ANNUAL REPORT 2010 COVER IMAGE: WINNER OF THE 2010 IMB ÅNGSTRÖM ART COMPETITION

DARREN BROWN: MACBEADS A merged image of two scanning electron microscope images of macrophages ingesting latex beads (dark orange) as part of the phagocytic process during the immune response. The macrophage is an immune cell that fights invading pathogens by ‘eating’ them – surrounding them and engulfing them.

INSTITUTE FOR MOLECULAR BIOSCIENCE ÅNGSTRÖM ART CENTENARY COLLECTION As part of our contribution to UQ’s Centenary in 2010, the Institute held an art competition. IMB researchers were invited to submit scientific images, and our judging panel selected a winner and two runners-up (see page 81 for more details).

Part of the winner’s prize was having his or her image featured on the front cover of the 2010 annual report. Darren Brown, from the Stow group, was awarded this honour for his image ‘MacBeads’. Altogether, 62 images were submitted, a selection of which makes up the artwork for this report. The image titles, authors and a brief description can be found alongside each.

To view the entire Centenary Collection, please visit www.angstrom-art.com IMB Annual Report 2010 1 IMB Vision Statement 2 Chair’s Message CONTENTS 3 Director’s Report 5 Deputy Directors’ Report 7 Feature: Pain Relief in a Cone Snail Shell 9 Organisational Chart 10 IMB Highlights 2010 16 IMB Advisory Board 19 Scientific Advisory Committee

IMB RESEARCHERS

 21 Division of Genomics and Computational Biology

29 Division of Molecular Genetics and Development

41 Division of Molecular Cell Biology

50 Division of Chemistry & Structural Biology

62 Joint Appointments 65 Affiliate Appointments

66 IMB Occupational Health and Safety Report 67 IMBcom 69 Postgraduate Research 74 Visiting Speakers 78 Collaborative Research Partnerships 81 Community Engagement 83 IMB Staff and Students 96 Financial Statements 99 Glossary of Terms 102 2010 Publications

JESS INESON: TREE OF LIFE Microscopic snapshot of a developing kidney IMB VISION STATEMENT

CREATIVITY, MOTIVATION AND we will be better equipped to understand INTELLECTUAL FREEDOM are the the basis of our differences and how and vital components of scientific discovery why things go wrong in disease states like and technological process, and underpin cancer. the research philosophy of the Institute In time, our collaborative research will lead for Molecular Bioscience. to improved therapies and diagnostics, Our research mission is to understand enhancing our ability to combat common the information contained in our genes diseases and genetic disorders. and proteins – the very foundation of our It will also give rise to new ideas, existence and health. technologies and knowledge-based By understanding how and why humans industries to improve the health and quality and animals develop the way they do, of life of future generations. imb annual report 2010 2

CHAIR’S MESSAGE

2010 WAS SIGNIFICANT FOR BOTH In other words, every $1 the Queensland The outcomes of the first 10 years The University of Queensland and the Government invested in IMB will return vindicate the calculated risks taken Institute for Molecular Bioscience. UQ between $4.50 and $6.50 to the state. by the founders and early funders of celebrated its Centenary, and January the IMB, who foresaw that it could The advantage conferred by this public 1 marked ten years since the IMB was influence a new direction in research and funding is reflected in human capital. officially established. Ninety years after its innovation for UQ – and for Queensland. The IMB has directly created 350 jobs birth, UQ had its first institute. since 2000, and Allen Consulting Group The Institute for Molecular Bioscience Since 2000, the IMB has been joined by projects that employment in Queensland has been instrumental to the growth in seven other UQ institutes and its budget will increase by between 800 and 1,100 global esteem for bioscience discovery has grown from $19.5 million to almost jobs by 2029, thanks to the Institute. conducted in Queensland and nationally, $90 million. and has established its own credentials These impressive numbers attest to address complex and urgent global Its second quinquennial review, covering to the sustained impact of strategic challenges. the institute’s performance from 2005- government support for research. 2009, was conducted by a distinguished The IMB’s vigour is linked to panel led by an eminent financial Professor Paul Greenfield, AO successful leveraging of seminal expert, Henry Smerdon. The review Vice-Chancellor funds from government, The Atlantic The University of Queensland demonstrates that the IMB has emerged, Philanthropies and UQ, and to networks in one decade, as equal in output to of outstanding partners in research, Australia’s long-established leaders in industry, philanthropy and not for profit biomedical discovery. organisations. The review process included an Fundamentally, the source of its strength assessment by the Allen Consulting is outstanding people – staff, students, Group of the IMB’s economic impact. the board, the scientific advisory This demonstrates that the Institute committee and directors. It has been my generated $220 (directly and indirectly) pleasure to interact with these people from a Queensland Government during 2010, as chair of the IMB board investment of $50 million. and Vice-Chancellor of the University. Further, the investment is forecast to have a significant expansionary effect, boosting Gross State Product by between $450 million and $650 million by 2029.

...every dollar the Queensland Government invested in IMB will return between $4.50 and $6.50 to the State’’ JOHN GRIFFIN: HOOP PINE POLLEN Hoop pines (Araucaria cunninghamii) are a species of tree endemic to eastern Australia.They produce prodigious amounts of pollen, making samples easy to obtain. 3 executive reports

DIRECTOR’S REPORT

2010 WAS A BIG YEAR AT THE Government, was critical in determining In a short ten-year Institute for Molecular Bioscience. The future funding arrangements with University celebrated its centenary the State Government after 2014. In period IMB has made a during 2010 and we marked our tenth addition to a submission prepared by significant contribution year as an institute, joining in with the IMB, the Allen Consulting Group was to scientific enquiry at a major university events and running engaged to provide an assessment of some of our own. The most significant our economic and social contributions to national and international of these was a competition for images the State. level through publication from scientific research that formed The IMB submission tracked the the Centenary Collection of the IMB in high-impact journals, performance of the Institute between Ångström Art initiative. The entire 2005 and 2009 across a range of graduation of over 180 PhD collection of 62 entries was on display measures including competitive for The University of Queensland students with specialised grant income, publication output, Centenary Community Day on the 18th postgraduate student graduations and skills in molecular of April, 2010, after which 25 of the commercialisation of research. Across images were selected for reproduction bioscience, bioinformatics all of these measures we performed on iPhone skins, which have been given and chemistry, and at a comparable level to three other away at a number of university and significant Australian biomedical science the spinning out of 14 industry events throughout the year. institutes – the WEHI, QIMR and the companies from research The early part of the year saw us Garvan Institute. This was particularly focused on preparations for the July pleasing when the relative age of each of and discovery 2010 Quinquennial Review of our State the benchmarking institutes was taken Government funding. This Review, into account, with IMB being by far the ’’ chaired by Mr Henry Smerdon, AM, youngest. In a short ten-year period, former Under-Treasurer of the State IMB has made a significant contribution to scientific enquiry at a national and CANCER BIOLOGY IMAGING international level through publication in FACILITY OPENING high-impact journals, graduation of over Our first major activity for 2010 was the 180 PhD students with specialised skills opening of the ACRF Cancer Biology in molecular bioscience, bioinformatics Imaging Facility by the Governor and chemistry, and the spinning out of 14 companies from research and of Queensland, Her Excellency Dr discovery. From a State Government Penelope Wensley, AO, in February of investment of $82.5 million (to the end this year. Funded with a $2.5 million of 2009), a total of $211.30 million in grant from the Australian Cancer additional income has been leveraged. Research Foundation, the new Facility combines with the existing ACRF At the time of going to press, the Dynamic Imaging Facility at the IMB to report from the Quinquennial Review provide the most sophisticated research Team had been presented to the State facility in Australia for fluorescence Government and preliminary discussion imaging of cancer cells. The advanced about future State Government funding laser microscopes in the facility will be of the IMB and other UQ research used by researchers at the IMB and institutes, including the Queensland Brain Institute and the Australian Institute throughout Queensland to research the for Bioengineering and Nanotechnology, origins of cancer, develop new drugs is now underway. and create prevention strategies for risk groups.

3 ANNUAL REPORT 2008 imbimb annualannual reportreport 2010 4

DARREN BROWN: SEADRAGONS A fluorescence microscope image of macrophages labelled with antibodies

QUEENSLAND CENTRE FOR Rohan Teasdale, who were successful in MEDICAL GENOMICS OPENING an $8.9 million NHMRC program grant The Premier the Honourable Anna Bligh, application to examine cell biology and MP, performed the honours at the opening inflammation and Professor Rob Parton, of the Queensland Centre for Medical who received a Best and Brightest Genomics, located within the Institute, on Achievement Award from the NHMRC June 16th. This facility has been funded in March for the highest-ranked project by the largest-ever NHMRC grant, a State grant nationally. Government NIRAP grant and cash and Overall our success in the major domestic in-kind support from a number of sources grant schemes for projects commencing including the Cancer Council of NSW, in 2011 was a little down on last year’s Applied Biosystems and The University success rates. We were, however, of Queensland. It was a pleasure to coming off a very high base, including welcome the Premier to the Institute and a 59% success rate in the NHMRC to showcase the new facility that will give schemes, and an adjustment down in our researchers a better understanding of overall success rate was inevitable. This pancreatic and ovarian cancer, with a view slight downward shift in the amount of to developing better treatments for these domestic competitive research funding diseases. Since the Centre’s opening, coming in for 2011 is offset, however, by work has been progressing well on the the success of Professor Matt Cooper sequencing of 500 different pancreatic and in obtaining a UK Wellcome grant for ovarian cancer genomes and data has his research into new therapies for been released to the research and general antibiotic-resistant infections. The community through the auspices of the amount of money being invested by International Cancer Genome Consortium. the Wellcome Trust in Matt’s research is It is a mark of the excellence of the IMB significant and will enable him to make that each year our researchers pick up major strides in understanding and awards from within the University and treating antibiotic-resistant infections. from external professional societies for 2011 is shaping up to be a busy year. outstanding contributions to science. Our first UQ Academic Board Review 2010 has been no exception and my occurs in April 2011. This Review congratulations go to Professor David will examine our contributions to the Craik who was awarded the Ralph F. University, particularly in the teaching Hirschmann Award in Peptide Chemistry and collaborative research areas, as well from the American Chemical Society, Dr as taking into account the performance Ben Hogan who received a UQ Research metrics already submitted to the Excellence Award for his research into the State Government. With a staff cohort human lymphatic system, Dr Ryan Taft committed to excellence across all areas who was a finalist in the People’s Choice of our operations I am confident that we Eureka Awards and Dr Richard Clark, who will come through this second review received a Queensland Health and Medical with flying colours. I look forward to Research Senior Researcher award. rising to the challenges of 2011. Other outstanding efforts during the year included Professor John Mattick, AO, who successfully applied for an NHRMC Australia Fellowship to follow on from his ARC Federation Fellowship, Professor Professor Brandon Wainwright Jenny Stow and Associate Professor IMB Director 5 executive reports

DEPUTY DIRECTORS’ REPORT

RESEARCH We aim to continue improving in the Professor John Mattick’s Australia The end of 2009 marked the close of future. Our achievements from the first Fellowship (see Professor Wainwright’s IMB’s first decade of existence and year of our second decade, outlined report, preceding page, or Highlights meant it was time for our second below, show that we are on track to section on page 10, for more details) quinquennial review. This document achieve this aim. means the IMB is now home to four recipients of this highly regarded award contained some very pleasing statistics Professor Sean Grimmond was part of a for medical research, and we are the that demonstrated how we have grown worldwide collaboration that published a only research institute in Australia to and strengthened as an organisation. paper in Nature in April. The International have received an Australia Fellowship For example, in the five years from 2005 Cancer Genome Consortium is working every year since the program’s inception. to 2009, our competitive grant income to map the genomes of 50 different from national and international sources types and subtypes of cancer. Professor While we rightly recognise our winners grew to over $160m, which represented Grimmond leads Australia’s research of national fellowships, the IMB is also an increase of 87 percent from the effort, which involves sequencing 500 committed to providing opportunities first five years. Two thirds of our group pancreatic and ovarian tumours in to support the work of outstanding leaders now support their own salaries collaboration with Professor Andrew early-career researchers to facilitate their with senior research fellowships, an Biankin from the Garvan Institute and move towards independent researcher increase of 50 percent in the number Professor David Bowtell from the Peter status. With this in mind, the institute’s of fellowships since 2005. We have MacCallum Cancer Centre. executive committee decided in 2010 published over 1050 papers in the to create the IMB Fellowship scheme. As Professor Wainwright noted in his last five years, a 60 percent increase Exceptional researchers from among report, our grant results for 2010 were in output. Many of these papers were our postdoctoral scientists would be not as spectacular as 2009 but we still accepted in top-rank international selected to receive financial support performed well. The IMB received nearly journals such as Science, Nature and for their projects, with up to four ‘IMB $10 million for projects and equipment Cell, and in leading disciplinary journals. Fellows’ resident at the Institute at any from the NHMRC and the ARC, and These publications were cited, on one time. average, more than 3000 times per year, six IMB researchers were offered a an increase of 74 percent from 2000- total of seven fellowships from the two Dr Joshua Mylne from the Craik group 2004. Our success rates in NHMRC and funding bodies. More details of these was chosen as the inaugural IMB Fellow. ARC funding schemes are consistently grants and fellowships can be found Dr Mylne was originally a botanist who higher than national and Queensland in the Highlights section beginning on studied vernalisation – the process averages; particularly notable is our 90 page 10, however I would like to make by which plants sense cold and alter percent success rate for ARC Linkage particular mention of Dr Matt Sweet, their flowering time. Within the Craik grants. who had the opportunity to take up group, which has a strong focus on both an ARC Future Fellowship and an developing improved protein frameworks NHMRC Research Fellowship. Dr Sweet for drugs, Dr Mylne has been examining was appointed as a group leader at the potential of a mechanism within IMB in 2007, and his excellent results in sunflower seeds to manufacture peptide these fellowship rounds are a testament drugs cheaply and quickly. This project to his leadership and the quality of his would allow the efficient production research. of drugs, particularly in third-world

We aim to continue improving in the future. Our achievements from the first year of our second decade, outlined here, show that we are on track to achieve this aim

– Professor’’ Jenny Stow Deputy Director (Research) imb annual report 2010 6

countries. Dr Mylne’s fellowship was to students who receive unanimous at The University of Queensland and named the John S. Mattick Fellowship commendations from their examiners, was recognised at a ceremony for long- after group leader Professor John and who make a significant contribution serving staff. Chris began with UQ in Mattick, who was both the co-founder to their field of research. No more than 1985 in the department of Physiology and inaugural Director of the IMB. 10 percent of research higher degree and Pharmacology, working on graduates are on this list every year, and developing drugs for asthma. He moved Many of our other researchers received the fact that well over 10 percent of our to the centre that preceded the IMB five recognition through prizes and awards. students were named is a credit to the years later. His first job at the institute Professor Wainwright has already students, their supervisors and the IMB was as a research assistant, looking made mention of many of the most graduate program. at the molecular biology of intracellular significant for 2010, however I would infection. Chris has since risen through like to highlight an award presented to the ranks and now manages our ADMINISTRATION AND one of our Joint Appointees, Professor laboratory support systems and liaises Geoffrey McLachlan. The Statistical INFRASTRUCTURE with UQ’s Properties and Facilities staff Society of Australia acknowledged Our systems and administration staff to ensure the smooth running of the IMB Professor McLachlan with the Pitman work ‘behind the scenes’ to allow IMB building and facilities. Medal, its highest honour, which scientists to perform our core business There were some senior staff movement recognises ‘outstanding achievement of research. The non-research tasks, during the year. Jeremy Kroes, IMB’s in, and contribution to, the discipline such as delivering mail, equipment Workshop Manager, left and was of Statistics’. The gold medal is maintenance, grant administration, replaced by Michael Thwaite. Jane awarded annually at most, and since its reception, sterilisation, receiving Weber, the Level 6 Floor Manager, inception 32 years ago has only been deliveries, purchasing and managing moved to Melbourne and Jacky Hung bestowed 18 times. In his role as a accounts, recruitment, communications, took the position. Joint Appointee, Professor McLachlan IT and other administrative functions works closely with researchers from the are all performed by these staff, and I IMB hosted 5000 visitors in 2010, Division of Genomics and Computational thank them for contributing to the IMB’s with visitors from universities in 27 Biology, and you can read more about success. other countries, a demonstration of his research on page 64. the strength of our reputation and One staff member who deserves collaborations with other institutions. We had 27 students graduate in 2010, special recognition is our Infrastructure and I am pleased to report all of these Manager, Chris Barnett. In 2010, Chris students have found employment, with recorded his 25th year of employment some remaining at IMB to continue working on projects they began in their PhDs, while a few have commenced positions in different departments of UQ or other organisations in Brisbane. One- IMB hosted 5000 visitors third of the group have chosen to start their postdoctoral careers overseas, in 2010, with visitors from with positions in Indonesia, the USA (California and Florida), Singapore, universities in 27 other Germany and Switzerland. While family countries, a demonstration and other circumstances can prevent some postdoctoral students from of the strength of our taking up work outside of Australia, reputation and collaborations the fact that so many of our students have found employment in international with other institutions laboratories speaks to the world- quality training they receive at IMB. This is further demonstrated by the – Dr Ian Taylor ’’ number of our students who receive a Deputy Director Dean’s Commendation for Outstanding (Systems and Administration) Research Higher Degree Thesis. The results for the 2009 graduates were released in 2010, and we were very pleased to see that five IMB students were recognised. This award is given 7 2010 feature

Dr Richard Clark with cyclotide-containing African plants and cone snail shells imb annual report 2010 8

2010 feature PAIN RELIEF IN A CONE SNAIL SHELL

Most people wouldn’t turn to a drug straight to the spinal cord can The cone snail deadly marine creature for pain ensure delivery, but increases the risk of infection. But research from another peptides, known as relief, but that’s exactly what IMB laboratory is overcoming even this conopeptides, have a high scientists at the IMB are doing, disadvantage. with promising results. Professor David Craik is a world specificity, meaning they hit expert on circular peptides, known only their target and not any The cone snail, found in the waters as cyclotides. He described the first of the Great Barrier Reef and tropical cyclotide, kalata B1, which is found in other receptors regions worldwide, has very toxic venom the African plant Oldenlandia affinis. that can kill a person in less than 30 African women use a tea made from minutes. This venom is delivered through the leaves of this plant to stimulate ’’ a barb sharp enough to pierce a diver’s childbirth, which caught the attention The team successfully engineered a wetsuit. Researchers became interested of a Red Cross doctor in the 1960s. synthetic version of a conopeptide and in the cocktail of toxins that make up Some kind of protein had to be present used amino acids to link the two ends the venom when they realised that in the tea to have an effect on the of the peptide, forming a circle. Testing survivors of cone snail stings reported uterus, but what type of protein could on this synthetic cyclotide proved feeling no pain. Investigations into the survive the boiling that is part of the tea- that it retained the biological activity it venom revealed it contained a powerful making process? When Professor Craik demonstrated while it was a straight analgesic. determined the structure of kalata B1 in peptide, i.e., it relieves pain. It is also the 1990s, this question was answered: very potent, meaning a drug made The applications to human health were a circular protein. immediately apparent. Chronic pain from this circular peptide could likely be occurs when the nerves themselves Digestive enzymes attack the ends administered in small doses, decreasing are damaged and is caused by a of proteins, but circular proteins have the risk of addiction. range of conditions including diabetes, no ends, meaning they can survive The next step in the process is human stroke, cancer and nerve damage the maelstrom of the body’s digestive trials, assessing the drug candidate for from surgery. It can be a debilitating system and travel to their target, making its safety and analysing the effect it has disease, and current treatments have them an ideal template for drugs. So the on the human body and the effect the significant drawbacks. For a start, they IMB researchers had the two ingredients human body has on it. The researchers are ineffective on some patients. Even necessary: the protein that relieved pain, hope the molecule will pass muster and when treatments do relieve pain, they and the protein that could survive in the go on to be a safe, low-dose, effective have other problems. Morphine is often body and be delivered to the correct treatment for chronic pain. The very fact used in pain relief, but sufferers become site for pain relief. The trick would be it has made it this far is testament to two used to the drug and, over time, need putting them together. IMB discoveries, one from animals and increasing amounts. It is also addictive Professor Craik and Dr Richard Clark one from plants, that have been brought and has side effects such as nausea and have been working on this challenge together to create a promising new drug vomiting. Clearly, improved treatments for a number of years. In 2010, they candidate. Watch this space. are needed. published the results of their work Enter the cone snail. Professors Richard in the journal Angewandte Chemie. Lewis and Paul Alewood isolated a number of molecules from cone snail venom that have the potential to relieve pain. These molecules are peptides, small proteins. The cone snail peptides, known as conopeptides, have a high Photograph of the specificity, meaning they hit only their plant Oldenlandia target and not any other receptors. affinis with the This is a sought-after attribute for drug structure of the candidates, as it lessens or eliminates prototypic cyclotide side effects. The drawback to peptides? kalata B1. They have trouble surviving in the body, and if administered orally, are broken down by digestive enzymes before they can reach their target. Injecting a peptide 9 2010 organisational chart

2010 IMB ORGANISATIONAL CHART

University of Queensland Senate UQ Holdings Pty Ltd

IMB Board Vice-Chancellor

Deputy Vice-Chancellor (Academic)

IMB Scientific Advisory Committee Institute Director IMBcom Pty Ltd

Deputy Director Deputy Director (Research) (Systems & Administration)

Division Head Division Head Division Head Division Head Graduate Administration Genomics & Molecular Chemistry & Molecular Cell Education Computional Genetics & Structural Biology Office Biology Development Biology

Information Technology Services

Marketing & Research Groups Communications Laboratory Services imb annual report 2010 10

IMB HIGHLIGHTS 2010

RESEARCHERS DELVE INTO GENETIC CODE OF TUMOURS IN HUNT FOR CANCER THERAPIES Australian scientists are playing a vital role in a worldwide search for cancer therapies, described in top scientific journal Nature. The scientists are part of the International Cancer Genome Consortium (ICGC), a group of researchers from 22 countries who are conducting large-scale studies on the genomes of different tumour types.

The ICGC members will together sequence the genetic codes of 25,000 tumours from 50 different types of cancer over five years. Professor Sean Grimmond is leading the Australian team, responsible for sequencing pancreatic and ovarian tumours.

“We have identified changes in the genetic code from normal tissues to tumours, but we don’t yet know if these changes are responsible for disease,” Professor Grimmond said. “Our next step is running tests in the lab to determine if these genetic changes have a biological effect. We will do this for every tumour we sequence over the five- year project.”

SOWING THE SEEDS OF MALE FERTILITY Australian scientists have discovered the chemical signals that ensure men produce sperm instead of eggs. Dr Josephine Bowles and Professor Peter Koopman led a team that found that a protein called FGF9 promotes the production of sperm in males while GENOME EXPLORATION FINDS KEYS TO GENE REGULATION AND suppressing the development of eggs. DISEASE “It sounds obvious, that men produce sperm and women produce eggs,” A deep genome exploration has abundant at the start of genes and Dr Bowles said. “But sperm and eggs found tens of thousands of tiny discovered they are also found at start out as identical cells, and it’s only pieces of genetic material, less that gene splice sites, where genes are through a complex process of signals one percent of the length of the turned on or off. that these cells end up as sperm in men average gene, that may regulate The work was published in the gene expression and disease. and eggs in women.” premier scientific journal Nature Professor John Mattick and Dr Ryan Structural and Molecular Biology, Taft (pictured) from IMB, and Dr Cas and led to Dr Taft being named a Simons from the Queensland Facility finalist in the Eureka Prizes Early for Advanced Bioinformatics, showed Career Research and People’s that these ‘tiny’ RNA molecules are Choice Awards. 11 highlights

IMB HIGHLIGHTS 2010

WORLD-CLASS GENOME CENTRE OPENS AT IMB Premier Anna Bligh opened a multi-million dollar genome research facility on June 16, 2010 that will help pave the way for personalised genetic treatment. The Queensland Centre for Medical Genomics was established with a $5 million grant from the Queensland Government and contains 11 next- generation sequencing machines that will allow researchers to compare the genomes of people with genetic diseases and determine which changes have occurred to cause the disease. “This will lead to the development of more accurate therapies as well as a better understanding of genetic diseases, QCMG Director Professor Sean Grimmond said. “We are moving rapidly towards a future in which individuals are diagnosed and treated according to their genetic code.”

QCMG Director Professor Sean Grimmond and Premier the Hon. Anna Bligh at the opening of the Queensland Centre for Medical Genomics

PROBING THE MACHINERY ‘STEM CELL DETECTIVES’ SCIENTIFIC IMAGES GO FROM BEHIND TISSUE HEALTH UNCOVER POTENTIAL CANCER LAB TO LIMELIGHT PROBING THE MACHINERY CAUSE IMB researchers were given the chance BEHIND TISSUE HEALTH Australian researchers have uncovered a to display their artistic skills in the new mutation in stem cells that may be revamped Ångström Art competition, A team of researchers has uncovered linked to the development of leukaemia, which aims to showcase stunning several key molecules that control the breast and colon cancer. scientific images. Entries were open to health of a major tissue in the body, the all IMB researchers and the organisers site of inflammation and 80 percent of A team led by Dr Peter Papathanasiou received 62 images altogether. cancers, in work published in Nature from the John Curtin School of Medical Chemical Biology. Research at the Australian National Judges Professor Stephen Walker, University and IMB’s Associate Professor Executive Dean of the Faculty of Science; Professor Alpha Yap led the researchers, Andrew Perkins have completed a Nick Mitzevich, Director of the UQ Art from the IMB and the National Institutes three-year screening project to find the Museum; and Mrs Beverley Trivett, of Health in the U.S.A., who probed the genes that control the development and Director of the John Trivett Foundation; molecular machinery of epithelial tissues, turnover of stem cells. chose the winner and two runners-up. which cover the internal and external surfaces of the body. They identified A major finding of the new study was the Mr Darren Brown, a research assistant two of the key molecules that keep discovery of a novel DNA mutation in the from the Stow group, contributed the epithelium healthy, as well as the c-Myb gene, which has previously been both the winning image, “MacBeads”, signalling pathways that control these linked to a number of different cancer and one of the runner-up images, molecules. types. The project was the first in the “RealMacAlien”. Dr Michael Landsberg, world to mutate the mammalian genome a Research Officer from the Hankamer “Understanding these signalling in a specific search for novel genetic group, rounded out the runners-up pathways will give us a better insight regulators of stem cells, and the findings with his image, “Insect Assassin”. The into how these diseases are caused, were published in the journal Blood. winning image can be viewed on the information that could lead to improved front cover of this report, while the treatments,” Professor Yap said. full collection can be seen at www. angstrom-art.com imb annual report 2010 12

Professor David Fairlie also received a $610,500 Development Grant to commercialise drugs for inflammatory diseases. The grant will allow him to test molecules he has designed to determine if they have the right pharmacological properties to provide therapeutic effects.

MILLION-DOLLAR FUNDING FOR IMB RESEARCH Researchers from the IMB will be leading projects such as improving pain treatments and developing clean fuels From left: Mr Tom Dery, Chair of ACRF; Professor Brandon Wainwright, Director of IMB; after receiving nearly $3.5 million in Her Excellency Dr Penelope Wensley AO, Governor of Queensland; and Professor Paul funding from the Australian Research Greenfield AO, Vice-Chancellor of UQ at the official opening of the ACRF Cancer Biology Council (ARC). Imaging Facility. Professor Glenn King received $550,000 ADVANCED CANCER RESEARCH CENTRE OPENS AT UQ to develop drugs for chronic pain based on compounds from spider venom, while IMB researchers now have access to Excellency Dr Penelope Wensley AO. Associate Professor Ben Hankamer was some of the world’s leading cancer The facility is an expansion of a $1.2 awarded $375,000 to improve the ability imaging equipment with the opening million facility at IMB funded by of microalgae to produce hydrogen. of a $2.5 million facility funded by ACRF in 2003. The new facility has $660,000 went to Professor Peter the Australian Cancer Research three advanced imaging microscopes Koopman and Dr Jo Bowles to study Foundation (ACRF). to conduct fluorescence imaging, how sperm and egg production begins The ACRF Cancer Biology Imaging which will allow researchers to in the foetus. Facility, the most advanced of its unravel the molecular reasons why kind in the Southern Hemisphere, healthy cells turn cancerous and TALENTED HEALTH AND MEDICAL was officially opened in February by spread through the body. RESEARCHERS WIN FUNDING the Governor of Queensland, Her Six IMB researchers were offered seven fellowships from the NHMRC and the ARC. grants IMB RESEARCH GETS $4.6 MILLION FUNDING BOOST Professor Jenny Stow and Dr Matt Sweet were offered NHMRC Research IMB received $4.6 million from the HEALTHY BOOST FOR MEDICAL Fellowships, while Dr Mathias Francois NHMRC in January 2010, including a RESEARCH from the Koopman group received a $4 million Australia Fellowship awarded The health industry of the future could Career Development Award and Dr to Professor John Mattick, AO. This is involve growing therapeutic drugs Richard Allen from the King group Australia’s most prestigious Fellowship in in seeds and fighting tumours with was awarded a Postdoctoral Training the fields of health and medical research. scorpion venom after these and other Fellowship. These four fellowships projects from the IMB were funded Professor Mattick will use the fellowship represent a quarter of the NHMRC by the National Health and Medical to further explore his theory that so- fellowships awarded to The University of Research Council (NHMRC). called ‘junk’ DNA actually specifies a Queensland. hidden layer of regulatory information IMB researchers received over $6 Dr Matt Sweet, Dr Brett Collins and Dr essential to human development, million in NHMRC grants, more than a Ben Hogan were all offered ARC Future brain function and gene-environment fifth of UQ’s total of around $29 million. Fellowships, which are aimed at mid- interactions. If Professor Mattick is Professor Melissa Little and Dr Nick career researchers and academics. correct, the project will transform our Hamilton received $691,310 to study understanding of human biology and kidney development to improve our intelligence and create an enlightened understanding of chronic kidney disease, framework for future research into while $689,784 went to Professor Matt human health and disease. Cooper to develop new antibiotics to treat resistant bacteria. 13 highlights

IMB HIGHLIGHTS 2010

QUEENSLAND GOVERNMENT $5 MILLION FOR RESEARCH INTO Aedes aegypti mosquito, BOOST FOR CLEAN FUELS BREAST CANCER RECURRENCE the carrier of dengue fever RESEARCH An IMB researcher is part of a team that Queensland Premier Anna Bligh received a $5 million National Breast announced nearly $1.5 million in Cancer Foundation grant to develop funding to Associate Professor treatments to target the recurrence of Ben Hankamer and collaborators breast cancer. for the development of low-cost, Professor Alpha Yap is one of eight high-productivity microalgal photo- chief investigators on the project, led bioreactors. by Professor Erik Thompson from St A photo-bioreactor is basically a Vincent’s Institute and the University of sealed aquaculture system that Melbourne. The team will focus on a brings in sunlight to provide the series of cellular changes that make cells energy the algae need to grow and more mobile and more likely to survive in produce biofuels such as biodiesel new environments. and hydrogen. Cells that have undergone this process The Queensland Government can move away from the primary tumour investment will enable the and plant themselves in a new part researchers to test the economic of the body, remaining dormant until RESEARCHERS LINK UP TO feasibility of scaled-up, new- they arise in the future as a secondary DEVELOP DENGUE TEST generation algal energy systems and tumour. Most fatalities in breast cancer Professor Matt Cooper and his has attracted a further $2 million in are due to secondary tumours, hence group will team with Alere Australia support from industry and UQ. the importance of studying this process. to develop a cheap, simple test for diagnosing dengue fever in its early stages. The project received RESEARCH INFRASTRUCTURE IMB RESEARCHERS BUILD LINKS $225,000 from the ARC’s Linkage GIVEN HALF-MILLION DOLLAR WITH THE WORLD program, which links university BOOST Two researchers from the IMB will researchers with industry partners. A team of scientists in Brisbane collaborate with international experts Dengue virus is re-emerging as a and Cairns, led by Professor Paul to overcome obstacles to algal biofuel global health problem, with over Alewood, received a half-million dollar production and the development 2.5 billion people in 100 countries grant to explore Queensland’s flora of drugs to treat antibiotic-resistant at risk. Early, accurate detection is and fauna for useful molecules. infections. vital both for limiting transmission and treating the patient so the The $550,000 Australian Research Professor Jenny Martin and Evan disease doesn’t progress to dengue Council Linkage Infrastructure, Stephens were both awarded Queensland haemorrhagic fever. Globally, only Equipment and Facilities grant, International Fellowships, which give about three percent of people awarded to a team of UQ and James researchers the opportunity to travel infected with the virus are currently Cook University (JCU) researchers, overseas for at least 12 weeks to undertake being accurate diagnosed. will be used to establish a facility for a high-quality, technically feasible and “A low-cost device able to diagnose identifying molecules that can act as strategically valuable project with a leading dengue in the field will be of major markers and treatments for disease. international knowledge partner. benefit in controlling a disease that predominantly affects developing “This new facility will markedly The applications from both IMB countries where ready access accelerate the discovery and researchers were selected as the best to high-level medical facilities is development of molecules from in their category, with Professor Martin’s limited,” Professor Cooper said. Queensland organisms with the in the Biotechnology category and Mr “The proposed device would remove potential to lead to new therapies for Stephens’ falling under Renewable subjectivity from the interpretation of a range of difficult-to-treat diseases Energies. Professor Martin travelled to the test results and provide accurate including pain, cancer, autoimmunity, the UK to work with leading membrane early diagnoses, which will lead to improved strategic containment of allergies, obesity and infection,” protein expert Professor So Iwata outbreaks and better treatments to Professor Alewood said. in Cambridge for four months; Mr avoid serious secondary dengue Stephens visited collaborators in infections.” Germany, with whom he has been developing methods to increase and harvest fuel production from microalgae. imb annual report 2010 14

IMB FELLOWSHIP FOR PLANT BIOLOGIST Research into using plant seeds to produce otherwise costly drugs has snagged Dr Joshua Mylne the inaugural IMB Fellowship, the Professor John S. Mattick Fellowship. The IMB Fellows program was established by the Institute in 2010 and aims to provide support for outstanding senior postdoctoral scientists to transition to independent researchers. The fellowship was named after Professor John Mattick, co-founder and inaugural Director of the IMB. Dr Mylne will use the $90,000 fellowship to help support his research into the way sunflower seeds manufacture proteins, a process he believes could be modified to produce protein drugs.

Professor John Mattick presents Dr Joshua Mylne with his John S. Mattick Fellowship certificate. awards IMB RESEARCHER ONE OF TOP HONOURS STUDENTS HIGHEST-RANKED IN NATION AWARDED

WORLD’S LARGEST SCIENTIFIC Professor Rob Parton was recognised The best IMB honours students of the SOCIETY AWARDS IMB as being one of the best and brightest past two years were recognised with an RESEARCHER in the country at the NHMRC awards, awards presentation in late March. The held in March. Professor Parton received Amgen Award is given to the overall best An IMB researcher developing a drug the Achievement Award for having the IMB honours student in a particular year, for pain from cone snail venom has Highest-Ranked Project Grant. with the winner being decided based on been awarded a prestigious prize from grades for the honours thesis and the the world’s largest scientific society. These grants are awarded by the council overall honours mark. Professor David Craik won the Ralph F. to fund specific projects, and each Hirschmann Award in Peptide Chemistry application is individually ranked. Out of The 2008 winner was Elanor Wainwright, from the American Chemical Society. the 683 grants awarded across Australia who completed her thesis in the in 2009, Professor Parton’s application Koopman/Wilhelm laboratories. Ms Peptides are small proteins that play was ranked the highest. Wainwright’s project explored the role a number of important roles in the of Mir-202, a type of RNA, in gonad body. Professor Craik was recognised His project will investigate ways of treating development. for his work with circular peptides, prostate cancer through suppressing the known as cyclotides. He described the secretion of a protein called caveolin. This Sheila Barbero and Anne Sawyer shared first cyclotide and has been a major protein is normally embedded in the cell the award in 2009. Ms Barbero, from contributor to the field ever since. surface but in aggressive forms of prostate the Fairlie group, studied a type of cancer it is secreted from cancerous cells enzyme that has potential therapeutic One of his most significant achievements and promotes the progression of the benefits if used after a stroke. Ms is the engineering of a new circular disease. Sawyer investigated the purification peptide to treat pain. Normal peptides and characterisation of a protein can relieve pain but are unstable, while from a species of green algae, which the circular version created by Professor IMB RESEARCHERS TOP STATE the Hankamer group are genetically Craik has proven effective at treating WITH PAIN AND IMMUNE modifying to produce commercial pain in early trials. RESEARCH quantities of hydrogen and other IMB researchers took out half of the biofuels. All three women have gone on awards on offer at the 2010 Queensland FIVE IMB GRADUATES’ THESES IN to PhD study within the IMB. TOP TEN PERCENT Health and Medical Research Awards. Dr Richard Clark won Senior Researcher Five IMB students made the Dean’s of the Year for his work on developing a STUDENT PRIZES Awards List for Outstanding Research medication for chronic pain using cone For a detailed list of other student prizes Higher Degree Theses: Dr Ming snail venom, while Dr Kate Schroder won in 2010, please turn to page 69. Chang (Sweet group), Dr Conan Wang Postdoctoral Researcher of the Year for (Craik group), Dr Markus Muttenthaler completing the first comparison of mice (Alewood group), Dr Ryan Taft and Dr and human innate immune systems. Tim Mercer (Mattick group). 15 highlights

IMB HIGHLIGHTS 2010

TINY FISH MAY HOLD KEY TO CANCER AND LYMPHATIC DISEASE BREAKTHROUGHS An IMB researcher is using small transparent fish as a weapon in the battle against cancer and lymphatic disease. Dr Ben Hogan won a $70,000 UQ Foundation Research Excellence Award to advance his work using zebrafish to study the development of the lymphatic system. Lymphatic vessels form a network similar to that of blood vessels to transport fluid, immune cells and fats around the body, and are also the route through which cancer spreads. “Despite these major functions, the lymphatic system remains one of the Ernest Tee, Bachelor of most understudied organ systems in Science Valedictorian and terms of its development,” Dr Hogan IMB honours student said. “We have identified several zebrafish mutants that develop without lymphatic vessels, and will genetically map four of these mutants and identify PERFECT SCORE FOR IMB HONOURS STUDENT genes essential for lymphatic vessel development.” Ernest Tee, an honours student from Mr Tee successfully manufactured an the Cooper group, was named the artificial version of essramycin and Valedictorian of the UQ Bachelor also confirmed its chemical structure. Dr Ben Hogan in the zebrafish facility. of Science, coming first in his However, he found that the synthetic graduating class of 332 Bachelor essramycin was inactive against of Science and 162 Bachelor of all major bacterial strains that were Science (Honours) students with tested. a grade point average of 7.0 – a “This was in direct contrast to its perfect score. reported antibacterial activity,” Mr Mr Tee’s honours project involved Tee said. “My project confirmed that synthesising a chemical compound essramycin is not a suitable molecule called essramycin that supposedly for treating antibiotic-resistant demonstrated antibacterial activity. bacteria.”

commercialisation

BIOTECH BOSS APPOINTED TO industry organisation for Australia’s NATIONAL BOARD biotechnology sector, representing over An IMBcom executive will have a hand 3000 members. in driving the nation’s biotechnology “I welcome the opportunity to contribute agenda with his appointment to the to the progress of the industry through Ausbiotech board. the governance system of a very Dr Peter Isdale, AM, CEO of IMBcom, effective advocate for its members,” the commercialisation company for the Dr Isdale said. “We are in exciting IMB, was appointed to the board in and prospective times where the life August 2010 to replace retiring member sciences-based industries are providing Dr Simon Carroll. AusBiotech is the responses to global challenges.” imb annual report 2010 16

IMB ADVISORY BOARD

PROFESSOR PAUL GREENFIELD In 2006 he was appointed an Officer in AO (CHAIR) the Order of Australia for his contribution Professor Paul Greenfield, AO, is to science and engineering through Vice-Chancellor of The University of research in chemical engineering, Queensland. Professor Greenfield wastewater and environmental graduated with first-class honours in management, biotechnology and to Chemical Engineering from the University the tertiary education sector. Professor of New South Wales (UNSW) and Greenfield won the Chemeca Medal in worked in the private sector before 1995, awarded jointly by the Institution completing a PhD at UNSW. He then of Chemical Engineers and the Institute worked at CSIRO before winning a of Engineers Australia for outstanding three-year fellowship to the U.S. contribution to the profession.

In 1975 Professor Greenfield joined The University of Queensland as a lecturer PROFESSOR BRANDON in chemical engineering, and a decade WAINWRIGHT (IMB DIRECTOR) later became Head of Department and Professor Brandon Wainwright was then Pro-Vice-Chancellor (Physical appointed Director of the Institute for Sciences and Engineering) before Molecular Bioscience in late 2006. being appointed an inaugural Executive Previously, he was the Deputy Director Dean. In 1997 he was appointed as (Research) of the IMB from 2002. Deputy Vice-Chancellor and from 2002 to 2007 served as UQ Senior Deputy Professor Wainwright completed his Vice-Chancellor, before becoming Vice- undergraduate and postgraduate studies Chancellor in 2008. at the University of Adelaide, after which he took up a postdoctoral fellowship at Professor Greenfield has extensive St Mary’s Medical School, the University experience as a Board Director and of London. He remained at St Mary’s for is currently Director on a number of six years, eventually becoming a Medical company boards. He has consulted and Research Council Senior Research Fellow. worked widely with industry on a range of projects, as well as on the economic In 1990, he moved back to Australia, evaluation of projects. His interests joining the Centre for Molecular and lie in biotechnology, environmental Cellular Biology (CMCB) at The University management, and R & D management of Queensland. Professor Wainwright and commercialisation. stayed with the CMCB when it was merged with another UQ Centre (the Professor Greenfield chairs the Group of Drug Design and Development Centre) in Eight, a network of research-intensive 2000 to create the Institute for Molecular Australian universities, and the Australian Bioscience. Nuclear Science and Technology Organisation. He is also Chair of the In addition to being Director of the IMB, Scientific Advisory Group of the South Professor Wainwright serves on a number East Queensland Healthy Waterways of boards, including those of the Australian Partnership, the Expert Panel on Purified Genome Research Facility, the Australian Recycled Water, the Riversymposium Stem Cell Centre, the Mater Medical Strategic Planning Committee, Research Institute and the Health and Medical Research Council of Queensland. Left column, from top: the Thiess International Riverprize Prof. Paul Greenfield, Prof. Brandon Wainwright, Committee and the International He has served as assessor for both Prof. Frank Gannon, Dr Russell Howard, Water Centre. Professor Greenfield the NHMRC and ARC on a number of Dr Peter Isdale is a member of the Defence Science occasions. Right column, from top: and Technology Organisation Advisory Professor Wainwright’s major research Prof. Nicos Nicola, Prof. Deborah Terry, Board, representing the academic and focus is the use of genomic approaches Prof. Stephen Walker, Dr Jane Wilson research community. to dissect the basis of common genetic 17 boards & committees

IMB Advisory Board

disease. He led the team responsible of the European Molecular Biology Australia’s national marine research for finding the origins of the often-fatal Council, and Senior Scientist at the agency. He is also a former Principal brain tumour, medulloblastoma, and he European Molecular Biology Laboratory Research Scientist at AIMS, and is also studying cystic fibrosis and basal (EMBL) in Heidelberg, Germany. His authored or co-authored more than 30 cell carcinomas of the skin. Through major research interest is the Estrogen papers in his field of marine and climate the mapping and isolation of the genes Receptor as a Transcription Factor and research. responsible for these diseases, he has epigenetics. He has 20 years of experience in the continued to follow through on each to He has published over 200 research operation and governance of private, understand how the genetic defects lead articles. In addition, he has been public and ASX-listed companies in to the disease. involved in the establishment of two Australia, Asia and the Pacific Rim. He The ultimate aim of his work is to discover spin-out companies and is a member is a Member of the Australian Institute of the genes which, when altered, cause of an advisory group to the European Company Directors. Dr Isdale currently the tumour cell to grow in an uncontrolled Commissioner for Research and holds six non-executive directorships fashion. Ultimately this will provide Innovation. in biotech companies, senior positions validated targets against which potential on Foundations around the world and therapeutics can be developed. is an Adjunct Professor at Texas A&M DR RUSSELL HOWARD University. Dr Howard is currently CEO and founder He holds a PhD in Marine IAN FLETCHER of Oakbio Inc., a cleantech company Geomorphology (1982) from James Ian Fletcher is the Director-General of the in California developing sustainable Cook University. In 2006 he was Queensland Government’s Department microbe-based technologies for making awarded an Order of Australia (AM) of Employment, Economic Development valuable chemicals currently made by for service to marine science through and Innovation (DEEDI). He has served the petrochemical industry. He is also research and as a contributor to the in a number of high-level public-sector founder and former CEO of Maxygen, a development and commercialisation of roles during his 27-year career. Mr company focused on optimisation and biotechnology. Fletcher held positions in the New development of significantly improved Zealand diplomatic service, then joined proprietary versions of marketed protein the United Kingdom civil service in 1989. pharmaceuticals. Maxygen also created PROFESSOR NICOS NICOLA, AO He worked for UK Trade and Investment businesses in agriculture (Verdia) and Professor Nicos Nicola is an ex officio in arranging the UK’s overseas chemicals manufacture (Codexis). member of the IMB Board, as he commercial network, before becoming Originally trained in biochemistry serves as the Chair of the IMB Scientific Chief Executive and Comptroller-General and chemistry at the University of Advisory Committee. He is Assistant of the Intellectual Property Office. Melbourne, Dr Howard spent over 20 Director of the Walter and Eliza Hall Mr Fletcher’s career comprises extensive years studying infectious diseases, Institute, as well as Joint Head of their experience in trade and investment, and primarily the molecular basis for the Cancer and Haemotology Division and a he has already established a substantial pathology of malaria. Before joining Research Professor of the University of understanding of DEEDI’S business and Maxygen, Dr Howard served at research Melbourne. the key economic drivers and challenges institutes, biotechnology companies Professor Nicola completed both his facing Queensland’s economy. and a pharmaceutical company both in undergraduate and postgraduate Australia and overseas, particularly in the degrees at the University of Melbourne, USA. In addition to numerous patents, before working for a year at Brandeis PROFESSOR FRANK GANNON Dr Howard has over 140 publications in University in Massachusetts, USA. He Professor Gannon has been the Director- peer-reviewed journals. then joined the Walter and Eliza Hall General of Science Foundation Ireland Institute in 1977. since mid-2007. In January 2011 he will relocate from Dublin to Brisbane to take DR PETER ISDALE, AM He is responsible for major discoveries up a role as Director of the Queensland Dr Peter Isdale, AM, is the CEO of including the purification of mouse Institute of Medical Research. IMBcom Pty Ltd., The University G-CSF, the definition of the human of Queensland’s commercialisation equivalent of G-CSF and the purification From 1994-2007, Professor Gannon company for the IMB. He is a former of Leukaemia Inhibitory Factor. Professor was the Executive Director of Business Director at the Australian Nicola has published over 250 journal the European Molecular Biology Institute of Marine Science (AIMS), articles and 20 patents. Organisation (EMBO), Secretary-General imb annual report 2010 18

PROFESSOR DEBORAH TERRY PROFESSOR STEPHEN WALKER DR JANE WILSON Professor Terry is the Deputy Vice- Professor Stephen Walker is the Dr Jane Wilson is a professional Chancellor (Academic) of The University Executive Dean of the Faculty of Science company director with a background of Queensland. Her role is to preserve at The University of Queensland. In this in medicine, finance, banking and UQ’s commitment to providing high- role, Professor Walker is responsible consulting and has over 20 years quality university teaching. for the academic leadership and of experience in business strategy, management of one of the largest corporate governance and the Areas under Professor Terry’s direct and most diverse science faculties in commercialisation of research in both management include the six UQ Australia. agricultural and biotechnology sectors. research institutes; the UQ Graduate School; Office of Undergraduate Professor Walker was appointed as She has a Masters degree in Business Education; Office of Prospective Executive Dean for Engineering, Physical Administration from the Harvard Students and Scholarships; the Teaching Sciences and Architecture at The Business School where she studied and Education Development Institute; University of Queensland in February agribusiness and the health sector. Centre for Educational Innovation and 2006 and then Executive Dean of the Dr Wilson is the current Chair of Technology; Centre for Innovation in Faculty of Science from January 2009. IMBcom (The University of Queensland’s Professional Learning; and the Student Prior to these positions, he spent commercialisation company for the and Administrative Services Division. five years at the Australian Research Institute for Molecular Bioscience) Council (ARC), as Executive Director Professor Terry completed a Bachelor and a Director of the General Sir John for Engineering and Environmental of Arts and a PhD in Psychology at the Monash Foundation, Sonic Healthcare Sciences, and as Acting CEO for a Australian National University and began Ltd, CathRx Ltd, UQ Holdings Ltd, substantial part of 2004. In these roles, at The University of Queensland as a Universal Biosensors Inc. and Union he was responsible for competitive postdoctoral research fellow, then as College. Dr Wilson is Finance Director research funding across a range of a lecturer. She was appointed Deputy of the Winston Churchill Memorial Trust discipline areas and schemes, including Head of the School of Psychology in and is a member of The University of management of the ARC Linkage 1997, then Head of School in 2000. Queensland Senate. Projects scheme, and had substantial Professor Terry accepted the position of input to Australian Government research Dr Wilson is also a Member of the Executive Dean, Faculty of Social and policy on issues such as research Yalari Advisory Board, a Fellow of Behavioural Sciences in 2006, before funding schemes, research infrastructure the Australian Institute of Company being appointed half-time as Pro-Vice- and research priority areas. Directors, past Queensland President of Chancellor (Teaching and Learning) the AICD and National Board Director Professor Walker has broad research in 2007and Deputy Vice-Chancellor of AICD and is currently on the AICD interests, including numerical modelling Advisory Panel. She was the inaugural (Teaching and Learning) in 2008. and development of instrumentation Chairman of Horticulture Australia Ltd in areas such as atmospheric and Professor Terry’s primary research from 2000 to 2004 and was a Director of oceanographic plume dispersion, interests are in the areas of attitudes, the National Archives Advisory Council remote sensing, coastal oceanography social influence, persuasion, group for six years from 2002 to 2008. processes and intergroup relations. She and eutrophication, and also in also has applied research interests in medical research (electrocardiology). She is involved in a number of charitable organisational and health psychology He has extensive experience in and cultural organisations and has and has published widely in these areas. collaborative research, in conjunction also served on the Premier’s Smart with Government agencies, utilities and State Council and the Queensland Professor Terry is a Fellow of the private industry. Government Biotechnology Taskforce Academy of Social Sciences in Australia, and the boards of Energex Ltd, a Fellow of the Australian Psychological WorkCover Queensland, AGEN Society, previous chair of the Australian Biomedical Ltd and Protagonist Ltd. Research Council’s College of Experts in the social, behavioural and economic sciences, and past President of the Society for Australasian Social Psychology. She currently holds editorial positions with the British Journal of Psychology and the European Journal of Social Psychology. 19 boards & committees

IMB SCIENTIFIC ADVISORY COMMITTEE

PROFESSOR NICOS NICOLA PROFESSOR CHRIS MARSHALL (CHAIR) Centre for Cell and Molecular Biology Professor of Molecular Haemotology Institute of Cancer Research UK Assistant Director Walter and Eliza Hall Institute of Medical PROFESSOR JILL MESIROV Research, Melbourne, Victoria Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA PROFESSOR CHRIS ABELL

Professor in Biological Chemistry PROFESSOR GREG PETSKO Department of Chemistry Gyula and Katica Tauber Professor of University of Cambridge, UK Biochemistry and Chemistry Director, Rosenstiel Basic Medical PROFESSOR DAVID GALAS Sciences Research Center Vice-President Brandeis University, Boston, Chief Academic Officer & Norris Professor Massachusetts, USA of Applied Life Sciences Keck Graduate Institute of Applied Life PROFESSOR MARINO ZERIAL Sciences, Claremont, California, USA Max Planck Institute of Molecular Cell Biology, Dresden, Germany PROFESSOR NANCY JENKINS Co-Director Institute of Molecular and Cell Biology, Singapore

PROFESSOR ROBB KRUMLAUF Left column, from top: Director Prof. Nicos Nicola, Prof. Chris Abell, Prof. David Stowers Institute, Kansas City, Galas, Prof. Nancy Jenkins, Missouri, USA Prof. Robb Krumlauf. Right column, from top: Prof. Chris Marshall, Prof. Jill Mesirov, Prof. Greg Petsko, Prof. Marino Zerial.

SUSAN NIXON: EMBER Mirror images of a human prostate cancer cell line (PC3) transfected with a mitochondrial marker imb annual report 2010 20

IMB RESEARCHERS 21 xxxxx

Division of GENOMICS & COMPUTATIONAL BIOLOGY

In 2010 the Division’s research in genomics, computational biology and bioinformatics was led by six Group Leaders (Dr Tim Bailey, Professor Sean Grimmond, Professor John Mattick, Professor Mark Ragan, Associate Professor Rohan Teasdale, Dr Nick Hamilton) one Joint Appointee (Professor Geoff McLachlan) and one Affiliate (Professor Jane Hunter).

NICOLE CLOONAN: COLOUR SPACE This image depicts the DNA sequence of human chromosome 21 represented in colour-­space, enhanced electronically to resemble an image seen in a kaleidoscope. imb annual report 2010 22

FELLOWSHIPS AND AWARDS three tumours and three matched GRANT FUNDING AND RESEARCH Professor John Mattick was awarded normals per month. The senior team In 2010, group leaders in the Division an NHMRC Australia Fellowship. This expect the sequencing rate to rise held over $14 million* in competitive five-year fellowship, worth $4 million, is in 2011, with the arrival of upgraded grants. Some of the new grants received designed for leading health and medical equipment from Applied Biosystems. in 2010 included a $691,310 grant from researchers both from Australia and The senior team for the National NHMRC, on which Dr Nicholas Hamilton overseas. Professor Geoffrey McLachlan Computational Infrastructure was a Chief Investigator with Professor was awarded the Pitman Medal by the Specialised Facility in Bioinformatics, Melissa Little from the Molecular Statistical Society of Australia. This gold and the EMBL Australia EBI Mirror, was Genetics and Development division. medal recognises great achievement appointed in 2010. Dr David Green The grant involves gaining a better in the field of statistics, and Professor was seconded as Project Manager understanding of kidney disease through th McLachlan is only the 18 recipient from his role as Manager of the high- studying nephron formation. Dr Hamilton since the prize was established in 1978. performance computing group at UQ will use his novel approaches to image- Dr Ryan Taft, a postdoctoral researcher ITS. Dr Gerald Hartig, Gavin Graham based modelling of cellular processes to in the Mattick group, was a finalist in two and Peter Scott accepted roles as contribute to improving our knowledge Eureka Prizes, the Early Career Research Senior IT Managers for development of of kidney development. Professor Mark Award and the People’s Choice Award. Applications, Systems and Web Services Ragan and Professor Lars Nielsen (AIBN) Dr Taft was selected for his examination respectively. Dr Hartig is a former IMB received a $340,000 grant from ARC to of the non-coding portion of the human PhD student who has since spent study the genetic sequences of more genome, known informally as ‘junk DNA’. time in IT management positions in than 700 pancreatic tumours. He will He discovered, in collaboration with telecommunications and biotechnology compare the tumour genomes to those Professor Mattick, tiny RNAs (tiRNA), organisations. of undiseased tissue in order to identify the smallest-yet discovered segments the mutations that disrupt the process of of genetic material that may play a The ARC Centre of Excellence in normal development and cause cancer. role in gene expression. Dr Taft was Bioinformatics marked its final year in 2010. The Centre links 16 groups of awarded a Dean’s Commendation for an MAJOR PUBLICATIONS Outstanding Research Higher Degree researchers at five Australian and four The division’s group leaders published Thesis, as was Tim Mercer, also from the international institutions to develop in a range of high-ranking international Mattick group. an understanding of how genomic information is translated into structures journals throughout the year, including and functions within the mammalian cell. Nature (Grimmond), Cell (Grimmond, CENTRES AND FACILITIES The Centre was originally funded for five Teasdale), Nature Methods (Grimmond, The Queensland Centre for Medical years, from 2003 until 2007, after which Hamilton, Ragan), Nature Structural Genomics (QCMG) was officially opened time the ARC conducted a review and and Molecular Biology (Mattick), in June by Queensland Premier Anna not only extended the funding for the Bioinformatics (Bailey, Ragan) Bligh. Professor Sean Grimmond, Centre for another three years, but also Developmental Cell (Mattick), Genome QCMG Director, and his team continue upgraded it to a Centre of Excellence. Research (Bailey, Mattick, Grimmond), to make rapid progress in sequencing Many components of the Centre’s and Stem Cells (Grimmond). pancreatic and ovarian tumours as part research will continue under external of the International Cancer Genome grant and fellowship funding. The Consortium. At the end of 2009, the Centre’s annual national Winter School team had sequenced around 1 terabase in Mathematical and Computational of patient samples. One year on, they Biology, which in 2010 attracted 261 are close to achieving 10 terabases of registrants from 41 institutions across genetic material, at a rate of roughly Australia and ten other countries, will be continued under funding from Bioplatforms Australia and EMBL Australia. 23 imb researchers: genomics & computational biology

TIMOTHY L. BAILEY PATTERN RECOGNITION AND MODELLING IN COMPUTATIONAL BIOLOGY

were then validated in the laboratory by KEY PUBLICATIONS the Richards group at QBI. This work Bailey, T.L. et al. (2010). The value of illuminates a small part of the regulatory position-specific priors in motif discovery network of neural development. Similarly, in using MEME. BMC Bioinformatics 11: collaboration with the Little group at IMB, 179. we made computational predictions of the binding targets of several transcription Bauer, D.C., Buske, F.A., and Bailey, T.L. factors that guide kidney development. (2010). Dual-functioning transcription These predictions are currently being factors in the developmental gene network verified in the lab, and we hope to publish of Drosophila melanogaster. BMC this work early in 2011. Bioinformatics 11: 366. Bauer, D.C. et al. (2010). Predicting Our continuing work on modelling SUMOylation sites in developmental transcriptional regulation in the fruit fly transcription factors of Drosophila uncovered a possible explanation for how melanogaster. Neurocomputing 73: 2300- some transcription factors can act both as 2307. activators and repressors of transcription. WE DEVELOP AND UTILISE The explanation lies in the ability of some Buske, F.A., Boden, M., Bauer, D.C., computational methods to understand transcription factors to be altered by the and Bailey, T.L. (2010). Assigning roles to biological processes, especially the addition of SUMO—a covalent protein DNA regulatory motifs using comparative regulation of gene expression. Knowing modification—possibly affecting their genomics. Bioinformatics 26: 860-866. how gene expression is regulated is regulatory function. We also developed essential to understanding cellular McLeay, R., and Bailey, T.L. (2010). a computational model for predicting processes such as reproduction and Motif Enrichment Analysis: A unified the trafficking of particular proteins to metabolism. Currently we focus on three framework and method evaluation. BMC compartments within the nucleus, and a areas: 1) regulation of transcription, Bioinformatics 11: 165. model for predicting the stability of proteins 2) the organisation and stability of directly from their sequence. Piper, M. et al. (2010). NFIA Controls nuclear proteins, and 3) the formation of Telencephalic Progenitor Cell nucleic acid triple helices. By studying We also continued our work on combining Differentiation through Repression of transcription, sub-cellular protein genomic and epigenomic data in a single the Notch Effector Hes1. Journal of organisation and protein stability, we focus model to predict where transcription Neuroscience 30: 9127-9139. on three key steps in gene expression. factors bind in the genome in a particular Our work on nucleic acid triple helices is tissue. This approach, pioneered by us, Sato, K. et al. “Improved Prediction of Transcription Binding Sites from partly motivated by recent evidence that proved to be much more effective than Chromatin Modification Data’’, suggests that these, too, may play a role in previous methods. We are continuing this Proceedings of the IEEE Symposium gene expression. work, and will be incorporating it into our on Computational Intelligence in sequence analysis workbench (MEME In 2010, we collaborated with three Bioinformatics and Computational Biology SUITE), which is used by thousands of groups at UQ to unravel the roles of key (CIBCB2010), pp. 1-7, May, 2010. biologists. This year we published three regulators of development. This work major improvements to the algorithms Tallack, M.R. et al. (2010). A global role for studied the molecular program controlling in the MEME SUITE, created a mirror KLF1 in erythropoiesis revealed by ChIP- the development of three types of cell: red site at QFAB, and finalised a licensing seq in primary erythroid cells. Genome blood cells, neurons and kidney cells. Our agreement among UQ, UCSD and the Research 20:1052-1063. study (in collaboration with the Perkins University of Washington for continued group at IMB) of how the transcription commercialisation of the software. factor Klf1 controls the development that LAB MEMBERS leads to red blood cells was made possible In the coming year we will continue Research Fellow: Dr Mikael Boden by the use of recently developed high- to develop models and predictors of throughput DNA-sequencing technology. transcriptional regulation and proteins. Research Officers: Dr Chris Leat, Dr We developed and refined several In collaboration with groups in the state Philip Machanick, Dr Kai Willadsen algorithms for analysing the DNA-binding of Washington and in Mexico, we will PhD Students: Denis Bauer, Tom signals of transcription factors contained develop more sensitive ways of predicting Whitington, Robert McLeay, Fabian in this new type of data. This allowed us to transcription-factor binding using Buske, Ahmed Mehdi map part of the genetic regulatory network epigenomic data. We will also continue Honours Student: Ralph Patrick controlling red blood cell development. our work on protein stability prediction and Using more conventional computational nuclear organisation. Finally, we are about Undergraduate Intern: Gabriel Cuellar means, we identified putative regulatory to start experimentation with a new type of Programmer: James Johnson targets of NFIA, a key regulator of neural microarray to study the formation of nucleic precursor cell development in certain acid triple helices, which we hope will shed regions of the brain. These predictions light on the potential in vivo roles of this structure. imb annual report 2010 24

SEAN GRIMMOND QUEENSLAND CENTRE FOR MEDICAL GENOMICS

THE QUEENSLAND CENTRE FOR sequence variation (SNPs and mutations). Medical Genomics (QCMG) was officially It also provides an opportunity to study opened by the Premier of Queensland, novel expression events (including the Hon. Anna Bligh, MP, on June 16, retrotransposon expression, the complexity 2010. The laboratory is focused on in small RNAs and identification of novel globally surveying genomic, transcriptomic non-coding RNAs). We are actively and epigenomic information using next- engaged in RNAseq studies to create a generation sequencing and array-based human and mouse tissue transcriptome approaches, and then integrating this atlas, study transcriptome complexity in data to define the underlying molecular human Embryonic Stem Cells (hESCs) and networks controlling biological processes inducible Pluripotent (iPS) cells, as well as (such as cell division and differentiation) surveying transcriptome content during the and pathological states (pancreatic, ovarian cell cycle. and breast cancer). This systems-wide approach will provide the means to identify key genes driving specific phenotypes RESEARCH PROJECTS and also the chance to model the different • Sequencing the mammalian of the technology and scientific steering layers of control guiding biological states. transcriptome in toto committees) (2010). International network of cancer genome projects. Nature 464: Defining the complete repertoire of • Phasevarions of pathogenic neisseria 993-998. mutations driving pancreatic and • Predicting the function of onco-miRs ovarian cancer development and through mRNA-mRNA networks progression LAB MEMBERS The next-generation sequencing facility • Functionally characterising mammalian Executive Officer: Dr Peter Wilson at QCMG has been actively scaling the microRNA-mRNA interactions Senior Research Officers: Dr Brooke output required for the International • Defining the complete repertoire of Gardiner, Dr Nicole Cloonan, Dr Nic Cancer Genome Consortium (ICGC) genetic damage driving development Waddell, Dr Lynn Fink, Dr Sarah Song project with Australia’s contribution and progression of breast cancer in a covering pancreatic cancer and a smaller Research Officers: Dr Karin Kassahn, Dr mouse model subset of ovarian cancer patients. The Katia Nones, Dr Craig Nourse, Dr Conrad informatics pipelines needed to handle Leonard, Dr Jason Steen, Dr Jill Shepherd the data output have been established, KEY PUBLICATIONS Research Assistants: Anita Steptoe, with many of the tools created in house; Chiu, H.-S. et al. (2010). A comprehensive Suzanne Manning, David Miller, Milena the focus for the informatics group over catalogue of gene expression in the Gongora, Shivangi Wani, Ehsan the next 12 months will be on automating developing lower urinary tract and genital Nourbakhsh, Ivon Harliwong, Senel many of the manual steps still used which tubercle reveals strong links with cadherin Idrisoglu, Scott Wood, Darrin Taylor, Oliver will allow the ICGC project to be scaled and Wnt signaling and identifies epidermal Holmes, Matthew Anderson, William appropriately. The ICGC’s ultimate aim gene networks in the developing genital Waterson, Qinying Xu is to create comprehensive genomic, tubercle. Developmental Biology 344: transcriptomic and epigenomic atlases of 1071-1087. PhD Students: Rathi Thiagarajan, the molecular changes arising in human Keerthana Krishnan, Mellissa Brown, Cloonan, N., and Grimmond, S.M. (2010). tumours. The consortium will achieve this David Wood Simplifying Complexity. Nature Methods by characterising up to 50 different tumour 7: 793-795. Honours Students: Hilary Martin, types and/or subtypes from across the Muhammad Fudlullah globe over the next five years. Mercer, T.R. et al. (2010). Regulated post- transcriptional RNA cleavage diversifies Studying mammalian the eukaryotic transcriptome. Genome transcriptomes at single nucleotide Research 20: 1639-1650. resolution Schmeier, S., et al. (2010). An Atlas of We are continuing to actively survey the Combinatorial Transcriptional Regulation transcriptional complexity in specific in Mouse and Man. Cell 140: 744-752. biological states using a next-generation sequencing approach (RNAseq) in an effort Tallack, M. et al. (Grimmond, S.M. listed to put newly discovered transcripts into a as a corresponding author) (2010). A functional context. RNAseq supersedes global role for KLF1 in erythropoiesis traditional array-based expression revealed by ChIP-seq in primary erythroid profiling as it allows us to simultaneously cells. Genome Research 20: 1052-1063. Heatmap of kidney markers from a panel of embryonic tissues (12.5dpc). monitor gene activity, study alternative The International Cancer Genome splicing events, identify promoter and Consortium (Grimmond, S.M., listed as 3’ UTR usage, and capture expressed leader of the Australian project & member 25 imb researchers: genomics & computational biology

NICK HAMILTON MODELLING, VISUALISATION AND CLASSIFICATION OF LIVE CELL IMAGING

(OBCoL) system to segment and quantify individual structures from 3D and 4D whole-cell imaging. This approach has enabled the detailed analysis of spatial distribution of proteins on individual subcellular structures. The second is in building mathematical models of the subcellular systems observed based on the quantification methodologies of the first stream. For instance, dynamic geometric models based on live cell imaging have provided surprisingly detailed information Modelling and interference from video and insights into the systems observed microscopy imaging of cells. and have been used to predict biologically relevant and experimentally verifiable quantities such as pH change. Other HIGH-THROUGHPUT SCREENS FOR interests include modelling of recruitment applications such as drug and genomic and expulsion of proteins from membranes. discovery are leading to massive image The group is strongly multidisciplinary and sets in need of new methods of analysis. collaborative, with a focus on delivering Further, live cells may now be imaged in methodologies and tools to be used by 3D over time with the interactions and researchers. dynamics of multiple proteins observed at high resolution. The core of my group’s research is to develop the methodologies, RESEARCH PROJECTS tools and mathematical models needed • Visualisation and automated to enable the full benefit of these rich new classification of bio-imaging via Visualising and quantifying protein data sources to be realised. distribution in the Visible Cell® machine learning [source data: K Beaumont]. As a Strategic Partner of the ARC Centre • The Visible Cell® software and science of Excellence in Bioinformatics, I am Science Leader on The Visible Cell® program project. This project integrates multi-scale • Mathematical modelling of kidney 3D cellular image data and reconstructions development with advanced bioinformatic methods for 75A: 941-950. • Statistical testing and content-based 3D spatial data query and annotation by incorporating an ontological foundation searching of bio-imaging Hamilton, N.A., Kerr, M.C., Burrage, K., and Teasdale, R.D. (2007). The dynamics with novel methods for processing • Mathematical modelling of endosomal and geometry of vesicles and tubules in semantic and imaging data. The aim systems from live cell video microscopy endocytosis. Current Protocols in Cell is to provide an environment in which imaging Biology Suppl. 35. K. Morgan, Ed. Wiley multiple sources of bio-data can be Interscience. easily integrated, queried, mathematically • Segmentation and quantification of 2D, modelled and visualised to generate 3D and 4D live cell imaging Hamilton, N.A., Pantelic, R.S., Hanson, and test biological hypotheses. Related K., and Teasdale, R.D. (2007). Fast projects include the Automated Subcellular KEY PUBLICATIONS automated cell phenotype image Phenotype Classifier (ASPiC), which classification. BMC Bioinformatics 8: 110. combines novel image statistics with Walter, T., Shattuck, D., Baldock, R., machine-learning methodologies to enable Bastin, M., Carpenter, A.E., Duce, S., Ellenberg, J., Fraser, A., Hamilton, N.A., rapid near-perfect-accuracy classification LAB MEMBERS Pieper, S., Ragan, M.A., Schneider, J., of high-throughput imaging and the iCluster Tomancak, P., and Hériché, J.-K. (2010). Research Officers: Dr Daniel Marshall, Dr high-throughput bioimage visualiser. Visualization of image data from cells to Oliver Caincross, Dr Matthew Moores Towards the analysis of 3D and 4D bio- organisms. Nature Methods 7: S26-S41. Co-supervised PhD Students: Alhadi imaging, the group has been developing Hamilton, N.A. (2009). Quantification and Bustamam, Mitchell Stanton-Cook, Intan two streams of research. The first is its applications in fluorescent microscopy Ruhaiyem, Josefine Sprenger in quantification, to extract the key imaging. Traffic 10: 951-961. Visiting Researcher: Dr John Belward parameters that describe the systems being observed. In this area we have Woodcroft, B.J., Hammond, L., Stow, developed the Object Based Colocalisation J.L., and Hamilton, N.A. (2009). Automated organelle-based colocalization in whole-cell imaging. Cytometry Part A imb annual report 2010 26

JOHN MATTICK THE CENTRAL ROLE OF RNA REGULATION IN HUMAN DEVELOPMENT AND COGNITION

IT APPEARS THAT THE GENETIC cells, neural stem cells, immune cells and programming of humans and other muscle, as well as in cancer, and that some complex organisms has been fundamentally of these RNAs are essential components misunderstood for the past 50 years, of subnuclear structures or complexed with because of the assumption that most particular types of activated chromatin. genetic information is transacted by We have also identified new classes of proteins. The human genome contains tiny RNAs associated with transcription about 20,000 conventional protein-coding start and splice sites, and shown that genes, surprisingly about the same number protein-coding sequences are preferentially and with largely similar functions as those located in nucleosomes, which provides in tiny worms that have only 1,000 cells. On a platform for epigenetic control of gene the other hand, the extent of non-protein- expression and transcript structure. coding DNA, traditionally thought to be We have also found that conventional junk, increases with increasing complexity, protein-coding mRNAs can also be reaching 98.8 percent in humans. Moreover, processed to produce regulatory RNAs, it is now evident that these non-coding and that RNA is the plastic substrate for sequences are transcribed in a dynamic epigenome-environment interactions. The Taft, R.J., et al. (2010). Nuclear-localized manner to produce tens, if not hundreds outcomes of our research will be to expand tiny RNAs are associated with transcription of thousands, of noncoding RNAs, and our understanding of human evolution, initiation and splice sites in metazoans. that most complex genetic phenomena are development, brain function and disease. Nature Structural & Molecular Biology 17: RNA-directed, which suggests that there 1030-1034. exists a vast hidden layer of regulatory RNAs that control human development and RESEARCH PROJECTS Mattick, J.S. (2009). The genetic signatures of noncoding RNAs. PLoS Genetics 5: brain function. • Characterisation of the transcriptome e1000459. Using a range of experimental and and identification of new classes of bioinformatic techniques, we are working in regulatory RNAs by targeted deep Mercer, T.R., et al. (2009). Long noncoding conjunction with collaborators in the United sequencing RNAs: insights into functions. Nature Reviews Genetics 10: 155-159. States, Europe and Japan to characterise • Characterisation and functional and understand the functions of these analysis of regulatory RNAs in normal Taft, R.J., et al. (2009). Tiny RNAs regulatory RNAs, and to validate our development and disease associated with transcription start sites in prediction that mammalian differentiation animals. Nature Genetics 41: 572-578. and development is primarily directed by • Characterisation of chromatin- sophisticated RNA regulatory networks that associated RNAs and identification of Amaral, P.P., Dinger, M.E., Mercer, T.R., interact with generic effector complexes RNA:DNA triplexes in the genome and Mattick, J.S. (2008). The eukaryotic genome as an RNA machine. Science 319: including transcription factors and • Characterisation of noncoding RNAs chromatin-modifying enzymes. 1787-1789. associated with subcellular organelles We have demonstrated that the majority • Analysis of the role of noncoding RNAs of long noncoding RNAs are expressed in in enhancer function LAB MEMBERS: precise cellular and subcellular locations Senior Research Officers: Dr Lynn Fink, • Analysis of the patterns of noncoding in the brain, that a subset of noncoding Dr Marcel Dinger RNAs are dynamically regulated during RNA evolution and structural parsing of the differentiation of embryonal stem the transcriptome Research Officers: Dr Marjan Askarian Amiri, Dr Joanna Crawford, Dr Lorenzo • Characterisation of the targets of RNA Malquori, Dr Timothy Mercer, Dr Ryan Taft editing enzymes and the phenotypic consequences of their inactivation Senior Research Assistant: Ke-Lin Ru PhD Students: Paulo Amaral, Pierre KEY RECENT PUBLICATIONS Cattenoz, Anupma Choudhary, Michael Clark, Dennis Gascoigne, Chol Hee Jung, Mattick, J.S. (2010). RNA as the substrate Darren Korbie, Ganqiang Liu, Satu Nahkuri, for epigenome-environment interactions. Vikram Ratnu, Martin Smith, Selene Bioessays 32: 548-552. Fernandez Valverde, Darya Vanichkina Mercer, T.R., et al. (2010). Regulated post- Honours Student: Rebecca Johnston transcriptional RNA cleavage diversifies the eukaryotic transcriptome. Genome Visiting Researchers: Anton Karlsbeek, Research in press. Dr Mythily Mariasegaram, Dr Johanna Vendelin 27 imb researchers: genomics & computational biology

MARK RAGAN COMPUTATIONAL GENOMICS

expression profiles, subcellular localisation, Lateral genetic transfer: open issues. cellular function, orthology maps and Philosophical Transactions of the Royal phylogenetic profiles. Society of London B: Biological Sciences 364: 2241-2251. For more information on our group and our research projects, please see www.imb. Darling, A.E., Miklós, I., and Ragan, M.A. uq.edu.au/index.html?page=11671 (2008). Selection on genome arrangement in circular bacterial chromosomes. PLoS Genetics 4: e1000128. RESEARCH PROJECTS • Investigating the impact of lateral LAB MEMBERS genetic transfer on the development of pathogenicity and virulence in bacteria Research Officers: Dr Melissa Davis (QFAB), Dr Stefan Maetschke, Dr Chenwei • Inferring biomolecular interaction Wang networks in mammalian cells based on Queensland Facility for Advanced expression profiles WE USE ADVANCED BIOINFORMATIC Bioinformatics Senior Team: Jeremy and computational methods to investigate • Understanding how heterogeneous Barker (CEO), Dr Dominique Gorse similarities and differences among genotypes (SNP, CNV) interact with (Technical Manager) cellular networks to cause or maintain genomes and the proteins they encode. NCI SF Bioinformatics / EMBL Australia Our goal is to make rigorous quantitative disease, particularly cancer EBI Mirror Team: Dr David Green (Project inferences, at both global and fine scales, • Abstracting and analysing biomolecular Manager), Gavin Graham, Dr Gerald about how genomes, gene and protein control networks as graphs Hartig families, regulatory networks and cellular functions have evolved and diversified. To • Fine-scale mapping of orthologous Manager, ARC Centre of Excellence in deal with very large quantities of data we and paralogous regions of mammalian Bioinformatics: Lanna Wong use advanced data-management methods, genomes Scientific Programmer: Chikako Ragan implement high-throughput computational • Studying protein-protein interaction PhD Students: JooYoung Choi, Piyush workflows, and develop new algorithms, networks in cellular context Madhamshettiwar, Chang Jin Shin, approaches and software. • Computationally discovering novel Elizabeth Skippington Genomes have diversified, both structurally miRNA targets in mammalian genomes International Trainees: Alexandra Diem and functionally, from shared ancestral (Friedrich-Schiller-University Jena), Martin states. We develop methods and employ Simonsen (Aarhus University) analytical pipelines to reconstruct the KEY PUBLICATIONS Undergraduate Research Trainee: Ann paths of descent (phylogenomics) and Maetschke, S.R. et al. (Ragan, M.A. Bui to study processes of change through listed as senior author) (2010). A visual time (evolutionary genomics). We have framework for sequence analysis using characterised pathways of lateral genetic n-grams and spectral rearrangement. transfer where genetic information moves Bioinformatics 26: 737-744. across, not within, genealogical lineages, and have developed statistically based Davis, M.J., Sehgal, M.S., and Ragan, BLAST Homologene approaches to discover genetically M.A. (2010). Automatic, context-specific recombined regions and recombination generation of Gene Ontology slims. BMC breakpoints. We are now applying these Bioinformatics 11: 498. approaches to understand genome Walter, T. et al. (2010). Visualization of diversification and the evolution of image data from cells to organisms. pathogenicity in bacteria. Nature Methods 7: S26-S41.

Nodes: 831 Nodes: 670 Edges: 1266 Edges: 1005 Another major direction of our research is in Chan, C.X., Darling, A.E., Beiko, R.G., and Clustering Coefficient: 0.017 Clustering Coefficient: 0.010 the inference, comparison and analysis of Ragan, M.A. (2009). Are protein domains Human Phylome Inparanoid biomolecular networks in mammalian cells modules of lateral genetic transfer? PLoS A multiple whole-genome alignment of six in normal development and disease. We ONE 4: e4524. strains of Escherichia coli consists of 34 are developing scalable approaches that let rearranged pieces larger than 1 kb. Kassahn, K.S., Dang, V.T., Wilkins, S.J., us interrogate diverse data types including Perkins, A.C., and Ragan, M.A. (2009). molecular sequences (single-nucleotide Evolution of gene function and regulatory polymorphisms and copy-number variation), control after whole-genome duplication: protein and RNA structures, metabolic Nodes: 367 Nodes: 503 comparative analyses in vertebrates. Edges: 493 Edges: 705 Clustering Coefficient: 0.013 Clustering Coefficient: 0.015 and signalling pathways, regulatory and Genome Research 19: 1404-1418. molecular interaction networks, gene MACHOS CORE Ragan, M.A., and Beiko, R.G. (2009).

Nodes: 147 Nodes: 875 Edges: 173 Edges: 2240 Clustering Coefficient: 0.019 Clustering Coefficient: 0.029 imb annual report 2010 28

ROHAN TEASDALE ENDOSOMAL DYNAMICS: REGULATED ENDOCYTOSIS, HOST-PATHOGEN INTERACTIONS AND PROTEIN TRAFFICKING

THE ENDOSOMAL/LYSOSOMAL macropinosomes. Based on our findings system of mammalian cells is a highly of a dynamic association of GFP-SNX5 dynamic organelle, and the trafficking with macropinosomes, we have detected pathways within the endosomal system a transient and very extensive tubular are fundamental for a wide variety of key network that is essential to the maturation cellular processes. My group is developing of the macropinosome in macrophages. cellular and computational approaches Macropinocytosis is a regulated form to identify novel mammalian proteins of endocytosis that mediates the non- associated with the endosomal system. selective uptake of extracellular material. The regulated movement of membrane Macropinocytosis is highly relevant to receptors and ligands between the cell many aspects of both normal cell function surface and intracellular compartments and disease with particular importance in is vital to many cellular operations, tumour progression and metastasis and including communication between cells in many infectious diseases. Recently I and their environment. A major current have focused on the establishment of a focus of the group is the characterisation systems biology approach to examine the of the mammalian retromer complex. My biogenesis of macropinosomes. I have KEY PUBLICATIONS research into defining the composition of a established a number of functional assays Kerr, M.C., Wang, J.T.H., Castro, N., mammalian endosomal protein complex, to quantify the kinetics of formation and Hamilton, N.A., Town, L., Brown, D.L., termed the retromer, has made major fate of individual macropinosomes. Meunier, F.A., Brown, N.F., Stow, J.L., contributions to its recent emergence as a and Teasdale, R.D. (2010). Inhibition of Numerous infectious pathogens exploit central critical regulator of early endosome the PtdIns(5) kinase PIKfyve disrupts macropinocytosis to invade the host. protein trafficking. I discovered a novel core intracellular replication of Salmonella. Characterisation of pathogen entry retromer complex, defined by a second EMBO Journal 29: 1331-1347. pathways is essential for understanding VPS26 paralog, and originally discovered Wang, J.T., Kerr, M.C., Karunaratne, S., infectious diseases but has also proven to multiple members of the sorting nexin Jeanes, A., Yap, A.S., and Teasdale, be a powerful tool for gaining insight into family that associate with retromer. Our R.D. (2010). The SNX-PX-BAR family normal cellular processes. We are currently recent work on sorting nexin 5 (SNX5) in macropinocytosis: the regulation of investigating the molecular details of these represents the first report of the association macropinosome formation by SNX-PX- pathways and how they are modulated in of sorting nexins and retromer proteins with BAR proteins. PLoS One 5: e13763. response to infection with Salmonella, a macropinosomes. This study involved the leading cause of human gastroenteritis. Kerr, M.C., and Teasdale, R.D. (2009). application of high-quality live cell imaging Currently we have established High Defining Macropinocytosis. Traffic 10: to visualise the maturation process of Content Screening (HCS) approaches, 364-371. combined with high-throughput RNA. Hamilton, N., and Teasdale, R.D. (2008). Visualizing and Clustering High Throughput Sub-cellular Localization RESEARCH PROJECTS Imaging. BMC Bioinformatics 9: 81. • Host-Pathogen interactions during Sprenger, J., Fink, J.L., Karunaratne, S., Salmonella infection Hanson, K., Hamilton, N., and Teasdale, • Maintaining and updating LOCATE: R.D. (2007). LOCATE: A Mammalian A Protein Subcellular Localisation Protein Subcellular Localization Database. Database – http://locate.imb.uq.edu.au Nucleic Acids Research 36(Database issue): D230-233. • Developing computational approaches to analyse image and real-time microscopy data LAB MEMBERS • Studying endosome dynamics, Research Officers: Dr Markus Kerr, Dr macropinocytosis and retromer Andrea Bugarcic, Dr Michael Hanzal- Bayer, Dr David Liebl • Systems biology of the mammalian endosome Research Assistants: Seetha Karunaratne, John Griffin, Zhe Yang, • Establishment of High Content Shara Close Screening (HCS) applications including high throughput RNA-interference PhD Students: Josefine Sprenger, Jack (RNAi) screens Wang 29 imb researchers: molecular genetics and development

Division of MOLECULAR GENETICS & DEVELOPMENT

This has been another outstanding year for the MGD Division, with our researchers continuing to make seminal contributions to our understanding of development, metabolism and genetic disease. A paper by Dr Josephine Bowles and Professor Peter Koopman in Developmental Cell, describing the discovery of a protein that promotes spermatogenesis while suppressing oogenesis, was an example of the high-quality research performed in the division in 2010.

KYLIE GEORGAS: KIDNEY ART A schematic diagram of embryonic mouse kidneys. The diagram has been modified from a kidney diagram designed and drawn for the GUDMAP website. imb annual report 2010 30

The Molecular Genetics and Development grants awarded to chief investigators institutes, and hosting visitors to the IMB Division currently consists of ten groups from the division in these funding rounds in return. These visitors included four containing around 100 researchers and went to: Dr Kelly Smith, a postdoctoral national and international speakers in students in total. A detailed description researcher from the Wicking group, Dr IMB’s Friday Seminar Series: Dr Stephen of each group’s research can be found Ben Hogan, the institute’s youngest Cohen, Deputy Director of the Institute of in the following pages, but briefly, group leader, who was awarded two, Molecular and Cell Biology in Singapore; the research focus of each group is: and Dr Mathias Francois, a Koopman Professor Christopher Goodnow, the development and function of the group postdoc who shared one of Director of the Australian Phenomics lymphatic vessels (Dr Ben Hogan); the Dr Hogan’s grants. The latter two Facility at the Australian National formation of the developing embryo, researchers were also successful in University in Canberra; Professor Simon particularly the gonads and blood Fellowship funding rounds, with Dr Foote, Director of the Menzies Research and lymphatic vessels (Professor Peter Hogan being awarded an ARC Future Institute at the University of Tasmania in Koopman); the development, repair and Fellowship and Dr Francois receiving an Hobart; and Professor Sharad Kumar regeneration of the kidney (Professor NHMRC Career Development Award. Dr from Adelaide’s Institute of Medical and Melissa Little); the role of nuclear hormone Matt Sweet was particularly successful Veterinary Science. Dr Dagmar Wilhelm receptors in metabolic disease (Professor in these rounds, being offered both an organised the Division’s fortnightly George Muscat); blood development NHMRC Research Fellowship and an seminar program, a forum for our staff (Associate Professor Andrew Perkins); ARC Future Fellowship. As always, it is and students to present their work the genetics of human pigmentation and encouraging to see early- and mid- to the rest of the division, and allow skin cancer risk (Associate Professor career researchers achieving success. each of us a wider understanding of Rick Sturm); the mechanisms by which the research being undertaken across The division’s researchers were not just the innate immune system responds to our ten laboratories. We continued recognised for their work through the infection (Dr Matt Sweet); the genetics to run the Brisbane Developmental awarding of competitive grants, but of tissue repair and heritable cancers, Biology Seminar Series, a monthly also through prizes. Dr Ben Hogan won including basal cell carcinomas and seminar for all developmental biologists a University of Queensland Research medulloblastomas (Professor Brandon in Brisbane. In October, Dr Dagmar Excellence Award, worth $70,000, to Wainwright); the molecular mechanisms Wilhelm and Dr Kelly Smith organised identify genes critical to the development behind limb and craniofacial development the inaugural Cell and Developmental of the lymphatic vessels through the use (Associate Professor Carol Wicking) Biology Meeting. This symposium is one of zebrafish models. Dr Kate Schroder and the elucidation of the regulatory of the few that allows junior scientists, from the Sweet group was awarded mechanisms of embryonic development including postgraduate students, to Postdoctoral Researcher of the Year (Dr Dagmar Wilhelm). share the stage with senior researchers, at the Queensland Health and Medical and was a huge success. Our division The division continues to sustain its Research Awards, the second year in a also sponsored the 6th Australian research through success in competitive row this prize was won by a researcher Developmental Biology Workshop in grant rounds. Our researchers received from our division. Dr Schroder Melbourne, a training ground for the next $1.5 million in project grants from completed the first comparison of mice generation of Australian developmental the National Health and Medical and human innate immune systems. In biologists. Research Council and $1 million our student cohort, Dr Ming Chang, also from the Australian Research Council from the Sweet group, was named on Last year I reported that the Division (ARC). These included IMB’s largest the Dean’s Awards List for Outstanding had been reviewed by Professor Robb grant across both schemes of $691k Research Higher Degree Theses. Only Krumlauf and Professor Nancy Jenkins to Professor Melissa Little. This grant the top ten percent of research higher from the IMB’s Scientific Advisory will fund Professor’s Little’s studies on degree students are recognised in this Committee. As a result of feedback kidney development, which aims to way each year. Vicki Metzis from the from that review, this year we instituted improve our understanding of chronic Wicking group won several awards a divisional retreat aimed at improving kidney disease. Professor Little is also in 2010, including the IMB and Inter- our collective sense of belonging and one of the investigators on another large Institute rounds of the Three-Minute gaining a better understanding the grant, $627k, led by Professor Karen Thesis competition, and the People’s division’s areas of research interest Moritz of UQ’s School of Biomedical Choice Award in the Inter-Institute round. and technical approaches. The retreat Sciences. This grant will examine the For a list of the remainder of Ms Metzis’s was very successful, with participants effect of lower oxygen levels on kidney awards, and for other student awards, emerging with an increased awareness development. Professor Peter Koopman please see page 69. of best practice in the field as a whole, and Dr Josephine Bowles received technology, equipment and services Our researchers continued to interact $660k from the ARC to continue the available at IMB and emerging research with the wider scientific community, work described in their Developmental trends and technologies. presenting at conferences and other Cell paper (see above). The other three 31 imb researchers: molecular genetics and development

BEN HOGAN MOLECULAR GENETICS OF VASCULAR DEVELOPMENT

RESEARCH PROJECTS • Identification and characterisation of mutants with abnormal vasculature THE DISTRIBUTION OF BLOOD • Identification and characterisation of cells, hormones and essential nutrients key regulators of lymphatic vessel throughout our bodies is dependent differentiation on the function of a healthy circulatory system. Blood and lymphatic vessels • Analysis of the role of the compose an organ network that distributes human disease gene Ccbe1 in blood and also drains waste and fluid lymphangiogenesis that accumulates in our tissues. We are • Live imaging of vascular development particularly interested in the development and function of lymphatic vessels, which play critical roles in human diseases KEY PUBLICATIONS including lymphoedema, inflammatory Alders, M., Hogan, B.M., Gjini, E., disorders, and cancer metastasis. Salehi, F., Al-Gazali, L., Hennekam, E.A., Importantly, the inhibition of lymphatic Holmberg, E.E., Mannens, M.M., Mulder, vessel growth has been identified to be a M.F., Offerhaus, G.J., Prescott, T.E., valid approach for inhibiting the metastatic Schroor, E.J., Verheij, J.B., Witte, M., spread of several types of cancer. Zwijnenburg, P.J., Vikkula, M., Schulte- Merker, S., and Hennekam, R.C. (2009). We study how lymphatic vessels form Mutations in CCBE1 cause generalized from pre-existing vasculature (a process lymph vessel dysplasia in humans. Nature called lymphangiogenesis) in the context Genetics 41: 1272-1274. of embryonic development. Our work is currently focused on identifying the Hogan, B.M., Bos, F.L., Bussmann, J., genes that regulate the earliest steps Witte, M., Chi, N.C., Duckers, H.J., and in the process of lymphangiogenesis. Schulte-Merker, S. (2009). Ccbe1 is required for embryonic lymphangiogenesis We primarily use the zebrafish embryo Hogan, B.M., Layton, J.E., Pyati, U.J., and venous sprouting. Nature Genetics as a model system as it offers a unique Nutt, S.L., Hayman, J.W., Varma, S., 41: 396-398. combination of direct imaging techniques, Heath, J.K., Kimelman, D., and Lieschke, embryological tools and genetic tools for Hogan, B.M., Herpers, R., Witte, M., G.J. (2006). Specification of the primitive the study of developmental processes. Heloterä, H., Alitalo, K., Duckers, H.J., myeloid precursor pool requires signaling In our inaugural year, the laboratory has and Schulte-Merker, S. (2009). Vegfc/ through Alk8 in zebrafish. Current Biology begun by identifying several key new Flt4 signalling is suppressed by Dll4 in 16: 506-511. regulators of lymphatic vessel development developing zebrafish intersegmental in the zebrafish. The characterisation of arteries. Development 136: 4001-4009. these genes in mammals, in health and GROUP MEMBERS Hogan, B.M., Bussman, J., Wolburg, H., disease scenarios, is ongoing and should Research Officers: Dr Neil Bower, and Sculte-Merkers, S. (2008). ccm1 serve to identify targets for the treatment cell autonomously regulates endothelial Dr Ludovic Le Guen of vascular diseases and the inhibition of cellular morphogenesis and vascular Research Assistants: Christine Neyt, cancer metastasis. tubulogenesis in zebrafish. Human Scott Paterson, Emmanuelle Frampton Molecular Genetics 17: 2424-2432. (née Lesieur) PhD Students: Joelle Kartopawiro, Baptiste Coxam imb annual report 2010 32

PETER KOOPMAN GENETIC REGULATION OF EMBRYO DEVELOPMENT AND HUMAN DISEASE

OUR GROUP FOCUSES ON GENES RESEARCH PROJECTS controlling the formation of various organs • Sex determination and gonadal in the developing embryo. development Our main interest is striving to understand • Development of male germ cells the events that determine whether an embryo develops as a male or a female. • Sox gene function and evolution We are studying the gene SRY, the • Molecular genetics of lymphatic Y-chromosome maleness gene, and how development it controls the genetic and cellular events leading to testis development and male sex determination. We also specialise in the KEY PUBLICATIONS identification and characterisation of other sex development genes using techniques Bowles, J., Feng, C.-W., Spiller, C., such as microarray screening and Davidson, T.-L., Jackson, A., and transgenic mouse models, and studying Koopman, P. (2010). FGF9 suppresses how these affect sex development. meiosis and promotes male germ cell fate Ultimately we hope to better understand in mice. Developmental Cell 19: 440-449. LAB MEMBERS the causes of human disorders of sex François, M., Caprini, A., Hosking, B., Senior Research Officer: Dr Josephine development. Orsenigo, F., Wilhelm, D., Browne, C., Bowles We are also interested in how an Paavonen, K., Karnezis, T., Shayan, Research Officers: Dr Mathias embryonic cell type known as germ cells R., Downes, M., Davidson, T., Tutt, D., Francois, Dr Terje Svingen, Dr Kallayanee comes to eventually develop as sperm Cheah, K.S.E., Chan, M., Stacker, S.A., Chawengsaksophak, Dr Kenichi in males or eggs in females. We have Muscat, G.E.O., Achen, M.G., Dejana, E., Kashimada, Dr Cassy Spiller, Dr Antoine discovered several molecular signals that and Koopman, P. (2008). SOX18 induces Rolland direct this decision, and are discovering development of the lymphatic vasculature Research Assistants: Tara Davidson, how these signals act. This work is helping in mice. Nature 456: 643-647. Allen Feng, Ee Ting Ng, Danielle Wilson, us understand the causes of infertility and Bowles, J., Knight, D., Smith, C., Wilhelm, Cameron Curtis of germ cell tumours such as testicular D., Richman, J., Mamiya, S., Yashiro, K., cancer. Chawengsaksophak, K., Wilson, M.J., Admin Assistant: Barbara Feenstra Rossant, J., Hamada, H., and Koopman, P. A third major focus in our group includes PhD Student: Tam Duong investigating the role of Sox18, a gene (2006). Retinoid signaling determines germ we discovered and have shown triggers cell fate in mice. Science 312: 596–600. the formation of the lymphatic system. Wilhelm, D., and Koopman, P. (2006). This discovery is expected to lead to The makings of maleness: Towards better ways of controlling lymphatic an integrated view of male sexual development and function in diseases such development. Nature Reviews Genetics 7: as lymphedema and cancer metastasis. 620-631. We are developing anti-Sox18 drugs as potential adjunct treatments for cancer.

In summary, the study of embryo development provides insight into mechanisms of disease and cancer, and provides a molecular and cellular basis for diagnostic and therapeutic approaches, Recombinant organ culture with GFP including stem cell therapies. expressing mesonephros (green) and wild type testis allows analysis of cell migration into the testis during development. Migrating endothelial cells integrate with endogenous vasculature (yellow and red respectively) which separate forming testis cords (blue). 33 imb researchers: molecular genetics and development

MELISSA LITTLE KIDNEY DEVELOPMENT, DAMAGE, REPAIR AND REGENERATION

RESEARCH PROJECTS Sims-Lucas, S. et al. (2010). Redirection of renal mesenchyme to stromal and • Modelling kidney development in 3D chondrocytic fates in the presence of • Investigating the specification and TGF-b2. Differentiation 79: 272-284. turnover of the nephron progenitor Williams, T.M., Little, M.H., and Ricardo, population during kidney development S.D. (2010). Macrophages in renal • Determining the basis of cessation of development and repair. Seminars in nephron formation and how nephron Nephrology 30: 255-267. number is varied genetically and Combes, A.N. et al. (2009). Three- environmentally dimensional visualisation of testis cord • Dissecting the nephron progenitor morphogenesis, a novel tubulogenic mechanism in development. niche so as to find ways to expand this Developmental Dynamics 238: 1033- population 1041. • Reinitiating kidney development to Georgas, K.M. et al. (Little, M.H. listed EACH OF US HAS A PAIR OF KIDNEYS repair an adult kidney that plays an important role in maintaining as senior author) (2009). Analysis of early nephron patterning reveals a role fluid balance, blood volume and electrolyte • Characterising stem cells in the adult for distal RV proliferation in fusion to the balance. On top of this, they regulate kidney ureteric tip via a cap mesenchyme-derived blood pressure, bone density and number • Dissecting the basis of progression to connecting segment. Developmental of red blood cells via the production of chronic renal disease Biology 332: 273-286. (Front cover) specific growth factors. As a result of the many complex roles played by the kidneys, kidney disease has a profound effect on KEY PUBLICATIONS LAB MEMBERS the patient. Chiu, H.S. et al. (Little, M.H. listed as Research Officers: Dr Lorine Wilkinson, Dr senior author) (2010). Comparative Chronic kidney disease (CKD) is a Joan Li, Dr Minoru Takasato, Dr Fiona Rae, gene expression analysis of genital devastating disease and an expensive one Dr David Pennisi tubercle development reveals a putative to treat. Once this condition has reached appendicular Wnt7 network for epidermal Research Assistants: Bree Rumballe, end-stage renal failure, it can only be differentiation. Developmental Biology Kylie Georgas, Jess Ineson, Melissa treated with dialysis or transplantation. 344: 1071-1087. Becroft, Han Chiu, Norseha Mohammed Each year, more than 4000 Australian Suhaimi adults will be diagnosed with CKD, which Lin, S.A. et al. (2010). Subfractionation costs the health system in excess of $2 of differentiating hES populations allows PhD Students: Caroline Hopkins, Yu Leng billion per annum. There is an urgent need the isolation of a mesodermal population Phua to develop novel therapies as the rate of enriched for intermediate mesoderm CKD is rising at 6-8 percent per annum, and renal progenitors. Stem Cells and Honours Student: Adler Ju Development 19: 1637-1648. primarily due to increasing rates of Type Undergraduate Student: Stephanie II diabetes and obesity. Sadly, only one Little, M.H., Georgas, K., Pennisi, Aroney in four patients will be lucky enough to D., and Wilkinson, L. (2010). Kidney receive a kidney transplant. development: two tales of tubulogenesis. Current Topics in Developmental Biology As for other organs, there are many 90: 193-229. conditions, both experimental and genetic, that result in impaired kidney function. Lusis, M., Li, J., Ineson, J., Li, J., and Perhaps more surprising is the fact that Little, M.H. (2010). Isolation and culture the risk of kidney failure during our lives is of metanephric mesenchyme-derived now known to be linked to what happens nephrospheres reinforces evidence during the development of our kidneys. Our that embryonic renal progenitors are laboratory is acknowledged internationally multipotent and exhaust during cessation for our work in defining the genes involved of nephron formation. Stem Cell Research in normal kidney development and in 5: 23-39. (Editorial comment on this article integrating this understanding with an published in same issue) understanding of how the adult kidney Rumballe, B., Georgas, K., Wilkinson, responds to damage. In this way, we L., and Little, M.H. (2010). Molecular hope to develop novel approaches to the anatomy of the kidney: what have we diagnosis and treatment of both acute and learnt from gene expression and functional chronic kidney disease. Such therapies genomics? Pediatric Nephrology 25: will grow out of our understanding of 1005-1016. the processes involved in normal kidney development. imb annual report 2010 34

GEORGE MUSCAT NUCLEAR HORMONE RECEPTORS, AND METABOLIC DISEASE

NUCLEAR HORMONE RECEPTORS We have utilised the Ski transgenic (NRs) function as ligand-dependent DNA- mouse model to investigate the role of binding proteins that translate nutritional, c-ski and NR crosstalk in regulating body metabolic and pathophysiological signals composition, and the response to dietary into gene regulation. My group’s research (high fat) challenges. Currently, other continues to focus on understanding studies have produced transgenic mouse the molecular role of nuclear hormone lines with muscle-specific perturbation of receptors (NRs) in the regulation of the nuclear receptor NOR-1 (a member of metabolism and body composition in the NR4A subgroup of NRs) to investigate transgenic mouse models. In addition, the effects of selective and specific we collaboratively examine the molecular crosstalk between beta-adrenergic and role of NRs in melanoma and breast NOR-1 signalling in skeletal muscle. These cancer. Moreover, we exploit these animal studies have indicated NOR-1 signalling models and studies to gain insights into controls glucose tolerance, and oxidative dyslipidemia, obesity, type II diabetes and metabolism in muscle. Moreover, we cancer. The insights obtained from in vivo have shown selective crosstalk between studies in animal models will be utilised to melanocortin 1 receptor (MC1R) and NR4A KEY PUBLICATIONS translate this research into understanding signalling in adipose in the context of human health and disease. metabolism. Leong, G.M., et al. (Muscat, G.E. senior author) (2010). The Ski proto-oncogene Our group has investigated the functional Current and future directions involve regulates body composition and role of the retinoic acid receptor - related translating this research into human health suppresses lipogenesis. International orphan receptor (Ror) alpha - a member and disease. For example, the insights Journal of Obesity 34: 524-536. of the nuclear hormone receptor (NR) obtained from the studies in lean, obese Pearen, M.A., and Muscat, G.E. (2010). superfamily. We have previously and diabetic murine models are being Minireview: Nuclear hormone receptor demonstrated that homozygous staggerer utilised (in collaboration with Dr Gary 4A signaling: implications for metabolic mice (sg/sg), with decreased and Leong) to profile the expression of the NRs, disease. Molecular Endocrinology 24: dysfunctional retinoic acid receptor-related NR-associated cofactors and metabolic 1891-1903. orphan receptor alpha (Rora) expression in genes in overweight and obese children all tissues, display a lean and dyslipidaemic before and after the implementation Raichur, S., et al. (Muscat, G.E. senior phenotype. Furthermore, these mice of a nutrition and lifestyle program. author) (2010). Identification and validation are resistant to (high-fat) diet-induced Furthermore, in the context of cancer, of the pathways and functions regulated obesity. This phenotype was mediated by we are also involved in an NBCF-funded by the orphan nuclear receptor, ROR the suppression of SREBP-1c (a master large collaborative research program to alpha1, in skeletal muscle. Nucleic Acids lipogenic transcription factor) and its completely profile NR and NR cofactor Research 38: 4296-4312. downstream targets (involved in fatty acid expression in several human cohorts, Lau, P., Fitzsimmons., R.L., Raichur, S., biosynthesis). Recently, we have targeted including (pre- and post-menopausal) Wang, S.C., Lechtken, A., and Muscat, muscle-specific expression of a truncated normal breast, estrogen receptor (ER)- G.E.O. (2008). The Orphan Nuclear (dominant negative) ROR alpha 1∆DE in positive and -negative breast cancers. Receptor, ROR {alpha}, Regulates transgenic mice to investigate ROR alpha 1 Gene Expression That Controls Lipid For more information, please see www. signalling in this tissue. Expression profiling, Metabolism: Staggerer (SG/SG) mice are imb.uq.edu.au/index.html?page=11687 qPCR, pathway, western and metabolic resistant to diet-induced obesity. Journal profiling analysis indicated that ROR of Biological Chemistry 283: 18411- 18421. alpha influenced pathways irregulating: RESEARCH PROJECTS (i) lipid and carbohydrate metabolism, cardiovascular and metabolic disease; (ii) • Examining the in vivo role of the ROR LXR nuclear receptor signalling and (iii) and NR4A subgroups in lipid and LAB MEMBERS Akt and AMPK signalling. The identified glucose homeostasis Research Officers: Dr Patrick Lau, Dr genes and pathways were in concordance • Elucidating the metabolic role of the Michael Pearen, Dr Mary Wang, Dr Gary with the demonstration that aberrant NR4A subgroup (Nur77 and NOR-1) in Leong (50% each IMB & NHMRC Clinical RORa1 expression/function affected adrenergic and melanocortin signalling CDA, Mater Children’s Hospital) glucose tolerance, insulin-stimulated Research Assistants: Rebecca phosphorylation of Akt and glucose uptake • Determining the role and function of Fitzsimmons, Nick Martel in the transgenic animals. In conclusion, the Ski gene in body composition we propose that Rora plays an important and metabolism via modulation of PhD Students: Natalie Eriksson, Lisa role in the regulation of lipogenesis, NR-dependent metabolism in skeletal Crowther adiposity, and the AKT2 signalling cascade muscle, fat and liver controlling glucose uptake in skeletal • Profiling NR and cofactor expression in muscle. normal, estrogen receptor (ER)-positive and ER-negative breast cancers 35 imb researchers: molecular genetics and development

ANDREW PERKINS BLOOD DEVELOPMENT

4. The genetics underpinning gastrulation and subsequent generation of haematopoietic stem cells in the mammalian embryo.

RESEARCH PROJECTS • Investigating the transcriptional regulation of erythropoiesis • Studying the roles of Kruppel-like factors in human diseases • Using chemical mutagenesis to Absent B cells and relatively reduced T cells discover new genes that regulate HSC in boo/boo spleen. (I-J) Increased frequency of CD71+/TER119+ mature erythroid cells generation and behaviour and also CD71lo immature cells in boo/boo • Studying the role of long non-coding spleen. (K-L) Increased Gr1hi neutrophils, OUR GROUP IS INTERESTED IN int RNAs in gastrulation Gr1 monocytes and TER119+ erythroid the transcriptional regulation of blood cells in boo/boo spleen. (M-N) Pie graphs formation. We are primarily concerned show percentage contribution of B220+ with transcriptional hierarchies and KEY PUBLICATIONS B cells (‘B’), CD3+ T cells (‘T’), TER119+ how transcription factors work within erythroid (‘E’) cells, Gr1 bright granulocytes Papathanasiou, P., Tunningley, R., (‘Gr’), Gr1 intermediate macrophages (‘M’), biochemical and genetic pathways, and Pattabiraman, D.R., Ye, P., Gonda, T.J., and precursor cells (‘Pr’, which are mostly also how deregulation of such programs Whittle, B., Hamilton, A.E., Cridland, S.O., CD71 weak early erythroid lineage cells) to leads to cancer. We have four primary Lourie, R., and Perkins, A.C. (2010). A the spleen. Numbers represent the mean of focus areas: recessive screen for genes regulating FACS analyses from 6 boo/boo mice and 6 wild-type (+/+) littermate controls. 1. Transcriptional hierarchies which are hematopoietic stem cells. Blood 116: 5849-5858. active during embryonic stem (ES) cell differentiation into mesoderm- Tallack, M.R., Whitington, T., Yuen, W.S., derived tissues. The methodologies Wainwright, E.N., Keys, J.R., Gardiner, used include: directed differentiation B.B., Nourbakhsh, E., Cloonan, N., Bruce, S.J., Gardiner, B.B., Burke, of ES cells in various recombinant Grimmond, S.M., Bailey, T.L., and Perkins, L.J., Gongora, M.M., Grimmond, S.M., growth factors, gene targeting and A.C. (2010). A global role for KLF1 in erythropoiesis revealed by ChIP-seq in and Perkins, A.C. (2007). Dynamic BAC recombineering for generating primary erythroid cells. Genome Research transcription programs during ES cell reporter ES cell lines and mice in 20: 1052-1063. differentiation towards mesoderm in which stem cells can be followed by serum versus serum-free (BMP4) culture. epifluorescence and FACS, expression Tallack, M., Keys, J.R., Humbert, P.O., BMC Genomics 8: 365. profiling and chromatin immuno- and Perkins, A.C. (2009). EKLF/KLF1 Perkins, A.C., Sharp, A.H., and Orkin, precipitation. controls the cell cycle via direct regulation of E2f2. Journal of Biological Chemistry S.H. (1995). Lethal β-thalassemia in mice 2. Transcriptional regulation of 284: 20966-20974. lacking the erythroid CACCC-transcription erythropoiesis. Mutations in the globin factor EKLF. Nature 375: 318-322. Dinger, M.E., Amaral, P.P., Mercer, T.R., genes are the most common genetic Pang, K.C., Bruce, S.J., Gardiner, B.B., mutations worldwide. These mutations Askarian-Amiri, M.E., Ru, K., Solda, LAB MEMBERS are responsible for thalassaemia G., Simons, C., Sunkin, S.M., Crowe, Research Officer: Dr Michael Tallack and sickle cell disease, which cause M.L., Grimmond, S.M., Perkins, A.C., serious morbidity and mortality. We and Mattick, J.S. (2008). Non-coding Research Assistant: Graham Magor are interested in trying to decipher RNA in Mouse ES cell pluripotency and PhD Student: Paulo Amaral the complex process of haemoglobin differentiation. Genome Research 18: Honours Student: Jessica Fittock switching at a molecular level. The 1433-1445. long-term goal is to design new drugs that target key regulators of this process and thereby reactivate foetal haemoglobin in adults. 3. The role played by the Kruppel-like factor (KLF) family of zinc finger genes in normal differentiation and human skin, colon and blood cancers. imb annual report 2010 36

RICK STURM MELANOGENIX RESEARCH GROUP

THE MELANOGENIX (MELANOCYTE and receptor activation is a major area biology and pigmentation genetics) of investigation. In addition, the group laboratory is studying the molecular, is studying the process of development genetic and cellular basis underlying and differentiation of the melanocytic normal human variation in the pigmentary cell lineage using primary melanoblast traits of skin, hair and eye colour. Several and melanocyte cell culture, as well as genome-wide association studies coculture of these cells with keratinocytes. (GWAS) for pigmentation have now been This will provide information to allow conducted and identified SNP markers in the genes and processes involved known (TYR, TYRP1, OCA2, SLC45A2, in melanoma tumour formation and SLC24A5, MC1R, ASIP, KITLG) and metastasis to be examined. Each of previously unknown (SLC24A4, IRF4, these aims centres on the identification TPCN2) candidate genes. We have and molecular characterisation of genes investigated skin and hair colour genetic involved in melanocyte cell function. associations in Europeans, and discovered that responsible polymorphisms are found within a range of pigmentation genes, RESEARCH PROJECTS Johanson, H.C., Chen, W., Wicking, whereas blue-brown eye colour can be • Understanding skin cancer risk C., and Sturm, R.A. (2010). Inheritance of a Novel Mutated Allele of the OCA2 explained by a single SNP proposed to phenotypes through studying the Gene Associated with High Incidence of regulate OCA2 expression. There is a interaction of genes involved in skin, Oculocutaneous Albinism in a Polynesian strong genotype-by-age effect of IRF4 on hair and eye colour nevus count, and the responsible SNP is Community. Journal of Human Genetics associated with increased melanoma risk. • Molecular, genetic and cellular analysis 55: 103-111. In addition, we have found that this SNP of melanin formation Sturm, R.A. (2009). Molecular genetics can modulate the transcriptional expression • Analysis of MC1R genotyped human of human pigmentation diversity. Human of the IRF4 gene in melanocytes. melanocytes in monoculture and in Molecular Genetics 18: R9-R17. Functional analysis of the human coculture with keratinocytes Sturm, R.A., and Larsson, M. (2009). pigmentation gene set will ultimately • Melanoma spheres as a model for Genetics of human iris colour and provide a full appreciation of this biological melanoma development and metastasis patterns. Pigment Cell and Melanoma system linking genotype with phenotype. Research 22: 544-562. Specifically the role of the MC1R gene • Role of NR4A nuclear hormone variants in directing skin phototype and receptors in melanocytic cells response to UV-induced ligand binding LAB MEMBERS KEY PUBLICATIONS Research Officers: Dr Kimberley Beaumont, Dr Aaron Smith, Dr Shu Shyan Duffy, D.L. et al. (2010). IRF4 variants have Wong age-specific effects on nevus count and predispose to melanoma. American Journal Research Assistants: Garth Douglas, of Human Genetics 87: 6-16. Matthew Harrison, Kasturee Jagirdar, Wen Lim, Darren Smit, Caroline Sturm Duffy, D.L., Zhao, Z.Z., Sturm, R.A., Hayward, N.K., Martin, N.G., and PhD Students: Stephen Ainger, Helene Montgomery, G.W. (2010). Multiple Johanson pigmentation gene polymorphisms Honours Student: Amanda Ong account for a substantial proportion of risk of cutaneous malignant melanoma. Visiting Students: Puya Gharahkhani Journal of Investigative Dermatology 130: (PhD Vet Science), Elizabeth Webb (USA 520-528. Fulbright Scholar)

Human melanoma tumour. 37 imb researchers: molecular genetics and development

MATT SWEET PATHOGEN SURVEILLANCE, INNATE IMMUNITY AND INFLAMMATION

identification of widespread differences between humans and mice in TLR target genes; (3) the identification of macrophages as an intracellular reservoir for the urinary tract pathogen, uropathogenic E. coli; and (4) the mapping of molecular mechanisms involved in immune cell death triggered by foreign DNA detected in the cytoplasm. Our immediate research objectives are to develop small molecule inhibitors against HDAC7 for testing as anti-inflammatory agents, to validate the importance of D.A., and Sweet, M.J. (2009). Colony species differences in TLR-activated anti- Stimulating Factor-1 (CSF-1) delivers microbial pathways, and to determine the a proatherogenic signal to human mechanisms used by uropathogenic E. macrophages. Journal of Leukocyte coli to subvert macrophage anti-microbial Biology 85: 278-288. ALL MULTICELLULAR ORGANISMS responses. Our ultimate goals are to are equipped with an immune system, generate new insights into the mechanisms Roberts, T.L., Idris, A., Dunn, J.A., Kelly, which provides protection against used by the host innate immune system to G.M., Burnton, C.M., Hodgson, S., Hardy, infectious diseases. In mammals, the innate destroy invading microbes, and to develop L., Garceau, V., Sweet, M.J., Ross, I.L., immune system acts as the first line of novel approaches to targeting inflammatory Hume, D.A., and Stacey, K.J. (2009). HIN- 200 proteins regulate caspase activation defence. Once activated, innate immunity diseases. in response to foreign cytoplasmic DNA. attempts to trigger direct microbial Science 323: 1057-1060. destruction, and to contain the invading pathogen by promoting inflammation. RESEARCH PROJECTS Bode, K.A., Schroder, K., Hume, D.A., Innate immune cells such as macrophages • Characterising the role of specific Ravasi, T., Heeg, K., Sweet, M.J., and use several families of pattern recognition histone deacetylases in Toll-like Dalpke, A.H. (2007). Histone deacetylase receptors (PRRs) to detect specific Receptor-mediated inflammatory inhibitors decrease Toll-like receptor- structural components on pathogens. responses mediated activation of pro-inflammatory PRRs also respond to endogenous host gene expression by impairing transcription ligands that are present in inflammatory • Human macrophage anti-microbial factor recruitment. Immunology 122: disease settings. Thus, PRRs are essential responses to Gram-negative bacterial 596-606. pathogens such as Salmonella for host defence against invading Schroder, K., Spille, M., Pilz, A., Lattin, typhimurium microbes, but also contribute to the J., Bode, K.A., Burrows, A.D., Ravasi, T., pathology of many inflammatory diseases. • Role of macrophages in uropathogenic Weighardt, H., Stacey, K.J., Decker, T., The most widely studied PRRs are the E. coli pathogenesis Hume, D.A., Dalpke, A., and Sweet, M.J. Toll-like Receptors (TLRs). We study (2007). Differential effects of CpG DNA TLR-dependent and TLR-independent • Characterisation of the cellular on IFNb induction and STAT1 activation mechanisms by which macrophages sense recognition system for detection of in murine macrophages versus dendritic and respond to invading microorganisms foreign DNA in the cytoplasm cells: alternatively activated STAT1 by focusing on recognition of Gram- negatively regulates toll-like receptor • Involvement of novel TLR-regulated negative bacterial pathogens (e.g. signaling in macrophages. Journal of genes in inflammatory and anti- Salmonella Typhimurium, uropathogenic Immunology 179: 3495-3503. microbial responses E. coli), as well as individual microbial components (e.g. lipopolysaccharide, LAB MEMBERS double-stranded DNA). KEY PUBLICATIONS Senior Research Officer: Dr Kate Stacey Our interests cover the actual PRR systems Halili, M.A., Andrews, M.R., Labzin, L.I., themselves (e.g. TLRs), the downstream Schroder, K., Matthias, G., Cao, C., Research Officers: Dr Steve Broomfield, signalling pathways that are activated Lovelace, E., Reid, R.C., Le, G.T., Hume, Dr Vitalia Sagulenko D.A., Irvine, K.M., Matthias, P., Fairlie, by TLR ligands (including cross-talk with Research Assistants: Greg Kelly, Juliana D.P., and Sweet M.J. (2010). Differential other signalling pathways e.g. CSF-1 Ariffin, Jasmyn Dunn signalling), and the functions of TLR effects of selective HDAC inhibitors on target genes, which ultimately promote macrophage inflammatory responses PhD Students: Melanie Andrews, Dr to the Toll-like Receptor 4 agonist LPS. inflammation and anti-microbial responses. Nilesh Bokil, Divya Ramnath, Kylie Journal of Leukocyte Biology 87: 1103- Research highlights for 2010 include: Alexander 1114. (1) the identification of a specific histone Honours Student: Nabilah Ahmad Kamal deacetylase (HDAC7) that promotes TLR- Irvine, K.M., Andrews, M.R., Fernandez- activated inflammatory pathways; (2) the Rojo, M.A., Schroder, K., Burns, C.J., Su, S., Wilks, A.F., Parton, R.G., Hume, imb annual report 2010 38

BRANDON WAINWRIGHT TISSUE REPAIR AND CANCER

USING GENOMIC APPROACHES, skin and medulloblastoma, a common our group mapped and isolated the gene brain tumour occurring predominantly in for the heritable cancer disorder, naevoid children. In the example of both tumour basal cell carcinoma syndrome (NBCCS). types we are examining how activation The patched gene, discovered from our of the hedgehog pathway causes the studies on NBCCS, has defined a signalling tumour, and defining the cell of origin of the pathway known as the “hedgehog tumour using a combination of molecular pathway”, which appears to be mutated genetics and cell biology. We are also or perturbed in a wide range of tumour defining the interaction of the hedgehog types, including lung, gastro-intestinal, skin, pathway with other genetic pathways, pancreatic, prostate, brain and ovarian such as Notch signalling, in order to cancer. This has led us to focus on the understand the normal development of role of hedgehog signalling, not only in the skin and the cerebellum, but also what cancer but also on the regulation of stem therapeutic strategies might be useful to cell compartments. Increasingly it appears treat the tumours. In addition to studying that in some tumour types there are cells known pathways, we are seeking new known as “cancer stem cells” which reside interactions through genomic approaches KEY PUBLICATIONS within the tumour and are responsible for to discovering new genes and pathways The International Cancer Genome the overall phenotype. Currently such cells in model systems such as mice and Consortium (Wainwright, B.J. listed can be partially defined functionally but zebrafish. The IMB has a well-developed as member of initial scientific planning their molecular signature remains elusive. drug discovery platform and we are committee) (2010). International network We believe that the patched/hedgehog using our knowledge of the biology of of cancer genome projects. Nature 464: pathway defines many of the characteristics these tumours to look for potential new 993-998. of such stem cells and is a powerful starting therapeutics. point for understanding tumour biology and Thomas, W.D., Chen, J., Gao, Y.R., As part of our experimental approach the development of new therapeutics. Cheung, B., Koach, J., Sekyere, our laboratory makes extensive use of E., Norris, M.D., Haber, M., Ellis, T., Given that cancer represents a state of transgenic and knockout mice. However Wainwright, B., and Marshall, G.M. unregulated cell growth, it is likely that at all points we refer back to the human (2009). Patched1 deletion increases the pathways that lead to cancer are diseases under study and have major N-Myc protein stability as a mechanism also involved in the normal process of activities based around mutation analysis, of medulloblastoma initiation and tissue growth and repair. Several of our transcriptomics and proteomics of human progression. Oncogene 28: 1605-1615. studies are particularly directed at the role material, integrating the data from all Yang, Z.J., Ellis, T., Markant, S.L., Read, of the hedgehog (and other pathways) systems. T.A., Kessler, J.D., Bourboulas, M., Schüller, in repair and regeneration. The two As a result of these studies we have a U., Machold, R., Fishell, G., Rowitch, most common cancer types in NBCCS particular interest in the interface between D.H., Wainwright, B.J., and Wechsler- patients are basal cell carcinoma of the developmental cell biology and human Reya, R.J. (2008). Medulloblastoma can genetics, and in therapeutic interventions be initiated by deletion of Patched in such as gene or cell therapies. lineage-restricted progenitors or stem cells. Cancer Cell 14: 135-145. Adolphe, C., Hetherington, R., Ellis, T., RESEARCH PROJECTS and Wainwright, B. (2006). Patched1 • Controlling neuronal stem cells and functions as a gatekeeper by promoting CNS by the patched/hedgehog cell cycle progression. Cancer Research pathway 66: 2081-2088. • Investigating the molecular basis of primary brain tumours Above and below: Loss of patched leads LAB MEMBERS directly to skin tumours. • Controlling the stem cell niche in Research Officers: Dr Richa Dave, Dr mammalian epidermis and skin cancer Rehan Villani, Dr Christelle Adolphe, Dr Jonathan Robson, Dr Elaine Julian • Discovery of new genes capable of suppressing tumour growth Research Assistant: Melissa Bourboulas • The role of microRNAs in brain tumour PhD Students: Uda Ho, Lena Constantin, development Rhonda Kan, Peter Yee Undergraduate Students: Eriza Secondes, Paul Joosa, Stephanie Kamp, Chun Tatt Lim Visitors: Luis Milla 39 imb researchers: molecular genetics and development

CAROL WICKING DEVELOPMENTAL GENES AND HUMAN DISEASE

In parallel studies Dr Kelly Smith has introduced the zebrafish model into the lab, having arrived from post-doctoral studies at the Hubrecht Institute in the Netherlands to continue her characterisation of early heart development. This is based on mutants identified in a forward genetic screen and has implications for human congenital heart disease.

RESEARCH PROJECTS • Using an ENU-derived mouse mutant to A scanning electron micrograph showing the investigate the role of the primary cilium surface of the embryonic mouse face looking in hedgehog signalling and disease into the nasal pit (image by Ashley Cooper).

DEFECTS ARISING FROM ABNORMAL • Trafficking within the primary cilium embryonic development are a major cause • Investigating the role of patched in of infant mortality and childhood disability. development of the face through mouse Many such disorders are characterised knockout studies by anomalies of the limbs and craniofacial region, making an understanding of the • A novel role for hedgehog signalling in molecules involved in patterning these the very early stages of chondrogenesis structures vital. The hedgehog pathway in the limb is one of the most pivotal signalling • Analysis of early heart development in cascades governing embryogenesis and its the zebrafish inappropriate activation in the adult leads Skeletal structure of the wild-type mouse skull to a myriad of tumours. My lab is focused at 16.5dpc (image by Vicki Metzis). on understanding the role of hedgehog KEY PUBLICATIONS signalling in development of the limb and Bruce, S.J., Butterfield, N.C., Metzis, V., face, and more broadly in organogenesis. Town, L., McGlinn, E., and Wicking, C. (2010). Inactivation of patched1 in the We primarily use the mouse as a model Buchtova, M., Handrigan, G.R., mouse limb has novel inhibitory effects on system and have a number of engineered Tucker, A.S., Lozanoff, S., Town, L., the chondrogenic programme. Journal of mouse mutants as well as those arising Fu, K., Diewert, V.M., Wicking, C., and Biological Chemistry 285: 27967-27981. from forward genetic screens. These Richman, J.M. (2008). Initiation and mutants have allowed us to uncover Butterfield, N.C., McGlinn, E., and patterning of the snake dental lamina are novel patterning and skeletal defects Wicking, C. (2010). The molecular dependent on Sonic Hedgehog signalling. arising from misregulation of hedgehog regulation of vertebrate limb development. Developmental Biology 319: 132-145. Current Topics in Developmental Biology signalling in the limb and face. In addition, McGlinn, E., Richman, J.M., Metzis, V., 90: 319-341. in collaboration with Emma Whitelaw at Town, L., Butterfield, N.C., Wainwright, QIMR, we have identified a mouse with Butterfield, N.C., Metzis, V., McGlinn, B.J., and Wicking, C. (2008). Expression an N-ethyl-N-nitrosourea (ENU) induced E., Bruce, S.J., Wainwright, B.J., and of the NET family member Zfp503 is point mutation in a gene involved in Wicking, C. (2009). Patched1 is a regulated by hedgehog and BMP signaling maintaining the primary cilium. The primary crucial determinant of asymmetry and in the limb. Developmental Dynamics 237: cilium is a solitary non-motile organelle digit number in the vertebrate limb. 1172-1182. that protrudes from the surface of virtually Development 136: 3515-3524. every vertebrate cell. Over the past several years the primary cilium has emerged as Town, L., McGlinn, E., Fiorenza, S., LAB MEMBERS Metzis, V., Butterfield, N.C., Richman, a novel cellular compartment required for Research Officers: Dr Steve Bruce, hedgehog signalling, and aberrant function J.M., and Wicking, C. (2009). The metalloendopeptidase gene Pitrm1 is Dr Fredrik Olsson, Dr Liam Town, leads to an array of human disorders regulated by hedgehog signalling in the Dr Kelly Smith known as ciliopathies. Characterisation of developing mouse limb and is expressed mouse mutants along with detailed cellular Research Assistant: Andrew Courtney in muscle progenitors. Developmental trafficking studies is allowing us to unravel PhD Student: Vicki Metzis Dynamics 238: 3175-3184. the function of this important organelle. Honours Student: Ashley Cooper imb annual report 2010 40

DAGMAR WILHELM TOWARDS A NEW UNDERSTANDING OF THE REPRODUCTIVE SYSTEM: FROM NON-CODING RNAS TO DISEASE

OUR GROUP FOCUSES ON THE The aims of our research are to address elucidation of regulatory mechanisms the intersections of the following questions: that control gene expression during embryonic development. One of the 1 What are the regulatory mechanisms most amazing biological processes is underlying the development of the the development of a fertilised egg into ovary? a complex organism. It involves the 2 What are the roles of ncRNAs, including orchestration of cellular processes such as long and small RNAs, during the cell proliferation, migration, differentiation development of testes and ovaries? and apoptosis, which is controlled by a delicate network of gene regulation and 3 What are the mechanisms of interaction. Disturbance of this network processing and function of small RNAs by gene mutation or misexpression during in fish? development results in malformation and malfunction of organs, diseases such as RESEARCH PROJECTS cancer, and often lethality. Therefore, each of these processes must involve a large • Characterisation of the role of miR- activate Sox9 during mammalian sex number of regulatory mechanisms. 202 and miR-140 during embryonic determination. Developmental Biology development 287: 111-124. Until recently our work centred around the conventional dogma, which states that • Analysis of novel microRNAs involved in Wilhelm, D., and Englert, C. (2002). The gene activity is controlled by transcription gonad development Wilms tumour suppressor WT1 regulates factor binding to proximal promoters and/ gonadal development by activation of Sf1. • Functional characterisation of ncRNAs or enhancers adjacent to genes. We are Genes and Development 16: 1839-1851. during embryonic development now extending these studies to include the fact that gene activity is also regulated • Studying the cellular and molecular post-transcriptionally by non-coding RNAs regulation of foetal ovary development LAB MEMBERS (ncRNAs), such as microRNAs. In addition • Characterisation of RNAi in fish Research Officer: Dr James Palmer to investigating the role of microRNAs Research Assistants: Vy Truong, Huijun during development, we have discovered Chen, Emmanuelle Frampton a new class of ncRNAs, uaRNAs (3’UTR- KEY PUBLICATIONS PhD Students: Lindsey McFarlane, Elanor associated non-coding RNAs), that displays Mercer, T.R.*, Wilhelm, D.*, Dinger, M.E.*, Wainwright a highly regulated stage- and sex-specific Solda, G.*, Korbie, D.J., Glazov, E.A., expression pattern during embryogenesis. Truong, V., Schwenke, M., Matthaei, K.I., Occupational Trainee: Nicolas Melin Furthermore, we want to use the Saint, R., Koopman, P., and Mattick, J.S. Honours Student: Joanna Rakoczy knowledge of small RNA processing and (2010). Expression of distinct RNAs from 3’ untranslated regions. Nucleic Acids function, also called RNA interference Research Epub November 12. (RNAi), as a tool to control pest species in Australia. The common carp represents an McFarlane, L., and Wilhelm, D. (2009). increasing menace to Australian freshwater Non-coding RNA in mammalian sexual ecosystems. Further unchecked growth development. Sexual Development 3: and spread of the carp population poses 302-316. a threat to many native fish species. In this Wilhelm, D., Hiramatsu, R., Mizusaki, project we are investigating the biology of H., Widjaja, L., Combes, A.N., Kanai, RNAi in carp and zebrafish, to investigate Y., and Koopman, P. (2007). SOX9 the potential of a “daughterless” approach regulates prostaglandin D synthase by making use of the endogenous RNAi gene transcription in vivo to ensure processing machinery to knock down testis development. Journal of Biological aromatase and thereby control carp Chemistry 282: 10553-10560. numbers. Wilhelm, D., Palmer, S., and Koopman, Our research uses mouse and zebrafish P. (2007). Sex determination and gonadal as model systems and integrates development in mammals. Physiological molecular and developmental biology to Reviews 87: 1-28. study mechanisms of gene regulation by transcription factors as well as Wilhelm, D., Martinson, F., Bradford, S., ncRNAs during embryonic development, Wilson, M.J., Combes, A., Beverdam, A., Bowles, J., Mizusaki, H., and Koopman, concentrating on sex determination and P. (2005). Sertoli cell differentiation is gonad development but extending to induced both cell-autonomously and other developmental systems such as through prostaglandin signalling to chondrogenesis. 41 imb researchers: molecular cell biology

Division of MOLECULAR CELL BIOLOGY

Cell Biology seeks to understand the molecular workings of the cell. This ambition encompasses efforts to elucidate how molecular and biochemical mechanisms are integrated to drive fundamental cellular events, such as metabolism, intracellular transport, growth, division and signalling. Ultimately such integration must extend to encompass the differentiation events and the interaction of cells with their environment that are the basis for tissue function. Such fundamental knowledge also forms the basis for a detailed understanding of cellular pathology in human diseases, such as inflammation and cancer. imb annual report 2010 42

THE RESEARCH GROUPS OF THE to a team of eight chief investigators, In addition to external visitors, a major Division of Molecular Cell Biology including Professor Alpha Yap. The team part of the intramural academic life of are tackling individual problems that aims to develop treatments to tackle the Division is the Cell Biology Forum speak to various key problems in cell the recurrence of breast cancer, and is (CBF). First established by Professor biology. These include the trafficking led by Professor Erik Thompson from Parton, and currently coordinated by of cytokines in inflammation (Stow); St Vincent’s Institute and the University Brett Collins, this weekly meeting is the biochemical dynamics of GTPase of Melbourne. The division received dedicated to research presentations by signalling (Alexandrov); the biogenesis $1.1 million from the NHMRC from two the students, post-doctoral fellows, and of membrane organisation (Parton); grants awarded to Professors Yap and affiliates of the Division. It serves both cell-cell adhesion and the cytoskeleton Mike Waters, to investigate cell adhesion to provide essential training in research (Yap); the role of membrane trafficking and permanently activated growth presentations, and also to promote in host-pathogen interactions (Teasdale, hormone respectively. Professor Jenny scientific exchange at all levels within the joint appointment with GCB); structural Stow received a Discovery grant from Division. biology of membrane transport (Collins); the ARC worth $315k to examine the Finally, Mr Darren Brown, a research high-resolution electron microscopy of secretory pathways that play a role in assistant in the Stow group, was the insulin-secreting pancreatic cells (Marsh); immune defence and are dysfunctional winner of the 2010 Ångström Art™ high-throughput computational analysis in disease. She was also awarded an Centenary Competition. His winning of cellular imaging (Hamilton, joint NHMRC Research Fellowship to study image is featured on the front cover of appointment with GCB); and cell biology protein trafficking in diseases including this report. One of Mr Brown’s images of growth hormone (Waters). These inflammation. Dr Brett Collins received was also chosen as one of two runner- snapshots highlight, however, only part an ARC Future Fellowship to study the up images. The Stow group researchers of each group’s research program, the control of protein transport in cells. focus on protein trafficking, particularly in range of which can be well appreciated in Members of the Division maintained the context of disease and the immune their individual laboratory reports. extensive engagement in the scientific system, and this is reflected in many of All the individual groups of the Division community both nationally and the images Mr Brown contributed to the are supported by external research internationally. Professor Stow is a competition. All of the images submitted funding. These include project and member of the Medical Advisory Board to the competition, and more information program grants from the NHMRC, and of the Australian Cancer Research about each, can be viewed at the project grants from the ARC, Cancer Foundation; Professor Rob Parton serves Ångström Art™ website: www.angstrom- Council, and Human Frontiers Science as a senior member of the editorial art.com Program (HFSP). Many group leaders boards for both The Journal of Cell in the Division are also supported by Biology and Molecular Biology of the Cell; Fellowships from the NHMRC and ARC. and Professor Alpha Yap served as the The awarding of $2.5 million from the Convenor of the 2010 Hunter Cellular

Australian Cancer Research Foundation Biology Meeting. JOHN allowed the establishment of the ACRF GRIFFIN: The Division played host to several POINCIANA Cancer Biology Imaging Facility, which distinguished national and international POLLEN was officially opened in February 2010 scientists who spoke at the IMB’s Curiosity is by Queensland Governor Her Excellency an important Friday Seminar Series. These included Dr Penelope Wensley AO. Professor quality for Professor Frances Brodsky (University Rob Parton received an award from the scientists and artists alike. of California San Francisco, USA), Knowing that pollen can NHMRC for having the highest-ranked Professor Vojo Deretic (University of New exhibit beautiful and surprising project grant in the nation. Each grant forms, I succumbed to my Mexico, Albuquerque, USA), Dr Michael is ranked according to its suitability curiosity when the Poinciana Way (Cancer Research UK London for receiving funding, and of the 2984 trees were in full bloom on our Research Institute, U.K.), Dr Brian Burke campus and collected some project grants submitted to the Council, (Institute of Medical Biology, Singapore), Poinciana stamens on my Professor Parton’s was awarded the and Professor Angel Lopez (Institute of way to the IMB one morning. most points. New grants awarded in This image was acquired on a Medical & Veterinary Science, Adelaide). 2010 included a $5m grant from the Zeiss LSM 510 confocal laser National Breast Cancer Foundation scanning microscope and the resulting confocal sections were depth-­coded individually in Adobe Photoshop CS3 and processed in ImageJ. 43 imb researchers: molecular cell biology

KIRILL ALEXANDROV NEXT-GENERATION TECHNOLOGIES FOR PROTEIN RESEARCH

• Quantitative analysis of protein:protein protein:small molecule interactions using in vitro protein expression systems • Proteome-wide analysis of protein prenylation and its variation in human diseases • Understanding of mechanisms regulating protein prenylation machinery • Identification of small molecules modulating prenylation and localisation of RabGTPases Suspension culture of Leishmania tarentolae cells expressing GFP protein. ADVANCES IN LIFE SCIENCES AND KEY PUBLICATIONS biotechnology are driven by our ability to replicate the building blocks of life Kovtun, O., Mureev, S., Johnston W., in vitro, modify them, and use them in and Alexandrov, K. (2010). Towards the academic and industrial applications. Much construction of expressed proteomes using a Leishmania tarentolae based biotechnological progress in the last 40 cell-free expression system. PLOS One 5: years stemmed from advances in analysis e14388. and synthesis technologies for DNA and proteins. However while orders-of- Mureev, S., Kovtun, O., Nguyen, U.T.T., magnitude cost reduction was achieved in and Alexandrov, K. (2009). Species- DNA sequencing and synthesis, the protein independent translational leaders enable technologies have changed comparatively the rapid development of novel cell-free little. expression systems. Nature Biotechnology 27: 747-752. Our group is focusing on filling this technological gap by developing new Nguyen, U.T., Guo, Z., Delon, C., Wu, methods for rapid in vitro synthesis of Y., Deraeve, C., Fränzel, B., Bon, R.S., proteins and analysis of their structure Blankenfeldt, W., Goody, R.S., Waldmann, and function. We have developed a novel H., Wolters, D., and Alexandrov, K. (2009). cell-free protein expression system based Analysis of the eukaryotic prenylome on protozoan Leishmania tarentolae. We by isoprenoid affinity tagging. Nature Chemical Biology 4: 227-235. demonstrate that, using this technology, large sets of genes can be converted Wu, Y., Tan, K.-T., Waldmann, H., into proteins within hours. We apply this Goody, S.R., and Alexandrov, K. (2007). technology to study cellular processes Quantitative analysis of the interaction of controlled by Rab GTPases and the role prenylated Rab proteins with REP and of protein prenylation in this process. Due GDI explains the requirement for both Expression of EGFP in L. tarentolae cell-free regulators in Rab function. Proceedings of to their importance in many signalling system. and trafficking pathways, a deregulation the National Academy of Sciences USA of the GTPases (expression defects, 104: 12294-12299. mutations, or defects in their prenylation status) is associated with numerous human pathologies. LAB MEMBERS Research Officers: Dr Sergey Mureev, Dr Viktor Stein, Dr Wayne Johnston, Dr RESEARCH PROJECTS Zhong Guo • Development of high-yield cell-free Research Assistants: Virajitha protein expression system based on Rajagopalan, Veronika Schreiber, Leishmania tarentolae Regina Hartmann, Nichole Giles, Florian Gebhardt, WooRam Jung PhD Students: Oleksiy Kovtun, Zakir Tnimov, Marta Kubala, Monika Koenke imb annual report 2010 44

BRETT COLLINS CELLULAR TRAFFICKING AT ATOMIC RESOLUTION

OUR LAB IS FOCUSED ON membrane transport system are linked to understanding the processes of intracellular many different human diseases, including a membrane trafficking within the secretory number of cancers, Alzheimer’s, lysosomal and endocytic systems of the human storage disease and hypercholesterolemia, cell. We do this using a multidisciplinary and it is also exploited by bacterial toxins approach that integrates the high- and viral pathogens such as HIV to gain resolution structural characterisation of entry into the cell. essential membrane trafficking machinery Membrane sorting between secretory and by X-ray crystallography with biochemical endocytic organelles is predominantly and cell biological experiments guided by controlled by small carrier vesicles these mechanistic details. and tubules that are layered on their We concentrate primarily on the process cytoplasmic faces by specific protein of protein sorting within the dynamic machineries. The roles of these organelles known as endosomes, which protein coats are threefold: (i) to select are key sorting stations for regulated transmembrane and lipid cargo to be exo- and endocytosis of cell surface packaged into vesicles forming at the Malintan, N.T., Nguyen, T.H., Han, L., receptors, signalling molecules and many donor membrane, (ii) to control vesicle Latham, C.F., Osborne, S.L., Wen, P.J., other cellular components. The regulated budding and scission and (iii) to specify Joo, L.S., Sugita, S., Collins, B.M., and trafficking of proteins and their ligands the final destination of the transport Meunier, F.A. (2009). Abrogating Munc18- between membrane-bound endosomal intermediates. Using a multidisciplinary 1-SNARE interaction has limited impact compartments, the plasma membrane and structural biology/biochemistry/cell on exocytosis in PC12 cells. Journal of other internal organelles is a fundamental biology approach, our goal is to reveal Biological Chemistry 284: 21637-21646. process in human cells, and indeed in how these machineries assemble, how all eukaryotes. Defects in the endosomal they are recruited to membranes and how Collins, B.M. (2008). The structure and they control receptor trafficking at the function of the retromer protein complex. molecular level. Current work focuses on Traffic 9: 1811-1822. the multi-subunit retromer protein complex Miller, S.E., Collins, B.M., McCoy, A.J., with a central role in directed transport of Robinson, M.S., and Owen, D.J. (2007). A endosomal cargo proteins, the PX-domain SNARE-adaptor interaction is a new mode family of proteins involved in sorting of of cargo recognition in clathrin-coated diverse proteins such as ion transporters vesicles. Nature 450: 570-574. and amyloid precursor protein, and a novel family of arrestin-related trafficking proteins. Collins, B.M., Skinner, C.F., Watson, P.J., Seaman, M.N.J., and Owen, D.J. (2005). Vps29: a phosphoesterase fold that acts RESEARCH PROJECTS as a protein-protein interaction scaffold for • Structure and function of the retromer assembly of retromer. Nature Structural & protein complex and its interaction Molecular Biology 12: 594-602. with cargo proteins and regulatory Collins, B.M., Watson, P.J., and Owen, molecules D.J. (2003). The structure of the GGA1- GAT domain reveals the molecular • Molecular characterisation of Crystals of the retromer subunit VPS26B. basis for ARF binding and membrane endosomal sorting by PX-domain recruitment of GGAs. Developmental Cell proteins and their associations with 4: 321-332. effector molecules Collins, B.M., McCoy, A.J., Kent, H.M., • Structure and function of arrestin- Evans, P.R., and Owen, D.J. (2002). related proteins Molecular architecture and functional • Munc/SNARE interactions during model of the endocytic AP2 complex. Cell 109: 523-535. neurosecretion

KEY PUBLICATIONS LAB MEMBERS Norwood, S.J., Shaw, D.J., Cowieson, Research Officers: Dr Suzanne Norwood, N.P., Owen, D.J., Teasdale, R.D., and Dr Ramya Mandyam Collins, B.M. (2010). Assembly and Research Assistant: Jasmine Davis solution structure of the core retromer protein complex. Traffic Epub 23/9/2010 PhD Students: Daniel Shaw, Rajesh Electron density for the VPS26B subunit of Ghai retromer. 45 imb researchers: molecular cell biology

BRAD MARSH STRUCTURE-FUNCTION STUDIES OF THE PANCREATIC BETA CELL – MAPPING INSULIN BIOSYNTHESIS AND TRAFFICKING IN SITU IN 3D AT THE NANOSCALE

RESEARCH PROJECTS • 3D reconstruction and quantitative/ computational analysis of mammalian (insulin-secreting) cells in situ in tissue at intermediate (~10nm) and high (~4nm) resolutions • Rotavirus-infection of pancreatic islets/ beta cells • Correlative light and electron microscopy of Golgi organisation and membrane traffic in mammalian cells • High-content screening of small OUR RESEARCH FOCUSES ON THE bioactive molecules as potential detailed characterisation of fundamental therapeutic agents for promoting structure-function relationships healthy pancreatic beta cell growth and underpinning the biosynthesis, trafficking function and secretion of the hormone insulin in mammalian cells - specifically, the • Development/characterisation of pancreatic beta cell. To achieve this goal, optimised liposomes as regulated we quantitatively map cellular organisation nanodevices for targeted peptide in beta cells in 3D at the nanoscale under delivery a range of physiological/disease conditions using cellular electron tomography (ET). Electron tomography uses mathematical KEY PUBLICATIONS methods to computationally reconstruct a Noske, A.B., and Marsh, B.J. (2011). 3D volume from a set of 2D images. This Mapping the Beta Cell in 3D at the is very similar to how diagnostic imaging Nanoscale Using Novel Cellular Electron techniques like computed tomography Tomography and Computational (CT), magnetic resonance imaging (MRI) Approaches, in: BetaSys - Systems Biology and positron electron tomography (PET) of Regulated Exocytosis in Pancreatic Noske, A.B., Costin, A.J., Morgan, are able to computationally reconstruct β-Cells (B Booß-Bavnbek, B Klösgen, G.P., and Marsh, B.J. (2008). Expedited 3D image maps for different parts (or J Larsen, F Pociot, E Renström, Eds.). approaches to whole cell electron even all) of the body. In our case, Series: Systems Biology. Springer (In Press) tomography and organelle mark-up in situ however, we generate 3D image maps in high-pressure frozen pancreatic islets. for different parts (or even all) of the cell at Dobrucki, W.L., Marsh, B.J., and Journal of Structural Biology 161: 298-313. nanometre resolution. This allows us to Kalinowski, L. (2009). Elucidating structure- Richter, T., Floetenmeyer, M., Ferguson, C., unambiguously visualise and characterise function relationships from molecule-to- Galea, J., Goh, J., Lindsay, M.R., Morgan, machinery in the ‘insulin factory’ at high cell-to-tissue: from research modalities to G.P., Marsh, B.J., and Parton, R.G. (2008). spatial resolution to gain fundamental new clinical realities. Journal of Physiology and High-resolution 3D quantitative analysis insights into how insulin is manufactured Pharmacology 60: 83-93. of caveolar ultrastructure and caveola- and released, and to identify how and Emr, S., Glick, B.S., Linstedt, A.D., cytoskeleton interactions. Traffic 9: 893- where defects in these basic processes Lippincott-Schwartz, J., Luini, A., Malhotra, 909. contribute to beta cell failure and/or death, V., Marsh, B.J., Nakano, A., Pfeffer, S.R., which leads to the set of diseases broadly Rabouille, C., Rothman, J.E., Warren, G., referred to as diabetes. Type 1 diabetes and Wieland, F.T. (2009). Journeys through LAB MEMBERS is now one of Australia’s fastest-growing the Golgi - taking stock in a new era. Research Officers: Dr Isabel Morrow, Dr chronic childhood diseases; currently, type Journal of Cell Biology 187: 449-453. 1 diabetes cannot be prevented, and a Neelima Sidharthan, Dr Massimo Micaroni cure remains to be found. McComb, T., Cairncross, O., Noske, A.B., Research Assistant: Garry Morgan Wood, D.L., Marsh, B.J., and Ragan, M.A. (2009). IllouraTM: a software tool PhD Students: Adam Costin, Alex Foo, for analysis, visualisation and semantic Andrew Noske, Peter van der Heide, querying of cellular and other spatial Timothy Pan, Nur Intan Ruhaiyem biological data. Bioinformatics 25: 1208- 1210. imb annual report 2010 46

ROB PARTON THE CELL SURFACE IN HEALTH AND DISEASE

OUR GROUP IS INTERESTED IN THE the molecular changes associated with organisation, dynamics, and functions of muscular dystrophy. An additional aim of the plasma membrane. The properties our work is to understand the link between of the plasma membrane rely on the caveolae and lipid-filled organelles termed specialisation of the plasma membrane lipid droplets, which are major storage into microdomains of specific function. organelles involved in obesity. We are also We are studying two types of surface using our knowledge of caveolin-induced microdomains: caveolae, a specialised vesicle formation to develop novel drug domain of the cell surface with a distinct encapsulation systems with potential structure, and clathrin-independent therapeutic applications. endocytic carriers (CLICs), that form the major endocytic pathway in mammalian cells. Caveolae have been implicated in RESEARCH PROJECTS regulation of cell growth and in maintaining • Analysis of the role of caveolae in lipid the balance of lipids in the cell. In addition, regulation and mechanosensing caveolins, the major membrane proteins of • Caveolae and obesity: dissecting the caveolae, and cavins, a newly-discovered capacity endocytic sorting system at the role of caveolins and Rab proteins in family of caveolar coat proteins, have leading edge of migrating cells. Journal of been implicated in a number of disease lipid droplet formation and function Cell Biology 190: 675-691. states including tumour formation, in adipose tissue and during liver lipodystrophies, and muscular dystrophy. regeneration Bastiani, M., Liu, L., Hill, M.M., Jedrychowski, M.P., Nixon, S.J., Lo, H.P., To study caveolae function we are using • Caveolae, caveolin-3, and cavins in Abankwa, D., Luetterforst, R., Fernandez- caveola-null mice, cells lacking caveolins muscle: analysing the role of caveolae Rojo, M., Breen, M.R., Gygi, S.P., Vinten, and/or cavins, and zebrafish embryos. in muscle development and in muscular J., Walser, P.J., North, K.N., Hancock, These systems are also being used to dystrophy J.F., Pilch, P.F., and Parton, R.G. (2009). study the role of caveolae in muscle and MURC/Cavin-4 and cavin family members • Caveolins and caveolin-interacting form tissue-specific caveolar complexes. proteins in zebrafish: using zebrafish Journal of Cell Biology 185: 1259-1273. as a model system to understand the role of caveolae during development Hill, M.M., Bastiani, M., Luetterforst, R., Nixon, S., Kirkham, M., Kirkham, A., and the effect of muscular dystrophy Nixon, S.J., Walser, P., Abankwa, D., mutants of caveolin-3 on muscle Ooschot, V.M.J., Martin, S., Hancock, structure and function J.F., and Parton, R.G. (2008). PTRF-cavin, • Clathrin-independent endocytosis: a conserved cytoplasmic protein required characterising the structure and for caveola formation and function. Cell function of a novel endocytic pathway 132: 113-124. in mammalian cells and the zebrafish • Caveola formation and structure: LAB MEMBERS studying caveola biogenesis and Senior Research Officer: Dr Susan Nixon caveolae structure in health and Research Officers: Dr Manuel disease using electron tomography and Fernandez-Rojo, Dr Harriet Lo, Dr Kerrie- novel cell systems Ann McMahon#, Dr Mark Howes#, Dr • Caveola formation in bacteria: Michele Bastiani#, Dr Ramya Mandyam#* characterisation of novel nanovesicles Research Assistants: Robert and their use as drug delivery vehicles Luetterforst*, Leanne Cooper, Rachel Hancock*, Charles Ferguson, James Rae, KEY PUBLICATIONS Nicole Schieber* Howes, M.T., Kirkham, M., Riches, J., PhD Students: Samantha Murphy, Carol Cortese, K., Walser, P.J., Simpson, F., Hill, Kistler, Nick Ariotti, Natalya Leneva, M.M., Jones, A., Lundmark, R., Lindsay, Satomi Okano#, Natasha Chaudhary M.R., Hernandez-Deviez, D.J., Hadzic, G., Visitors: Dr. Ian Prior#, Lindsey Murphy# McCluskey, A., Bashir, R., Liu, L., Pilch, P., McMahon, H., Robinson, P.J., Hancock, # part of year J.F., Mayor, S., and Parton, R.G. (2010). * part-time Clathrin-independent carriers form a high 47 imb researchers: molecular cell biology

JENNY STOW PROTEIN TRAFFICKING IN HUMAN DISEASE

molecules in three and four dimensions is a core technology for the research in our group and a rapidly advancing technology of the future.

RESEARCH PROJECTS • Secretory pathways for cytokines and anti-microbial peptides in immune cells • New targets for regulating cytokine secretion in arthritis and inflammatory bowel disease • Structure and function of recycling endosomes in secretory and endocytic pathways Our research group studies protein trafficking in human and animal cells. The • Phagocytosis and trafficking of bacterial Proceedings of the National Academy of intracellular trafficking of membranes and pathogens, including Salmonella Sciences USA 105: 3351-3356. proteins is a fundamental cell process • Epithelial cell polarity and tumour that also impacts on all human diseases. Bryant, D.M., Kerr, M.C., Hammond, L.A., prevention Our studies in cells of the immune system Joseph, S.R., Mostov, K.E., Teasdale, relate to infectious and inflammatory • Imaging live cells to create 3D and R.D., and Stow, J.L. (2007). EGF induces diseases and our work in epithelial cells 4D maps of trafficking pathways: macropinocytosis and SNX1-modulated aims to investigate their transition to fluorescence imaging, computer recycling of E-cadherin. Journal of Cell Science 120: 1818-1828. cancer cells. In macrophages and other modelling and animation cells of the immune system, we are Manderson, A.P., Kay, J.G., Hammond, studying the process of phagocytosis and L.A., Brown, D.L., and Stow, J.L. (2007). other pathways through which bacterial KEY PUBLICATIONS Subcompartments of the macrophage pathogens enter cells, escape our immune Low, P.C., Misaki, R., Schroder, K., recycling endosome direct the differential defenses and set up infections. Our goal in Stanley, A.C., Sweet, M.J., Teasdale, secretion of IL-6 and TNFalpha. Journal of this work is to identify new targets for anti- R.D., Vanhaesebroeck, B., Meunier, Cell Biology 178: 57-69. bacterial treatments or disease prevention. F.A., Taguchi, T., and Stow, J.L. (2010). Immune cells also secrete a plethora Phosphoinositide 3-kinase regulates Stow, J.L., Manderson, A.P., and Murray, of cytokines as part of their immune membrane fission of Golgi carriers for R.Z. (2006). SNAREing immunity: the role response. Our studies are revealing the selective cytokine secretion. Journal of of SNAREs in the immune system. Nature Reviews Immunology 6: 919-929. genes, molecules and cell compartments Cell Biology 190: 1053-1065. involved in secretory pathways for Reefman, E., Kay, J.G., Wood, S.M., Murray, R.Z., Kay, J.G., Sangermani, inflammatory cytokines in macrophages, Offenhäuser, C., Brown, D.L., Roy, S., D.G., and Stow, J.L. (2005). A role for the natural killer cells and other cell types. This Stanley, A.C., Low, P.C., Manderson, phagosome in cytokine secretion. Science work aims to develop new therapeutic A.P., and Stow, J.L. (2010). Cytokine 310: 1492-1495. strategies for controlling cytokines in secretion is distinct from secretion of chronic inflammatory diseases. Trafficking cytotoxic granules in NK cells. Journal of regulators, including Rabs, SNAREs Immunology 184: 4852-4862. LAB MEMBERS: and PI3K proteins, are investigated as Senior Research Officers: Dr Tom Wood, S.M., Meeths, M., Chiang, S.C., part of our research, and key functional Taguchi, Dr Amanda Stanley members of these protein families have Bechensteen, A.G., Boelens, J.J., Research Officers: Dr Ryo Misaki, Dr been identified. In epithelial cells we are Heilmann, C., Horiuchi, H., Rosthøj, S., Rutynowska, O., Winiarski, J., Stow, J.L., interested in many of these same proteins Adam Wall Nordenskjöld, M., Henter, J.I., Ljunggren, and their roles in cell polarity and cancer Research Assistants: Darren Brown, H.G., and Bryceson, Y.T. (2009). Different prevention. Gene expression arrays, gene Tatiana Khromykh, Juliana Venturato, NK cell-activating receptors preferentially knockouts or mutations, and biochemical recruit Rab27a or Munc13-4 to perforin- Teresa Munchow, John Griffin analyses are used in our research. Since containing granules for cytotoxicity. Blood Research Coordinator: Dr Fiona Wylie trafficking is a highly dynamic process 114: 4117-4127. in cells, a major scientific approach we PhD Students: Carolin Offenhauser, employ is live cell fluorescence imaging Lieu, Z.Z., Lock, J.G., Hammond, L.A., Regine Low, Marga Gual Soler to track fluorescently tagged proteins and La Gruta, N.L., Stow, J.L., and Gleeson, fluorescent probes. Imaging cells and P.A. (2008). A trans-Golgi network golgin is required for the regulated secretion of TNF in activated macrophages in vivo. imb annual report 2010 48

MIKE WATERS ROLE OF GROWTH HORMONE AND RELATED CYTOKINES IN GROWTH, CANCER, DIABETES AND OBESITY

ADULT HEIGHT IS DETERMINED BY The absolute requirement for GH in liver the actions of growth hormone (GH) during regeneration has led us to use our panel of childhood and adolescence. In the adult, GH receptor signalling mutants to find the growth hormone is an important metabolic identity of the regeneration signal. agent regulating body composition, opposing the actions of insulin. In old age, growth hormone status determines RESEARCH PROJECTS lifespan, at least in animal models. We • Investigating the mechanism of study the means used by growth hormone activation of growth hormone and to achieve these changes, using a variety related cytokine receptors, including of approaches directed to the growth the mechanism of activation of the hormone receptor, from high-resolution Src kinase constitutively bound to the protein structures to genetically-engineered receptor animals. • Elucidating the role of the growth The growth hormone receptor determines hormone receptor in the cell nucleus the degree of the cell response to growth in relation to proliferation, oncogenesis hormone, which we originally cloned and stem cell proliferation Schirra, H.J., Anderson, C.G., Wilson, collaboratively with Genentech. Through W.J., Kerr, L., Craik, D.J., Waters, FRET, BRET, crystallography and targeted • Determining the role of GH-dependent M.J., and Lichanska, A.M. (2008). mutagenesis we have developed a new Stats 5/3/1 in lipid and carbohydrate Altered metabolism of growth hormone model of how the GH receptor is activated metabolism, including insulin action receptor mutant mice: a combined NMR by GH, involving realignment of receptor metabonomics and microarray study. • Establishing the molecular basis for subunits within a constitutive dimer. An PLoS ONE 3: e2764. GH-dependent liver regeneration extension of this model describes how a rearrangement of an extracellular b-loop • Establishing the molecular mechanism of the GH receptor selectively controls underlying the long-term activation of LAB MEMBERS ERK activation without influencing Stat5 neural stem cells by GH Research Officers: Dr Andrew Brooks, Dr activation through the use of an alternate: Tim McPhee Src kinase. KEY PUBLICATIONS Research Assistants: Kathryn Tunny, By creating targeted knock-in mutations to Tania Brooks Blackmore, D.G., Golmohammadi, M.G., signalling domains within the GH receptor Large, B., Waters, M.J., and Rietze, R.L. PhD Students: Caroline Nelson, Yash cytoplasmic domain, we have shown that (2009). Exercise increases neural stem cell Chhabra enhancement of postnatal somatic growth number in a growth hormone-dependent Masters Student: Qiushi Chen by GH is dependent on its ability to activate manner, augmenting the regenerative the transcription factor Stat5. Because response in aged mice. Stem Cells 27: Occupational Trainee: Morgane Roussel these mice become strikingly obese 2044-2052. after 6 months of age, we are currently investigating the role of Stat5a/b in control Conway-Campbell, B.L., Brooks, A.J., of lipid and carbohydrate metabolism using Robinson, P.J., Perani, M., and Waters, tissue-targeted gene deletion of Stat5a/b. M.J. (2008). The extracellular domain of We have found that insulin secretion and the growth hormone receptor interacts action are altered in these mice, and with coactivator activator to promote cell their livers are grossly steatotic. We are proliferation. Molecular Endocrinology 22: 2190-2202. identifying the molecular targets of GH that regulate these changes, using in vivo Cre Lichanska, A.M., and Waters, M.J. (2008). deletion of key transcription factors. How growth hormone controls growth, obesity and sexual dimorphism. Trends in The surprising finding that the growth Genetics 24: 41-47. hormone receptor is located in the cell nucleus of dividing cells has led us to Rowlinson, S.W., Yoshizato, H., Barclay, discover that nuclear localised receptor J.L., Brooks, A.J., Behncken, S.N., Kerr, induces the expression of a key stem cell L.M., Millard, K., Palethorpe, K., Nielsen, marker. Because we have shown that GH K., Clyde-Smith, J., Hancock, J.F., and Human melanoma line infected with mKATE2 Waters, M.J. (2008). An agonist-induced expressing chicken virus, demonstrating ability promotes neural stem cell proliferation, we to deliver STAT5 dominant negative to halt conformational change in the growth are studying the mechanism of this direct metastasis. gene induction by the GH receptor. hormone receptor determines the choice of signalling pathway. Nature Cell Biology 10: 740-747. 49 imb researchers: molecular cell biology

ALPHA YAP CADHERIN ADHESION AND TISSUE ORGANISATION IN HEALTH AND DISEASE

actin cytoskeleton, thereby influencing cell shape, adhesion, and cell-cell cohesion. Relevant signals include the Rho family GTPases and Src family kinases. These affect a range of cytoskeletal regulators, including actin nucleators, cross-linking proteins, scaffolds and the myosins II and VI. We aim to understand the dynamic spatial and temporal regulation of the cytoskeleton by cadherin signalling, with a view to understanding how these key elements are used during development and tissue maintenance, and how they are disrupted in human disease.

An important challenge we are beginning to confront is how to understand the CELLS ARE THE BUILDING BLOCKS complexity of cytoskeletal regulation KEY PUBLICATIONS of our bodies. Interactions between at cell-cell junctions. Our research Smutny, M., Cox, H.L., Leerberg, J., different cells are important to shape experience, accrued over the past several Kovacs, E.M., Conti, M.A., Ferguson, C., our developing bodies and maintain the years, indicates that multiple cytoskeletal Hamilton, N.A., Parton, R.G., Adelstein, organisation of our tissues in health. A regulators are coordinated at cadherin R.S., and Yap, A.S. (2010). Myosin range of diseases occur when those adhesion to control junctional dynamics, II isoforms identify distinct functional interactions are disturbed, including homeostasis and integrity. How then do we modules that support integrity of the cancer and inflammation. My laboratory develop a coherent model to encompass epithelial zonula adherens. Nature Cell studies one set of cell-to-cell interactions, Biology 12: 696-702. this complex system? A significant those that occur when cells attach to one breakthrough is our recent discovery, * another. We focus on the cadherin family Den Elzen, N., Buttery, C.V., Maddugoda , published in Nature Cell Biology (Smutny M.P., Ren*, G., and Yap, A.S. (2009). of cell-cell adhesion receptors. These et al., 2010), that these cell signals and Cadherin adhesion receptors orient the critically determine the ability of cells effectors function in modules, where key mitotic spindle during symmetric cell to recognise one another and organise effectors are subject to specific signal division in mammalian epithelia. Molecular into coherent tissues. The importance of regulation and have distinct cellular Biology of the Cell 20: 3740-3750. (*Equal these receptors is emphasised by the fact functions, that synergise to support contributions) that loss of cadherin function promotes junction integrity. This work was the subject cancer progression in epithelial tissues Ren, G*., Helwani*, F.M., Verma*, S., of an editorial review in Nature Cell Biology (such as the breast and colon) – the McLachlan, R.W., Weed, S.A., and Yap, and highlighted on Faculty of 1000. We commonest form of human cancers. A.S. (2009). Cortactin is a functional target are now working with Dr Nick Hamilton to Cadherin dysfunction also contributes to of E-cadherin-activated Src family kinases develop mathematical tools to measure the breakdown of epithelial barriers during in MCF-7 epithelial monolayers. Journal and model these complex systems. inflammation, notably in chronic disease of Biological Chemistry 284: 18913- * of the intestine. By understanding the 18922. ( Equal contributions) basic biological mechanisms of cadherin- RESEARCH PROJECTS Akhmanova, A. and Yap, A.S. (2008). mediated cell recognition, we thus hope Organizing junctions at the cell-cell • Regulation of the actin cytoskeleton by to provide vital insights into the basis of interface. Cell 135: 791-793. developmental patterning and common E-cadherin human diseases. • Cooperation between cadherins and Currently we focus on understanding myosin motors at cell-cell contacts how cadherins cooperate with the actin • Cooperativity between cadherins and LAB MEMBERS cytoskeleton, long believed to be central to microtubules Senior Research Officer: Dr Eva Kovacs cadherin function. Our experience makes Research Officers: Dr Guillermo it increasingly clear that this cooperation • Cadherin signalling to Src family kinases: involves a complex interplay between defining the pathway(s) Gomez, Dr Michael Smutny, Dr Aparna Ratheesh, Dr Robert McLachlan, Dr Karen adhesion receptors and diverse distinct • The morphogenetic consequences of Chambers, Dr Siew Ping Han states of the cytoskeleton, coordinated cadherin-activated cell signalling and by a variety of signalling pathways at the cooperativity with the actin cytoskeleton Research Assistants: Suzie Verma, Kris cell membrane. In particular, our work Blucher demonstrates that cadherins function as PhD Students: Sabine Mangold, Joanne adhesion-activated cell signalling receptors Leerberg, Vincent Leong, Selwin Wu that stimulate pathways to regulate the imb annual report 2010 50

Division of CHEMISTRY AND STRUCTURAL BIOLOGY

In 2010, the Division of Chemistry and Structural Biology consisted of 10 groups led by Professors David Fairlie, Jenny Martin, Paul Alewood, David Craik, Richard Lewis, Rob Capon, Glenn King, Matt Cooper, and Associate Professors Mark Smythe and Ben Hankamer, with five Affiliates: Professors Alan Mark, Bostjan Kobe, Istvan Toth, Paul Young, and Kirill Alexandrov. The group collectively published 135 papers in the chemical and biological sciences; held ARC Federation, Laureate, Professorial and Future Fellowships as well as NHMRC Australia, PRF and SRF Fellowships; operated 2 NHMRC program grants; and participated in over 20 international and national conferences.

EMILY KNAUTH: PREPARATION The preparation of any experiment is of utmost importance. Here is an example of algae cell Chlamydomonas reinhardtii that have been badly damaged by ice crystal formation. The ice crystal form when the cells are not frozen fast enough to form vitreous ice. But just because preparations can leave a lot to be desired, it doesn’t mean you can’t get a pretty picture out of it. 51 imb researchers: chemistry and structural biology

DIVISION OF CHEMISTRY AND STRUCTURAL BIOLOGY

FELLOWSHIPS & AWARDS Dean’s List for Outstanding Research RESEARCH GRANTS Professor David Craik won the Higher Degree Theses. Dr Wang’s The Division’s Group Leaders were lead prestigious Ralph F. Hirschmann thesis focused on cyclotides, a family of investigators in attracting 7 new NHMRC Award in Peptide Chemistry bestowed circular proteins, while Dr Mutthenthaler project grants (>$3M, 47% success) and by the American Chemical Society, studied molecules isolated from the 2 new ARC Discovery grants (∼$1M) for the world’s largest scientific society. venom of marine cone snails. Dr Joshua commencement in 2011. This compares Professor Craik was recognised Mylne from the Craik group was named favourably with the IMB (NHMRC $6M, for his studies on circular peptides, the first IMB Fellow. This position offers 36% success; ARC $3.5M). In addition, particularly those related to plant support to senior postdoctoral scientists significant grants were received by peptides called cyclotides and venom- to transition towards independent Professors Lewis and Alewood (NHMRC derived conotoxins. Dr Richard Clark, research. Dr Mylne studies the protein Program grant, ∼$6.4M) and Associate a postdoc in the Craik group, was processing machinery of sunflowers, Professor Hankamer (Queensland State named Senior Researcher of the Year which could be used as a quicker and Government National and International at the Queensland Health and Medical cheaper method of producing drugs. Research Alliances Program, $1.5M). Research Awards for engineering a Professors Cooper and King both The IMB recognises its top-performing compound that was effective in a rodent received ARC Linkage grants to partner honours student each year with the model of chronic pain. Dr Richard with Alere Australia and Barmac Amgen Award. The Award is presented Allen, who is currently at the Australian respectively; Professor Fairlie received to the student who achieved the highest National University, won an NHMRC a Development grant from the NHMRC; honours mark in the previous year, Postdoctoral Training Fellowship to while teams of group leaders from the so in 2010, the award was presented join the King group and study the Division led by Professors Alewood based on 2009 results. Two students physiological processes the malaria and Lewis received separate ARC LEIF tied for the award, and both were from parasite employs to survive in the red equipment grants. For more details the Chemistry and Structural Biology blood cells of its host. Dr Tim Hill in on these grants, please see the News division. Sheila Barbero from the Fairlie the Fairlie group won a University of section of the IMB website. group and Anne Sawyer from the Queensland Early Career Researcher Hankamer group were presented with grant to work on diabetes. Professor their awards in a ceremony in late March. Martin and Evan Stephens, a PhD DIVISION PROMOTION Ms Barbero investigated inhibitors of student in the Hankamer group, were In 2010 the Division instituted a secretory phospholipase A2 enzymes awarded Queensland International promotional and marketing campaign, that are important in inflammatory Fellowships from the State Government, including targeted symposia, a diseases, while Ms Sawyer studied which allowed them to spend time promotional booklet and a new website. the protein NAB-1 from a species of working with collaborators overseas. The inaugural Chemistry and Structural green algae that the Hankamer group Professor Martin travelled to Cambridge Biology Divisional Symposium was held is genetically modifying to produce to learn new technologies in membrane on the 18th of November 2010, with commercial quantities of biofuels. protein structural biology with Professor an Industry Affiliate Program on 17th So Iwata, particularly focussing on Finally, a divisional researcher was November. Group leaders, researchers, bacterial infection and diabetes. Mr a runner-up in the Ångström Art™ students and industry affiliates Stephens visited collaborators in Centenary Competition. Dr Michael attended to hear about our discoveries Germany, with whom he and Associate Landsberg from the Hankamer group in structural biology, chemistry, Professor Hankamer are developing entered the image ‘Insect Assassin’, biochemistry, pharmacology and drug a bioreactor to produce biofuels from which depicts an insecticidal molecule. It discovery and to discuss collaborative algae. Ernest Tee, an honours student is featured on page 81 of this report. opportunities. It was a great success, in the Cooper group, was named with nearly 300 attendees and Valedictorian among 492 students in numerous sponsors, and has resulted the UQ Bachelor of Science achieving in new research and development a perfect 7.0 grade point average. Dr collaborations in 2011. A similar event Conan Wang from the Craik group will be held on 9th and 10th November and Dr Markus Mutthenthaler from the 2011. The website showcasing the Alewood group were both named on the division is: http://casb.imb.uq.edu.au/.

imb annual report 2010 52

PAUL ALEWOOD DESIGN AND DISCOVERY OF BIOACTIVE PEPTIDES AND PROTEINS

THE OVERALL FOCUS IN THE RESEARCH PROJECTS group www.uq.edu.au/alewood/ is the • Identification and characterisation of identification of bioactive molecules that novel peptides from Australian animals have the potential to play important roles that target ion channels, transporters in human health and wellbeing. Some specific interests include: the discovery and GPCR receptors and total synthesis of potent and selective • Dissecting chronic neuropathic pain peptides (toxins) from Australia’s venomous pathways with receptor-selective toxins creatures; the chemical synthesis of • Protein mimetics proteins and bioactive peptides; the development of new synthetic and • Development of new enabling synthetic analytical chemistry; and protein structure chemistry to access disulfide-rich and function. Special emphasis is placed peptides and small bioactive proteins on determining the structure-function and enzymes (up to 200 residues) relationships of natural and designed molecules. Current research programs • Design and synthesis of novel small molecules that mimic peptide structure involve: the discovery, isolation and Vernall, A.J., Cassidy, P., and Alewood, P.F. and function (peptidomimetics) characterisation of toxins from snakes, (2009). A single a-helical turn stabilized spiders, cone snails, platypus, ticks and by replacement of an internal hydrogen- scorpions; mimetics of calcium-binding KEY PUBLICATIONS bond with a covalent ethylene bridge. inflammatory proteins from the S100 class; Angewandte Chemie International Edition Morales, R.A.V., Daly, N.L., Vetter, I., the chemical engineering of disulfide-rich 48: 5675-5678. peptides and proteases; elucidating the Mobli, M., Napier, I.A., Craik, D.J., Lewis, structure and function of milk proteins and R.J., Christie, M.J., King, G.F., Alewood, Sharpe, I., Gehrmann, J., Loughnan, their role in human health; and uncovering P.F., and Durek, T. (2010). Total chemical M., Thomas, L., Adams, D., Atkins, A., new pain pathways in chronic pain. Synthesis and Structure of the Prokineticin Craik, D.J., Adams, D., Alewood, P.F., Bv8. Chembiochem 11: 1882-1888. and Lewis, R.J. (2001). Two new classes of conopeptides inhibit the alpha1- Muttenthaler, M., Nevin, S.T., Grishin, A.A., adrenoceptor and the noradrenaline Ngo, S.T., Choy, P.T., Daly, N.L., Hu, S.-H., transporter. Nature Neuroscience 4: 902- Armishaw, C.J., Wang, C.I.A., Lewis, R.J., 907. Martin, J.L., Noakes, P.G., Craik, D.J., Adams, D.J., and Alewood, P.F. (2010). Solving the a-conotoxin folding problem: LAB MEMBERS selenium-directed on-resin generation Senior Research Officers: Dr John of more potent and stable nicotinic acetylcholine receptor antagonists. Journal Holland, Dr Lachlan Rash, Dr Andreas of the American Chemical Society 132: Brust 3514-3522. Research Officers: Dr Aline Dantas, Dr Tom Durek, Dr Jean Jin, Dr Markus Beatrix, M., Ueberheide, D.F., Alewood, Muttenthaler P.F., and Chait, B.T. (2009). Rapid, sensitive analysis of cysteine rich peptide venom Research Assistant: Zoltan Dekan components. Proceedings of the National PhD Students: Rod Morales, Jen Smith, Academy of Sciences USA 106: 6910- Kalyani Akondi, Simone Vink, Vincent 6915. Lavergne Brust, A., Palant, E., Croker, D.E., Visiting Students: Soren Langer Colless, B., Drinkwater, R., Patterson, B., (University of Copenhagen), Louise Anker Schroeder, C.L., Wilson, D., Nielsen, C.K., (University of Copenhagen), Claudia Smith, M.T., Alewood, D., Alewood, P.F., Hjørringgård (Aarhus University, Denmark) and Lewis, R.J. (2009). Chi-conopeptides Pharmacophore Development: Towards a novel class of Norepinephrine Transporter Inhibitor (Xen2174) for Pain. Journal of Medicinal Chemistry 52: 6991-7002. 53 imb researchers: chemistry and structural biology

ROB CAPON BIODISCOVERY: PATHWAYS TO NEW BIOACTIVE CHEMICAL DIVERSITY

disulfide and only the second known natural nucleoside to incorporate a xylose sugar residue.

Heronapyrroles: the first reported natural examples of nitropyrroles, and a new class of Gram +ve selective antibacterials (target – antibiotics).

Ircinialactams: new examples of a rare class of terpenyl glycinyl-lactams, and the first reported isoform selective potentiators of GlyR (target – chronic inflammatory pain).

Raju, R., Piggott, A.M., Conte, M.M., and KEY PUBLICATIONS Capon, R.J. (2010). Heronamides A-C, new polyketide macrolactams from an Zhang, H., Conte, M.M., and Capon, Australian marine-derived Streptomyces MY RESEARCH GROUP EXPLORES R.J. (2010). Franklinolides A-C from sp. A biosynthetic case for synchronized the chemical diversity of Australian plants, an Australian marine sponge complex: tandem electrocyclization. Organic and animals and microbes as a source of novel Phosphodiesters dramatically enhance Biomolecular Chemistry 8: 4682-4689. products to (i) advance our knowledge polyketide cytotoxicity. Angewandte of the natural world, (ii) provide insights Chemie International Edition 122: 1-4. Capon, R.J. (2010). Marine natural into chemical ecology to assist in the products chemistry: Past, present, and Salim, A.A., Rae, J., Fontaine, F., Conte, control of invasive pests, and (iii) inspire future. Australian Journal of Chemistry 63: M.M., Khalil, Z., Martin, S., Parton, R.G., the development of new pharmaceuticals, 851-854. and Capon, R.J. (2010). Heterofibrins: agrochemicals and bioprobes. These Inhibitors of lipid droplet formation from Raju, R., Piggott, A.M., Conte, M., investigations require the use and a deep-water southern Australian marine Aalbersberg, W.G.L., Feussner, K., and continued refinement of sophisticated sponge, Spongia (Heterofibria) sp. Capon, R.J. (2010). Naseseazines A-B: A chromatographic (HPLC-DAD-ELSD), Organic and Biomolecular Chemistry 8: new dimeric diketopiperazine framework spectroscopic (NMR, MS) and chemical 3188-3194. from a marine-derived actinomycete, (synthesis, degradation, derivatisation, Steptomyces sp. Organic Letters 11: Raju, R., Piggott, A.M., Conte, M., biotransformation) technologies, 3862-3865. supported by a wide array of innovative Tnimov, Z., Alexandrov, K., and Capon, bioassays aimed at multiple targets R.J. (2010). Nocardiopsins: New FKBP12- Hayes, R.A., Piggott, A.M., Dalle, K., across such indications as infectious and binding macrolide polyketides from an and Capon, R.J. (2010). Microbial Australian marine-derived actinomycete, neurodegenerative disease, pain, cancer biotransformation as a source of chemical Nocardiopsis sp. Chemistry: A European diversity in cane toad steroid toxins. and diabetes. Metabolites encountered Journal 16: 3194-3200. Bioorganic and Medicinal Chemistry during our studies span all biosynthetic Letters 19: 1790-1792. pathways, feature unprecedented carbon Peng, C., Gunaherath, G.M.K.B., Piggott, skeletons, heterocycles and functional A.M., Khalil, Z., Conte, M., and Capon, groups, and can possess potent and R.J. (2010). 9-(5’-Deoxy-5’-thio-β-D- LAB MEMBERS selective biological properties with high xylofuranosyl) adenine disulfide from value across basic and applied science. the southern Australian marine sponge Personal Assistant: Naomi Epstein Recent examples include: Trachycladus lasvispirulifer: The first Research Officers: Dr Angela Salim, Dr natural occurrence of a nucleoside Andrew Piggott, Dr Hua Zhang, Dr Sean Franklinolides: the first reported natural disulfide. Australian Journal of Chemistry Xiao example of a polyketide-phosphodiester, 63: 873-876. with an exceptional enhancement in PhD Students: Walter Balansa, Raju cytotoxicity (target - cancer). Raju, R., Piggott, A.M., Barrientos Diaz, Ritesh, Soumini Vijayasarathy, Fabien L.X., Khalil, Z., and Capon, R.J. (2010). Plisson, Zeinab Khalil, Victor Huang, Heterofibrins: the first reported natural Heronapyrroles A-C: Farnesylated Venkat Kamalakkannan examples of lactyl-lipid esters and a new 2-nitropyrroles from an Australian marine- class of lipid droplet inhibitor (target - derived Streptomyces sp. Organic Letters Undergraduate Students: Siti Zulkifli, obesity, atherosclerosis and diabetes). 12: 5158-5161. Angel Koo, Ahmad Bin Rosli, Kylie James International Occupational Trainee: Nocardiopsins: the first reported natural Balansa, W., Islam, R., Fontaine, F., examples of the rapamycin class to be Piggott, A.M., Zhang, H., Webb, T.I., Olusegun Ajala (Nigeria) described in over a decade (target - Gilbert, D.F., Lynch, J.W., and Capon, International Visiting Scientists: Fuhang immunosuppressive agents). R.J. (2010). Ircinialactams: Subunit- Song (China), Leticia Barrentos Diaz selective glycine receptor modulators from (Chile) 5’-Xyloadenosine Disulfide: the first Australian sponges of the family Irciniidae. reported natural example of a nucleoside Bioorganic & Medicinal Chemistry 18: 2912-2919. imb annual report 2010 54

MATT COOPER CHEMICAL AND BIOPHYSICAL TOOLS FOR HEALTH MANAGEMENT: DIAGNOSIS AND THERAPY

OUR RESEARCH INVOLVES THE Cambridge University Press, 2009, ISBN- discovery and exploitation of novel 13: 9780521711517. biophysical methods for characterising Cooper, M.A. (2009). Signal transduction molecular pathways involved in disease, profiling using label-free biosensors. and for rapid in vitro and ex vivo diagnosis Journal of Receptor and Signal of disease, with an emphasis on viral and Transduction Research 29: 224-233. bacterial infection. Natesan, M., Cooper, M.A., Tran, J., We have a major effort on rational design Rivera, V.R., and Poli, V.R. (2009). and development of novel antibiotics and Quantitative detection of Staphylococcal anti-virals active against drug-resistant enterotoxin B by Resonant Acoustic pathogens, in particular those responsible Profiling. Analytical Chemistry 81: 3896- for hospital-acquired infections such as 3902. MRSA. Trmcic-Cvitas, J., Hasan, E., Ramstedt, We have a strong translational research M., Li, X., Cooper, M.A., Abell, C., focus in all of our project areas and work Huck, W.T.S., and Gautrot, J.E. (2009). on those indications in which there is a Bio-functionalized protein resistant LAB MEMBERS clear commercial case and market need oligo(ethylene glycol)-derived polymer Senior Professional Officers: Dr Mark for innovative and disruptive solutions. brushes as selective immobilization and Blaskovich, Dr Mark Butler Many of the research team have significant sensing platforms. Biomacromolecules experience in both academia and industry, 10: 2885–2894. Senior Research Officers: Dr Bernd with past projects leading to products on Becker, Dr Frank Fontaine, Dr Tomislav Ndieyira, J., Watari, M., Batchelor, M., the market today. We collaborate with Zhou, D., Cooper, M.A., Horton, M., Karoli, Dr Craig Muldoon, Dr Rajaratnam government agencies and companies Renner, C., Cox, I., Abell, C., Rayment, Premraj, Dr Johannes Zuegg locally in Australia and internationally in the T., Aeppli, G., and McKendry, R.A. Research Officers: Dr Yujing Gong, Dr US, UK, and Europe. (2008). Nanomechanical detection of Reena Halai, Dr Xiao (Johnny) Huang antibiotic-mucopeptide binding and drug Research Assistants: Yuen Chi (Ann) resistance on cantilever arrays. Nature RESEARCH PROJECTS Nanotechnology 3: 691-696. Lam, Ruby Pelingon, Soumya Ramu • Antibiotic derivatives active against PhD Students: Mu Cheng, Daniel Croker, Godber, B., Thompson, K.S., Rehak, drug-resistant bacteria David Thomson M., Uluda, Y., Kelling, S., Sleptsov, A., • Interfacial chemistries for facilitated Frogley, M., Wiehler, K., Whalen, C., and Honours Students: Noor Huda Daud, capture of biological molecules Cooper, M.A. (2005). Direct quantification Nor Hana Hamzah, June Lee, Ernest Tee of analyte concentration by resonant Summer Students: Joanna Adie, • Novel approaches for mapping protein acoustic profiling. Clinical Chemistry 51: Matthew Heidecker, Andrew Laloo, signalling pathways with GPCRs 1962-1972. Nurzatil Matjalaluddin, Mahitha • Bacterial and viral bioinformatics for Cooper, M. (2004). Advances in Ramakrishna, Karen Wong, Benjamin target validation and development of membrane receptor screening and Yakimoff tests for rapid early-onset diagnosis of analysis. Journal of Molecular Recognition Office Coordinator/Team Support: Jan infection 17: 286-315. Pinder • Integrated diagnostics and discovery Astrahan, P., Kass, I., Cooper, M.A., for theranostic intervention against and Arkin, I.T. (2004). A novel method of flaviviruses such as dengue resistance for influenza against a channel- blocking antiviral drug. Proteins: Structure, • Drug screening against novel and Function, and Genetics 55: 251-257. validated biological targets Cooper, M. (2002). Optical Biosensors in Drug Discovery. Nature Reviews Drug KEY PUBLICATIONS Discovery 1: 515-528. Butler, M.S., and Cooper, M.A. (2010). Cooper, M., Dultsev, F.N., Minson, T., Screening strategies to identify new Ostanin, V.P., Abell, C., and Kleneman, D. antibiotics. Current Drug Targets In press (2001). Direct and sensitive detection of Uluda, Y., Hammond, R., and Cooper, a human virus by rupture event scanning. M.A. (2010). A signal amplification for Nature Biotechnology 19: 833-837. HSV type 1 viral DNA detection using Ellson, C. et al. (2001). nanoparticles and direct acoustic profiling. Phosphatidylinositol 3-phosphate Journal of Nanobiotechnology 8: 3. regulates the neutrophil oxidase complex Vancomycin binding to Ac-D-Ala-D-Ala “Label-free Biosensors: Techniques by binding to the PX domain of p40phox. subunit of Lipid II. and Applications” Ed. M.A. Cooper, Nature Cell Biology 3: 679-682. 55 imb researchers: chemistry and structural biology

DAVID CRAIK NMR AND PROTEIN STRUCTURE IN DRUG DESIGN

ion channels and other receptors. We also study the protein-folding problem, i.e., how do proteins fold into the complex shapes that determine their functions?

Highlights of 2010 included the development of an orally active peptide for the treatment of pain. This molecule, IMB007, is an engineered form of a native conotoxin that we had earlier structurally characterised. Our structural studies were used to design a cyclic analogue that Viola hederaceae in flower with the structure proved to be more potent and more stable of a cyclotide overlaid. than the natural conotoxin, and is orally active in an animal model of neuropathic pain. We also developed cyclotides with improved potency against parasites of at the a9a10 nicotinic acetylcholine OUR GROUP USES PEPTIDE chemistry receptor. Journal of Biological Chemistry sheep and cattle and have advanced and NMR spectroscopy to determine the 284: 20275-20284. our understanding of structure-activity structures of proteins that are important relationships in this class of cyclic proteins. Huang, Y.H., Colgrave, M.L., Daly, N.L., in drug design and in agriculture. By Keleshian, A., Martinac, B., and Craik, elucidating the structures of biologically D.J. (2009). The biological activity of the active proteins we are able to identify RESEARCH PROJECTS cyclotides is modulated by the formation regions crucial for activity and use this of a multimeric pore. Journal of Biological information to design new drugs or crop • Discovery, biosynthesis and Chemistry 284: 20699-20707. protection agents. The proteins we study applications of circular proteins come from a range of animal and plant • Defining the structure-activity Craik, D.J. (2006). Seamless proteins tie up their loose ends. Science 311: 1563- sources. Examples include conotoxins relationships of toxins (venom components from marine snails) 1564. and cyclotides (ultra-stable circular proteins • Development of new drugs for pain, from plants). cancer and cardiovascular disease LAB MEMBERS We have a particular interest in the • Investigating plants as production Research Officers: Dr Norelle Daly, Dr discovery and structural characterisation factories to make peptide-based drugs Richard Clark, Dr Masa Cemazar, Dr of novel protein topologies. We aim to Joshua Mylne, Dr Quentin Kaas, Dr Jan determine the mechanisms of biosynthesis KEY PUBLICATIONS Westermann, Dr Sonia Henriques, Dr Karl and evolutionary origin of circular proteins and to apply protein-engineering principles Clark, R.J., Jensen, J., Nevin, S.T., Johan Rosengren to explore applications of circular proteins Callaghan, B.P., Adams, D.J., and Craik, Research Assistants: Dr David Wilson, D.J. (2010). The engineering of an orally in drug design and agriculture. Circular Chia-Chia Tan, Ashley Cooper, Aurelia active conotoxin for the treatment of proteins are particularly stable and thus Chanson, Amy Argyros, Uru Malik, neuropathic pain. Angewandte Chemie have advantages over conventional 49: 6545-6548. Phillip Walsh, Philip Sunderland, Olivier proteins. Cheneval, Dr Peta Harvey Huang, Y.-H., Colgrave, M.L., Clark, We undertake protein-engineering studies PhD Students: Laura Cascales, Philip R.J., Kotze, A.C., and Craik, D.J. (2010). in which we modify protein frameworks by Lysine scanning mutagenesis reveals an Nguyencong, Crystal Yen-Hua Huang, “grafting” new biologically active epitopes amendable face of the cyclotide kalata Louise Thorstholm, Phillippa Smith, Basar onto them, or by stabilising them by B1 for the optimisation of nematocidal Oku, Muharrem Akcan, Angeline Chan, cyclisation. We currently have molecules activity. Journal of Biological Chemistry Aaron Poth, Rilei Yu, Alysha Elliot under development for the treatment 285: 10797-10805. Masters Students: Bodil Carstens, of multiple sclerosis, cardiovascular Tilman Plass, Zhinous Nowrouzi, Zai Yang disease, cancer and chronic pain. We Gunasekera, S., Foley, F.M., Clark, R.J., also undertake fieldwork in Australia and Sando, L., Fabri, L.J., Craik, D.J., and Phua overseas for the collection of plant species Daly, N.L. (2009). Engineering stabilized Occupational Trainees/Visiting VEGF-A antagonists: Synthesis, structural so that we can explore the diversity and Students: Elizabetha de Souza, Philipp characterization and bioactivity of grafted evolution of the cyclotide family of plant Cromm, Marcus Gerlach, Iselin Elvheim analogues of cyclotides. Journal of proteins. We study the structures of a Medicinal Chemistry 51: 7697-7704. Undergraduate Student: Reynold Phillip range of toxins from cone snails, spiders and snakes and use this information to Halai, R., Clark, R.J., Nevin, S., Jensen, Sabbatical Visitors: Dr Octavio Franco, understand their mode of action against J.E., Adams, D.J., and Craik, D.J. (2009). Dr Chongxu Fan Scanning mutagenesis of a-conotoxin Vc1.1 reveals residues crucial for activity imb annual report 2010 56

DAVID FAIRLIE CHEMISTRY AND HUMAN THERAPEUTICS

OUR GROUP WORKS AT THE interface KEY PUBLICATIONS of chemistry, biology and disease to better Barry, G.D., Suen, J.Y., Le, G.T., Cotterell, understand molecular mechanisms of life, A., Reid, R.C., and Fairlie, D.P. (2010). ageing, disease and death. Novel Agonists and Antagonists for Chemistry researchers develop expertise Human Protease Activated Receptor 2. in: organic, medicinal or biological Journal of Medicinal Chemistry 53: 7428- 7440. chemistry; computer-aided drug design; organic synthesis; structure determination Harrison, R.S., Shepherd, N.E., Hoang, using 2D NMR; and interactions between H.N., Abbenante, G., Reid, R.C., and small molecules, proteins, RNA and DNA. Fairlie, D.P. (2010). Downsizing Human, Outcomes are new compounds/structures, Bacterial and Viral Proteins To Short chemical reactions/mechanisms, enzyme Water-Stable Alpha Helices That Maintain inhibitors, protein agonists/antagonists, Biological Potency. Proceedings of the and structural mimics of protein surfaces. National Academy of Sciences USA 107: 11686-11691. Biology researchers use our novel compounds to interrogate human Harrison, R.S., Ruiz-Gómez, G., Hill, T.A., Kahnberg, P., Lucke, A.J., Glenn, M.P., protein, cellular and animal function Chow, S.Y., Shepherd, N.E., Lohman, Boyle, G.M., Tyndall, J.D., Parsons, P.G., and to elucidate mechanisms of protein R.J., Abbenante, G., Hoang, H.N., and Fairlie, D.P. (2006). Design, Synthesis, activation, biological/physiological and Fairlie, D.P. (2010). Novel Helix- Potency and Cytoselectivity Of Anticancer processes, disease development, and Constrained Nociceptin Derivatives Are Agents Derived By Parallel Synthesis drug action. Researchers gain insights to Potent Agonists and Antagonists of ERK From Alpha-Aminosuberic Acid. Journal of Phosphorylation and Thermal Analgesia processes pivotal to human physiology or Medicinal Chemistry 49: 7611-7622. in Mice. Journal of Medicinal Chemistry aberrant in disease, and develop skills in Epub ahead of print November 10. Levick, S., Loch, D., Rolfe, B., Reid, R.C., pharmacology, enzymology, biochemistry, Fairlie, D.P., Taylor, S.M., and Brown, L. immunology, virology, oncology or Iyer, A., Fairlie, D.P., Prins, J.B., (2006). Antifibrotic Activity of an Inhibitor neurobiology. Hammock, B.D., and Brown, L. (2010). of Group IIa Secretory Phospholipase A2 Inflammatory lipid mediators in adipocyte in Young Spontaneously Hypertensive function and obesity. Nature Reviews Rats. Journal of Immunology 176: 7000- RESEARCH PROJECTS Endocrinology 6: 71-82. 7007. (http://fairlie.imb.uq.edu.au/) Shepherd, N.E., Hoang, H.N., Abbenante, • Drug discovery (for inflammatory G., and Fairlie, D.P. (2009). Left- and LAB MEMBERS disorders, cancers, viral infections, Right-Handed Alpha-Helical Turns neurodegeneration, obesity and in Homo- and Hetero-Chiral Helical Senior Research Officers: Dr Ligong Liu, metabolic dysfunction) Scaffolds. Journal of the American Dr Robert Reid, Dr Martin Stoermer Chemical Society 131: 15877-15886. • Organic and medicinal chemistry Research Officers: Dr Jade Blakeney, Stoermer, M.J., Chappell, K.J., Liebscher, Dr Frederik Diness, Dr Tim Hill, Dr Huy • Pharmacology: molecular (cellular) and S., Jensen, C.M., Gan, C.H., Gupta, P.K., Hoang, Dr Fredrik Lindahl, Dr Rink-Jan experimental (animal models) Xu, W.J., Young, P.R., and Fairlie, D.P. Lohman, Dr Andrew Lucke, Dr Praveen (2008). Potent cationic inhibitors of West • Structures by 2D NMR spectroscopy Madala, Dr Gloria Ruiz-Gómez, Dr Conor Nile virus NS2B-NS3 protease with serum Scully, Dr Jacky Suen • Enzymes, GPCRs & protein-protein stability, cell permeability and antiviral interactions activity. Journal of Medicinal Chemistry Research Assistant: Adam Cotterell 51: 5714-5721. • Mimicry of protein surfaces PhD Students: Sheila Barbero, Shaio Blakeney, J.S., Reid, R.C., Le, G.T., and Chow, Anh Do, Russell Driver, Praveer Fairlie, D.P. (2007). Nonpeptidic Ligands Gupta, Maria Halili, Rose Harrison, For Peptide-Activated GPCRs. Chemical Junxian Lim, Ranee Singh, Vernon Seow Reviews 107: 2960-3041. Masters Student: Annika Yau Honours Students: Peifei Chu, Johan Hamidon Undergraduate Students: Sok Lin Foo, Lisa Redlingshoefer, Annette Spierings, Benjamin Wong Occupational Trainee: Daniel Nielsen Office Manager: Barbara Feenstra/ Lyn Fairlie 57 imb researchers: chemistry and structural biology

BEN HANKAMER STRUCTURAL BIOLOGY OF MEMBRANE PROTEINS, MACROMOLECULAR ASSEMBLIES AND VIRUSES

templates that chelate Ni at the surface, to 3D structure of the AAA ATPase Vps4: facilitate the systematic production of 2D Advancing structural insights into the crystals of tethered His-tagged membrane mechanisms of endosomal sorting and proteins. Using these twin approaches we enveloped virus budding. Structure 17: are studying a wide range of important 427-437. membrane proteins (e.g. photosynthetic Yang, X., Molimau, S., Doherty, G.P., membrane protein complexes, Marles-Wright, J., Rothnagel, R., ATPases, mechanosensitive channels), Hankamer, B., Lewis, R.J., and Lewis, macromolecular assemblies (AAA ATPases P.J. (2009). The structure of bacterial RNA THE SOLAR BIO-FUELS CONSORTIUM and related proteins, ferritin, NS1 & toxin polymerase in complex with the essential (www.solarbiofuels.org), co-directed complexes) as well as icosahedral viruses. transcription elongation factor NusA. by Ben Hankamer, has brought These structures provide fundamental new EMBO Reports 10: 997-1002. together eight international teams and insights into many fascinating molecular approximately 100 researchers to develop machines and feed into the Visible Cell® Pantelic, R.S., Lockett, L.J., Rothnagel, high-efficiency microalgal bio-fuels and project. R., Hankamer, B., and Both, G. (2008). bio-product production systems. This Cryo-electron microscopy map of represents a rapidly expanding area of Atadenovirus reveals cross-genus biotechnology of global significance. The RESEARCH PROJECTS structural differences from human adenovirus. Journal of Virology 82: 7346- consortiums work covers all aspects of • High-Resolution Single Particle 7356. the process from economic modelling, Analysis: biology and process purification of microalgae, optimisation of development Mussgnug, J., Thomas-Hall, S., production conditions and the scale up of Rupprecht, J., Foo, A., Klassen, V., ® photobioreactor systems. • The Visible Cell Project: resolving the McDowall, A., Schenk, P., Kruse, O., 3D structure of the macromolecular and Hankamer, B. (2007). Engineering Structural Biology: The first step of assemblies and biophysical modelling photosynthetic light capture: Impacts all biofuel production processes is light on improved solar energy to biomass • Template mediated 2D crystallisation: capture. Using single particle analysis, conversion. Plant Biotechnology Journal crystallography and electron tomography towards streamlined membrane protein 5: 802-814. as part of the IMB Visible Cell® project crystallisation we are developing a pseudo-atomic Iwata, M., Imamura, H., Stambouli, E., • Micro-algal biofuel and bioproduct resolution 3D atlas of the model alga Ikeda, C., Tamakoshi, M., Nagata, K., systems: development of bio-fuels Chlamydomonas reinhardtii. Such 3D Makyio, H., Hankamer, B., Barber, J., systems for bio-H , bio-diesel and BTL- molecular atlases guide the enhancement 2 Yoshida, M., Yokoyama, K., and Iwata, diesel production that are coupled to of light capture and conversion efficiency of S. (2004). Crystal structure of a central stalk subunit C and reversible association/ the photosynthetic machinery. CO2 sequestration dissociation of vacuole-type ATPase. Membrane proteins, macromolecular Proceedings of the National Academy of assemblies and viruses: To increase KEY PUBLICATIONS Science USA 101: 59-64. the speed of structure determination Stephens, E., Ross, I.L., King, Z., we have established a powerful single Mussgnug, J.H., Kruse, O., Posten, C., particle analysis pipeline, as well as new Borowitzka, M.A., and Hankamer, B. LAB MEMBERS biotechnologies for template assisted 2D (2010). 2nd generation microalgal biofuels: Research Officers: Dr Ian Ross, Dr crystal production. The single particle Economic and technical evaluation Michael Landsberg, Dr Melanie Oey process involves the semi-automated of the hope, hype and reality. Nature Research Assistant: Rosalba Rothnagel merging of large numbers of 2D projection Biotechnology 28: 126-128. PhD Students: Evan Stephens, Erin images of randomly-oriented molecules to Kruse, O., and Hankamer B. (2010). Ahern, Drew Ringsmuth, Emily Knauth, calculate 3D reconstructions. Our current Microalgal hydrogen production. Current benchmark resolution is ~10 Å at which Opinion in Biotechnology 21: 238-243. Winnie Waudo, Khairul Radzun, Maurizio individual a-helices begin to be resolved, Chioccioli, Eugene Zhang, Alex Foo Landsberg, M.J., Vajjhala, P.R., Rothnagel, and we are actively developing processes MSc Students: Gisela Jakob, Johannes R., Munn, A.L., and Hankamer, B. (2009). to improve this further. In parallel we Kügler have developed detergent-resistant 2D Honours Students: Hong Wai Tham, Anne Sawyer imb annual report 2010 58

GLENN KING BUGS AND DRUGS: RATIONAL DEVELOPMENT OF NOVEL ANTIBIOTICS, ANALGESICS, AND ENVIRONMENTALLY-FRIENDLY INSECTICIDES

RESEARCH IN MY LABORATORY by harnessing the remarkable chemical is aimed at the development of diversity encoded in the venoms of spiders novel pharmaceutical agents and and scorpions. Most research projects are environmentally-friendly insecticides. highly interdisciplinary and the experimental Approximately half of the group is studying techniques employed range from molecular bacterial cytokinesis or signalling by biology through protein chemistry to bacterial histidine kinases in order to structure determination using NMR provide a molecular understanding of spectroscopy and X-ray crystallography. these key biological processes and to Research in the lab is currently funded by establish a platform for the development three ARC and five NHMRC research grants. of novel antimicrobial agents. The remainder of the group is focused on developing novel antinociceptive agents RESEARCH PROJECTS and environmentally-friendly insecticides • Developing novel antibiotics targeted against Gram-positive pathogens LAB MEMBERS • Investigating the architecture of the Senior Research Officers: Dr Susan L. bacterial cell division machinery Rowland, Dr Mehdi Mobli • Using venom peptides to characterise Research Officers: Dr Raveendra Anangi, ion channels involved in sensing pain Dr Kathryn Greenwood, Dr Volker Herzig, Dr Rikki Hvorup, Dr Brit Winnen • Developing environmentally-friendly insecticides based on spider-venom Research Assistant: Radha Seshadri peptides PhD Students: Margaret Hardy, Sandy Gonzalez, Jonas Jensen, David Morgenstern, Natalie Saez KEY PUBLICATIONS MSc Students: Sing Yan Er, Lena Mobli, M., Dantas de Araújo, A., Lambert, Grimm, Madeleine Kuenz, Xiao Zhen Lin, L., Pierens, G.K., Alewood, P.F., and King, G.F. (2009). Direct visualization of disulfide Chek-Fong Low, Ramya Ramachandran, bonds via diselenide proxies using 77Se Sebastian Senff, Nga Pham, Xiao Lin Model of the interactions between various NMR. Angewandte Chemie International Honours Students: Carus Lau, Tomas components of the Escherichia coli divisome. Edition 48: 9312-9314. Miljenovic, Darshani Rapasinghe Gorbatyuk, V.Y., Nosworthy, N.J., Robson, S.A., Bains, N.P.S., Maciejewski, M.W., dos Remedios, C.G., and King, G.F. (2006). Mapping the phosphoinositide- binding site on chick cofilin explains how

PIP2 regulates the cofilin-actin interaction. Molecular Cell 24: 511–522.

Robson, S.A., and King, G.F. (2006). Domain architecture and structure of the bacterial cell division protein DivIB. Proceedings of the National Academy of Schematic of a voltage-gated calcium Sciences USA 103: 6700–6705. channel. Sollod, B.L., Wilson, D., Zhaxybayeva, O., Gogarten, J.P., Drinkwater, R., and King, G.F. (2005). Were arachnids the first to use combinatorial peptide libraries? Peptides 26: 131–139. Rowland, S.L., Burkholder, W.F., Cunningham, K.A., Maciejewski, M.W., Grossman, A.D., and King, G.F. (2004). Structure and mechanism of Sda, an inhibitor of the histidine kinases that regulate initiation of sporulation in Bacillus Home page for the ArachnoServer database Mexican red-kneed tarantula (Brachypelma subtilis. Molecular Cell 13: 689–701. (www.arachnoserver.org). smithii). 59 imb researchers: chemistry and structural biology

RICHARD LEWIS MOLECULAR PHARMACOLOGY OF MARINE PEPTIDES

responses without the side effects that currently limit the clinical potential of this class of analgesics. Our research into the mechanisms of a-conotoxin interaction with nicotinic acetylcholine receptors resulted in the discovery of a new allosteric site on the receptor and uncovered a pharmacologically important role for the fifth subunit in heteromeric forms of this petameric receptor.

RESEARCH PROJECTS • Discover conopeptides that modify pain pathways (NHMRC Program Grant) • Determine the sites of conotoxin A MAJOR FOCUS OF MY GROUP is the discovery and development of binding to membrane proteins including peptides as research tools and leads to the a1-adrenoceptor, noradrenaline new therapeutics, especially the conotoxins transporter and nicotinic acetylcholine from predatory marine snails that have receptor potential in pain management. This research • Discover conotoxins that modulate involves the assay-guided isolation of LC/MS reveals 1000s of different venom calcium and sodium channels peptides in each species of cone snail (from venom peptides, peptide synthesis, tissue Davis et al., Peptides 2009). and receptor pharmacology, high-content • Use high-content functional screens cellular imaging of functional effects, to discover and characterise new radioligand binding to receptor mutagenesis, bioactives homology modelling, and finally co-crystal Dutertre, S., Ulens, C., Büttner, R., Fish, • Develop mass spectrometric and structures and docking of the peptide to A., van Elk, R., Kendel, Y., Hopping, G., transcriptomic approaches to unravel its target to identify how it binds. Most of Alewood, P.F., Schroeder, C., Nicke, A., the peptide diversity of cone snail our research focuses on the discovery Smit, A.B., Sixma, T.K., and Lewis, R.J. venoms (venomics) -conotoxin and characterisation of venom peptides, (2007). AChBP-targeted a correlates distinct binding orientations with especially the conotoxins produced by • Determine the mode of action and nAChR subtype selectivity.EMBO Journal the predatory cone snails found on the improve the detection of ciguatoxins 26: 3858-3867. Great Barrier Reef. These highly structured responsible for ciguatera peptides, or mini-proteins, act selectively Lewis, R.J., and Garcia, M.L. (2003). at a wide range of ion channels, G-protein Therapeutic potential of venom peptides. coupled receptors and transporters found KEY PUBLICATIONS Nature Reviews Drug Discovery 2: 790-802. in the membranes of cells. Interestingly, Berecki, G. et al. (2010). Analgesic several conotoxins have been taken into the w-conotoxins CVIE and CVIF selectively and clinic, including Xen2174 for severe pain, voltage-dependently block recombinant and LAB MEMBERS developed from a lead originally discovered native N-type calcium channels. Molecular Research Officers: Dr Irina Vetter (CDA), in my group. In addition, we are studying Pharmacology 77:139-48. Dr Anderson Wang, Dr Sebastien Dutertre how ciguatoxins produce the debilitating Luo, S. et al. (2010). The atypical (UQ Fellowship), Dr Lotten Ragnarsson- disease known as ciguatera, and working a-conotoxin LtIA from Conus litteratus McGrath towards improving methods to detect these targets a novel microsite of the a3b2 Research Assistant: Asa Anderson toxins at sub ppb levels in fish flesh. nicotinic receptor. Journal of Biological PhD Students: Marco Inserra, Vu Bach, Highlights for 2010 include the renewal Chemistry 285: 12355-12366. Josh Wingerd, Silmara Rodrigues de of our Program Grant for a further five Grishin, A.A. et al. (2010). a-Conotoxin Sousa years, award of a Linkage grant for a AuIB isomers exhibit distinct inhibitory FLIPR platform that allows rapid functional mechanisms and differential sensitivity to MSc Students: Dewi Fajarningsih, Prerna screening of ion channels and GPCRs, stoichiometry of a3b4 nAChRs. Journal of Jha, Mriga Dutt, Nikita Abraham, Prasanth and the announcement of the next Biological Chemistry 285: 22254-22263. Jutty Rajan Venoms to Drugs meeting scheduled Honours Student: Zhenyao Luo for May 2011. Research highlights Lewis, R.J., Yang, A., and Jones, A. (2009). Rapid extraction combined with LC-tandem Program Grant Administration Officer: include the discovery and patenting of a mass spectrometry (CREM-LC/MS/MS) Thea Monks new w-conotoxin that can reverse pain for the determination of ciguatoxins in International Visiting Scientists: Dr ciguateric fish flesh.Toxicon 54: 62-66. Katharina Zimmermann (Germany), Dr Cheryl de Valliere (Switzerland) imb annual report 2010 60

JENNY MARTIN PROTEIN STRUCTURE AND DRUG DESIGN

OUR GOAL IS TO BETTER UNDERSTAND of techniques. Collaborations have been the role of proteins in disease and to established with Associate Professor Martin develop novel drugs targeting disease- Scanlon at Monash and Professors David causing proteins. We use a range of Fairlie, Matt Cooper and Mark Schembri at biochemical and biophysical techniques UQ. This research led to the award of an to investigate the structure, function and ARC Australian Laureate Fellowship that interactions of proteins, with a particular was taken up in late 2009. emphasis on high-throughput protein We have successfully applied a fragment- crystallography and structure-based screening approach to PNMT, the approaches for inhibitor design. adrenaline synthesising enzyme, using the A major outcome over the past few automated UQ ROCX diffraction facility years has been the tremendous advance (Drinkwater et al., Biochem J 2010). More in our understanding of the regulation than 140 PNMT crystals were used to of SNARE proteins involved in insulin- screen ~380 drug-like fragments: 12 hits stimulated trafficking of the GLUT4 glucose were identified and confirmed by isothermal transporter. This process, which is critical calorimetry. Six elaborated compounds Heras, B. et al. (Martin, J.L. listed as to the regulation of blood glucose levels, is were designed and synthesised (in senior author) (2009). Dsb proteins and affected in Type II Diabetes. We had shown collaboration with Gary Grunewald, Kansas bacterial pathogenicity. Nature Reviews in collaboration with Professor David U) and shown to inhibit enzyme activity (in Microbiology 7: 215-225. James (Garvan Institute), that the regulatory collaboration with Michael McLeish, Indiana protein Munc18c may stimulate delivery U). Hu, S.-H., Latham, C.F., Gee, C.L., of GLUT4 vesicles to the cell membrane, James, D.E., and Martin, J.L. (2007). through binding to a short N-terminal Structure of the Munc18c/Syntaxin4 peptide of the SNARE syntaxin4 protein RESEARCH PROJECTS N-peptide complex defines universal (Latham et al. Traffic 2006; Hu et al. Proc • Structure, function and interactions of features of the N-peptide binding mode of Natl Acad Sci USA 2007). Very recently we proteins associated with insulin action SM proteins. Proceedings of the National identified that the Syntaxin N-peptide does Academy of Sciences USA 104: 8773- not discriminate well between cognate • Structure, function and inhibition of 8778. redox folding factors involved in disease and non-cognate Munc18 proteins and Gruber, C., Cemazar, M., Heras, B., that its role may instead be to induce a • Novel inflammation drug targets using Martin, J.L., and Craik, D.J. (2006). conformational change in Munc18 proteins high-throughput structure approaches Protein disulfide isomerase: The structure (Hu and Christie et al. Proc Natl Acad Sci of oxidative folding. Trends in Biochemical • Structure, function and inhibition of USA 2010). Sciences 31: 455-464. transferase enzymes involved in disease Our long-running interest in bacterial redox folding factors led to the determination LAB MEMBERS of the crystal structure of a key virulence KEY PUBLICATIONS factor, DsbA from Pseudomonas Drinkwater, N. et al. (Martin, J.L. listed Senior Research Officers: Dr Begoña aeruginosa (Shouldice et al., AntiOx Redox as senior author) (2010). Fragment- Heras, Dr Shu-Hong Hu Signal 2009) using data measured at screening by X-ray crystallography, mass Research Officers: Dr Andrew Whitten the Australian Synchrotron. We are now spectrometry and isothermal titration (NHMRC Fellow), Dr Stephen Shouldice focusing our attention on developing calorimetry to identify PNMT inhibitors. (UQ Postdoctoral Fellow), Dr Gordon King, inhibitors of several DsbA proteins as Biochemical Journal 431: 51-61. Dr Maria Halili, Dr Karl-Fredrik Lindahl, Dr potential antibacterial agents (Heras et al. Hu, S.-H. et al. (Martin, J.L. listed as Morten Groftehauge, Dr Mathieu Coincon Nature Rev Microbiol 2009), using a range senior author) (2010). Possible roles for UQ ROCX Diffraction Facility Manager: Munc18-1 domain 3a and Syntaxin1 Karl Byriel N-peptide and C-terminal anchor in SNARE complex formation. ] Proceedings Research Assistants: Russell Jarrott, of the National Academy of Sciences USA Stephanie Tay, Fabian Kurth Epub December 30. PhD Students: Michelle Christie, Kevin Shouldice, S.R. et al. (Martin, J.L. listed Chen, Asma Rehman, Patricia Walden, as senior author) (2010). Characterisation Wilko Duprez of the DsbA oxidative folding catalyst Undergraduate Student: Heather Nutt from Pseudomonas aeruginosa reveals a Pooja Sharma (Monash highly oxidizing protein that binds small Visiting Student: molecules. Antioxidants & Redox Signaling University) 12: 921-931. (Front cover) 61 imb researchers: chemistry and structural biology

MARK SMYTHE COMBINATORIAL CHEMISTRY AND MOLECULAR DESIGN

• Developing new computational algorithms and strategies for sampling biologically-relevant chemistries • Developing a synthetic process for the combinatorial synthesis of biologically- relevant compounds • Developing in vitro and cell-based assays for screening arrays of compounds

KEY PUBLICATIONS Horton, D.A., Horton, G.T., Coughlan, J., Kaiser, S.M., Jacobs, C.M., Jones, A., Ruhmann, A., Turner, J.Y., and Smythe, OUR RESEARCH FOCUSES ON M.L. (2008). Cyclic tetrapeptides via advancing drug design and synthetic the ring contraction strategy: chemical organic and peptide chemistry to discover techniques useful for their identification. novel biologically-active molecules. We Organic & Biomolecular Chemistry 6: apply these new drug design and discovery 1386-1395. methodologies to discover drugs to treat unmet medical needs or provide better Severinsen, R., Bourne, G.T., Tran, T.T., therapeutic solutions to existing marketed Ankersen, M., Begtrup, M., and Smythe, M.L. (2008). Library of Biphenyl Privleged drugs. Substructures using a Safety-Catch Using a combination of mathematics, Linker Approach. Journal of Combinatorial software development, drug design, Chemistry 10: 557-566. combinatorial chemistry and phage display, Horton, D.A., Severinsen, R., Kofod- we are developing new approaches to Hansen, M., Bourne, G.T., and Smythe, identify biologically-active molecules. Thus, M.L. (2005). A versatile synthetic projects are multidisciplinary and focused approach to peptidyl privileged structures on achieving medical outcomes. using a safety catch linker. Journal of We have recently developed several Combinatorial Chemistry 7: 421-435. small molecule anti-TNF compounds for Horton, D.A., Bourne, G.T., and Smythe, treatment of inflammatory diseases and M.L. (2003). The Combinatorial Synthesis specific small molecule modulators of of Bicyclic Privileged Structures or prostaglandin D2 synthase for treatment of Privileged Substructures. Chemical asthma. In addition we have designed and Reviews 103: 893-930. synthesised a new spin label to accurately Meutermans, W.D.F., Bourne, G.T., determine distances in biological systems. Golding, S.W., Horton, D.A., Campitelli, M.R., Craik, D., Scanlon, M., and Smythe, RESEARCH PROJECTS M.L. (2003). Difficult Macrocyclisations: New Strategies for Synthesising Highly • Modulating haematopoietic Strained Cyclic Tetrapeptides. Organic prostaglandin D2 synthase for allergic Letters 5: 2711-2714. disease • Studying antagonists of Myb for LAB MEMBERS treatment of leukaemia Senior Research Officers: Dr Craig • Designing SHP-1 inhibitors to boost Murphy, Dr Greg Bourne, Dr Nicole haematopoiesis Lawrence • Developing antipathogenic compounds Research Officers: Dr Katie Glenn, Dr to treat microbial infections Jenny Zhang, Dr Rosemary Harrison • Developing structure-based phage Research Assistants: Jill Turner, Jaimee display Duncan, Angelika Christ, Aleisha Griffin, Phillip Walsh PhD Student: Christina Kulis imb annual report 2010 62

JOINT APPOINTMENTS at the IMB

The purpose of joint appointments is to foster collaborations in teaching, research and related activities between the IMB and Schools of The University of Queensland.

Joint appointments involve a split in salary between the IMB and the relevant UQ School, and a joint appointee’s commitment to the research and teaching activities at the IMB is greater than that of affiliate appointees.

Joint appointees participate in all Institute activities, including laboratory research, supervision of research higher degree students, and attendance at seminars, Divisional meetings and IMB Group Leader retreats.

Joint appointees in 2010 were Professor Alan Mark and Professor Geoffrey McLachlan.

LINDA LUA AND PANG CHUAN: BOUQUET A virus is a piece of mosaic art perfected by Nature. The viral shell is made up of hundreds of copies of identical protein molecules arranged in a highly sophisticated pattern, giving a unique architecture for each type of virus. A close-­up of the computer-­generated three dimensional structure of a mouse polyomavirus particle is shown here. In the background, an assemblage of electron micrographs depicting viral shells constructed at UQ. 63 imb researchers: joint appointments

ALAN E. MARK MOLECULAR DYNAMICS OF BIOMOLECULAR SYSTEMS

surface receptors. In particular, we are investigating how the binding of human growth hormone to the extra-cellular growth hormone receptor is coupled to structural changes within the cell. We are also investigating the mechanism by which the E or envelope proteins of the Dengue and Ebola viruses facilitate the entry of these viruses into cells.

Third, how do membrane-protein complexes assemble? Cell membranes are the archetypal self-organised The interaction of the peptide D-ala-D-ala supramolecular structure. In addition to (solid representation) with the antibiotic being of critical importance in structural vancomycin. The red spheres indicate the biology, membrane-protein complexes distribution of structural waters observed during the simulations. are also prime therapeutic targets. Using THE GROUP CONCENTRATES ON simulations, we are investigating the modelling the structural and dynamic assembly of functional structures such as properties of biopolymers such as proteins, the assembly of anti-microbial peptides nucleic acids and lipid aggregates. In into transmembrane pores. This is being particular, we use computer simulations to used to understand the mechanism understand and predict the macroscopic by which larger complexes form in (experimentally observable) behaviour of heterogeneous environments as well as to complex biomolecular systems based understand in detail how smaller antibiotics on the interactions between atoms. We such as vancomycin recognise membrane develop the software, atomic force fields targets. and theoretical models needed to address a range of fundamental questions.

First, how do proteins fold? Understanding RESEARCH PROJECTS how proteins fold is one of the grand • Peptide folding and assembly Rotation of the extracellular domains of challenges of modern biology and a critical the growth hormone receptor associated • Mechanism of action of antimicrobial test of our ability to accurately predict with activation by growth hormone. A peptides. interactions in protein systems. The failure superposition of the hormone free form obtained from the simulations (green and of proteins to fold correctly is also linked to • The nucleation and growth of amyloid red) on to the hormone bound (activated) a range of debilitative diseases including fibrils conformation (yellow) Alzheimer’s Disease, BSE and some • Mechanism of activation of type 1 forms of Type II diabetes where misfolded cytokine receptors proteins form destructive aggregates called amyloid fibrils. Dramatic progress Yesylevskyy, S., Marrink, S.J., and Mark, is being made in the de novo folding of KEY PUBLICATIONS small peptides and the refinement of larger A. E. (2009). Alternative mechanisms Malde, A., and Mark, A.E. (2010). for the interaction of the cell-penetrating proteins. Research on folding is conducted Challenges in the determination of the peptides Penetratin and the TAT peptide at multiple levels. Small model systems are binding modes of non-standard ligands with lipid bilayers. Biophysical Journal 97: used to refine force fields and simulation in X-ray crystal complexes. Journal of 40-49. techniques. On a larger scale we are Computer-Aided Moecular Design 25: simulating how multiple copies of certain 1-12. van Gunsteren, W.F., Dolenc, J., and peptides aggregate in order to understand Mark, A.E. (2008). Molecular simulation how amyloid fibrils form. Poger, D., and Mark, A. E. (2010). Turning as an aid to experimentalists. Current the growth hormone receptor on: Direct Opinion in Structural Biology 18: 149-153. Second, how do cell surface receptors evidence that hormone binding induces transmit a signal through the cell subunit rotation. Proteins: Structure, membrane? Receptor proteins on the Function, and Bioinformatics. 7: 1163- LAB MEMBERS surface of cells play a vital role in cellular 1174. Research Officers: Dr David Poger, Dr communication. However, little is known Periole, X., Rampioni, A., Vendruscolo, Alpesh Malde, Dr Megan O’Mara, Dr in regard to the mechanism by which the M., and Mark, A.E. (2009). Factors that Mortiz Wigner binding of a molecule to an extracellular affect the degree of twist in b-sheet receptor transfers a signal across the PhD Students: Daniela Mueller, Ying Xue, structures: A molecular dynamics cell membrane or even how changes in Rong Chen, Pramod Nair, Zhi Guang Jia simulation study of a cross-ß filament the environment can activate certain cell of the GNNQQNY peptide. Journal of Physical Chemistry B 113: 1728-1737. imb annual report 2010 64

GEOFFREY McLACHLAN APPLIED STATISTICS AND BIOINFORMATICS

MY RESEARCH IN APPLIED STATISTICS biologist at the Broad Institute of the is in the related fields of classification, Massachusetts Institute of Technology. In cluster and discriminant analyses, data our initial work on this problem (Pyne et mining, image analysis, intelligent systems, al., 2009), we have produced a software machine learning, neural networks, and tool called flow analysis with automated pattern recognition, and in the field of multivariate estimation (FLAME), for such statistical inference. The focus in the flow cytometric data. latter field has been on the theory and applications of finite mixture models and on estimation via the E(expectation)- RESEARCH PROJECTS M(maximisation) algorithm. • The development of automated, I am also actively involved in the field high-dimensional methods based of bioinformatics with the focus on the on mixtures of skew normal and development of methods and software for t-distributions for the rich data the analysis of data from high-throughput generated by new and powerful flow genomics projects, with particular cytometers emphasis on gene-expression profiles. in mucinous ovarian cancer. European • Development of very fast methods Journal of Cancer 46: 170-179. The limitations of conventional methods of based on factor models for the analysis cancer classification and diagnosis based of data arrays, such as microarray data McLachlan, G.J., and Ng, S.K. (2009). on the site and appearance of the tumour The EM Algorithm. In The Top-Ten matrices, involving sets of extremely or organ are well known. With microarrays Algorithms in Data Mining, X. Wu and high dimensions, for use in supervised allowing genome-scale measures of gene V. Kumar (Eds.). Boca Raton, Florida: expression, attention has turned to using and unsupervised classification of Chapman & all/CRC, pp. 93-115. differences in the activity of the gene tissue samples on patients Pyne, S., Hu, X., Wang, K., Rossin, E., expressions (gene profiling) to classify and • Development of diagnostic methods Lin, T.-I., Maier, L.M., Baecher-Allan, diagnose tumours. for cancer, using multiple indices in C., McLachlan, G.J., Tamayo, P., Hafler, Concerning statistical methodology conjunction with clinical factors D.A., De Jager, P.L., and Mesirov, J.P. (2009). Automated high-dimensional flow being developed for the aforementioned • Ongoing research into the modelling of cytometric data analysis. Proceedings of problems, I am working on very fast gene profiles for use in the detection methods based on factor models for the the National Academy of Sciences USA of differentially expressed genes and in 106: 8519-8524. analysis of observation vectors of extremely time-course studies high dimension to produce observations McLachlan, G.J., Wang, K., and Ng, on so-called meta-variables (metagenes) • Modifications to existing statistical S.K. (2008). Large-scale simultaneous of small dimension. Consideration is methodology and the development of inference with applications to the given to the use of resources such as new techniques for the next generation detection of differential expression Gene Ontologies and pathway analysis to of high-throughput technology with fast with microarray data (with discussion). determine the biological significance of the sequencing platforms Statistica 68: 1-30. metagenes. Specific applications include McLachlan, G.J., Bean, R.W., and Ng, A. the supervised classification of tissue (2008). Clustering of microarray data via samples for use in diagnosis and prognosis KEY PUBLICATIONS mixture models. In Statistical Advances of diseases and the unsupervised Baek, J., McLachlan, G.J., and Flack, L. in Biomedical Sciences: Clinical Trials, classification (clustering) of tissue samples (2010). Mixtures of factor analyzers with Epidemiology, Survival Analysis, and common factor loadings: applications to in the search for new subclasses of Bioinformatics, A. Biswas et al. (Eds.). the clustering and visualisation of high- diseases. I am also concerned with the Hoboken, New Jersey: Wiley, pp. 365- dimensional data. IEEE Transactions on development of methodology for the 384. simultaneous testing of thousands of Pattern Analysis and Machine Intelligence hypotheses at a time. This problem occurs 32: 1298-1309. McLachlan, G.J., and Krishnan, T. (2008). The EM Algorithm and Extensions. in many applications in bioinformatics, Le Cao, K.-A., Meugnier, E., and Second Edition. Hoboken, New Jersey: such as with the detection of differentially McLachlan, G.J. (2010). Integrative Wiley. expressed genes in two or more conditions mixture of experts to combine clinical (diseases). Methods that provide increased factors and gene markers. Bioinformatics power in small-sample size situations are 26: 1192-1198. LAB MEMBERS: being developed. Tang, L., Yang, J., Ng, S.K., Rodriguez, Research Officer: Dr Suren Rathnayake Also, I have been working with N., Choi, P.-W., Vitonis, A., Wang, K., PhD Students: Leesa Wockner, Sharon computational and experimental biologists McLachlan, G.J., Caiazzo Jr., R.J., to develop a new approach to the analysis Liu, B.C., Welch, W.R., Cramer, D.W., Lee of the rich data generated by new and Berkowitz, R.S., and Ng, S.W. (2010). powerful flow cytometers. The team is Autoantibody profiling to identify led by Dr Jill Mesirov, a computational biomarkers of key pathogenic pathways 65 affiliate appointments

AFFILIATE APPOINTMENTS

THE PURPOSE OF AFFILIATE PROFESSOR IAN FRAZER DR ALLISON PETTIT appointments is to foster collaborations Diamantina Institute for Cancer, UQ Centre for Clinical Research in teaching, research and related Immunology and Metabolic Medicine activities between the Institute DR LIZA RAGGATT for Molecular Bioscience (IMB) PROFESSOR JANE HUNTER UQ Centre for Clinical Research and Schools at The University of School of Information Technology and Electrical Engineering ASSOCIATE PROFESSOR JOE Queensland. Affiliate appointees to ROTHNAGEL the IMB contribute through active ASSOCIATE PROFESSOR STUART School of Molecular and Microbial involvement with relevant IMB Groups, KELLIE Sciences facilities or research programs and School of Chemistry and Molecular PROFESSOR RANJENY THOMAS through joint supervision of research Biosciences higher degree students. Affiliate Diamantina Institute for Cancer, Immunology and Metabolic Medicine appointees contribute to the intellectual PROFESSOR BOSTJAN KOBE life of the Institute through attendance at School of Chemistry and Molecular ASSOCIATE PROFESSOR PETER IMB seminars, Divisional meetings and Biosciences THORN IMB Group Leader retreats. Salary for School of Biomedical Sciences PROFESSOR DANIEL MARKOVICH affiliate appointees is paid by the relevant University of Queensland School. School of Biomedical Sciences PROFESSOR ISTVAN TOTH School of Chemistry and Molecular PROFESSOR MATT BROWN ASSOCIATE PROFESSOR FRED Biosciences MEUNIER Diamantina Institute for Cancer, Immunology and Metabolic Medicine Queensland Brain Institute PROFESSOR PAUL YOUNG School of Chemistry and Molecular PROFESSOR NICHOLAS FISK Biosciences Faculty of Health Sciences

Prof.Matt Brown Prof. Nicholas Fisk Prof. Ian Frazer Prof. Jane Hunter Assoc. Prof. Stuart Kellie

Assoc. Prof. Bostjan Kobe Prof Daniel Markovich Assoc. Prof. Fred Meunier Dr Allison Pettit Dr Liza Raggatt

Assoc. Prof. Joe Rothnagel Prof. Ranjeny Thomas Assoc. Prof. Peter Thorn Prof. Istvan Toth Prof. Paul Young imb annual report 2010 66

IMB OCCUPATIONAL HEALTH AND SAFETY REPORT

THIS YEAR WAS AN EXTREMELY • implementation of a scheduled Drugs • monitoring infrastructural and staffing busy one. In addition to the normal and Poisons purchase alert system, changes to ensure safe equipment and appropriate training needs analysis and schedule of audits by Biosafety, AQIS, • continuation of periodic online safety provision, ARPANSA and the local WHSO network, audits, the IMB was visited and audited by • reducing the incidence of needlestick • maintenance of a tasks database to representatives of Radiation Health injuries - four incidents were reported in systematically monitor compliance and the Environmental Health Unit 2010 compared to one in 2009, (Drugs and Poisons). The IMB was also with various regulatory bodies and visited by an external OH&S systems legislation, • maintaining compliance with UQ OH&S Goals for 2011. auditor working to assess risk for the • design and implementation of Safety- University’s application for renewal of its Based KPI for supervisors at the IMB. The overall performance of the IMB self-insurance policy. in terms of safety and compliance in Challenges for the IMB’s safety 2010 has been high. Discussions at Overall, the Institute’s performance in infrastructure in 2011 include: the quarterly floor safety committee all of these audits was strong. Where • implementing policies and procedures meetings and in more informal venues suggested, minor corrective actions to ensure compliance with new reflect an active safety culture at the have been taken. Thanks in part to the Australian Standards such as AS2243.3 IMB, and provide a lively venue for the performance of the IMB, the University (2010), exchange of safety-related information passed the audit and our self-insurance and policies. Crucially, there is also policy has been renewed. Passing the • maintaining IMB’s good safety record significant ‘buy in’ to safety issues from AQIS audits in 2010 allows us to move for hosting of summer students, upper management at the IMB - this closer to earning the privilege of annual, volunteers and work experience factor particularly is of enormous value rather than six-monthly, audits in 2011. personnel, to maintaining a safety culture within any The hard work and dedication from the organisation. IMB Floor Managers and Support staff was pivotal to this success, and their commitment to maintaining safety and compliance systems in the building was clear to all auditors visiting us in 2010.

During the year, the OH&S infrastructure at the IMB continued to evolve, with the following main areas being developed for, or adapted to, a changing research environment:

• revised induction process to comply with UQ OH&S goals for 2010 and to simplify the process for users and trainers, • risk assessment database review and modification to reflect new Australian Standards requirements,

SUSAN NIXON: iFISH Zebrafish embryos have been used for fast freezing, electron microscopy and tomography, and immunofluorescence. 67 IMBcom

IMBcom

IMBCOM PTY LTD is The IMBcom uses a model of cooperative In 2010, IMBcom negotiated several significant biotechnology deals, including University of Queensland’s integration with the discovery activities of the research labs. The company’s contracts for collaborative research, company for commercialisation staff are involved from the earliest partnering and licences. The company of valuable discovery research of disclosure stages with the planning helped secure more than $4 million in and delivery of ways to add value to industry research grants for the IMB, the IMB. It is responsible for the emergent innovations. The company with another $10 million in applications protection and development of manages the IMB’s Intellectual Property submitted. as custodians, developers and drivers, the University’s IMB intellectual The IMB has a commitment to the resulting in licences, contracts and the property portfolio. Established training of high-quality graduate formation of start-up companies to take students in molecular bioscience and in 2000, the company has a discovery to products and services into provides a more holistic training that markets. skilled, independent Board includes commercial dimensions. of Directors, operating as a IMBcom has had a historical strategic IMBcom delivers this objective through focus on developing new companies and the provision of special workshops. separate commercial entity, but has established 12 new biotechnology These “bootcamps”, or BioBusiness with a charter of service to the startup companies, two in conjunction Retreats, incorporate elements of University’s commercialisation with UniQuest. These companies have career preparation, understanding and raised more than $80 million through working in a commercial environment, objectives. The company has private sector investment, $18 million and working in teams to produce ten employees who provide the in federal and state government valuable outcomes. The training specialist skills to commercialise commercial grants and currently employ engages experienced professionals or contract over 50 individuals in R&D from the pharmaceutical, biotechnology, the results of IMB researchers’ and commercialisation. These spinouts investment and research industries, discoveries. have gone on to develop strategic and has provided one of the building relationships in their own right with blocks of the commercial culture many other Australian and international emerging in the IMB. These programs biotechnology and pharmaceutical have provided commercial, project and companies, and have encouraged team management skills to over 1000 the growth and establishment of individuals to date, some of whom have service providers, adding to the fabric adopted careers in the industry, being and critical mass of the industry in placed in Queensland biotechnology Queensland. The companies continue companies and IMBcom itself. The to mature under their own management IMBcom model is now widely offered once substantial investment is raised. by organisations that recognise that IMBcom has sold its interest in one of the preservation of value in intellectual the companies developed in partnership property is the key to building assets with UniQuest, Xenome, and the funds upon which industry develops. generated for the IMB and IMBcom IMBcom provides assistance to are being used to provide “proof-of- Queensland and Commonwealth concept” funds for future IP and product government departments and development. agencies with respect to biotechnology industry development, and is well regarded as an effective advocate for Queensland’s consistent promotion of the Smart Queensland agenda. IMBcom showcases not only the IMB and the University to industry and investment, but also Queensland as an industry destination.

ROB PARTON: FIRE Electron micrograph from a mammalian cell that has been colourized and blurred. imb annual report 2010 68

Dr Peter Isdale, CEO of IMBcom, with Dr Jane Wilson, Chair of IMBcom Board 69 postgraduate research

POSTGRADUATE RESEARCH

We had 31 students join the IMB program throughout the year, 21 of whom were international students from countries as diverse as China, India, Denmark, Norway, France and Singapore. This continues the recent trend of increased international enrolments, with overseas students now comprising slightly over 50 percent of our cohort. Our total number of active RHD students has stabilised at around 130 students, with 27 students completing their degree in 2010 (for a full list see page 73). While some of our graduates have remained within IMB to complete research projects, many have taken up positions both locally and overseas (for details see page 73). imb annual report 2010 70

AS IN PAST YEARS, a number of our IMB Division of Chemistry & Structural OUR HONOURS COHORT was small students received accolades throughout Biology Symposium held in November but continued to excel. We had 17 2010. Vicki Metzis from the Wicking 2010. students commencing in Feb 2010, two group had a wonderful year, winning Stephen Ainger from the Sturm students who carried over from July the David Walsh Prize for the best group won a poster prize of $250 at 2009 and four others who commenced cell and development biology student the Society for Melanoma Research in July 2010. As in previous years, 80 presentation at Ozbio2010, from the Congress in Sydney and Oleksiy Kovtun percent of those students completing Australian and New Zealand Society of the Alexandrov group won 1st prize their year in 2010 obtained a grade of of Cell and Developmental Biology in the poster competition of the UQ First Class Honours. Amgen Australia (ANZSCDB). She was also awarded a Centennial Postgraduate Biomedical has been presenting our honours student travel award from ANZSCDB Conference. He also presented an students with the Amgen Award for the to attend the OzBio conference oral talk at the XII ICOPA International most outstanding honours student at and was a winner of the ANZSCDB Congress in Melbourne. the IMB for over a decade and we are image competition to form part of the thrilled by their continued support of our ANZSCDB logo (one of five selected). In Sabine Mangold of the Yap group young researchers. addition, she was chosen to speak at obtained an OzBio2010 conference The Amgen Award for 2009 was jointly the Gordon-Kenan Research Conference registration fee waiver (from the awarded to Anne Sawyer (Hankamer on Craniofacial Morphogenesis and ANZSCDB) and a poster award at group) and Sheila Barbero (Fairlie Tissue Regeneration in Italy in April the Brisbane Cell and Developmental group). Ms Sawyer’s honours project 2010 and, as a speaker, received a Biology Meeting, while Caroline Hopkins investigated the Purification and small travel award from the Society for of the Little group won the best PhD talk characterization of NAB-1, an RNA Developmental Biology for attending at the same meeting. Ms Hopkins also binding protein from Chlamydomonas and presenting. She also excelled in a won an International Society for Stem reinhardtii, while Ms Barbero’s honours number of “Three-Minute Thesis” (3MT) Cell Research Travel Award to present in project was titled “Studies of Secretory oral presentation competitions. San Francisco and as part of this award presented her data to leaders of the field Phospholipase A2 Inhibitors”. We Ms Metzis won the IMB 3MT at both Harvard Medical School (Boston) were naturally delighted when both Ms competition and thus went on to and Mt Sinai School of Medicine (NYC). Sawyer and Ms Barbero indicated they represent the Institute at the inter- She subsequently received postdoctoral wished to further pursue their studies Institute Semi-Final. At this event, she offers from both groups and will be at the PhD level, each subsequently won the People’s Choice Award and taking up a position in NYC in mid-2011. being awarded an APA scholarship to was also chosen by the judges as the In August she also received a travel undertake PhD studies at the IMB in the overall winner, meaning Ms Metzis award to present at the International labs in which they had completed their proceeded to represent all the Institutes Workshop in Developmental Nephrology honours years. at the UQ-wide competition as one of in New York. eight finalists. She also competed in IN SEPTEMBER 2010, UQ conducted Muharrem Akcan from the Craik group the 3MT section of the UQ Centennial the Inaugural Undergraduate Research received a Gordon Research Conference Postgraduate Biomedical Conference, Conference, bringing students at the Travel Award to attend the meeting coming second. Bachelors and honours level from all covering the Chemistry and Biology Faculties and Institutes together for this IMB did extremely well in this event of Peptides and studied at the Fred cross-disciplinary event. Once again our with Elizabeth Skippington (Ragan Hutchinson Cancer Research Center, students did us proud with Rebecca group), who was runner-up in the IMB Seattle, USA, as a visiting scholar from Johnston (an honours student from the competition, receiving first place and January 16-April 16 2010, as part of Mattick group) winning a $600 “Best Natalie Saez (King group) receiving the a UQ Trans-Pacific Fellowship (see Poster Award” and Hilary Martin (an People’s Choice Award. Ms Saez also 2009 report). We also had five students honours student from the Grimmond won a poster award at the 2010 XXIVth appearing on the UQ Dean’s List for group) obtaining an honourable mention International Conference on Magnetic 2009: congratulations to Ming Kang and a special prize ($500) in the oral Resonance in Biological Systems Chang (Sweet group), Tim Mercer presentation category. (ICMRBS). Maggie Hardy (also from (Mattick group), Markus Mutthenthaler the King group) continued as a high (Alewood group), Ryan Taft (Mattick The IMB also continued the achiever in 2010, receiving the J. H. group) and Conan Wang (Craik group) Undergraduate Research Scholarship Comstock Graduate Student Award for joining this elite group. Scheme (URSS) in 2010, placing to promote interest in the science of 20 second- and third-year students entomology from the Entomological within laboratories in one of our four Society of America International Branch, divisions for eight hours per week during and the First Place Poster Prize for the semester. Additionally, a number of third- 71 postgraduate research

Postgraduate research

year students completed mini-research OUR IMB STUDENT ASSOCIATION, THE IMB EARLY CAREER projects as part of the “Introduction SIMBA, organised a range of social Researcher (ECR) Committee also had a to Research” module of their degrees, events throughout the year, which very productive year. In addition to again and several Advanced Studies students promoted engagement within our running the annual mentoring afternoon completed research projects as part student body, with students from other tea, the committee hosted Guntram of their program. We also placed 19 research institutes on campus, and with Bauer for a session on the Human students in summer projects of six to members of the community. Frontier Science program of funding ten weeks duration as part of the UQ opportunities, initiated a Brisbane-wide The events conducted throughout 2010 Summer Research program, which meeting of ECR representatives from included several themed movie nights, this year included students from New local institutes to allow ECRs from the annual IMB/AIBN Trivia night (which Zealand, Singapore, Western Australia different organisations to meet and we won this year!), an opportunity to and even a high-calibre candidate from exchange ideas, contributed to the band together to join the “Brisbane the University of Belgrade. MMRI-run Hugh Kearns session “The Zombie Walk” in October as part of a Balanced Researcher” and continued to Once again, the IMB hosted many charity event for the Brain Foundation of arrange for IMB ECRs (and occasional international students, who joined IMB Australia, and a Movember moustache- undergraduates) to meet and lunch with for up to one year as occupational growing competition to raise money for speakers after the Friday Seminar Series. trainees, undertaking overseas men’s health issues. They also launched the inaugural research placements as part of their There were also several IMB-based Brisbane Inter-Institute Poster degree requirements within their BBQs to meet and greet new students, Symposium held on 8th October at the home institution. We also welcomed a and the AGM, held in August to usher IMB, which proved a huge success. number of Year 10, 11 and 12 students in the new SIMBA Executive for 10/11. This event brought together researchers from schools throughout Queensland We welcomed Wilko Duprez (President), from IMB, AIBN, DI, MMRI, QBI and to undertake a brief period of work Drew Ringsmuth (Vice President), UQCCR at UQ as well as scientists experience within research laboratories. Silmara Rodrigues de Sousa (Secretary), from the institutes at Griffith University, This included the placement of 12 Kalyani Akondi (Treasurer), Martin Smith several from QIMR and some from IHBI students from Gregory Terrace who (SIMBAlize editor-in-chief) and Baptiste at QUT, with slightly over 60 abstracts. completed a three-week Science Coxam (Event Co-ordinator). The atmosphere was wonderful as Immersion program as part of their young researchers from all over Brisbane Year 10 curriculum, and three Year 12 Each year the SIMBA Executive brings exchanged ideas in this industry- students from Brisbane Boy’s College an energy to the role which ensures our sponsored event. The committee must who spent an afternoon a week for six students have a collective identity within be congratulated on organising what is months in a designated laboratory to the institute. We continue to be delighted definitely set to become an annual event. complete an extended research project by their enthusiasm and commitment. as part of their Year 12 assessment.

EMILY KNAUTH: SUNSPOT Every organism on Earth is reliant on the sun for survival. Plants and algae use specialised structures to capture light and convert it into chemical energy which is used as a food and fuel source. The thylakoid membranes inside the chloroplast, pictured here, adapt their structure in response to light and other conditions and are a key factor in overall light capture. The algae cell pictured here has been purposely stylised to resemble the sun, an essential part of photosynthesis and life. Photosynthesis is Nature’s solar cell. imb annual report 2010 72

In addition, the ECR committee continued to support an ECR website, produce a newsletter, and maintain an active and very positive presence throughout the IMB. During 2010, the members of the ECR committee were Dr James Palmer (President), Peter van der Heide (Vice-President), Natalie Eriksson (Treasurer), Amanda Stanley (Secretary), Dr Cassy Spiller (Friday Lunch Mediator), Dr Eva Kovacs (Website Coordinator), Dr Andrew Brooks, Dr Andrea Bugarcic, Dr Michael Hanzal-Bayer, Dr Elaine Julian, Dr Karin Kassahn, Vicki Metzis, Evan Stephens and Dr Rehan Villani. SAM MURPHY: LAVA FIELD An electron microscopy image of mylinated nerves in the retina of a bamboo shark. THE WORKSHOPS RUN BY THE Myolin sheaths form rivers of larva surrounding nerve cells which make gaping holes ECR committee were complemented and hot rocks in a volcanic landscape. by a set organised by the Postgraduate Program, designed to assist students in overall career development. These included IMBcom’s three-day Bronwyn Adams, our Marketing and His commitment to the IMB BioBusiness Retreat for the third-year Communications Officer, organised Postgraduate Program (and in fact all PhD students. Once again, feedback several training sessions for students student matters) is amazing, and was from the retreat was extremely positive, chosen to be IMB Science Ambassadors highlighted in 2010 by the launch of his with participants really enjoying the (see page 81) and we again conducted brainchild, PEBBLES, the web portal information and interactive sessions. the IMB Three-Minute Thesis challenge to the IMB postgraduate database. Congratulation must go to Maggie Hardy in which our 2nd year PhD students PEBBLES, created in conjunction with (King group) who won best individual gave presentations as part of their OzData Solutions, provides a secure and pitch at the retreat, the combination Candidature Milestone. easily accessible link for IMB academics of Angeline Chan, Marco Inserra, to keep pace with their student Lindsey McFarlane, Tim Pan and Tom commitments, creates a repository for THE IMB, ONCE AGAIN, HAS Whitington, who won the overall best reports and notes and allows for the been extremely fortunate to have Biopitch and Daniel Shaw who won real-time generation of milestone reports Professor Rob Capon continue in his role the 1800 award for demonstrating the online during student interviews. These as the IMB Postgraduate Coordinator biggest change in attitude during the can be freely shared and endorsed and IMB representative on the UQ RHD event. by IMB members of the candidature Committee of the Academic Board. We also offered our students an committee, triggering the automated Part of this role involves informing the introductory statistics course run by generation of completed administrative rest of the IMB about changes to the Carl Sherwood from the School of forms for submission to the Graduate administration of RHD recruitment and Economics at UQ, which provided 18 School to complete each Milestone candidature. For example, in 2010 the hours of tuition at IMB over eight weeks. process, both ensuring best practice in UQ Graduate School re-introduced Students from QBI, AIBN and DI also providing feedback to students and also scholarship rounds for international and attended the course and overall we markedly lessening the administrative domestic students. had over 50 registrants. In addition, Dr burden. This year, Professor Capon also served Joan Leach from the School of English, Needless to say, the original IMB as an Elected Member of the UQ Media Studies, and Art History at UQ, database and its new incarnation as Academic Board and the Institutes’ who is also the Convener of the Science PEBBLES is continuing to be adopted Elected Member of the Academic Communication Program on campus, by other schools on campus, with Board’s Standing Committee. Although delivered two sessions on scientific several new schools purchasing the all these responsibilities are voluntary, writing in October, which proved to be package in 2010. This innovative and he continues to take on these many very popular. This was run in conjunction constructive approach is yet another additional tasks with enthusiasm and with the SCMB Honours coordinator, example of how Professor Capon dedication in order to help shape a Dr Horst Schirra, and it is hoped this ensures the IMB Postgraduate Program vibrant future for research science on program will expand in 2011. continues to remain fresh and proactive campus. for its student body. 73 postgraduate research

PhD conferrals for 2010

LAST NAME FIRST NAME GROUP THESIS TITLE WHERE ARE THEY NOW? Oganes Biology of Sex Determination and Sexual Development in University of California at Abramyan Koopman (John) the cane toad (Bufo marinus) Riverside, USA Osteal macrophages (osteomacs) are pivotal for intramembranous bone formation in vivo: Osteomacs Queensland Institute of Medical Alexander Kylie Sweet facilitate osteoblast maintenance in vivo and enhance Research, Brisbane osteoblast-mediated bone deposition in a murine model of bone healing Integrating sequence and structure for annotating proeins Sepuluh Nopember Institute of Arieshanti Isye Bailey in the twilight zone: A machine learning approach Technology, Surabaya, Indonesia The cavin proteins as regulators of caveolae formation and Bastiani Michele Parton Parton group, IMB function Thermodynamic models for the analysis of quantitative Bauer Denis Bailey Queensland Brain Institute, UQ transcriptional regulation Characterization of interactions formed by the SNARE Christie Michelle Martin Martin group, IMB Syntaxin4 protein and the Sec/Munc protein Munc18c Cridland Simon Perkins Stromal support of erythropiesis during development Koopman group, IMB Substrate, inhibitor, and mutational studies of the human Kings College London, England, Drinkwater Nyssa Martin adrenaline synthesising enzyme Phenylethanolamine UK N-Methyltransferase Driver Russell Fairlie Structural studies of Cyclic Peptides Fairlie group, IMB Goh Felicia Sweet Antigen presenting cell involvement in Th2 response Prince Charles Hospital, Brisbane The story of a-conotoxins, Vc1.1 and RgIA, on their journey Halai Reena Craik Cooper group, IMB to becoming therapeutics Halili Maria Fairlie Regulation of inflammatory proteins Martin group, IMB Bain & Company, Sydney, New Harrison Rosemary Fairlie Alpha Helices Mimetics South Wales Hedgehog signalling in lung development and airway Queensland Institute of Medical Ho Uda Wainwright regeneration Research, Brisbane Clathrin Independent Carriers: Molecular characterisation Howes Mark Parton Parton group, IMB of a novel clathrin-independent endocytic pathway The mode of action of cyclotides [electronic resource] : Huang Yen-Hua Craik Craik group, IMB functional studies of the prototypic cyclotide kalata B1 The molecular basis of medulloblastoma: interaction of Julian Elaine Wainwright hedgehog and Notch signalling in brain development and Wainwright group, IMB cancer Jung CholHee Mattick Classifying non-protein-coding RNA sequences University of Melbourne, Victoria McLachlan Robert Yap The role of c-Src in E-cadherin activity Yap group, IMB Analysis of conservation and chromatin structure at Swiss Federal Institute of Nahkuri Satu Mattick metazoan splice sites Technology, Zürich Multi-scale, spatio-temporal analysis of mammalian cell University of California San Diego, Noske Andrew Marsh tomograms USA Beta-adrenergic regulation of the nuclear hormone Pearen Michael Muscat receptor 4A subgroup in skeletal muscle: insights into the Muscat group, IMB control of metabolism Eludicating the metabolic function of RoR alpha and Prakash Surya Muscat Lilly Pharmaceuticals, Singapore gamma in skeletal muscle Rev-erb beta regulates the expression of genes involved in Harvard Medical School, Boston, Ramakrishnan Sathiya Muscat metabolism Massachusetts, USA SmartNet Presence, and Sprenger Josefine Teasdale Computational methods to define the endosomal proteome Information Professionals, Brisbane Munn/ Max Planck Institute for Plant Molecular analysis of fungal pathogenicity in crown rot Stephens Amber Manners Breeding Research, Cologne, disease of wheat caused by Fusarium graminearum (CSIRO) Germany Tsang-Hsing Investigating macropinocytosis: the role of sorting nexins in School of Chemistry and Molecular Wang Teasdale (Jack) macropinosome biogenesis Bioscience, UQ imb annual report 2010 74

VISITING SPEAKERS

Dr Ruben Abagyan Adjunct Professor Peter Beattie School of Pharmacy and Former Premier & Queensland Trade Pharmaceutical Sciences Commissioner for the Americas University of California San Diego, USA Our biotech future: not a destination but Computational structural a continuing journey chemogenomics and drug discovery Dr Jennifer Becker Maud Achard US Army Research Office, Adelphi, School of Chemistry and Molecular Maryland, USA Biosciences, UQ Basic research needs in hazardous Copper trafficking in murine materials management macrophages in response to Salmonella infection Dr Nouri Ben Zakour School of Chemistry and Molecular Dr Daniel Aguirre Biosciences, UQ CSIRO, St Lucia, Brisbane Understanding the genome evolution of High-throughput technologies in the staphylococci of animal origin study of the gut microbiome; usefulness of numerical ecology methods and other Paul Berkman DARREN BROWN: NEWCLEUS considerations Australian Centre for Plant Functional A fluroescent microscope image Genomics, UQ montage of a macrophage labelled Dr Florent Angly Towards sequencing the haploid wheat with a probe to identify the nucleus. The image has been multicoloured Advanced Wastewater Management genome Centre, UQ and arranged in a really nice pattern.

Computational methods for studying Carlo Bertozzi uncultured viral communities Department of Biochemistry University of Zürich, Switzerland Dr Ruth Arkell Structural basis for ion permeation and Dr Toula Bouras Australian National University, Canberra, block in a prokaryotic pentameric ligand- Walter & Eliza Hall Institute, Melbourne, Australian Capital Territory gated ion channel Victoria Building the mammalian forebrain: Notch signalling regulates mammary the role of the /Zic/ gene family of Dr Helle Bielefeldt-Ohmann stem cell function and luminal cell-fate transcription factors commitment School of Veterinary Science, UQ Macaque rhadinoviruses: models for Professor Shankar HHV-8 associated diseases? Associate Professor Neil Box Balasubramanian Department of Dermatology Cambridge University, United Kingdom University of Colorado at Denver, USA Dr Antje Blumenthal Quadruplex nucleic acids as functional RpI27a mutation in the Sooty Foot Ataxia Diamantina Institute, UQ elements and therapeutic targets mouse phenocopies high p53 mouse Interactions between Mycobacterium models and identifies a new negative tuberculosis and the host Professor Philippe Bastiaens regulator of p53 Department of Systemic Cell Biology Max Planck Institute for Molecular Professor Alexandre Bonvin Professor Frances Brodsky Physiology, Dortmund, Germany Biojvoet Center for Biomolecular University of California San Francisco, Research Spatial organisation in growth factor USA Utrecht University, the Netherlands signalling Diversity of clathrin structure and Information-driven modelling of function biomolecular complexes: challenges and Dr Denis Bauer perspectives Queensland Brain Institute, UQ Dr Brian Burke Combined association and deep Institute of Medical Biology, Singapore resequencing study of DISC1 in a Nucleocytoplasmic coupling and LINCs population from Tamil Nadu, India to human disease 75 visiting speakers

Visiting speakers

Dr Alistair Chalk Dr Yann Gambin Dr Albert Guskov Eskitis Institute Department of Molecular Biology Nanyang Technical University, Griffith University, Brisbane The Scripps Research Institute, USA Singapore Stem cell bioinformatics in general and Combining single-molecule FRET and The crystal structure of Photosystem II at approaches towards understanding microfluidics to explore protein folding 2.9 Å resolution: role of lipids, quinones alternate splicing in stem cells and pathways and chloride ions Stem cell bioinformatics Professor Rex Gaskins Professor John Hardy Dr Paul Chambers Visiting CSIRO Scientist Reta Lila Weston Institute of Research Manager University of Illinois, Urbana- Neurological Studies The Australian Wine Research Institute, Champaign, USA University College London, UK Urrbrae, South Australia On contributions of sulfate-reducing Genetic analysis of neurodegeneration Lessons in winemaking: an example of bacteria to chronic disorders of the integrated ‘Omics at work human colon Dr Dirk Haussecker RNAi Therapeutics Consulting Service, Dr Stephen Cohen Dr Arnaud Gaudin Malaysia Deputy Director School of Biomedical Sciences, UQ RNAi therapeutics - where are we and Institute of Molecular and Cell Biology, Axonal guidance defects in the forebrain: where are we going? Singapore tracking down and identifying the MicroRNA functions culprits Dr Jermone Korzelius Utrecht University, the Netherlands Dr Alex Cristino Dr Tanja Gesell Cell cycle entry in C. elegans Queensland Brain Institute, UQ Center for Integrative Bioinformatics development Unravelling brain networks associated Vienna (CIBIV) with cognitive disorders Max F. Perutz Laboratories (MFPL), Vienna, Austria Professor Kurt Krause Director Another view on RNA structure and Dr Robert James Dancer Webster Centre for Infectious Diseases A phylogenetic structure (PS) and its H. Lundbeck A/S, Denmark University of Otago, Dunedin, New application to gene predictions Re-examination of published procedures Zealand for the resolution of Citalopram and Alanine Racemase as a template for Didesmethylcitalopram Clare Giacomantonio antimicrobial drug design Queensland Brain Institute, UQ Nick Davis-Poynter Creating the cortex: modelling the Sir Albert Sakzewski Virus Research Dr Jens Krömer patterns of gene expression underlying Centre, Herston, Brisbane Queensland Node Manager cortical development Metabolomics Australia Constitutive endocytosis and signalling of cytomegalovirus 7 transmembrane Metabolomics and fluxomics: getting Dr James Godwin receptor homologues: importance for closer to the metabolic phenotype biological function Australian Regenerative Medicine Institute Professor Sharad Kumar Monash University, Melbourne, Victoria Professor Vojo Deretic Institute of Medical & Veterinary Characterising the immunological University of New Mexico, Albuquerque, Science, Adelaide, South Australia response to wounding and regeneration USA Expected and unexpected functions of in the Salamander Autophagy – biological paradigm for the canonical cell death machinery everyone and Professor Christopher Goodnow Autophagy in infection and immunity Dr Lawrence Lee Director, Australian Phenomics Facility Victor Chang Cardiac Research Institute Professor Simon Foote Australian National University, Canberra, The structure of the torque ring of Director Australian Capital Territory Menzies Research Institute Genes, failsafes and control systems to the bacterial flagellar motor and the University of Tasmania, Hobart avoid immunological catastrophes molecular basis for rotational switching Host response to malaria: a genetic approach imb annual report 2010 76

Professor Malcolm Harris Levitt Nick Matigian Dr Megan O’Mara FRS Eskitis Institute for Cell and Molecular School of Chemistry and Molecular Professor in Physical Chemistry, School Therapies Biosciences, UQ of Chemistry Griffith University, Gold Coast Determining the physiological state Southampton University, UK Disease-specific, neurosphere-derived of a membrane protein: a molecular Singlet nuclear magnetic resonance cells as models for brain disorders dynamics odyssey

Dr Graham Lieshke Roberto Munita Professor Scott O’Neill Walter and Eliza Hall Institute, Pontifica Universidad Catolica de Chile, Head Melbourne, Victoria Santiago School of Biological Sciences, UQ Zebrafish mutants lead into unexplored MirrorRNA and non-consensus splicing: Bacterial symbionts of insects and the corners of haemopoiesis experimental artefact or sign of another possible control of dengue fever biological surprise? Dr Sara Linden Professor Arthur R Pardi Mucosal Immunobiology and Vaccine Dr Gene Myers Department of Chemistry and Center, Gothenburg, Sweden Janelia Farms Research Campus Biochemistry Mucins in Helicobacter phylori infection: Howard Hughes Medical Institute, University of Colorado, Boulder, USA a dynamic defence which differs Ashburn, Viriginia, USA NMR and single molecule studies between individuals Decoding the genome with bioimaging of RNA folding and RNA-protein informatics recognition Dr Jimmy Liu Queensland Institute of Medical Professor Robert Nabi Dr Matt Perugini Research, Brisbane University of British Columbia, Bio21 Institute A versatile gene-based test for genome- Vancouver, Canada University of Melbourne, Victoria wide association studies Lattice, rafts and scaffolds: plasma Multiple personalities of an essential membrane domain organisation in bacterial enzyme Professor Angel Lopez cancer Institute of Medical and Veterinary Professor Robert Phillips Science, Adelaide, South Australia Professor Jim Naismith California Institute of Technology, The mechanism of cytokine receptor Biomedical Sciences Research Complex Pasadena, USA activation The University of St Andrews, Fife, Order of magnitude biology Scotland, UK Membrane protein conformation states Dr Madhavi Maddugoda Dr Simon Phipps Molecular Research Centre for School of Biomedical Sciences, UQ Dr Greg Neely Molecular Medicine, Nice, France Respiratory virus infections and innate Membrane and cytoskeletal dynamics Marie Curie Fellow inflammatory pathways that underlie the Institute of Molecular Biotechnology during transendothelial permeability of onset of asthma pathogens Austria (IMBA), Vienna Genome-wide screening in Drosophila to Dr Pamela Pollock identify new mammalian disease genes Dr Igor Makunin Institute of Health and Biomedical Queensland Institute of Medical Innovation Research, Brisbane Dr Mathias Nilsson Queensland University of Technology, Paucity and preferential suppression of School of Chemistry Brisbane transgenes in late replication domains of University of Manchester, UK FGFR2 mutations in endometrial cancer: the D. melanogaster genome Advances in DOSY and pure shift, prognostic and therapeutic implications techniques and applications Dr Jessica Mar Erin Poth Harvard School of Public Health, Dr Páraic Ó Cuív Department of Neuroscience Boston, Massachusetts, USA CSIRO, St Lucia, Brisbane Johns Hopkins University School of Modeling variance as a measure of Exploring the role of the colonic Medicine, Baltimore, Maryland, USA network topology in Waddington’s canals microbiota in human health and disease Teaching an old dogma new tricks: the role of the long ncRNA Six3OS in retinal development 77 visiting speakers

Visiting speakers

Associate Professor Thomas Dr Fiona Simpson Professor Mark Walker Preiss Diamantina Institute, UQ University of Wollongong, New South Victor Chang Cardiac Research EGF trafficking in squamous cell Wales Institute, Sydney, New South Wales carcinoma Evolution and emergence of invasive Mechanisms and patterns of post- serotype M1T1 group A streptococci transcriptional gene control Hugh Simpson Queensland Brain Institute, UQ Dr Michael Way Dr Oliver Rackham Computational modelling of visual Cancer Research UK London Research Western Australian Institute for Medical topographic map development Institute Research Using Vaccinia virus to understand University of Western Australia, Perth signalling network dynamics and Professor John A. Re-engineering cellular protein synthesis Stamatoyannopoulos regulation of actin polymerisation Department of Genome Sciences, Michael Reich School of Medicine Dr Christine Wells Director of Cancer Informatics University of Washington, Seattle, USA Eskitis Institute for Cell and Molecular Development The human cis-regulatory map Therapies Broad Institute of MIT and Harvard, Griffith University, Gold Coast Boston, Massachusetts, USA Alternate splicing as a mechanism to Professor Francis Stewart Broad Institute tools for integrative diversify innate immune responses and Technische Universitaet and genomics Australian stem cell database BioInnovationZentrum, Dresden, Germany Professor Robert Richards Dr Ian Wilkie The epigenetics and development School of Veterinary Science, UQ University of Adelaide, South Australia biology of histone 3 lysine 4 methylation FHIT happens when you get your WWOX Acute cytokine responses by circulating off - or the contribution of chromosomal macrophages, in chickens exposed to Dr Tuomas Tammela fragile site genes to cancer biology highly virulent & non-virulent strains of Biomedicum Helsinki, Finland Pasteurella multocida Therapeutic targeting of the lymphatic Dr Kathy Ruggiero system School of Biological Sciences Dr Rohan Williams University of Auckland, New Zealand John Curtin School of Medical Research Dr Tim Thomas Australian National University, Canberra, Designing experiments utilising multi- Walter & Eliza Hall Institute, Melbourne, ACT plexing biotechnologies Victoria A gene set approach to understanding MYST histone acetyltransferases, inter-individual variation in mRNA levels Adam Salmon chromatin structure and development Eskitis Institute for Cell and Molecular Therapies Thorsten Wohland Griffith University, Gold Coast Dr Makrina Totsika Chemistry Department School of Chemistry and Molecular National University of Singapore Protein X-ray crystallography studies of Biosciences, UQ metallocene-based sulfonamide/hCA II Quantitative measurements of molecular complexes Understanding the role of macrophages interaction in living organisms by Single in uropathogenic Escherichia Wave length Fluorescence Cross- coli infections correlation Spectroscopy (SW-FCCS) Dr Bernadette Saunders Centenary Institute, Sydney, New South Wales Thomas Ve Xing Yu School of Chemistry and Molecular Glycomics Institute TNF, microparticles and regulation of Biosciences, UQ Griffith University, Gold Coast macrophage activation and inflammation during tuberculosis infection Molecular basis of plant disease Rotavirus and sialic acid recognition resistance imb annual report 2010 78

COLLABORATIVE RESEARCH PARTNERSHIPS

Further underlining the Institute’s commitment to research excellence, IMB Group Leaders collaborate extensively with partners both within Australia and internationally. The IMB is a core partner and participant in many research centres around the country, including three Major National Research Facilities (MNRFs) and two Cooperative Research Centres (CRCs).

These programs are integral to building Australia’s national and international research capabilities. They aim to create the scale and focus necessary to maintain and develop Australia’s world- class standing in priority areas ARC CENTRE OF EXCELLENCE IN first instance towards understanding through highly innovative research BIOINFORMATICS human health and development, the that addresses challenging and The ARC Centre of Excellence in Centre’s technologies and output are generally applicable to biotechnology, significant problems. CRCs and Bioinformatics, with headquarters at IMB, brings Australian and overseas while building critical mass in advanced COEs make vital contributions to researchers together into interdisciplinary bioinformatics is vital to Australia’s Australia’s research landscape and programs designed to explore international competitiveness in bio- how information in the genome is based industries. produce outcomes with economic, transformed into structure and function social and cultural benefits to in the mammalian cell. Perspectives and ARC CENTRE OF EXCELLENCE the country. Involvement in these technologies of mathematics, statistics, IN BIOTECHNOLOGY AND high-performance computation, ventures reflects very highly on DEVELOPMENT information technology, genomics and The ARC Centre of Excellence in the participating researchers, high-throughput experimental phenomic Biotechnology and Development (CBD) indicating the value of their work biology are focused on representing the was established in 2003 to focus on the mammalian cell as a complex system in both scientific and commercial biology of male germ cells – embryonic of molecular networks, and building a stem cells that eventually produce sperm terms. common modeling and visualisation cells in men. A review of the Centre in environment to simulate its development 2007 confirmed its status as a Centre and behaviour. Although directed in the of Excellence, and extended its funding 79 collaborative research partnerships

Collaborative research partnerships

for a further three years. Collaborating animal pests as well as those that have AUSTRALIAN MICROSCOPY & institutions include the IMB, the the potential to cause catastrophic MICROANALYSIS RESEARCH Universities of Queensland, Melbourne, impacts in the future. Professor Peter FACILITY and Newcastle, Monash University and Koopman from the IMB is part of the The Advanced Cryo-Electron Microscopy the Australian National University, with Daughterless Carp Program of the Laboratory – the Queensland node Professor Peter Koopman from IMB one AIACRC. This program, based at CSIRO of the Australian Microscopy & of the Centre’s Chief Investigators. Unlike fisheries in Hobart, uses innovative Microanalysis Research Facility – is many other types of stem cells, germ technologies with a view to skewing housed in a purpose-built facility at IMB. cells represent a truly “blank slate” that the sex ratios of wild populations of This facility, funded under the National can develop into any tissue in the body. the common carp, one of the most Collaborative Research Infrastructure Understanding their specification and widespread threats to indigenous Strategy, is a collaboration between the programming is central to contemporary fish species in our larger waterways. Universities of Queensland, Western efforts to harness stem cell technologies. Lindsay McFarlane, a PhD student from Australia, Melbourne, New South Since male fertility depends on the Wilhelm group, is also a member Wales and Sydney. Its 300kV Technai generating sperm cells in vast numbers, of the AIACRC. His project focuses microscope is one of the flagship and since genetic and environmental on gene silencing in fish as part of the instruments of the AMMRF. The facility factors commonly disturb the quantity Daughterless Carp Program. is currently the only one in Australia and quality of sperm produced, or New Zealand capable of collecting the research will further impact on AUSTRALIAN GENOME RESEARCH and processing atomic-resolution understanding and possible treatment FACILITY images at low temperature, as well as of infertility, a distressing condition that The Australian Genome Research undertaking a 3D electron microscope represents a massive healthcare burden Facility (AGRF) is an MNRF of the (EM) tomography of organelles, cells in Australia and worldwide. Disorders Commonwealth Government and and tissues at both ambient and of germ cells are often accompanied by was established in 1996 through an low temperature. Only a handful of testicular cancer, and so the potential MNRF application led by Professor international (and no other Australian) medical significance of this research John Mattick, who served as the laboratories can offer researchers is twofold. It has become increasingly inaugural director until 2002, and equivalent state-of-the-art research tools clear that manipulating the quantity Board Member until 2004. Professor for high-resolution 3D structure studies and/or quality of germ cells, particularly Brandon Wainwright currently serves of cells and molecules. The AMMRF is a male germ cells, presents powerful on the AGRF Board. The AGRF is a successor to the Nanostructural Analysis opportunities in the pest management state-of-the-art facility for the collection Network Organisation (NANO). arena, and in other biotechnological of molecular genetic information pursuits such as the management of covering large-scale DNA sequencing, AUSTRALIAN PHENOMICS endangered wildlife species. genotyping, microarraying, agricultural FACILITY genomic services and other resources The Australian Phenomics Facility (APF) AUSTRALASIAN INVASIVE for the genetic and physical mapping is based at the John Curtin School for ANIMALS CRC of chromosomes, mutation detection Medical Research at the Australian Australasian Invasive Animals CRC and associated bioinformatic analysis. National University (ANU) and is a Major is a venture aiming to counteract the It serves several hundred research National Research Facility (MNRF) impact of invasive animals through the groups across all states and territories formed by support from the IMB, ANU development and application of new of Australia from nodes at The University and the Garvan Institute for Medical technologies and integrating approaches of Queensland, the Walter and Eliza Research. The APF is based around the across agencies and jurisdictions. It is Hall Institute of Medical Research in use of mouse genetics to discover novel the first time that research, industry, Melbourne, the Waite Campus of the genes that influence traits of medical environmental, commercial and University of Adelaide, the Western relevance. Large populations of mice government agencies have combined to Australian Institute of Medical Research are exposed to a mutagen, traits are create and apply solutions for invasive in Perth, and Sydney’s Westmead identified and selected then genetic animal threats, which cost Australasia Millennium Institute. mapping is used to locate the general at least $720 million per annum. This regions where the genes reside. The unique partnership will deliver the means mutagen used to create the mutants to deal with existing high-profile invasive leaves a particular genetic fingerprint that can be discerned by sequencing candidate genes, thus identifying the gene responsible for the trait under imb annual report 2010 80

consideration. This is a very powerful Professor Little’s PhD students, Caroline QUEENSLAND FACILITY FOR approach to biology which enables Hopkins, won an International Travel ADVANCED BIOINFORMATICS gene function to be elucidated based Award from the ASCC, designed to (QFAB) upon the high-throughput analysis of allow junior researchers to attend QFAB is based at the IMB and was phenotypes (“phenomics”). international stem cell meetings. established in 2006 with a $1.9 million Professor Sean Grimmond is also funded Queensland State Government grant AUSTRALIAN STEM CELL CENTRE by the ASCC. He is leader of a module that has been leveraged to provide $9 in Stream 2. This stream focuses on The Australian Stem Cell Centre (ASCC) million worth of resources available understanding reprogramming of cells is a national research and funding for client projects. It supports the and the introduction of pluripotency. facility set up by the ARC, the Victorian bioinformatics requirements of the Professor Grimmond’s module is Department of Industry, Innovation and biotechnology, pharmaceutical, defining the underlying genetics of Regional Development, and the Federal clinical and research communities by these processes. He is also a Chief Department of Education, Science and providing broad expertise and access Investigator on a project supported Training. The ASCC is primarily based to large databases, high-performance by the ASCC’s Strategic Development at Monash University, but through the computing and storage, and to specialist Fund. He, along with Dr Christine Wells guidance of the Scientific Management software and services. Since beginning from Griffith University and Professor Advisory Committee (SMAC) and a operations, it has completed over 50 Doug Hilton from the Walter and Eliza process of due diligence, the ASCC projects with another 15 underway. IMB Hall Institute, is developing a database funds research which falls within its projects on which QFAB has worked containing multiple datasets of genetic core expertise platform areas or its include helping to find the basis for information across stem cell lines to help therapeutic focus areas. The IMB childhood obesity (KOALA), building a Australian scientists to better compare has very close links with the ASCC. database for spider venom research and the chracteristics of different types of Professor Brandon Wainwright served analysis of a transposon-based forward stem cells. on the Board from April 2009 until genetic screen. QFAB has helped October 2010. Professor Melissa Little researchers attract $52.7 million in grant spent a period as Chief Scientific Officer, NETWORK FOR PANCREATIC funding to Queensland. responsible for developing strategy, ORGAN DONORS WITH DIABETES scientific review and management, and (NPOD) RIKEN/FANTOM developed a Queensland division of the nPOD is an initiative of the Juvenile RIKEN is the Institute for Physical and ASCC based at UQ. She is a member Diabetes Research Foundation Chemical Sciences of the Japanese of the Centre’s Senior Scientific Faculty, International (JDRF) and brings together Science and Technology Agency, and a group of eminent and internationally organ procurement organisations, a major site of genomics research in regarded Australian researchers who academic institutions and leading Japan. The RIKEN Genome Sciences monitor scientific progress, provide diabetes researchers from Europe and Centre is based at Yokohama, Japan’s advice to the ASCC and act as the America. IMB’s Dr Brad Marsh is an second-largest city, and Wako, both key public scientific spokespeople. investigator in the Pathology category. in the Tokyo area. In the late 1990s, The Centre distributes its funds to Dr Marsh studies the 3D characterisation RIKEN established a program aimed at collaborative groups of researchers in of islet cell function and dysfunction. elucidating the complete transcriptional four key areas, known as streams, of nPod aims to improve the procurement output of the mouse. More recently, stem cell research. Professor Little is of pancreatic tissue specifically from the program has shifted focus towards Deputy Leader of Collaborative Stream patients and donors at high risk of the elucidation of transcriptional control 4: Adult Stem Cell Program. She is also developing type 1 diabetes. It is the first networks. Both activities have involved leader of a module within this stream trial of its kind anywhere in the world the establishment of large international that aims to further characterise the and it is hoped that it will improve our consortia, firstly the FANTOM consortium origin and properties of endogenous understanding of the onset and progress (Functional Annotation of Mouse), and renal MSCs and investigate their role in of type 1 diabetes. Together with more recently the Genome Network responding to renal damage. Professor Professors Thomas Kay at St Vincent’s consortium. The consortium has Little is leader of another module, Institute and Peter Colman at the Royal previously published a comprehensive “Regenerative Therapies for Renal Melbourne Hospital, one goal of the analysis of the human and mouse Repair”. This module is in Stream 3: nPOD program is to establish a similar transcriptome and a series of papers Pluripotent Stem Cell Differentiation. initiative among groups leading type 1 on gene control in mammals. IMB Professor Little is screening for novel diabetes research within Australia. researchers were involved as authors chemical compounds that can direct and senior authors on these papers. stem cells to form a kidney. One of 81 community engagement

COMMUNITY ENGAGEMENT

MUCH OF THE COMMUNITY in total. A judging panel consisting of at an internal IMB exhibition, and at engagement that took place in 2010 Professor Stephen Walker, Dean of UQ’s external exhibitions at UQ’s Celebration was based around UQ’s Centenary Faculty of Science; Mrs Beverley Trivett, of Centenary on Sunday April 18, and at year. IMB decided to mark the occasion Director of the John Trivett Foundation, UQ’s Open Day on August 1. by resurrecting the Ångström Art™ which supported earlier Angstrom Art IMB’s Marketing team also produced competition. Originally held in 2001, competitions; and Mr Nick Mitzkevich, iPhone skins and postcards with the Ångström Art™ was the result of an Director of the UQ Art Gallery; selected Angstrom Art images, which have Australia-wide imaging competition one winner and two runners-up. proven immensely popular at both run by the IMB. Several collections Mr Darren Brown from the Stow community and scientific events. If you of images were produced before the group contributed the winning image, would like some postcards or an iPhone competition went on hiatus. MacBeads (seen on the front of skin, please contact [email protected] In 2010, we decided to restrict the this report) and runner-up image competition to IMB researchers only, RealMacAlien. Dr Michael Landsberg THE IMB WEBSITE (www.imb.uq.edu. transforming Ångström Art™ into from the Hankamer group was the other au) continues to be the main portal of a visual showcase of the Institute’s runner-up for his image, Insect Assassin. information about the institute, including research. Researchers from all divisions All 62 images can be viewed on the its newsletter Output (to subscribe, of the IMB were inspired by the Angstrom Art website at www.angstrom- please click on the green ‘Subscribe’ competition, with 62 images entered art.com. These images were displayed button on the IMB homepage). The IMB News section of the website nearly tripled the number of hits it received in 2010 compared to 2009, with around RUNNER UP: ÅNGSTRÖM ART CENTENARY COLLECTION 125,000 in 2009 and nearly 350,000 in 2010. The website remains in the number one position when ‘molecular bioscience’ is searched in Google.

THE IMB SCIENCE AMBASSADOR program continued to be a success. We had some turnover of ambassadors from our first cohort, ending up with 18 ambassadors in total, including a mid-year intake. In its pilot year, the ambassador program was run by a committee consisting of two staff members and an ambassador. In 2010, the committee decided to expand, and allow more ambassadors a chance to assist in guiding the program. The 2010 committee was: Phillippa Smith (Craik group) – Co-ordinator; Dr Richa Dave (Wainwright group) – Worksheet Manager; Dr Denis Bauer (Bailey group) – Vodcast Manager; Maggie Hardy MICHAEL LANDSBERG: INSECT ASSASSIN (King group) – Committee Adviser; Dr A number of techniques exist for studying protein complexes, computational the structure of proteins – the “worker image averaging and three-dimensional Amanda Carozzi – Postgraduate Student molecules” of the cell. This image draws reconstruction – to obtain a final three- Co-ordinator; and Bronwyn Adams – inspiration from the technique of single dimensional structure. Marketing and Communications Officer. particle analysis, highlighting how it is The structure shown floating in the centre Each of these committee members did now possible with current technology to of the room is around 30 nanometres an excellent job in ensuring the success reconstruct in three-dimensions, images in length (around one millionth of a of the program beyond its pilot year. of individual macromolecular protein centimetre) and was determined by complexes. combining over 10 000 images captured The “walls” of the room illustrate various by electron microscopy. It is being steps in the process of single particle investigated because of its insecticidal analysis – the visualisation of individual properties. imb annual report 2010 82

Darren Brown and Dr Michael Landsberg, winner and runner-up of the Ångström Art™ Centenary competition.

IMB SCIENTISTS WERE PART OF The remaining ambassadors were: Dr These ambassadors promoted science CSIRO’s Scientists in Schools program, Nilesh Bokil (Sweet group), Dr Andrew at events such as Brisbane’s Royal which pairs a teacher and a scientist. Brooks (Waters group), Natasha Show (the “Ekka”), UQ’s Experience The partnership is flexible, allowing Chaudhary (Parton group), Dr Nicole Science, Open Day, Celebration of scientists to engage with the class in the Cloonan (Grimmond group), Baptiste Centenary and Biofutures. They also way in which they and the teacher feel is Coxam (Hogan group), Dr Marcel assisted with visits from groups ranging best for both the time available and the Dinger (Mattick group), Marga Gual from international scientific and political needs of the students. Soler (Stow group), Dr Michael Hanzal- delegates to the Double Helix Club for Bayer (Teasdale group), Dr Elaine Julian primary school children, and hosted Dr Brad Marsh and Dr Melissa Davis (Wainwright group), Dr Praveen Madala work experience students from schools continued their partnerships with (Fairlie group), Anne Sawyer (Hankamer around Brisbane. Dr Michael Tallack Graceville State School and Ironside group), Evan Stephens (Hankamer even appeared on Channel 10 science State School respectively. Dr Bernd group), Dr Michael Tallack (Perkins show Scope, in a segment on bacteria Becker donated his time to both group), and Dr Brit Winnen (King group). and exponential growth. IMB welcomes Centenary State High School and the enquiries from media and tour groups Mater Hospital Special School, while – please contact [email protected] to Peter van der Heide spent time with arrange a tour. Brisbane State High School students. 83 staff and students

IMB Staff and Students imb annual report 2010 84 85 staff and students

IMB Staff and Students imb annual report 2010 86 87 staff and students

IMB Staff and Students imb annual report 2010 88 89 staff and students

IMB Staff and Students imb annual report 2010 90 91 staff and students

IMB Staff and Students imb annual report 2010 92 93 staff and students

IMB Staff and Students imb annual report 2010 94 95 staff and students

IMB Staff and Students

IMBcom imb annual report 2010 96

FINANCIAL STATEMENT STATEMENT OF OPERATING INCOME AND EXPENDITURE YEAR ENDED 31 DECEMBER 2010

INCOME Note 2006 2007 2008 2009 2010 University of Queensland (Operating Grant) 1 10,767,311 11,087,942 11,062,918 13,383,853 10,920,370 University of Queensland Research Grants 252,252 300,436 190,291 311,370 260,901 State Government 10,175,000 11,127,168 10,857,620 14,867,120 10,824,480 SRC Grant (Australian Research Council) 1,159,047 1,182,516 1,206,166 0 0 Australian Research Council 2 5,218,279 6,010,239 5,977,542 7,637,369 8,624,071 Australian Cancer Research Foundation 0 0 0 1,250,000 1,250,000 Australian National University 0 0 0 0 55,800 Australian Nuclear Science & Technology 78,757 230,492 61,326 8,540 992 Organisation Australian Stem Cell Centre 159,780 467,335 770,065 1,342,609 425,442 Baker IDI Heart & Diabetes Institute 0 0 0 76,237 735 Bioplatforms Australia 0 0 0 0 1,029,675 Cancer Council Queensland (previously 148,700 312,000 554,000 402,000 182,000 QCF) Clive and Vera Ramaciotti Foundation 0 60,000 30,000 0 0 Community Health + Tuberculosis Australia 49,000 0 0 0 0 CRC for Chronic Inflammatory Diseases 1,326,058 1,462,776 1,214,510 0 0

Invasive Animals CRC 122,210 0 47,952 0 0 (was Pest Animal Control)

CSIRO 0 0 0 0 627,789 Cystic Fibrosis UK 0 0 0 0 10,000 Dairy Australia 167,644 700,321 333,084 0 0

Dept Industry Science and Technology 0 200,000 135,000 37,245 4,853 (Commonwealth) was DISR

Department of Primary Industries 0 50,000 0 0 0 Diabetes Australia Research Trust 45,000 0 50,008 60,000 0

Grain Research and Development 0 0 0 0 399,640 Corporation

Human Frontiers Science Program 0 81,783 58,180 279,530 113,522 Japanese Science & Technology Agency 0 0 106,462 142,331 0 The John Trivett Foundation 0 267,817 0 0 0 Juvenile Diabetes Foundation International 178,634 147,708 110,723 167,904 136,109 The Mazda Foundation 0 0 150,000 0 0 Monash University – 0 0 0 0 400,000 ARDC Subcontract (EBI Mirror) The Murdoch Childrens Research Institute 0 347,527 235,515 379,122 10,899 National Breast Cancer Foundation 0 0 0 413,490 65,997 National Institute of Health (US) 1,176,642 969,415 561,829 503,882 432,842 National Health and Medical Research 2 7,888,967 11,054,142 12,445,955 15,622,119 21,197,020 Council National Heart Foundation 0 0 65,800 0 2,000 New Zealand Dept Science & Technology 0 81,392 40,738 0 0 Oncology Children’s Foundation 0 0 0 100,000 0 97 financial statement

Financial Statement

INCOME (continued) Note 2006 2007 2008 2009 2010 Postgraduate Scholarships 261,263 305,255 234,520 142,619 132,703

Queensland Cyber Infrastructure 0 0 0 0 600,000 Foundation Ltd

University of Alberta 0 0 0 0 20,752 University of Alabama 0 0 0 0 22,786 University of Sydney (Analytical Services) 0 0 0 0 100,000 Wellcome Trust 0 0 0 0 15,957 Commercial Income 2,018,054 4,880,234 4,585,955 2,521,961 2,269,267 Cross-Institutional contributions to LIEF or 509,472 188,000 50,000 0 230,000 Facilities University of Newcastle (re ARC Centre) 252,562 128,218 153,218 150,000 553,930 Marjory A Welford Bequest 0 0 0 0 58,799 Dr Rosamond Siemon Postgraduate Renal 30,000 30,000 30,000 30,000 30,000 Research Scholarship Rina Martina (Donation) 20,000 20,000 20,000 0 15,000 The Simon Axelsen Memorial Fund 0 0 0 0 180,000 QBP recoveries 386,092 371,257 363,065 346,442 386,301 Facilities – Analytical Services 0 0 0 0 471,896 Shared Grants 234,685 4,000 40,772 0 0 Conference Income 66,615 184,340 70,558 91,656 152,840 QBP Store 276,819 314,057 326,215 357,613 332,675 Victor Chang Cardiac Research Institute 0 0 0 0 86,000 Wesley Research Institute 20,000 93,645 98,423 101,628 0 Miscellaneous Income 399,887 357,293 391,776 186,154 338,924

TOTAL INCOME 43,338,729 52,967,307 52,580,186 60,882,794 62,972,966 Funds brought forward from previous 3 9,050,612 11,441,270 15,641,004 18,495,763 24,755,723 year TOTAL FUNDS AVAILABLE 52,389,341 64,408,577 68,221,189 79,378,557 87,728,689

EXPENDITURE: Salaries – Research 20,110,376 22,878,237 24,750,517 24,717,110 29,518,795 – Administration 1,205,466 1,349,056 1,345,709 1,548,200 1,713,594 – Infrastructure 2,673,620 2,368,795 2,862,623 3,090,792 3,179,745 Research Services 10,995,871 13,099,865 13,091,734 14,696,645 19,154,756 Education Programs 4 358,445 332,919 380,733 458,699 458,558 Administration 5 529,612 521,743 496,666 370,541 395,422 Corporate Services (UQ) 1 0 0 0 0 0 Infrastructure 6 1,295,139 1,862,212 2,160,052 1,693,759 1,616,966 Capital Equipment 7 2,569,801 5,156,825 3,438,525 6,847,087 5,923,904 IMBcom 1,209,741 1,197,920 1,198,528 1,200,000 1,200,000

TOTAL EXPENDITURE 40,948,071 48,767,573 49,725,426 54,622,833 63,161,739 Funds carried forward 8 11,441,270 15,641,004 18,495,763 24,755,723 24,566,950 imb annual report 2010 98

Explanatory notes to Statement of Income and Expenditure

1a In-kind Contributions 5 Administration

Figure does not include the following salaries for affiliate appointments Annual Report 14,377 paid externally or by other departments: Marketing 51,706 Location Percentage Personnel Recruitment and Training 25,669 G. McLachlan UQ Mathematics 90 Visiting Scientists/Seminars 37,001 P. Hugenholtz UQ SCMB 80 Fees 44,218 b) Gross Income & Corporate Services Charge Quinquennial Review - The 2006 Annual Report showed University of Queensland Operating Entertaining 36,777 Grant Income as a gross amount and Corporate Services charge shown seperately under expenditure. Subsequent years have reverted to the Photocopying 57,851 previous method for better direct comparison. 2006 figures have been Postage and Freight 3,696 adjusted accordingly and now show the nett. Printing & stationery 31,893 2 Fellowship/Projects from Government Agencies Telephone 55,775 Australian Research Council Travel Expenses 17,178 Projects 6,884,148 Board Fees 19,280 Fellowships 1,739,923 Total Administration 395,422 8,624,071 6 Infrastructure National Health and Medical Research Council Building Maintenance 107,383 Projects 17,157,634 Rental – Storage 12,658 Fellowships 4,039,386 Safety Equipment 43,401 21,197,020 Laundry 13,361 3 Funds carried forward to 2010 Minor Equipment & Furniture 134,232

University of Queensland Operating Grant 11,316,716 Equipment Maintenance 325,977 University of Queensland Research Grants 835,049 Animals 335,864 Postgraduate Scholarships 32,278 Computer Services 613,778 State Government 1,943,883 Glass washing and replacement 55,516 SRC Grant -92,174 Reticulated gases, RO water & dry ice 73,765 Fellowships (as approved by funding bodies) 397,160 Cost Recovery -98,969 Overseas Grants funded mid year 370,795 Total Infrastructure 1,616,966 Contract Research 1,952,377 7 Capital Equipment Project Grants (as approved by funding bodies) 7,999,639 Scientific Equipment 4,934,972 24,755,723 Minor Equipment 988,932 4 Education Programs Total Capital Equipment 5,923,904

Postgraduate scholarships 406,263 8 Funds carried forward to 2011 Postgraduate recruitment & training 52,295 University of Queensland Operating Grant 9,593,969 ^ Total Education Services 458,558 Research O’head, Dir. Strategic, Recoveries 590,906

^ Of this $883k is committed to QBP Shared Services, $154k to Postgraduate Scholarships 56,481 Core Facilities and $89k to 2010 Purchase Order Committments. State Government 1,260,377 # # Of this $815K is the carry forward on State Govt projects, $445k Fellowships (as approved by funding bodies) 221,971 is carry forward on Core and Core Facilities including $194k Purchase Order committments. Overseas Grants funded mid year 271,673

Contract Research 2,837,145

Project Grants (as approved by funding bodies) 9,734,428

24,566,950 99 glossary

Glossary of terms

Actin A protein, along with myosin, Chromosome A long coiled strand of Enzymes A protein produced by living responsible for muscle contraction. DNA, wound around a protein. organisms that catalyses chemical reactions of other substances without Adipose Fat or fatty tissue. Chromotographic Involving the being altered itself by the reactions. Agonist A molecule that interacts with a separation of compounds into their receptor, triggering a cellular response. constituent parts. Epifluorescence A type of microscopy using a very bright light source. This light CNV Copy number variant. A sequence of Agrochemicals Chemicals used in is used to energise the sample into re- DNA that is repeated a different number of agriculture. emitting light (or “fluorescing”) at various times in different genomes. Allele Different varieties of a gene that wavelengths, which allows researchers to produce different traits. Coculture A culture (preparation) in produce an image of the sample. which more than one type of cell is grown. Allosteric A site on a protein that isn’t Epigenetic The changes in phenotype active. Conotoxins Toxic peptides from marine that occur without a corresponding cone snail venom. change in genotype. AMPK An enzyme involved in the maintenance of cellular energy. Covalent A bond in which electrons are Epigenomic A cataloguing of the non- shared between atoms. genetic changes that occur in the genome Amyloid A type of protein deposited in organs in certain diseases. eg. amyloid Crystallography The use of X-rays to that affect gene expression. deposits are found in the brain of determine the structure of crystallised Epithelial Of the membranous cellular Alzheimer’s patients. molecules. tissue that covers the internal and external Antagonist A molecule that blocks a Cytokines Small proteins released by surfaces of the body. chemical from binding to its receptor. cells that affect the behaviour of other Epitopes The site on the surface of cells. Apoptosis Programmed cell death. a foreign substance that triggers the Cytoplasm All the contents of a cell, production of antibodies, and to which Aromatase An enzyme that causes excepting the nucleus. these antibodies bind. testosterone to transform into estrogen. Cytoskeleton The protein framework of Erythropoiesis The development of Arrays An ordering of samples on a slide. a cell. mature red blood cells. Assay Qualitative or quantitative analyses Eukaryotes Organisms whose genetic of a substance performed in order to Cytotoxicity Toxic to cells. material is enclosed in a membrane- determine its components. De novo Not previously present. bound nucleus. Includes all organisms Atherosclerosis A disease in which Differentiation The process by which except viruses and bacteria. cholesterol builds up on artery walls, cells become more specialised. Ex vivo Taking place outside an causing the arteries to narrow. Diffraction The scattering of light waves organism. BAC recombineering A method of as they pass through or around an object. Exocytosis The discharge of material introducing genetic material into an DNA Deoxyribonucleic acid. The chemical from the cell. organism through a bacterial vector. chain that carries the genetic instructions FACS Fluorescent-activated cell sorting. A Beta-adrenergic Receptors in the for making a living organism. method of sorting a heterogeneous group nervous system that sense hormones of cells using the light scattering and such as adrenaline. Dyslipidemia A disorder that occurs when there is an excess of lipids in the fluorescent characteristics of each cell. Bioactive Has an effect on a living blood. organism. Flavivirus One of a family of small RNA Effector complexes A molecule that viruses that are often transmitted by Bioinformatics The use of alters the activity of a protein by binding mosquitoes and ticks. computational resources in the study of to it. biological information. Gastrulation An embryonic stage of Electron tomography A microscopy development where the embryo turns from Biomolecule Molecules containing technique that samples a specimen at a blastula (ball of cells) into three layers of carbon found in living organisms. different angles and builds the resulting cells, from which organs develop. information into a 3D image. Biophysical The intersection between Gene Considered the basic unit of physics and biology. Embryogenesis The development of an heredity, a gene is a region of DNA that Bioprobes A probe containing embryo. encodes all of the information to make a biomolecules that measures some type of protein. Endocrine A system of glands that biological phenomena. secrete hormones directly into the Genome All DNA contained in an Biosynthesis The production of material bloodstream. organism or cell. from living organisms. Endocytosis Uptake of material into a Genotype The specific set of alleles Chondrogenesis The development of cell. possessed by an individual, either in cartilage. whole or at one loci. Endogenous Within the body. Chromatin The complex of DNA and Globin The protein component of Endosomes An organelle involved in proteins that form a chromosome. haemoglobin. protein trafficking. imb annual report 2010 100

Golgi An organelle that packages and Kinase An enzyme that catalyses the Membrane A thin layer of tissue distributes chemicals within and outside transfer of a phosphate group from a surrounding a cell and separating it from the cell. donor to a target molecule. the rest of the environment. GPCRs G protein-coupled receptors, the Knockouts Organisms in which specific Mesoderm The middle layer of cells in largest family of membrane receptors. genes have been made inactive, so the early embryo. scientists can determine their effect. Gram-negative A type of bacteria with a Metastasis Migration of cancer cells double cell wall, which lessens the effect Ligands A chemical that binds to a larger from their original site to other parts of the of some antibiotics. molecule/receptor. body. Haemoglobin The molecule in blood that Lipid Any of a group of heterogeneous fat Microarray A technique for studying how carries oxygen around the body. or fat-like compounds that are insoluble large numbers of genes interact and how in water. a cell’s regulatory network controls vast Heterocycles Compounds containing a amount of genes simultaneously. ring of atoms of different elements. Lipodystrophies Disorders that result in the abnormal accumulation or loss of fat MicroRNAs Also known as MiRNA, Heteromeric Made up of different in different areas of the body. microRNAs are RNA molecules around subunits. 20 nucleotides long that regulate gene Lipogenic Related to the production of Heterogeneous Consisting of varied expression. fat. constituents. Mimetics Artificial molecule that mimics Lipopolysaccharides A molecule made Histone deacetylase An enzyme the structure of a natural molecule. up of a lipid (fat) and a polysaccharide (a that can catalyse the inhibition of gene type of carbohydrate) found in the cell wall Monoculture A culture (preparation) in transcription. of Gram-negative bacteria. which only one type of cell is grown. Homeostasis A condition where the Liposomes Artificial vesicles capable of Monomer A molecule that can be body uses negative feedback processes delivering drugs to target tissues. bound to others to form polymers (large to maintain its systems at a constant molecules consisting of repeating smaller equilibrium. LXR Liver X receptor, which regulates molecules). cholesterol, fat and sugar levels. Homology Similarity due to common mRNA Messenger RNA. The type of RNA ancestry. Lymphatic system The circulatory that carries the instructions for coding network of vessels that produce and store Homozygous Having the same two proteins from DNA to the ribosomes, the cells that fight infection. copies of alleles at a gene. where proteins are assembled. Lymphedema A condition that occurs Hormone Any of a type of chemical Metacillin-resistant when excess lymph fluid collects in a MRSA secreted by one tissue that has an effect Staphylococcus aureus. A species localised area. on another tissue. of bacteria that is resistant to broad- Lysosome An organelle capable of Hypercholesterolemia High blood spectrum antibiotics and thus can cause digesting microorganisms and cellular cholesterol. infections that are difficult to treat. debris. Immuno-precipitation The process Munc A protein essential for the process Macrophage A large cell that engulfs whereby an antigen is formed in a solution of secreting neurons. and absorbs waste material, harmful using a specific antibody. Relating to mice or rats. microbes or other foreign bodies in the Murine In toto Totally. bloodstream and tissues. Mutagenesis The process of intentionally creating mutations in an In vitro A process occurring in an artificial Macropinocytosis The formation of organism’s DNA. environment that would normally occur in fluid-filled macropinosomes. an organism. Myosins A protein, along with actin, Macropinosomes Large, responsible for muscle contraction. Informatics The science of using heterogeneous, dynamic vesicles. technology to better process, store and Nanometre One billionth of a metre. Mass spectrometry A technique for analyse information. determining the chemical constituents and Neisseria A family of bacteria, two Ion A particle or atom with a charge. structure of a sample. species of which cause diseases in humans (N. meningitides and N. Ion channels Protein pores in the Mechanosensing Responsive to gonorrhoeae). membrane that control the flow of ions mechanical (as opposed to eg. chemical) into and out of the cell. stimuli. Nephron Tubes within the kidney that act as filters. Isothermal calorimetry A technique Melanin Skin and hair pigment. of measuring the heat and heat capacity Neuropathic Pain from nerves Melanoblast Precursor of a melanocyte. of chemical reactions; often used to themselves, as opposed to injured or characterise potential drug candidates. Melanocyte A cell that produces diseased body parts. melanin, the pigment that gives skin, hair Keratinocytes Cells that make keratin, Neurosecretion The production and and eyes their colour. a substance found in hair and nails (hard secretion of hormones by neurons. keratin) and skin (soft keratin). 101 glossary

Glossary of terms

Nevus A birthmark. Phenotype The characteristics of an RNA A chemical similar to a single strand organism resulting from the interaction of DNA, except that RNA contains ribose Nexin (sorting) A group of proteins, some between its genotype and its environment. instead of deoxyribose and uracil instead of which play a role in sorting proteins. of thymine. RNA delivers DNA’s message Phosphorylation The addition of a NMR spectroscopy Nuclear to the site of protein synthesis. phosphate group to another molecule, Magnetic Resonance spectroscopy. A which often alters the activity of an Scission Splitting. spectroscopic technique that analyses enzyme. the disruptions to a high magnetic field Secretory Relating to secretion. to elucidate the chemical structure and Phototype A category into which people Single-nucleotide polymorphisms molecular dynamics of a sample. are placed depending on the amount of (SNPs) A single base of DNA which can melanin in their skin. Nucleators Something that either forms differ in a population. into a nucleus or aids in this formation. Phylogenetic Of the evolutionary SNARE A family of proteins, the main development of organisms. Nucleic acid The molecules that carry function of which involves directing genetic information. DNA and RNA are PNMT Phenylethanolamine vesicles out of the cell. examples of nucleic acids. N-methyltransferase. An enzyme that SNP Single nucleotide polymorphism. A catalyses the production of adrenalin. Nucleosomes The repeating subunit of single base of DNA which can differ in a chromatin. Polymorphism The existence of multiple population. forms of a gene or DNA sequence. Nucleus A large, membrane-bound, Spectroscopy The study of the usually spherical structure within a living Prenylation A process whereby interaction between matter and radiation cell, containing the cell’s hereditary hydrophobic molecules are added to a (eg. light). material and controlling its metabolism, protein. Thalassaemia An inherited blood growth and reproduction. Protease Any enzyme that causes the disorder where the body has difficulty Onco-MIRs A microRNA associated with interior peptide bonds of a protein to split. producing haemoglobin. cancer. Protein A large molecule composed of Theranostic Therapy that tests Organelle A discrete subcellular one or more chains of amino acids in a patients to determine if they are suitable structure with a specialised function. specific order. Proteins are required for the candidates for a new medication. structure, function and regulation of the Organic chemistry The chemistry of Transcription The formation of RNA body’s cells, tissues and organs, and each compounds containing carbon. from a DNA template. protein has a unique function. Examples Orthologous Any gene found in more are hormones and antibodies. Transcription factors Proteins that than one species that can be traced back control the transfer of genetic information Protozoan A type of one-celled organism to the same common ancestor. from DNA to messenger RNA. with a defined nucleus. Oxidative Relating to the addition of Transcriptome All RNA molecules qPCR Real-time polymerase chain oxygen. produced in a cell or organism at any one reaction. A technique that allows the point in time. Paralogous Two genetic sequences that detection and quantification of a sequence have the same evolutionary ancestor and in a DNA sample as the analysis is Transferase An enzyme that transports arose through gene duplication. occurring. a chemical from one molecule to another. Pathogenicity The capacity to cause Quantitative A measurement based on Transgenic An organism that has a disease. numerical data. transferred gene (transgene) incorporated into the chromosome of all its cells. Pathogens Disease-causing organisms. Radioligand A radioactive substance Triplex Consisting of three parts. Pathophysiology A change in function injected into tissue that binds to receptors caused by a disease or condition. and allows researchers to study its UTR Untranslated Region. The non- behaviour. coding sections at the beginning and end Peptides A compound of two or more of a protein-coding segment of mRNA. amino acids. Redox A reduction/oxidation reaction, where the oxidation number of an atom UQ ROCX University of Queensland Petameric Made up of five identical changes. Remote Operation Crystallization and monomers. Retinoic acid A derivative of Vitamin A. X-Ray Diffraction Facility. Phagocytosis The process by which Vasculature Network of conductive cells engulf material in order to destroy or Retromer A protein complex that is vessels, eg. blood vessels, lymphatic digest it. involved in the transport of proteins to the Golgi. vessels. Pharmacology The study of drugs and Vesicle A closed membrane shell. their effect on organisms. Retrotransposon A segment of DNA that can move around the genome and X-ray crystallography A method of Phasevarions Genetic systems where amplify itself. determining the structure of a sample phase variation (reversible, high-frequency by bouncing an X-ray off a crystallised on/off switching of expression) regulates version of the sample and analysing the the expression of multiple genes. resulting light diffraction pattern. imb annual report 2010 102

2010 PUBLICATIONS

Buske, F.A., Boden, M., Bauer, D.C., Duran, C., Boskovic, Z., Imelfort, M., and Bailey, T.L. (2010). Assigning roles to Batley, J., Hamilton, N.A., and Edwards, D. DNA regulatory motifs using comparative (2010). CMap3D: a 3D visualization tool for genomics. Bioinformatics 26: 860-866. comparative genetic maps. Bioinformatics 26: 273-274. Choi, J., Davis, M.J., Newman, A.F., and Ragan, M.A. (2010). A semantic web Fernandez-Valverde, S.L., Taft, R.J., and ontology for small molecules and their Mattick, J.S. (2010). Dynamic isomiR biological targets. Journal of Chemical regulation in Drosophila development. RNA Information and Modeling 50: 732-741. 16: 1881-1888. Chung, T.L., Brena, R.M., Kolle, G., Hudson, T.J., Anderson, W., Aretz, A., Grimmond, S.M., Berman, B.P., Laird, Barker, A.D., Grimmond, S.M., Pearson, NICK HAMILTON: FISHING IN THE CELLULAR SEA P.W., Pera, M.F., and Wolvetang, E.J. J.V., Cloonan, N., Gardiner, B.A., Waddell, (2010). Vitamin C Promotes Widespread N.J., Wilson, P.J., Wainwright, B.J., Fluorescently tagged proteins light up the interior of a cell allowing the Yet Specific DNA Demethylation of the and The International Cancer Genome intricate structures floating within to be Epigenome in Human Embryonic Stem Consortium. (2010). International network seen. Cells. Stem Cells 28: 1848-1855. of cancer genome projects. Nature 464: 993-998. Chung, T.-L., Turner, J.P., Thaker, N.Y., Kolle, G., Cooper-White, J.J., Grimmond, Jung, C.-H., Hansen, M.A., Makunin, I.V., S.M., Pera, M.F., and Wolvetang, E.J. Korbie, D.J., and Mattick, J.S. (2010). GENOMICS AND COMPUTATIONAL (2010). Ascorbate promotes epigenetic Identification of novel non-coding RNAs BIOLOGY activation of CD30 in human embryonic using profiles of short sequence reads from Aung, H.T., Harrison, D.K., Findlay, I., stem cells. Stem Cells 28: 1782-1793. next generation sequencing data. BMC Mattick, J.S., Martin, N.G., and Carroll, Genomics 11: 77. B.J. (2010). Stringent programming of DNA Cloonan, N., and Grimmond, S.M. (2010). methylation in humans. Twin Research and Simplifying complexity. Nature Methods 7: Jung, C.-H., Makunin, I.V., and Mattick, Human Genetics 13: 405-411. 793-795. J.S. (2010). Identification of conserved Drosophila-specific euchromatin-restricted Baek, J., McLachlan, G.J., and Flack, L.K. Cloonan, N., Waddell, N., and Grimmond, non-coding sequence motifs. Genomics S. M. (2010). The clinical potential and (2010). Mixtures of factor analyzers with 96: 154-166. common factor loadings: Applications to challenges of sequencing cancer genomes the clustering and visualization of high- for personalized medical genomics. I Drugs Kerr, M.C., Wang, J.T.H., Castro, N.A., dimensional data. IEEE Transactions on 13: 778-781. Hamilton, N.A., Town, L., Brown, D.L., Meunier, F.A., Brown, N.F., Stow, J.L., Pattern Analysis and Machine Intelligence Da Silva, L., Simpson, P.T., Smart, C.E., 32: 1298-1309. and Teasdale, R.D. (2010). Inhibition of Cocciardi, S., Waddell, N., Lane, A., the PtdIns(5) kinase PIKfyve disrupts Barclay, J.L., Kerr, L.M., Arthur, L., Morrison, B.J., Vargas, A.C., Healey, intracellular replication of Salmonella. S., Beesley, J., Pakkiri, P., Parry, S., Rowland, J.E., Nelson, C.N., Ishikawa, M., EMBO Journal 29: 1331-1347. d’Aniello, E.M., White, M., Noakes, P.G., Kurniawan, N., Reid, L., Keith, P., Faria, and Waters, M.J. (2010). In vivo targeting P., Pereira, E., Skalova, A., Bilous, M., of the growth hormone receptor (GHR) Balleine, R.L., Do, H., Dobrovic, A., Fox, Box1 sequence demonstrates that the S., Franco, M., Reynolds, B., Khanna, GHR does not signal exclusively through K., Cummings, M., Chenevix-Trench, JAK2. Molecular Endocrinology 24: 204- G., and Lakhani, S.R. (2010). HER3 and 217. downstream pathways are involved in colonization of brain metastases from Bauer, D.C., Buske, F.A., and Bailey, T.L. breast cancer. Breast Cancer Research (2010). Dual-functioning transcription 12: R46. factors in the developmental gene network of Drosophila melanogaster. BMC Davis, M.J., Sehgal, M.S.B., and Ragan, Bioinformatics 11: 366. M.A. (2010). Automatic, context-specific generation of Gene Ontology slims. BMC Bauer, D.C., Buske, F.A., Bailey, T.L., and Bioinformatics 11: 1-13. NICOLE CLOONAN: Boden, M. (2010). Predicting SUMOylation SHORT SEQUENCE DE NOVO ASSEMBLY sites in developmental transcription de Hoon, M.J.L., Taft, R.J., Hashimoto, Being able to read the order factors of Drosophila melanogaster. T., Kanamori-Katayama, M., Kawaji, H., (sequence) of the DNA gives us Neurocomputing 73: 2300-2307. Kawano, M., Kishima, M., Lassmann, T., amazing insight into our genes and Faulkner, G.J., Mattick, J.S., Daub, C.O., how they contribute to biological Boden, M., Dellaire, G., Burrage, K., and Carninci, P., Kawai, J., Suzuki, H., and processes. This image depicts the de Bailey, T.L. (2010). A bayesian network Hayashizaki, Y. (2010). Cross-mapping and novo assembly of human chromosome model of proteins’ association with the identification of editing sites in mature 21 using short sequences. The four promyelocytic leukemia (PML) nuclear microRNAs in high-throughput sequencing building blocks (nucleotides) that make up the DNA are represented by the bodies. Journal of Computational Biology libraries. Genome Research 20: 257-264. letters A, C, G, and T. 17: 617-630. 103 publications

Publications 2010

GENOMICS AND COMPUTATIONAL Maleknia, S.D., and Green, D.C. McLachlan, G.J., and Wockner, L. BIOLOGY (CONTINUED) (2010). eCRAM computer algorithm for (2010). Use of mixture models in multiple implementation of the charge ratio analysis hypothesis testing with applications in method to deconvolute electrospray bioinformatics. In Hermann Locarek-Junge Kubosaki, A., Lindgren, G., Tagami, M., ionization mass spectra. International and Claus Weihs (Ed.), Classification as Simon, C., Tomaru, Y., Miura, H., Suzuki, Journal of Mass Spectrometry 290: 1-8. a Tool for Research: Proceedings of the T., Arner, E., Forrest, A.R.R., Irvine, K.M., 11th IFCS Biennial Conference and 33rd Schroder, K., Hasegawa, Y., Kanamori- Mattick, J. (2010). Video Q&A: Non-coding Annual Conference of the Gesellschaft fr Katayama, M., Rehli, M., Hume, D.A., RNAs and eukaryotic evolution - a personal Klassifikation (pp. 177-184) Heidelberg, Kawai, J., Suzuki, M., Suzuki, H., and view. BMC Biology : 67. 8 Germany: Springer-Verlag Hayashizaki, Y. (2010). The combination Mattick, J.S. (2010). Deconstructing the of gene perturbation assay and ChIP-chip McLeay, R.C., and Bailey, T.L. (2010). Motif dogma : A new view of the evolution reveals functional direct target genes for Enrichment Analysis: A unified framework and genetic programming of complex IRF8 in THP-1 cells. Molecular Immunology and an evaluation on ChIP data. BMC organisms. In: Douglas Braaten, Annals 47: 2295-2302. Bioinformatics 11: 165. of the New York Academy of Sciences.. Lai, J., Lehman, M.L., Dinger, M.E., Hendy, Conference on Natural Genetic Engineering Melykuti, B., Burrage, K., and Zygalakis, S.C., Mercer, T.R., Seim, I., Lawrence, and Natural Genome Editing, Salzburg, K.C. (2010). Fast stochastic simulation of M.G., Mattick, J.S., Clements, J.A., and Austria, (29-46). 3-6 July, 2008 biochemical reaction systems by alternative Nelson, C.C. (2010). A variant of the KLK4 formulations of the chemical Langevin Mattick, J.S. (2010). Linc-ing long gene is expressed as a cis sense-antisense equation. Journal of Chemical Physics 132: noncoding RNAs and enhancer function. chimeric transcript in prostate cancer cells. 164109. RNA 16: 1156-1166. Developmental Cell 19: 485-486. Mercer, T.R., Dinger, M.E., Bracken, C.P., Le, S.J., Gongora, M., Zhang, B., Mattick, J.S. (2010). RNA as the substrate Kolle, G., Szubert, J.M., Korbie, D.J., Grimmond, S., Campbell, G.R., Campbell, for epigenome-environment interactions: Askarian-Amiri, M.E., Gardiner, B.B., J.H., and Rolfe, B.E. (2010). Gene RNA guidance of epigenetic processes and Goodall, G.J., Grimmond, S.M., and expression profile of the fibrotic response the expansion of RNA editing in animals Mattick, J.S. (2010). Regulated post- in the peritoneal cavity. Differentiation 79: underpins development, phenotypic transcriptional RNA cleavage diversifies 232-243. plasticity, learning, and cognition. the eukaryotic transcriptome. Genome Bioessays : 548-552. 32 Research 20: 1639-1650. Le Cao, K.-A., Meugnier, E., and McLachlan, G.J. (2010). Integrative mixture Mattick, J.S., Taft, R.J., and Faulkner, G.J. Mercer, T.R., Qureshi, I.A., Gokhan, S., of experts to combine clinical factors and (2010). A global view of genomic information Dinger, M.E., Li, G., Mattick, J.S., and gene markers. Bioinformatics 26: 1192- - moving beyond the gene and the master Mehler, M.F. (2010). Long noncoding RNAs 1198. regulator. Trends in Genetics 26: 21-28. in neuronal-glial fate specification and oligodendrocyte lineage maturation. BMC Lin, S.A., Kolle, G., Grimmond, S.M., Zhou, Mazar, J., Sinha, S., Dinger, M.E., Neuroscience 11: 1-15. Q., Doust, E., Little, M.H., Aronow, B., Mattick, J.S., and Perera, R.J. (2010). Ricardo, S.D., Pera, M.F., Bertram, J.F., Protein-coding and non-coding gene Mercer, T., Wilhelm, I.D., Dinger, M., Solda, and Laslett, A.L. (2010). Subfractionation expression analysis in differentiating human G., Korbie, D., Glazov, E., Thuy, V.T., of differentiating human embryonic stem keratinocytes using a three-dimensional Schwenke, M., Simons, C., Matthaei, K.I., cell populations allows the isolation of epidermal equivalent. Molecular Genetics Saint, R., Koopman, P.A., and Mattick, a mesodermal population enriched for and Genomics 284: 1-9. J.S. (2010). Expression of distinct RNAs intermediate mesoderm and putative renal from 3 untranslated regions. Nucleic Acids progenitors. Stem Cells and Development Research Epub ahead of print 19: 1637-1648. Mohamad, N., and Bodén, M. (2010). The MacNamara, S., and Burrage, K. (2010). proteins of intra-nuclear bodies: A data- Stochasic modelling of naïve T cell driven analysis of sequence, interaction and homeostasis for competing clonotypes via expression. BMC Systems Biology 4: 44. the master equation. Multiscale Modeling and Simulation 8: 1325-1347. Oldmeadow, C., Mengersen, K., Mattick, J.S., and Keith, J.M. (2010). Multiple Maetschke, S.R., Kassahn, K.S., Dunn, evolutionary rate classes in animal genome J.A., Han, S.-P., Curley, E.Z., Stacey, evolution. Molecular Biology and Evolution K.J., and Ragan, M.A. (2010). A visual 27: 942-953. framework for sequence analysis using n-grams and spectral rearrangement. Piper, M., Barry, G., Hawkins, J., Mason, SEETHA KARUNARATNE: S., Lindwall, C., Little, E., Sarkar, A., Bioinformatics 26: 737-744. MOLECULAR COMPUTERS Smith, A.G., Moldrich, R.X., Boyle, G.M., Visualising genetic material that drives Tole, S., Gronostajski, R.M., Bailey, T.L., life by a simple staining technique is a and Richards, L.J. (2010). NFIA controls fascinating experience. Each living cell has its own molecular computer which telencephalic progenitor cell differentiation is busy all the time. through repression of the Notch effector Hes1. Journal of Neuroscience 30: 9127- 9139. imb annual report 2010 104

Qureshi, I.A., Mattick, J.S., and Mehler, Waddell, N., Arnold, J., Cocciardi, S., da M.F. (2010). Long non-coding RNAs in Silva, L., Marsh, A., Riley, J., Johnstone, nervous system function and disease. C.N., Orloff, M., Assie, G., Eng, C., Reid, Brain Research 1338: 20-35. L., Keith, P., Yan, M., Fox, S., Devilee, P., Godwin, A.K., Hogervorst, F.B.L., Couch, Ravasi, T., Suzuki, H., Cannistraci, C.V., F., kConFab Investigators, Grimmond, S., Katayama, S., Bajic, V.B., Tan, K., Akalin, Flanagan, J.M., Khanna, K., Simpson, P.T., A., Schmeier, S., Kanamori-Katayama, Lakhani, S.R., and Chenevix-Trench, G. M., Bertin, N., Carninci, P., Daub, C.O., (2010). Subtypes of familial breast tumours Forrest, A.R.R., Gough, J., Grimmond, revealed by expression and copy number S., Han, J.-H., Hashimoto, T., Hide, W., profiling. Breast Cancer Research And Hofmann, O., Kamburov, A., Kaur, M., Treatment 123: 661-677. Kawaji, H., Kubosaki, A., Lassmann, T., van Nimwegen, E., MacPherson, C.R., Waddell, N., Cocciardi, S., Johnson, J., Ogawa, C., Radovanovic, A., Schwartz, Healey, S., Marsh, A., Riley, J., da Silva,

A., Teasdale, R.D., Tegner, J., Lenhard, B., L., Vargas, A.C., Reid, L., Simpson, P.T., JESS INESON: KIDNEY KALEIDOSCOPE Teichmann, S.A., Arakawa, T., Ninomiya, Lakhani, S.R., and Chenevix-Trench, The image is from a section of mouse N., Murakami, K., Tagami, M., Fukuda, G. (2010). Gene expression profiling of embryonic kidney at 15.5 days of S., Imamura, K., Kai, C., Ishihara, R., formalin-fixed, paraffin-embedded familial development. It has been stained by Kitazume, Y., Kawai, J., Hume, D.A., breast tumours using the whole genome- immunofluorescence for two markers Ideker, T., and Hayashizaki, Y. (2010). DASL assay. Journal of Pathology 221: of early kidney development, Calbindin An atlas of combinatorial transcriptional 452-461. (red), which marks the utereic bud and regulation in mouse and man. Cell 140: Pax2 (green), an early nephron marker. 744-752. Walker, L.C., Thompson, B.A., Waddell, Nuclei of each cell are shown in blue. N., kConFab Investigators, Grimmond, Risueno, A., Fontanillo, C., Dinger, M.E., S.M., and Spurdle, A.B. (2010). Use of and De Las Rivas, J. (2010). GATExplorer: DNA-Damaging Agents and RNA Pooling Genomic and Transcriptomic Explorer; to Assess Expression Profiles Associated mapping expression probes to gene loci, with BRCA1 and BRCA2 Mutation Status transcripts, exons and ncRNAs. BMC in Familial Breast Cancer Patients. PLoS MOLECULAR GENETICS AND Bioinformatics 11: 221. Genetics 6: e1000850. DEVELOPMENT Abramyan, J., Wilhelm, D., and Koopman, Rue, P., Villa-Freixa, J., and Burrage, K. Walter, T., Shattuck, D.W., Baldock, R., P. (2010). Molecular Characterization of (2010). Simulation methods with extended Bastin, M.E., Carpenter, A.E., Duce, S., the Bidder’s Organ in the Cane Toad (Bufo stability for stiff biochemical Kinetics. BMC Ellenburg, J., Fraser, A., Hamilton, N., marinus). Journal of Experimental Zoology Systems Biology 4: 110. Pieper, S., Ragan, M.A., Schneider, J.E., Part B-Molecular and Developmental Tomancak, P., and Heriche, J.-K. (2010). Evolution 314B: 503-513. Sims-Lucas, S., Young, R.J., Martinez, G., Visualization of image data from cells to Taylor, D., Grimmond, S.M., Teasdale, R., organisms. Nature Methods 7: S26-S41. Achard, M.E.S., Tree, J.J., Holden, J.A., Little, M.H., Bertram, J.F., and Caruana, G. Simpfendorfer, K.R., Wijburg, O.L.C., (2010). Redirection of renal mesenchyme Wang, J.T.H., Kerr, M.C., Karunaratne, Strugnell, R.A., Schembri, M.A., Sweet, to stromal and chondrocytic fates in the S., Jeanes, A., Yap, A.S., and Teasdale, M.J., Jennings, M.P., and McEwan, A.G. presence of TGF-beta 2. Differentiation 79: R.D. (2010). The SNX-PX-BAR Family (2010). The Multi-Copper-Ion Oxidase 272-284. in Macropinocytosis: The Regulation of CueO of Salmonella enterica Serovar Macropinosome Formation by SNX-PX- Suen, J.Y., Gardiner, B., Grimmond, S., Typhimurium Is Required for Systemic BAR Proteins. PLoS One 5: e13763. and Fairlie, D.P. (2010). Profiling Gene Virulence. Infection and Immunity 78: Expression Induced by Protease-Activated Wu, H.-J., Seib, K.L., Srikhanta, Y.N., 2312-2319. Receptor 2 (PAR2) Activation in Human Edwards, J., Kidd, S.P., Maguire, T.L., Bagheri-Fam, S., Sinclair, A.H., Koopman, Kidney Cells. PLoS ONE 5: e13809. Hamilton, A., Pan, K.-T., Hsiao, H.-H., P., and Harley, V.R. (2010). Conserved Yao, C.-W., Grimmond, S.M., Apicella, regulatory modules in the Sox9 testis- Taft, R., Simons, C., Nahkuri, S., Oey, H., M.A., McEwan, A.G., Wang, A.H.-J., specific enhancer predict roles for SOX, Korbie, D.J., Mercer, T.R., Holst, J., Ritchie, and Jennings, M.P. (2010). Manganese TCF/LEF, Forkhead, DMRT, and GATA W., Wong, J.J.-L., Rasko, J.E.J., Rokhsar, regulation of virulence factors and oxidative proteins in vertebrate sex determination. D.S., Degnan, B.M., and Mattick, J.S. stress resistance in Neisseria gonorrhoeae. (2010). Nuclear-localized tiny RNAs are International Journal of Biochemistry & Cell Journal of Proteomics 73: 899-916. associated with transcription initiation and Biology 42: 472-477. splice sites in metazoans. Nature Structural You, L., Brusic, V., Gallagher, M., and Bailey, T.L., Bodén, M., Whitington, T., and Molecular Biology 17: 1030-1035. Boden, M. (2010). Using Gaussian and Machanick, P. (2010.) The value of Process with Test Rejection to Detect position-specific priors in motif discovery T-Cell Epitopes in Pathogen Genomes. using MEME. BMC Bioinformatics 11: 179. IEEE-ACM Transactions on Computational Biology and Bioinformatics 7: 741-775. 105 publications

Publications 2010

MOLECULAR GENETICS AND Duffy, D.L., Iles, M.M., Glass, D., Zhu, G., Georges, A., Ezaz, T., Quinn, A.E., DEVELOPMENT (CONTINUED) Barrett, J.H., Hoiom, V., Zhao, Z.Z., Sturm, and Sarre, S.D. (2010). Are reptiles R.A., Soranzo, N., Hammond, C., Kvaskoff, predisposed to temperature-dependent M., Whiteman, D.C., Mangino, M., sex determination? Sexual Development Beverdam, A., Svingen, T., Bagheri-Fam, Hansson, J., Newton-Bishop, J.A., Bataille, : 7-15. S., McClive, P., Sinclair, A.H., Harley, V.R., 4 V., Hayward, N.K., Martin, N.G., Bishop, and Koopman, P. (2010). Protein tyrosine D.T., Spector, T.D., and Montgomery, G.W. Harrison, M.J., Tang, Y.H., and kinase 2 beta (PTK2B), but not focal (2010). IRF4 Variants Have Age-Specific Dowhan, D.H. (2010). Protein arginine adhesion kinase (FAK), is expressed in a Effects on Nevus Count and Predispose methyltransferase 6 regulates multiple sexually dimorphic pattern in developing to Melanoma. American Journal of Human aspects of gene expression. Nucleic Acids mouse gonads. Developmental Dynamics Research : 2201-2216. Genetics 87: 6-16. 38 239: 2735-2741. Duffy, D.L., Zhao, Z.Z., Sturm, R.A., Johanson, H.C., Chen, W., Wicking, Bowles, J., Feng, C.-W., Spiller, C., Hayward, N.K., Martin, N.G., and C., and Sturm, R.A. (2010). Inheritance Davidson, T.-L., Jackson, A., and Montgomery, G.W. (2010). Multiple of a novel mutated allele of the OCA2 Koopman, P. (2010). FGF9 suppresses pigmentation gene polymorphisms account gene associated with high incidence of meiosis and promotes male germ cell fate for a substantial proportion of risk of oculocutaneous albinism in a Polynesian in mice. Developmental Cell 19: 440-449. cutaneous malignant melanoma. Journal of community. Journal of Human Genetics 55: 103-111. Bowles, J., and Koopman, P. (2010). Investigative Dermatology 130: 520-528. Sex determination in mammalian germ Endo-Munoz, L., Cumming, A., Rickwood, Julian, E., Dave, R.K., Robson, J.P., cells: extrinsic versus intrinsic factors. D., Wilson, D., Cueva, C., Ng, C., Hallahan, A.R., and Wainwright, B.J. Reproduction 139: 943-958. Strutton, G., Cassady, A.I., Evdokiou, A., (2010). Canonical Notch signaling is not required for the growth of Hedgehog Bruce, S.J., Butterfield, N.C., Metzis, V., Sommerville, S., Dickinson, I., Guminski, pathway-induced medulloblastoma. Town, L., McGlinn, E., and Wicking, C. A., and Saunders, N.A. (2010). Loss of Oncogene : 3465-3476. (2010). Inactivation of Patched1 in the Osteoclasts Contributes to Development 29 mouse limb has novel inhibitory effects of Osteosarcoma Pulmonary Metastases. Julian, E., Hallahan, A.R., and on the chondrogenic program. Journal of Cancer Research 70: 7063-7072. Wainwright, B.J. (2010). RBP-J is not Biological Chemistry 285: 27967-27981. Ewen, K., Jackson, A., Wilhelm, D., and required for granule neuron progenitor development and medulloblastoma Butterfield, N.C., McGlinn, E., and Wicking, Koopman, P. (2010). A male-specific role initiated by Hedgehog pathway activation C. (2010). Chapter nine: The molecular for p38 mitogen-activated protein kinase in the external germinal layer. Neural regulation of vertebrate limb patterning. in germ cell sex differentiation in mice. Development : 27. Current Topics in Developmental Biology Biology of Reproduction 83: 1005-1014. 5 90: 319-341. Ewen, K., and Koopman, P. (2010). Mouse Kadekaro, A.L., Leachman, S., Kavanagh, R.J., Swope, V., Cassidy, P., Supp, D., Chiu, H.S., Szucsik, J.C., Georgas, K.M., germ cell development: From specification Sartor, M., Schwemberger, S., Babcock, Jones, J.L., Rumballe, B.A., Tang, D., to sex determination. Molecular and G., Wakamatsu, K., Ito, S., Koshoffer, A., Grimmond, S.M., Lewis, A.G., Aronow, Cellular Endocrinology 323: 76-93. Boissy, R.E., Manga, P., Sturm, R.A., and B.J., Lessard, J.L., and Little, M.H. (2010). Abdel-Malek, Z.A. (2010). Melanocortin Comparative gene expression analysis 1 receptor genotype: an important of genital tubercle development reveals a determinant of the damage response of putative appendicular Wnt7 network for the melanocytes to ultraviolet radiation. FASEB epidermal differentiation. Developmental Journal 24: 3850-3860. Biology 344: 1071-1087. Kashimada, K., and Koopman, P. (2010). Christ, A.N., Labzin, L., Bourne, G.T., Sry: the master switch in mammalian sex Fukunishi, H., Weber, J.E., Sweet, M.J., determination. Development : 3921- Smythe, M.L., and Flanagan, J.U. (2010). 137 3930. Development and characterization of new inhibitors of the human and Koopman, P. (2010). The delicate balance mouse hematopoietic prostaglandin D-2 between male and female sex determining synthases. Journal of Medicinal Chemistry pathways: potential for disruption of early 53: 5536-5548. steps in sexual development. In: Ewa Rajpert-De Meyts, International Journal Combes, A.N., Spiller, C.M., Harley, V.R., of Andrology. Proceedings of the 5th Sinclair, A.H., Dunwoodie, S.L., Wilhelm, KYLIE GEORGAS: POP NEON KIDNEYS Copenhagen Workshop on Endocrine D., and Koopman, P. (2010). Gonadal This artwork is a pop art version of Disrupters. 5th Copenhagen Workshop defects in Cited2 -mutant mice indicate a schematic diagram of embryonic on Endocrine Disrupters: Ubiquitous a role for SF1 in both testis and ovary mouse kidneys. The diagram has Endocrine Disrupters and Possible Human differentiation. International Journal of been modified from a kidney diagram Health Effects, Copenhagen, Denmark, Developmental Biology 54: 683-689. designed and drawn by Kylie Georgas for the GUDMAP website and has (252-258). 20-22 May 2009 been enhanced and stylised for the competition. imb annual report 2010 106

Leong, G.M., Kee, A.J., Millard, S.M., Raggatt, L.J., and Partridge, N.C. (2010). Martel, N., Eriksson, N., Turner, N., Cellular and molecular mechanisms of Cooney, G.J., Hardeman, E.C., and bone remodeling. Journal of Biological Muscat, G.E.O. (2010). The Ski proto- Chemistry 285: 25103-25108. oncogene regulates body composition Raichur, S., Fitzsimmons, R.L., Myers, and suppresses lipogenesis. International S.A., Pearen, M.A., Lau, P., Eriksson, Journal of Obesity 34: 524-536. N., Wang, S.M., and Muscat, G.E.O. Little, M., Georgas, K., Pennisi, D., and (2010). Identification and validation of the Wilkinson, L. (2010). Kidney development: pathways and functions regulated by the two tales of tubulogenesis. Organogenesis orphan nuclear receptor, ROR alpha1, in in Development 90: 193-229. skeletal muscle. Nucleic Acids Research 38: 4296-4312. Lusis, M., Li, J., Ineson, J., Christensen, HAN SHENG CHIU: ART OF SEX SCIENCE M.E., Rice, A., and Little, M.H. (2010). The art is a mosaic picture containing all Rumballe, B., Georgas, K., Wilkinson, L., Isolation of clonogenic, long-term self of my whole-mount in situ hybridisation and Little, M. (2010). Molecular anatomy renewing embryonic renal stem cells. Stem results on an organ called genital of the kidney: What have we learned from Cell Research 5: 23-39. tubercle also known as external genitalia, gene expression and functional genomics? with a combination of 81 different Pediatric Nephrology 25: 1005-1016. MacDonald, K.P.A., Palmer, J.S., Cronau, pictures of mouse genital tubercle. S., Seppanen, E.J., Olver, S., Raffelt, Sabin, M.A., Clemens, S.L., Saffery, R., N.C., Kuns, R., Pettit, A.R., Clouston, A., McCallum, Z., Campbell, M.W., Kiess, Wainwright, B.J., Branstetter, D., Smith, W., Crimmins, N.A., Woo, J.G., Leong, J., Paxton, R.J., Cerretti, D.P., Bonham, Journal of Clinical Endrocrinology and G.M., Werther, G.A., Ukoumunne, O.C., L., Hill, G.R., and Hume, D. (2010). An Metabolism 95: 297-302. and Wake, M.A. (2010). New directions antibody against the colony-stimulating in childhood obesity research: how a factor 1 receptor (CSF1R) depletes the Ovchinnikov, D.A., DeBats, C.E.E., Sester, comprehensive biorepository will allow resident subset of monocytes and tissue D.P., Sweet, M.J., and Hume, D.A. (2010). better prediction of outcomes. BMC and tumor-associated macrophages but A conserved distal segment of the mouse Medical Research Methodology 10: 100. does not inhibit inflammation. Blood 116: CSF-1 receptor promoter is required for Schroder, K., and Tschopp, J. (2010). The 3955-3963. maximal expression of a reporter gene in macrophages and osteoclasts of inflammasomes. Cell 140: 821-832. Markey, K.A., Burman, A.C., Banovic, T., transgenic mice. Journal of Leukocyte Schroder, K., Zhou, R., and Tschopp, Kuns, R.D., Raffelt, N.C., Rowe, V., Olver, Biology 87: 815-822. J. (2010). The NLRP3 inflammasome: a S.D., Don, A.L.J., Morris, E.S., Pettit, A.R., sensor for metabolic danger? Science : Wilson, Y.A., Robb, R.J., Randall, L.M., Papathanasiou, P., Tunningley, R., 327 269-300. Korner, H., Engwerda, C.R., Clouston, Pattabiraman, D.R., Ye, P., Gonda, T.J., A.D., MacDonald, K.P.A., and Hill, G.R. Whittle, B., Hamilton, A.E., Cridland, S.O., Smith, A.G., and Sturm, R.A. (2010). (2010). Soluble lymphotoxin is an important Lourie, R., and Perkins, A.C. (2010). A Multiple genes and locus interactions effector molecule in GVHD and GVL. Blood recessive screen for genes regulating in susceptibility to vitiligo. Journal of 115: 122-132. hematopoietic stem cells. Blood 116: Investigative Dermatology 130: 643-645. 5849-5858. McCann, F.E., Palfreeman, A.C., Andrews, Sousa, K.M., Villaescusa, J.C., Cajanek, M., Perocheau, D.P., Inglis, J.J., Schafer, Pearen, M.A., and Muscat, G.E.O. (2010). L., Ondr, J.K., Castelo-Branco, G., Hofstra, P., Feldmann, M., Williams, R.O., and Minireview: Nuclear hormone receptor W., Bryja, V., Palmberg, C., Bergman, T., Brennan, F.M. (2010). Apremilast, a novel 4A signaling: Implications for metabolic Wainwright, B., Lang, R.A., and Arenas, PDE4 inhibitor, inhibits spontaneous disease. Molecular Endocrinology 24: E. (2010). Wnt2 regulates progenitor production of tumour necrosis factor-alpha 1891-1903. proliferation in the developing ventral from human rheumatoid synovial cells and Pennisi, D.J., Chiu, H.S., Vinay, K.S., midbrain. Journal of Biological Chemistry ameliorates experimental arthritis. Arthritis Wilkinson, L., Zhang, P.M., and Little, 285: 7246-7253. Research & Therapy 12: R107. M.H. (2010). Mice null for Crim1 display Spiller, C.M., Wilhelm, D., and Koopman, McFarlane, L., and Wilhelm, D. (2010). altered BMP/TGF beta signaling, defects P. (2010). Retinoblastoma 1 protein Non-Coding RNAs in Mammalian Sexual in multiple organ systems and die in utero modulates XY germ cell entry into G(1)/G(0) Development. Sexual Development 3: with severe cardiovascular defects. In arrest during fetal development in mice. 302-316. 69th Annual Meeting of the Society-for- Biology of Reproduction 82: 433-443. Developmental-Biology/Japanese-Society- McMahon, S.K., Pretorius, C.J., of-Developmental-Biologists, AUG 05-09, Stark, M.S., Tyagi, S., Nancarrow, D.J., Ungerer, J.P.J., Salmon, N.J., Conwell, 2010, (480-481), Albuquerque NM. Boyle, G.M., Cook, A.L., Whiteman, L.S., Pearen, M.A., and Batch, J.A. D.C., Parsons, P.G., Schmidt, C., (2010). Neonatal Complete Generalized Polanco, J.C., Wilhelm, D., Davidson, T.L., Sturm, R.A., and Hayward, N.K. (2010). Glucocorticoid Resistance and Growth Knight, D., and Koopman, P. (2010). Sox10 Characterization of the melanoma Hormone Deficiency Caused by a gain-of-function causes XX sex reversal in miRNAome by deep sequencing. PLoS Novel Homozygous Mutation in Helix mice: implications for human 22q-linked One 5: e9685-1-e9685-9. 12 of the Ligand Binding Domain of the disorders of sex development. Human Glucocorticoid Receptor Gene (NR3C1). Molecular Genetics 19: 506-516. 107 publications

Publications 2010

MOLECULAR GENETICS AND Falconer, R.J., and Collins, B.M. (2010). DEVELOPMENT (CONTINUED) Survey of the year 2009: applications of isothermal titration calorimetry. Journal of Molecular Recognition 24: 1-24. Takizawa, F., Kashimada, K., Enomoto, K., Miyai, K., Ono, M., Asada, G., Falconer, R.J., Penkova, A., Jelesarov, Shimizu, J., and Mizutani, S. (2010). Two I., and Collins, B.M. (2010). Survey of preterm infants with late onset circulatory the year 2008: applications of isothermal collapse induced by levothyroxine sodium. titration calorimetry. Journal of Molecular Pediatrics International 52: e154-e157. Recognition 23: 395-413. Tallack, M.R., Whitington, T., Yuen, W.S., Gazdag, E.M., Cirstea, I.C., Breitling, Wainwright, E.N., Keys, J.R., Gardiner, ANDREW NOSKE: R., Lukes, J., Blankenfeldt, W., and APPROACHING A BETA CELL B.B., Nourbakhsh, E., Cloonan, N., Alexandrov, K. (2010). Purification This image is a rendering of a pancreatic Grimmond, S.M., Bailey, T.L., and Perkins, and crystallization of human Cu/Zn beta cell imaged at high resolution in A.C. (2010). A global role for KLF1 in true 3D using whole cell tomography superoxide dismutase recombinantly erythropoiesis revealed by ChIP-seq in with a transmission electron microscope. produced in the protozoan Leishmania primary erythroid cells. Genome Research As the first mammalian cell imaged in tarentolae. Acta Crystallographica Section 20: 1052-1063. its entirety at 15-20nm resolution, it F – Structural Biology and Crystallization highlights how complex and crowded Communications 66: 871-877. Tschopp, J., and Schroder, K. (2010). the internal organisation of a cell can be. NLRP3 inflammasome activation: The Gillespie, L.K., Hoenen, A., Morgan, convergence of multiple signalling G., and Mackenzie, J.M. (2010). The pathways on ROS production? Nature Endoplasmic Reticulum Provides the Reviews Immunology 10: 210-215. Membrane Platform for Biogenesis of the MOLECULAR CELL BIOLOGY Flavivirus Replication Complex. Journal of Villani, R.M., Adolphe, C., Palmer, J., Virology 84: 10438-10447. Waters, M.J., and Wainwright, B.J. (2010). Abankwa, D., Gorfe, A.A., Inder, K., and Patched1 Inhibits Epidermal Progenitor Hancock, J.F. (2010). Ras membrane Han, G.A., Malintan, N.T., Collins, Cell Expansion and Basal Cell Carcinoma orientation and nanodomain localization B.M., Meunier, F.A., and Sugita, S. Formation by Limiting Igfbp2 Activity. generate isoform diversity. Proceedings of (2010). Munc18-1 as a key regulator of Cancer Prevention Research 3: 1222- the National Academy of Sciences of the neurosecretion. Journal of Neurochemistry 1234. United States of America 107: 1130-1135. 115: 1-10. Wainwright, E.N., and Wilhelm, D. Ariotti, N., Liang, H., Xu, Y., Zhang, Y., Han, S.P., Friend, L.R., Carson, J.H., (2010). The game plan: cellular and Yonekubo, Y., Inder, K., Du, G., Parton, Korza, G., Barbarese, E., Maggipinto, molecular mechanisms of mammalian R.G., Hancock, J.F., and Plowman, S.J. M., Hatfield, J.T., Rothnagel, J.A., and testis development. Organogenesis in (2010). Epidermal growth factor receptor Smith, R. (2010). Differential subcellular Development 90: 231-262. activation remodels the plasma membrane distributions and trafficking functions of lipid environment to induce nanocluster hnRNP A2/B1 spliceoforms. Traffic 11: Wang, S.-C.M., Myers, S., Dooms, C., formation. Molecular and Cellular Biology 886-898. Capon, R., and Muscat, G.E.O. (2010). An 30: 3795-3804. ERRB/gamma agonist modulates GRalpha Howes, M.T., Kirkham, M., Riches, J., expression, and glucocorticoid responsive Bastiani, M., and Parton, R.G. (2010). Cortese, K., Walser, P.J., Simpson, F., Hill, gene expression in skeletal muscle cells. Caveolae at a glance. Journal of Cell M.M., Jones, A., Lundmark, R., Lindsay, Molecular and Cellular Endocrinology 315: Science 123: 3831-3836. M.R., Hernandez-Deviez, D.J., Hadzic, G., 146-152. Brooks, A.J., and Waters, M.J. (2010). The McCluskey, A., Bashir, R., Liu, L., Pilch, P., McMahon, H., Robinson, P.J., Hancock, Wicking, C. (2010). Embryos direct the growth hormone receptor: mechanism of J.F., Mayor, S., and Parton, R.G. (2010). traffic. Traffic 11: 1263-1264. activation and clinical implications. Nature Reviews Endocrinology 6: 515-525. Clathrin-independent carriers form a high Williams, T.M., Little, M.H., and Ricardo, capacity endocytic sorting system at the S.D. (2010). Macrophages in Renal Crouthamel, M., Abankwa, D., Zhang, leading edge of migrating cells. Journal of Development, Injury, and Repair. Seminar in L., DiLizio, C., Manning, D.R., Hancock, Cell Biology 190: 675-691. Nephrology 30: 255-267. J.F., and Wedegaertner, P.B. (2010). An N-Terminal Polybasic Motif of G alpha(q) Howes, M.T., Mayor, S., and Parton, Winkler, I.G., Sims, N.A., Pettit, A.R., Is Required for Signaling and Influences R.G. (2010). Molecules, mechanisms, Barbier, V., Nowlan, B., Helwani, F., Membrane Nanodomain Distribution. and cellular roles of clathrin-independent Poulton, I.J., van Rooijen, N., Alexander, Molecular Pharmacology 78: 767-777. endocytosis. Current Opinion In Cell K.A., Raggatt, L.J., and Levesque, J.-P. Biology 22: 519-527. (2010). Bone marrow macrophages Evesson, F.J., Peat, R.A., Lek, A., Brilot, F., Jackson, L.P., Kelly, B.T., McCoy, A.J., maintain hematopoietic stem cell (HSC) Lo, H.P., Dale, R.C., Parton, R.G., North, Gaffry, T., James, L.C., Collins, B.M., niches and their depletion mobilizes HSCs. K.N., and Cooper, S.T. (2010). Reduced Honing, S., Evans, P.R., and Owen, D.J. Blood 116: 4815-4828. plasma membrane expression of dysferlin mutants is attributed to accelerated (2010). A large-scale conformational endocytosis via a syntaxin-4-associated change couples membrane recruitment to Pathway. Journal of Biological Chemistry cargo binding in the AP2 clathrin adaptor 285: 28529-28539. complex. Cell 141: 1220-1229. imb annual report 2010 108

Jeffery, J.M., Urquhart, A.J., Subramaniam, Naughtin, M.J., Sheffield, D.A., Rahman, Reefman, E., Kay, J.G., Wood, S.M., V.N., Parton, R.G., and Khanna K.K. P., Hughes, W.E., Gurung, R., Stow, Offenhauser, C., Brown, D.L., Roy, S., (2010). Centrobin regulates the assembly J.L., Nandurkar, H.H., Dyson, J.M., and Stanley, A.C., Low, P.C., Manderson, of functional mitotic spindles. Oncogene Mitchell, C.A. (2010). The myotubularin A.P., and Stow, J.L. (2010). Cytokine 29: 2649-2658. phosphatase MTMR4 regulates sorting Secretion Is Distinct from Secretion of from early endosomes. Journal of Cell Cytotoxic Granules in NK Cells. Journal of Koutsopoulos, O.S., Laine, D., Osellame, Science 123: 3071-3083. Immunology 184: 4852-4862. L., Chudakov, D.M., Parton, R.G., Frazier, A.E., and Ryan, M.T. (2010). Human Nguyen, U.T.T., Goody, R.S., and Schieber, N.L., Nixon, S.J., Webb, R.I., Miltons associate with mitochondria and Alexandrov, K. (2010). Understanding Oorschot, V.M.J., and Parton, R.G. (2010). induce microtubule-dependent remodeling and exploiting protein prenyltransferases. Modern approaches for ultrastructural of mitochondrial networks. Biochemicia et ChemBioChem 11: 1194-1201. analysis of the zebrafish embryo. In Biophysica Acta - Molecular Cell Research Thomas Mller-Reichert, Leslie Wilson and Nguyen, U.T.T., Wu, Y., Goodall, A., and 1803: 564-574. Paul Matsudaira (Ed.), Electron Microscopy Alexandrov, K. (2010). Analysis of Protein of Model Systems (pp. 425-442) Kovtun, O., Mureev, S., Johnston, W.A., Prenylation In Vitro and In Vivo Using Amsterdam, Netherlands: Academic Press and Alexandrov, K. (2010). Towards the Functionalized Phosphoisoprenoids. construction of expressed proteomes using Current Protocols in Protein Science 14: Smutny, M., Cox, H.L., Leerberg, J.M., a Leishmania tarentolae-based cell-free 14.3.1-14.3.15. Kovacs, E.M., Conti, M.A., Ferguson, C., expression system. PLoS One 5: e14388- Hamilton, N.A., Parton, R.G., Adelstein, 1-e14388-11. Owen, D.J., and Collins, B.M. (2010). R.S., and Yap, A.S. (2010). Myosin II Vesicle Transport: A New Player in isoforms identify distinct functional modules Kubala, M.H., Kovtun, O., Alexandrov, K., APP Trafficking. Current Biology 20: that support integrity of the epithelial zonula and Collins, B.M. (2010). Structural and R413-R415. adherens. Nature Cell Biology 12: 696-702. thermodynamic analysis of the GFP:GFP- Parton, R.G., and Howes, M.T. (2010). nanobody complex. Protein Science 19: Smutny, M., and Yap, A.S. (2010). 2389-2401. Revisiting caveolin trafficking: the end of Neighborly relations: Cadherins and the caveosome. Journal of Cell Biology mechanotransduction. Journal of Cell Low, P.C., Misaki, R., Schroder, K., : 439-441. 191 Biology 189: 1075-1077. Stanley, A.C., Sweet, M.J., Teasdale, R.D., Vanhaesebroeck, B., Meunier, Puthenveedu, M.A., Lauffer, B., Temkin, P., Stanley, A.C., and Lacy, P. (2010). F.A., Taguchi, T., and Stow, J.L. (2010). Vistein, R., Carlton, P., Thorn, K., Taunton, Pathways for Cytokine Secretion. J., Weiner, O.D., Parton, R.G., and von Phosphoinositide 3-kinase delta regulates Physiology 25: 218-229. membrane fission of Golgi carriers for Zastrow, M. (2010). Sequence-Dependent selective cytokine secretion. Journal of Cell Sorting of Recycling Proteins by Actin- Tian, T.H., Plowman, S.J., Parton, R.G., Stabilized Endosomal Microdomains. Cell Kloog, Y., and Hancock, J.F. (2010). Biology 190: 1053-1065. 143: 761-773. Mathematical Modeling of K-Ras Meeths, M., Bryceson, Y.T., Rudd, E., Nanocluster Formation on the Plasma Quinlan, K.G.R., Seto, J.T., Turner, N., Zheng, C.Y., Wood, S.M., Ramme, K., Membrane. Biophysical Journal 99: 534- Beutel, K., Hasle, H., Heilmann, C., Vandebrouck, A., Floetenmeyer, M., 543. Hultenby, K., Ljunggren, H.G., Fadeel, B., Macarthur, D.G., Raftery, J.M., Lek, M., Nordenskjold, M., and Henter, J.I. (2010). Yang, N., Parton, R.G., Cooney, G.J., Veale, K.J., Offenhauser, C., Whittaker, Clinical Presentation of Griscelli Syndrome and North, K.N. (2010). alpha-Actinin-3 S.P., Estrella, R.P., and Murray, R.Z. Type 2 and Spectrum of RAB27A deficiency results in reduced glycogen (2010). Recycling Endosome Membrane phosphorylase activity and altered calcium Incorporation into the Leading Edge Mutations. Pediatric Blood and Cancer 54: 563-572. handling in skeletal muscle. Human Regulates Lamellipodia Formation and Molecular Genetics 19: 1335-1346. Macrophage Migration. Traffic 11: 1370- Micaroni, M. (2010). The Role of Calcium in 1379. Intracellular Trafficking. Current Molecular Rae, J., Fontaine, F.R., Salim, A., Lo, H., Capon, R., and Martin, S. (2010). High- Medicine 10: 763-773. throughput screening of Australian marine Micaroni, M., Perinetti, G., Di organism extracts for bioactive molecules Giandomenico, D., Bianchi, K., Spaar, A., affecting the cellular storage of neutral and Mironov, A.A. (2010). Synchronous lipids. PLoS One : . 8 intra-Golgi transport induces the release of Ca2+ from the Golgi apparatus. Ratheesh, A., and Yap, A.S.K. (2010). Doing cell biology in embryos: regulated Experimental Cell Research 316: 2071- 2086. membrane traffic and its implications for cadherin biology. F1000 Biology Reports Misaki, R., Morimatsu, M., Uemura, T., 2: 30. Waguri, S., Miyoshi, E., Taniguchi, N., Matsuda, M., and Taguchi, T. (2010). SUSAN NIXON: TRACKS Palmitoylated Ras proteins traffic through Mirror image of developing muscle in a recycling endosomes to the plasma zebrafish embryo. membrane during exocytosis. Journal of Cell Biology 191: 23-29. 109 publications

Publications 2010

MOLECULAR CELL BIOLOGY Burman, R., Gruber, C.W., Rizzardi, K., (CONTINUED) Herrmann, A., Craik, D.J., Gupta, M.P., and Goransson, U. (2010). Cyclotide proteins and precursors from the Weinrich, D., Lin, P.-C., Jonkheijm, P., genus Gloeospermum: Filling a blank Nguyen, U.T., Schroder, H., Niemeyer, spot in the cyclotide map of Violaceae. C.M., Alexandrov, K., Goody, R., Phytochemistry 71: 13-20. and Waldmann, H. (2010). Oriented Immobilization of Farnesylated Proteins Burman, R., Svedlund, E., Felth, J., by the Thiol-Ene Reaction. Angewandte Hassan, S., Hermann, A., Clark, R.J., Chemie International Edition 49: 1252- Craik, D.J., Bohlin, L., Claeson, P., 1257. Goransson, U., and Gullbo, J. (2010). ANDREW RINGSMUTH: PHOTOFUEL FUTURE Evaluation of toxicity and anti-tumour Weller, S.G., Capitani, M., Cao, H., activity of cycloviolacin O2 in mice. In: This piece depicts the potential for Micaroni, M., Luini, A., Sallese, M., and Peptide Science. Proceedings of the photosynthetic bio-fuels to ease the McNiven, M.A. (2010). Src kinase regulates 1st International Conference on Circular the integrity and function of the Golgi impending transition from a fossil oil- based global economy to a carbon- Proteins. 1st International Conference apparatus via activation of dynamin 2. neutral future. The limitation in energy on Circular Proteins, Heron Island, Qld, Proceedings of the National Academy of availability caused by this peak is Australia, (626-634). 18-21 October, 2009. Sciences USA 107: 5863-5868. predicted to pose a major problem for 7 the global economy. Wu, Y.-W., Oesterlin, L.K., Tan, K.-T., Capon, R. (2010). Marine natural products Waldmann, H., Alexandrov, K., and chemistry: Past, present, and future. Goody, R.S. (2010). Membrane targeting Australian Journal of Chemistry 63: 851- mechanism of Rab GTPases elucidated CHEMISTRY AND STRUCTURAL 854. by semisynthetic protein probes. Nature Chemical Biology 6: 534-540. BIOLOGY Cascales, L., and Craik, D.J. (2010). Alewood, D., Hopping, G., Brust, A., Naturally occurring circular proteins: Yan, Y., Johnston, A.P.R., Dodds, S.J., Reid, R.C., and Alewood, P.F. (2010). Distribution, biosynthesis and evolution. Kamphuis, M.M.J., Ferguson, C., Parton, Benzhydrylamine linker grafting: A strategy Organic and Biomolecular Chemistry 8: R.G., Nice, E.C., Heath, J.K., and Caruso, for the improved synthesis of C-terminal 5035-5047. F. (2010). Uptake and Intracellular Fate peptide amides. Journal of Peptide of Disulfide-Bonded Polymer Hydrogel Science 16: 551-557. Christ, C.D., Mark, A.E., and van Capsules for Doxorubicin Delivery to Gunsteren, W.F. (2010). Feature Article Colorectal Cancer Cells. ACS Nano 4: Armishaw, C.J., Dutton, J.L., Craik, D.J., Basic Ingredients of Free Energy 2928-2936. and Alewood, P.F. (2010). Establishing Calculations: A Review. Journal of regiocontrol of disulfide bond isomers of Computational Chemistry 31: 1569-1582. Yang, N., Jiang, J., Deng, L.Q., Waters, alpha-conotoxin ImI via the synthesis of M.J., Wang, X.D., and Frank, S.J. (2010). N-to-C cyclic analogues. Biopolymers: Clark, R.J., and Craik, D.J. (2010). Native Growth hormone receptor targeting to Peptide Science 94: 307-313. chemical ligation applied to the synthesis lipid rafts requires extracellular subdomain and bioengineering of circular peptides and 2. Biochemical and Biophysical Research Balansa, W., Islam, R., Fontaine, F., proteins. Biopolymers 94: 414-422. Communications 391: 414-418. Piggott, A.M., Zhang, H., Webb, T.I., Gilbert, D.F., Lynch, J.W., and Capon, R.J. Clark, J., Jensen, J., Nevin, S., Brid, C., Zallen, J.A., and Yap, A.S.K. (2010). (2010). Ircinialactams: Subunit-selective Adams, D., and Craik, D. (2010). The Morphogenesis in Kyoto: A confluence of glycine receptor modulators from Australian Engineering of an Orally Active Conotoxin cell an developmental biology. Molecular sponges of the family Irciniidae. Bioorganic for the Treatment of Neuropathic Pain. Biology of The Cell 21: 845-847. and Medicinal Chemistry 18: 2912-2919. Agnew Chemie International Edition 49: 6545-6548. Barry, G.D., Suen, J.Y., Le, G.T., Cotterell, A., Reid, R.C., and Fairlie, D.P. (2010). Colgrave, M.L., Huang, Y.-H., Craik, Novel agonists and antagonists or human D.J., and Kotze, A.C. (2010). Cyclotide protease activated receptor 2. Journal of interactions with the nematode external Medicinal Chemistry 53: 7428-7440. surface. Antimicrobial Agents and Chemotherapy 54: 2160-2166. Batchelor, M., Zhou, D., Cooper, M.A., Abell, C., and Rayment, T. (2010). Colgrave, M., Korsinczky, M.L.J., Clark, Vancomycin dimer formation between R.J., Foley, F., and Craik, D.J. (2010). analogues of bacterial peptidoglycan Sunflower trypsin inhibitor-1, proteolytic surfaces probed by force spectroscopy. studies on a trypsin inhibitor peptide Organic and Biomolecular Chemistry 8: and its analogs. In: , Peptide Science. 1142-1148. Proceedings of the 1st International Conference on Circular Proteins. 1st International Conference on Circular Proteins, Heron Island, Qld, Australia, (665- 672). 18-21 October 2009 imb annual report 2010 110

Colgrave, L., Poth, A., Kaas, Q., and Craik, Dekan, Z., Andersson, A.C., Lewis, R.J., Grice, D.M., Vetter, I., Faddy, H.M., D. (2010). Advances in MS/MS Sequencing and Alewood, P.F. (2010). Replacement Kenny, P.A., Roberts-Thomson, S.J., of Cyclic Peptides: What’s around the of disulfide bonds with ditellurides: and Monteith, G.R. (2010). Golgi calcium Bend? Journal of Peptide Science 16: 113. Synthesis and biological activity of ditelluro- pump secretory Pathway calcium ATPase oxytocin. In The 31st European Peptide 1 (SPCA1) is a key regulator of Insulin- Colgrave, M.L., Poth, A.G., Kaas, Q., Symposium, 5-9 September 2010, (60-60), like Growth Factor Receptor (IGF1R) and Craik, D.J. (2010). A new “Era” for Copenhagen, Denmark. processing in the basal-like breast cancer cyclotide sequencing. In: , Biopolymers cell line MDA-MB-231. Journal of Biological Peptide Science. Ist International Doebbe, A., Keck, M., La Russa, M., Chemistry 285: 37458-3746. Conference on Circular Proteins, Heron Mussgnug, J.H., Hankamer, B., Tekce, Island, Qld, Australia, (592-601). 18-21 E., Niehaus, K., and Kruse, O. (2010). Grishin, A., Wang, C.-I.A., Muttenthaler, October, 2009 The Interplay of Proton, Electron, and M., Alewood, P.F., Lewis, R.J., and Adams, Metabolite Supply for Photosynthetic H-2 D.J. (2010). alpha-Conotoxin AuIB isomers Conlan, B.F., Gillon, A.D., Craik, D.J., Production in Chlamydomonas reinhardtii. exhibit distinct inhibitory mechanisms and Anderson, M.A. (2010). Circular Journal of Biological Chemistry 285: and differential sensitivity to stoichiometry proteins and mechanisms of cyclization. 30247-30260. of alpha 3 beta 4 nicotinic acetylcholine In: Peptide Science. Proceedings of the receptors. Journal of Biological Chemistry 1st International Conference on Circular Drinkwater, N., Vu, H., Lovell, K.M., 285: 22254-22263. Proteins. 1st International Conference Criscione, K.R., Collins, B.M., Prisinzano, on Circular Proteins, Heron Island, Qld, T.E., Pulsen, S., McLeish, M.J., Grunewald, Groothuizen, F.S., Poger, D., and Mark, Australia, (573-583). 18-21 October, 2009 G.L., and Martin, J.L. (2010). Fragment- A.E. (2010). Activating the prolactin based screening by X-ray crystallography, receptor: Effect of the ligand on the Cooper, M. (2010). How to stress MS and isothermal titration calorimetry conformation of the extracellular superbugs. Australasian Science 31: 31- to identify PNMT (phenylethanolamine domain. Journal of Chemical Theory and 32. N-methyltransferase) inhibitors. Computation 6: 3274-3283. Biochemical Journal 431: 51-61. Cooper, M., and Mayr, L.M. Label-Free Gruber, C.W., Muttenthaler, M., and Technologies for Drug Discovery. Edited Dunse, K.M., Kaas, Q., Guarino, R.F., Freissmuth, M. (2010). Ligand-Based by Cooper, Matthew and Mayr ,Lorenz M Barton, P.A., Craik, D.J., and Anderson, Peptide Design and Combinatorial Peptide United States: John Wiley & Sons, 2010. M.A. (2010). Molecular basis for the Libraries to Target G Protein-Coupled Craik, D.J. (2010). Discovery and resistance of an insect chymotrypsin Receptors. Current Pharmaceutical Design applications of the plant cyclotides. Toxicon to a potato type II proteinase inhibitor. 16: 3071-3088. 56: 1092-1102. Proceedings of the National Academy of Sciences of the United States of America Gupta, P.K., Reid, R.C., Liu, L., Lucke, A.J., Broomfield, S.A., Andrews, M.R., Craik, D.J. (2010). Forward for ICCP2009 107: 15016-15021. Issue of Biopolymers Peptide Science. Sweet, M.J., and Fairlie, D.P. (2010). Biopolymers 94: III-V. Dutertre, S., and Lewis, R.J. (2010). Use Inhibitors selective for HDAC6 in enzymes of venom peptides to probe ion channel and cells. Bioorganic & Medicinal Craik, D. (2010). PepTalk - CHI’s Ninth structure and function. Journal of Biological Chemistry Letters 20: 7067-7070. Annual Meeting Engineering Protein & Chemistry 285: 13315-13320. Peptide Therapeutics: Peptides 14-15 January 2010, San Diego, CA, USA. I El-Naggar, M., Conte, M., and Capon, Drugs: The Investigational Drugs Journal R.J. (2010). Mirabilins revisited: Polyketide 13: 156-158. alkaloids from a southern Australian marine sponge, Clathria sp. Organic and Craik, D.J., Mylne, J.S., and Daly, N.L. Biomolecular Chemistry 8: 407-412. (2010). Cyclotides: macrocyclic peptides with applications in drug design and Forwood, J.K., Lange, A., Zachariae, U., agriculture. Cellular and Molecular Life Marfori, M., Preast, C., Grubmuller, H., Sciences 67: 9-16. Stewart, M., Corbett, A.H., and Kobe, B. (2010). Quantitative Structural Analysis Daly, N.L., Chen, B., Nguyencong, P., and of Importin-beta Flexibility: Paradigm for Craik, D.J. (2010). Structure and activity of MAGGIE HARDY: Solenoid Protein Structures. Structure 18: THE DOSE MAKES THE POISON the leaf-specific cyclotide vhl-2. Australian 1171-1183. Journal of Chemistry 63: 771-778. Paracelsus was among the first Gentz, M.C., Murdoch, G., and King, scientists to realise that anything can Daly, N.L., Lovelace, E., Gunasekera, G.F. (2010). Tandem use of selective be poisonous, and harm or good to the patient depends on the dose. Recently, S., Alvarmo, C., Clark, R., Nevin, S., insecticides and natural enemies for Grishin, A., Adams, D., and Craik, D. drugs to lower blood pressure have effective, reduced-risk pest management. been developed from the venom (2010). Stabilization of a-conotoxin AulB: Biological Control 52: 208-215. of vipers, and medications to treat influences of disulfide connectivity and people’s chronic pain could be isolated backbone cyclization. Antioxidants and from the venom of cone snails and Redox Signaling 14: 87-96. spiders. My PhD research is focused on isolating novel, environmentally- friendly insecticides from the venom of native Australian spiders. 111 publications

Publications 2010

CHEMISTRY AND STRUCTURAL Ireland, D.C., Clark, R.J., Daly, N.L., and Landsberg, M.J., Ruggles, J.L., Hussein, BIOLOGY (CONTINUED) Craik, D.J. (2010). Isolation, sequencing, W.M., McGeary, R.P., Gentle, I.R., and and structure - Activity relationships of Hankamer, B. (2010). Molecular Packing Halili, M.A., Andrews, M.R., Labzin, L.I., cyclotides. Journal of Natural Products 73: of Functionalized Fluorinated Lipids in Schroder, K., Matthias, G., Cao, C., 1610-1622. Langmuir Mono layers. Langmuir 26: 18868-18873. Lovelace, E., Reid, R.C., Le, G.T., Hume, Iyer, A., Fairlie, D.P., Prins, J.B., Hammock, D.A., Irvine, K.M., Matthias, P., Fairlie, B.D., and Brown, L. (2010). Inflammatory Lewis, R.J., and Poli, M. (2010). Toxins in D.P., and Sweet, M.J. (2010). Differential lipid mediators in adipocyte function and Seafood. Toxicon 56: 107. effects of selective HDAC inhibitors on obesity. Nature Reviews Endocrinology 6: macrophage inflammatory responses to 71-82. Liebscher, S., Stoermer, M.J., Watterson, the Toll-like receptor 4 agonist LPS. Journal D., Chappell, K.J., Webb, R.I., Khromykh, of Leukocyte Biology 87: 1103-1114. Iyer, A., Fenning, A., Lim, J., Le, G.T., A.A., Fairlie, D.P., and Young, P.R. (2010). Reid, R.C., Halili, M.A., Fairlie, D.P., and Sneaking up on West Nile Virus NS2B/ Harrison, R.S., Ruiz-Gomez, G., Hill, T.A., Brown, L. (2010). Antifibrotic activity of an NS3 protease subcellular activity utilising Chow, S.Y., Shepherd, N.E., Lohman, inhibitor of histone deacetylases in DOCA- dye-quenched substrates. In: Plusstrand R.J., Abbenante, G., Hoang, H.N., and salt hypertensive rats. British Journal of 2010: The Ninth International Symposium Fairlie, D.P. (2010). Novel Helix-Constrained Pharmacology 159: 1408-1417. on Positive-Strand RNA Viruses, Atlanta, Nociceptin Derivatives Are Potent Agonists GA, U.S.A.,17-21 May 2010 and Antagonists of ERK Phosphorylation Jarrott, R., Shouldice, S.R., Guncar, G., and Thermal Analgesia in Mice. Journal of Totsika, M., Schembri, M.A., and Heras, Loo, D., Jones, A., and Hill, M.M. (2010). Medicinal Chemistry 53: 8400-8408. B. (2010). Expression and crystallization Lectin magnetic bead array for biomarker of SeDsbA, SeDsbL and SeSrgA from discovery. Journal of Proteome Research Harrison, R.S., Shepherd, N.E., Hoang, Salmonella enterica serovar Typhimurium. 9: 5496-5500. H.N., Ruiz-Gomez, G., Hill, T.A., Driver, Acta Crystallographica Section F: R.W., Desai, V.S., Young, P.R., Abbenante, Structural Biology and Crystallization Loser, R., Abbenante, G., Madala, P.K., Halili, M., Le, G.T., and Fairlie, D.P. (2010). G., and Fairlie, D.P. (2010). Downsizing Communications 66: 601-604. human, bacterial, and viral proteins to short Noncovalent tripeptidyl benzyl- And water-stable alpha helices that maintain Johnstone, K.D., Karoli, T., Liu, L., Dredge, cyclohexyl-amine inhibitors of the cysteine biological potency. Proceedings of the K., Copeman, E., Li, C.P., Davis, K., protease caspase-1. Journal of Medicinal National Academy of Sciences of the Hammond, E., Bytheway, I., Kostewicz, E., Chemistry 53: 2651-2655. United States of America 107: 11686- Chiu, F.C.K., Shackleford, D.M., Charman, Loser, R., Gut, J., Rosenthal, P.J., Frizler, 11691. S.A., Charman, W.N., Harenberg, J., Gonda, T.J., and Ferro, V. (2010). Synthesis M., Gutschow, M., and Andrews, K.T. Henriques, S.T., and Castanho, M.A.R.B. and Biological Evaluation of Polysulfated (2010). Antimalarial activity of azadipeptide (2010). Is PrP(106-126) Fragment Involved Oligosaccharide Glycosides as Inhibitors of nitriles. Bioorganic and Medicinal in the Membrane Activity of the Prion Angiogenesis and Tumor Growth. Journal Chemistry Letters 20: 252-255. Protein? Current Protein and Peptide of Medicinal Chemistry 53: 1686-1699. Loughlin, W.A., Tyndall, J.D.A., Glenn, M.P., Science 5: 326-333. Kaas, Q., and Craik, D.J. (2010). Analysis Hill, T.A., and Fairlie, D.P. (2010). Update Henriques, S.T., Tan, C.C., Craik, D.J., and classification of circular proteins in 1 of: Beta-strand mimetics. Chemical and Clark, R.J. (2010). Structural and CyBase. In: , Biopolymers Peptide Science. Reviews 110: 1-38. Functional Analysis of Human Liver- Ist International Conference on Circular Luo, S., Akondi, K.B., Zhangsun, D., Wu, Expressed Antimicrobial Peptide 2. Proteins, Heron Island, Qld, Australia, (584- Y., Zhu, X., Hu, Y., Christensen, S., Dowell, Chembiochem 11: 2148-2157. 591). 18-21 October, 2009 C., Daly, N.L., Craik, D.J., Wang, C.-I.A., Heras, B., Totsika, M., Jarrott, R., Kaas, Q., Westermann, J.-C., and Craik, Lewis, R.J., Alewood, P.F., and McIntosh, Shouldice, S.R., Guncar, G., Achard, D.J. (2010). Conopeptide characterization J. M. (2010). Atypical alpha-conotoxin M.E.S., Wells, T.J., Argente, M.P., and classifications: An analysis using LtIA from Conus litteratus targets a novel microsite of the alpha 3 beta 2 nicotinic McEwan, A.G., and Schembri, M.A. (2010). ConoServer. Toxicon 55: 1491-1509. Structural and Functional Characterization receptor. Journal of Biological Chemistry of Three DsbA Paralogues from Salmonella Khambati, H.K., Moraes, T.F., Singh, J., 285: 12355-12366. enterica Serovar Typhimurium. Journal of Shouldice, S.R., Yu, R.H., and Schryvers, Madala, P., Tyndall, J., David, A., Nall, Biological Chemistry 285: 18423-18432. A.B. (2010). The role of vicinal tyrosine residues in the function of Haemophilus T., and Fairlie, D. (2010). Update 1 of: Huang, Y.-H., Colgrave, M.L., Clark, influenzae ferric-binding protein A. Proteases universally recognize Beta Strands in their active sites. Chemical R.J., Kotze, A.C., and Craik, D.J. (2010). Biochemical Journal 432: 57-64. Lysine-scanning mutagenesis reveals an Reviews 110: 1-33. amendable face of the cyclotide kalata B1 Kirkby, B., Roman, N., Kobe, B., Kellie, Marles-Wright, J., and Lewis, R.J. (2010). for the optimization of nematocidal activity. S., and Forwood, J.K. (2010). Functional The stressosome: molecular architecture Journal of Biological Chemistry 285: and structural properties of mammalian of a signalling hub. Biochemical Society 10797-10805. acyl-coenzyme A thioesterases. Progress Transactions : 928-933. in Lipid Research 49: 366-377. 38 Kruse, O., and Hankamer, B. (2010). Microalgal hydrogen production. Current Opinion In Biotechnology 21: 238-243. imb annual report 2010 112

Mobli, M., and King, G.F. (2010). NMR Muttenthaler, M.M., de Araujo, A.D., methods for determining disulfide-bond Andersson, A., Vetter, I., Gruber, C., connectivities. Toxicon 56: 849-854. Ramos, Y.G., Feytens, D., Bergmayr, C., Freissmuth, M., Lewis, R., and Alewood, Mobli, M., Stern, A.S., Bermel, W., King, P. (2010). Oxytocin agonist design - A G.F., and Hoch, J.C. (2010). A non- selenocysteine mimetic reveals a functional uniformly sampled 4D HCC(CO)NH-TOCSY selectivity switch for the human oxytocin experiment processed using maximum receptor. In The 31st European Peptide entropy for rapid protein sidechain Symposium, 5-9 September 2010, (161- assignment. Journal of Magnetic Resonance 161), Copenhagen, Denmark. 204: 160-164. Muttenthaler, M., Nevin, S.T., Grishin, EMILY KNAUTH: STACKED UP Moloney, G.P., Iskander, M.N., and Craik, A.A., Ngo, S.T., Choy, P.T., Daly, N.L., Plants and algae have a particular D.J. (2010). Stability studies of oxazolidine- Hu, S.-H., Armishaw, C.J., Wang, C.I.A., interesting internal structure, especially based compounds using 1H NMR Lewis, R.J., Martin, J.L., Noakes, P.G., inside the thylakoid membrane. The spectroscopy. Journal of Pharmaceutical Craik, David J., Adams, D.J., and Alewood, structures, proteins and pigments here give these organisms their well known Sciences 99: 3362-3371. P.F. (2010). Solving the -conotoxin folding green colour. In particular, the thylakoid Morales, R.A.V., Daly, N.L., Vetter, I., Mobli, problem: Efficient selenium-directed on- membrane shown here forms stacks M., Napier, I.A., Craik, D.J., Lewis, R.J., resin generation of more potent and stable which help these algae capture the Christie, M.J., King, G.F., Alewood, P.F., nicotinic acetylcholine receptor antaqonists. maximum amount of light possible. and Durek, T. (2010). Chemical synthesis Journal of the American Chemical Society and structure of the prokineticin Bv8. 132: 3514-3522. ChemBioChem 11: 1882-1888. Muttenthaler, M., Ramos, Y.G., Feytens, D., Morrow, C.A., Stamp, A., Valkov, E., de Araujo, A.D., and Alewood, P.F. (2010). Plan, M., Rosengren, K.J., Sando, L., Daly, Kobe, B., and Fraser, J.A. (2010). p-Nitrobenzyl Protection for Cysteine and N.L., and Craik, D.J. (2010). Structural Crystallization and preliminary X-ray Selenocysteine: A More Stable Alternative to and biochemical characteristics of the analysis of mycophenolic acid-resistant the Acetamidomethyl Group. Biopolymers cyclotide kalata B5 from Oldenlandia affinis. and mycophenolic acid-sensitive forms 94: 423-432. In: Peptide Science. Proceedings of the of IMP dehydrogenase from the human Mylne, J.S., Wang, C., van der Weerden, 1st International Conference on Circular fungal pathogen Cryptococcus. Acta N.L., and Craik, D.J. (2010). Cyclotides Proteins. 1st International Conference Crystallographica Section F - Structural are a component of the innate defense of on Circular Proteins, Heron Island, Qld, Biology and Crystallization Communications Oldenlandia affinis. In: , Peptide Science. Australia, (647-658). 18-21 October 2009 66: 1104-1107. Proceedings of the 1st International Poger, D., and Mark, A.E. (2010). Turning Morweiser, M., Kruse, O., Hankamer, B., Conference on Circular Proteins. 1st the growth hormone receptor on: Evidence and Posten, C. (2010). Developments and International Conference on Circular that hormone binding induces subunit perspectives of photobioreactors for biofuel Proteins, Heron Island, Qld, Australia, (635- rotation. Proteins – Structure, Function and production. Applied Microbiology and 645). 18-21 October, 2009 Bioinformatics 78: 1163-1174. Biotechnology 87: 1291-1301. Nguyen-Huu, T.D., Mattei, C., Wen, P.J., Poger, D., Van Gunsteren, W.F., and Mulvenna, J., Moertel, L., Jones, M.K., Bourdelais, A.J., Lewis, R.J., Benoit, E., Mark, A.E. (2010). A New Force Field for Nawaratna, S., Lovas, E.M., Gobert, G.N., Baden, D.G., Molg, J., and Meunier, F.A. Simulating Phosphatidylcholine Bilayers. Colgrave, M., Jones, A., Loukas, A., and (2010). Ciguatoxin-induced catecholamine Journal of Computational Chemistry 31: McManus, D.P. (2010). Exposed proteins secretion in bovine chromaffin cells: 1117-1125. of the Schistosoma japonicum tegument. Mechanism of action and reversible International Journal For Parasitology 40: inhibition by brevenal. Toxicon 56: 792-796. Pomorska, A., Shchukin, D., Hammond, 543-554. Pang, S.S., Berry, R., Chen, Z.J., Kjer- R., Cooper, M.A., Grundmeier, G., and Johannsmann, D. (2010). Positive Mulvenna, J., Sripa, B., Brindley, P.J., Nielsen, L., Perugini, M.A., King, G.F., Frequency Shifts Observed Upon Adsorbing Gorman, J., Jones, M.K., Colgrave, Wang, C., Chew, S.H., La Gruta, N.L., Micron-Sized Solid Objects to a Quartz M.L., Jones, A., Nawaratna, S., Laha, T., Williams, N.K., Beddoe, T., Tiganis, T., Crystal Microbalance from the Liquid Phase. Suttiprapa, S., Smout, M.J., and Loukas, Cowieson, N.P., Godfrey, D.I., Purcell, Analytical Chemistry 82: 2237-2242. A. (2010). The secreted and surface A.W., Wilce, M.C.J., McCluskey, J., and proteomes of the adult stage of the Rossjohn, J. (2010). The structural basis for Qin, Q., McCallum, E.J., Kaas, Q., Suda, carcinogenic human liver fluke Opisthorchis autonomous dimerization of the pre-T-cell J., Saska, I., Craik, D.J., and Mylne, J.S. viverrini. Proteomics 10: 1063-1078. antigen receptor. Nature 467: 844-U110. (2010). Identification of candidates for Peng, C., Gunaherath, G.M., Kamal, B., cyclotide biosynthesis and cyclisation Piggott, A.M., Khalil, Z., Conte, M., and by expressed sequence tag analysis of Capon, R.J. (2010). 9-(5-Deoxy-5-thio- Oldenlandia affinis. BMC Genomics 11: 111. -d-xylofuranosyl)adenine disulfide from the Southern Australian marine sponge trachycladus laevispirulifer: The first natural occurrence of a nucleoside disulfide. Australian Journal of Chemistry 63: 873- 876. 113 publications

Publications 2010

CHEMISTRY AND STRUCTURAL Shouldice, S.R., Heras, B., Jarrott, R., Uluda, Y., Hammond, R., and Cooper, BIOLOGY (CONTINUED) Sharma, P., Scanlon, M.J., and Martin, M.A. (2010). A signal amplification assay J.L. (2010). Characterisation of the DsbA for HSV type 1 viral DNA detection using oxidative folding catalyst from pseudomonas nanoparticles and direct acoustic profiling. Raju, R., Piggott, A.M., Conte, M.M., and aerugionsa reveals a highly oxidizing protein Journal of Nanobiotechnology 8: 3. Capon, R.J. (2010). Heronamides A-C, new that binds small molecules. Antioxidants & Vetter, I., and Lewis, R.J. (2010). polyketide macrolactams from an Australian Redox Signaling 12: 921-931. marine-derived Streptomyces sp A Characterization of endogenous calcium biosynthetic case for synchronized tandem Soowannayan, C., Cowley, J.A., Pearson, responses in neuronal cell lines. Biochemical electrocyclization. Organic & Biomolecular R.D., Wallis, T.P., Gorman, J.J., Michalski, Pharmacology 79: 908-920. Chemistry 8: 4682-4689. W.P., and Walker, P.J. (2010). Glycosylation of gp116 and gp64 envelope proteins of Wang, C., Huang, Y.-H., Greenwood, K., Raju, R., Piggott, A.M., Conte, M., Tnimov, yellow head virus of Penaeus monodon and Craik, D.J. (2010). Membrane binding of cyclotides. In Miguel A.R.B. Castanho Z., Alexandrov, K., and Capon, R.J. (2010). shrimp. Journal of General Virology 91: Nocardiopsins: New FKBP12-binding 2463-2473. (Ed.), Membrane-Active peptides: Methods macrolide polyketides from an Australian and results on structure and function First marine-derived actinomycete, Nocardiopsis Stephens, E., Ross, I.L., King, Z., ed. (pp. 597-672) La Jolla, CA, U.S.A.: sp. Chemistry - A European Journal 16: Mussgnug, J.H., Kruse, O., Posten, C., International University Line 3194-3200. Borowitzka, M.A., and Hankamer, B. (2010). An economic and technical evaluation of Wang, C.I.A., and Lewis, R.J. (2010). Raju, R., Piggott, A.M., Diaz, L.X.B., Khalil, microalgal biofuels. Nature Biotechnology Emerging structure-function relationships defining monoamine NSS transporter Z., and Capon, R.J. (2010). Heronapyrroles 28: 126-128. A-C: Farnesylated 2-nitropyrroles from an substrate and ligand affinity. Biochemical Australian marine-derived Streptomyces sp.. Stephens, E., Ross, I.L., Mussgnug, J.H., Pharmacology 79: 1083-1091. Organic Letters 12: 5158-5161. Wagner, L.D., Brorwitzka, M.A., Posten, C., Kruse, O., and Hankamer, B. (2010). Future Weber, J.E., Oakley, A.J., Christ, A.N., Rowland, S.L., Wadsworth, K.D., Robson, prospects of microalgal biofuel production Hayes, J.D., Hall, R., Hume, D.A., Board, P.G., Smythe, M.L., and Flanagan, J.U. S.A., Robichon, C., Beckwith, J., and King, systems. Trends in Plant Science 15: 554- G.F. (2010). Evidence from artificial septal 564. (2010). Identification and characterisation of targeting and site-directed mutagenesis new inhibitors for the human hematopoietic that residues in the extracytoplasmic beta Stewart, I., Lewis, R.J., Eaglesham, G.K., prostaglandin D-2 synthase. European domain of DivIB mediate its interaction Graham, G.C., Poole, S., and Craig, S.B. Journal of Medicinal Chemistry 45: 447- with the divisomal transpeptidase PBP 2B. (2010). Emerging tropical diseases in 454. Journal of Bacteriology 192: 6116-6125. Australia. Part2. Ciguatera fish poisoning. Annals of Tropical Medicine & Parasitology Wheatley, N.C., Andrews, K.T., Tran, T.L., Lucke, A.J., Reid, R.C., and Fairlie, D.P. Ruiz-Gomez, G., Tyndall, J.D.A., Pfeiffer, 104: 557-571. B., Abbenante, G., and Fairlie, D. (2010). (2010). Antimalarial histone deacetylase Update 1 of: Over one hundred peptide- Tang, J., Wang, C.K., Pan, X., Yan, H., inhibitors containing cinnamate or NSAID activated G protein-coupled receptors Zeng, G., Xu, W., He, W., Daly, N.L., Craik, components. Bioorganic & Medicinal recognize ligands with turn structure. D.J., and Tan, N. (2010). Isolation and Chemistry Letters 20: 7080-7084. characterization of cytotoxic cyclotides from Chemical Reviews 110: 1-41. Williams, M.L., Chalmers, D.K., Martin, J.L., Viola tricolor. Peptides 31: 1434-1440. Salim, A.A., Rae, J., Fontaine, F., Conte, and Scanlon, M.J. (2010). Backbone and M.M., Khalil, Z., Martin, S., Parton, R.G., Tee, E.H.L., Tomislav K., Ramu, S., Huang, side chain H-1, N-15 and C-13 assignments and Capon, R.J. (2010). Heterofibrins: J.X., Butler, M.S., and Cooper, M.A. (2010). for the oxidised and reduced forms of Inhibitors of lipid droplet formation from Synthesis of Essramycin and Comparison of the oxidoreductase protein DsbA from a deep-water southern Australian marine Its Antibacterial Activity. Journal of Natural Staphylococcus aureus. Biomolecular NMR sponge, Spongia (Heterofibria) sp. Organic Products 73: 1940-1942. assignments [electronic resource] 4: 25-28. and Biomolecular Chemistry 8: 3188-3194. Tran, T.T., Kulis, C., Long, S.M., Bryant, Yang, S.N.Y., Takeda, A.A.S., Fontes, Scully, C.C.G., Blakeney, J.S., Singh, D., Adams, P., and Smythe, M.L. (2010). M.R.M., Harris, J.M., Jans, D.A., and Kobe, R., Hoang, H.N., Abbenante, G., Reid, Defining scaffold geometries for interacting B. (2010). Probing the Specificity of Binding R.C., and Fairlie, D.P. (2010). Selective with proteins: Geometrical classification of to the Major Nuclear Localization Sequence- hexapeptide agonists and antagonists for secondary structure linking regions. Journal binding Site of Importin-alpha Using human complement C3a receptor. Journal of Computer-Aided Molecular Design 24: Oriented Peptide Library Screening. Journal of Medicinal Chemistry 53: 4938-4948. 917-934. of Biological Chemistry 285: 19935-19946. Shouldice, S.R., Cho, S.H., Boyd, D., Troeira Henriques, S., and Craik, D.J. Zhang, H., Conte, M.M., and Capon, Heras, B., Eser, M., Beckwith, J., Riggs, P., (2010). Cyclotides as templates in drug R.J. (2010). Franklinolidesa A - C from Martin, J.L., and Berkmen, M. (2010). In vivo design. Drug Discovery Today 15: 57-64. an Australian marine sponge complex: oxidative protein folding can be facilitated Phosphodiesters strongly enhance by oxidation-reduction cycling. Molecular polyketide cytotoxicity. Angewandte Chemie Microbiology 75: 13-28. International Edition 49: 9904-9906. imb annual report 2010 114

NOTES NOTES

The University of Queensland St Lucia Queensland Australia Telephone: +61 7 3346 2100 Facsimile: +61 7 3346 2101 Email: [email protected]