Australian Life Scientist Mar/Apr 2013 by Westwick-Farrow Media

PP100009448 ISSN 1448-9791

The Professor Ian Chubb on the importance of science on our future prosperity and wellbeing 16

BIOTECH 2013 PREVIEW

voice of reason Vol 10 Issue 2 • March / April 2013

GENE SEQUENCING | HUNTER MEETING | BIOINFORMATICS | MEDICAL APPS

Contents FACE TO FACE

16 The voice of reason Hailing from rural Victoria, Professor Ian Chubb’s career has moved from research lab to university vice chancellor to Chief Scientist. As well as reflecting on his career trajectory, he shares his views on science literacy, science education and how he thinks Australia is doing in science.

BIO 2013 PREVIEW

20 Beyond the debate Whilst opposition to genetically modified crops continues, Australian researchers are developing GM crops with traits that provide tangible benefits the plants themselves as well as to farmers and global food production.

HUNTER MEETING REVIEW The ZIC gene family collectively shapes the nervous system during very early embryonic development in vertebrates. Associate Professor Ruth Arkell is looking at the five genes that code for ZIC proteins and whether they are linked by function as well as conserved expression. HUNTER MEETING REVIEW

32 BIO 2013 PREVIEW

24 Delayed reaction This preview of the international biotech convention, BIO 2013, overviews the volatility of 2012 and the potential, if potential turbulence, 2013 holds.

32 Balancing act

Dr Robin Hobbs’ serendipitous finding of one of the first transcription factors that regulates spermatogonial stem cells in the mouse testis has led to his continued investigations into the resident stem cells of the testis.

RESEARCH

36 The rise of smartphone health and medical apps The boom in smartphone apps has not missed the healthcare sector.

REGULARS

IN THE NEXT ISSUE OF ALS

6 12 14 45 46

• Personalised medicine • Proteomics • Biochemistry • Microscopy and image analysis Editorial deadline: 18/04/13 Advertising deadline: 18/04/13

Movers and shakers GrantWatch AusBiotech Publish or perish Events

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Apps are being developed that can improve management of acute and chronic conditions and provide more personalised medical treatment.

28 Family Affair

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RESEARCH

38 10 commandments for next-gen sequencing Geneticist Dan Koboldt from the Genome Institute at Washington University in St Louis provides his decalogue on next-generation sequencing. RESEARCH

42 Resistance to computation is futile

People with computer programming and mathematical skills will not have a problem funding work with the need for high-performance computing to analyse the data sets being generated in research today. Here we take a look at an account of how bioinformatics can be used in biological research.

M A R C H / A P R I L 2 013

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Change

at the wheel

im Dean has left the helm of Australian Life Scientist to nurture his PhD for the next nine months and I have returned to the driving seat, at least for the interim. As readers of ALS will have witnessed, Tim is a prolific and skillful wordsmith and I’m sure he will find the writing up process an enjoyable and productive one. I wish him all the best in getting to that place of submitting his PhD. It’s good to be back and to see the magazine is in tiptop shape and still covering the fine life science research that is happening across Australia. First up in this issue, Australia’s Chief Scientist, Professor Ian Chubb, reflects on his career in the science research sector on page 16. Chubb is passionate about science education, scientific literacy and people being given the knowledge to make informed choices and ask appropriate questions. We preview the BIO 2013 meeting in this issue on page 20. The first of these international biotech conventions was held in 1993. Since then this gathering has grown to become the largest global event for the biotechnology industry. Despite the trials and tribulations of 2012, the strength in the commercial side of the Australian life sciences sector can be seen in the 100 biotech companies currently listed on the Australian stock exchange. With a federal election coming up this year, 2013 may or may not be the breakthrough year the sector has been waiting for.

The Hunter Meeting is a meeting of cell biologists held each year in the wine country of the Hunter Valley, NSW. In this review, starting on page 28, we feature articles on two presentations at the meeting. Dr Robin Hobbs’ work with the resident stem cells of the testis has led to some useful systems for studying stem cells. Being able to monitor these cells in culture for relatively long times has allowed Hobbs and colleagues to gain a better understanding of how these cells function. Another researcher who presented at the Hunter meeting, Associate Professor Ruth Arkell, is investigating the ZIC gene family, five genes whose protein products are involved in collectively shaping the nervous system during very early embryonic development in vertebrates. The ZIC proteins appear to switch from their roles in transcription to become co-factors in gene suppression, and Arkell’s work is beginning to link these proteins to adult onset diseases. We also take a look at geneticist Dan Koboldt’s decalogue on next-generation sequencing on page 38, the rise in health and medical smartphone apps on page 36 and how bioinformatics is used in biological research on page 42. I hope you enjoy reading this issue. I’d like to encourage you all to keep in touch with any research news, people movements, events or highlights you think worthy of sharing with the ALS readership. Please forward your ideas to als@westwick-farrow.com.au.

September 2012 Total CAB Audited Circulation 7053 (Aust + NZ)

Susan Williamson

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INDEX OF ADVERTISERS Agilent Technologies 11 AusBiotech 27 Australian Genome Research Facility 41 Australian Scientific 47 Bio-Strategy 19 Cryosite 44

Eppendorf 7 Interpath Services 23, 40 Labtek 44 Laftech 2 Life Sciences Queensland 48 Lonza 4, 13

AU S T R A L I A N L I F E S C I E N T I S T

Millennium Science MP Biomedicals RACI Biomolecular Division Sarstedt Sartorius United Bioresearch

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9 31 41 35 15 26

MOVERS & SHAKERS

Phosphagenics working on topical opioid patch

Allied finds CardioCel better at seeding stem cells © iStockphoto.com/Sebastian Kaulitzki

Allied Healthcare (ASX:AHZ) said the results of a joint study with the CSIRO show its CardioCel tissue patch is superior at stem cell seeding than gold-standard alternatives in surgical use. The preclinical study evaluated the ability of CardioCel tissue, produced using the company’s ADAPT tissue engineering technology, to maintain a population of mesencymal stem cells (MSCs). CardioCel tissue was measured against the MPC-maintaining ability of the glutaraldehyde-prepared tissue widely used in current cardiac repair surgeries. Allied Healthcare said the results show that CardioCel engineered tissue demonstrated significantly better stem cell viability at one day post-seeding and high cell viability at day seven. By comparison, by the seventh day, virtually no MSCs had survived on the control tissue. Allied Healthcare CEO Lee Rodne said the in situ data suggests that CardioCel tissue could support seeding by endogenous stem cells. “[This] broadens the potential of ADAPT prepared tissue to be used as scaffolds to seed and deliver stem cells for soft tissue repair, [which] expands the potential of our ADAPT tissue to be used as a truly regenerative treatment for a number of diseases and conditions,” he said. Rodne added that the data also supports the company’s preclinical research into using CardioCel patches in heart valve reconstruction. CardioCel was used for the first time outside of clinical trials in October last year, during a procedure at the Mater Hospital in Brisbane.

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AU S T R A L I A N L I F E S C I E N T I S T

Sirtuin is something of a wonder protein, with it being linked to cellular longevity and ageing. Now researchers from Belgium and Australia have uncovered a link between sirtuin regulation and pancreatic cancer, potentially leading to new avenues for treatment. They found that in some circumstances sirtuin-1 can be co-opted to aid cancer cells in developing and surviving. © iStockphoto.com/Sebastian Duda

Phosphagenics (ASX:POH) has expanded its pain patch portfolio to include an oxycodone-based patch designed for local pain relief without the opioid entering the bloodstream. The company said preclinical studies of the underlying technology used in the oxycodone pain patches it has under clinical development demonstrated an ability to reduce local pain through topical administration. Phosphagenics is now planning to commence clinical trials of a similar version of the patch in the third quarter. Phosphagenics’ pain patches use its TPM (targeted penetration matrix) drug delivery technology, which allows molecules to be delivered either into the skin or through the skin into the bloodstream. The preclinical trial involved a formulation designed to deliver oxycodone into the skin only. The study in a pain model shows that the formulation reduced pain, worked rapidly and did not seep through into the bloodstream. Phosphagenics CEO Dr Esra Ogru said the potential market for a topically administered opioid was large. “Delivering a powerful opioid like oxycodone topically has never been achieved commercially,” he said. “It has been widely assumed that opioids can only treat pain ... via the bloodstream. Our study confirms more recent findings that opioid receptors are up-regulated in tissue in response to pain, particularly pain associated with inflammation.” Ogru said a topical opioid product could eliminate the side effects associated with oral delivery and could be suitable for a number of hard-to-treat pain types such as diabetic neuropathy. Phosphagenics is also currently conducting a clinical trial of a pain patch that uses its TPM technology to deliver oxymorphone.

Anti-ageing protein linked to pancreatic cancer

Normally sirtuin-1 is inhibited in the pancreas by another protein in exocrine cells, called KIAA1967. However, during the development of pancreatic cancer, sirtuin-1 can be disconnected from its normal inhibiting protein and can begin to aid tumour cell development. The researchers, led by Dr Elke Wauters and Dr Ilse Rooman from the Diabetes Research Centre at the Free University of Brussels in Belgium as well as a scientist at Sydney’s Garvan Institute of Medical Research, used a mouse model and cell cultures from human tumour samples to observe how sirtuin-1 influenced pancreatic cancer development. They reason that inhibiting sirtuin-1 may help prevent the initiation of pancreatic cancer and may help slow or prevent the growth of existing tumours. “The next stage of our work will be to further test our hypothesis in preclinical models,” said Dr Rooman The paper was published in Cancer Research.

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MOVERS & SHAKERS

Gene patent upheld by Federal Court

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The gene patent debate has progressed another step with a landmark ruling from the Federal Court in favour of Myriad Genetics, and its local licensee Genetic Technologies, and its patent of mutations in the BRCA1 gene. The case was brought by Brisbane woman Yvonne D’Arcy in 2010 along with charity group Cancer Voices Australia. Myriad Genetics argued that their patent didn’t cover a discovery of something pre-existing in nature but an “artificial state of affairs”, thus qualifying it for patent protection. According to Dr Tania Obranovich, Partner at Davies Collison Cave, the judgement provides a measure of increased certainty over what qualifies as patentable subject matter. “This is a good decision, and a well-reasoned decision,” she said. “The law, as it stands, is that for material to be patentable, it has to be an artificially created state of affairs and have economic application. “The question has always been what is it that amounts to an artificially created state of affairs.” In the judgement, Justice John Nicholas pointed out that nucleic acid sequences do not exist outside their natural environment with a cell, and isolated nucleic acid sequences - such as those covered by Myriad Genetics’ patent - do not exist within the cell. As such, the isolated nucleic acid sequences do qualify as an artificially created state of affairs and thus qualify for patent protection. However, as Obranovich stresses, this means they only pass the first threshold for patentability; just because they are patentable subject matter doesn’t mean they will be awarded patent protection if they fail to be novel or inventive. Some academics and members of the healthcare industry, however, have seen this judgement as being a radical decision that could change the way patents are handled in Australia. “This ruling means that anything that is artificial is now patentable subject matter,” said Dr Luigi Palombi, patent lawyer and visitor at the Centre for Governance and Knowledge and Development at the Australian National University. “It doesn’t matter where the biological material has actually come from. Corporations are now able to patent any genes connected to a disease or trait - like hair colour. It’s a fairly radical decision. “It turns patent law on its head. Patents were originally created for something which someone had invented. No matter how important it is to identify a gene linked to a disease, it’s still not something that Myriad or anyone else has invented. It’s now a matter for politicians to get together and correct this through legislation.”

Professor Ian Olver, CEO of Cancer Council Australia, also expressed concern over the implications of the judgement. “Discovering and isolating genetic materials is not inventive, yet the current law gives licence to biotechnology companies to claim ownership of naturally occurring substances. “Today’s outcome shows that the law must be changed to protect the community from gene monopolies,” he said. The Royal College of Pathologists of Australasia (RCPA) also expressed disappointment at the Federal Court’s decision on the grounds that the BRCA1 mutation is a naturally occurring discovery and not an invention, thus should not be patentable. Professor Yee Khong, President of RCPA, warned that the ruling could have a negative impact on healthcare in Australia. “Gene patenting has the potential to directly affect the healthcare and medical research industry, and may have an adverse impact on medical testing,” he said. “Therefore, the battle is not over. We need a system that supports creativity and investment in research and healthcare, while ensuring that the ability to make a diagnosis is not restrained.” However, Dr Obranovich stresses that this decision is unlikely to have a negative impact on the research or medical industries. “In practice, this decision does not change anything. The status quo in Australia and overseas has always been that isolated nucleic acid sequences and proteins are patentable. In that regard, nothing has changed,” she said. “To date there has not been a health crisis. Research continues to be performed and technology is brought to market from the lab to the patient. I do not see any reason why that would change.”

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MOVERS & SHAKERS

Cynata’s stem cells show promise in treating critical limb ischemia Cynata’s mesenchymoangioblasts (MCA) cells have offered a hint of their therapeutic potential in an animal trial, the results of which have just been released by the company. MCA cells are stem cells that are precursors to the betterknown mesenchymal stem cells (MSCs) and are the precursor to fully differentiated vascular cells. The trial, which was conducted by the University of Wisconsin School of Medicine and Public Health, looked at the potential of these MCA cells to treat critical limb ischemia (CLI), which is a disease caused by poor blood supply and is commonly found in diabetic patients. Mice first had critical limb ischemia induced and then they were either injected with MSCs grown from MCAs or with a saline solution. The study found that mice injected with the stem cells demonstrated significantly improved blood flow and thus a substantially diminished impact from the ischemia. Cell-treated mice lost significantly fewer nails and toes than did saline-treated control animals. In fact, while the worst that happened to any of the treated mice was a lost toenail, some of the saline-treated animals

lost their entire foot. Gastrocnemius muscle injected with the stem cells were also found to be larger, heavier and healthier looking. “This experiment is an excellent demonstration of the potential effectiveness of Cynata’s cellular therapeutics platform,” said Professor Igor Slukvin, who discovered the MCA cells. “The mouse high limb ischemia model is widely used as a test for therapies for CLI, and here we have seen that Cynata’s MCA derived MSCs preserved limb form and function. Since prevention of amputation is a key goal of physicians treating CLI, we find these data extremely encouraging.” “These results give us great confidence to press on with our development program,” said Cynata CEO Dr Allen Bollands. The company is now looking to conduct further research into the potential for MCA cells to stimulate blood vessel formation. Cynata received a $250,000 funding injection from Eco Quest (ASX:ECQ) in November last year, and the company has since more than doubled that investment in Cynata.

New insight into the catch-22 of dieting

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Any sensible diet advice will tell you not to starve yourself because your body will react by storing as much energy as it can in the form of fat. This mechanism, which evolved to keep us going in times of famine, introduces a vicious cycle for many obese people, making it nearly impossible to eat less and burn more energy at the same time. Now researchers from Sydney’s Garvan Institute and the University of New South Wales have revealed the neural circuitry underlying this phenomenon, raising the prospect of new ways to break the cycle. The team of scientists led by Dr Shu Lin, Dr Yanchuan Shi and Professor Herbert Herzog focused on the neurotransmitter neuropeptide Y (NPY) and its role in regulating the body’s energy expenditure. NPY is already well known as an appetite stimulator. However, amongst other effects, its signalling also has an effect on brown adipose tissue, known as ‘brown fat’. While white fat is the tissue that stores energy, and thus can make one obese when the storage becomes excessive, brown fat is known to work as a heat generator that burns energy, helping keep the body warm. Using various mouse models, the researchers were able to determine that NPY produced in the arcuate nucleus (Arc) of the hypothalamus in the brain could control the way the body regulated temperature while maintaining a steady equilibrium of energy use.

It appears to do this by decreasing sympathetic nervous system activity, so when brown fat activation is inhibited and it does not generate as much heat, the body burns fewer calories. Thus the catch-22 of dieting. According to Professor Herzog, this study is the first to show a direct connection between Arc NPY, the sympathetic nervous system and the control of energy expenditure. With an understanding of this brain circuit in place, researchers are now looking towards tinkering with it to aid weight loss. “Obesity is a modern epidemic, and the challenge will be to find ways of tricking the body into losing weight - and that will mean somehow circumventing or manipulating this NPY circuit, probably with drugs,” said Herzog. The study was published in Cell Metabolism.

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MOVERS & SHAKERS

GrantWatch Research news © iStockphoto.com/David Gunn

Victorian Infection and Immunity Network gets $300K injection from Vic government A $300,000 grant from the Victorian government will promote collaborations between researchers and the industry focused on developing new innovations in infection and immunity. The Victorian Infection and Immunity Network represents over 900 infection and immunity researchers across the state and is jointly led by Professor Paul Hertzog from the Monash Institute of Medical Research and Professor Elizabeth Hartland from the University of Melbourne. The money will go towards encouraging linkages between academia and biotechnology companies and will help

showcase new research as well as assisting in placing recent graduates in the industry. “This initiative will address the perceived gap in bidirectional interactions between industry and academia, enhance the education and training of a highly skilled workforce, and refine the commercial acumen of academic research programs,” said Hertzog. “Having already established strong membership and activities, VIIN has positioned itself to form an industry alliance with businesses interested in cutting-edge platform technologies and innovative research,” said Hartland.

Alchemia reaps $4.4m from R&D Tax Incentive The R&D Tax Incentive has so far returned tens of millions to Australian life science companies, with Alchemia (ASX:ACL) being the latest beneficiary, announcing a receipt of $4.4 million through the scheme. The company received $3.4m through Alchemia Oncology, which is developing the company’s HyACT platform technology of targeted drug delivery to cancers. It also received an additional $1m to Alchemia Ltd, which handles fondaparinux, a generic version of GlaxoSmithKline’s Arixtra. According to the company, the funding comes from its domestic and overseas R&D expenditure, principally covering phase III trial expenses. “We are delighted that applications submitted by Alchemia and Alchemia Oncology have been successful under this progressive and innovative government program,” said Alchemia CEO Charlie Walker.

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“Payments arising from this program are expected to considerably reduce our financial requirements for this and coming years.” The company also announced a total revenue for the 1HFY13 of $9.4 million and receipt of its first fondaparinux profit share from Dr Reddy’s of US$3.4m ($3.3m) shaved to US$2.9m ($2.82m) after a payment to Dr Reddy’s to help improve yields. Fondaparinux sold by Dr Reddy’s has now established a 25% market share by volume with net sales of US$12.3 million ($12m). Alchemia Oncology also announced it has continued recruitment for its phase III trial of HA-Irinotecan in metastatic colorectal cancer, with the first patient being dosed on 4 January last year and the 390th patient being recruited on 31 January 2012. Alchemia has ended the first half of FY13 with a net loss after tax of $5.9m, down fractionally from the $6m over the same period the previous year.

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AUSBIOTECH | VIEWPOINT

Driving innovation AusBiotech welcomes the federal government’s Plan for Australian Jobs, which will aid innovative companies and help support the biotechnology sector. Dr Anna Lavelle, CEO, AusBiotech

e at AusBiotech, along with the wider biotechnology industry, have welcomed the federal government’s release of its long-awaited Industry and Innovation Statement, ‘A Plan for Australian Jobs’, which promises a venture capital boost and a raft of programs for innovative companies. Venture capital funds of $350 million, 10 Industry Innovation Precincts worth $500 million and support for pharmaceutical clinical trials are amongst the top-billing items of interest to the biotechnology sector. The 76-page policy document outlines the Labor Government’s plan to spend $1 billion to “boost Australian innovation, productivity and competitiveness … to support and create jobs.” Funded by a $1 billion cut for large corporations (over $20 billion in turnover) under the R&D Tax Incentive, the policy allows for new and revamped programs. The industry’s reaction was upbeat, and I commend the government on a comprehensive top-level policy. I was pleased to see the positioning of innovation as central to jobs, productivity and a thriving economy, which is where it belongs. It’s also good to see the government has been listening to the concerns of industry, and I note the policy responds to many of the initiatives that have been well articulated by industry and AusBiotech for some years. While the statement is very welcome, I look forward to clarifying the details of many of the policy planks and hope that the positive elements of the policy can enjoy an expedited and rapid implementation after the election is decided.

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One of the pillars of the policy is to improve access to finance for innovative start-ups through Venture Australia via a $378 million package. This includes a new $350 million round of the Innovation Investment Fund (IIF); changes to venture capital tax concession programs to provide clarity for investments and facilitate ‘angel’ syndicates; a new platform to market the successes of our start-ups; and a commitment to reinvest all government returns from the package into venture capital support. AusBiotech applauds the continuation of the IIF, especially in light of the imminent cessation of the current final round. The program has been critical to the biotechnology industry to date. Access to capital, and at the right price, is a serious bottleneck to innovation, as Australia has substantially more innovation than capital. It is fantastic to see that IIF money generated by the sector and returned to the government will be reinvested to support new innovative enterprises. We are pleased to see a commitment to venture capital tax concession programs and would be pleased to engage with government to explore at length what is being considered in terms of preferential tax treatment for investors to ensure a suitable outcome for the sector, which will generate more investment in Australian innovation. The government also says it will invest more than $500 million in establishing up to 10 Industry Innovation Precincts to drive business innovation and growth in areas of Australian competitive advantage. The notion of clusters was recommended

AU S T R A L I A N L I F E S C I E N T I S T

by AusBiotech in its 2012 submission to the Prime Minister’s Science, Engineering and Innovation Council (PMSEIC), Chaired by Professor Chubb, and is therefore supportive of the concept. Innovation precincts can be extremely valuable in leveraging expert critical mass; however, they don’t always succeed. AusBiotech looks forward to more details about how these can be developed and where they will be located. In acknowledgement of the Australian pharmaceutical industry’s positive outlook - exporting around $4 billion per year, employing over 40,000 people and investing more than $1 billion a year in R&D - and the current pressures it faces, the government says it will spend $9.9 million over five years to expedite the recommendations from the Clinical Trial Action Group (CTAG) Report. The recommendations are aimed at advancing Australia’s position as a leader in clinical research and improve our attractiveness as a destination for clinical research investment. Australia has traditionally been a destination of choice for the conduct of clinical trials; however, our competitive advantage has declined over the last five years. Rising and varying costs between clinical trial sites and jurisdictions, delays in approving trials and difficulty recruiting patients are some of the causes. We applaud the government’s support to act on the recommendations of CTAG, while noting that implementation is well overdue. The CTAG recommendations are good policy, for which the industry has been advocating for many years. ALS

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FACE TO FACE | IAN CHUBB

The voice of reason Tim Dean

Professor Ian Chubb has used his considerable reach as Australia’s Chief Scientist to speak up for the importance of science on our future prosperity and wellbeing. Australian Life Scientist: How was it that you first became interested in science while growing up on a farm in rural Victoria? Professor Ian Chubb: Growing up in those early years, when it is just you and your dog and a few adults, you look at the world around you and you wonder why are things like they are? Why do ants do what they do, in the way they do? How well do they do what they do? My parents encouraged me to be curious about how the world worked. In essence, if you’re thinking about how the natural world works, there’s only one place for you to go: science.

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ALS: What drew you specifically into neuroscience when you started studying in the 1960s? IC: It was partly the excitement of the time. It was like we were standing at the front door of house with a long corridor, but we still haven’t got to the back door yet. We still don’t know how the brain works. We still don’t know a lot about how the nervous system develops and how so many things work so well, so often, for so long. For a person who was encouraged from an early age to be naturally curious, and to question, this was a great unknown.

AU S T R A L I A N L I F E S C I E N T I S T

Then I met people whose interests were in neuroscience and whose enthusiasm infected me, probably still to this day. Although, of course, I’m now a real amateur. I’m a long way from the frontier. ALS: What do you enjoy about the process of discovery? IC: The enjoyment is really the pitting of your ideas and your interpretations of evidence against the ideas and interpretations of others. I’ve said many times to students: there’s nothing quite like the thrill of designing an experiment that works how you want it to work and reveals something being seen for the first time in the world. You’re accumulating evidence, you’re unpicking it, you’re questioning it. I don’t think I’ve ever stopped thinking like that; that you don’t take too much at face value

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IAN CHUBB | FACE TO FACE

so you question it. The basic enjoyment of the hunt is trying to learn more, trying to understand better, trying to be as accurate as you can, as careful as you can. But not being too risk averse. My view is that good scientists take risks, but they understand and manage the risk. They don’t just sit back and say ‘I won’t do this or that because it mightn’t work.’ You try to get better at making sure it does work. I also enjoy the process itself. The constant questioning of data, of information, of evidence. Of not taking things as they’re presented to you until you understand how they were determined. I don’t think I’ve ever stopped thinking like a scientist in whatever it is I’ve been doing. I hope my colleagues agree! ALS: After two decades working in the lab, you made your move into academic administration. Do you ever yearn to get back into the lab? IC: The answer to that is: no. Basically because I’d be a very sad old man by now if I were lamenting that move. But I do like talking to people who are still in the lab. And I still like to see the fire in the spirit of the young researchers who are coming through and who are looking at the world as I look at it, or used to. I also like to engage with even younger people

Talking to these young people is one of the great starts to the calendar year. I’ve done it for 10 years or so and I’ve always enjoyed it. You get buoyed and boosted by seeing such levels of enthusiasm and I enjoy talking to them and encouraging them. ALS: Why did you undertake the move from the lab into more administrative roles? IC: I’m happier when I’m being stretched. I like thinking: can you do that, can you reach that, can you do better? I remember sitting in my backyard in Adelaide when I was turning 40, and I said to my wife that life had to be harder than this. I had a job teaching medical students, and medical students were for the most part highly intelligent and highly motivated, so they were easy to teach. I had a good research lab, I had a lot of funding. So I can indeed remember saying life has got to be harder than this. And I found that to be true, if still enjoyable. Shortly afterwards there was a job advertised for deputy vice chancellor at the University of Wollongong. At the time I was at Flinders and had taken on more roles, such as chairing the research committee, and had grown up through the library committee and the various other roles academics accept.

“Science is everywhere, and there are a whole lot of people who think it’s nowhere. That is sad.” who are looking at the options that are available to them. I was talking to a group recently at the National Youth Science Forum - they’re in senior secondary school - and these are bright, talented, interested young people who want to do something good. And that’s good for Australia: when people are really engaged with the issues and want get into the substance of them. It’s a bit like reading a book: you read all of each chapter, not just the chapter headings. But there are a lot of people in this world who read the chapter headings and think they know everything there is to know.

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The University of Wollongong had one of the very best vice chancellors that Australia has had - Ken McKinnon - and he was looking for someone like me. He was the best mentor I could have had at that stage of my career. He offered me the job, I did it, I grew and, basically, here I am. ALS: You have made a number of public comments about scientific literacy and science education. How important is it to have a scientifically literate population today? IC: I think it’s critically important. People are being asked to make increasingly

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important choices within increasingly complex issues. I’d feel much more secure if we had people who were making better informed choices. You can think of a whole host of things, from vaccination, to medical advice, to advice from the pharmacist etc, where we are better off both individually and as a community if we can sit back and make a reasonably informed decision. Most people won’t be as expert as a professor of clinical medicine, but if they can ask the right question - like why are they recommending this one and not that one - it is a step towards making the community better for all of us. I think we’re letting ourselves down by not pursuing that broader education early enough in our education process. Not that I want everybody to study science. I think it would be horrible to be in a world populated exclusively by scientists and engineers and mathematicians. I like the fact that there are people who engage with the social sciences and the humanities who are also contributing to questioning, advancing knowledge through information and evidence and rational debate. ALS: Does science education today imbue students with a critical eye as well as it does the more technical aspects of science? IC: The science students themselves need to have their content, or technical, knowledge put into a context. The context is the process of science - how it is conducted, how it is based, its ethics and the like. The content is important, but it is thinking like a scientist that the individual carries through their life - long after much of the content knowledge has been replaced by newer information, evidence and knowledge. Overall, I don’t think we do it as well as we should, for the community. The fact that we don’t do that well is illustrated by the way science is questioned by people without a science background. They ask why scientists can’t give them certainty. Well, any self-respecting scientist will always be talking about a probability, because they know in the experimental observational sciences we very rarely

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FACE TO FACE | IAN CHUBB

Professor Ian William Chubb, AC, was appointed Australia’s Chief Scientist on 19 April 2011. He has an MSc, DPhil (Oxford), Hon DSc (Flinders), Hon DLitt (CDU), Hon DUniv (ANU), Hon LLD (Monash). He has served as the Vice Chancellor of the Australian National University, Vice Chancellor of Flinders University and Senior Deputy Vice Chancellor of Monash University. He has also worked as a research scientist in the neurosciences with over 70 publications to his name.

deal with certainty. There’s always room for questioning. You accumulate evidence and you work with an increasingly high level of probability, and it’s not wrong, it’s not weak. It’s not throwing great doubt onto an issue simply because a scientist says it’s highly likely that climate change, for example, is caused by increasing carbon dioxide in the atmosphere and that it comes from human activity. That will always be a probability. We will never get to 100%, but if the experts agree that it’s better than a 95% chance, we should listen. To see two people having an argument about that last 5% does not mean that one is wrong. That’s how science works. There’s evidence, you draw your conclusions, somebody else draws a slightly different conclusion, but it’s still based on evidence rather than belief or hearsay. And they will debate that, sometimes quite robustly. I think that’s good, and that should happen, and it should be obvious that it does happen. The public needs to understand that it is a part of the scientific process. ALS: What are some of the hurdles to overcome in making science attractive to high school students? IC: I think we need to make it interesting. All the evidence I’ve read shows that we, like many countries, have tended to focus a lot on the content and much less on making the process obvious. My view is that science ought to be taught more like it’s practised. The practice of science is compellingly interesting.

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The teaching of science can be unbelievably boring - memorising the elements on the periodic table is not the most intellectually stimulating thing you can do. However, students like field work, or laboratory work, or practical science. In a way I was doing field work from the age of three. Part of the public debate hints that if you teach science interestingly, you’re dumbing it down. That’s ridiculous. If you teach science interestingly, you’re encouraging people to engage with science. Some of them might not go on to become a scientist, but they’ll know how science works. When they see an argument about climate change or vaccination or antibiotic resistance, they won’t be an expert in the field, but they’ll understand why the debate is taking place in the way that it is. A recent survey done by the Australian Academy of Science showed that a vanishingly small proportion of students not studying science thought it useful to their future. About half think it’ll never be of use. Yet they put down their smartphone they paid for with plastic - card or banknotes - to answer the questionnaire. Science is everywhere, and there are a whole lot of people who think it’s nowhere. That is sad. ALS: University funding has long been a contentious issue in Australia. Do you think universities are sufficiently funded by the government? IC: Government does have a role to play. It gets down to the fact that anyone with talent should not be denied the

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top level of education they can achieve. And you can’t leave that process to individuals. Australia has spent too much of its early history not sufficiently supporting public access to education of high quality. The idea that if you want it, you can pay for it is not where I would like it to go. That’s to our country’s disadvantage. I think that people with talent should be able to achieve at the highest level, and it ought not cost them an arm and a leg to get there. That’s a real part of government responsibility to make sure that price does not preclude. ALS: What legacy would you like to leave after your tenure as Chief Scientist? IC: I’d like to see science up front and centre in the community’s mind. I would like to see people pushing their local politicians and reminding them of how important science is to Australia’s future. How important science is to Australia’s place in the world. When we talk about food security and engagement with our region, a lot of that engagement will be through work of our scientists. I’d like to have the work we do educating people from countries in our region much more front and centre. I’d like to think that some - maybe even most! - of the advice we give has been adopted, and that there are changes through our science that position Australia well in a sometimes hostile world. And if I thought I had no influence, I wouldn’t be here. ALS

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BIO 2013 PREVIEW | AGBIOTECH

Beyond the

debate

A leading opponent of transgenic crops in Britain recants. But Australian scientists developing GM crops to help feed the world aren’t waiting for local anti-GM campaigners to see the scientific light. Graeme O'Neill

he earth beneath the meadows and crop fields of Europe moved perceptibly early in January when British journalist, author and environmental activist Mark Lynas renounced his opposition to genetically modified crops in a frank address to the Oxford Farming Conference. Lynas’s conversion to the GM cause was not entirely unexpected: he had shown signs of wavering in an article in New Statesman in 2010, titled ‘Why We Greens Keep Getting it Wrong’. Early in 2012, he published an article advocating the use of nuclear power to reduce carbon emissions and climate change, and in September published another saying that, without nuclear power, the battle against global warming was as good as lost. In his Oxford address, Lynas apologised for his involvement in vandalising field trials of GM crops and criticised organisations with which he had previously been associated, including Greenpeace and the organic farming lobby group, the UK Soil Association. He admitted that before 2008 he had never read a peer-reviewed paper on biotechnology or plant science. He explained that anti-science environmentalism had become increasingly inconsistent with his pro-science environmentalism on the issue of climate change. With uncanny prescience, given the recent meteoric blast in Russia, he said: “You are more likely

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to get hit by an asteroid than to get hurt by GM food.” Lynas was as formidable an opponent of GM agriculture as is his durable Australian counterpart, expatriate New Zealander Bob Phelps. Phelps, director of Gene Ethics, has been an environmental activist since the mid-1970s, and an implacable opponent of genetically modified organisms since the early 1980s. What chance that Phelps, or his Western Australian ally Julie Newman, of the Network of Concerned Farmers, will renounce their opposition GMOs? Keith Alcock, retired director of agricultural research in the Department of Agriculture and Food Western Australia under the anti-GM Labor Government of Geoff Gallop, doubts it. “We were conscious that there would be challenges in getting the GM crops message across,” said Alcock. “Clearly, the general public would find it hard or even impossible to comprehend the science, or it just didn’t want to know and hoped it would go away. “People prefer not to have pesticides on their food but, given that this is impossible, they simply prefer not to know about it. Few understand what a huge challenge it is to feed the world, and that it’s going to become harder and harder each decade as the global population increases, even as the area of arable land declines through salinity, desertification or urban sprawl.

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“We knew the best answer was a GM trait that had consumer benefits that could be sold to the public, but the trouble was we didn’t have any at the time. But what we had were insect-resistance traits that massively decreased the need for insecticide spraying in Australian cotton and herbicide-tolerant canolas that could greatly reduce herbicide use.” The Liberal Government of Colin Barnett eventually ended WA’s ban on GM crops in 2006, and the state is now Australia’s largest producer of GM herbicide-tolerant canola. A common criticism of GM crops is that they provide no benefit to consumers, only risk. But the argument did not prevent Greenpeace activists making a nocturnal raid on trial plots of a GM wheat with modified starch for improved nutrition at CSIRO’s experiment farm near Canberra, in July 2011. LOW GI STARCH

Developed by CSIRO’s Plant Industry researchers, the wheat is engineered to produce low glycaemic index starch, with potential benefits for bowel health and reducing the risk of type 2 diabetes. CSIRO is also close to commercialising oilseed crops engineered to produce high levels of omega-3 polyunsaturated fatty acids (PUFAs) in their seeds. Currently, omega-3 PUFAs are extracted from marine fish, a shrinking global resource. Omega-3 PUFAs are essential for human health, playing crucial roles in the development of the brain and visual system in the embryo and in maintaining cognitive function and optimal metabolism through life. While such developments offer direct benefits to consumers, Australian plant biotechnology research institutions are well advanced on developing GM crops that will defend themselves against fungal pathogens and parasites. If they provide less obvious benefits to consumers, they promise tangible benefits to farmers and to global food production, as the planet’s human population careers towards a peak of 9 billion-plus by 2050. Root-lesion nematodes (Pratylenchus spp) are part of a $120 billion problem for global agriculture caused by nematodes that attack a wide range of horticultural crops and field crops like cereals, legumes, beets and canola. Mike Jones, Professor of Agricultural Biotechnology at Perth’s Murdoch University, says root-lesion nematodes are an increasing problem for grain farmers who have adopted zero-till systems. Jones has exploited the discovery of RNA-induced gene silencing in the nematode Caenorhabditis elegans by US Nobel laureates Andy Fire and Craig Mello, to develop prototype crops that are resistant to root lesion nematodes. In 1997 Mello and Fire observed that small molecules of RNA could suppress the activity of target genes in C. elegans via the phenomenon now known as RNA interference. By injecting the nematode with single-stranded RNAs complementary to the messenger RNAs of a target gene, they were able to silence the target gene. The interference effect eventually diffused from the original cell through the nematode’s body, silencing the target gene in all of its 959 cells. “We’ve been doing deep sequencing of the transcriptomes of root-lesion nematodes and comparing them with the transcriptome of C. elegans, looking for genes we can knock down with RNA

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interference,” Jones says. “Plant nematodes have been very much a neglected subject in crop research. But fortunately, science chose C. elegans as the model multicellular organism for the first genome project, and around 700 laboratories in 33 countries have worked on it, so it’s the best annotated and understood genome of any multicellular organism, and a fantastic resource for comparative genomics research on plant nematodes. “We’ve been able to identify a variety of target genes that, when silenced by RNA interference, prevent root-lesion nematodes completing their life cycle. By modifying plants to express small RNA molecules that target these genes, we can make them resistant to the nematodes.” According to Jones, there are various ways to make crops resistant, such as locking the nematode out of the host plant’s roots or producing small interfering RNAs in the cytoplasm of the cell that will be ingested when the nematode feeds on the plant’s roots. This use of RNA interference to protect crops against root lesion nematodes is a world first. Other Australian and overseas researchers are attempting to develop RNA-interference systems that will protect crops against insect pests, including aphids, which also spread plant viruses that can severely reduce the productivity of plants. The sap-sucking habits of aphids that make them such effective transmitters of plant viruses, also make them highly vulnerable to gene-silencing RNAs expressed in sap.

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BIO 2013 PREVIEW | AGBIOTECH

STACKED TRAITS

The attraction of ‘stacking’ traits mediated by RNA interference is that it exploits a natural mechanism that operates in all plants, and in all higher life forms. The fact that RNA interference is a natural mechanism that switches off gene expression should make transgenic crops exploiting the technology more acceptable to regulators and less targeted by anti-GM activists. Much of the opposition to transgenic crops has centred around the supposed health risks associated with ‘contamination’ by transgenic proteins, like the Bt proteins used to confer resistance to chewing insects in crops like cotton and maize, and herbicide-resistant proteins in canola and soybean. The GM-shy nations of the European Union have introduced laws specifying that ‘contamination’ of conventional produce by transgenic proteins must not exceed 0.9%. The choice of a 1% threshold was entirely arbitrary and not indicative of any scientifically verifiable risk. For EU nations that provide large subsidies to farmers, it serves as a non-tariff barrier to imports from nations that grow GM crops. Anti-GM activists in the EU regard any level of ‘contamination’ as unacceptable and continue to lobby for a zero-tolerance policy. At Melbourne’s La Trobe University, Professor Marilyn Anderson is leading Hexima’s research into natural anti-fungal proteins in plants to develop transgenic maize varieties that will be resistant to a variety of economically important fungal pathogens. Hexima is a biotechnology that developed from basic research conducted in biochemistry at La Trobe University and botany at the University of Melbourne. Maize is still a minor crop in Australia, but has overtaken wheat and rice as the world’s most important cereal crop. At least 10% of global production is lost to fungus diseases. “Maize is such a huge crop that, if we are successful at reducing disease, even a 5% increase in productivity will significantly benefit global food and biofuel production,” Anderson says. Maize breeding is a big industry in its own right in the US, and seed companies invest heavily in developing varieties with new or improved traits. Maize varieties with Bt genes that protect against European corn borer and maize root worm were among the first transgenic crops grown in the world, and transgenic varieties so dominate the modern industry that anti-GM activists in North America ignore them. All these factors make it attractive for Australian plant molecular geneticists to develop transgenic maize with traits that could benefit the US-dominated global maize industry. Maize can act as a test-bed for new types of transgenes, like genes that could one day be repatriated to Australia to protect local staples like wheat and canola against fungus attack. America’s largest producer of hybrid crop seeds, Dupont Pioneer - formerly Pioneer Hi-Bred, is a major partner of Hexima’s research. Hexima has built a biosecure greenhouse and tissueculture facility on the La Trobe University campus to generate, grow on and evaluate maize lines containing anti-fungal transgenes. Early on, Anderson’s group focused on the natural antibiotics in plant floral tissues which protect the valuable sexual

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The new $100 million La Trobe Institute for Molecular Science (LIMS) was officially opened in February of this year and includes 34 research and support laboratories and the latest equipment for conducting biotechemistry and genetics work.

tissues from damage by fungal pathogens; even in susceptible crop plants, fungi often do not infect reproductive tissues. The La Trobe team had to learn how to make transgenic maize, using Pioneer’s high-efficiency protocols. “In less than three years we attained the same level of efficiency as Pioneer, which has been making transgenic maize lines for years,” she says. “It’s plant transformation on a scale far beyond anything that you would see in a typical research setting. We had to build a tissueculture factory, as well as the greenhouse, and start pumping genes through. We created our 10,000th transgenic maize line last August.” Without giving away proprietary secrets, Anderson says her team has widened its search for anti-fungal compounds, and most transgenic lines contain pairings of different transgenes, because ‘stacking’ compounds yields synergies resulting in levels of protection that would not have been predicted from the simple additive effects of two compounds. The reduced fungal infections due to such synergies yield a double benefit: increases in yield, at reduced cost, and greatly reduced levels of potentially carcinogenic compounds such as aflatoxins, which are a major cause of deaths from liver cancer from grain stored in crude village silos in Africa. Anti-GM activists would face a moral dilemma if they sought to argue against transgenic proteins that actually protect humans against long-term damage to their health, by warding off diseases that contaminate dietary staples in developing nations against potent liver toxins. The debate over the safety and efficacy of GM crops will likely long outlive the scientific research that settles their safety and efficacy. However, the more individuals, such as Lynas, who can be encouraged to engage with the science, the greater the awareness of the true costs and benefits of GMOs. And despite the public resistance from some quarters - and some governments - the science will continue to develop new crops with improved characteristics and nutrition profiles. ALS

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BIO 2013 PREVIEW | AUSTRALIAN BIOTECHS

Delayed

reaction 2012 wasn’t the breakthrough year many were expecting for Australian biotechs, but 2013 could be. Tim Dean

t was a year of great expectations. 2012 saw a second wave of Australian biotechnology companies about to break, with a new generation of ‘major minors’ close to turning the corner and turning a profit. Instead, where the start of the year enticed, the second half disappointed. A number of high-visibility setbacks and a flagging stock market midyear took the edge off the sector’s eager anticipation of a watershed year. However, a disappointing 2012 is not necessarily a sign of weakness in the life sciences sector, but rather a reminder of the volatility that is intrinsic to it. The setbacks through the year and into early 2013 have also not necessarily stalled progress, only delayed it. As such, 2013 could be the year that the sector has been waiting for since the arrival, and lingering, of the global financial crisis in 2008. This is not to suggest that 2013 is expected to be smooth sailing. There are a number of entrenched factors that threaten to keep the industry on its toes, not least of which is the unpredictability inherent in dealing with regulators, along with

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an unprecedented political climate in Australia culminating in an election, the outcome and implications of which is anyone’s guess. 2013 looks to be yet another turbulent year, and another where life science companies will have to battle a headwind in order to make significant progress. Yet, should they prevail, 2013 could be the breakthrough year the sector has been waiting for. SPEED BUMPS

Many of the expected star performers in early 2012 were struck by a stark reality check in the back end of the year. One such was Starpharma, which is developing its dendrimer nanotechnology platform to enhance the effectiveness of a wide range of compounds. Starpharma’s strength is that it is not bundling all its eggs into only a handful of drug candidates but developing a platform with a broad range of applications, from treating infections to enhancing anticancer drugs, to boosting the effectiveness of agrichemicals. However, it still needs to visibly demonstrate to the market its platform’s effectiveness through a flagship product, which in this case is VivaGel, a treatment for bacterial vaginosis. After a string of positive news in the second half of 2012, Starpharma received a blow when the results of the largest yet phase III trial of VivaGel failed to reach its primary end point in late November last year. While there was mention of possible irregularities in the trial, the fact remains that the Food and Drug Administration (FDA) is unlikely to be persuaded to give the go-ahead for VivaGel without additional data, or a shift in indication, which is being explored. While VivaGel remains in limbo for the time being, the company does have its wider portfolio, which is progressing thanks to partnering arrangements signed last year. Another star performer in recent years in Pharmaxis, which has taken its treatment for cystic fibrosis, Bronchitol, from spark of an idea right the way through to manufacturing and marketing approval here in Australia and in Europe. 2012 was an auspicious year for the company, with it seeing Bronchitol launched in Europe, the National Institute for Health and Clinical Excellence in the UK recommending it for reimbursement under the National Health Service, and a listing on the Pharmaceutical Benefits Scheme back home. Pharmaxis is a great Australian biotechnology success story, although that image was tarnished somewhat in January this year by a negative recommendation from the committee advising the FDA on its approval in the US. Pharmaxis’s stock went from $1.25 to 64c overnight following the news. The recommendation brought with it the prospect of running new trials to hone in on the dosage and details of treatment, which could be a costly exercise. That said, Pharmaxis remains in a strong cash position - as it has done throughout the GFC - and is still working aggressively to achieve marketing approval in the US. One company that appeared to be a relatively safe bet (if there exists such a thing in this industry) was QRxPharma. Instead of dragging an entirely novel compound through the regulatory process, QRxPharma is taking two already approved drugs - the

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opiates morphine and oxycodone - and combining them at a 3:2 ratio, with trials showing good efficacy with lower side effects than conventional opiates. Its first formulation, MoxDuo IR (immediate release), hit a roadblock in June last year when it received a Complete Response Letter from the FDA, which was unsatisfied with the data provided showing MoxDuo is safer or more effective than its two component opioids used in combination. QRxPharma is in the process of refiling its New Drug Application and expects a decision from the FDA in Q3 of this year. Another blow to the sector came as Alchemia failed to excite investors in its cancer arm, which it was seeking to skive off into a new company, Audeo Oncology. Alchemia is also behind fondaparinux, which is a generic version of GlaxoSmithKlein’s injectable anticoagulant, Arixtra, which is being marketed in the US by Dr Reddy’s. With fondaparinux bringing in greater revenues, and the oncology arm consuming greater resources, management was partial to the idea of keeping the two at arm’s length. However, in December last year, Alchemia pulled the plug on the demerger - or “deferred” it, as it has stated since - citing insufficient interest and concerns from investors over the timing and market conditions. The company continues trials of HA-Irinotecan to treat metastatic colorectal cancer, with results expected in 2014. Other biotechs also experienced setbacks, including the otherwise impressive ImpediMed, which posted a $12.3 million loss in the first half of FY2013 and shed 85% of its share price over that period. Immuron also lost 80% of its share price, posting a $2.3 million loss in 1H of FY13 and predicted a negative cash flow for the year. HURDLES

That’s quite a list of sour news, although as Manoj Santiago from PricewaterhouseCoopers points out, it’s not all unexpected. “From another angle, it is a reaffirmation of what companies in this sector face and the challenges they have to go through,” he says. “In the past, such challenges have proven to be a great way for companies to go on to bigger and better things. So it can be seen as a setback or as a stepping stone where they can end up with a better offering in the long run. It is also a wakeup call for anyone who thought these companies were going to be overnight sensations.” The year was also not without its environmental hazards. Besides the ongoing debt crisis in Europe and the self-inflicted budget crisis in the United States, the Australian economy also flagged midyear. The All Ordinaries showed promising signs early in 2012 but fell backwards around May, finally recovering and ending the year around 500 points up on its start. The life science index, as it has been in the past, was a twohorse race, with the ‘majors’ (CSL, ResMed and Cochlear) performing strongly, particularly towards the back end of the year, while the ‘ex-majors’ (ie, everybody else) underperformed the broader All Ordinaries.

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According to AusBiotech CEO Dr Anna Lavelle, biotechs also had to face uncertainty in the policy sphere as well. While the introduction of the R&D Tax Incentive was seen as a great boon to the sector, with it returning at least $28 million particularly to cash-hungry, early-stage companies, the rest of the policy story is less positive. Much of this appears to be driven by federal Labor’s penchant for reviews. “In the last three to four years we have had a huge number of reforms and reviews,” says Lavelle. “The volume of reforms and reviews is such that even the larger companies can’t keep track of it all.” She cites the Therapeutic Good Administration (TGA) blueprint reforms and the Australia New Zealand Therapeutic Products Agency (ANZTPA) harmonisation and the ongoing reviews into gene and biological patents. All these are contributing to the bureaucratic overhead that biotechs face and increase uncertainty over what the policy landscape might look like in years to come. Add to that a looming election in September of this year which only elevates the unpredictability of policy. LOOKING UP

That’s not to say it is all bad news. In fact, Labor has enacted some reforms that have been welcomed by the sector, such as the R&D Tax Incentive - although the occasional murmurs that the scheme might be altered or scrapped have left a few CEOs and CFOs on edge.

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“It is also a wakeup call for anyone who thought these companies were going to be overnight sensations.” Labor’s jobs plan, announced in February, also made a $9.9 million commitment to “fast track” the recommendations of the Clinical Trial Action Group Report from 2011, which should streamline trial approval and recruiting processes. It also promised more cash for the Innovation Investment Fund and a vision to establish up to 10 Industry Innovation Precincts. Several life science companies also managed to beat the odds and had stellar years in 2012. CSL underwent a company restructure of its local operations, lumping its plasma operations under the banner of CSL Behring and placing the vaccines, pharmaceuticals and in vitro diagnostics under bioCSL. The company also managed to bring in healthy profits and hit a string of record share prices. However, the departure of longstanding CEO Dr Brian McNamee will mean investors will keep a close eye on the company and how it is steered by incoming CEO Paul Perrault, who takes the big chair in July. ResMed is also breathing easy after a cracking year, with strong revenue increases even with the high Aussie dollar. It, too, saw a change of leadership, with Dr Peter Farrell’s son, Mick Farrell, taking the reins on 1 March this year. Another star performer was Sirtex, which has been beavering away selling its SIR-Spheres for the treatment of liver cancer. Profits for 2011-2012 were up 49% and the first half of FY2013 looks to be going strong, with a 25% lift in revenues over the period. As a result, the company is in a stronger cash position and its share price soared a dizzying 193% through the 2012 calendar year. While IPOs remain as rare as hen’s teeth, financing does appear to be slowly rebounding following a few anaemic postGFC years, and the R&D Tax Incentive is taking some of the pressure of start-ups funding the pivotal proof-of-concept trials needed to attract funding. There is also the prospect of more acquisitions this coming year as more companies mature. However, one feature of the coming 12 months will be continued volatility, says Lavelle. Although, on the up side, many of the companies that encountered setbacks last year may finally break through in 2013, thus turning the tide of confidence and bad news. One thing to watch out for in 2013 and 2014 will be the next wave of biotechs, says Santiago. The GFC saw a great deal of start-up funding evaporate. Yet research has continued, and there are likely to be many terrific discoveries that are ripe for commercialisation just waiting to hit the market. 2012 was hardly the year the life science sector had been hoping for, but amongst the setbacks and the continued economic and policy instability, there are still the seeds of success just waiting to sprout. On the whole, the sector is in much the same position it was in 12 months ago, with the same challenges and opportunities, and with the same prospects of breakthrough success in 2013. ALS

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HUNTER MEETING REVIEW | CELL BIOLOGY

Family

affair

Associate Professor Ruth Arkell is revealing the mysteries of the ZIC family of genes, which have been coordinating the development of the nervous system in vertebrate embryos for hundreds of millions of years. Graeme O’Neill

he ZIC family of genes has been a team through time and tide since Adam was a teleost fish around half a billion years ago. Their role throughout this stretch of time has been to collectively shape the nervous system during very early embryonic development. The question is: have the five genes that code for ZIC proteins been conserved over this enormous time span because they are functionally interdependent? And if so, how do they interact? Australian National University molecular embryologist Dr Ruth Arkell spoke about her work investigating this mystery at the 13th annual Hunter Meeting in March. According to Arkell, modern fish have seven zic genes, two more than

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their land-going descendants. That’s unusual, given that the modern vertebrate genome is thought to have arisen when the entire genome of a direct fish ancestor of vertebrates was doubled, then redoubled, before the first tetrapod vertebrate made landfall some 400 million years ago. In humans, the genes are spread around. We have two tandem pairs of ZICs on chromosomes 3 and 13, while the unpaired gene is on the X-chromosome. But that’s not necessarily odd; in some strains of Drosophila even the ancient Hox body-segmentation genes, which are conserved in four co-linear clusters on different chromosomes of species as divergent as insects and mammals, have been separated and scattered across the

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fly genome with no apparent effect on embryonic development. “The highly conserved, co-linear linkage of the Hox genes was thought to maintain tight control over the timing and spatial pattern of expression,” says Arkell. “But apparently, it doesn’t have to be like that.” However, while mouse Zic genes exhibit overlapping patterns of expression that recapitulate their genomic arrangement, Arkell has wondered for a long time whether there’s more to their durable linkage than conserved expression. Her team’s research indicates they may indeed be linked by function. They have worked on three of the mammalian ZIC genes - the ones expressed at a critical stage of embryogenesis called

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CELL BIOLOGY | HUNTER MEETING REVIEW

gastrulation - the paired ZIC2 and ZIC5 genes, and the unpaired ZIC3. These are all of interest seeing as they are closely linked to a range of developmental disorders. ZIC5 is of interest because of its association with ventricular defects in the brain and hydrocephalus. ZIC2 defects are associated with a rare and usually lethal congenital disorder called holoprosencephaly, in which the embryonic forebrain remains undivided instead of forming two hemispheres. At an extreme, holoprosencephaly results in cyclopia, an unsettling congenital defect where the face is absent and the skull develops a single orbital cavity on the midline of the skull. “In humans the frequency of holoprosencephaly at birth is around one in 10,000, and only one in 16,000 babies with the condition survives the immediate post-natal period,” she says. “But while holoprosencephaly is very rare at birth, the frequency during early embryogenesis is very high: about one in 250.” ZIC3 defects are associated with another congenital disorder called heterotaxy, characterised by disordered development of usually asymmetric body organs such as the heart, the lungs and the kidneys. These disease associations are likely only just the tip of the iceberg when it comes to defining the role of the ZIC proteins in embryonic development and adult homeostasis. CUMULATIVE EFFECTS

According to Arkell, one of the things we tend to forget is that the effects of genetic defects tend to be cumulative over time. “A subtle gene defect may at birth be of little consequence, causing only an unrecognised weakness or susceptibility in some aspect of cell function. Then feedback mechanisms may amplify the effect through life, resulting in the onset of serious disease later in life. “One of the most exciting aspects of the new genomics capabilities is that we will be able to link mutations in genes that give rise to subtle functional differences to diseases. Already the first inklings of ZIC involvement in adult onset diseases are beginning to emerge. “The Hunter Meeting is about cell biology, not embryology, so I talked about the way in which ZIC proteins appear

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Associate Professor Ruth Arkell and her team. Back row (from left): Helen Bellchambers; Koula Diamond; Ruth Arkell; Abby D’Cruz. Front row (from left): Radiya Ali; Kristen Barratt; Alaa Alzahrani; Jehangir Ahmed.

“The highly conserved, co-linear linkage of the Hox genes was thought to maintain tight control over the timing and spatial pattern of expression. But apparently, it doesn’t have to be like that.” to be able to switch from their roles in transcription, to become co-factors in gene suppression.” Arkell’s talk particularly focused on her team’s investigation of the mechanisms behind ZIC’s Janus faces. “Posttranscriptional modification of the proteins seems to be involved, and we think the modification involves a modification called SUMOylation,” she says. SUMO refers to small ubiquitin-like modifier. Small molecules of ubiquitin ‘tag’

lysine residues of other proteins, directing them to a variety of cellular fates, including the proteasome, where they are recycled. Small SUMO molecules - those around 10 kilodaltons - modify the activity of proteins by targeting the same lysine residues as ubiquitin. SUMO, also like ubiquitin, forms chains by ‘tagging’ itself. Ubiquitin, as its name suggests, is ubiquitous in cells, and its multiple functions are now reasonably well understood. But SUMO’s workings are a

Associate Professor Ruth Arkell heads the Early Mammalian Development Laboratory in the Australian National University’s Research School of Biology. In 2000, she received a UK Medical Research Council Development Award and established a research group in Oxfordshire to study gene function in gastrulation in mouse embryos. After moving to the ANU in 2006, she received an AustraliaNew Zealand Young Investigator Award in 2009.

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HUNTER MEETING REVIEW | CELL BIOLOGY

The change is catastrophic for the orderly development of the cranial neural tube, which forms the central nervous system, and the neural crest, which forms the peripheral nervous system. SUMOYLATION ERROR

A mouse with hydrocephaly due to mutation in Zic5.

long way from being understood. “The activity of every transcription factor is likely to involve SUMOylation in some way,” she says. “But SUMOylation also seems to be associated with almost every type of cellular change one could imagine. “We’ve been working primarily on SUMOylation of ZIC5, because we have identified a mouse strain in which the alteration of one amino acid produces a phenotype that resembles complete loss of

function of ZIC5 in human hydrocephalus.” The mutation, at the third position a wild-type lysine codon, changes it to an arginine. “It’s is about as conservative a change as you can get in a protein, because lysine and arginine have the same size and charge, and you would think it would be a silent mutation. Yet, in the whole mouse genome, this conservative change in just one amino acid, it partially abolishes ZIC5 function.”

ZIC'S ROLE IN CANCER

According to Arkell, the functional redundancy of the ZIC genes has hampered studies of the networks they regulate: knock out one ZIC and the others tend to compensate, in varying degrees, for its absence. However, loss-of-function mutants in mice exhibit a range of phenotypes that hint at their involvement of ZIC genes in multiple signalling pathways - including cancers in which Wnt signalling defects are known to be involved. Wnt signalling defects have also been implicated in a variety of cancers. In a paper in the International Journal of Biochemistry and Cell Biology last year, Arkell and ANU colleagues Radiya Ali and Helen Bellchambers suggested that in addition to causing a range of congenital disorders in mice and humans, the involvement of ZIC genes as factors or co-factors in maintaining pluripotency in stem cells hints at a possible a role in cancer. They note that dysregulated Wnt signalling is associated with a growing range of cancers. In particular, mutations that affect Wnt signalling are associated with more than 90% of colorectal carcinomas. The ANU researchers suggested that an understanding of the mechanisms of ZIC-mediated Wnt inhibition may lead to new ways of preventing the uncontrolled proliferation of cancerous cells.

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Arkell believes that post-translational SUMOylation of the wild-type lysine residue at that position is essential for the protein to perform its normal function as a transcription activator. The substituted arginine residue prevents SUMOylation at that position, and the protein becomes an inhibitor, repressing downstream gene networks that ZIC5 would normally activate. The resulting, partial abolition of ZIC5 function disrupts development of the central and peripheral nervous systems. Could SUMOylation and the apparent alteration it brings in ZIC protein function be part of the reason the ZICs have stuck together? “We have evidence from lots of mutational studies in mice that the ZIC proteins somehow regulate the expression levels of their linked partners,” says Arkell. “In this scenario, we usually think of the proteins as being able to cross-regulate each other’s transcription. But we wonder if, in the case of the ZICs, the genetics can be explained by the proteins crossregulating each other - rather than their level of expression. “One way that a protein can regulate a related protein’s function is by dominantnegative interference, which involves the two protein forms competing with each other. For example, many genes produce transcripts that are alternately spliced to produce proteins of different size. In some cases a shorter, or truncated, version of the protein can compete with and decrease the function of the fulllength protein.” Arkell suggests that, in the case of the ZIC proteins, the non-SUMOylated form of the protein may act as a dominant negative, preventing the SUMOylated form activating gene expression. Co-expression of the linked proteins, along with differential SUMOylation, may allow the two proteins forms to regulate each other’s activity. ALS

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HUNTER MEETING REVIEW | STEM CELLS

Balancing

act

Fiona Wylie

Dr Robin Hobbs got off to a stellar start with a breakthrough finding published in Nature. Now he’s continuing to investigate a delicate balancing act that occurs within stem cells in the testis.

y the very nature of scientific research, which often mimics the convoluted and complex pathways it studies, many scientists end up following a circular research route, often unintentionally and usually over the span of many years. Dr Robin Hobbs, a relatively new addition to the Australian Regenerative Medicine Institute (ARMI) at Monash University, managed to do it within a year or so of finishing his PhD, and rather spectacularly at that, with a landmark finding published in Nature Genetics. After undergraduate studies at the University of Oxford, Hobbs completed his PhD at University College London in 2003 under the guidance of stem cell guru Professor Fiona Watt. He then moved fields and countries to take up a postdoc first at Memorial Sloan-Kettering Cancer Center, then at Harvard Medical School, with Professor Pier Paolo Pandolfi, a leader in the field of cancer genetics. There he planned to work on the molecular mechanisms underlying leukaemia. However, he was immediately thrust straight back into the world of stem cells with his first major experimental finding. Characteristic of many scientific breakthroughs, Hobbs serendipitously managed to identify one

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of the first transcription factors needed to regulate germ-line or spermatogonial stem cells in the mouse testis. When Hobbs joined the Memorial Sloan-Kettering Cancer Center lab in New York as a postdoc in 2003, the team there was working on the transcription factor promyelocytic leukaemia zinc finger (PLZF) because of its reported association with chromosomal abnormalities in rare cases of leukaemia. “We wanted to model the human disease, so we made a PLZFknockout mouse in the hope of seeing leukaemia or some sort of solid tumour develop,” says Hobbs. “However, one of the most striking phenotypes of this mouse was actually male infertility. We saw a loss of germline stem cell self-renewal capability in the knockout mice followed by a progressive depletion of germ cells and, eventually, infertility.” Hobbs subsequently found that while expressed at moderate levels in haemopoietic cells, PLZF is expressed strongly in the spermatogonial stem cells in the testis in both mouse and human, making these stem cells his new obsession. Maintenance of a wide array of adult tissues is dependent on a resident population of stem cells that must self-renew and generate differentiating daughter cells. However, at that

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STEM CELLS | HUNTER MEETING REVIEW

time, very little was known about how the mitotic spermatogonia of the testis manage to continually self-renew and differentiate into sperm over much of the adult lifetime. Even less was known about the testis-resident stem cells that generate differentiating spermatogonia, the spermatogonial stem or progenitor cells (SPCs). “This pool of cells within the testis is required for lifelong maintenance of the male germ line cells and, of course, for maintaining fertility,” he says. “SPCs have all the typical characteristics of adult stem cells: they reside in the tissue; are able to self-renew; have a high proliferative potential; and are able to generate differentiating spermatogonia, which then go on through meiosis to generate

“One of the most striking phenotypes of this mouse was actually male infertility. We saw a loss of germline stem cell self-renewal capability in the knockout mice followed by a progressive depletion of germ cells and, eventually, infertility.” sperm. These stem cells are also heavily dependent on their unique niche within the testis.” CULTURED CELLS

Based on this new and exciting finding about the life and times of SPCs, and building on the few other reports of factors needed for SPC growth, Hobbs spent the rest of his postdoc studies developing a mouse testis model system for isolating, growing and maintaining his new favourite cells in culture so they could be studied further. Due to the work of a number of pioneers in the germ cell field, including Hobbs, SPCs could now be grown and monitored for relatively long periods of time - up to one year - under highly specialised cell culture conditions while still maintaining their full developmental potential. At the time, this technical advance made the testis stem cell model unique among the commonly studied adult stem cell systems such as bone

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marrow, neural or skin. “We ended up with a very useful system for studying stem cells,” says Hobbs. Primarily, the cell culture model allows scientists to interrogate SPC behaviour and regulation by in vitro techniques such as biochemistry that require large numbers of cells. “Then, at any time, we can assess the stem cell potential in vivo by transplanting the cultured cells back into recipient mouse testis, which have been depleted of endogenous germ cells, and looking for differentiation into sperm. So you have a very nice in-built assessment of your cells in culture.” Hobbs continued to develop these experimental systems to purify and culture the SPCs through his postdoc years as a critical part of finding out more them. He also hoped to identify novel functions of PLZF and other gene regulators that could then potentially be translated into other adult stem cell systems important to human disease. According to Hobbs, while the PLZF finding was undoubtedly important,

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it really was just a very simple observation of an unexpected role in male germ cell differentiation, and just the start of finding out what makes the SPC system tick. One of the central questions for Hobbs to address was how the SPCs integrate all the signals in the testis. Some tell them to keep self-renewing and maintaining the stem cell pool while others tell them to get on with the job of differentiating into sperm. Indeed, this is a question of importance to all adult stem cell systems. “The appropriate control of stem cell self-renewal and differentiation is critical for tissue homeostasis while disruption of the balance between these processes can contribute to tissue degeneration or cancer,” he says. “Using our testis model and the PLZF knockout mice, we then went on to identify

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HUNTER MEETING REVIEW | STEM CELLS

Dr Robin M Hobbs is a pioneering young researcher in the germ cell field. He recently relocated from Beth Israel Deaconess Medical Center associated with Harvard Medical School in Boston and has a joint appointment with Monash Immunology and Stem Cell Laboratories and the Australian Regenerative Medicine Institute (ARMI). His research is supported by NHMRC funding and by a Monash University Larkins Fellowship.

a couple of key downstream targets of PLZF in the SPCs that are important in regulating their function,” says Hobbs. “One of these turned out to be a signalling pathway pivotal to cell growth, the mTORC1 complex.” mTORC1, or the mammalian target of rapamycin complex 1m, was the topic of his talk at the Hunter Meeting. mTORC1 is a large and ubiquitously expressed signalling complex that promotes protein translation and, through this, controls multiple cellular functions including organelle synthesis, metabolic and biosynthetic pathways, and energy use by the cell. “Basically, mTORC1 controls most of the key pathways needed for cell growth. If you activate mTORC1, the cells grow. Upstream, mTORC1 integrates a whole variety of signals, so it is turned on in response to many different stimuli that a cell faces including nutrient availability, energy status, growth factors and cellular stress.” In other words, the mTORC1 pathway, and therefore cell growth, is turned off in conditions that are not favourable, such as stress, but turned on in the good times, when nutrients are plentiful and the right growth factors are present. Thus, mTORC1 controls the pivotal cell question of whether or not to grow. KEEPING THE BALANCE

This complex is well studied and is dysregulated in many human illnesses, particularly cancer and metabolic disease, which is not surprising given its pivotal

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role in the cell. “Importantly for my work, mTORC1 is also very important for stem cell function, which has been increasingly recognised in the last few years,” says Hobbs. If you aberrantly activate mTORC1, inevitably this is detrimental to maintenance of the stem cell pool. It is easy to imagine that anything that strongly promotes cell growth is bad for keeping stem cells in their place, so to speak, and eventually you get depletion of the population. “So, it is critical to correctly regulate mTORC1 in the SPC system.” What Hobbs found in his knockout mice lacking PLZF expression was abnormally high mTORC1 activity in the SPCs. In trying to find out why this was happening, he showed that PLZF could transcriptionally regulate some of the upstream regulators of the mTORC1 pathway. In other words, PLZF indirectly regulates mTORC1 signalling to control cell proliferation. The next questions Hobbs and his colleagues addressed were why is it bad to have aberrant activation of mTORC1 in the SPCs, and whether they could develop models to correlate the perturbed signalling activity with the effects on stem cell maintenance and fertility. A key observation in answering these questions was that high levels of mTORC1 activity activates negative feedback effects and inhibits the cell’s response to a crucial growth factor, glial cell-derived neurotrophic factor (GDNF). This factor

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is secreted by other cells within the testis niche and is absolutely required by the SPCs for self-renewal and growth. Indeed, SPCs cannot grow in culture without GDNF. “So, we found that PLZF promotes SPC self-renewal through its ability to inhibit mTORC1, and in doing, increase the sensitivity of the cells to GDNF. In this context it could be an important mechanism to maintain stem cell homeostasis, ultimately to balance growth against selfrenewal and maintain the pool of stem cells within the testis.” Now based at ARMI in Melbourne, and with the mTORC1 findings published in Cell in 2010, Hobbs is continuing his search for other downstream targets of the mTORC1-PLZF axis in SPCs. He is interested in finding out how mTORC1 can control signalling through the GDNF receptor pathway and the effects of this on stem cell function. “I also want to further explore the crosstalk between the different targets of mTORC1 and identify those co-regulated by PLZF and other genes to control cell fate. At some level everything talks to each other and it is just a question of working out what is required and what is not.” An important conclusion in terms of translating these findings, according to Hobbs, is that changes in mTORC1 activity can change cell fate. “For example, if you have high activity the cells can differentiate as opposed to self-renew. So inhibitors to the TORC1 pathway might be one way to disrupt that balance and influence stem cell function to, for example, improve tissue regeneration. “Of course, the details are somewhat complex because a certain amount of mTORC1 activity is needed for normal cell growth, so you would need something like a treatment regimen that would partially or temporarily inhibit the signalling in a way that would change the fate decisions of these stem cells and leave them to selfrenew more, but then of course also allow them to grow and differentiate correctly. “I would also really like to start looking at whether these findings in the SPC system could be translated to other adult stem cell compartments, such as the haematopoietic system, back where I started.” ALS

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PERSONALISED MEDICINE | SMARTPHONE APPS

The rise smartphone of health and medical apps

Health and medical smartphone apps can help improve the management of acute and chronic conditions and provide more personalised medical treatment. Michael Sutton and Megan Fraser

ith the proliferation of mobile telecommunications devices, the smartphone apps market has created an ‘app economy’ heavily impacting on many industries. Healthcare is one of these industries, with the potential value of developing innovative smartphone apps to improve the management of acute and chronic conditions and provide more personalised medical treatment being realised internationally. Smartphone apps within the healthcare industry fall into two main categories: 1. Health apps 2. Medical apps Health apps do not require approval in Australia from the Therapeutic Goods Administration (TGA). These apps relate to the general health and wellbeing of the individual and involve non-invasive monitoring programs such as monitoring calorie intake.

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By contrast, medical apps can be utilised for the purpose of providing diagnostic tools and remote monitoring, and can include sensor-based applications. There are far fewer medical apps than there are health apps. Medical apps that make certain diagnostic or treatment claims (as opposed to just providing information) may be classified as medical devices, in which case they would require approval from the TGA before they could be marketed and sold. Medical apps can be designed to operate in collaboration with other devices, with the purpose of providing a medically beneficial outcome, for example: • Sanofi Aventis’s sensor-based iBGStar Diabetis monitoring app that measures blood glucose; • An insulin pump, where the app controls the delivery of insulin; • A blood pressure cuff, where the app

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controls the inflation and deflation of the cuff; • The AliveCor iPhone ECG, where the app allows for the measurement, storage and display of ECG signals; and • The Mobisante MobiUS, which allows for the miniaturisation of ultrasound devices and attaches a probe to show images on a smartphone screen. While numerous health and medical apps are available through marketplaces such as iTunes, certain medical apps (and particularly those that would be classified as a medical device) would more likely be privately distributed to relevant patients. THE MARKET FOR HEALTH AND MEDICAL APPS

In 2011 the global smartphone market for both medical and health apps was worth US$718 million and it is estimated by research2guidance that in 2012 that market

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SMARTPHONE APPS | PERSONALISED MEDICINE

was worth US$1.3 billion. The US Food and Drug Administration expects there will be 500 million smartphone users downloading healthcare-related apps worldwide by 2015. Despite this substantial growth, the market has likely got a long way to develop yet. This seems especially the case in relation to medical apps in Australia, as we are yet to see a medical app registered or approved as a medical device on the Australian Register of Therapeutic Goods (ARTG). By way of contrast, in the US there are approximately 75 ‘mobile medical apps’ that have received clearance from the FDA under section 510(k) of the Federal Food Drug and Cosmetic Act. Medical apps have the potential to risk public health where they are used for diagnostic and treatment purposes. For this reason, regulatory bodies oversee the safety and effectiveness of medical apps. In Australia, the TGA’s medical device regulatory framework provides for the regulation of medical device software, so a medical app with a therapeutic purpose would be held to the same level of scrutiny as other medical devices. This would cover any app that is intended to be used for the: • Diagnosis, prevention, monitoring, treatment or alleviation of disease; • Diagnosis, monitoring, treatment, alleviation of an injury or disability; • Investigation, replacement or modification of the anatomy or of a physiological process; or • Control of conception. In the US, the FDA is in the process of forming a specific policy to better regulate mobile medical apps. Once this is settled, Australian policy may take guidance from it and follow suit. DEVELOPING AND MARKETING SMARTPHONE HEALTH OR MEDICAL APPS

In Australia, any development of health or medical apps must be carried out with regard to four key areas: regulatory compliance, intellectual property, privacy and data collection, and marketing claims. When developing the app, consideration needs to be given to: • Compliance with the medical device standards in the Therapeutic Goods Act

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1989 (Cth) and the Therapeutic Goods Advertising Code; • The name and branding of the app; • Copyright ownership in the app’s underlying software code; • The patentability of the app; • The protection of the ideas underpinning the app prior to and during development; • Data security; • Privacy policies and the collection of sensitive information; and • Ensuring that all claims made regarding the app comply with the Australian Consumer Law and are not unsubstantiated or likely to mislead or deceive consumers. The health and medical claims that are permitted to be made about the app will depend on the registration status of the app under the TG Act. If registration as a ‘medical device’ in Australia is possible, more substantial claims will be permitted and this may give the app a distinct advantage over its competitors. With such a rapid increase in the use of medical apps, there will be an increase in the need to address the concerns associated with this technology, including the accuracy of information, diagnosis and treatment, says Eric Wicklund of Government Health IT. According to David Brill at the The Medical Observer, there is concern that some medical and health apps may make unsubstantiated claims, especially those purporting to be diagnostic. In those circumstances, the TGA would be able to take regulatory action as if the app were a medical device. The legal consequences of making unsubstantiated claims regarding treatment by using a medical app have been tested in the US. In one particular case the Federal Trade Commission commenced an action against three individuals for making unsubstantiated claims in relation to the treatment of acne with coloured light emitted from a smartphone. The individuals falsely claimed the treatment was supported by a study in the British Journal of Dermatology. The matter settled with the individuals paying a civil penalty and being barred from making claims about other medical devices without competent and reliable scientific evidence.

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Michael Sutton is a Senior Associate with DibbsBarker, a commercial law firm that advises the medical and pharmaceutical industry. He is a Certified Licensing Professional, specialising in technology licensing and competition and consumer law. Megan Fraser is a Lawyer at DibbsBarker, focusing on intellectual property and technology.

WHAT NEXT?

There is clearly a booming market for health and medical apps. Medical apps that make certain diagnostic and treatment claims will require approval from the TGA in Australia and will be held to the same level of scrutiny as other medical devices. Those that can stand up to that scrutiny have the potential to provide lucrative revenue streams that, not so long ago, would not have been envisaged. While there are clear advantages to being the first on the market, this should not be at the expense of neglecting the need for proper regulatory compliance, and the appropriate development and marketing of a health or medical app. It remains to be seen who will be the first to obtain registration of an app as a medical device in Australia, but it cannot be far away. ALS

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RESEARCH | SEQUENCING EXPLOSION

commandments ÂŠ iStockphoto.com/luchschen

for next-gen sequencing Geneticist Dan Koboldt from the Genome Institute at Washington University in St Louis gives his decalogue on nextgeneration sequencing. Dan Koboldt

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ust as the reach of next-generation sequencing (NGS) has continued to grow - in both research and clinical realms - so too has the community of NGS users. Some have been around since the early days. The days of 454 and Solexa sequencing. Since then, the field has matured at an astonishing pace. Many standards were established to help everyone make sense of this flood of data. The recent democratisation of sequencing has made next-gen sequencing available to just about anyone. And yet, there have been growing pains. With great power comes great responsibility. To help some of the newcomers into the field, Iâ&#x20AC;&#x2122;ve drafted these ten commandments for nextgen sequencing.

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SEQUENCING EXPLOSION | RESEARCH

NGS ANALYSIS

Thou shalt not reinvent the wheel. In spite of rapid technological advances, NGS is not a new field. Most of the current ‘workhorse’ technologies have been on the market for a couple of years or more. As such, we have a plethora of short read aligners, de novo assemblers, variant callers and other tools already. Even so, there is a great temptation for bioinformaticians to write their own ‘custom scripts’ to perform these tasks. There’s a new ‘Applications Note’ every day with some tool that claims to do something new or better. Can you really write an aligner that’s better than BWA? More importantly, do we need one? Unless you have some compelling reason to develop something new (as we did when we developed SomaticSniper and VarScan), take advantage of what’s already out there.

Thou shalt not coin any new term ending with “ome” or “omics”. We have enough of these already, to the point where it’s getting ridiculous. Genome, transcriptome and proteome are obvious applications of this nomenclature. Epigenome, sure. But the metabolome, interactome and various other “ome” words are starting to detract from the naming system. The ones we need have already been coined. Don’t give in to the temptation.

Thou shall follow thy field’s conventions for jargon. Technical terms, acronyms and abbreviations are inherent to research. We need them both for precision and brevity. When we get into trouble is when people feel the need to create their own acronyms when a suitable one already exists. Is there a significant difference between next-generation sequencing (NGS), high-throughput sequencing (HTS) and massively parallel sequencing (MPS)? Widely accepted terms provide something of a standard, and they should be used whenever possible. Insertion/deletion variants are indels, not InDels or INDELs DIPs. Structural variants are SVs, not SVars or GVs. We don’t need any more acronyms!

NGS PUBLICATIONS

These commandments address behaviours that get on my nerves, both as a blogger and a peer reviewer.

Thou shalt not publish by press release. This is a disturbing trend that seems to happen more and more frequently in our field: the announcement of ‘discoveries’ before they have been accepted for publication. Peer review is the required vetting process for scientific research. Yes, it takes time and yes, your competitors are probably on the verge of the same discovery. That doesn’t mean you get to skip ahead and claim credit by putting out a press release. There are already examples of how this can come back to bite you. When the reviewers trash your manuscript, or (gasp)

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“Simulations simply can’t replicate the true randomness of nature and the crap-that-can-go-wrong reality of next-gen sequencing.” you learn that a mistake was made, it looks bad. It reflects poorly on the researchers and the institution, both in the field and in the eyes of the public.

Thou shalt not rely only on simulated data. Often when I read a paper on a new method or algorithm, they showcase it using simulated data. This often serves a noble purpose, such as knowing the ‘correct’ answer and demonstrating that your approach can find it. Even so, you’d better apply it to some real data too. Simulations simply can’t replicate the true randomness of nature and the crap-that-cango-wrong reality of next-gen sequencing. There’s plenty of freely available data out there; go get some of it.

Thou shalt obtain enough samples. One consequence of the rapid growth of our field (and accompanying drop in sequencing costs) is that small sample numbers no longer impress anyone. They don’t impress me, and they certainly don’t impress the statisticians upstairs. The novelty of exome or even whole-genome sequencing has long worn off. Now, high-profile studies must back their findings with statistically significant results, and that usually means finding a cohort of hundreds (or thousands) of patients with which to extend your findings. This new reality may not be entirely bad news, because it surely will foster collaboration between groups that might otherwise not be able to publish individually. DATA SHARING AND SUBMISSIONS

Thou shalt withhold no data. With some exceptions, sequencing datasets are meant to be shared. Certain institutions, such as large-scale sequencing centres in the US, are mandated by their funding agencies to deposit data generated using public funds on a timely basis following its generation. Since the usual deposition site is dbGaP, this means that IRB approvals and dbGaP certification letters must be in hand before sequencing can begin. Any researchers who plan to publish their findings based on sequencing datasets will have to submit them to public datasets before publication. This is not optional. It is not “something we should do when we get around to it after the paper goes out”. It is required to reproduce the work, so it should really be done before a manuscript is submitted. Consider this excerpt from Nature’s publication guidelines: Data sets must be made freely available to readers from the date of publication, and must be provided to editors and peer-

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journal editors (and referees) haven’t always enforced. Just because you can scoop someone doesn’t mean that you should. It’s not only bad karma but bad for your reputation. Scientists have long memories. They will likely review your manuscript or grant proposal sometime in the future. When that happens, you want to be the person who took the high road. RESEARCH ETHICS AND COST

reviewers at submission, for the purposes of evaluating the manuscript. For the following types of data set, submission to a community-endorsed, public repository is mandatory. Accession numbers must be provided in the paper. The policies go on to list various types of sequencing data: • DNA and RNA sequences • DNA sequencing data (traces for capillary electrophoresis and short reads for nextgeneration sequencing) • Deep sequencing data • Epitopes, functional domains, genetic markers, or haplotypes Every journal should have a similar policy; most top-tier journals already do. Editors and referees need to enforce this submission requirement by rejecting any manuscripts that do not include the submission accession numbers.

Thou shalt not take unfair advantage of submitted data. Many investigators are concerned about data sharing (especially when mandated upon generation, not publication) from fear of being scooped. This is a valid concern. When you submit your data to a public repository, others can find it and (if they meet the requirements) use it. Personally, I think most of these fears are not justified I mean, have you ever tried to get data out of dbGaP? The time it takes for someone to find, request, obtain and use submitted data should allow the producers of the data to write it up. Large-scale efforts to which substantial resources have been devoted - such as the Cancer Genome Atlas - have additional safeguards in place. Their data use policy states that, for a given cancer type, submitted data can’t be used until the ‘marker paper’ has been published. This is a good rule of thumb for the NGS community and something that

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Thou shalt not discount the cost of analysis. It’s true that since the advent of NGS technology, the cost of sequencing has plummeted. The cost of analysis, however, has not. And making sense of genomic data - alignment, quality control, variant calling, annotation, interpretation - is a daunting task indeed. It takes computational resources as well as expertise. This infrastructure is not free; in fact, it can be more expensive than the sequencing itself. Without analysis, your sequencing data, your $1000 genome, is about as useful as a chocolate teapot.

10.

Thou shalt honour thy patients and their samples. Earlier this month, I wrote about how supposedly anonymous individuals from the CEPH collection were identified using a combination of genetic markers and online databases. It is a simple fact that we can no longer guarantee a sequenced sample’s anonymity. That simple fact, combined with our growing ability to interpret the possible consequences of an individual genome, means a great deal of risk for study volunteers. We must safeguard the privacy of study participants - and find ways to protect them from privacy violations and/or discrimination - if we want their continued cooperation. This means obtaining good consent documents and ensuring that they’re all correct before sequencing begins. It also means adhering to the data use policies those consents specify. As I’ve written before, samples are the new commodity in our field. Anyone can rent time on a sequencer. If you don’t make an effort to treat your samples right, someone else will. ALS This post first appeared on Dan Koboldt’s blog, MassGenomics.

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RESEARCH | BIOINFORMATICS

Resistance to computation is futile Andrew Lonie

veryone will have heard of the ‘junk DNA is not junk after all’ story published in Nature in September 2012. Known as ENCODE, this worldwide effort to profile all the different elements of the human genome has created even more opportunities for people with computer programming and mathematical skills. It will also increase the level of frustration felt by people in large research projects when progress depends on opening the high-end computation ‘door’. Demand for computational modelling, image analysis and bioinformatics means those with these skills will be in business for quite a while. Those of us working at the coalface of bioinformatics and computational imaging often find ourselves needing to manage the expectations of our collaborators.

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Understanding the data generated by the new technologies requires complex and often experimental analysis techniques combined with computational grunt. This means we need to talk the language of computers to researchers who sometimes only speak biology and convey the realities of analysing massive sets of error-prone data using approaches that are still developing. Occasionally we’ll find that the data doesn’t exactly match the outcome that a collaborator is after, which is why we like to get in early to help with experimental planning, if we can. One thing that is certain is that bioinformatics and computational biology are part of the research, not a post-experiment addon, and the best analyses require lots of interaction between us all. And as a researcher, you really need to understand what is being done to your data.

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So what is the best way to proceed? At the VLSCI Life Sciences Computation Centre we have found the right way is to collaborate with groups who already understand what the work involves and are prepared to partner with us to achieve the best results. Not only is their data higher quality and they appreciate the nature of our work, but they also understand that subscribing to a pool of experts who will share their knowledge and networks to help build the researchers’ own skill sets produces quality research and clinical outcomes in this relatively new industry. Those productive researchers are the ones who have taken it upon themselves to learn these new skills. One such is Dr Victoria Perreau, who is a senior researcher in the Centre for Neurosciences Research, at the University of Melbourne.

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Associate Professor Andrew Lonie outlines the importance of bioinformatics to today’s research labs and showcases one researcher who talks about how it has changed the way she works.

BIOINFORMATICS | RESEARCH

“There is no avoiding getting some computer knowledge in the new age of biology.” software packages that allowed me to do some comprehensive analysis whilst staying ignorant of any programming knowledge. I just didn’t have the time to re-train. However, I realised over the last two to three years that the advent of nextgeneration sequencing would have many repercussions, including eventually making microarray array technology obsolete. It would also force analysts to use highperformance computing, and thus off-theshelf software won’t work because the size of the average datasets could no longer be handled by a desktop computer. Therefore, it became clear that if I wanted to continue a career path in research in front-line technologies applied to neuroscience, particularly expression analysis and genomics, I would need to learn enough to be able to send jobs to high-end computers using the Unix command line and also have an understanding of programming. I am a firm believer that there is a lot of expression and genomic data out on the web that can be utilised for hypothesis testing and development in an inexpensive and efficient way. I have already identified She works on projects related to multiple sclerosis with Professor Trevor Kilpatrick, who is Division Head of MS at the Florey Institute of Neuroscience and Mental Health. She recently reflected on her own experience (see below). With the ENCODE announcement we can see the future and it is not slowing down. Those who are not already thinking this way have a steep learning curve ahead of them. There is no avoiding getting some computer knowledge in the new age of biology.

some RNA-seq data that has been published that I wish to analyse with a novel perspective and identify different splice variants. But first I need to build up the required skill set to do it efficiently and with best practice. Towards the end of 2011, I made contact with Andrew Lonie at the Victorian Life Sciences Computation Initiative (VLSCI) and attended a one-day

Victoria Perreau. (Image: Casamento Photography)

Dr Victoria Perreau is a bioinformatician and is Group Leader of the Bioinformatics and Gene Expression Analysis Group, Centre for Neuroscience Research, Department of Anatomy and Neuroscience at the University of Melbourne. She has a PhD and post doc in molecular biology, and she has many years of experience at the wet bench investigating RNA expression in many aspects of health and disease in the CNS.

VICTORIA’S STORY

I was originally trained as a molecular biologist and have developed an expertise in microarray analysis and pathway analysis over the last eight to 10 years. I somehow managed to avoid having to do any command line analysis by sticking to

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One of the IBM Blue Gene/Q supercomputers installed at the VLSCI facility in Parkville, Melbourne. (Image: VLSCI)

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RESEARCH | BIOINFORMATICS

RNA-seq workshop at the Life Science Computation Centre (LSCC). This gave me sufficient introduction to give me confidence that I could achieve my goals and have a basic understanding of the processes involved and allowed me startup access to the VLSCI. In semester one this year I took an accredited undergraduate subject, ‘Introduction to computing’. In addition to basic principles of managing computational data, I learned how to write programs in the Python programming language. I am now doing some other online courses. I also attended some introductory Unix workshops run by VLSCI and have been helped to troubleshoot some problems in my work by Dr Bernard Pope at VLSCI. I am also teaching myself how to use the University of California Santa Cruz table browser and the Galaxy project website to get genomic data, and filter and manage this data to use in my analyses. I am already writing my own

Andrew Lonie. (Image: VLSCI)

Associate Professor Andrew Lonie is a computer scientist and bioinformatician, and is head of the Victorian Life Sciences Computation Initiative (VLSCI) Life Sciences Computation Centre (LSCC) at the University of Melbourne. His background is in genetics, molecular biology, information systems and computer science and he uses all of these disciplines daily, analysing and visualising very complex datasets generated by highthroughput genomic technologies.

short Python programs to do analysis on CHPseq data on transcription factor binding sites for a colleague and am producing graphs for him that answer questions of his data he could not otherwise ask.

It is very clear to me now that, as a biologist, I have to be prepared to put in the hard work to simply learn (and practise) the basics to improve my capacity to communicate with the computer scientists who are trying to help me. ALS

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PUBLISH OR PERISH

PUBLISH OR PERISH The return of our regular round-up of some of the best Australian research published each month in leading peer-reviewed journals. Chan JY, Luzuriaga J, Bensellam M, Biden TJ, Laybutt DR. St. Vincent’s Hospital, NSW Failure of the adaptive unfolded protein response in islets of obese mice is linked with abnormalities in -cell gene expression and progression to diabetes.

Diabetes 2012 Dec 28 Chang CW, Cou–ago RL, Williams SJ, Bodén M, Kobe B. University of Queensland Crystal structure of rice importin- and structural basis of its interaction with plantspecific nuclear localisation signals.

Plant Cell 2012 Dec Choat B, Jansen S, Brodribb TJ, Cochard H, Delzon S, Bhaskar R, Bucci SJ, Feild TS, Gleason SM, Hacke UG, Jacobsen AL, Lens F, Maherali H, Martinez-Vilalta J, Mayr S, Mencuccini M, Mitchell PJ, Nardini A, Pittermann J, Pratt RB, Sperry JS, Westoby M, Wright IJ, Zanne AE. Hawkesbury Institute for the Environment, NSW Global convergence in the vulnerability of forests to drought.

Nature2012 Nov 29 Davis SJ, Sheppard KE, Pearson RB, Campbell IG, Gorringe KL and Simpson KJ. Peter MacCallum Cancer Centre, Vic Functional analysis of genes in regions commonly amplified in high-grade serous and endometrioid ovarian cancer.

Clinical Cancer Research 2013 Jan 29 (Epub 2012 Dec 16) Devi S, Li A, Westhorpe CL, Lo CY, Abeynaike LD, Snelgrove SL, Hall P, Ooi JD, Sobey CG, Kitching AR, Hickey MJ. Monash Medical Centre, Vic Multiphoton imaging reveals a new leukocyte recruitment paradigm in the glomerulus.

Nat Med 2013 Jan Hayes BJ, Lewin HA, Goddard ME Dept Primary Ind, Dairy Futures CRC, La Trobe University, Vic The future of livestock breeding: genomic selection for efficiency, reduced emissions intensity, and adaptation.

Trends Genet 2012 Dec 19 Fleming NI, Jorissen RN, Mouradov D, Christie M, Sakthianandeswaren A, Palmieri M, Day F, Li S, Tsui C, Lipton L, Desai J, Jones IT, McLaughlin S, Ward RL, Hawkins NJ, Ruszkiewicz AR, Moore J, Zhu HJ, Mariadason JM, Burgess AW, Busam D, Zhao Q, Strausberg RL, Gibbs P, Sieber OM. Ludwig Institute for Cancer Research,

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University of Melbourne, Vic SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer.

Cancer Res 2013 Jan 15 Kelley LA, Endler JA. Deakin University, Vic Male great bowerbirds create forced perspective illusions with consistently different individual quality.

PNAS USA 2012 Dec 18 Kirszenblat L, Neumann B, Coakley S, Hilliard MA. University of Qld A dominant mutation in mec-7/beta-tubulin affects axon development and regeneration in Caenorhabditis elegans neurons.

Mol Biol Cell 2013 Feb Klonis N, Xiea SC, McCawb JM, CrespoOrtiza MP, Zaloumisc SG, Simpson JA and Tilley L University of Melbourne and Murdoch Children’s Research Institute, Vic Altered temporal response of malaria parasites determines differential sensitivity to artemisinin. PNAS 2013 Jan 17 McMorran BJ, Wieczorski L, Drysdale KE, Chan JA, Huang HM, Smith C, Mitiku C, Beeson JG, Burgio G, Foote SJ. Macquarie University, Sydney Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum.

Science 2012 Dec 7

Sathe P, Vremec D, Wu L, Corcoran L, Shortman K. WEHI, Vic Convergent differentiation: myeloid and lymphoid pathways to murine plasmacytoid dendritic cells.

Blood 2013 Jan 3 Stroud DA, Formosa LE, Wijeyeratne XW, Nguyen TN, Ryan MT. La Trobe University, Vic Gene knockout using transcription activator-like effector nucleases (TALENs) reveals that human NDUFA9 protein is essential for stabilizing the junction between membrane and matrix arms of complex I.

J Biol Chem 2013 Jan 18 Todd JR, Scurr LL, Becker TM, Kefford RF, Rizos H. Westmead Hospital, NSW The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma.

Oncogene 2012 Dec 17 Vaux DL. WEHI, Vic Research methods: Know when your numbers are significant.

Nature 2012 Dec 13 Walters SB, Kieckbusch J, Nagalingam G, Swain A, Latham SL, Grau GE, Britton WJ, Combes V, Saunders BM. Centenary Institute, NSW Microparticles from mycobacteria-infected macrophages promote inflammation and cellular migration.

Neller MA, Burrows JM, Rist MJ, Miles JJ, Burrows SR. QIMR, Qld

J Immunol 2013 Jan 15

High frequency of herpesvirus-specific clonotypes in the human T cell repertoire can remain stable over decades with minimal turnover.

Weller JL, Liew LC, Hecht VF, Rajandran V, Laurie RE, Ridge S, Wenden B, Vander Schoor JK, Jaminon O, Blassiau C, Dalmais M, Rameau C, Bendahmane A, Macknight RC, Lejeune-Hénaut I. University of Tasmania, Tas A conserved molecular basis for photoperiod adaptation in two temperate legumes.

J Virol 2013 Jan Nyholt DR, Low SK, Anderson CA, Painter JN, Uno S, Morris AP, MacGregor S, Gordon SD, Henders AK, Martin NG, Attia J, Holliday EG, McEvoy M, Scott RJ, Kennedy SH, Treloar SA, Missmer SA, Adachi S, Tanaka K, Nakamura Y, Zondervan KT, Zembutsu H, Montgomery GW. QIMR, Qld

PNAS USA 2012 Dec 18

Genome-wide association meta-analysis identifies new endometriosis risk loci.

Yang YH, Song W, Deane JA, Kao W, Ooi JD, Ngo D, Kitching AR, Morand EF, Hickey MJ. Monash Medical Centre, Vic Deficiency of annexin A1 in CD4+ T cells exacerbates T cell-dependent inflammation.

Nat Genet 2012 Dec

J Immunol 2013 Feb 1

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EVENTS

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

ComBio2013 September 29-October 3, Perth

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Human Genome Meeting 2013 and 21st International Congress of Genetics April 13-18, Singapore In 2013, the HGM and International Congress of Genetics join forces this year for those interested in the latest developments in genetics and genomics. HGM is the key annual conference organised by the Human Genome Organisation (HUGO). Initially structured as a dedicated meeting for human genome mapping, the HGM has evolved into a major scientific conference for human genetics and genomics, genomic medicine and genomic biology. The International Congress of Genetics is an open conference for geneticists held once every five years since the founding of the science of genetics more than a century ago. The aim of the congress is to create the opportunity for researchers from around the world to hear about up-to-date developments in their discipline. www.hgm2013-icg.org

The Annual Endocrine Society of Australia Seminar 2013 April 5-7, Sunshine Coast, Queensland

www.esaseminar.org.au The Drug Information Association’s 7th Annual Conference for Asian New Drug Development April 15-16, Japan

www.diahome.org Stem Cells and Cancer Symposium April 17, Parkville

www.sapphirebioscience.com/symposium

4th International NanoMedicine Conference July 1-3, Sydney

www.oznanomed.org Australian Society for Microbiology ASM 2013 July 7-10, Adelaide

www.theasm.org.au Biomolecular in the Bush July 14-17, Leura

www.raci-bio-conf.org ASID Gram-Negative 'Superbugs' Meeting August 2-3, Gold Coast

BIO 2013 April 22-25, Chicago

http://convention.bio.org 12th International Symposium on Mutation in the Genome April 22-26, Lake Louise, Canada

www.mutationdetection.org

The Australasian Bioenergy and Bioproducts Symposium 2013 October 25, Brisbane

www.tabbs.com.au 15th World Conference on Lung Cancer October 27-31, Sydney

www.2013worldlungcancer.org 5th Asia-Pacific NMR Symposium (APNMR5) and 9th Australian & New Zealand Society for Magnetic Resonance (ANZMAG) October 27-30, Brisbane

http://apnmr2013.org AusBiotech 2013 October 29-November 2, Brisbane

www.ausbiotech.org HPLC 2013 November 18-21, Hobart

www.hplc2013-hobart.org Laboratory Management & Design Conference November 18-20, Brisbane

www.labmanagers.org.au/ Australian Society for Biophysics Annual Meeting - ASB 2013 November 24-27, Melbourne

www.asid.net.au/gramnegative

www.biophysics.org.au/Meetings/2013/index.html

Familial Aspects of Cancer Meeting August 25-28, Cairns

International Symposium on Computational Models for Life Sciences November 27-29, Sydney

www.meeting-makers.com/fac International Society for Gastrointestinal and Hereditary Tumours August 28-31, Cairns

http://cmls-conf.org/2013/

www.ausbiotech.org

www.insight-group.org

15th International Conference on Systems Biology in Melbourne September 13-19, 2014, Melbourne

ASPCR-ASDR 2013 May 17-19, Sydney

www.aspcr-asdr2013.org

Australasian College for Infection Prevention and Control Conference September 30-October 2, Gold Coast

ComBio2014 September 28-October 2, 2014, Canberra

www.acipcconference.com.au/

www.asbmb.org.au

24th International Conference on Arabidopsis Research (ICAR) June 24-28, Sydney

Tech Transfer Summit Australia 2013 September 3-4, WEHI, Melbourne

AusBiotech 2014 October 28-31, 2014, Gold Coast

www.sallyjayconferences.com.au/icar2013/

www.ausbiotech.org

AusMedtech 2013 May 15-16, Melbourne

www.emblaustralia.org

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Friday, 25th October 2013 Brisbane Convention and Exhibition Centre,

Brisbane, Australia.

TABBS the australasian bioenergy and bioproducts symposium Hosted by Life Sciences Queensland Limited

The Australasian Bioenergy and Bioproducts Symposium (TABBS) will engage high-level leaders from the national and international Bioenergy and Bioproducts industry and research community to explore the enormous opportunities this area provides. With large investments needed to drive development from PoC to commercialisation, there are potential risks that need to be identified and managed to provide investor confidence, and grow this sector. This symposium, hosted by Life Sciences Queensland Limited will provide an opportunity for global industry stakeholders to come together, share their experiences and cooperate to grow their businesses and help create a dynamic, internationally competitive and sustainable life sciences industry.