradicate malaria.

The $50,000 prize recognises Cowman’s career of almost 30 years that has increased our understanding of the malaria parasite, Plasmodium falciparum.

Cowman and his research team have made significant inroads into understanding how the malaria parasite infects humans and persists in the body by evading the immune system.

He has also made major contributions to understanding malarial drug resistance and unravelling the mechanisms the parasite uses to become resistant to antimalarial drugs. This has had implications for the development of new antimalarial treatments and surveillance of the geographic spread of drug-resistant strains of malaria.

Cowman’s work has also led to the development of two potential malaria vaccines, one of which has reached clinical trials in the US and a second of which is in preclinical development.

“Throughout my career I have been fortunate to work with some incredibly talented researchers and I would like to thank them for their support,” Cowman said in a statement. “Science research in Victoria and across the country is world class and I am lucky to be able to facilitate these potentially life-changing discoveries.”

The Victoria Prize was first awarded in 1998 and celebrates leadership, determination, endeavour and creativity as well as highlighting the many ways in which research and development of international significance are conducted in Victoria.

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GrantWatch

MOVERS & SHAKERS

A new human systems biology centre

NHMRC 2013 grants announced

The recipients of the Ramaciotti Awards for biomedical research, worth over $2.2 million, have been announced with the Centenary Institute and the University of Sydney receiving the $1 million Ramaciotti Biomedical Research Award.

The award was made to Professor Barbara Fazekas de St Groth and Dr Adrian Smith of the Centenary Institute and Professor Nicholas King from University of Sydney, and will be used to establish the Ramaciotti Centre for Human Systems Biology in 2014.

The researchers are investigating how regulatory T-cells modulate the immune system and prevent autoimmune diseases such as psoriasis, multiple sclerosis and inflammatory bowel disease.

The new Centre will buy Australia’s first CyTOF (cytometry by time of flight) mass spectrometer which can track up to 100

different cellular processes simultaneously in a thousand cells each second. Existing technology can track up to 15-20 molecules simultaneously.

Professor Douglas Hilton, Director of the Walter and Eliza Hall Institute for Medical Research and head of the Department of Medical Biology at the University of Melbourne, was awarded the Ramaciotti Medal for Excellence and $50,000 grant for his discoveries in blood cell production.

Equipment and establishment grants of up to $75,000 each, totalling over $1.2 million, were also given to 17 recipients.

The biannual $1 million Ramaciotti Biomedical Research Award was only open to NSW applicants this year. The next $1 million grant in 2015 will consider applications from all other states, excluding NSW, as per its alternating scope.

The NHMRC delivered its 2013 funding round of $559.1 million to health and medical researchers across Australia in October.

The announcement, made by Prime Minister Tony Abbott accompanied by Minister for Health Peter Dutton, supports the best Australian health and medical research and the best researchers leveraged around national priority areas.

Funding support was given to 963 grants across three NHMRC research support schemes and five fellowship schemes.

This year’s round of funding included 652 project grants worth $423.5 million and will support investigator-initiated research projects in clinical, biomedical, public health and health services research. From over 5000 applications, 19% were funded.

“It was a tough year,” said Brendan Crabb, president of the Australian Association of Medical Research Institutes. “The project grant scheme had a 16.9% success rate - that’s the lowest we’ve had. It’s getting into the red zone.”

In last year’s round, 20.5% of project grants were funded, previously the success rate has been up around 30%.

“If you’re in the top 20% then you are up there,” said Crabb. “We have a primed system with a lot of researchers and postdocs coming through but with a flat budget this means the success rate for grant applications is low.

“This is concerning because we don’t know where the tipping point is. Somewhere along the line the psychology of positivity will change and it will become too hard.”

Grants for early-career fellowships did make up some of the mix, with 128 worth $38.6 million being given, along with 60 career development grants of $23.9 million.

Six partnership projects worth $4.5 million were funded and will support researchers and policymakers to identify ways to improve health practice and 12 European Union Collaborative Research Grants worth $4 million will support multinational research collaborative projects.

Victoria received the highest amount of funding, with $236.4 million for 414 grants. This was helped by the University of Melbourne drawing the largest funding package of $80.1 million for 145 grants followed by Monash University at $67.2 million.

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AUSBIOTECH | VIEWPOINT

Dr Anna Lavelle, CEO , AusBiotech

The scale and pace of Asia’s transformation in recent years is unprecedented and provides opportunities and challenges as Australian companies seek to respond to the rising demands for medical devices in Asia.

Asian countries present fast-growing markets via their expanding middle classes and

economic growth. The size of the markets, such as China, are of interest to the Australian medical devices industry and its global orientation.

This transformation prompted the Australian Government to release the Australia in the Asian Century White Paper (October 2012), which was commissioned to analyse economic and strategic changes in Asia and what can be done to position Australia to participate in the opportunities within the region.

China has made a clear commitment to develop life sciences, with biotechnology one of seven priority industries in China’s 10th Five-Year Plan. China recently announced expenditure of $9.2 billion on technological research and development, with the biotechnology sector highlighted as a major funding recipient. China is keen to develop its science, technology or innovation, and wants to focus on developing intellectual property through partnering and investing. Australia has the talent, technologies and right business acumen

Australian medical devices seeking new markets in Asia

to meet these needs. The partnering and investment opportunities between Australia and Asia, particularly China and Hong Kong, are compelling.

China’s healthcare sector is developing at an astonishing rate. Spending is projected to grow from AU$357 billion in 2011 to AU$1 trillion in 2020. The Ministry of Health’s ‘Health China 2020 Strategy’ calls for investment of AU$62 billion in the health system.

But there are barriers too. Aside from the obvious cultural and language differences, the intellectual property landscape is quite different from that in Australia and different business structure types adds to the list.

AusBiotech has been working in the Asian region on a small scale for many years, and recognising the importance of this region as a life science growth hub, has this year ramped up efforts. AusBiotech has won a federal grant to conduct the ‘Australian Medical Devices & Diagnostics to China’ project, which aims to facilitate medical devices trade with China by breaking down the major barriers to entry. This activity received funding from the Australian Trade Commission as part of the Asian Century Business Engagement Plan and

the project application was made with partners FB Rice, Deloitte and the Burnet Institute.

It will result in much-needed information for Australian companies about intellectual property (IP) management in China and outline the types of business structures that are possible for Australian companies entering China for the first time.

The project will produce an extensive report and a training module for Australian companies seeking to establish markets and/or businesses in China. It will also include an AusBiotech-led business mission to China in 2016 of Australian companies.

The project is to be delivered via AusBiotech’s AusMedtech and will be guided by a selected committee of industry experts from Australia and China and phased over three years.

AusBiotech will be conducting and scoping a research project initially to determine the more detailed needs of Australian medical device and diagnostic companies.

For further information, please contact Project Manager, Lorraine Chiroiu, Communications Manager, AusBiotech ([email protected]).

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Immortal science

Susan Williamson

Professor Martin Pera, Program Leader of the ARC-supported national research consortium Stem Cells Australia, reflects on his involvement in the discovery of human embryonic stem cells and where the research field is at today.

FACE TO FACE | STEM CELLS


Australian Life Scientist: What sparked your interest in science?Professor Martin Pera: I actually studied English literature as an undergraduate. I grew up in New York and Washington, and in the US you can have a bit more diversity in your program as an undergraduate. So along with poetry and novels, I also studied some science. I very much enjoyed literature but the only thing I was interested in doing with it was writing, and I never thought I’d be a good enough writer, so I decided to try my hand at science instead.

I went back part-time as a student to fill in science courses in chemistry. I decided I wanted to do something where I could apply some of what I’d learnt to human health issues. Then, with a chemistry background I pursued a PhD in pharmacology.ALS: What led you to come to Australia?MP: That’s a long story. I did my PhD in the US in pharmacology studying the cancer drug cisplatin. Cisplatin became the mainstay of treatment for human germ cell tumours of the testis and my first couple of postdocs involved studying that drug.

Then I decided the cells we were killing with the drug were more interesting than the actual drug itself.

Germ cell tumours of the testis are the original paradigm for a cancer stem cell. The stem cells of those tumours are very much like embryonic stem cells. They can divide to form more tumour cells but they can also differentiate into normal tissues.

I went on to set up my own lab at the Royal Marsden Hospital in England studying germ cell tumours of the testis and their biology. We isolated pluripotent stem cell lines from those tumours and characterised them.

I spent some time at Oxford University where we first made attempts to derive embryonic stem cells (ESCs) from human embryos. Those attempts didn’t work out.

In a kind of roundabout way I got in touch with Alan Trounson who was interested in recruiting me to really have another go at deriving human ESCs. And that’s how I came to Australia.

I moved out to work with Alan down in Monash University in 1996. By 1998 we

had got our first ESC lines going, with the help of Ben Reubinoff, a clinician from Israel, and Ariff Bongso, an embryologist from Singapore. But then we learned of Jamie Thomson’s discovery - he had already derived human ESCs - and that’s how we became the second group in the world to report human ESCs.ALS: So the work with the germ cell tumours set the scene for isolating ESCs?MP: Yes, the history of the whole field of ESCs really begins with germ cell tumours both in the mouse and the human. We were isolating these cells in the late ’80s and early ’90s.

Back in those days there were only a few groups around the world working on human pluripotent cells from germ cell tumours.

We showed that we could isolate cells that could differentiate into a whole range of tissues of the body and we used that information as the basis for trying to derive the normal equivalent of these cancer cells directly from embryos.

We made our first attempts to make human stem cells from embryos at Oxford around the mid-1990s. What we did very much paralleled what had gone on before in the mouse. People first studied germ cell tumours in the mouse and from that basis they went on to make mouse ESCs. Essentially we were following that same pathway.ALS: Were there any eureka moments in the lab?MP: One major breakthrough was when we injected human germ cell tumours into immune-deprived mice.

We’d isolated many cell lines from patients with germ cell tumours but because they were cancer cells many of them didn’t behave normally. But with one or two cell lines, when we grafted them into immune-deprived mice, we removed the cancers that formed and began to see a whole range of cell types like nerves and cartilage developing.

Then we were able to go back and clone individual cell lines from cancers from particular patients and show that they would spontaneously differentiate both in culture and in an animal. That was a pretty big deal because it was probably

the most convincing evidence that there were human pluripotent stem cells.

That was when we began working with embryos. And at about that time Jamie Thomson published the first derivation of stem cells from monkey embryos.

This was a real breakthrough because we knew all along that our human cells from the tumours were different from their mouse counterparts - they had different markers and they looked different and grew differently. Although, like the mouse cells, they could turn into all the tissue of the body, we didn’t understand whether those differences were because these were malignant cells and just abnormal or whether there were real species differences.

When Jamie identified the stem cells from monkey embryos they looked exactly like the human cells we’d been isolating from cancers of the testis. And that told us immediately there was no doubt we could make these cells from a human embryo. More importantly, it told us what to look for and how to handle the cells, because they are quite different to handle from mouse ESCs.ALS: And isolating cells from human embryos was quite controversial back then?MP: Absolutely it was, yes.

In England the attempts that were made to isolate the cells, although unsuccessful, were approved by the Human Fertilisation and Embryology Authority (HFEA). The regulatory framework to do those experiments was there and we had a licence from the HFEA to do that.

When I came to Australia in 1996, any destructive manipulation of the human embryo for experimental purposes was illegal at that time in Victoria.

We wound up collaborating with Ariff Bongso’s group in Singapore. We would initiate the cell lines there and bring them back to Melbourne for further characterisation. Once we’d turned the embryo into a cell line it was outside of the restrictions, provided it was derived using an acceptable ethical approach.

One of the things we and others did in the early days of the field was to do

STEM CELLS | FACE TO FACE


our best to disseminate this technology, to teach others, to share the cell lines and share reagents so that the field could move forward.

People accused us of going offshore to accomplish something that we couldn’t accomplish in Australia, but there were other states in Australia where this research would have been permissible at that time. Before there was uniform national legislation each of the states had a different approach to the regulation of human embryo research, and Victoria had a particularly restrictive environment.ALS: What are some of the challenges that have arisen with researching ESCs and understanding their role in repair?MP: In the early days there was a lot of scepticism about whether true ESCs could be derived from any species other than the mouse. And to this day, there are some people in the field who would still say that the only true ESCs are those described in mouse and rat.

It wasn’t at all clear whether human ESC could ever be isolated or, once it was apparently accomplished, that we’d in fact isolated the right cells. There were enormous issues around just propagating the cells. Now the technology is much better but back then the methodology for growing ESCs was in its infancy - we were developing it and it was always a struggle to keep the cell lines going and to stop them from differentiating.

Then there was the whole question of having made pluripotent stem cells, how to turn them into useful cell types for use in therapy. That’s an ongoing saga.

But the field has progressed. When I was at the University of Southern California, I was part of a group that was doing work toward developing an ESC-based treatment for macular degeneration. I’m very pleased that that work is going forward and heading towards clinical trials. It’s a little over a decade since the early discoveries and it’s remarkable to see that kind of progress.

The key thing for any therapeutic application is that you have to be able to expand the cells first, so you have to be able to keep them going in the undifferentiated state and then you have to turn them into the cell type of interest for a particular disease application.

That’s been an enormous challenge in the field but it’s been one that has been overcome for many types of tissue.

The real challenge now is not making a particular type of cell but how to get it to mature completely - in other words, how to make it fully functional just like the normal cell in the adult tissue.

Making sufficient differentiated cells safely and in a pure form also remains a big challenge. This is applied biotechnology research and I’m not sure that many academic labs are focused on these issues of production, scale-up, cost and the like.ALS: And understanding the biology of differentiation is still ongoing?MP: That’s right. We and others have been guided by decades of work on model systems, animal embryos from the fruit fly through to Xenopus to fish to the mouse.

Because many developmental mechanisms are conserved evolutionarily, you can take a lot of that information and apply it to understanding how to manipulate stem cells. But a human isn’t a mouse, and the devil is in the detail, so often there are aspects of stem cell regulation that are specific to human cells that we have to come to understand.

ALS: How do ESCs compare to adult stem cells? Do they have a greater degree of plasticity?MP: They do.In the early 2000s, there were a lot of papers published claiming that stem cells from adult tissue could turn into virtually anything - a lot of that work turned out not to be robust in the end.

Now we know that through the process of reprogramming, in the laboratory at least, we can take cells from adult tissues and reset them back to the early embryonic state and turn them into cell lines that very much resemble ESCs. This is the

remarkable work of Shinyaya Yamanaka, who received a Nobel Prize last year for this discovery.

So now, more and more, we work with these so-called induced pluripotent stem cells that are made from adult cells. They have opened up a whole new range of possibilities.ALS: Does the use of adult stem cells help get around the legislative and ethical issues?MP: It certainly gets around the ethical issues relating to the provenance of the cells because you don’t have to use an embryo anymore to make a stem cell line.

Nevertheless, there are certainly ethical issues around the use of these cells, including genetic privacy issues for the donors of the tissues and what we might ultimately be allowed to do in the laboratory with these cells.

For instance, one day - and we can already do this in the mouse - it may be possible to turn these cells into human gametes; that is, sperm and egg. That might be a very powerful tool for studying and even treating infertility, but it will raise ethical questions along how far we want to go with these cell lines in terms of introducing them into the human reproductive cycle. And these are big questions.ALS: Where is the legislation for using ESCs now at in Australia?MP: As a result of the legislation in Australia in the early 2000s, which was

The lab team at Monash in 2004.

FACE TO FACE | STEM CELLS


recently updated, we can use embryos to make new embryonic stem cell lines - provided we’ve gone through the appropriate review and application process. We can even do somatic cell nuclear transfer, which is the use of cloning technology, to make stem cell lines from particular individuals.

The controversy over the use of embryos will never completely disappear, because there will always be a minority who will be opposed to this work. But its practical implications for the field are much less than they were 10 or 15 years ago.

The reasons for this are that we now have many thousands of ESC lines, which is more than ample for most research purposes. And now we also have this alternate technology - the induced pluripotent stem cell, which really gives us another system to work with. We don’t really know yet whether induced pluripotent stem cells are a replacement for human ESCs, but they are certainly a very promising alternative at the very least.ALS: What about the unethical use of stem cell therapies, is this happening in Australia?MP: With the exception of bone marrow transplantation and one or two other applications, almost all stem cell medicine is experimental medicine, and it really should be carried out in the context of a proper controlled clinical trial.

Unfortunately, one of the biggest issues the field faces now is that of clinics providing so-called ‘stem cell therapies’ that are unproven and unfounded.

Clinics are popping up and offering a range of treatments for a staggering array of diseases using cell therapies. These clinics call the treatments stem cell therapies but in many cases it’s not clear whether they are using stem cells at all - many use crude and poorly characterised tissue extracts. And in many cases this is being done without any scientific basis for what is being offered or even appropriate safety evaluations. This is a big concern for us and an enormous issue for the field in Australia and internationally.

There are clinics in Australia offering such unproven stem cell treatments. In general, the regulations we have around

cell therapies in this country are very good, and they are enforced by the Therapeutic Goods Association. Unfortunately, there is an exemption to this set of regulations that says that if a clinic or physician is dealing with a patient’s own cells, so-called autologous therapy, then that approach is exempt from these regulations. And that’s a loophole that allows for clinics to offer unproven and untested stem cell treatments. We’re seeing this as an increasing trend.

We’re very concerned that the government go back and take another look at this autologous therapy, as jurisdictions elsewhere are. The International Society for Stem Cell Research, one of the leading international bodies in this field, recently issued a very strong position paper on this because it’s an issue that extends beyond borders. We are working with others to see if we can get this policy reviewed.

One of the biggest challenges we faced from the very first days in the field is getting across the promise of the work and its great potential but not promising too much too quickly. There is understandably a lack of clarity in the public mind about stem cells. We try and educate the public but there is still confusion around what stem cells really are and what they actually can do now versus the long-term promise.ALS: Do you see a healthy future for stem cell therapies?MP: Oh yes. Remarkably, we now have the first clinical trials on products derived from

embryonic stem cells, as I said for macular degeneration, but we are going to see trials for diabetes and possibly other indications soon.

Japan is moving ahead with parallel trials for products derived from induced pluripotent stem cells. I think these early clinical trials will probably wind up raising more questions than they answer and posing more challenges, but it’s remarkable how far we have come today from 1998.

I’ve been personally amazed at the pace of the progress. The potential was always there but it’s surprised me how fast we’ve actually moved.

One of our big challenges in this field in Australia is pushing translational research and making sure that outstanding clinicians, physicians in training, have an opportunity to do research and to have fulfilling careers as academic physicians in this area.

It’s going to be absolutely critical for the future of this field that we have strong communication between the basic science and the physicians - that we have people who understand both the science and the clinical side.

There has to be funding to facilitate that interchange, and there has to be funding for the translational research which, of course, is expensive and high risk.

I think we can do this a lot better. But recognising the problem and doing something about it of course is two different things.

It’s very important that Australia maintain and build its strength in both basic and applied research in this area because in many respects this is a different model to a pharmaceutical model. Cell therapy will be carried out in the context of experimental medicine for a long time, as we constantly refine and improve the technology. In this respect it is similar to cancer medicine, which requires high-level tertiary specialist referral centres steeped in the research enterprise to deliver the latest advances to patients. Unless we have that fundamental strength in basic and applied research in regenerative medicine, Australian patients are going to miss out on the benefits. ALS

STEM CELLS | FACE TO FACE

The launch of Stem Cells Australia. (L to R) Professor Margaret Sheil, Natasha Stott Despoja, Professor Martin Pera and Professor Glyn Davis.


Anatomy of an HCV infection

At least 250,000 Australians are chronically infected by hepatitis C virus (HCV). They are hosts to a molecular shape-shifter - a single-stranded RNA virus with an

inherent capacity to mutate rapidly and present a constantly shifting target to the human immune system.

Dr Rowena Bull, of the University of NSW’s (UNSW’s) School of Medical Sciences, has taken on some of the unanswered questions about a virus that still heads the rollcall of notifiable new infections in Australia.

How does a virus that mutates rapidly and randomly maintain its ability to infect new hosts? And, post-infection, how does it evade the immune system’s multipronged defensive responses to establish a chronic infection in the host’s liver cells?

The other side of the infection equation is how individuals differ in their immune response to the virus - some rapidly clear an initial HCV infection, while others become chronically infected.

Bull says answers to these questions will inform efforts to develop a vaccine to protect against hepatitis C infection.

Some individuals who become chronically infected with HCV remain asymptomatic and lead normal lives, untroubled by the virus. But nearly half will develop cirrhosis and around 1 in 100 will develop liver cancer.

HCV IN THE PRISON POPULATION

Bull and UNSW colleague Dr Fabio Luciani led a study, published in 2011, that traced the early phases of new infections in four NSW prisoners. HCV infections are common in the prison population because prisoners share needles to inject drugs.

Dr Andrew Lloyd, at UNSW, established a monitoring program in a cohort of 600 NSW prisoners. This helped Bull and colleagues identify four subjects with newly acquired HCV infections.

“All of the recruits in the cohort admit to using drugs and to actively injecting while they are in prison,” she said. “Dr Lloyd screens the high-risk subjects every three months and medium-risk subjects every six months - basically, we wait for individuals to become infected, then study them intensively.”

Graeme O'Neill

Hepatitis C researcher Rowena Bull and her colleagues have provided an intimate account of the surprising behaviour of the hepatitis C virus during the first 100 days of infection. Their findings point towards new strategies to prevent chronic HCV infection, cirrhosis and liver cancer.

NEXT GENERATION SEQUENCING | HEPATITIS C VIRUS


Anatomy of an HCV infection

Bull said they tracked the virus’s evolution from blood samples taken from four newly infected individuals over the course of several months - two cleared the infection and two developed chronic HCV infections.

FOCUSING ON HYPERVARIABLE REGIONS

Bull says HCV’s single-stranded RNA genome, of around 9.5 kilobases, evolves rapidly in the absence of a template strand to maintain its fidelity as it replicates in its host’s hepatocytes.

There are seven basic HCV genotypes in circulation globally, which differ by ~30% at the nucleotide level. This effectively renders them distinct species.

HCV packages its RNA genome into a capsid of two envelope proteins - Env1 and Env2.

“The protein envelope is quite rigid,” said Bull, “and both Env proteins undergo post-translational modification by glycosylation. These glycosylation sites remain fairly consistent between variants of both proteins, despite variation within and near the receptor-binding domains.”

In the absence of vaccine-induced herd immunity, HCV is virtually free to explore the extensive landscape of structures available for escaping its host’s immune response. The search is on for highly conserved domains that could be targeted by a vaccine.

Hypervariable domains, which may serve to decoy antibodies away from conserved receptor-binding sites, provide a means to track the virus’s evolution.

The work Bull and colleagues conducted in prisoners revealed how HCV undergoes two genetic bottlenecks in the first 100 days post-infection, both driven by the host’s immune response.

They synthesised near full-length HCV cDNAs from frequently taken samples of viral RNA. After amplifying the whole genome in two or three fragments, the resulting DNA was sequenced with Murdoch University’s 454 next-generation pyrosequencer in Perth.

“The advantages of next-generation 454 sequencing are that it’s fast, requires less manpower and can tell you about all the variants within a sample from a single individual,” Bull said. “Sanger sequencing is much more labour-intensive, although it has a much lower error rate.

“We actually sequence the whole genome of each strain, but we then focus on the hypervariable region because it produces a strong signature when the genomes of the different strains are compared. We look at the sequences that are changing the most, because they’re most likely to be involved in the transition from the acute to chronic phase of infection.”

By taking frequent samples, including a sample from each subject prior to the appearance of serum antibodies to HCV, Bull has recorded genomic changes in the virus throughout its pas-de-deux with the immune system.

IMMUNE-ESCAPE MUTATIONS

Little is known about the phenotypic characteristics of founder viruses in HCV infections.

However, a recent analysis of HCV variants that emerged in a transplant patient who contracted HCV from a donor liver

suggested successful strains have an increased ability to enter hepatocytes. These variants also exhibited lower neutralising affinities in the face of the host’s antibody response after seroconversion.

One of the prisoners Bull and colleagues studied, subject 23_Ch, was infected with at least two founder viruses that differed by only three nucleotides in their Env protein-coding regions. The variable loci, at residues 443 and 446, lie close to the CD81 receptor binding domain - the CD81 receptor interacts with the HCV Env2 protein.

As infection progressed, the HCV variant 23BF outcompeted rival variant 23AF, suggesting 23BF possessed superior infectivity during the acute phase of infection.

“The ability of any variant to persist in its host is probably due in part to chance mutations that allow the virus to stay a step ahead of the immune response and generate the correct immune-escape mutations,” said Bull.

But once a variant establishes a chronic infection, it persists because some as-yet unidentified factor down-regulates the host’s immune response - in particular, cytotoxic T cells (CD8(+) T-lymphocytes) no longer kill virus-infected hepatocytes.

“We need to look at how CD4 and CD8 lymphocytes work together with neutralising antibodies during HCV infection, and which of the factors contribute to persistence of the virus in some subjects and clearance in others,” Bull said.

“We particularly want to see how mutations emerge in chronic infections and whether the selection of persistent variants of the virus is driven by CD8 T-lymphocytes or by neutralising antibodies.”

Dr Rowena Bull is currently an NHMRC Training Postdoctoral Research Fellow with the School of Medical Sciences at the University of New South Wales. She completed a PhD looking at mechanisms of replication and genomic diversity in the human caliciviruses in Professor Peter White’s lab at UNSW in 2007. She was been a visiting Research Fellow, La Trobe University in 2008 and at Stanford University in 2011.

Graeme O'Neill

HEPATITIS C VIRUS | NEXT GENERATION SEQUENCING


GENETIC BOTTLENECKS

Bull says the current dogma is that neutralising antibodies aren’t important in the early phase of infection and, ultimately, to whether the virus is cleared or establishes a chronic infection.

Testing this proposition is problematic in the absence of an animal model for human HCV infection - HCV also infects chimpanzees, but most rapidly clear the infection.

Bull says the value of their project was the access they had to a prospective cohort of subjects who were at high risk of HCV infection. This enabled the identification of subjects within the first few days or weeks of their new HCV infection. This had been challenging in past research because the majority of HCV infections are asymptomatic and it can be years or decades before an individual presents clinically with hepatitis.

Detailed analysis of the pattern and kinetics of viral evolution revealed that early primary HCV infections involve at least two

HEPATITIS C FACTS

In the mid-1970s, US health authorities became alarmed as increasing numbers of US patients who had undergone blood transfusions developed chronic hepatitis infections. After excluding the hepatitis A and hepatitis B viruses as culprits, researchers in the Department of Transfusion Medicine at the National Institutes of Health gave the new disease a temporary name: hepatitis non-A, non-B.

By the time the mystery hepatitis virus was identified and described in 1989, a pandemic of hepatitis C virus (HCV) was underway in Western nations, predominantly among recreational drug users who had shared needles.

In 2010, around 250,000 Australians were living with chronic HCV infections and around 9700 new cases were estimated to be occurring each year.

Because infection tends to be asymptomatic in its early years, many more infections remain undiagnosed.

Advances in detection, diagnosis and treatment have since reduced the rate of transfusion-acquired infection to near zero, but HCV infections remain the most common notifiable diseases in Australia. There is still no vaccine.

According to a hepatitis C fact sheet published by Hepatitis NSW, for every 100 patients who have had the disease for 20 years but remain untreated, 45 will escape serious liver damage, 47 will develop progressive mild-to-moderate liver damage, seven will develop cirrhosis and one will develop liver cancer or suffer liver failure requiring a transplant.

Current antiviral therapies for chronic infection include pegylated interferon and ribovarin, but the success of these therapies in clearing the infection appears to depend on the patient’s genotype. New treatment strategies, such as Gilead’s sofosbivir, that offer higher clearance rates and are predicted to have little opportunity for drug resistance to develop are on the horizon.

significant genetic bottleneck events, when variation in founder virus strains is tightly constrained by the host’s immune response.

The first occurs during or immediately after infection - just one or two founder viruses from the potentially large range of variants circulating in the general population are involved in establishing the initial infection. The rest presumably to not get to replicate.

A successful founding strain - or strains - then replicates within its new host, spawning new variants as replication errors accumulate across the genome.

Around 100 days post-infection, the new variants are subjected to a selective sweep as they come under fire from the immune system, and another bottleneck occurs. In some cases there are no survivors and the infected subject clears the infection. In others, one or more strains survive the elimination process and go on to establish a chronic infection.

A RAPID EVOLUTION

Subject 23_Ch had two founder strains when tested, whereas the other three subjects were colonised by a single strain - and two cleared the infection.

The presence of a single founder virus in three of four intravenous-drug user-transmitted HCV subjects is comparable to studies in HIV which have shown that the majority of subjects with mucosal transmission had a single founder virus.

However, in contrast to HCV, HIV infection resulting from intravenous drug use typically involves multiple virus strains - although five appears to be the limit.

Moreover, studies of HIV Env sequences in 20 heterosexual transmission pairs revealed that the founder variant(s) in the recipient comprised a small fraction of the viral variants in the donor.

From a limited sample number, HCV appears to have the same potential for more than one variant to establish an initial infection.

However, it remains unclear whether the transmission bottleneck is attributable to a lower number of variants being transferred between hosts or is the result of early evolutionary events where a larger number of strains are rapidly eliminated due to varying fitness constraints.

Given that the two founder viruses identified in subject 23_Ch were very similar, Bull and colleagues think it plausible that a single founder virus rapidly evolved in the first few days post-infection.

The novel finding that a genetic bottleneck occurred during the acute phase of infection in subjects studied, regardless of the long-term consequences of infection, is driving Bull and colleagues to better understand the selective pressures imposed by the host’s immune response early in HCV infections.

The aim is to identify factors that drive the evolution of HCV towards chronicity in the hope that this may lead to new vaccines or antiviral therapies that could eliminate ‘escape’ variants before they can establish a chronic infection. The group is about to publish a paper on how the immune system reacts to HCV infection. ALS

NEXT GENERATION SEQUENCING | HEPATITIS C VIRUS


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Melanoma

The Melanoma Genome Project (MGP), a large-scale national collaboration based at the

Melanoma Institute Australia (MIA) and managed by the infrastructure-enabling body, Bioplatforms Australia (BPA), is gearing up to deliver its data early in 2014.

Researchers involved in the two-year project are analysing genome sequences from primary tumours and metastases to identify common genetic mutations that cause this deadly cancer. Ideally, this will lead to more personalised and better treatment options for patients.

“The samples come from an incredibly well-curated BioSpecimen Bank at MIA,” said Anna Fitzgerald, project manager with BPA, explaining that the Melanoma Foundation established a tissue bank 14 years ago. “The Peter Mac and Ludwig Institutes have contributed samples as

well. The samples have all gone through a single pathologist to ensure there is uniformity in the diagnosis.”

AN AUSTRALIAN DISEASE

Although malignant melanoma represents only 15% of skin cancers, it accounts for almost all skin-cancer deaths – and Australia has the highest mortality rate from malignant melanoma worldwide.

Melanoma can rapidly metastasise, spreading via the blood and lymphatic system from a primary tumour in the skin to form aggressive secondary tumours throughout the body.

Despite having one of the highest 5-year survival rates (90%) of any cancer, once melanoma metastasises, the 5-year survival rate drops dramatically to 45–10% (regional and systemic metastasis, respectively).

A FOCUSED APPROACH

To date, tissue and DNA from 146 patients has been quality control tested and sequenced. The raw sequencing data of 87 somatic genomes has been processed and genetic variants identified.

“We are sequencing tissue from another 51 patients now,” said Dr James Wilmott, Project Manager at the Melanoma Institute Australia. “By the end of the year the project will have sequenced 311 somatic genomes from 208 patients.”

The project is taking a focused approach, aiming to generate data that will provide answers to clinical questions.

“Where we can, we look at primary tumours and metastases in the same patient, as well as blood control tissue,” explained Wilmott. “This data will provide insights into the evolution and

Genome Project

on trackSusan Williamson

NEXT GENERATION SEQUENCING | MELANOMA GENOME


progression of melanoma. We are also looking at brain and bowel metastases, with the aim of identifying factors that favour metastases to these often deadly sites.”

“The project has also prioritised a large cohort of tumours from patients with either primary or stage III metastatic melanoma with long and short survival times so we can compare their data.”

TERABYTES TO ANALYSE

The researchers intend for data from the MGP to be made publically available, in the International Cancer Genome Consortium (ICGC) repository or equivalent database.

Whole genome sequencing (>60X coverage) and array comparative genomic hybridisation (aCGH) is being conducted at the Australian Genome Research Facilities (AGRF), the Ramaciotti Centre for Genomics at UNSW and John Curtin School of Medical Research at the Australian National University

(ANU), while aCGH, whole genome (>40X coverage) and exome sequencing (75X coverage) is taking place at Axeq Technologies (Macrogen) in Korea.

This next generation sequencing of the genomes generates significant amounts of raw data, an estimated 400TB of data, the analysis of which Wilmott says is the most time consuming part of the work.

“We can sequence and generate the raw data pretty quickly,” he said. “The time-consuming bit is taking these nucleotide sequences and comparing them to the normal genome, which can take weeks for one patient.”

Fitzgerald and Wilmott admit it’s too early to tell yet whether any patterns are emerging in the data. Although Wilmott said they are identifying the genetic mutations they expect to be seeing, it is too early to draw too many conclusions.

The aim is to finalise the data input by the end of this year and begin assessing patterns of activity and what the biology means at a meeting in early 2014.

“It is a large collaboration and analysing the data is an enormous task,” Fitzgerald added. “It has been a massive education process and to date has cost about $5.5 million to sequence tissue and controls.”

Developing a collaborative approach to support people in tackling these big problems is a key approach in BPA’s work. The data generated is then made available to any number of researchers, which fosters national and international collaborations with the Australian researchers.

“When we select these projects, the money BPA invests goes directly into BPA’s facilities, such as the AGRF, Ramaciotti Centre or ANU who generate the data,” Fitzgerald explained. “It’s not a grant, the grant is the data we generate that in turn enables collaborations between Australian researchers. And because we are doing this for a large pool of researchers it really is a true enabling resource.” ALS

MELANOMA GENOME | NEXT GENERATION SEQUENCING

http://www.ramaciotti.unsw.edu.au


Early-career researchers will be taken on a journey through the seven stages of an academic career, from

honours student to postdoctorate to lab leader, institute director and retirement, in Professor Alan Baxter’s postgraduate lecture at the Australasian Society for Immunology (ASI) conference.

With biomedical sciences graduates on the decrease, people like Baxter are a much-needed resource to motivate students and help them establish their goals.

Baxter’s career has not just entailed life at the bench as an immunology researcher. At the same time as running an internationally competitive research lab, he has delved into public outreach work with community organisations and charities, written a popular science book, given talks on the radio and taught students.

“I’ve explored the boundaries of the box in which a researcher lives,” Baxter admitted.

Currently about halfway through his professional life, Baxter thinks his audience may laugh when he tells them he’s 50 years old.

“Most people would think I am a long way past halfway,” he said. “But by the time you have done a PhD and training fellowship most people are in their 30s. Then by the time you’ve got your first NHMRC fellowship most people are in their mid- to late-40s.”

THE OVERSEAS TRANSFER

“Moving is usually a part of a career in science,” said Baxter, whose career path started in medicine at the University of Melbourne followed by a PhD in immunogenetics at the Walter and Eliza Hall Institute.

Making the career choice to move overseas is a relatively easy one given the strong international reputation Australia and New Zealand immunologists have. Although finding a suitable lab that supports the breadth of a person’s professional and cultural life can be challenging.

“It really is something people need to think through,” said Baxter, adding that he had good and bad postdoctoral experiences overseas.

“You may pick up new techniques or a new understanding so that when you come back to Australia you can make a great contribution to a lab and it’s easier for you to establish a niche. And for many people, it is probably their only chance in their life to explore another culture in a serious way.

“On the other hand, you can lose a lot of productivity. I think a fair few people

Hooked on immunologySusan Williamson Professor Alan Baxter, Head of the Comparative Genomics Centre

at James Cook University, will deliver the annual Australasian Society for Immunology (ASI) Postgraduate Lecture to inspire a new crop of immunologists to take on a career in science.

ASI PREVIEW | INSPIRING POSTGRADUATES


THE SEVEN AGES OF SCIENCE

All the world’s a stage, And all the men and women merely players: They have their exits and their entrances; And one man in his time plays many parts, His acts being seven ages.

HONOURS

At first, the infant, Mewling and puking in the nurse’s arms.

PHD

And then the whining school-boy, with his satchel And shining morning face, creeping like snail Unwillingly to school.

JUNIOR POSTDOC

And then the lover, Sighing like furnace, with a woeful ballad Made to his mistress’ eyebrow.

SENIOR POSTDOC

Then a soldier, Full of strange oaths and bearded like the pard, Jealous in honour, sudden and quick in quarrel, Seeking the bubble reputation Even in the cannon’s mouth.

who go overseas as a postdoc come back without having published anything as first or last author. And if you move somewhere that is culturally different or has a language difference you can lose a lot more than that.”

AM I SUITED TO SCIENCE?

Wondering whether a career in science is the right path is something most people go through early in their career.

For students contemplating this choice, Baxter’s advice is to go to a quiet, dimly lit room for half an hour or so and just sit.

“The question is do you sit and think or do you just sit there?” said Baxter, who believes the key to doing science is to be a habitual thinker. “If you’re the kind of person who, when sitting alone in a quiet room, there’s nothing going on upstairs, then maybe science isn’t for you.”

LAB HEAD

And then the justice, In fair round belly with good capon lined, With eyes severe and beard of formal cut, Full of wise saws and modern instances; And so he plays his part.

CENTRE/INSTITUTE DIRECTOR

The sixth age shifts Into the lean and slipper’d pantaloon, With spectacles on nose and pouch on side, His youthful hose, well saved, a world too wide For his shrunk shank; and his big manly voice, Turning again toward childish treble, pipes And whistles in his sound.

EMERITUS PROFESSOR

Last scene of all, That ends this strange eventful history, Is second childishness and mere oblivion, Sans teeth, sans eyes, sans taste, sans everything.

After Jaques, Act II Scene VII, William Shakespeare’s As You Like It.

According to Baxter, feelings of self-doubt need to be understood in the context of key aspects of work as a scientist - the peer review process and the fundamental scepticism that scientists possess. He says they are integral to a career in science and, rather than undermining an individual’s self esteem, they can be used to improve performance.

“Peer review means that no matter how good you are there will be people questioning whether what you have shown really matters,” Baxter said.

“People worry and have self-doubt but the important point is that almost everybody has doubts - even the most productive or successful researchers in Australia have expressed doubts about their capabilities or getting their fellowships renewed.”

STRATEGIC GOALS

A second theme Baxter will cover in his talk is about having strategic goals, such as developing a niche.

“Within immunology you need to develop a niche so that you can be recognised for work that is your area,” he said. “But your niche needs to be broad enough for general appeal so that the people who review your grant or paper, who work in a different niche, recognise that your work is of value.”

Getting funding for salaries and to support research work, and developing security in a research career are other goals Baxter says are key.

Once a person has made their way along the career path to the senior postdoc level, for example, decisions about whether to pursue a career as a research fellow or running a lab arise. This type of career is very much performance based and requires regular application for funding.

“It’s almost to be expected that sooner or later you will lose that funding stream regardless of performance,” said Baxter.

“There’s trade-offs,” he added. “If you run your own lab you have more freedom

INSPIRING POSTGRADUATES | ASI PREVIEW


in a sense. For example, if I moved my lab, the people who work with me would need to decide whether to move too or find another boss.” Nevertheless, someone running a lab may find it more difficult to move because of the facilities they need and the expense involved in establishing these.

Baxter thinks that one of the most secure positions is to be second-in-command in a lab.

“Becoming invaluable begins early on in a postdoc where the secret to being employable is to be invaluable in a technical sense,” Baxter explained. “This

then makes you highly competitive and can bring a measure of job security.”

Moving into an academic position that involves mixed duties (teaching and research) provides another way of finding job security. An academic career offers more security because the university provides a salary, which means research performance is not so critical to getting funding.

OUTSIDE THE RESEARCH BOX

Baxter is keen for early-career researchers to look outside of the lab and take advantage of the range of opportunities available to them in their working life.

Professor Alan Baxter is Head of the Comparative Genomics Centre at James Cook University in Townsville. He studied medicine at Melbourne University and completed a PhD in immunogenetics at the Walter and Eliza Hall Institute under the supervision of Tom Mandel. He is known internationally for his contributions to the genetics of autoimmune disease, having established the Autoimmunity Research Group at the Centenary Institute where he worked for 10 years. He has published pioneering work on the genetics of gastritis and the role of NKT cells in autoimmunity, and made major contributions to our understanding of gene/environment interactions in autoimmune disease. He has been a member of the Australasian Society for Immunology since 1994 and was president of the Society from 2006-2008.

ASI PREVIEW | INSPIRING POSTGRADUATES

“Some people think that all you do in biomedical research is biomedical research,” he said. “But aside from the mixed duties of an academic with teaching and research, there’s a wide range of opportunities supported by and sponsored by ASI and other organisations, including in some cases employers, that can enrich your life and are generally viewed favourably when applying for grants as well.”

Baxter cites broadcasting and writing books as well as travelling overseas and giving talks and teaching in the third world as examples of ways his working life has been enhanced. ALS

http://www.mpbio.com


The basis of Wolfgang Weninger’s work at the Centenary Institute and the Sydney Medical School is

the involvement of the immune system in skin diseases.

Recent work Weninger’s team has been pursuing focuses on a subset of innate lymphoid cells called group 2 innate lymphoid cells or ILC2 cells. These cells were identified only a couple of years ago and are known to play a role in immune responses to parasitic infections - for example, helminths - as well as in allergic conditions such as asthma and chronic sinusitis.

“This is a relatively newly discovered cell population that is related to T lymphocytes,” Weninger explained, “but in contrast to T lymphocytes they do not have an antigen or T cell receptor.

“Morphologically they look similar to T cells. The defining feature of the ILC2 cells is that they produce the cytokines

IL5 and IL13, which are usually found in T helper cells.”

Type 2 T helper cells are known to produce cytokines including IL-4, IL-5, IL-10, and IL-13. Type 2 cytokines are essential for protection against helminthic infections and also underlie the development of inflammatory allergic conditions, such as dermatitis.

DISTINCT DERMAL RESIDENTS

Weninger’s group recently discovered ILC2 cells in the skin of mice and found that they play an important role during in inflammatory skin reactions.

“We described these cells for the first time in the skin of mice a few months ago,” said Weninger, referring to work that was published in Nature Immunology. “We characterised their development, what cytokines they require and we also managed to visualise them for the first time using microscopy in live mice.”

Using a multiphoton microscopy technique with infrared laser light that enables fluorescent cells to be visualised in intact organs in live mice, Weninger’s team visualised the behaviour of ILC2 cells in real time in intact skin.

“We monitored how these cells migrate within the skin and what other cells they interact with,” said Weninger. “We saw that the ILC2 cells continuously screened the dermis and were communicating with mast cells, which is interesting because mast cells are also implicated in allergies and infections.”

The idea is that the ILC2 cells reside in a normal quiescent state in the dermal layer of the skin, along with a variety of leukocytes such as mast cells and macrophages, and if a worm invades, these cells kick-start inflammation by producing their type 2 cytokines.

“On the flip side, they may also be involved in driving the allergies because

LYMPHOCYTE BIOLOGY | ASI PREVIEW

Susan Williamson

Shedding light on a new type of lymphoid cell that appears to play a role in defence against cutaneous infection and the development of allergies will form the basis of Wolfgang Weninger’s presentation at the Australasian Society for Immunology meeting.

A new

lymphoid cell


the allergies depend on the same cytokines,” he said.

Weninger’s team has also been looking at how to activate the ILC2 cells in the skin and found that they could dramatically increase their numbers by giving mice systemic treatment with complexes of IL-2 and antibody to IL-2.

“When we activate them with IL-2, they not only increase in number, they make much more IL-5 and IL-13, and this leads to spontaneous skin inflammation that looks a bit like eczema,” Weninger said.

Thus, as well as having the potential to initiate type 2 immune responses through the release of these cytokines, ILC2 cells also have the potential to regulate the function of other immune cells residing in the dermis.

LOOKING AT THE LUNGS

Now that they have published their work in skin, Weninger’s team is turning its attention to how ILC2 cells contribute to lung inflammation.

“We found ILC2 cells also play an important role in lung inflammation. We are trying to find out how these cells are activated and what cytokines they produce during lung infections and allergic responses,” Weninger said. “We are interested in how this works and what the consequences of this are for lung pathology.”

From their work in mice, Weninger said they plan to move into humans to see whether a similar pathway exists in humans. ILC2 cells are most likely involved in the pathogenesis of allergic diseases of the lung such as asthma.

Multiphoton microscopy image of intact mouse skin showing group 2 innate lymphoid cells in green, blood vessels in red and collage fibres in blue.

They are beginning to look in human skin and in fluid from the lungs, but this work is in its early days.

The immune pathways involved in responses to helminthic infections and allergies have been well studied and the ILC2 cells provide a potential new angle for therapeutic intervention. Although whether they show potential as a new therapeutic is yet to be seen.

“They seem to be very early responders because they sit inside the organs and their function can be increased quite quickly compared to T cells, but they also may be effector cells downstream of the T cell response. So it’s complicated - they may play a role very early on and also late during immune responses.” ALS

Professor Wolfgang Weninger leads an independent research group at the Centenary Institute of Cancer Medicine and Cell Biology and is Chair of the Discipline of Dermatology at the University of Sydney. He also heads the Department of Dermatology at Royal Prince Alfred Hospital. He trained as a clinical dermatologist at the University of Vienna Medical School in Austria, after which he spent four years at the Harvard Medical School learning about the regulation of immune responses in vivo and cutting-edge approaches to track immune cells in vivo. Between 2003-2007 he was a Faculty member at the Wistar Institute and the Department of Dermatology, University of Pennsylvania. For the past eight years, Weninger’s research has focused on elucidating the trafficking pathways of T cells and dendritic cells in health and disease. He has made numerous important contributions to the understanding of tissue-specific migration pathways of immune cells, in particular to and within sites of inflammation and tumours.

ASI PREVIEW | LYMPHOCYTE BIOLOGY

The 43rd Annual Scientific Meeting of the Australasian Society for Immunology will be held in Wellington, New Zealand, from 2-5 December 2013. www.asi2013.org


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Perceptual distortions

Stanton knows a thing or two about pain. Originally trained as a physiotherapist, she has probably dealt with the intractable effects of chronic pain more than most.

Eventually, this experience led her into the field of neuroscience in a quest to understand pain. In particular, she became fascinated with how the brain perceives pain and what is different in the brain when pain persists. These days, Stanton is a postdoctoral research scientist who splits her time between the Body and Mind Centre at the University of South Australia, in Adelaide, where she now lives, and Neuroscience Research Australia in Sydney.

At the Australasian Neuroscience Society meeting in January, Stanton will present her work as part of what promises to be a fascinating session on neuroperception.

“Specifically, I will present the idea that changing how a painful body part looks or feels can actually influence pain levels. I will discuss the background of this work and why we think such a perplexing effect might be happening.”

IT IS ALL IN OUR MINDS

Pain is primarily a useful tool for us mammals - it allows us to know when something is wrong and we need to act. What is important, however, is how and when pain occurs.

Threatening or damaging stimuli alert our neural system by activating specialised receptors called nociceptors, and this information is transmitted to the brain to decide whether to perceive this information as painful. This decision then sets off a whole stack of pathways to act appropriately.

However, chronic pain has gone far beyond the acute nociceptor stimulus to an ongoing interpretation by our brain that

something is wrong. The pain experience, and chronic pain in particular, is modulated by a variety of factors including motor control, emotional state, visual cues, memory cues and even neuropsychological factors such as anxiety and depression - and each of these factors is known to involve different areas of the brain in terms of neural activity.

Scientists like Stanton are increasingly interested in just how these brain areas work together to heighten or diminish the pain experience.

“We just don’t have good treatments for chronic pain, despite all the excellent work that has been done, and perhaps we just don’t have the whole picture.”

STRETCHING THE ‘TRUTH’ COULD HELP

Professor Roger Newport from the University of Nottingham in the UK was a pioneer in the concept of illusory modification of the body to influence pain. Recently, he designed a specialised machine called the MIRAGE multi-sensory illusions box, which contains a combination of cameras, mirrors, computers and monitors to deliver a range of illusions.

Subjects insert their painful body part into the machine and can view it in real time. Then the MIRAGE machine is used to alter how the body part looks.

“For instance, someone who has painful hand osteoarthritis can view their hand ‘shrinking’ or ‘stretching’ in real time,” explained Stanton. “So visually, they see the hand changing, but then we also provide tactile input, that is, a ‘push’ or a ‘pull’ to their finger that matches the visual changes. So it actually ‘feels’ like the finger is physically altered - it is a very weird sensation.”

Fiona Wylie

Adelaide researcher Dr Tasha Stanton has always been frustrated by pain. Not her own but that of others and why, with all of our scientific advances and very large brains, we can’t do more to alleviate it, especially in those who live with chronic pain.

of the body in pain

ANS PREVIEW | EMBODIED SENSORY EXPERIENCE


In 2011, Newport used his MIRAGE machine to study the effect of illusory stretching or shrinking in people with hand osteoarthritis and reported an immediate pain reduction of around 35-50% in most participants. The effect was greater with stretching in some patients and with shrinking in others, while some cases responded favourably to both illusions.

Importantly, his and other studies confirmed, with control conditions and by testing a non-painful area of the body part, that the effect of pain reduction was not simply related to distraction or attention.

On reading about Newport’s findings and machine, Stanton wondered if the same effect would come into play for patients with knee osteoarthritis and she is now collaborating closely with Newport to find out.

“Osteoarthritis of the knee affects around 2.6 million working-age Australians and, in combination with hip osteoarthritis, results in about 80,000 joint replacements every year. It causes significant pain and disability, often limiting the ability to work. So, if we could help to reduce pain or at least make it manageable in these patients, that is a huge step forward in many respects.”

PLAYING WITH REALITY

The background to Stanton’s work is that people with chronic pain often have altered physical self-awareness or a distorted perception of their painful body part, such as feeling that their affected limb is larger or more swollen than it actually is.

“It is like when you have been to the dentist and have had your lip frozen - your lip feels huge but, in reality, it is not,” said Stanton. “We know, for example, that people with hand osteoarthritis often perceive their hand as smaller than it is, and when shown pictures of their own hand that has been altered in size, they will often choose a smaller picture as most visually representative, compared with what healthy controls choose.”

What causes this perception in terms of neuroscience is not clear. According to Stanton, brain imaging studies in patients with chronic pain have provided some hints.

These studies show reorganisation, or changes to the brain’s representation of a body part, in certain areas of the brain that we believe to be involved in spatial perception. For example, areas such

as the primary somatosensory cortex, that allows a person to know where they are being touched, show functional reorganisation.

Indeed, in his 2011 paper, Newport suggested that the illusion-induced reduction in pain for patients with hand osteoarthritis possibly represented a correction of this inaccurate perception of the painful body part - thus removing the incongruence between what is real and what is felt (a factor thought to contribute to pain).

And, according to Stanton, that opens the door for different, non-pharmaceutical and non-invasive treatment options for chronic pain, especially for people in whom movement is painful and drugs no longer work.

GETTING DOWN TO BUSINESS

Stanton is now recruiting people with painful knee osteoarthritis for the multi-sensory illusion studies.

“We will get each participant in a few times initially and determine how various illusions affect their pain levels. We will then extend this work with the osteoarthritic patients by completing brain-imaging studies. Currently, we are looking at brain activity in pain-free healthy controls using electroencephalography (EEG) to establish what is going on in the brain during these various illusions.” Not a lot of work has been done in this area so all of it will be informative.

In a big boost to this part of the project, Stanton recently received an international travel award from the University of South Australia to visit Professor Robert Coghill, who heads one of the top neuroimaging labs in the United States. Stanton plans to use their functional magnetic resonance imaging (fMRI) facilities to find out more about the analgesic effects of multi-sensory illusions on osteoarthritic pain.

“The fMRI will allow us to actually visualise activity in discrete areas of the brain following a specific event or, in this case, an illusion.”

What Stanton does next and into the future will be determined by these early illusion and imaging studies. There is certainly a lot of very basic work to be done, but hopefully scientists like Stanton will gain some practical insights into how sensory perception in the brain could be harnessed to alleviate pain … and everybody can be less frustrated. ALS

Tasha Stanton is a Canadian Institutes of Health Research postdoctoral research fellow working conjointly at the University of South Australia in Adelaide and Neuroscience Research Australia in Sydney. Stanton completed her PhD in 2010 at The George Institute of Global Health through the University of Sydney and received her original training as a physiotherapist at The University of Alberta, Canada (BScPT, MScRS).

of the body in pain

EMBODIED SENSORY EXPERIENCE | ANS PREVIEW

The MIRAGE in action - watching the finger stretch. Photo courtesy of Dr Roger Newport, University of Nottingham.


Putting the brain back

Professor James Vickers is co-director of the Wicking Dementia Research and Education Centre, a University of Tasmania facility housed in a spiffy new building in downtown Hobart.

Established in 2008 to provide a unique combination of translational research and support specifically for issues surrounding dementia, the activities at the centre are incredibly diverse encompassing health services, lab-based neuroscience studies, research with carers and nursing staff, a Dementia Massive Open Online Course and, most recently, a long-term cohort study called the Tasmanian Healthy Brain Project.

Dementia is not a single disease, but rather a broad syndrome comprising a spectrum of degenerative disorders affecting the brain. It manifests as a progressive functional decline in thinking, memory, problem-solving skills and social behaviour - eventually affecting all aspects of everyday life.

Dementia has a profound impact on individuals, families and communities - even a glance at the statistics on dementia are quite sobering. In Australia, over 320,000 people are living with dementia and around 1.2 million are caring for someone with dementia. These numbers will increase each year as our population ages. Most startlingly, in less than 50 years, spending on dementia is set to outstrip that of any other health condition.

A BANK YOU CAN TRUST

Vickers’ own 20 years of research has focused on Alzheimer’s disease, the most common form of dementia. His group conducts

laboratory-based research using cell culture and transgenic animal models of the disease as well as human brain tissue - and it is the latter aspect he wants to highlight at the ANS meeting in January.

Vickers is part of a session spruiking the lessons to be learned from human brain research and the value of modern brain banking. “There is still so much we can learn only by looking at the human brain at various stages of a disease,” he said.

Much of the early research on Alzheimer’s disease in the 1980s and 1990s centred on establishing the pathological changes that progressively accumulate during the course of the disease by studying post-mortem human brain tissue. Indeed, the degenerative changes of Alzheimer’s disease may be present many years before any clinical symptoms appear.

“By that time, a whole bunch of nerve cells and synapses have degenerated irreversibly,” Vickers explained, “and from there it only gets worse, which can happen quite quickly over 2-3 years or it can take a decade or more.”

Fully understanding that pathological course was therefore crucial for establishing diagnostic criteria and early clinical management strategies for Alzheimer’s disease.

THE NEW WAVE

Most of the laboratory studies on Alzheimer’s disease, which is probably the single biggest area neuroscience research these days, are heavily based around disease models, both transgenic animals and cell culture. Vickers estimates that a whole generation of scientists

ANS PREVIEW | HUMAN BRAIN TISSUE RESEARCH

Fiona Wylie

Facilities that store human brain tissue, so-called ‘brain banks’, are finding it harder than ever to get a share of the medical research dollar in Australia. Yet they remain an incredibly important, relevant and valuable resource for many studies in neuroscience, and Tasmanian neuroscientist James Vickers is keen to explain why.

into brain research

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Putting the brain back

who have developed their career in Alzheimer’s disease research may not have spent any time actually looking at the brain tissue of affected humans or considering the substantial literature of what actually happens in the human brain during the disease.

This is not to say that the disease model studies are not incredibly important and informative - they are often the only way to really get at the biochemical and genetic mechanisms at play in diseases like Alzheimer’s. But what Vickers wants to do at ANS is remind everybody how valuable human brain tissue studies are within the overall neuroscience research picture.

“Human brain studies tell us for example that Alzheimer’s disease progresses very slowly in terms of how nerve cells degenerate and that it affects only a particular subset of cells and synapses - we call that selective vulnerability - but probably many model-based studies do not reference that framework,” said Vickers.

“For instance, there is a whole lot of literature around cell culture models of Alzheimer’s disease that involve acute poisoning of nerve cells, and that kills a lot of cells quickly, but trying to relate that back to how nerve cells die during the human disease can be quite difficult. Also, as the

Human cortex with Alzheimer's disease. Labelled for Aß plaques (blue), axons (neurofilaments, green) and a marker for a subset of neurons (calretinin, red). Autofluorescent lipofuscin shown in grey. Photo credit: Dr Stan Mitew.

On the left is a model of a nerve cell showing how it's axon (green) swells as it is damaged by a plaque (red). A similar immunolabelled image on the right shows axons (green) being affected by an Aß plaque in red (human cortex).

THE TASMANIAN HEALTHY BRAIN PROJECT

The Tasmanian Healthy Brain Project (THBP) is a world-first, prospective longitudinal study of up to 1000 people aged 50-79 years to determine if tertiary education later in life reduces age-related cognitive decline and significantly decreases the risk or onset of dementia. Led by Vickers, the project commenced in 2011 and is planned to run for 10-20 years.

According to Vickers, there are increasing suggestions that complex mental stimulation could protect against ageing-related cognitive decline and that building up cognitive resilience might lower the risk of dementia.

“Basically, the older people in this study will undertake university study as a form of complex stimulation and then we will follow how that plays out in terms of cognitive measures … and eventually brain pathology in consenting subjects. We will also look at risk factors in these patients and genetic variations that have been implicated in loss of cognition and dementia - there is quite a bit of work going on currently in that area.”

transgenic models become more and more sophisticated over time, how closely do they actually model the whole of Alzheimer’s disease, or are we instead studying parts of the disease process or pathology that may indeed be specific for a particular model?”

RESISTANCE MAY NOT BE FUTILE

The other thing that Vickers will mention in his talk is the significant clinical inter-individual variability observed in Alzheimer’s disease and how difficult it is to relate this particular aspect to the experimental models.

“For instance, patients with the same amount of pathology may be affected quite differently - one person may be severely demented while another person with almost identical pathological changes is much less affected.”

What is unknown, however, is the basis for that variability. Is it genetic, do we build up different levels of cognitive resilience or brain reserve during our lifespan that have an effect and do risk factors affect the disease response?

HUMAN BRAIN TISSUE RESEARCH | ANS PREVIEW

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“The thing with the models, and transgenic lines in particular, is that by the very nature of them there is not a lot of variability. While this is a good thing with many laboratory-based investigations, again you always have to keep the clinical disease story in the back of your mind.”

GETTING THE BIGGER PICTURE

In a final key example, Vickers will present some of his own group’s results.

In a study published this year in the Journal of Neurochemistry, his team looked at synapse vulnerability in Alzheimer’s disease, both in human brain tissue at different pathological stages and in a commonly used transgenic model. It turned out that the

transgenic mice developed the characteristic Alzheimer’s plaques in their brains but did not exhibit much neuronal degeneration, which is reminiscent of preclinical disease in humans before the dementia symptoms become really obvious.

Their analysis also revealed similar levels of synapse loss in brains from people with early-stage disease and those of the transgenic mice.

“So the whole story became so much more important for potential

early interventions as a result of bringing in the human tissue comparison,” said Vickers. “Indeed, most of the transgenic models used in this field are not full models of Alzheimer’s disease but probably represent specific stages of the disease.”

This could actually become incredibly useful. Not only does it make any mechanistic studies using that model more relevant and powerful, but in the case of early-stage models, it could be very important for drug development.

“We know that a lot of Alzheimer’s drug trials have failed and that is probably because they have been focused on humans who just have too much pathology built up. So, now the whole field is moving towards trying to identify sufferers at the early stages of the disease as a better point of intervention.” ALS

Professor James Vickers originally trained as a psychologist and, like many others, eventually made his way into neuroscience. He completed a BSc (Hons) at the University of Tasmania, a PhD at the Flinders University of South Australia and was awarded a DSc from the University of Tasmania in 2005. He has previously held NHMRC CJ Martin, RD Wright and Senior Research Fellowships and currently holds the Chair of Pathology at the University of Tasmania and is Deputy Dean of the Faculty of Health Science.

ANS PREVIEW | HUMAN BRAIN TISSUE RESEARCH

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from biomolecular interactions.

All binding parameters (affinity, stoichiometry, enthalpy

and entropy) are available in a single experiment. The

product is quick to first results, with no assay develop-

ment labelling or immobilisation. It has the sensitivity to

investigate any biomolecular interaction using as little as

10 µg of protein.

The system is suitable for a range of applications,

including the characterisation of molecular interactions of

small molecules, proteins, antibodies, nucleic acids, lipids

and other biomolecules, enzyme kinetics, and the effects

of molecular structure changes on binding mechanisms.

GE Healthcare - Biosciences


http://www.interpath.com.au



M953 ret_adv_MM400_20131112_040x252.indd 112/11/2013 11:30

Biological safety cabinetThe Baker SterilGARD e3 Class II Type A2 Biosafety Cabi-

net offers an adaptive ergonomic design, combined with an

airflow management system and containment technology,

to improve comfort, increase productivity and reduce the

costs of ownership.

Designed with the operator in mind, the product is said

to be the quietest cabinet available, with low heat generation

and minimal vibration. The ReadySAFE mode allows the

cabinet to continuously operate while the screen is closed,

allowing the user to maintain safe conditions while leaving

for lunch, meetings or even overnight.

Cleaning is made easy with a membrane-sealed control

panel, a one-piece work surface and radiused, cove corners.

Maintenance is also simplified with an innovative electronic

controller with diagnostic LEDs, detachable side panels, front-

loading filters and a reinforced overall panel design.

For cost efficiency, the StediFLOW airflow management system with a self-

adjusting motor technology uses less energy and extends filter life without sac-

rificing performance.

The product is available in one person (1.2 m) and two person (1.8 m) models.

Abacus ALS Australia


Cell-repellant surface rangeThe Greiner Bio-One CELLrepellant Surface range is now available from Interpath

Services.

The surface technology effectively inhibits cell attachment, making the range

suitable for applications such as spheroid cultures, embryoid body formation and

suspension culture of semi-adherent and adherent cell lines (eg, macrophages).

The range, containing 6-well plates, 96-well plates (in both F and U bottom vari-

ations) and a 100 mm culture dish, have a two-year shelf life, are non cytotoxic,

non pyrogenic and are free of detectable DNase, RNase and human DNA.

Interpath Services Pty Ltd


http://www.mep.net.au


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.Ashman LK. Univ Newcastle, NSWRenal disease as a potential compounding factor in carcinogenesis experiments with Cd151-null mice.Oncogene 2013 Sep 12;32(37):4457.

Bankovacki A, Nachbur U, Infusini G, Webb AI, Silke J, Strasser A, Frankel G, Hartland EL. Univ Melb, VicA type III effector antagonizes death receptor signalling during bacterial gut infection.Nature 2013 Sep 12;501(7466):247-51.

Beavis PA, Divisekera U, Paget C, Chow MT, John LB, Devaud C, Dwyer K, Stagg J, Smyth MJ, Darcy PK. Peter Mac, VicBlockade of A2A receptors potently suppresses the metastasis of CD73+ tumors.Proc Natl Acad Sci USA 2013 Sep 3;110(36):14711-6.

Brock J. ARC CofE in Cog DisordsConnectivity and cognition in autism spectrum disorders: Where are the links?Proc Natl Acad Sci USA 2013 Oct 15;110(42):E3973.

Butt N, Beyer HL, Bennett JR, Biggs D, Maggini R, Mills M, Renwick AR, Seabrook LM, Possingham HP. UQConservation. Biodiversity risks from fossil fuel extraction.Science 2013 Oct 25; 342(6157):425-6.

Cho JH, Kim HO, Kim KS, Yang DH, Surh CD, Sprent J. Garvan, NSWUnique features of naive CD8+ T cell activation by IL-2.J Immunol 2013 Oct 28. [Epub ahead of print]

Clark GM. Univ Melb, VicThe multichannel cochlear implant for severe-to-profound hearing loss.Nat Med 2013 Oct 7;19(10):1236-9.

Demaere MZ, Williams TJ, Allen MA, Brown MV, Gibson JA, Rich J, Lauro FM, Dyall-Smith M, Davenport KW, Woyke T, Kyrpides NC, Tringe SG, Cavicchioli R. UNSWHigh level of intergenera gene exchange shapes the evolution of haloarchaea in an isolated Antarctic lake.Proc Natl Acad Sci USA 2013 Oct 15;110(42):16939-44.

Dong L, Jin L, Tseng HY, Wang CY, Wilmott JS, Yosufi B, Yan XG, Jiang CC, Scolyer RA, Zhang XD, Guo ST. Univ Newcstle, NSWOncogenic suppression of PHLPP1 in human melanoma.Oncogene 2013 Oct 14. [Epub ahead of print]

Duijf PH, Benezra R. MSKCC, NY and UQDI, Princess Alex Hosp, BrisThe cancer biology of whole-chromosome instability.Oncogene 2013 Oct;32(40):4727-36.

Fisher DO, Dickman CR, Jones ME, Blomberg SP. UQSperm competition drives the evolution of suicidal reproduction in mammals.Proc Natl Acad Sci USA 2013 Oct 29;110(44):17910-4.

Godfrey DI, Pellicci DG, Rossjohn J. Univ Melb, VicNKT cells: the smoking gun in fungal-induced asthma?Nat Med 2013 Oct 7;19(10):1210-1.

Good MF. Griffith Univ, Gold CoastImmunology. Pasteur approach to a malaria vaccine may take the lead.Science 2013 Sep 20;341(6152):1352-3.

Greenfield JR, Chisholm DJ. Garvan, NSWHow sweet it is: intestinal sweet taste receptors in type 2 diabetes.Diabetes 2013 Oct;62(10):3336-7.

Li S, Haigh K, Haigh JJ, Vasudevan A. Monash Univ, VicEndothelial VEGF sculpts cortical cytoarchitecture.J Neurosci. 2013 Sep 11;33(37):14809-15.

Hutson JM, Southwell BR, Li R, Lie G, Ismail K, Harisis G, Chen N. Royal Child’s Hosp, VicThe regulation of testicular descent and the effects of cryptorchidism.Endocr Rev. 2013 Oct;34(5):725-52.

Jones G. Sthn Cross Univ, Lismore Marine biology: Coral animals combat stress with sulphur.Nature 2013 Oct 31;502(7473):634-5.

Pearson JS, Giogha C, Ong SY, Kennedy CL, Kelly M, Robinson KS, Lung TW, Mansell A, Riedmaier P, Oates CV, Zaid A, Mühlen S, Crepin VF, Marches O, Ang CS, Williamson NA, O’Reilly LA, Bankovacki A, Nachbur U, Infusini G, Webb AI, Silke J, Strasser A, Frankel G, Hartland EL. Univ Melb, Vic.A type III effector antagonizes death receptor signalling during bacterial gut infection.Nature 2013 Sep 12;501(7466):247-51.

Raina JB, Tapiolas DM, Forêt S, Lutz A, Abrego D, Ceh J, Seneca FO, Clode PL, Bourne DG, Willis BL, Motti CA. AIMS and JCU, TownsvilleDMSP biosynthesis by an animal and its role in coral thermal stress response.Nature 2013 Oct 31;502(7473):677-80.

Remnant EJ, Good RT, Schmidt JM, Lumb C, Robin C, Daborn PJ, Batterham P. Univ Melb, VicGene duplication in the major insecticide target site, Rdl, in Drosophila melanogaster.

Proc Natl Acad Sci USA 2013 Sep 3;110(36):14705-10.

Shetty A, Sytnyk V, Leshchyns’ka I, Puchkov D, Haucke V, Schachner M. UNSWThe neural cell adhesion molecule promotes maturation of the presynaptic endocytotic machinery by switching synaptic vesicle recycling from adaptor protein 3 (AP-3)- to AP-2-dependent mechanisms.J Neurosci. 2013 Oct 16;33(42):16828-45.

Stuart-Smith RD, Bates AE, Lefcheck JS, Duffy JE, Baker SC, Thomson RJ, Stuart-Smith JF, Hill NA, Kininmonth SJ, Airoldi L, Becerro MA, Campbell SJ, Dawson TP, Navarrete SA, Soler GA, Strain EM, Willis TJ, Edgar GJ. Univ of TasIntegrating abundance and functional traits reveals new global hotspots of fish diversity.Nature 2013 Sep 26;501(7468):539-42.

Sullivan K, El-Hoss J, Quinlan KG, Deo N, Garton F, Seto JT, Gdalevitch M, Turner N, Cooney GJ, Kolanczyk M, North KN, Little DG, Schindeler A. Child’s Hosp Westmead, NSWNF1 is a critical regulator of muscle development and metabolism.Hum Mol Genet 2013 Oct 24. [Epub ahead of print]

Tarlinton D, Good-Jacobson K. WEHI, VicDiversity among memory B cells: origin, consequences, and utility.Science 2013 Sep 13;341(6151):1205-11.

Trejo CL, Green S, Marsh V, Collisson EA, Iezza G, Phillips WA, McMahon M. Peter Mac, VicMutationally activated PIK3CAH1047R cooperates with BRAFV600E to promote lung cancer progression.Cancer Res 2013 Nov 1;73(21):6448-61.

Tumer E, Broer A, Balkrishna S, Julich T, Broer S. ANU, ACTEnterocyte-specific regulation of the apical nutrient transporter SLC6A19 (B0AT1) by transcriptional and epigenetic networks.J Biol Chem. 2013 Oct 11. [Epub ahead of print]

Ve T, Williams SJ, Catanzariti AM, Rafiqi M, Rahman M, Ellis JG, Hardham AR, Jones DA, Anderson PA, Dodds PN, Kobe B. Aust Infect Dis Res Ctr and IMB, UQ, QldStructures of the flax-rust effector AvrM reveal insights into the molecular basis of plant-cell entry and effector-triggered immunity.Proc Natl Acad Sci USA 2013 Oct 22;110(43):17594-9.

Wilcken B. Child's Hosp Westmead, NSWMedicine. Newborn screening: gaps in the evidence.Science 2013 Oct 11;342(6155):197-8.



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


EVENTS

Australian Society for Biophysics Annual Meeting November 24-27, Melbournewww.biophysics.org.au/Meetings/2013/index.html

International Symposium on Computational Models for Life SciencesNovember 27-29, Sydneyhttp://cmls-conf.org/2013/

Australasian Flow Cytometry Group 36th Annual MeetingNovember 28-30, Wellington, New Zealandwww.malaghan.org.nz/afcg2013

19th NSW Stem Cell Workshop, Innovating the Marketplace with Stem CellsNovember 29, Sydneywww.stemcellnetwork.org.au/

34th Annual Meeting of the Australasian Neuroscience SocietyJanuary 28-31, 2014www.aomevents.com/ANS2014

19th Proteomics Symposium 2014February 6-9, 2014, Lorne, Vicwww.australasianproteomics.org/

39th Lorne Conference on Protein Structure and FunctionFebruary 9-13, Lorne, Vicwww.lorneproteins.org

25th Lorne Cancer Conference 2014February 13-15, 2014, Lorne, Vicwww.lornecancer.org

35th Lorne Genome Conference 2014February 16-18, 2014, Lorne, Vicwww.lornegenome.org

Lorne Infection and Immunity Conference 2014February 19-21, 2014, Lorne, Vicwww.lorneinfectionimmunity.org

Pathology update 2014February 21-23, 2014, Melbournewww.rcpa.edu.au/Continuing/PathologyUpdate/PathologyUpdate2014.htm

The Future of Experimental Medicine Conference – Inflammation in disease and ageingMarch 16-19, 2014, Manly Beach, Sydneyhttp://femc.mtci.com.au/

11th Annual Conference of the Society for Brain Mapping and TherapeuticsMarch 17-19, 2014, Sydneywww.worldbrainmapping.org/11th-annual-congress/welcome-message

5th New Directions in Leukaemia Research (NDLR) meeting30 March-2 April, 2014, Noosa, Queenslandhttp://sapmea.asn.au/conventions/ndlr2014/

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

International Union for the Study of Social Insects international CongressJuly 13-18, 2014, Cairnshttp://www.iussi2014.com/

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

Joint International Symposium on the Nutrition of Herbivores/International Symposium on Ruminant Physiology International Conference8-12 September, Canberrahttp://www.herbivores2014.com/

15th International Conference on Systems Biology September 13-19, 2014, Melbournewww.emblaustralia.org

ComBio2014September 28-October 2, 2014, Canberrawww.asbmb.org.au

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

Australian Health and Medical Research CongressNovember 16-19, 2014, Melbournewww.ahmrcongress.org.au/

11th Annual World Congress of the Society for Brain Mapping and Therapeutics - Brain therapeutics, breaking boundaries of science, technology, medicine, art and healthcare policyMarch 17-19, 2014, SydneyThe three-day 11th Annual World Congress of the Society for Brain Mapping and Therapeutics will bring together physicians, scientists, policymakers, funding agencies and industry.Taking an interdisciplinary approach, the meeting will draw together researchers with diverse backgrounds in engineering, science and medicine with a collective interest in various aspects of the function and structure of the brain in both normal and dysfunctional states. Advancements at the forefront of brain sciences will be covered, such as brain and spinal cord mapping and image-guided therapies (operative and non-operative), and neural stem cell interventions.www.worldbrainmapping.org/11th-annual-congress/welcome-messagewww.bioprocessingnetwork.com.au/Conferences.html

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