ANNUAL REPORT 2007 IMB VISION STATEMENT CONTENTS

Creativity, motivation and intellectual By understanding how and why humans and CHAIR’S MESSAGE 2 Division of Molecular Cell Biology AFFILIATE APPOINTMENTS 53 freedom are the vital components of animals develop the way they do, we will be John Hancock 32 DIRECTOR’S MESSAGE 4 IMBcom 54 scientifi c discovery and technological better equipped to understand the basis of Brad Marsh 33 process, and underpin the research our differences and how and why things go DEPUTY DIRECTOR (RESEARCH) REPORT 6 Alan Munn 34 POSTGRADUATE RESEARCH 55 philosophy of the Institute for Molecular wrong in disease states like cancer. Rob Parton 35 Bioscience. DEPUTY DIRECTOR (SYSTEMS Jennifer Stow 36 VISITING SPEAKERS 58 In time, our collaborative research will lead & ADMINISTRATION) REPORT 7 Matt Sweet 37 Our research mission is to understand to improved therapies and diagnostics, Michael Waters 38 COLLABORATIVE the information contained in our genes enhancing our ability to combat common ORGANISATIONAL STRUCTURE 8 Alpha Yap 39 RESEARCH PARTNERSHIPS 60 and proteins – the very foundation of our diseases and genetic disorders. IMB 2007 HIGHLIGHTS 9 Division of Chemical COMMUNITY ENGAGEMENT 64 existence and health. It will also give rise to new ideas, and Structural Biology IMB ADVISORY BOARD 14 IMB STAFF AND STUDENTS 65 technologies and knowledge-based industries Paul Alewood 40 to improve the health and quality of life of SCIENTIFIC ADVISORY COMMITTEE 16 Robert Capon 41 FINANCIAL STATEMENTS 76 future generations. David Craik 42 IMB RESEARCHERS 18 David Fairlie 43 GLOSSARY OF TERMS 79 Division of Genomics Ben Hankamer 44 and Computational Biology Glenn King 45 2007 PUBLICATIONS 82 Richard Lewis 46 Tim Bailey 20 Jennifer Martin 47 Sean Grimmond 21 Mark Smythe 48 John Mattick 22 Mark Ragan 23 Joint Appointments at the IMB Rohan Teasdale 24 Kevin Burrage 49 Division of Molecular Genetics Geoff Goodhill 50 and Development Alan Mark 51 Peter Koopman 25 Geoffrey McLachlan 52 Melissa Little 26 George E.O. Muscat 27 Andrew Perkins 28 Rick Sturm 29 Brandon Wainwright 30 Carol Wicking 31

Institute for Molecular Bioscience • Annual Report 2007 CONTENTS 1 CHAIR’S MESSAGE

This is my last report as Chair of the Board of the Thanks must also be extended to Chuck Feeney. The establishment phase of the Institute is now Institute for Molecular Bioscience (IMB), before my His generosity, through The Atlantic Philanthropies, over, and the IMB is building on its strong base and retirement as Vice-Chancellor of The University of enabled not only the construction of the IMB consolidating its world-class research reputation. Queensland (UQ) on December 31, 2007. building, but that of several other institutes at In this it will be ably guided by Professor Brandon UQ, including the Queensland Brain Institute, and Wainwright, the current IMB Director, who in When I arrived at UQ in 1996, there were no the Australian Institute for Bioengineering and his two years at the helm has already seen institutes; today, there are six: the IMB, the Nanotechnology as well as the refurbished James considerable success and is well placed to drive Australian Institute of Bioengineering and and Mary Emelia Mayne Centre housing the UQ art the research agenda of the Institute and ensure Nanotechnology, the Queensland Brain Institute, collection. World-class research requires world- the highest quality research output. Under the the Diamantina Institute for Cancer, Immunology class infrastructure, and Chuck Feeney’s generosity auspices of the IMB Board, which will be chaired and Metabolic Medicine, the Sustainable Minerals has been a major driver behind the delivery of this from 2008 by my successor as Vice-Chancellor, Institute and the Institute for Social Science in Queensland. Professor Paul Greenfi eld, I am confi dent that Research. Professor Wainwright and the IMB will continue Professor John Mattick and Professor Peter The IMB was the fi rst of these to be established, to go from strength to strength. Andrews were the fi rst co-directors of the IMB. and there can be no doubt that it has been an They were the driving force behind merging UQ’s unqualifi ed success. An independent review in Centre for Molecular and Cellular Biology and Drug Professor John Hay, AC 2005 of the fi rst fi ve years of operation concluded Design and Development Centre to establish the UQ 2007 Vice-Chancellor that the IMB had surpassed expectations in all key IMB. They are now applying their talent to other areas, with one commentator estimating that it challenges: Professor Mattick stepped down as was “one of the two leading research institutes Director to concentrate on his research after in Australia”. receiving a Federation Fellowship, while Professor Since this review, the IMB has continued to build on Peter Andrews is Queensland Chief Scientist. its research strengths, and in the pages that follow, I also acknowledge those who have contributed you will read of its achievements in 2007. The to the IMB in less visible, but no less meaningful success of the IMB is due to a collection of talented ways: the IMB Board and Scientifi c Advisory people, and I would like to acknowledge their Committee members, the staff, both research and contributions and my appreciation of their efforts. general staff, and the students. The IMB would not Peter Beattie and the Queensland State be the leading research institute it is today without Government have been instrumental in the the contributions each of these people have made. continued success of the IMB, providing not only $15 million towards the construction of the building, but also recurrent operational funding of $10 million per annum to 2014. Peter Beattie’s “Smart State” vision has transformed Queensland into a powerhouse of bio research, which shows every sign of continuing under the new Premier, Anna Bligh.

2 CHAIR’S MESSAGE Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 CHAIR’S MESSAGE 3 DIRECTOR’S MESSAGE

The Institute for Molecular Bioscience celebrated Professor Peter Koopman was awarded an Professor Glenn King joined the IMB in December of the Australian Stem Cell Centre until 2011. Finally, I would like to record my thanks and another successful year in 2007, with a number ARC Federation Fellowship in May for his world- 2006 and had an outstanding year in 2007, Melissa’s work in renal disease and regeneration appreciation for the contributions of the outgoing of our scientists receiving prestigious awards and renowned work in the fi eld of developmental succeeding as chief investigator on four grant is well known and highly regarded and she was an Chairman of the IMB Board, Professor John Hay, an average 40 percent success rate over both biology. The ARC Federation Fellowship will applications and as co-investigator on a further obvious choice for this position with the Australian AC, who retired as Vice-Chancellor of The University major funding schemes (ARC and NHMRC); well allow him to concentrate on his research work two grants. Glenn’s work on environmentally Stem Cell Centre. The position is based in Brisbane of Queensland at the end of 2007. During his above the national average. I was very pleased and is richly deserved. Professor Koopman joins friendly insecticides has already received at the AIBN and Melissa continues to have a lab twelve-year tenure at UQ, Professor Hay drove the to acknowledge the calibre and contribution Professors John Mattick and David Fairlie as considerable attention both in Australia and presence at the IMB. establishment of four major research institutes of our Group Leaders to the Institute’s success current IMB Federation Fellows, with IMB joint overseas and his grant success last year will at the University, including the IMB, through the Activities during 2007 included our annual Dr at a special dinner held at Customs House in appointees Professors Kevin Burrage and Alan enable him to extend his research to include a brokering of a unique funding relationship between Toshiya Yamada Memorial Lecture, in honour of Brisbane in July 2007. Professor David Siddle, UQ’s Mark and affi liate Professor Bostjan Kobe also study of antimicrobial agents to treat antibiotic- the University, the Queensland State Government the late Dr Toshi Yamada; a Group Leader scientifi c Deputy Vice-Chancellor (Research) and our guest holding this prestigious award. The Federation resistant strains of golden staph. and Atlantic Philanthropies. Both the building retreat in November; showcasing of the Institute speaker at the event, noted it is easy to overlook Fellowship announcement was followed shortly that the IMB occupies and the annual operational Professor Matt Cooper, who has been at Cambridge at the University Open Day; and attendance the personal and family sacrifi ces that go into thereafter by Professor Koopman winning the funding grant from the State Government are due for the last decade, was awarded one of only two at Bio2007 in Boston and at Ausbiotech 07 in producing world-class science and the dinner was GlaxoSmithKline Award for Research Excellence in no small part to the efforts of Professor Hay. It prestigious NHMRC Australia Fellowships, worth $4 Brisbane. Both Bio and Ausbiotech are principally one way of saying thank you to an exceptional at a ceremony held in Melbourne in June. Koops was fi tting, therefore, that on December 4, 2007 million. Matt is originally from Adelaide and will trade exhibitions and IMB is ably supported group of people who continue to produce is the second IMB researcher to receive this the IMB facility was named the John Hay Building use the award to return to Australia to take up a by IMBcom at both events, where commercial outstanding results on behalf of the IMB. prestigious award, with Professor Melissa Little – testament to a man who has left a lasting legacy Group Leader position at the IMB in 2009. We are output of research is an important topic of receiving the award for her work on renal to the University and to Queensland. looking forward to welcoming Matt to the IMB. discussion. A visible presence at these events disease in 2005. increases awareness of the IMB at a national and Professor Brandon Wainwright These are just some of the highlights for Professor Jenny Stow was awarded a Smart international level and supports the strategies IMB Director Institute personnel but I would like to offer my Women: Smart State in 2007, hot on the heels of of our major stakeholders: The University of congratulations to all Group Leaders, laboratory Smart Women awards for Professors Jenny Martin Queensland and the Queensland State Government. and support staff for their efforts in 2007. Our and Melissa Little in 2005 and 2006 respectively. scientists are world-class and it is through their Jenny Stow is researching immune cells in order efforts that the IMB goes from strength to strength, to understand how they function and how they proving that we are indeed a smart state! malfunction in infl ammatory disease and this award recognises her outstanding contribution in Farewells during 2007 included Professor David this fi eld. Our Smart Women provide excellent role Hume, who left to take up a position as Director models to young female researchers, showing that of the Edinburgh Bioscience Research Centre. a successful scientifi c career is within their reach. David had been with us since the establishment of Centre for Molecular and Cellular Biology, one Professors Rob Parton and John Hancock were of the centres that amalgamated to form the IMB. notifi ed thatthat they had been awardedawarded an inaugural He was Director of the ARC Special Research NHMRC Achievement Award late in 2007 for Centre for Functional and Applied Genomics their work in Ras proteins and the dynamicsdynamics and has had a distinguished scientifi c career and functions of the plasma membrane. These while at the University. His appointment to the awardsawards recognise outstanding Australians for their Edinburgh Bioscience Research Centre was richly contributions and achievements in health and deserved and we are looking forward to fruitful medical research. collaborations with that institution once David has settled into his new role. His enthusiasm, insight and vision will be missed by us all. We have said a temporary farewell to Professor Melissa Little, who was seconded as Chief Scientifi c Offi cer

4 DIRECTOR’S MESSAGE Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 DIRECTOR’S MESSAGE 5 DEPUTY DIRECTOR DEPUTY DIRECTOR (Research) REPORT (Systems & Administration) REPORT

2007 has been a highly successful year for IMB Altogether the IMB received $11.5 million for 14 that includes the Roslin Institute. Although we will The research achievements detailed in the report imaging of trays, remote viewing of images, as an Illumina oligo library. This will result in a research. Our researchers continued to publish project grants from the NHMRC, while Associate miss David’s friendship and vision, it is a fantastic of my fellow Deputy Director, Professor John remote scoring of images, as well as searching of greatly enhanced ability to determine how genes papers in high-impact journals, be invited to Professor Rick Sturm and Dr Rohan Teasdale both opportunity and a worthy use of the talents of this Hancock, would not be possible without the images/data and generation of optimised screens. work, and a pipeline for screening Australia’s rich speak at international conferences, and receive received NHMRC Senior Research Fellowships. world-leading genomic scientist. His research support and expertise of the administrative and This upgraded system allows diffraction images source of natural products and chemical libraries substantial numbers of grants and fellowships. We From the ARC, the IMB received more than $2.5 group at the IMB has been taken over by Dr infrastructure staff of the IMB. Over 60 staff work to be collected in as little as one second, beating for activities against common human diseases have also established new strategies to ensure that million spread over seven projects. Our success Matt Sweet, formerly a Senior Research Offi cer in a range of areas including: administration, HR, the previous best by 59 seconds. The speed and such as cancer, dementia and muscle diseases the IMB’s current success continues. rates for both agencies continue to be well above within the group. Dr Sweet is one of our fi rst true fi nance, grants, marketing and communication, automation of the diffraction facility means that a using zebrafi sh models. the national average, and more than half of our “homegrown” group leaders, as he began at the postgraduate student co-ordination, information complete data set can be measured in a matter One of the most basic measurements of research The Queensland Department of Primary Industries group leaders are now supported by fellowships, IMB as an honours student, before undertaking technology services, laboratory and infrastructure of minutes, and allows the overnight screening of performance is the quality and quantity of and Fisheries moved out of the 6th level of the an important objective assessment of the quality his PhD with Professor Hume. After completing management, reception, stores, building multiple crystals without intervention. The UQ ROCX papers published. I am pleased to say that IMB IMB after their lease ended, freeing up a fl oor for of our senior researchers. post doctoral training overseas, Dr Sweet returned maintenance, technical services, animal house, upgrade automates protein crystallisation through researchers published 195 papers in 2007, many in us to use for our own research. This extra space to the IMB. He has already begun to put his own mail and central sterilising. These staff members to structure determination and has already proven high-impact journals including Nature, Nature Cell Outside the two main grant rounds, but worthy of will allow us to recruit new groups (see Professor stamp on the research of the group, while ensuring ensure the smooth operation of non-research invaluable for high-throughput crystallography Biology and PNAS. special mention, was a $5 million grant from the Hancock’s report) and shuffl e our existing groups that it retains the high standards it achieved under services, and I would like to thank them for a applications such as fragment-based screening of National Breast Cancer Foundation awarded to a around the fl oors to encourage interaction, and IMB continued to perform well in attracting Professor Hume. job well done in 2007. drug targets. Access to the facility is available on a consortium of nine researchers, two of whom were integration of new groups. These will be spaced competitive grant funding - receiving over $19 cost-recovery basis. IMB’s Professor Mark Ragan and Professor George Laboratory space previously rented from us by There was some movement of staff over the year. throughout the fl oors, and we are hopeful that million from the National Health and Medical Muscat. This grant will allow a large-scale, long- the Queensland Department of Primary Industries Dr James Springfi eld from Coherent Scientifi c Pty Another upgrade is underway for the IMB’s the new ordering will result in novel and exciting Research Council (NHMRC) and the Australian term study of breast cancer, in which Professors and Fisheries has now become available, and Ltd came on board to work on light and confocal Zebrafi sh Facility, thanks to a $1.5m NHMRC collaborations. Research Council (ARC). This included a $5 million Ragan and Muscat will play leading roles. You can we will use this to house new research groups. microscopy and imaging systems. He will advise Enabling Grant awarded to Associate Professor NHMRC Program Grant to myself and Professor Dr Ian Taylor read more about all of these grants and fellowships An IMB search committee has been formed and scientists on how they can use the IMB’s microscopy Andrew Perkins. Zebrafi sh are becoming a global Robert Parton to study the cell surface, and one of IMB Deputy Director in our Highlights section, starting on page 9. we have already begun to receive and assess resources to their full advantage in imaging model of choice for biomedical research due only two $4 million Australia Fellowships, awarded applications. Over the next two years at least six research. His expertise will ensure our researchers to a number of factors including: their ability to to Dr Matt Cooper. Dr Cooper is currently based In addition to receiving grants for individual new groups will be established. These will further get the most out of their equipment, and refl ects be housed cheaply, transparent eggs for easy in the United Kingdom, but will use the Australia research programs, our research group leaders are lift the research profi le and increase the critical the range and breadth of the microscopy equipment visualisation of early developmental processes, Fellowship to move to the IMB in 2009 and involved in, and often lead, collaborative scientifi c mass of researchers at IMB. The fi rst one of these at the IMB. Another staff member who deserves rapid development and breeding and similarity continue his research on developing treatments centres. In 2007, Professor Melissa Little was new group leader appointments at the very close to be acknowledged is Mileta Duggleby. Mileta to human gene complement. In Australia there for drug-resistant pathogens. appointed Chief Scientifi c Offi cer of the Australian of 2007 was Dr Brett Collins to the Division of was a Purchasing Offi cer in the fi nance group, and are several strong basic research teams who Stem Cell Centre, and will head its scientifi c Molecular Cell Biology. retired in 2007 after 13 years at The University of have embraced zebrafi sh models, but until now program, developing strategy, scientifi c review Queensland. Her warmth, wit and knowledge of her not much specifi c funding has been allocated to and management. In addition, two ARC Centres For more details on IMB research achievements area has been much missed. building the necessary infrastructure. This grant at the IMB were named Centres of Excellence, a in 2007 please turn to the group leader reports will allow the IMB to expand its aquarium facilities scheme that recognises exceptional performances beginning on page 18. The IMB continued to embark on infrastructure and purchase associated research equipment such by Centres with an extension of funding for three upgrades in 2007, to ensure our researchers Professor John Hancock years. These are the ARC Centre of Excellence have access to world-leading equipment. One IMB Deputy Director in Biotechnology and Development and the ARC such upgrade was to the macromolecular X-ray Centre of Excellence for Bioinformatics. diffraction facility, made possible through a $1m Australian Research Council Linkage Infrastructure, It is natural, and in fact necessary, that Equipment and Facilities Grant to Professor generational change will occur in any organisation. Jenny Martin. The new University of Queensland In 2007 Professor David Hume, who has been Remote-Op Crystallisation and X-ray (UQ ROCX) associated with the IMB and its predecessor, the Facility includes two Formulatrix Rockimagers CMCB, since 1988 was offered the directorship that allow incubation of up to 1000 crystallisation of a new bioscience research centre in Scotland trays at each of two temperatures, automated

6 DEPUTY DIRECTOR REPORT Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 DEPUTY DIRECTOR REPORT 7 2007 IMB ORGANISATIONAL CHART IMB 2007 HIGHLIGHTS The Year In Review

University of Queensland Senate UQ Holdings Pty Ltd

IMB Board Vice-Chancellor

Senior Deputy Vice Chancellor

IMB Scientifi c Advisory Board Institute Director IMBcom Pty Ltd

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

Division Head Division Head Division Head Division Head Graduate Administration Genomics & Molecular Chemical & Chemical & Education Computional Genetics & Structural Structural Offi ce Biology Development Biology Biology Information Technology Services

Marketing & Research Groups Communications Laboratory Services

8 IMB ORGANISATIONAL CHART Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB 2007 HIGHLIGHTS 9 2007 HIGHLIGHTS

highlights THE EYES HAVE IT ON IMB SCIENTISTS DEVELOPING CLEAN NEW ROLE FOR LEADING According to Professor King, the primary reasons “This lecture is held each March and is an MULTIPLE GENE QUESTION ENERGY SYSTEMS FROM MICRO-ALGAE QUEENSLAND STEM CELL SCIENTIST behind his move were the advanced infrastructure opportunity for us to honour Toshi’s memory and collaborative opportunities available at the IMB, and to celebrate his scientifi c achievements,” $50 MILLION FUNDING FOR IMB A study by IMB and Queensland Institute of An international consortium established by an IMB IMB researcher Professor Melissa Little was while Professor Brandon Wainwright said Professor Professor Brandon Wainwright said. The 2007 Queensland Premier Anna Bligh signed a $50 Medical Research scientists was the fi rst to scientist is developing a clean source of energy appointed to the position of Chief Scientifi c King’s move from the United States to Brisbane lecture, co-hosted with the Queensland Brain million funding agreement between the Queensland prove conclusively that there is no single gene for that could see some of our future fuel and possibly Offi cer of the Australian Stem Cell Centre (ASCC), highlighted the region’s growing reputation as a Institute, was given by Professor Ryoichiro Government and UQ in November 2007 to fund the eye colour. Instead, it found that several genes water needs being generated by solar-powered responsible for developing strategy, scientifi c hub for scientifi c research. Kageyama, Director of the Institute for Virus IMB for a further fi ve years. The IMB was scheduled determine the colour of an individual’s eyes, bio-reactors and micro-algae, while absorbing CO . review and management. She will be seconded to 2 Research at Kyoto University, Japan. to receive operational funding from the Queensland although some have more infl uence than others. the ASCC until mid-2011, but will continue running Associate Professor Ben Hankamer has Government until the 2008-2009 fi nancial year, and her research program at the IMB where she and QUEENSLANDER RUNS MAJOR NEW “The model of eye colour inheritance using a single established the Solar Bio-fuels Consortium, which this new agreement will extend this funding until her team are investigating the potential of stem INTERNATIONAL RESEARCH CENTRE IMB GETS IN SYNC WITH gene is insuffi cient to explain the range of eye is engineering green algal cells and advanced 2013-2014. cells in treating chronic kidney disease. AUSTRALIAN SYNCHROTRON colours that appear in humans. We believe instead bio-reactor systems to produce bio-fuels such as Professor David Hume was appointed Director of “Continued funding for another fi ve years will give that there are two major genes – one that controls hydrogen. Using algae has several advantages the Edinburgh Bioscience Research Centre after Professor Jenny Martin from the IMB was the the IMB the security it needs to conduct research for brown or blue, and one that controls for green over traditional bio-fuel crops: the hydrogen can EUROPEAN HONOUR FOR a worldwide search. The new research centre fi rst Queensland researcher to use the Australian which will lead to improvements in the lives of or hazel – and others that may modify this trait,” be produced using saltwater rather than fresh QUEENSLAND SCIENTIST was created from an amalgamation of several Synchrotron in Victoria, which opened in 2007. prestigious Scottish research centres, including Professor Martin works on chronic infl ammation as Queenslanders and people around the world,” 2007 Associate Professor Rick Sturm, who headed water, and the reactors can be placed on arid land, A Queensland scientist was elected as a member the Roslin Institute. well as the way adrenaline functions in the brain. UQ Vice-Chancellor Professor John Hay, AC, said. “ the study, said. eliminating competition with food production for of one of the world’s most respected scientifi c The State Government, through funding from its arable land and water. The energy production could organizations, the European Molecular Biology “Although we are very sorry to lose Professor Smart State strategy, has been a key player in the GROWTH HORMONE COULD PROMOTE also theoretically be coupled with desalination. Organization (EMBO). Professor John Mattick Hume, it is a fantastic opportunity to lead an success of the IMB.” An independent review of the CANCER, ACCORDING TO IMB RESEARCHER from the IMB was one of only eight scientists internationally signifi cant research institute. grants Institute’s operations in its fi rst fi ve years showed that worldwide in 2007 to be offered Associate His friendship, energy, intellect and vision will be Growth hormone and associated proteins could be RESEARCH POINTS TO FIGHTING GOLDEN STAPH the IMB would generate up to 1000 jobs and grow the Membership of EMBO. very much missed by us all,” Professor Brandon responsible for promoting many types of cancer, POSSIBLE NEW STROKE THERAPY AND REGENERATING SKIN SHARE economy by $400 million in its fi rst 15 years. Wainwright, IMB Director, said. including breast and prostate cancer, according to Research from an international team of scientists, EMBO draws together top researchers from the IN OVER $19 MILLION OF FUNDING Professor Mike Waters. Blocking growth hormone including Professor David Fairlie from the IMB, molecular life sciences in Europe to promote The IMB was awarded over $19 million from GRADUATE TO GROUP LEADER could thus be a useful avenue for cancer therapy, has identifi ed a possible new therapy for stroke excellence through targeted programs and the National Health and Medical Research Professor Waters said. He also found that growth that is likely to be more effective than the current activities. Members come from European countries, Dr Matt Sweet was appointed Group Leader of Council (NHMRC) and the Australian Research hormone receptor could induce tumour growth treatments. while Associate Membership is a special honour the former Hume group after Professor Hume’s Council (ARC) in the latest round of grant funding when sent to the cell nucleus. available to outstanding researchers from outside The team found that administering departure. Dr Sweet was previously a Senior announced in late September. of Europe. 2007 was the fi rst year that any Research Offi cer within the IMB, and he fi rst immunoglobulin directly into the veins via This included nearly $17m from the National Health Australian scientist was invited to join. entered the institute as an honours student. intravenous injection protected brain cells against and Medical Research Council for fellowships and the effects of stroke. Immunoglobulin is a class Professor Mattick’s research explores the idea The Sweet group primarily focuses on how innate projects including regenerating wounded skin of protein manufactured by the blood to fi ght off that so-called “junk” DNA actually functions as a immune cells detect invading pathogens and the and fi ghting golden staph. Altogether, the IMB foreign substances in the body. sophisticated regulatory system that directs the impact of innate immune cell activation on both received more than $11.5 million from the NHMRC differentiation and development of humans and acute and chronic infl ammation. spread over 14 projects, and more than $5 million other complex organisms. in fellowships, including a $4 million Australia “Such processes underlie the basis of resistance Fellowship to Dr Matt Cooper (please see below for and susceptibility to infectious disease, and for this RESEARCHER RETURNS TO more details). From the ARC, the IMB received more reason have obvious importance to human health,” FIGHT INSECTS WITH SPIDER VENOM than $2.5 million spread over seven projects. Dr Sweet said. A researcher who has spent most of the past decade working in the U.S. has returned to UQ CELEBRATES BRAIN AWARENESS WEEK Australia to continue working on developing environmentally friendly insect control methods The IMB marked Brain Awareness Week with based on spider venom compounds. a free public memorial lecture for a celebrated researcher whose discoveries form much of the “Since spiders have been developing insecticidal basis of modern neurobiology. The Dr Toshiya compounds for almost 400 million years, I decided Yamada Memorial Lecture, held on Wednesday to interrogate their venoms to fi nd natural toxins March 14, commemorated Dr Toshiya Yamada, that might kill insects without harming vertebrates,” a neuroscientist with the IMB until his sudden Professor Glenn King, formerly of the University of death in 2001. Connecticut, said.

10 IMB 2007 HIGHLIGHTS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB 2007 HIGHLIGHTS 11 2007 HIGHLIGHTS

IMB SHARES IN $9.72M IMB RESEARCHER HONOURED will investigate a genetic pathway which is altered awards HAT TRICK OF AWARDS PHD STUDENT WINS ROCHE AWARD CENTRES OF EXCELLENCE FUNDING WITH LEADING FELLOWSHIP in many forms of cancer, which will lead to a better FOR IMB SMART WOMEN Rehan Villani, from Professor Brandon Wainwright’s understanding of how to treat certain tumours. Two Australian Research Council (ARC) Centres Professor Peter Koopman received one of the IMB RESEARCH OFFERS HOPE Professor Jennifer Stow became the third lab, won the 2007 Roche Award for Postgraduate Professor John Hancock will study K-Ras, a protein at the IMB have been named as Centres of highest academic accolades in Australia, being FOR CHILDREN OF UNCERTAIN SEX woman in as many years from the IMB to win a Career Development. The award recognises the frequently mutated in human cancers, which will Excellence, a scheme that recognises exceptional awarded an ARC Federation Fellowship for his Professor Peter Koopman received what is arguably Smart Women: Smart State award. Professor Stow contribution of a postgraduate student to advancing allow the design of drugs to specifi cally target the performances with an extension of funding for a research into developing new and vastly more Australia’s most prestigious medical research received the award for her work on cells, which research in their fi eld in new and innovative protein. Associate Professor Rick Sturm will move a further three years. effi cient ways of identifying which of our 30 000 award – the GlaxoSmithKline Australia Award may lead to alternative treatments for infl ammatory directions. It is designed to further develop the step closer to treating melanomas by studying skin genes are important for embryonic development. for Research Excellence. Professor Koopman’s disease. She is researching immune cells in order career of the recipient by enabling them to attend The ARC Centre of Excellence in Biotechnology and cells that become malignant. research offers hope to children born with sexually to understand how they function, and then how conferences or present papers and publications. Development, which has a node at IMB, will receive Professor Koopman is world renowned in the fi eld ambiguous genitalia and other sexual development they malfunction, in infl ammatory disease and a further $6.42 million from 2008, while the ARC of developmental biology, and was part of the team After being selected as a fi nalist on the basis of DR ROSAMOND SIEMON SCHOLARSHIP conditions, which are more common than most cancer. She is the third IMB researcher to receive Centre for Bioinformatics, headquartered at IMB, that discovered the gene that determines gender her initial application, Mrs Villani won with her AWARDED TO IMB STUDENT people imagine. a Smart Women: Smart State award in as many will have its status upgraded to become a Centre in mammals, which has been called one of the presentation, “Hedgehog Signalling: Balancing years. of Excellence, and will receive a further $3.3 million most important biological discoveries of the 20th Caroline Hopkins (Little lab) from the IMB was Professor Koopman is the second IMB researcher Skin Turnover and Skin Cancer”. from 2008. century. He is the sixth researcher at or affi liated awarded the inaugural Dr Rosamond Siemon to receive the Award in the last three years, after Postgraduate Renal Research Scholarship. The SUPERB SUPERVISOR with the IMB to receive a Federation Fellowship. Professor Melissa Little’s win in 2005 for her DNA ALGORITHM WINS AMGEN AWARD scholarship is awarded to the best postgraduate MULTIMILLION-DOLLAR contribution to the development of new treatments Professor David Craik won an Award for Excellence student undertaking multidisciplinary, collaborative The Amgen Award for best honours student of GRANT TO BEAT BREAST CANCER IMB RESEARCH GETS A SMART BOOST for renal disease. in Research Higher Degree Supervision. He has research into renal disease, repair and regeneration. 2007 at the IMB was won by a student from successfully supervised to completion more IMB researchers Professor George Muscat and Professor Melissa Little received $1 million the Bailey lab who developed a discriminative Mrs Hopkins’s honours project at the IMB in 2006 than 20 PhD students, has 10 currently under Professor Mark Ragan will be lead investigators from the Queensland Government’s Smart State PRESTIGIOUS NATIONAL AWARD algorithm for detecting motifs (repeating elements) investigated the potential for adult kidney cells supervision, and his group’s publication record on a $5 million National Breast Council Foundation Innovation Funding Program to further her research FOR PIGMENTATION RESEARCHER in DNA and protein sequences. Emma Redhead’s to revert back to an embryonic form, where they is outstanding. Nominations for the award must grant that will take new approaches to treating into cell-based regenerative therapies for chronic Associate Professor Rick Sturm was awarded algorithm was found to be more effective than the could be prompted to regenerate kidney tissue. be supported by at least four people: a staff women for whom available therapies offer kidney disease. the Julian Wells Medal at the Lorne Genome non-discriminative approach when applied to a For her PhD, Mrs Hopkins will continue and expand member, current research student and two former little hope, and women who develop treatment Conference. It is awarded every year to an well-studied synthetic motif discovery problem. Professor Little said the aim of the research is to this project. The scholarship was donated by Dr (completed) research higher degree students. resistance. Australian scientist who has “made an outstanding enable repair to damaged kidneys and is expected Rosamond Siemon, a historian and UQ alumnus. contribution to our understanding of gene action, The team, which includes researchers from to be more effective than current treatments such genome organisation or genomic evaluation,” HIGHLY COMMENDED PHD STUDENTS around the nation, will study nuclear receptors, as dialysis. US GRANT FOR OBESITY RESEARCHER according to the prize committee. Dr Sturm has Four IMB PhD graduates were included on the UQ proteins found in cells that receive information Dr Gary Leong, from the IMB and the Mater been studying the human genes that control skin, Dean’s Commendation List, recognising the few from molecules and then alter gene expression INTERNATIONAL GRANT Hospital, was awarded a US$50 000 grant to study hair and eye colour for many years. He is the postgraduate students who receive unanimously accordingly. TO IMB RESEARCHER a protein that may eventually lead to treatments second IMB researcher to receive the medal, outstanding reports from their examiners, who Professor Rob Parton received a $408 000 for diseases such as obesity and type 2 diabetes. after Professor Peter Koopman in 1998. commend them on making genuine and substantial $4 MILLION AUSTRALIA grant from the prestigious Human Frontier He received the grant from the US Endocrine contributions to their fi eld of research. The four FELLOWSHIP TO SCIENTIST Science Program (HFSP), which he will share Society to investigate the actions of the protein IMB RESEARCHERS RECOGNISED students were: Alistair Forrest (Grimmond lab), One of Australia’s most prestigious fellowships with collaborators in France and India. The HFSP Ski on muscle and fat metabolism. IN NHMRC AWARDS Markus Kerr (Teasdale lab), Benjamin Clark for medical researchers has been awarded to Dr supports international collaborations in basic (Capon lab) and Matthew Kirkham (Parton lab). Two IMB researchers were recognised in the Matt Cooper, who will use the $4 million NHMRC research focused on the complex mechanisms QFAB CEO AWARDED inaugural National Health and Medical Research Australia Fellowship to join the IMB. Dr Cooper, who of living organisms. CHURCHILL FELLOWSHIP Council Awards in December 2007, which is currently working in the UK, will use the fellowship Professor Parton was awarded the grant to study recognises outstanding Australians for their to establish a research program into novel antibiotics Dr Jeremy Barker, the CEO of the Queensland endocytosis, to better understand how healthy cells contributions to health and medical research. and antifungals that combat drug-resistant Facility for Advanced Bioinformatics, was awarded work and what goes wrong in disease conditions. Professors John Hancock and Robert Parton pathogens, especially those that cause hospital- a Churchill Fellowship from the Winston Churchill Endocytosis describes the process whereby animal received the NHMRC Achievement Award acquired infections. Memorial Trust. The fellowships aim to enrich cells are constantly sampling their environment and Australia by providing fi nancial support for the – Program Grant for their work in studying the engulfi ng parts of their surface membrane. Fellow to travel overseas and gain experience in surface of the cell, for which they received a $5 their area of expertise that could not be gotten in million Program Grant earlier in 2007. FUNDING BOOST FOR CANCER RESEARCH Australia. Dr Barker travelled to the USA and the UK to study bioinformatics. Three projects led by IMB researchers received $156 000 in funding each from the Queensland Cancer Fund. Professor Brandon Wainwright’s team

12 IMB 2007 HIGHLIGHTS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB 2007 HIGHLIGHTS 13 IMB ADVISORY BOARD

Professor John Hay Professor Brandon Wainwright Professor Frank Gannon Professor Paul Greenfi eld Dr Russell Howard Dr Peter Isdale Professor Mick McManus Professor Nicos Nicola

PROFESSOR JOHN HAY, AC (CHAIR) PROFESSOR BRANDON WAINWRIGHT and Senior Scientist at the European Molecular DR RUSSELL HOWARD positions on Foundations around the world and PROFESSOR NICOS NICOLA, AO Biology Laboratory (EMBL) in Heidelberg, Germany. is an Adjunct Professor at Texas A&M University. Professor John Hay, AC, was Vice-Chancellor of (DIRECTOR) Dr Howard is CEO of Maxygen and one of the Professor Nicos Nicola, AO, is an ex offi cio member His major research interest is the Estrogen He holds a B.A. with fi rst-class honours and a PhD The University of Queensland from 1996 until Professor Brandon Wainwright was appointed company’s founders. Since the creation of of the IMB Board, as he serves as the Chair of the Receptor as a Transcription Factor and he has in Marine Geomorphology (1982) from James Cook his retirement on December 31, 2007. He was Director of the Institute for Molecular Bioscience in Maxygen in 1997, its core technologies have been IMB Scientifi c Advisory Council. He is Assistant published over 200 research articles. He serves on University of North Queensland. previously Vice-Chancellor of Deakin University, late 2006. Previously, he was the Deputy Director used to create several independent businesses. Director of the Walter and Eliza Hall Institute, a number of scientifi c advisory boards at institutes and under his leadership both UQ and Deakin were (Research) of the IMB from 2002. Today, Maxygen is focused on optimisation where he also serves as Head of the Cancer and throughout the world. In 2006 he was awarded as a Member in the named Australia’s University of the Year by the and development of signifi cantly improved Haemotology Division. Professor Wainwright completed his undergraduate General Division of the Order of Australia (AM) Good Universities Guide. UQ has now won far more proprietary versions of several marketed protein and postgraduate studies at the University of for service to marine science through research teaching awards than any other university. PROFESSOR PAUL GREENFIELD, AO Professor Nicola completed both his undergraduate pharmaceuticals. Originally trained in biochemistry and as a contributor to the development and Adelaide, after which he took up a postdoctoral and postgraduate degrees at the University of Professor Paul Greenfi eld, AO, was Senior Deputy and chemistry at the University of Melbourne, commercialisation of biotechnology. Professor Hay has an outstanding record for fellowship at St Mary’s Medical School, the Melbourne, before working for a year at Brandeis Vice-Chancellor of The University of Queensland Dr Howard spent over 20 years studying infectious attracting government and private funding, and University of London. He remained at St Mary’s for University in Massachusetts, USA. He then joined from 2002 to 2007, and became VIce-Chancellor diseases, primarily malaria. Before joining has led UQ to establish a series of internationally six years, eventually becoming a Medical Research PROFESSOR MICK MCMANUS the Walter and Eliza Hall Institute in 1977. He is recognised new research institutes: the Institute Council Senior Research Fellow. In 1990, he moved on January 1, 2008. Professor Greenfi eld Maxygen, Dr Howard served at research institutes, Professor Mick McManus has been Executive Dean responsible for major discoveries including the for Molecular Bioscience, the Queensland Brain back to Australia, joining the Centre for Molecular graduated with fi rst-class honours in Chemical biotechnology companies and a pharmaceutical at the Faculty of Biological and Chemical Sciences purifi cation of mouse G-CSF, the defi nition of the Institute, the Australian Institute for Bioengineering and Cellular Biology (CMCB) at The University of Engineering from the University of New South company both in Australia and overseas. In addition of The University of Queensland since 1998. Prior to human equivalent of G-CSF and the purifi cation and Nanotechnology, the Sustainable Minerals Queensland. Professor Wainwright stayed with the Wales (UNSW), then worked in the private sector to numerous patents, Dr Howard has over 140 of Leukaemia Inhibitory Factor. Professor Nicola Institute, the Centre for Clinical Research and the CMCB when it was merged with another UQ Centre before completing a PhD at UNSW. He then worked publications in peer-reviewed journals. this he was Head of the Department of Physiology has published over 200 journal articles and Diamantina Institute for Cancer, Immunology and (the Drug Design and Development Centre) in 2000 at CSIRO before winning a three-year fellowship and Pharmacology from 1993 to 1997, and was to the U.S. In 1975 he joined The University of initially appointed to the University as Foundation has 17 patents. Metabolic Medicine. to create the Institute for Molecular Bioscience. DR PETER ISDALE, AM Queensland as a lecturer in chemical engineering, Professor of Pharmacology. Mick trained as a In 2002 Professor Hay was appointed by the Federal In addition to being Director of the IMB, Professor and a decade later became Head of Department Dr Peter Isdale, AM, is the CEO of IMBcom Pty Ltd., pharmacist at Curtin University of Technology and Minister for Education to the Higher Education Wainwright continues his research into the use and then Pro-Vice-Chancellor (Physical Sciences The University of Queensland’s commercialisation completed his PhD at the University of Western Review Reference Group. He was Chair of the Group of genomic approaches to dissect the basis and Engineering) before being appointed an company for the IMB. He is a former Business Australia in 1978. He has held research positions of Eight from January 2002 to May 2003, and was of common genetic disease. In particular, his inaugural Executive Dean in 1997. Currently, he Director at the Australian Institute of Marine in universities in Australia and London, and at the Chair of Universitas 21 from 2003-2006. He is laboratory focuses on two heritable conditions: chairs several committees, including an expert Science (AIMS), Australia’s national marine National Institutes of Health in the U.S. He was now Chair of the Carrick Institute for Learning and cystic fi brosis and basal cell carcinoma of the skin, advisory panel providing independent advice research agency. He is also a former Principal President of the Australasian Society of Clinical and Teaching in Higher Education, and is a member of and he was responsible for the discovery of the on delivering purifi ed recycled water to South Research Scientist at AIMS, and authored or Experimental Pharmacologists and Toxicologists numerous state and national committees, including basal cell carcinoma gene, patched. East Queensland. He is also a Director of several co-authored more than 30 papers in his fi eld of from 2000-2001. He continues to have a strong the National Library of Australia. University companies including UniQuest Pty Ltd. marine and climate research. He has 20 years research interest in the area of xenobiotic PROFESSOR FRANK GANNON In 2006 he was appointed an Offi cer in the Order of experience in the operation and governance metabolism, especially on the role human of Australia for his contribution to environmental of private, public and ASX-listed companies in Frank Gannon is the Director General of Science sulfotransferases play in this process. management, biotechnology and tertiary education, Australia, Asia and the Pacifi c Rim. He is a Member Foundation Ireland. From 1994-2007, Frank and in 1995, he won the Chemeca Medal, awarded Gannon was the Executive Director of the European of the Australian Institute of Company Directors. jointly by the Institution of Chemical Engineers and Molecular Biology Organisation (EMBO), Secretary Dr Isdale currently holds fi ve non-executive the Institute of Engineers Australia for outstanding General of the European Molecular Biology Council, directorships in biotech companies, senior contribution to the profession.

14 IMB ADVISORY BOARD Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB ADVISORY BOARD 15 IMB SCIENTIFIC ADVISORY COMMITTEE

The Institute for Molecular Bioscience would like to acknowledge the valuable contribution that Dame Professor Anne McLaren made to the Scientifi c Advisory Committee. Professor McLaren, from the Institute of Cancer and Developmental Biology at the University of Cambridge, was a pioneering fi gure in the fi eld of mammalian genetics and developmental biology. She served on the Committee from its inception in 2000 until her death on July 7, 2007. The IMB would like to extend condolences to her family, friends and colleagues. Top Row: Prof. Ken-ichi Arai, Prof. Wah Chiu, Prof. David Galas, Prof. Robert Graham, Prof. Peter Gunning, Prof. Steve Kent, Prof. Edison Liu, and Prof. Chris Marshall. Second Row: Prof. Garland Marshall, Prof. Ira Mellman, Prof. Nicos Nicola, Prof. Greg Petsko, Prof. Robert Saint, Prof. Patrick Tam, Prof. Marino Zerial and Prof. Dame Anne McLaren.

PROFESSOR KEN-ICHI ARAI PROFESSOR EDISON LIU PROFESSOR GREG PETSKO Dean, The Institute of Medical Science Executive Director Gyula and Katica Tauber Professor of The University of Tokyo, Japan Genome Institute of Singapore Biochemistry and Chemistry National University of Singapore Director, Rosenstiel Basic Medical Sciences PROFESSOR WAH CHIU Research Center Alvin Romansky Professor of Biochemistry PROFESSOR CHRIS MARSHALL Brandeis University, USA Director, National Center for Macromolecular Imaging Chair and Director Director, Graduate Program in Structural and PROFESSOR ROBERT SAINT Cancer Research UK Computational Biology and Molecular Biophysics Director Centre for Cell and Molecular Biology Verna and Marrs McLean Department of Biochemistry ARC Special Research Centre for the Molecular and Molecular Biology Institute of Cancer Research UK Genetics of Development Baylor College of Medicine, USA Research School of Biological Sciences PROFESSOR GARLAND MARSHALL Australian National University PROFESSOR DAVID GALAS Department of Biochemistry and Molecular Biophysics and the Center for Computational Biology Vice-President PROFESSOR PATRICK TAM School of Medicine Chief Academic Offi cer & Norris Professor of Applied Head, Embryology Unit Washington University in St Louis, USA Life Sciences Children’s Medical Research Institute Keck Graduate Institute of Applied Life Sciences, USA Westmead, Sydney PROFESSOR IRA MELLMAN PROFESSOR ROBERT GRAHAM Chair, Department of Cell Biology PROFESSOR MARINO ZERIAL Ludwig Institute for Cancer Research Executive Director Max Planck Institute of Molecular Cell Biology Yale University School of Medicine, USA Victor Chang Cardiac Research Institute, Sydney Dresden, Germany

PROFESSOR NICOS NICOLA PROFESSOR PETER GUNNING Professor of Molecular Haemotology Head, Oncology Research Unit Assistant Director Westmead Children’s Hospital, Sydney Walter and Eliza Hall Institute of Medical Research, Melbourne PROFESSOR STEVE KENT Biochemistry and Molecular Biology and Chemistry Institute for Biophysical Dynamics The University of Chicago, USA

16 IMB SCIENTIFIC ADVISORY COMMITTEE Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB SCIENTIFIC ADVISORY COMMITTEE 17 IMB RESEARCHERS The People & Their Passion

The highly integrated research environment at abnormalities responsible for many common Division of Genomics & Computational Biology Research Group Leaders the IMB facilitates the fertile exchange of ideas human diseases and to fi nd treatments for them. Tim Bailey and experimental approaches across the broad IMB researchers are particularly interested in the RESEARCH FOCUS Sean Grimmond spectrum of molecular bioscience. genetic programming of mammalian development This program includes the ARC Centre of Excellence in Bioinformatics and the Queensland Facility for Advanced Bioinformatics. John Mattick and variation, the mapping of the structure, It intersects with the Department of Mathematics and the School of Information Technology and Electrical Engineering. It focuses on Mark Ragan This enables a whole-of-system approach to growth and dynamics of mammalian tissues and understanding the genetic programming of humans, specifi cally, comparative mammalian and vertebrate functional genomics; rnomics; Rohan Teasdale TM understanding the basis of human and mammalian cells, and the development of new medicines and and computational modelling of genetic and cellular regulatory networks (i.e. the Visible Cell project). growth and development at the molecular, cellular technologies. and organ levels. This research will lead to new pharmaceuticals, Research Group Leaders Only by understanding the complex molecular gene therapies, technologies and diagnostics Division of Molecular Genetics & Development Peter Koopman and cellular events that occur throughout a normal capable of identifying, halting or even reversing RESEARCH FOCUS Melissa Little human life can scientists begin to understand the progress of many diseases. George Muscat This program includes IMB’s participation in the Cooperative Research Centre for Chronic Infl ammatory Diseases; the Centre for Andrew Perkins Biotechnology and Development; and the NIH-funded project Nephrogenix, an initiative designed to develop new therapies for renal Rick Sturm regeneration. It focuses on urogenital development, infl ammation, cell signalling and cancer, molecular genetics and molecular biology Brandon Wainwright of human diseases. Carol Wicking

Division of Molecular Cell Biology Research Group Leaders John Hancock RESEARCH FOCUS Brad Marsh This program has received considerable support from the NANO Major National Research Facility; the Australian Cancer Research Alan Munn Foundation; Juvenile Diabetes Research Foundation International; and NIH. It is a major initiative of the IMB with the application of Rob Parton cryo-electron microscopy, cellular tomography, advanced visualisation and high-performance computing. It also includes the ARC Jennifer Stow Centre of Excellence in Bioinformatics. It focuses on the Visible Cell ProjectTM; and cell architecture and traffi cking. Matt Sweet Michael Waters Alpha Yap

Division of Chemical & Structural Biology Research Group Leaders Paul Alewood RESEARCH FOCUS Robert Capon David Craik This program has some of the most advanced equipment for structural biology in Australia, used in the development of new medicines David Fairlie and technologies, especially through exploration of Queensland’s biodiversity. It has been responsible for a number of IMB spin-out Ben Hankamer companies based on new platform technologies for drug discovery, as well as developing novel drugs for human disease. It focuses on Glenn King membrane protein structures; soluble protein and nucleic acid structures; and new drugs and therapies. Richard Lewis Jenny Martin Mark Smythe

Joint Appointments at the IMB Research Group Leaders Kevin Burrage RESEARCH FOCUS Geoff Goodhill The purpose of joint appointments is to foster collaborations in teaching, research and related activities between the IMB and Schools Alan Mark at The University of Queensland. Joint appointments involve a split of salary between the IMB and the relevant University of Queensland Geoffrey McLachlan School and a joint appointee’s commitment to the research and teaching activities at the IMB is greater than that of affi liate 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.

18 IMB RESEARCHERS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB RESEARCHERS 19 Pattern Recognition Expression Genomics & Machine Learning in Biology

Tim Bailey Sean Grimmond

New computational algorithms are required for a tool for scanning sequence databases for Buske, F., and Bodén, M. (2007). Decoupling signal The central theme to my research to date has organisms and integrating these with existing transcriptomic and epigenomic data, in an effort the analysis of high-throughput biological data matches to known patterns; MCAST, a tool for recognition from sequence models of protein secretion, been the capture of information contained within forms of data. These focus areas are outlined in to make more accurate molecular control of and for modelling biological systems. My group scanning sequences for clusters of transcription in Proceedings of 2007 International Symposium on the transcriptome and the study of transcriptome more detail below: biological processes. applies expertise in the development of computer factor binding sites; and Meta-MEME, a general- Computational Models for Life Sciences – CMLS’07, dynamics to identify key genes or transcriptional Integration of transcriptome content is necessary algorithms - using machine learning, data mining, purpose sequence modelling tool. Some of Accepted. programs. to identify key transcripts and novel gene RESEARCH PROJECTS pattern recognition and statistical analysis - to these tools are among the most widely used Dufton, L. and Bodén, M. (2007). Reducing the number The central focus of my research is to perform products driving key phenotypes in model biological problems. Using these technologies, bioinformatics algorithms. For example, the of support vectors to allay ineffi ciency of large-scale • Redefi ning total transcriptome content and global surveys of the transcriptome and systems. The combination of array and sequence dynamics of the mammalian transcriptome and we develop computational tools to help biologists MEME algorithm is used via the UCSD website models in computational biology, in Proceedings of 2007 to use computational mining and genomic tag-based profi ling approaches are providing the studying the role of novel RNAs controlling cellular make predictions from data. by over 1000 biologists around the world each International Symposium on Computational Models for screening techniques to uncover the genes and unprecedented opportunity to survey all variant differentiation and development month. Maintaining these websites and supporting Life Sciences – CMLS’07, Accepted. Our recent work has focused mainly on developing transcriptional programs controlling important transcripts expressed from each locus in model the biologists who use them is an important Frith, M.C., Carninci, P., Kai, C., Kawai, J., Bailey, T.L., • Creating complete transcriptional programs computational tools for studying the process of biological processes such as cell differentiation, systems. Furthermore we are able to study the commitment for us. Hayashizaki, Y., and Mattick, J.M. (2007). Splicing of models of ES differentiation, cell division transcriptional regulation. These include better bypasses 3’ end formation signals to allow complex organogenesis, and tissue repair, as well as role of novel RNA species in RNA-mediated control and organogenesis algorithms for discovering the DNA-binding profi les gene architectures. Gene 403: 188-193. pathological states such as tumour initiation of processes (such as non-coding RNAs, repeat of transcription factors, search algorithms for RESEARCH PROJECTS and progression. Over the last six years we have expression, miRNAs etc) in a non-biased fashion • Creating a combined microarray and in situ Gupta, S., Stamatoyannopolous, J.A., Bailey, T.L., and comparing DNA-binding profi les, search algorithms • Identifying the targets of key transcription factors worked with the FANTOM consortia to re-defi ne using next-generation sequencing approaches. transcriptome atlas for the mammalian Noble, W.S. (2007). Quantifying similarity between for predicting transcription factor binding involved in erythropoiesis transcriptional output for each locus in mouse We are actively pursuing these studies in models urogenital tract motifs. Genome Biology 8: R24. sites (TFBSs), and a computational model of and man, with particular attention paid to: genes of the role of cell-cell communication in ES cell- • Identifying targets of transcription factors using • Analysing Analysing the transcriptome of the extracellular Hawkins, J., Davis, L., and Bodén, M. (2007). Predicting transcriptional control by a cis-regulatory element functional annotation data whose products are associated with developmental directed differentiation and survival, the control of space in mammalian development in Drosophila. We also developed an algorithm Nuclear Localization. Journal of Proteome Research 6: pathways, the phosphoregulators network, and the normal cell division and for the identifi cation of new • Developing next-generation sequencing for predicting the statistical power of comparative • Improving TFBS prediction using epigenetic 1402-1409. extracellular space. bio-markers associated with different subtypes of modifi cation data technologies to allow for combined genomic, genomics approaches to TFBS prediction. Hawkins, J., Mahony, D., Maetschke, S., Wakabayashi, breast cancer. Central to our research is the ability to rapidly transcriptomic and epigenomic profi ling of • Improving TFBS prediction using comparative M., Teasdale, R.D., and Bodén, M. (2007). Identifying We are also interested in proteins, and recently survey transcriptome content and dynamics in Accurately surveying transcriptional complexity in model systems genomics Novel Peroxisomal Proteins. Proteins: Structure, Function developed GLAM2, a motif discovery algorithm that and Bioinformatics 69: 606-616. model systems. The laboratory is heavily involved multicellular organisms has the added complexity allows for gaps in the motif, and DEME, a motif • Improving the training and application of models of in creating and exploiting platform technologies that gene expression needs to be surveyed in a KEY PUBLICATIONS discovery algorithm that discovers motifs that regulation Redhead, E., and Bailey, T.L. (2007). Discriminative motif to create accurate catalogues of gene expression histological context, if one is to accurately model discovery in DNA and protein sequences using the DEME FANTOM3 Consortium and The RIKEN Genome discriminate between two sets of protein or DNA in model systems. Microarray profi ling is used to gene networks controlling development and • Improving motif discovery algorithms Algorithm. BMC Bioinformatics 8: 385. Exploration Research Group Phase I & II Team sequences. We are also studying machine learning monitor the gene activity of loci, next-generation pathology. We are pioneering a joint microarray- (Grimmond, S.M. identifi ed as one of the senior core Tino, P., Hammer, B., and Bodén, M. Markovian bias of approaches for improving protein design. sequencing approaches have been developed to in situ hybridisation screening regime to develop team members.) (2006). Genome-wide analysis of KEY PUBLICATIONS neural-based architectures with feedback connections, survey transcriptional complexity, and robotic in a temporal and spatial gene expression atlas of mammalian promoter architecture and evolution. We place a strong emphasis in delivering useful Perspectives of Neural-Symbolic Integration, Hitzler and Bodén, M. (2008). Predicting nucleolar proteins using situ screening is used to put gene expression into urogenital organogenesis in the mouse (as part Nature Genetics 38: 626-635. computational tools to biologists. We make the Hammer (eds.), Springer Verlag, 2007. In press. support-vector machines, in Proceedings of the a histological context. of the NIH Genito-Urinary Development MAP algorithms we develop available as interactive The FANTOM Consortium and The RIKEN Genome Asia-Pacifi c Bioinformatics Conference – APBC 2008, You, L., Zhang, P., Bodén, M. and Brusic, V. L. program GUDMAP). tools over the web. We support these tools via Accepted. Understanding Prediction Systems for HLA-Binding The next fi ve years will build upon these Exploration Research Group Phase I & II Team websites located at IMB and UCSD. These include recent efforts and focus on the integration of With the avalanche of data being created by (Grimmond, S.M. identifi ed as a senior author.) Hawkins, J., and Bailey, T.L. (2008). “The power of Peptides and T-cell Epitope Identifi cation, in Proceedings MEME, a tool for discovering motifs (sequence transcriptome content, the accurate surveying these approaches, we are actively pursuing new (2005). The transcriptional landscape of the phylogenetic motif models” accepted for publication at of the 2nd IAPR Workshop on Pattern Recognition in patterns) in protein and DNA sequences; MAST, mammalian genome. Science 309: 1559-1563. Recomb 2008. Bioinformatics, Singapore, Springer Verlag, 2007. of transcriptional complexity in multicellular ways to integrate these surveys with genomic,

LAB MEMBERS LAB MEMBERS Research Fellow: Dr Mikael Bodén Senior Research Offi cer: Dr Paul Leo Masters Students: Rathi Thiagarjan, Ajay Panwar Honours Student: Alan Robertson (seconded from ITEE) Research Offi cers: Dr Brooke Gardiner, Dr Alistair Research Offi cers: Dr Martin Frith, Dr John Hawkins Forrest, Dr Nicole Cloonan, Dr Gabriel Kolle, Dr Nicola Waddell, Dr Logan Walker, Dr Ehsan Nourbkash, Programmers: Emma Redhead, Stefan Maetschke Dr Ben Wilson Denis Bauer, Tom Whitington PhD Students: Senior Research Assistants: Graeme Bethel, MPhil Student: Isye Arieshanti Anita Steptoe Visitors: Professor Osamu Maruyama, Fabian Buske, Research Assistants: Milena Gongora, Zuzana Cienikova, Liang Ma Shivangi Wani, Michelle Chan Heatmap of kidney markers from a panel of embryonic Photomicrograph of HEK cells transfected using a PhD Students: Geoff Faulkner, Melissa Brown tissues (12.5dpc). robotically generated cell microarray. Hidden Markov model.

20 Division of Genomics & Computational Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Genomics & Computational Biology 21 Rnomics: Noncoding RNA Computational in Mammalian Evolution Genomics & Development

John Mattick Mark Ragan

We are exploring the thesis that the genetic the tens of thousands of longer non-coding RNAs • Targeted functional analysis of selected non-coding We use advanced computational and data For more information on two specifi c projects, Beiko, R.G., Harlow, T.J., and Ragan, M.A. (2006). programming of higher organisms has been that are dynamically expressed in mammalian RNAs involved in developmental processes and management methods to investigate similarities the Visible CellTM e-project and the Modelling and Searching for convergence in phylogenetic Markov fundamentally misunderstood for the past 50 years, cells. Among our recent fi ndings we have shown neurogenesis and differences among genomes and the proteins Analysis of Biological Network Activity (BioMANTA) chain Monte Carlo. Systematic Biology 55: 553-565. because of the assumption that most genetic that it is possible, if not likely, that most of • Re-aligning the human genome with other they encode. Our goal is to make rigorous project, please see: www.visiblecell.com and Chan, C.X., Beiko, R.G., and Ragan, M.A. (2006). information is transacted by proteins. It is now the mammalian genome is under evolutionary mammalian genomes on the basis of RNA quantitative inferences, at both global and fi ne www.biomanta.org Detecting recombination in evolving nucleotide clear, despite the fact that only a small fraction selection, and demonstrated that the majority of structural rules scales, about how genomes, gene and protein sequences. BMC Bioinformatics 7: 412. encodes proteins, that the majority of the genomes long non-coding RNAs are expressed in the brain, families, regulatory networks and cellular functions • Developing new algorithms for the prediction of RESEARCH PROJECTS Garcia Castro, A., Rocca-Serra, P., Stevens, R., Taylor, of mammals and other complex organisms is many in precise cellular and subcellular locations. have evolved and diversifi ed. different classes of functional non-coding RNAs • Automatically Automatically inferring vertical and lalateralteral C., Nashar, K., Ragan, M.A., and Sansone, S-A. transcribed, apparently in a developmentally We also participated in the international ENCODE To deal with the large quantities of data available, gene transmission, genetic recombination and (2006). The use of concept maps during knowledge regulated manner, and that most complex genetic project to functionally analyse one percent of • Identifying non-coding RNAs as diagnostics and we use advanced data management methods, breakpoints in pathogenic bacteria elicitation in ontology development processes. BMC phenomena in these organisms are RNA-directed. the human genome, and further characterised prognostic markers in cancer implement high-throughput computational Bioinformatics 7: 267. Working in conjunction with collaborators in Japan, unusual features of the non-coding landscape of • Investigating genome dynamics and the evolution workfl ows, and develop new algorithms, Beiko, R.G., Chan, C.X., and Ragan, M.A. (2005). Europe and the United States, we are working the genome, including ultraconserved sequences KEY PUBLICATIONS of new protein functions in teleosts approaches and software. We are particularly A word-oriented approach to alignment validation. to characterise and understand the functions of and transposon-free regions. We use advanced • Fine-scale mapping of orthologous and paralogous Mattick, J.S. (2007). A new paradigm for interested in approaches that let us interrogate Bioinformatics 21: 2230-2239. the mammalian transcriptome, and to validate computational and experimental methods, regions of mammalian genomes developmental biology. Journal of Experimental diverse data types including molecular sequences the prediction that most genetic information in integrating in silico, in vitro and in vivo approaches. Beiko, R.G., Harlow, T.J., and Ragan, M.A. Biology 210: 1526-1547. and structures, signalling pathways, regulatory • Studying protein-protein interaction networks in mammals is conveyed by RNAs that control the The outcomes of our research will be to refi ne our (2005). Highways of gene sharing in prokaryotes. and molecular interaction networks, gene cellular context trajectories of our differentiation and development. understanding of the genomic factors underpinning Taft, R.J., Pheasant, M., and Mattick, J.S. (2007). Proceedings of the National Academy of Sciences The relationship between non-protein-coding DNA expression patterns, subcellular localisation and This includes the identifi cation of small regulatory human development, diversity and disease, • Computationally discovering novel miRNA targets in USA 102: 14332-14337. and eukaryotic complexity. Bioessays 29: 288-299. cellular function. RNAs that control gene expression at various with practical implications in medicine, genetic mammalian genomes Garcia, A., Thoraval, S., Garcia, L.J., and Ragan, levels, including transcription and splicing, and to engineering and advanced programming of self- Mattick, J.S., and Makunin, I.V. (2006). Non-coding Genomes have diversifi ed, both structurally • Integrating bioinformatic information using M.A. (2005). Workfl ows in bioinformatics: meta- determine the expression patterns and function of assembling information systems. RNA. Human Molecular Genetics 15: R17-R29. and functionally, from shared ancestral states. Semantic Web technologies analysis and prototype implementation of a workfl ow We develop methods and employ analytical generator. BMC Bioinformatics 6: 87. Ravasi, T., Suzuki, H., Pang, K.C., Katayama, S., • Implementing the Visible CellTM Project: software pipelines to reconstruct the paths of descent RESEARCH PROJECTS Furuno, M., Okunishi, R., Fukuda, S., Ru, K., Frith, M., and data infrastructure Mar, J.C., Harlow, T.J., and Ragan, M.A. (2005). Gongora, M., Grimmond, S., Hume, D.A., Hayashizaki, (phylogenomics) and to study processes of • Bioinformatically predicting and experimentally Bayesian and maximum likelihood phylogenetic Y., and Mattick, J.S. (2006). Experimental validation • Implementing a data grid for very large molecular validating new microRNAs and other small RNAs in change through time (evolutionary genomics). analyses of protein sequence data under branch- of the regulated expression of large numbers of and image datasets mouse and human We have characterised pathways of lateral length differences and model violation. BMC noncoding RNAs from the mouse genome. genetic transfer where genetic information moves Evolutionary Biology 5: 8. Genome Research 16: 11-19. • Analysing Analysing the dynamic expression of long across, not within, genealogical lineages, and KEY PUBLICATIONS non-coding RNAs during differentiation of Bejerano, G., Pheasant, M., Makunin, I., Stephen, S., have developed a statistically based approach embryonal stem cells, neural stem cells, muscle, Höhl, M., and Ragan, M.A. (2007). Is multiple- Kent, W.J., Mattick, J.S., and Haussler, D. (2004). to discovery of genetically recombined regions macrophages, T-cells and developing tissues such sequence alignment required for accurate inference Ultra-conserved elements in the human genome. as the male and female genital ridge and recombination breakpoints. We are now of phylogeny? Systematic Biology 56: 206-221. Science 304: 1321-1325. applying these approaches to understand • Analysing Analysing the cellular and subcellular expression Beiko, R.G., and Hamilton, N. (2006). Phylogenetic Mattick, J.S. (2004). RNA regulation: a new genetics. genome diversifi cation and the evolution of novel Dynamic expression of non-coding RNAs patterns of non-coding RNAs in brain and other identifi cation of lateral genetic transfer events. BMC Nature Reviews Genetics 5: 316-323. biological properties in bacterial pathogens, during embryonal stem cell differentiation. tissues Evolutionary Biology 6: 15. fi sh and mammals.

LAB MEMBERS LAB MEMBERS Research Offi cers: Dr Marjan Askarian-Amiri, PhD Students: Paulo Amaral, Michael Clark, Senior Research Offi cers: Dr Nicholas Hamilton Queensland Facility for Advanced Manager, ARC Centre of Excellence in Dr Larry Croft, Dr Marcel Dinger, Dr Martin Hansen, Chol Hee Jung, Darren Korbie, Tim Mercer, Bioinformatics Senior Team: Jeremy Barker Bioinformatics: Lanna Wong Research Offi cers: Dr Aaron Darling, Dr Igor Makunin, Dr Harald Oey, Dr Michael Pheasant, Satu Nakhuri, Cas Simons, Stefan Stanley, (CEO), Dr Dominique Gorse (Technical Manager from Dr Karin Kassahn, Dr Simon Wong PhD Students: Cheong Xin Chan, Alex Garcia, Dr Giulia Solda, Dr Lorenzo Malquori Stuart Stephen, Ryan Taft 5/2007), Dr David Hansen (Technical Manager to Chang Jin Shin Research Webmaster: Dr J. Lynn Fink (to 4/2007) 5/2007) Senior Research Assistant: Ke-lin Ru MSc Students: Emmanuelle Billon, Jan Szubert Masters Student: JooYoung Choi Database and Application Developers: BioMANTA-Pfi zer: Dr Melissa Davis, Oliver Cairncross, Dr Ingrid Jakobsen, Dr Muhammad Shoaib Seghal Honours Student: Andrés Esteban-Marcos Dr Tim McComb, Tim Sullivan, David Wood QosCosGRID: Dr Pamela Burrage, International Interns: Arnab Saha Mandal (Indian Data Grid Developers / Administrators: Dr Krzysztof Kurowski Institute of Technology, Kharagpur) Kimberly Begley (Griffi th University/APAC), Validation of bioinformatically Scientifi c Programmer: Chikako Ragan Research Trainees: Vinh Dang, Liam McIntyre predicted small RNAs from mice Mhairi Marshall (ARC Centre of Excellence/APAC) using high-density arrays.

22 Division of Genomics & Computational Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Genomics & Computational Biology 23 Computational How Genes Regulate Cellular Biology Embryo Development

Rohan Teasdale Peter Koopman

Individual cells contain a number of distinct Endosomal Dynamics – The endosomal/lysosomal • Developing algorithms for prediction of protein Our group specialises in studying genes controlling the formation of the lymphatic system. KEY PUBLICATIONS features sub-compartments, termed organelles. These system of mammalian cells is a highly dynamic the formation of various organs in the developing The signifi cant discovery that disruption of Wilhelm, D., Palmer, S., and Koopman, P. (2007). Sex organelles compartmentalise distinct biochemical organelle and the traffi cking pathways within the • Developing computational approaches to analyse embryo. In particular we are striving to understand SOX18 leads to a delay of tumour formation determination and gonadal development in mammals. pathways and cell-based physiological processes. endosomal system are fundamental for a wide image and real-time microscopy data the events that regulate the development of has highlighted SOX18 as a potential target for Physiological Reviews 87: 1-28. Many proteins reside in one specifi c compartment variety of key cellular processes. My group is functional male and female gonads and the antiangiogenic therapy of human cancers. • Studying endosome dynamics, macropinocytosis Bowles, J., Knight, D., Smith, C., Wilhelm, D., Richman, while others are dynamically localised in multiple developing cellular and computational approaches formation of the blood and lymphatic vessels. compartments. My research group is investigating to identify novel mammalian proteins associated and retromer The study of embryo development gives us J., Mamiya, S., Yashiro, K., Chawengsaksophak, K., The discovery of the gene SRY, which acts as profound insight into mechanisms of disease Wilson, M.J., Rossant, J., Hamada, H., and Koopman, P. how individual proteins are compartmentalised with the endosomal system. A major current • Investigating the systems biology of the (2006). Retinoid signaling determines germ cell fate in and defi ning the protein machinery responsible focus of the group is the characterisation of the mammalian endosome a single switch to initiate the male pathway of and cancer. In particular, a detailed knowledge mice. Science 312: 596–600. for their transport with a focus on the mammalian mammalian retromer complex. We have implicated development, was over a decade ago. However, of sex determination will have vast biomedical few pivotal genes up- or down-stream of SRY signifi cance, with up to 80 percent of human endosomal system. this complex, using real-time microscopy and KEY PUBLICATIONS Wilhelm, D., and Koopman, P. (2006). The makings of molecular interaction techniques, in the sorting of have been identifi ed since then, and the exact sex reversal cases currently unexplained. The maleness: Towards an integrated view of male sexual Using a multidisciplinary approach combining Hamilton, N.A., Pantelic, R.S., Hanson, K., and numerous membrane receptors, including EGFR, interactions and functions of those such as SOX9 use of new technologies and the availability of development. Nature Reviews Genetics 7: 620-631. computational biology with cell biology techniques, Teasdale, R.D. (2007). Fast automated cell phenotype within the endosomal system. With my group, Dr B. and WT1 remain elusive. Our lab specialises in multiple species’ genomes may allow us to better we investigate all aspects of this process. My image classifi cation. BMC Bioinformatics 8: 110. Young, N., Hahn, C.N., Poh, A., Dong, C., Wilhelm, Collins has determined the high-resolution crystal the identifi cation and characterisation of genes in understand these cases, and aid in new therapies research combines computational analysis across D., Olsson, J., Muscat, G.E.O., Parsons, P., Gamble, structures of individual retromer proteins and is Sprenger, J. Fink, J.L., Karunaratne, S., Hanson, K., this pathway using techniques such as microarray for patients. Our research also has the potential to entire proteomes with focused investigation into J.R., and Koopman, P. (2006). Effect of disrupted currently attempting to determine the structure of Hamilton, N., and Teasdale, R.D. (2007). LOCATE: A screening and transgenic mouse models created assist the industrial sector through possible pest individual proteins. Consequently, there are two SOX18 transcription factor function on tumor growth, the entire complex. Currently we are undertaking Mammalian Protein Subcellular Localization Database. via pronuclear injection, tetraploid aggregation management and livestock sex-ratio manipulation vascularization, and endothelial development. Journal overlapping streams of work: Nucleic Acids Research 36 (Database issue). a systems biology approach to examine the and RNAi. contributing to the Australian economy and of the National Cancer Institute 98: 1060-1067. Subcellular Localisation - Determination of the biogenesis of macropinosomes. Aturaliya, R.N., Fink, J.L., Davis, M.J., Teasdale, agricultural sectors. subcellular localisation or compartmentalisation M.S., Hanson, K.A., Miranda, K.C., Forrest, A.R.R., Of particular interest are those genes that shape is an essential step in characterising the protein’s Grimmond, S.M., Suzuki, H., Kanamori, M., Kai, C., the somatic cell environment of the gonad in RESEARCH PROJECTS RESEARCH PROJECTS function across all types of biomedical research, Kawai, J., Carninci, P., Hayashizaki, Y., and Teasdale, addition to those that co-ordinate germ cell entry and its modulation needs to be considered when • Annotating Annotating the membrane organisaorganisationtion of R.D. (2006). Subcellular Localisation of Mammalian into mitotic arrest or meiosis. The recent discovery • Understanding Sex Determination and Gonadal mammalian secretory pathway proteins developing pharmaceutical agents. Our major Type II Membrane Proteins. Traffi c 7: 613-625. in our lab that retinoic acid controls germ cell Development long-term objective is to document the subcellular • Maintaining and updating LOCATE: A Mouse Davis, M.J., Hanson, K.A., Clark, F., Fink, J.L., Zhang, meiosis entry in the female gonad has provided a • Studying the Development of Male Germ Cells localisation of every protein within the mouse Protein Subcellular Localisation Database - F., Kasukawa, T., Kai, C., Kawai, J., Carninci, P., pivotal point to understanding this process. Current proteome. This will be achieved by a combination http://locate.imb.uq.edu.au Hayashizaki, Y., and Teasdale, R.D. (2006). Differential projects are also focused on identifying the timing • Investigating Sox Gene Function and Evolution of experimental evidence, computational prediction use of endoplasmic reticulum signal peptides and and mechanism of sex differentiation in the animal • Studying the Molecular Genetics of Vascular and data mining. transmembrane domains is a common occurrence models of bovine and cane toads, in an effort to and Lymphatic Development within the variable protein output of transcriptional manipulate sex ratios and population numbers units. PLOS Genetics 2: e46. • Developing Daughterless Cane Toads respectively. Recombinant organ culture with GFP expressing Kerr, M., Lindsay, M., Luetterforst, R., Hamilton, N., • Triggering Male-Only Offspring Production in A second major focus in our group includes mesonephros (green) and wild type testis allows analysis Simpson, F., Parton, R., Gleeson, P.A., and Teasdale, Beef Cattle investigating the function of Sox genes during of cell migration into the testis during development. R.D. (2006). Visualisation of macropinosome Migrating endothelial cells integrate with endogenous embryo development. Specifi cally we are maturation by the recruitment of sorting nexins. vasculature (yellow and red respectively) which separate Journal of Cell Science 119: 3967-3980. investigating the role of SOX18 in angiogenesis and forming testis cords (blue).

LAB MEMBERS LAB MEMBERS Senior Research Offi cers: Dr Brett Collins, Research Assistants: Seetha Karunaratne, Senior Research Offi cers: Dr Josephine Bowles, PhD Students: Katherine Ewen, Juan Carlos Dr Nick Hamilton, Dr Zheng Yuan Shane Zhang Dr Catherine Browne, Dr Dagmar Wilhelm Polanco, Stephen Bradford, Alexander Combes, Cassy Spiller, Diana Farkas, John Abramyan Research Offi cers: Dr Lynn Fink, Dr Markus Kerr, PhD Students: Rajith Aturaliya, Melissa Davis, Research Offi cers: Dr Annemiek Beverdam, Dr Stefan Maetschke, Dr Suzanne Norwood Daniel Shaw, Josefi ne Sprenger, Jack Wang Dr Mathias Francois, Dr Terje Svingen, UROP Students: James Holland Dr Brett Hosking, Dr Kallayanee Chawengsaksophak

Research Assistants: Tara Davidson, Deon Knight, Desmond Tutt, Allen Feng, Vy Truong, Arief Mulyadi, Danielle Wilson Platelet endothelial cell adhesion molecule (red) vividly Admin Assistant: Rebekka van Kampen outlines germ cell clusters and endothelial cells in a recombinant organ culture. Migrating endothelial cells marked by GFP (green) integrate into the endogenous population to establish testis vasculature.

24 Division of Genomics & Computational Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division Of Molecular Genetics And Development 25 Renal Development, Nuclear Receptors, Disease & Regeneration Skeletal Muscle & Metabolic Disease

Melissa Little George E.O. Muscat

The central theme of this laboratory is the RESEARCH PROJECTS F., and Little, M.H. (2007). Crim1KST264/KST264 Nuclear Hormone Receptors (NRs) control is to examine the role of orphan NRs in skeletal KEY PUBLICATIONS mice display a disruption of the Crim1 gene resulting molecular basis of kidney development, • Characterising the function of potential adult renal metabolism in metabolic, cardiovascular and muscle cell and animal models. We will test the Pearen, M.A., Myers, S.A., Raichur, S., Ryall, J.G., in perinatal lethality with defects in multiple organ disease and repair. stem cells endocrine organs. The importance of NRs in hypothesis that the orphan NR4A and 1F subgroups Lynch, G.S., and Muscat, G.E. (2008). The Orphan systems. Developmental Dynamics 236: 502-511. safeguarding human wellbeing is underscored regulate lipid and energy homeostasis in skeletal Nuclear Receptor, NOR-1, a Target of {beta}- Each of us has a pair of kidneys that functions • Characterising the cap mesenchyme on a Rae, F., Woods, K., Sasmono, T., Campanale, N., by the curative effi cacy of medicinals that target muscle. Recently, our group has provided evidence Adrenergic Signaling, Regulates Gene Expression that to excrete waste products in the form of urine. molecular level Taylor, D., Ovchinnikov, D., Grimmond, S., Hume, D.A., dysfunctional hormone signalling in the context for regulatory crosstalk between beta-adrenergic Controls Oxidative Metabolism in Skeletal Muscle. The kidneys therefore play an important role • Creating an atlas of gene expression during Ricardo, S., and Little, M.H. (2007). Characterisation of infl ammation, cancer, endocrine and metabolic and Nuclear Receptor (NR) 4A signalling in slow- Endocrinology Epub ahead of print in maintaining fl uid balance, blood volume and urogenital development and trophic functions of murine embryonic diseases. Nuclear hormone receptors function twitch oxidative soleus muscle and fast-twitch Raichur, S., Lau, P., Staels, B., and Muscat, G.E. electrolyte balance. On top of this, they regulate macrophages based upon the use of a CSF-1R-EGFP as agonist-dependent DNA-binding factors that glycolytic tibialis anterior muscle in the context of (2008). Retinoid-related orphan receptor gamma blood pressure, bone density and number of • Investigating the role of the resident tissue transgene reporter. Developmental Biology 308: translate nutritional (eg. dietary lipids), metabolic oxidative metabolism. The process involved PKA, regulates several genes that control metabolism in red blood cells via the production of specifi c macrophage in renal regeneration 232-246. and pathophysiological signals into gene regulation. MAPK and phosphorylation of CREB. Secondly, we skeletal muscle cells: links to modulation of reactive growth factors. • Analysing Analysing the role of specifi c ggrowthrowth factors in Wilkinson, L., Gilbert, T., Pennisi, D., Challen, G., Proteins have been identifi ed that belong to the have utilised several mouse models to demonstrate oxygen species production. Journal of Molecular renal development, repair and regeneration Chronic kidney disease (CKD) is a devastating Ruta, L.-A., Kett, M., Cummings, M., and Little, M.H. NR superfamily on the basis of sequence identity, that NR1F subgroup is involved in the regulation of Endocrinology 39: 29-44. (2007). Crim1KST264/KST264 mice implicate Crim1 disease and an expensive one to treat. Once this • Screening the directed dedifferentiation of proximal but the molecules that regulate their activity are (i) serum and liver triglycerides and (ii) adiposity. Smith, A.G., Luk, N., Newton, R.A., Roberts, D.W., in the regulation of VEGF–A activity during glomerular condition has reached end-stage renal failure, it tubule cells using lentiviruses unknown and they are denoted as orphan NRs. Sturm, R.A., and Muscat, G.E. (2008). Melanocortin- vasculature development. Journal of the American In addition, in collaboration with Dr Gary Leong can only be treated with dialysis or transplantation. The orphans provide a platform for the unearthing 1 receptor signalling markedly induces the • Characterising the role of Crim1 in kidney and Society of Nephrology 18: 1697-1708. (joint IMB/Mater Hospital) and Dr Edna Hardeman Each year, more than 4000 Australian adults will be of new signalling cascades that may have potential expression of the NR4A nuclear receptor subgroup vascular development at Children’s Medical Research Institute, Sydney, diagnosed with CKD, which cost the health system Challen, G.A., Bertoncello, I., Deane, J., Ricardo, S., therapeutic utility. in melanocytic cells. Journal of Biological Chemistry we are utilising the Ski transgenic mouse model to $1.8 billion dollars in 2006. This cost is likely to and Little, M.H. (2006). Kidney side population cells Epub ahead of print KEY PUBLICATIONS represent a non-haematopoietic but heterogeneous Many orphan NRs are expressed in skeletal muscle, investigate the role of the ski gene in the metabolic escalate to $4.7 billion by 2010. There is an urgent Myers, S.A., Wang, S.C., and Muscat, G.E. (2006). population with multilineage and renal potential. a peripheral tissue that accounts for ~40 percent changes associated with increased skeletal and need to develop novel therapies as the rate of CKD Little, M., Brennan, J., Georgas, K., Davies, J., The chicken ovalbumin upstream promoter- Journal of the American Society of Nephrology of the total body mass and energy expenditure, and decreased fat mass. is rising at 6-8 percent per annum, primarily due Davidson, D, et al. (2007). A high-resolution transcription factors modulate genes and pathways anatomical ontology of the developing murine 17: 1896-1912. is a major site of fatty acid and glucose oxidation. to increasing rates of Type II diabetes and obesity, involved in skeletal muscle cell metabolism. Journal genitourinary tract. Gene Expression Patterns Moreover, this lean tissue is involved in cholesterol and as only 1 in 4 patients will be lucky enough to Little, M.H. (2006). Regrow or repair – potential RESEARCH PROJECTS of Biological Chemistry 281: 24149-24160. 7: 680-699. effl ux, expresses myostatin and cytokines that receive a kidney transplant. regenerative therapies for the kidney. Journal of the control infl ammation, energy expenditure, lean • Examining the role of the NR1D and F subgroups Pearen, M.A., Ryall, J.G., Maxwell, M.A., Ohkura, N., Pennisi, D.J., Wilkinson, L., Kolle, G., Sohaskey, American Society of Nephrology 17: 2390-2401. (Rev-erb and RORs) in lipid homeostasis and Our laboratory is acknowledged internationally body mass and adiposity. Consequently, muscle Lynch, G.S., and Muscat, G.E. (2006). The orphan M.L., Gillinder, K., Piper, M.J., McAvoy, J., Lovicu, infl ammation nuclear receptor, NOR-1, is a target of beta- for our work in defi ning the genes involved in has a signifi cant role in insulin sensitivity, the blood adrenergic signaling in skeletal muscle. Endocrinology lipid profi le, and energy balance. Therefore, the • Elucidating the role of the NR4A subgroup (Nur77, normal kidney development and in dissecting the 147: 5217-5227. molecular basis of renal disease. The long-term tissue has a notable role in the development of NOR-1) in skeletal muscle energy balance and aim of our laboratory is to develop novel cell-based metabolic disease, and it is not surprising that NRs adrenergic signalling Smith, A.G., and Muscat, G.E. (2006). Orphan and skeletal muscle are emerging as targets in the nuclear receptors: therapeutic opportunities in or factor-based therapies for both acute and • Determining the role and function of the Ski chronic kidney disease. Such therapies will grow battle against diabetes and obesity. skeletal muscle. American Journal of Physiology: Cell gene in body composition and metabolism via Physiology 291: C203-17. out of our understanding of the processes involved Surprisingly, the function of these orphan NRs modulation of NR-dependent metabolism in in normal kidney development. in skeletal muscle metabolism has not been skeletal muscle, fat and liver Reaggregation assay – proof of concept. Live imaging (70kDa Rhodamine-dextran) of adult examined. The objective of our current research kidneys shows profound leakiness across the GBM.

LAB MEMBERS LAB MEMBERS Research Offi cers: Dr Thierry Gilbert, Research Offi cers: Dr Patrick Lau, Dr Lorine Wilkinson, Dr David Pennisi, Dr Fiona Rae, Dr Stephen Myers, Dr Mary Wang, Dr Aaron Smith Dr Joan Li Research Assistants: Rebecca Fitzsimmons, Research Assistants: Kylie Georgas, Bree Rumballe, Rachel Burow Jess Ineson, Emmanuelle Lesieur, Han Chui, Crystal McGirr PhD Students: Michael Pearen, Sathiya Ramakrishnan, Suryaprakash Raichur, Lisa Crowther PhD Students: Genevieve Kinna, Michael Lusis, Muscat2.tif - β2-adrenergic2-adrenergic aagonistgonist increases Caroline Hopkins Dr Gary Leong (Joint appointment Senior Research NR4A2/Nurr1 mRNA expression in slow oxidativeoxidative Offi cer, IMB, and Staff Specialist, Mater Childrens (soleus) and fast glycolyticglycolytic (tibialis anterior & Hospital, NHMRC Clinical CDA & QLD Smart State plantaris) skeletal muscle. Clinical Research Fellow) Rhodamine-dextran is evident in proximal tubules of KST264 adults. Research Assistant: Nick Martel

26 Division of Molecular Genetics & Development Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division Of Molecular Genetics And Development 27 Blood Development Human Pigmentation Genetics, Melanocyte Biology & Melanoma

Andrew Perkins Rick Sturm

Our group is interested in the transcriptional which lead to the generation and ‘education’ of Gardiner, M.R., Gongora, M.M., Grimmond, S.M., and The genetic and cellular understanding of human white populations. SNPs spanning the OCA2 region • Undertaking parallel genetic and cellular analysis regulation mesoderm specifi cation. We are primarily stem cells within the mesoderm germ layer. Once Perkins, A.C. (2007). A global role for zebrafi sh klf4 in pigmentary traits is vital to assess an individual’s were typed in a collection of 3839 adolescent twins, of human melanogenesis embryonic erythropoiesis. Mechanics of Development response to sun exposure and their risk of skin their siblings, and parents. The highest association concerned with transcriptional hierarchies and how again we are concerned primarily with the activities • Investigating eye colour as a genetic trait transcription factors work within biochemical and of key ‘master regulator’ transcription factors of 124: 762-764. cancer. We are investigating loci within the human for blue:non-blue eye colour was found for a major • Researching melanocytic spheroids as a model genetic pathways, and also how deregulation of such zinc fi nger and homeodomain classes. We have Wilkins, S.J., Yoong, S., Verkade, H., Mizoguchi, T., genome that are responsible for an individual’s haplotype block mapping within the fi rst intron for melanoma development and metastasis programs leads to cancer. Our group uses mouse established expression profi ling in zebrafi sh and Plowman, S.J., Hancock, J.F., Kikuchi, Y., Heath, J.K., pigmentation phenotype and identifying polymorphic of the OCA2 gene, notably this haplotype (TGT) and zebrafi sh model systems to examine gene have established assays and systems for study of and Perkins, A.C. (2007). Mtx2 directs zebrafi sh alleles of these genes. A number of proteins representing 78.4 percent of alleles. The TGT/TGT function in vivo, and a wide variety of biochemical morphogenesis. morphogenetic movements during epiboly by essential to normal melanin biosynthesis have so far diplotype found in 62.2 percent of samples was the KEY PUBLICATIONS been identifi ed and include the enzymes tyrosinase, major genotype seen to modify eye colour, with a assays to examine gene function in vitro. regulating microfi lament formation. Developmental Beaumont, K.A., Shekar, S.N., Newton, R.A., James, 4. The role played by the Kruppel-like factor (KLF) tyrosinase-related protein-1 and dopachrome frequency of 0.905 in blue or green compared to Biology 314: 12-22. M.R., Stow, J.L., Duffy, D.L., and Sturm, R.A. (2007). We have four primary focus areas: family of zinc fi nger genes in normal differentiation tautomerase (TYR, TYRP1 and DCT), while the only 0.095 in brown eye colour. Hodge, D., Coghill, E., Maguire, T., Keys, J., Hartmann, Receptor function, dominant negative activity and and human skin, colon and blood cancers. P-protein (OCA2) is associated with blue eye 1. Transcriptional hierarchies which are active B., Weiss, M., McDowall, A., Grimmond, S., and Investigations into pigment cell biology have utilised phenotype correlations for MC1R variant alleles. colour, and the melanocortin-1 receptor (MC1R) is Human Molecular Genetics 16: 2249-2260. during embryonic stem (ES) cell differentiation Perkins, A.C. (2006). A global role for EKLF in cultures of both murine and human melanocytes, responsible for red hair colour. Furthermore, recent into mesoderm-derived tissues such as the kidney RESEARCH PROJECTS defi nitive and primitive haematopoiesis. Blood 107: as well as numerous melanoma cell lines. We Duffy, D.L., Montgomery, G.W., Chen, W., Zhao, Z.Z., population-specifi c polymorphisms within the MATP and blood. The methodologies used include: • Studying transcriptional hierarchies active during 3357-3370. have published conditions for the isolation and Le, L., James, M.R., Hayward, N.K., Martin, N.G., (SLC45A2) and NCKX5 (SLC24A5) protein-coding directed differentiation of ES cells in various ES cell differentiation into mesoderm-derived propagation of human epidermal melanocyte and Sturm, R.A. (2007). A three-SNP haplotype in Papathanasiou, P., Perkins, A.C., Cobb, B.S., Ferrini, regions have been correlated with the degree of recombinant growth factors, gene targeting and BAC tissues precursors, termed melanoblasts, using medium the intron 1 of OCA2 explains most human eye color R., Sridharan, R., Hoyne, G.F., Nelms, K.A., Smale, pigmentation in human skin. recombineering for generating reporter ES cell lines supplemented with a range of growth factors variation. American Journal of Human Genetics • Investigating the transcriptional regulation of S.T., and Goodnow, C.C. (2003). Widespread failure of and mice in which stem cells can be followed by Our group has found that coding region variation and which differentiate into melanocytes upon 80: 241-252. erythropoiesis hematolymphoid differentiation caused by a recessive epifl uorescence and FACS, expression profi ling and niche-fi lling allele of the Ikaros transcription factor. within the MC1R gene can result in altered receptor mitogen withdrawal. Recent publications have Sturm, R.A. (2006). A golden age of human chromatin immuno-precipitation. • Studying morphogenesis using zebrafi sh models Immunity 19: 131-144. activity and that this underlies the association with suggested that melanoma may arise from the pigmentation genetics. Trends in Genetics the red hair and fair skin phenotype (RHC). Nine malignant transformation of melanocytic precursor 22: 464-468. (Journal Cover) 2. Transcriptional regulation of erythropoiesis. • Investigating the role of KLFs in differentiation and Perkins, A.C., Sharp, A.H., and Orkin, S.H. (1995). common alleles have been studied and designated cells residing in the skin. Our proposal is to Mutations in the globin genes are the most common cancer Lethal β-thalassemia in mice lacking the erythroid Beaumont, K.A., Newton, R.A., Smit, D.J., Leonard, as either R (strongly associated with the RHC study potential differences in the transcriptional J.H., Stow, J.L., and Sturm, R.A. (2005). Altered cell genetic mutations worldwide. These mutations are CACCC-transcription factor EKLF. Nature 375: 318- 322. phenotype) or r (with lower penetrance). Using and signalling network of skin-derived precursor surface expression of human MC1R variant receptor responsible for thalassaemia and sickle cell disease, KEY PUBLICATIONS immunofl uorescence and ligand binding studies, (SKP) cells, when grown in vitro as spheroids and alleles associated with red hair and skin cancer risk. which cause serious morbidity and mortality around Bruce, S.J., Gardiner, B.B., Burke, L.J., Cridland, S., we have found that melanocytic cells expressing differentiated into melanocytes. We aim to identify Human Molecular Genetics 14: 2145-2154. the world. We are interested in trying to decipher Steptoe, A., Flanagan, J., Gongora, M., Grimmond, MC1R show strong surface localisation of the the differentiation and regulatory pathways active Duffy, D.L., Box, N.F., Chen, W., Palmer, J.S., the complex process of haemoglobin switching at a S.M., and Perkins, A.C. (2007). Dynamic transcription wildtype receptor but markedly reduced cell surface in normal melanocyte growth that differ to those Montgomery, G.W., James, M.R., Hayward, N.K., molecular level. The long-term goal is to design new programs during ES cell differentiation towards expression of some R variants. Moreover, MC1R responsible for melanoma development, and Martin, N.G., and Sturm, R.A. (2004). Interactive drugs that target key regulators of this process and mesoderm in serum versus serum-free (BMP4) variants can exert dominant negative activity on formation of spheroids from melanoma cell lines. effects of MC1R and OCA2 on melanoma risk thereby reactivate foetal haemoglobin in adults. culture. BMC Genomics 8: 365. the wildtype receptor indicative of the ability of the phenotypes. Human Molecular Genetics receptor to homodimerize. We have also conducted 13: 447-461. (Journal Cover) 3. Zebrafi sh are used as a vertebrate model for Bruce, S.J., Rossiter, A.L., Steptoe, A.L., Busslinger, RESEARCH PROJECTS M., Bertram, J.F., and Perkins, A.C. (2007). A late genotyping studies to investigate the role of the dissection of some of the earliest transcriptional • Understanding skin cancer risk phenotypes through Sturm, R.A., and Frudakis, T.N. (2004). Eye colour: Kidney Gene Expression Program within Mouse OCA2 locus in inheritance of eye colour and other studying the interaction of genes involved in skin, portals into pigmentation genes and ancestry. events which underpin morphogenetic movements pigmentary traits associated with skin cancer risk in Embryoid Bodies. Differentiation 75: 337-349. hair and eye colour Trends in Genetics 20: 327-332. (Journal Cover)

LAB MEMBERS LAB MEMBERS Senior Research Offi cer: Dr Janelle Keys Research Assistants: Aliesha Griffi n, Research Offi cer: Dr Anthony Cook (Cooley’s Anemia Post-doctoral Research Fellow) Natalie Eriksson Research Assistants: Darren Smit, Caroline Sturm, Research Offi cers: Dr Christine Neyt, PhD Students: Simon Wilkins, Simon Cridland, Amy Thurber Dr Stephen Bruce Melissa Gardiner, Michael Tallack, Paulo Amaral, Helene Johanson, Luke Kirkwood, Tom Whittington PhD Students: Senior Research Assistants: Angela Lawton, Don Roberts, Kimberley Beaumont Anita Steptoe Honours Student: Wen Lim Undergraduate Student: Poh Yuen Chin

Melanocytes and melanosomes.

28 Division of Molecular Genetics & Development Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division Of Molecular Genetics And Development 29 Tissue Repair & Cancer Developmental Genes & Human Disease

Brandon Wainwright Carol Wicking

Using genomic approaches our group mapped fi brosis we are gaining an understanding of how • Controlling the stem cell niche in mammalian Defects arising from abnormal embryonic patterning in the vertebrate limb. We are therefore Simpson, F., Lammerts van Bueren, K., Butterfi eld, and isolated genes affecting two human genetic infection and infl ammation in this disorder damage epidermis and skin cancer development are a major cause of infant mortality using a number of mouse models of Hedgehog N., Bennetts, J.S., Bowles, J., Adolphe, C., Simms, conditions, cystic fi brosis (CF) and naevoid basal the lung epithelium and severely compromise lung and childhood disability. Many such disorders signalling to further explore the function of this L.A., Young, J., Walsh, M.D., Leggett, B., Fowles, • Studying infection, infl ammation and repair in L.F., and Wicking, C. (2006). The PCNA-associated cell carcinoma syndrome (NBCCS). From this work function. At the same time, in order to provide cystic fi brosis mice and cystic fi brosis infants are characterised by anomalies of the limbs and pathway in limb development. has emerged a focus upon the pathways that lead new therapeutic avenues, we are analysing the craniofacial region, suggesting a conservation of factor KIAA0101/p15PAF binds the potential tumour suppressor product p33ING1b. Experimental Cell to infl ammation, tissue repair and proliferation in molecular signature of repair of the lung epithelium • Controlling lung regeneration following injury the molecular development of these structures. RESEARCH PROJECTS Research 312: 73-85. the context of these two diseases. In particular using the patched/hedgehog pathway as a start Using the mouse as a model system, we aim • Studying conditional knockout of the Hedgehog the patched gene, discovered from our studies on point. The processes of infl ammation, damage, KEY PUBLICATIONS to identify and characterise novel molecules McGlinn, E., Lammerts van Bueren, K., Fiorenza, receptor patched in the developing mouse limb contributing to the development of the limb S., Mo, R., Poh, A., Forrest, A., Soares, M.B., NBCCS, has defi ned a signalling pathway known repair and cancer are intimately connected and to Ingram, W., McCue, K., Tran, T., Hallahan, A., and Bonaldo, M., Grimmond, S., Hui, C.C., Wainwright, as the (“hedgehog pathway”) which appears to be gain an insight into one process enables progress Wainwright, B. (2007). Sonic hedgehog regulates and face, with particular emphasis on genes • Identifying and analysing genes regulated by the B., and Wicking, C. (2005). Pax9 and Jagged1 act mutated or perturbed in a wide range of tumour in all to be made. This will lead us to a better Hes1 through a novel mechanism that is independent regulated by the Hedgehog signalling pathway. transcription factor Gli3 in the developing limb downstream of Gli3 in vertebrate limb development. types, including lung, gastro-intestinal, skin, understanding of how cell-based therapies might of canonical Notch pathway signalling. Oncogene Because of the importance of Hedgehog and • Identifying and analysing genes expressed in the Mechanisms of Development 122: 1218-1233. pancreatic, prostate, brain and ovarian cancer. be used to treat lung diseases as well as likely 27: 1489-1500. other developmental signalling pathways in facial primordia This has led us to focus on the role of hedgehog provide valuable insights into the mechanism of tumorigenesis, many of these genes will also be Simpson, F., Martin, S., Evans, T., Kerr, M., James, McMorran, B., Patat, S., Carlin, J., Grimwood, K., important in cancer. • Analysing Analysing a novel regularegulatortor of cell migmigrationration on a D.E., Parton, R.G., Teasdale, R.D., and Wicking, C. signalling, not only in cancer but also on the lung cancer. Jones, A., Armstrong, D., Galati, J., Cooper, P., Byrnes, cellular level (2005). A novel Hook-related protein family and the regulation of stem cell compartments. Increasingly C., Francis, P., Robertson, C., Hume, D., Borchers, Using genomics-based approaches we have As part of our experimental approach our characterisation of Hook-related protein 1. Traffi c 6: it appears that in some tumour types there are C., Wainwright, C., and Wainwright, B. (2007). Novel laboratory makes extensive use of transgenic identifi ed a number of novel or poorly characterised 442-458. cells known as “cancer stem cells” which reside neutrophil-derived proteins in bronchoalveolar lavage KEY PUBLICATIONS and knockout mice. However at all points we refer genes with potential roles in embryonic within the tumour and are responsible for the fl uid indicate an exaggerated infl ammatory response development and disease. For those genes of Bennetts, J.S., Rendtorff, N.D., Simpson, F., Evans, T.M., Ferguson, C., Wainwright, B.J., Parton, back to the human diseases under study and have in pediatric cystic fi brosis patients. Clinical Chemistry overall phenotype. Currently such cells can be interest we are undertaking a more detailed Tranebjaerg, L., and Wicking, C. (2007). The coding R.G., and Wicking, C. (2003). Rab23, a negative major activities based around mutation analysis, 53: 182-91. partially defi ned functionally but their molecular characterisation at both the cell and whole- region of TP53INP2, a gene expressed in the regulator of hedgehog signaling, localizes to the transcriptomics and proteomics of human material, developing nervous system, is not altered in a family plasma membrane and the endocytic pathway. signature remains elusive. We believe that the Adolphe, C., Hetherington, R., Ellis, T., and organism level. We employ standard cell biology integrating the data from all systems. with autosomal recessive non-progressive infantile Traffi c 4: 869-884. patched/hedgehog pathway defi nes many of the Wainwright, B. (2006). Patched1 functions as a and biochemical techniques to shed light on the ataxia on chromosome 20q11-q13. Developmental characteristics of such stem cells and is a powerful As a result of these studies we have a particular gatekeeper by promoting cell cycle progression. cellular role of these molecules, and in some cases Dynamics 236: 843-852. Whole mount in situ starting point for understanding tumour biology and interest in the interface between developmental Cancer Research 66: 2081-2088. are using transgenic or knockout approaches in hybridisation in mouse the development of new therapeutics. Bennetts, J.S., Fowles, L.F., Berkman, J.L., Lammerts cell biology and human genetics, and in therapeutic Adolphe, C., Narang, M., Ellis, T., Wicking, C., Kaur, the mouse to elucidate function. We are currently embryos is used to van Bueren, K., Richman, J.M., Simpson, F., and interventions such as gene or cell therapies. P., and Wainwright, B. (2004). An in vivo comparative pursuing analysis of a protein that we have determine spatio-temporal Given that cancer represents a state of unregulated Wicking, C. (2006). Evolutionary conservation and study of sonic, desert and Indian hedgehog reveals shown regulates cell migration. Our ultimate aim gene expression. cell growth, it is likely that the pathways that lead murine embryonic expression of the gene encoding that hedgehog pathway activity regulates epidermal is to correlate the genes we identify with human to cancer are also involved in the normal process RESEARCH PROJECTS the SERTA domain-containing protein CDCA4 (HEPP). stem cell homeostasis. Development 131: disease, and we are currently analysing a number of tissue growth and repair. Several of our studies • Controlling neuronal stem cells and CNS by the Gene 374: 153-165. 5009-5019. of genes for a role in tumour formation and/or are particularly directed at the role of the hedgehog patched/hedgehog pathway progression. Hollway, G.E., Maule, J., Gautier, P., Evans, T.M., (and other pathways) in repair and regeneration. • Investigating the molecular basis of primary brain Keenan, D.G., Lohs, C., Fischer, D., Wicking, C., and The limb bud has long been considered a In our laboratory this is a developing theme and tumours Currie, P.D. (2006). Scube2 mediates Hedgehog focused upon the lung. From our studies on cystic paradigm for analysis of embryonic development, signaling in the zebrafi sh embryo. Developmental and Hedgehog signalling is a key determinant of Biology 294: 104-118.

LAB MEMBERS LAB MEMBERS Senior Research Offi cer: Dr Tammy Ellis Senior Research Offi cer: Dr Fiona Simpson (RD Wright Fellow) Research Offi cers: Dr James Palmer, Dr Richa Dave, Dr Elaine Costelloe Research Offi cer: Dr Kerry Manton Research Assistants: Ailsa McCormack, Research Assistant: Vicki Metzis High density micromass culture established from limb Melissa Bourboulas mesenchymal cells and stained with Alcian blue to detect PhD Students: Natalie Butterfi eld, Liam Town PhD Students: Karen McCue, Rehan Villani, Uda Ho, sulfated proteoglycans associated with cartilage. This Elaine Haase, Jonathon Robson, Lena Constantin, Loss of patched leads directly to skin tumours. method is used to study chondrogenesis in vitro. Honours Student: Amanda Bain Azita Ahadizadeh Visiting Student: Diane Schluep (Netherlands) Masters Student: Ann-Marie Michalski Immunofl uorescence analysis to reveal subcellular Honours Student: Larissa Upward localisation of proteins can provide insight into function.

30 Division of Molecular Genetics & Development Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division Of Molecular Genetics And Development 31 Plasma Membrane Microstructure Structure-function Studies & Signal Transduction of The Endocrine Pancreas – Comparative Studies of Mouse & Human Pancreatic Islet Biology

John Hancock Brad Marsh

Our group studies mammalian intracellular RESEARCH PROJECTS Harding, A., Tian, T., Westbury, E., Frische, E., The ß-cells of the endocrine pancreas are the To complement our move toward an integrated donors obtained within Australia. These human and Hancock, J.F. (2005). Subcellular localization studies will be carried out concurrently with key signalling. We are especially interested in the • Molecular mapping of the proteins and lipids of sole source of insulin in mammals. Death of the or more holistic approach to understanding determines MAP Kinase signal output. Current Biology mouse models for T1D and viral uptake/infection of function of Ras proteins. These small GTP binding plasma membrane microdomains ß-cells, or their abnormal processing, traffi cking cells as examples of complex systems, we have proteins operate as molecular switches in signal 15: 869-873. and/or secretion of insulin, results in the disease undertaken a multi-scale/multi-resolution approach islet cells. • Electron microscopic visualisation and quantitative transduction pathways and are present in a Plowman, S., Muncke, C., Parton, R.G., and Hancock, commonly known as diabetes. This disease is whereby we have started reconstructing entire characterisation of surface microdomains to build mutant, activated state in many human tumours. J.F. (2005). H-ras, K-ras and inner plasma membrane one of Australia’s national health priority areas mammalian (ß) cells in 3D at both high (≤5nm) KEY PUBLICATIONS up a high-resolution 2D map of the microdomains Understanding the basic biology of Ras has raft proteins operate in nanoclusters with differential and represents the fastest-growing epidemic and intermediate (15-20nm) resolutions. These of the inner plasma membrane Noske, A.B., Costin, A.J., Morgan, G.P., and Marsh, internationally. More than 230 million people approaches underpin the Visible CellTM project major implications for the development of novel dependence on the actin cytoskeleton. Proceedings B.J. (2008). Expedited approaches to whole cell anticancer therapeutics. • Investigating the dynamic regulation of of the National Academy of Sciences USA 102: worldwide currently live with the disease, but this (www.visiblecell.com) coordinated between the electron tomography and organelle mark-up in situ microdomain localisation of Ras and Ras- 15500-15505. number is expected to rise to 350 million within IMB and the Australian Centre of Excellence in high-pressure frozen pancreatic islets. Journal of Specifi cally, we are investigating how the Ras interacting proteins in response to physiological 20 years. In 2007, the world spent an estimated in Bioinformatics (ACB) at The University of Roy, S., Plowman, S., Rotblat, B., Prior, I.A., Muncke, Structural Biology 161: 298-313. membrane anchors cooperate with the G-domain stimuli US$215-375 billion to care for diabetes and its Queensland. Our group’s data will uniquely inform C., Parton, R.G., Henis, Y.I., Kloog, Y., and Hancock, and peptide sequences fl anking the anchor to drive complications. In particular, type 1 diabetes is one advanced in silico studies of 3D cell and molecular Brunham, L.R., Kruit, J.K., Pape, T.D., Timmins, J.M., • Characterising the mechanism(s) whereby K-ras is J.F. (2005). Individual palmitoyl residues serve distinct Reuwer, A.Q., Vasanji, Z., Marsh, B.J., Rodrigues, lateral segregation. Our work suggests new models of Australia’s fastest-growing chronic diseases, organisation in mammalian cells that are focused transported to the plasma membrane roles in H-Ras traffi cking, microlocalization and B., Johnson, J.D., Parks, J.S., Verchere, C.B., and are needed to explain how lipidated proteins and represents a life-long autoimmune disease on developing the capacity to model and predict signaling. Molecular Cell Biology 25: 6722-6733. Hayden, M.R. (2007). Beta-cell ABCA1 infl uences interact with, and use, the plasma membrane to • Mathematically modelling Ras signal transduction that usually begins in childhood and results in cellular differentiation during normal development, insulin secretion, glucose homeostasis and response generate signalling platforms. premature death through health complications. as well as the pathophysiology of chronic diseases • Monte Carlo modelling of plasma membrane (a) Depleting plasma to thiazolidinedione treatment. Nature Medicine 13: membrane cholesterol with Type 1 diabetes cannot be prevented, and a cure like type 1 diabetes. We remain interested in how confi nement of microdomain dynamics 340-347. the drug MCD reorganises remains to be found. signalling complexes onto a 2D surface in general, the actin cytoskeleton: Marsh, B.J., Soden, C., Alarcón, C., Wicksteed, B.L., and in plasma membrane microdomains in KEY PUBLICATIONS compare the control panel Our group’s research is focused on understanding NEW RESEARCH PROJECTS Yaekura, K., Costin, A.J., Morgan, G.P., and Rhodes, (a) with a cholesterol- particular, regulates the kinetics and sensitivity of Tian, T., Harding, A., Inder, K., Plowman, S.J., Parton, the basic mechanisms related to ß-cell function As the only Australian research group within the C.J. (2007). Regulated autophagy controls hormone depleted cell (b). Raf/MEK/Erk signal output. Similarly, as we develop R.G., and Hancock, J.F. (2007). Plasma membrane and dysfunction from a structural cell biology nPOD program (Network for Pancreatic Organ donors content in secretory-defi cient pancreatic endocrine our spatial and proteomic maps of the plasma nanoswitches generate high-fi delity Ras signal perspective, so that we can precisely identify with Diabetes) in North America, we are currently beta-cells. Molecular Endocrinology 21: 2255-2269. (b) how and where defects in these steps occur. working to establish high-resolution structural studies membrane, we can address how the composition transduction. Nature Cell Biology 9: 905-914. Uchizono, Y., Alarcón, C., Wicksteed, B.L., Marsh, By necessity, this work has led us to develop or of human islet tissue from islet autoantibody-positive and organisation of the membrane alters in B.J., and Rhodes, C.J. (2007). The balance between Hancock, J.F. (2006). Lipid rafts: contentious only donors to detect/compare early changes in islet cell response to specifi c growth factors. The integration advance techniques for the improved preservation proinsulin biosynthesis and insulin secretion: from simplistic standpoints. Nature Reviews Molecular health and topology against baseline data that we are of complex spatial, kinetic and biochemical data and imaging of pancreatic ß-cells in situ within where can imbalance lead? Diabetes, Obesity and Cell Biology 7: 456-462. now acquiring regularly from human islets isolated pancreatic islets of Langerhans isolated from Metabolism 9: 56–66. sets increasingly requires mathematical modelling from both normal/healthy and type 2 diabetic (T2D) to generate and test our novel hypotheses of Nicolau Jr., D.V., Burrage, K., Parton, R.G., and both mice and humans, so that we are positioned Hancock, J.F. (2006). Identifying optimal lipid raft microdomain structure and function. to reliably elucidate the basic cell biology and characteristics required to promote nano-scale physiology of the ß-cell — and islet biology more We also have a major interest in characterising the protein-protein interactions on the plasma membrane. generally — through comparative studies of islet K-ras ER to plasma membrane traffi cking pathway Molecular Cell Biology 26: 313-323. cell structure-function. and studying the biology of Ras prenyl binding Hancock, J.F., and Parton, R.G. (2005). Ras plasma proteins such as PDE delta. membrane signalling platforms. Biochemical Journal 389: 1-11.

LAB MEMBERS: LAB MEMBERS Research Offi cers: Dr Michael Hanzal-Bayer, Research Offi cers: Dr Isabel Morrow, Dr Michelle Hill, Dr Sarah Plowman, Dr Tobias Richter, Dr Neelima Pottekkat Dr Daniel Abankwa, Dr Kerry Inder Sidharthan

Research Assistants: Annette Lane, Dorothy Loos, Research Assistants: Janette Galea, (b) Natasha Ray, Nicholas Ariotti Jaclyn Goh, Garry Morgan, Timothy Pan

Cholesterol depletion also causes the lipid raft marker PhD Students: Andrew Goodall, Kwang-Jin Cho PhD Students: Adam Costin, Alex Foo, protein GFP-Th, imaged on intact plasma membrane Andrew Noske, Peter van der Heide sheets by immunogold labelling (a) to de-cluster: M.Phil Student: Daniel Nicolau Jr. immunogold-point patterns are analysed using spatial Visiting Scholar: Meike Leuger statistics (b).

(a)

32 Division of Molecular Cell Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Molecular Cell Biology 33 Fungal Genetics Applied to The Cell Surface in Human Disease & Crop Protection Health & Disease

Alan Munn Rob Parton

High-throughput approaches have facilitated may have the ability to permanently alter the RESEARCH PROJECTS Our group is interested in the organisation, • Caveolae and caveolin-3 in muscle: analysing Kirkham, M., Fujita, A., Chadda, R., Nixon, S.J. the role of caveolin-3 and caveolae in muscle Kurzchalia, T.V., Sharma, D.K., Pagano, R.E., the identifi cation of genes whose expression conformation and physiological activity of proteins • The actin cytoskeleton in health and disease dynamics, and functions of the plasma membrane. is altered during development or in disease. they transiently interact with. The process we The properties of the plasma membrane rely development and in muscular dystrophy Hancock, J.F., Mayor, S., and Parton, R.G. (2005). • Endosomal sorting machinery as a novel target for Ultrastructural identifi cation of uncoated caveolin- Identifi cation of the genes affected is, however, have uncovered may play a profound, but as yet on the specialisation of the plasma membrane • Caveolae and obesity: dissecting the role of antivirals independent early endocytic vehicles. Journal of Cell only a starting point. There is an increasing largely unexplored, role in human maladies such into microdomains of specifi c function. We have caveolins and Rab proteins in lipid droplet Biology 168: 465-476. realisation that a single gene and its product(s) as cancer, immunodefi ciency and neurological • Fungal pathogens of wheat particularly focused our attention on caveolae, formation and function in adipose tissue and often have multiple and sometimes diverse, diseases. a fascinating domain of the cell surface with a during liver regeneration Martin, S., Driessen, K., Nixon, S.J., Zerial, M., and distinct structure. Caveolae have been implicated Parton, R.G. (2005). Regulated localization of Rab18 complex, and even antagonistic roles in the cell. • Caveolins and caveolin-interacting proteins in Virus infection is another area where human and KEY PUBLICATIONS to lipid droplets: effects of lipolytic stimulation and Understanding the role(s) of the affected genes in regulation of cell growth and in maintaining the zebrafi sh: using zebrafi sh as a model system yeast processes are similar. Viruses hijack and Desmond, O.J., Manners, J.M., Stephens, A.E., inhibition of lipid droplet catabolism. Journal of and their products is essential for translation of balance of lipids in the cell. In addition, caveolae to understand the role of caveolae during utilise host cell machineries during infection. This Maclean, D.J., Schenk, P.M., Gardiner, D.M., Munn, Biological Chemistry 280: 42325-42335. basic discoveries into outcomes for human health. and caveolins, the major proteins of caveolae have development and the effect of muscular dystrophy makes these host machineries potential anti-viral A.L., and Kazan, K. (2008). The Fusarium mycotoxin For many disease genes and their products the been implicated in a number of disease states mutants of caveolin-3 on muscle structure and Matsuo, H., Chevallier, J., Mayran, N., Le Blanc, deoxynivalenol elicits hydrogen peroxide production, drug targets. Work from a number of virology including tumour formation, atherosclerosis, and function I., Ferguson, C., Faure, J., Blanc, N.S., Matile, S., available functional data are severely limited programmed cell death and defence responses in groups has identifi ed the endosomal sorting muscular dystrophy. To study caveolae function Dubochet, J., Sadoul, R., Parton, R.G., Vilbois, F., or non-existent. Much of the work in the Munn wheat. Molecular Plant Pathology In press • Clathrin-independent endocytosis: characterising machinery as a host cell machinery utilised by and Gruenberg, J. (2004). Role of LBPA and Alix in group has focused on understanding the role(s) and, in particular, the link between lipid regulation the structure and function of a novel endocytic an especially diverse group of viruses (e.g. ebola, Vajjhala, P.R., Nguyen, C.H., Landsberg, M.J., Kistler, C., multivesicular liposome formation and endosome of genes and their products linked to human and cancer, we are using caveolae-null mice, cells pathway in mammalian cells and the zebrafi sh herpes, HIV, hepatitis B, mumps). In healthy cells Gan, A., King, G.F., Hankamer, B., and Munn, A.L. (2008). organization. Science 303: 531-534. diseases. Assigning functions to disease genes lacking caveolins, and zebrafi sh embryos. These this machinery works to package and dispose of The Vps4 C-terminal helix is a critical determinant for • Caveolae formation and structure: studying systems are also being used to study the role of Miaczynska, M., Christoforidis, S., Giner, A., has relied very heavily on genetic approaches Vps4 assembly and ATPase activity and has elements caveolae biogenesis and caveolae structure in cellular waste products. In infected cells, however, caveolae in muscle and the molecular changes Shevchenko, A.,Uttenweiler-Joseph, S., Habermann, using model organisms. Yeast (a unicellular conserved in other members of the meiotic clade of AAA health and disease using electron tomography it packages and exports viruses. Discoveries B., Wilm, M., Parton, R.G., and Zerial, M. (2004). fungus) is the most powerful and widely used ATPases. FEBS Journal 275: 1427-1449. associated with muscular dystrophy. In 2007 we made in the Munn group over the past year have (with Dr Brad Marsh) and novel cell systems of these model organisms. Not every human discovered a new caveolar coat protein, which APPL proteins link Rab5 to nuclear signal identifi ed how this machinery is targeted to Thanabalu, T., Rajmohan, R., Meng, L., Ren, G., Vajjhala, transduction via an endosomal compartment. disease gene or drug target is present in the yeast regulates caveolae formation. An additional aim membranes and assembles into an active complex P.R., and Munn, A.L. (2007). Verprolin function in KEY PUBLICATIONS Cell 116: 445-456. genome, but several hundred are represented. of our work is to understand the link between – processes that may provide opportunities for endocytosis and actin organisation: roles of the Las17p Study of these yeast genes can provide the clues caveolae and lipid-fi lled organelles termed lipid Hill, M.M., Bastiani, M., Luetterforst, R., Nixon, S., therapeutic intervention in viral infection. (yeast WASP)-binding domain and a novel C-terminal needed to interpret high-throughput human data droplets, which are major storage organelles Kirkham, M., Kirkham, A., Nixon, S.J., Walser, P., actin-binding domain. FEBS Journal 274: 4103-4125. Abankwa, D., Ooschot, V.M.J., Martin, S., Hancock, and translate this knowledge into outcomes for Using yeast as a model organism has also allowed involved in obesity. We have shown that caveolins Vajjhala, P.R., Catchpoole, E., Nguyen, C.H., Kistler, J.F., and Parton, R.G. (2007). PTRF-cavin, a human health. our group to work on pathogens that affect plants. are essential for the formation of lipid droplets C., and Munn, A.L. (2007). Vps4 regulates a subset of conserved cytoplasmic protein required for caveola Fusarium graminearum is a pathogenicpathogenic fi lamentous during liver regeneration. For example, the actin cytoskeleton is a protein interactions at the multivesicular endosome. formation and function. Cell 132: 113-124. fungus. Fusarium infects wheatwheat plants and not only protein scaffold, present in both humans and FEBS Journal 274: 1894-1907. Parton, R.G., and Simons, K. (2007). The multiple reduces crop yields by destroying the grain, but RESEARCH PROJECTS yeast, comprising building blocks known as faces of caveolae. Nature Reviews Molecular Cell also contaminates the remaining grain with potent Wiradjaja, F., Ooms, L.M., Tahirovic, S., Kuhne, E., Munn, actin fi laments. The actin cytoskeleton undergoes A.L., Piper, R., Mayinger, P., and Mitchell, C.A. (2007). • Caveolae, cancer and cholesterol: investigating Biology 8:185-194. toxins. We have identifi ed a set of F. graminearum dynamic changes and these govern changes Inactivation of the phosphoinositide phosphatases Sac1p the link between caveolins, cell cycle regulation genes that are expressed at elevated levels during and cholesterol regulation (with Professor John Fernandez, M.A., Albor, C. Ingelmo-Torres, M., Nixon, in cell shape and internal organisation. Our and Inp54p leads to accumulation of phosphatidylinositol infection. Some of these fungal genes may be Hancock) S.J., Ferguson, C., Kurzchalia, T., Tebar, F., Enrich, Electron micrograph of muscle in a cryofi xed zebrafi sh results suggest that some cytoskeletal proteins 4,5-bisphosphate on vacuole membranes and vacuolar C., Parton, R.G., and Pol, A. (2006). Caveolin-1 embryo (collaboration with Rick Webb, CMM). essential for pathogenicity. fusion defects. Journal of Biological Chemistry 282: is essential for liver regeneration. Science 313: 16295-16307. 1628-1632.

LAB MEMBERS LAB MEMBERS Research Offi cer: Dr Parimala Vajjhala Senior Research Offi cer: Dr Sally Martin PhD Students: Mark Howes, Michele Bastiani, Samantha Murphy PhD Students: Gang Ren, Amber Stephens (CSIRO- Research Offi cers: Dr Manuel Fernandez, IMB Joint PhD Student) Dr Michelle Hill, Dr Isabel Morrow#, Visiting Scientists: Dr. Katia Cortese, Dr Susan Nixon, Dr Tobias Richter, Dr Piers Walser, Viola Oorschot#, Dr. Cynthia Corley-Mastick#, Dr Lars Kuerschner#, Dr Harriet Lo# Prof Jean Gruenberg#, Prof Gisou van der Goot#

Research Assistants: Robert Luetterforst, # part of year Rachel Hancock, Nicole Schieber# Fusarium spores germinating on wheat stem surface, highlighting the affi liation the germ tubes have for the stem hairs, growing around and up the hairs.

Video sequence showing fusion of lipid droplets (labelled with a blue fl uorescent marker) in an adipocyte.

34 Division of Molecular Cell Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Molecular Cell Biology 35 Protein Traffi cking Pathogen Surveillance, in Human Disease Innate Immunity & Infl ammation

Jennifer Stow Matt Sweet

Our research group studies protein traffi cking in studying the secretion of pro-infl ammatory KEY PUBLICATIONS The major research streams of this group are innate resorption and maintenance of bone homeostasis. activated STAT1 negatively regulates TLR signaling in macrophages. Journal of Immunology 179: 3495- human and animal cells with the aim of mapping cytokines such as TNF, IL-6 and IL-1. In addition Manderson, A.P., Kay, J.G., Hammond, L.A., Brown, immunity, infl ammation and bone biology. Our Dysregulated osteoclast function contributes 3503. the cellular organelles and molecules that function to their roles in immunity, these cytokines all D.L., and Stow, J.L. (2007). Subcompartments of work in innate immunity focuses on elucidating the to several diseases including osteoporosis, in the secretion and endocytosis of disease- contribute to the onset and progression of chronic the macrophage recycling endosome direct the mechanisms by which macrophages sense invading arthritis and osteolytic bone diseases. Our group Meadows, N.A., Sharma, S.M., Faulkner, G.J., related proteins. In this work we use a range of infl ammatory diseases, and understanding how differential secretion of IL-6 and TNFalpha. Journal of pathogens. The detection of specifi c molecular is identifying osteoclast-specifi c genes and Ostrowski, M.C., Hume, D.A., and Cassady, A.I. cellular, molecular and biochemical approaches. they are traffi cked and secreted may lead to the Cell Biology 178: 57-69. components of bacteria, viruses, intracellular characterising their contribution to the pathology (2007). The expression of Clcn7 and Ostm1 in Traffi cking is a highly dynamic process and development of new therapeutic strategies in parasites and helminths by macrophages enables of bone disease. We have also defi ned a novel osteoclasts is coregulated by microphthalmia Bryant, D.M., Kerr, M.C., Hammond, L.A., Joseph, transcription factor. Journal of Biological Chemistry studies in this fi eld have been greatly enhanced infl ammation. Gene expression arrays, live cell S.R., Mostov, K.E., Teasdale, R.D., and Stow, J.L. these cells to coordinate the most appropriate host macrophage population that is associated with bone 282: 1891-1904. by the development of fl uorescent probes and imaging, FACS and biochemical approaches are (2007). EGF induces macropinocytosis and SNX1- response to deal with an infectious challenge. We surfaces: osteomacs. Future research is aimed at microscopic techniques for imaging in living cells. used to map out intracellular pathways for cytokine modulated recycling of E-cadherin. Journal of Cell have previously concentrated on the recognition characterising osteomac function in bone biology. Ripoll, V.M., Irvine, K.M., Ravasi, T., Sweet, M.J., Live cell imaging, combined with other forms traffi cking and secretion. Based on recent fi ndings, Science 120: 1818-1828. of bacterial CpG-containing DNA by macrophages, and Hume, D.A. (2007). Gpnmb is induced in of microscopy, has thus become a major core we are now also studying the pathways for but have more recently focused on elucidating the macrophages by IFN-gamma and lipopolysaccharide Stow, J.L., Manderson, A.P., and Murray, R.Z. (2006). RESEARCH PROJECTS technology for the research in our group. phagocytosis or ingestion of different microbes by detection systems for viral DNA in the cytoplasm and acts as a feedback regulator of proinfl ammatory SNAREing immunity: the role of SNAREs in the • Investigating novel genes and signalling pathways macrophages. and helminth products at the cell surface. responses. Journal of Immunology 178: 6557-6566. In epithelial cells we are studying E-cadherin, immune system. Nature Reviews Immunology 6: in macrophages that regulate infl ammation Characterisation of such detection systems not 919-929. Irvine, K.M., Burns, C.J., Wilks, A.F., Su, S., Hume, an essential adhesion protein and a vital tumour • Studying molecular mechanisms that enable innate RESEARCH PROJECTS only allows us to understand infectious disease D.A., and Sweet, M.J. (2006). A CSF-1 receptor suppressor. E-cadherin is traffi cked to and from the Bryant, D.M., Wylie, F.G., and Stow, J.L. (2005). immune cells to sense and respond to different processes, but also provides an opportunity to kinase inhibitor targets effector functions and inhibits cell surface to regulate cadherin-based cell–cell • Mapping traffi cking pathways using live cell Regulation of endocytosis, nuclear translocation, types of pathogen modulate immune responses for therapeutic pro-infl ammatory cytokine production from murine adhesion and to jointly regulate other proteins, imaging; fl uorescence imaging and 4D computer and signaling of fi broblast growth factor receptor 1 by applications. • Characterising prostaglandin synthases in macrophage populations. FASEB Journal 20: 1921- including growth factor receptors. The pathways modelling E-cadherin. Molecular Biology of the Cell 16: 14-23. infl ammation 1923. and molecules involved in E-cadherin traffi cking • Studying E-cadherin traffi cking: morphogenesis, Murray, R.Z., Kay, J.G., Sangermani, D.G., and Stow, Macrophages are not only important for anti- Aung, H.T., Schroder, K., Himes, S.R., Brion, K., have seminal roles in epithelial cell polarity, the tubulogenesis and tumorigenesis in cyst cultures J.L. (2005). A role for the phagosome in cytokine microbial responses, but they also contribute to the • Investigating regulation of gene expression in van Zuylen, W., Trieu, A., Suzuki, H., Hayashizaki, integrity of epithelial tissues and in the transition secretion. Science 310: 1492-1495. pathology of both acute and chronic infl ammatory osteoclasts • Investigating regulated endocytosis of E-cadherin of normal epithelial cells to cancer cells. A main diseases. Within the CRC for Chronic Infl ammatory Y., Hume, D.A., Sweet, M.J., and Ravasi, T. (2006). for growth factor signalling in cancer cells • Developing novel biomaterials for use in bone LPS regulates proinfl ammatory gene expression goal of this work is to understand how E-cadherin Diseases we have focused on identifying novel repair in macrophages by altering histone deacetylase traffi cking functions during the opposing processes • Researching protein sorting and cell polarity in macrophage-expressed genes as candidate expression. FASEB Journal 20: 1315-1327. of morphogenesis and cancer progression. As a epithelial cells regulators of infl ammation in the specifi c disease • Characterising osteomacs, a macrophage population associated with bone surfaces Roberts, T.L., Sweet, M.J., Hume, D.A., and model system for these experiments we are • Studying traffi cking and secretion of infl ammatory areas of Rheumatoid Arthritis and Chronic Stacey, K.J. (2005). Cutting edge: species-specifi c growing epithelial cells in mini-organ cultures cytokines in macrophages Obstructive Pulmonary Disease. Our focus in 2007 where the effects of gene expression or gene has been on the identifi cation of novel secreted or KEY PUBLICATIONS TLR9-mediated recognition of CpG and non-CpG phosphorothioate-modifi ed oligonucleotides. silencing can be analysed using fl uorescence • Investigating phagocytosis in macrophages cell-surface macrophage-specifi c proteins and our Schroder, K., Spille, M., Pilz, A., Lattin, J., Bode, K.A., Journal of Immunology 174: 605-608. imaging and computer modelling. major goal for 2008 is to validate the involvement Irvine, K.M., Burrows, A.D., Ravasi, T., Weighardt, H., Transmission electron micrographs of a section through of these proteins in infl ammation. Stacey, K.J., Decker, T., Hume, D.A., Dalpke, A.H., and Cells of the immune system secrete tightly human breast cancer cells. Sweet, M.J. (2007). Differential effects of CpG DNA orchestrated arrays of cytokines to control Osteoclasts are a cell lineage closely related on IFN-beta induction and STAT1 activation in murine immune responses. In macrophages we are to macrophages that have a specialised role in bone macrophages versus dendritic cells: alternatively

LAB MEMBERS: LAB MEMBERS Research Offi cers: Dr Fiona Wylie, Senior Research Fellow: Dr Ian Cassady Research Assistants: Greg Kelly, Allan Burrows, Dr Esther Reefman, Dr Marion Desclozeaux, Jasmyn Dunn, Stephen Cronau, Jane Weber, Senior Research Offi cers: Dr Ian Ross, Valerie Garceau, Samantha Hodgson, Erica Lovelace, Dr Sandrine Roy, Dr Tony Manderson Dr Kate Stacey, Dr Elizabeth Fowler Rhonda Hall, Tiffany Young, Erin Maylin, Angelika Research Assistants: Darren Brown, Research Offi cers: Dr Kate Irvine, Christ, Claire Debats, Tricia Lusby, Lani Hardy Tatiana Khromykh, Juliana Venturato, Dr Dmitry Ovchinnikov, Dr Allison Pettit, Teresa Munchow Dr Liza-Jane Raggatt, Dr Jack Flanagan, PhD Students: Andy Wu, Wendy van Zuylen, Dr Kate Schroder, Dr Jodie Robinson, Ming Chang, Jane Lattin, Felicia Goh, Adi Haji Idris, PhD Students: Carolin Offenhauser, Jason Kay, Dr Nicholas Meadows, Dr Vera Ripoll, Dr Tara Roberts Kylie Alexander, Angela Trieu, Melanie Andrews Immunofl uorescence image of a macrophage displaying Scanning electron microscope images of macrophages Daniele Sangermani, Wang Bo, Luke Hammond large phagocytic cups (Red). ingesting foreign particles. Administrative Offi cer: Dr Julie Osborne Honours Students: Carol Burnton, Jessica Malcolm, Honours Students: Huong Le, Regine Pei Low Larisa Labzin Lab Manager: Greg Young Undergraduate Students: Hanneke Peeters, Rachel Thijssen Plasma membrane localisation of a macrophage-specifi c protein

36 Division of Molecular Cell Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Molecular Cell Biology 37 Role Of Growth Hormone Cadherin Adhesion & Related Cytokines in Growth, & Tissue Organisation: Cancer, Metabolism & Obesity Molecular Mechanisms & Morphogenetic Consequences

Mike Waters Alpha Yap

Adult height is determined by the actions of growth the receptor artifi cially can result in cancer. The Barton, C.L., Boyle, G.M., Parsons, P.G., Jans, D.A., Cells are the building blocks of our bodies. and PI3-kinase. These affect a range of cytoskeletal Stehbens, S.J.*, Paterson*, A.D., Crampton, M.S., hormone (GH) during childhood and adolescence. mechanism involved is being actively pursued as a and Waters, M.J. (2007). Nuclear targeting of the Interactions between different cells are important regulators, including actin nucleators, cross-linking Shewan, A.M., Ferguson, C., Akhmanova, A., Parton, In the adult, growth hormone is an important potential therapeutic target, and complements the growth hormone receptor results in dysregulation of to shape our developing bodies, and a range proteins, scaffolds and the myosins II and VI. R.G., and Yap, A.S. (2006). Dynamic microtubules cell proliferation and tumorigenesis. Proceedings of metabolic agent regulating body composition, recent realisation that GH acts as a tumour promoter. of diseases occur when those interactions are regulate the local accumulation of E-cadherin and the National Academy of Sciences USA 104: opposing the actions of insulin. In old age, growth disturbed, including cancer and infl ammation. activity of Myosin 2 at cell-cell contacts. Journal of Modulation of target tissue response to hormone 13331-13336. RESEARCH PROJECTS hormone status determines lifespan, at least in Cell Science 119: 1801-1811. (*Equal contributions.) stimulation is an important aspect of physiology. My laboratory studies one set of cell-to-cell animal models. We study the means used by growth Waters, M.J., and Barclay, J.L. (2007). Does GH • Cadherin-activated cell signalling: coordinating Regulation of reproductive function is particularly interactions, those that occur when cells attach Shewan, A.M., Maddugoda, M., Kraemer, A., hormone to achieve these changes, using a variety drive breast and other cancers? Endocrinology protein and lipid kinases at cell adhesions dependent on levels of expression of the SOCS to one another. We focus on the cadherin family Stehbens, S.J., Verma, S., Kovacs, E.M., and Yap, of approaches directed to the growth hormone 148: 4533-4535. A.S. (2005). Myosin 2 is a key target for Rho kinase genes, which determine tissue sensitivity to GH of cell-cell adhesion receptors. These critically • Analysing Analysing Arp2/3 activity aatt cadherin contacts: receptor, from high-resolution protein structures to necessary for the local concentration of E-cadherin and the related cytokine, prolactin. In this context, Anderson, S.T., Barclay, J.L., Fanning, K.J., Kusters, determine the ability of cells to recognise one molecular regulators and functional consequences genetically engineered animals. D.H., Waters, M.J., and Curlewis, J.D. (2006). at cell-cell contacts. Molecular Biology of the Cell 16: we study the roles of CIS and SOCS-3 and their another and organise into coherent tissues. Mechanisms underlying the diminished sensitivity to • Regulation of the actin cytoskeleton by E-cadherin 4531-4542. The growth hormone receptor determines the regulation in control of reproductive function, The importance of these receptors is emphasised prolactin negative feedback during lactation: reduced • Cooperation between cadherins and Myosin motors degree of the cell response to growth hormone, and in the etiology of breast cancer. by the fact that loss of cadherin function promotes Helwani, F.M.*, Kovacs*, E.M., Paterson, A.D., Verma, Stat5 signalling and upregulation of CIS expression at cell-cell contacts which we originally cloned collaboratively with in tuberoinfundibular dopaminergic neurons. cancer progression in epithelial tissues (such S., Ali, R.G., Fanning, A.S., Weed, S.A., and Yap, A.S. (2004). Cortactin is necessary for E-cadherin- Genentech. Through FRET, BRET, crystallography RESEARCH PROJECTS Endocrinology 147: 1195-1202. as the breast and colon) – the commonest form • Cooperativity between cadherins and microtubules and targeted mutagenesis we have developed a of human cancers. By understanding the basic mediated contact formation and actin organization. • Investigating the mechanism of activation of growth Waters, M.J., Hoang, H.N., Fairlie, D.P., Pelekanos, • The morphogenetic consequences of cadherin- new model of how the GH receptor is activated by biological mechanisms of cadherin-mediated cell Journal of Cell Biology 164: 899-910. (*Equal hormone and related cytokine receptors R.P., and Brown, R.J. (2006). New insights into activated cell signalling and cooperativity with the GH, involving realignment of receptor subunits within contributions.) growth hormone action. Journal of Molecular recognition we thus hope to provide vital insights actin cytoskeleton a constitutive dimer. An extension of this model • Researching the role of nuclear localised growth Endocrinology 36: 1-7. into the basis of developmental patterning and Verma, S., Shewan, A.M., Scott, J.A., den Elzen, describes how a rearrangement of an extracellular hormone receptor in cell proliferation and common human diseases. N.R., Helwani, F.M., Miki, H., Takenawa, T., and Yap, Brown, R.J., Adams, J.J., Pelekanos, R.A., Wan, Y., b-loop of the GH receptor selectively controls ERK oncogenesis KEY PUBLICATIONS A.S. (2004). Arp 2/3 activity is necessary for effi cient McKinstry, W.J., Palethorpe, K., Seeber, R.M., Monks, activation without infl uencing Stat5 activation Currently we focus on understanding how extension of cadherin adhesive contacts. Journal of • Researching the role of GH-dependent Stat5 in lipid T.A., Eidne, K.A., Parker, M.W., and Waters, M.J. Maddugoda, M.P., Crampton, M.S., Shewan, cadherins cooperate with the actin cytoskeleton, Biological Chemistry 279: 34062-34070. through the use of an alternate: Src kinase. and carbohydrate metabolism (2005). Model for growth hormone receptor activation A.M., and Yap, A.S. (2007). Myosin VI and vinculin based on subunit rotation within a receptor dimer. long believed to be central to cadherin function. cooperate during the morphogenesis of cadherin cell- By creating targeted knock-in mutations to • Researching the role of suppressors of cytokine Kovacs, E.M.*, Ali*, R.G., McCormack, A., and Yap, Nature Structural & Molecular Biology 12: 814-821. Our experience makes it increasingly clear that this cell contacts in mammalian epithelial cells. Journal of signalling domains within the GH receptor signalling in prolactin and GH physiology A.S. (2002). E-cadherin ligation directly activates PI3- cooperation involves a complex interplay between Cell Biology 178: 529-540. cytoplasmic domain, we have shown that Rowland, J.E., Lichanska, A.M., Kerr, L.M., White, kinase and Rac GTPase signals to stabilize adhesion • Researching the role of GH in promoting breast and adhesion receptors and diverse distinct states of enhancement of postnatal somatic growth by GH is M., D’Aniello, E., Maher, S.L., Brown, R.J., Teasdale, McLachlan, R.W., Kraemer, A., Helwani, F.M., Kovacs, Journal of Biological Chemistry 277: 6708-6718. prostatic cancer the cytoskeleton that are coordinated by a variety dependent on its ability to activate the transcription R., Noakes, P.G., and Waters, M.J. (2005). In vivo E.M., and Yap, A.S. (2007). E-Cadherin adhesion (*Equal contributions.) analysis of growth hormone receptor signalling of signalling pathways at the cell membrane. In activates c-Src signaling at cell-cell contacts. factor Stat5. Because these mice become strikingly Kovacs, E.M., Goodwin, M., Ali, R.G., Paterson, domains and their associated transcripts. Molecular particular, our work demonstrates that cadherins Molecular Biology of the Cell : 3214-3223. obese after six months of age, we are currently KEY PUBLICATIONS 18 A.D., and Yap, A.S. (2002). Cadherin-directed actin and Cellular Biology 25: 66-77. function as adhesion-activated cell signalling investigating the role of Stat5a/b in control of lipid Barclay, J.L., Anderson, S.T., Waters, M.J., and Scott, J.A., Shewan, A.M., den Elzen, N.R., Loureiro, assembly: E-cadherin physically associates with the receptors that stimulate pathways to regulate the and carbohydrate metabolism using tissue-targeted Curlewis, J.D. (2007). Regulation of Suppressor of Wan, Y., McDevitt, A., Shen, B., Smythe, M.L., J.J., Gertler, F.B., and Yap, A.S. (2006). Ena/VASP Arp 2/3 complex to direct actin assembly in nascent actin cytoskeleton, thereby infl uencing cell shape, gene deletion of Stat5a/b. cytokine signalling-3 by GH in pro-B cells. Molecular and Waters, M.J. (2004). Increased Site 1 affi nity proteins critically determine distinct modes of actin adhesive contacts. Current Biology 12: 379-382. Endocrinology 21: 2503-2515. improves biopotency of porcine growth hormone: adhesion, and cell-cell cohesion. Relevant signals organization that can coexist at cadherin adhesive The surprising fi nding that the growth hormone Evidence against diffusion dependent receptor include the Rho family GTPases, Src family kinases Conway-Campbell, B.L., Wooh, J.W., Brooks, A.J., contacts. Molecular Biology of the Cell 17: 1085-1095. receptor is located in the cell nucleus of dividing dimerization. Journal of Biological Chemistry 279: Gordon, D., Brown, R.J., Lichanska, A.M., Chin, H.S., cells has led us to discover that nuclear localising 44775-44784.

Diagrammatic representation of LAB MEMBERS mechanism of growth LAB MEMBERS Research Offi cers: Dr Andrew Brooks, hormone receptor activation Research Offi cers: Dr Nicole den Elzen, Dr Johanna Barclay, Dr Tim McPhee by hormone binding. The Dr Matthew Crampton, Dr Michael Smutny hormone possesses two Visiting Research Fellow: Dr Mayumi Ishikawa receptor binding sites Research Assistants: Suzie Verma, Carmen Buttery which are asymmetrically Research Assistants: Kathryn Tunny, Linda Kerr placed. Engagement of PhD Students: Madhavi Maddugoda, Angela Jeanes, both receptor binding sites Robert McLachlan, Sabine Mangold, Samantha by the hormone results in Stehbens the relative rotation of the receptor subunits, rotating Marked adiposity in mature male mice lacking Left Picture: Myson II (green) accumulates with actin the associated JAK2 kinases growth hormone receptor (GHR-/-), lacking ability fi laments (red) at E-cadherin cell-cell adhesions (blue). to generate STAT5 in response to GH (receptor together so that they can truncated at 391), or able to generate only 30% cross-phosphorylate and Right Picture: Microtubules (red) decorated at the ends of the normal STAT5 response to GH (receptor autoactivate, initiating with CLIP170 (blue) extend into E-cadherin adhesions truncated at 569). signalling. (green).

38 Division of Molecular Cell Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Molecular Cell Biology 39 Design & Discovery of Biodiscovery: From Biodiversity Bioactive Peptides & Proteins & Biology to Bioactives & Beyond

Paul Alewood Rob Capon

The overall focus in the group (www.uq.edu. RESEARCH PROJECTS Lewis, R.J., Schroeder, C.I., Ekberg, J., Nielsen, K.J., The Capon research group (CMB) has a thematic RESEARCH PROJECTS Clark, B., Capon, R.J., Lacey, E., Tennant, S., and Gill, Loughnan, M., Thoma, L., Adams, D., Drinkwater, J.H. (2006). Quinolactacins Revisited: From Lactams au/alewood/) is the identifi cation of bioactive • Identifi cation and characterisation of novel peptides biodiscovery focus that employs a collaborative • Detecting, isolating, characterising and elucidating R., Adams, D.J., and Alewood, P.F. (2007). Isolation to Imide and Beyond. Organic and Biomolecular molecules that have the potential to play from Australian animals that target ion channels, multi-disciplinary approach to exploring Australian the structure of novel bioactive metabolites from and structure-activity of mu-conotoxin TIIIA. A Potent Chemistry 4: 1512-1519. important roles in human health and wellbeing. transporters and receptors biodiversity to discover valuable molecular Australian marine and terrestrial biodiversity Inhibitor of Tetrodotoxin-Sensitive Voltage-Gated Some specifi c interests include: the discovery products that have potential application as Ratnayake, R., Lacey, E., Tennant, S., Gill, J.H., and • Dissecting pain pathways with receptor- Sodium Channels. Molecular Pharmacology • Biomimetically synthesising novel bioactive and total synthesis of potent and selective pharmaceuticals and research tools. Specialists Capon, R.J. (2006). Isokibdelones: Novel heterocyclic selective toxins 71: 676-685. metabolites peptides (toxins) from Australia’s venomous in the acquisition, detection, isolation, structure polyketides from a Kibdelosporangium sp. Organic creatures; the chemical synthesis of proteins • Antiinfl ammaammatorytory protein mimetics Armishaw, C.J., Daly, N., Nevin, S., Adams, D.J., elucidation and synthesis of bioactive molecules, • Bio-evaluating and SAR of novel bioactive Letters 8: 5267-5270. and bioactive peptides; development of new Craik, D.J., and Alewood, P.F. (2006). Alpha- the research group is well equipped with modern metabolites against the indications of: bacterial • Discovery of new bioactive peptides and proteins Ratnayake, R., Lacey, E., Tennant, S., Gill, J.H., and selenoconotoxins: A new class of potent alpha 7 infection (non-cytotoxic control of virulence synthetic and analytical chemistry; and protein from bovine and human milk chromatographic and spectroscopic technologies, Capon, R.J. (2006). Kibdelones: Novel anticancer neuronal nicotinic receptor antagonists. Journal of factors), fungal infection (synergists of azole structure and function. Special emphasis is and innovative chemical and biological approaches polyketides from a rare Australian actinomycete. Biological Chemistry 281: 14136-14143. antifungals), parasitic infection (gastrointestinal placed on determining the structure-function • Development of enabling new synthetic chemistry to molecular discovery. The breadth of biodiversity Chemistry - A European Journal 13: 1610-1619. nematodes), viral infection (inhibiting infectivity), relationships of natural and designed molecules. to access disulfi de-rich peptides and small Holland, J.W., Deeth, H.C., and Alewood, P.F. (2006). explored ranges across terrestrial and marine cancer (novel cytotoxins, plus selective inhibitors bioactive proteins and enzymes (up to 200 Resolution and characterisation of multiple isoforms Current research programs involve: the discovery, ecosystems, and includes plants, animals and of K-Ras), diabetes (controlling beta and stem residues) of bovine k-casein following by 2-DE a reversible isolation and characterisation of toxins from microbes. The array of novel molecules studied is cell differentiation), pain (ion channel and opioid cysteine-tagging enrichment strategy. snakes, spiders, cone snails, platypus, ticks • Design and synthesis of novel molecules equally broad, and extends across all biosynthetic agonists and antagonists) and neurodegenerative Proteomics 6: 3087-3095. and scorpions; mimetics of calcium-binding that mimic peptide structure and function classes and includes many molecules with diseases infl ammatory proteins from the S100 class; the (peptidomimetics) Fry, B.G., Wickramaratana, J.C., Lemme, S., Beuve, unprecedented structural features, and a wide • Investigating cane toad chemical ecology, and chemical engineering of disulfi de-rich peptides A., Garbers, D., Hodgson, W.C., and Alewood, P.F. spectrum of biological properties. Working in close developing innovative natural control solutions and proteases; elucidating the structure and KEY PUBLICATIONS (2005). Novel natriuretic peptides from the venom collaboration with colleagues across academia, of the inland taipan (Oxyuranus microlepidotus): function of milk proteins and their role in human Dutertre, S., Ulens, C., Büttner, R., Fish, A., van Elk, industry and government, within Australia and isolation, chemical and biological characterization. KEY PUBLICATIONS health; and uncovering new pain pathways in R., Kendel, Y., Hopping, G., Alewood, P.F., Schroeder, internationally, Professor Capon and his team Biochemical and biophysical research chronic pain. This has led to the development of C., Nicke, A., Smit, A.B., Sixma, T.K., and Lewis, R.J. address key areas of opportunity and need, Capon, R.J., Hayes, R.A., and Grigg, G.C. In communications 327: 1011-1015. three new classes of drugs addressing chronic (2007). AChBP-targeted α-conotoxin correlates based around specifi c diseases and therapeutic proceedings of the Cane Toad Workshop, Cane pain and congestive heart failure. distinct binding orientations with nAChR subtype Sharpe, I., Gehrmann, J., Loughnan, M., Thomas, indications. With support from the Queensland toad chemical ecology: getting to know your enemy., selectivity. EMBO Journal 26: 3858-3867. L., Adams, D., Atkins, A., Craik, D.J., Adams, Government, Professor Capon is also leading a Brisbane, 2006; Invasive Animals Cooperative Research Centre: Brisbane, 2006; 171-175. D., Alewood, P.F., and Lewis, R.J. (2001). Two research initiative that seeks to use knowledge of new classes of conopeptides inhibit the alpha1- chemical ecology as a means to control invasive Clark, B., Capon, R.J., Lacey, E., Tennant, S., and adrenoceptor and the noradrenaline transporter. pests, with a particular emphasis on the cane toad. Gill, J.H. (2006). Citrinin Revisited: From Monomers Nature Neuroscience 4: 902-907. The Capon group has a strong multinational fl avour to Dimers and Beyond. Organic and Biomolecular with research collaborations into Spain, Denmark, Chemistry 4: 1520-1528. New Zealand and the USA, and with members of Clark, B., Capon, R.J., Lacey, E., Tennant, S., and the research team drawn from many countries Gill, J.H. (2006). Polyenylpyrroles and polyenylfurans across the Asia-Pacifi c region and Europe. from an Australian isolate of the soil Ascomycete Gymnoascus reessii. Organic Letters 8: 701-704. HPLC installation.

LAB MEMBERS LAB MEMBERS Research Manager: Dianne Alewood Visiting Students: Len Sorensen (Danish Personal Assistant: Nadine Coleman Occupational Trainees: Monika Hermann, Pharmaceutical University), Debby Feytens Christina Gosmann Dr Andrew Piggott, Senior Research Offi cer: John Holland (Free University of Belgium) Research Offi cers: Dr Andrew Hayes, Dr Cedric Dooms, Dr Hua Zhang, Visiting Research Student: Kenneth Johansen Research Offi cers: Dr Gene Hopping, Dr Frank Fontaine, Dr Kim Dastlik, Dr Xin Liu Dr Aline Dantas, Dr Andrea Vernal, Dr Raj Gupta, Dr Tom Durek, Dr Lachlan Rash, Dr Jean Jin, PhD Students: Mohammed El-Nagger, Leith Fremlin, Dr Marion Loughnan, Dr Boris Zhang Walter Balansa, Raju Ritesh, Ranjala Ratnayake

Research Assistants: Aaron Poth, Zoltan Dekan Undergraduate Students: Caitlin Rudorfer, Kristian Dalle, Rachel Slade PhD Students: Marcus Muttenthaler, Rod Morales, Jen Smith, Kalyani Abondi

40 Division of Chemical & Structural Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Chemical & Structural Biology 41 NMR & Protein Structure Chemistry in Drug Design & Human Therapeutics

David Craik David Fairlie

Our group uses NMR spectroscopy to determine We use computer modelling and NMR spectroscopy RESEARCH PROJECTS Our group works at the interface of chemistry, • Investigating biological activities of small molecules Macrocycles Constrained By Oxazoles and that structurally mimic protein surfaces Thiazoles. Journal of the American Chemical the structures of proteins that are important in to design novel proteins that are stabilised for • Bioengineering circular proteins biology and disease. Some researchers study just drug design programs and in agriculture. By drug design applications. We then synthesise them Society 127: 6563-6572. chemistry, others just biology, and some work on • Studying mechanisms of disease development & • Discovering new circular proteins elucidating the structures of biologically active using solid-phase peptide synthesis or recombinant both chemistry and biology to better understand drug action in human infl ammatory disorders, viral March, D.R., Proctor, L.M., Stoermer, M.J., Sbaglia, proteins we are able to identify regions crucial molecular biology methods. We currently have • Pharming cyclic peptides the biology of life, ageing, disease and death. or parasitic infections, cancers, neurodegenerative R., Abbenante, G., Reid, R.C., Wadi, K., Paczkowski, for activity and can use this information to design molecules under development for the treatment of and cardiovascular diseases N., Tyndall, J.D.A., Taylor, S.M., and Fairlie, D.P. Chemistry researchers in our group develop new drugs. The proteins we study come from a multiple sclerosis, cardiovascular disease, cancer • Studying the structure-activity relationship of toxins (2004). Potent Cyclic Antagonists Of The Complement expertise in one or more of: computer-aided range of animal and plant sources but are often and chronic pain. C5a Receptor On Human Polymorphonuclear • Investigating plant proteinase inhibitors KEY PUBLICATIONS involved in host defence. Examples include the molecular and drug design; solid and solution Leukocytes. Relationships Between Structures and Our group discovered a family of proteins called conotoxins (venom components from marine • Conducting metabolomic screening phase organic synthesis; structure determination Blakeney, J.S., Reid, R.C., Le, G.T., and Fairlie, D.P. Activity. Molecular Pharmacology 65: 868-879. cyclotides that are exceptionally stable and appear snails) and the cyclotides (novel circular proteins using NMR techniques; and interactions between (2007). Nonpeptidic Ligands For Peptide-Activated to be a natural combinatorial protein template. GPCRs. Chemical Reviews 107: 2960-3041. from plants). small molecules, proteins, DNA and RNA. Outcomes We undertake fi eldwork in Australia and overseas KEY PUBLICATIONS include new chemical reactions/mechanisms/ Chappell, K.J., Stoermer, M.J., Fairlie, D.P., and Craik, D.J., and Adams, D.J. (2007). Chemical We have an interest in the discovery and for the collection of plant species so that we can compounds, some compounds being enzyme Young, P.R. (2006). Insights to Substrate Binding and modifi cations of conotoxins to improve stability and structural characterisation of novel protein explore the diversity and evolution of this novel inhibitors, protein agonists/antagonists, Processing by West Nile Virus NS3 Protease through activity. ACS Chemical Biology : 457-468. topologies. In particular we aim to determine the protein family. 2 or structural mimics of protein surfaces. Combined Modelling, Protease Mutagenesis, and mechanisms of biosynthesis and evolutionary Craik, D.J., Cemazar, M., and Daly, N.L. (2007). The Kinetic Studies. Journal of Biological Chemistry By unravelling the necessary elements for the Biology researchers in our group use our small origin of circular proteins and to apply protein chemistry and biology of cyclotides. Current Opinion 281: 38448-38458. processing and cyclisation of natural cyclic molecules to interrogate specifi c protein functions engineering principles to explore applications of in Drug Discovery and Development 10: 176-184. peptides we are working towards being able to on/in cells and unravel mechanisms of protein Kahnberg, P., Lucke, A.J., Glenn, M.P., Boyle, G.M., circular proteins in drug design and agriculture. Tyndall, J.D.A., Parsons, P.G., and Fairlie, D. P. (2006). transfer the precursors and processing machinery Daly, N.L., Chen, Y-K., Rosengren, K.J., Marx, U.C., activation, biological/physiological processes, Human MM96L melanoma cells treated with novel Design, Synthesis, Potency and Cytoselectivity Of differentiating drug. We undertake protein engineering studies in into a wide range of crop plants for pharming and Phillips, M.L., Waring, A.J., Wang, W., Lehrer, R.I., disease development, and drug action. Researchers Anticancer Agents Derived By Parallel Synthesis which we modify protein frameworks either by crop protection initiatives. and Craik, D.J. (2007). Retrocyclin-2: Structural gain insights to processes that are pivotal to From Alpha-Aminosuberic Acid. Journal of Medicinal “grafting” new biologically active epitopes onto analysis of a potent anti-HIV θ-defensin. We study the structures of a range of toxins from human physiology or aberrant in disease, as well Chemistry 49: 7611-7622. them, or by stabilising them by cyclisation. We Biochemistry 46: 9920-9928. cone snails, spiders and snakes and use this as interdisciplinary skills/knowledge/collaborations also study the protein-folding problem, i.e., how Levick, S., Loch, D., Rolfe, B., Reid, R.C., Fairlie, D.P., information to understand their mode of action Gillon, A.D., Saska, I., Jennings, C.V., Renda, R.F., in enzymology, biochemistry, immunology, do proteins fold into the complex shapes that Taylor, S.M., and Brown, L. (2006). Antifi brotic Activity against ion-channels and other receptors. Craik, D.J., and Anderson, M.A. (2007). Biosynthesis pharmacology, oncology, parasitology, virology determine their functions? of an Inhibitor of Group IIa Secretory Phospholipase of circular proteins in plants. The Plant Journal 53: and neurobiology. A2 in Young Spontaneously Hypertensive Rats. With our collaborator, Professor Marilyn Anderson The highlights of last year included our isolation 505-515. Journal of Immunology 176: 7000-7007. of La Trobe University, we are studying the and characterisation of a pair of key cyclic Greenwood, K.P., Daly, N.L., Brown, D.L., Stow, RESEARCH PROJECTS structure-activity relationships of naturally Shepherd, N.E., Hoang, H.N., Desai, V.S., Letouze, peptide-processing enzymes (asparaginyl J.L., and Craik, D.J. (2007). The cyclic cystine occurring proteins involved in plant defense • Designing and Discovering Drugs (e.g. for GPCRs, E., Young, P.R., and Fairlie D.P. (2006). Modular endoprotease and peptide disulfi de isomerase) knot miniprotein MCoTI-II is internalized into cells against insect attack. proteases,etc) Alpha Helical Mimetics With Antiviral Activity Against and our identifi cation of potential common by macropinocytosis. International Journal of Respiratory Syncitial Virus. Journal of the American processing mechanisms of circular proteins Variations in the chemical composition of Biochemistry and Cell Biology 39: 2252-2264. • Synthetic Organic Chemistry (solution & solid phase) Chemical Society 128: 13284-13289. across divergent plant families. physiological fl uids are being analysed by NMR Gruber, C.W., Cemazar, M., Anderson, M.A., and • Determining Structure using NMR spectroscopy Singh, Y., Stoermer, M.J., Lucke, A., Guthrie, T., spectroscopy to study the diagnosis and underlying Some of the other projects on which we are Craik, D.J. (2007). Insecticidal plant cyclotides and • Enzymology & Molecular Pharmacology and Fairlie, D.P. (2005). Structural Mimicry of Human histone deacetylase bound to novel anticancer causes of such diverse conditions as schizophrenia, inhibitors. currently working are outlined below: related cystine knot toxins. Toxicon 49: 561-575. Two Cytochrome b562 Interhelical Loops Using growth defects and obesity.

LAB MEMBERS LAB MEMBERS Research Offi cers: Dr Norelle Daly, Masters Students: Natasha Chaduhary, Senior Research Offi cers: Dr John Abbenante, Dhiraj Hans, Rose Harrison, Dr Richard Clark, Dr Horst Schirra, Dr Masa Cemazar, Charlotta Alvarmo Dr Robert Reid, Dr Yogendra Singh, Praveen Madala, Ranee Singh, Jacky Suen Dr Joshua Mylne, Dr Quenkin Kaas, Dr Martin Stoermer Dr Jan Westerman, Dr. Ute Marx Honours Students: Angeline Chan, James Lo, Masters Student: Praveer Gupta, Nicole Wheatley Shaffi naz Abdrahman, Alysha Elliot Research Offi cers: Dr Huy Hoang, Dr Giang Le, Adam Crompton, Adam Cotterell Research Assistants: Dr Shane Simonsen, Dr Andrew Lucke, Dr Reik Löser, Dr Gloria Ruiz Honours Students: Jonas Jensen, Prascilla Tagore, Chia-Chia Tan, Undergraduate Students: Andrew Kinghorn, Gómez, Dr Conor Scully, Dr Nick Shepherd Anzari Atic Undergraduate Students: Bruce Chau, Emily McCallum, Jakov Kulis, Ernie Yulyaningsih Simon Chen, Ya-Mi Chuang, Kristian Dalle, PhD Students: Grant Barry, Jade Blakeney, Gavin Dr Terry Qin, Dr Nina Tan Patricia Garcia PhD Students: Laura Cascales, Philip Nguyencong, Visitors: Bryant, Renee Beyer, Russell Driver, Maria Halili, Sunithi Gunasekara, Christian Gruber, Crystal Yen-Hua Huang, David Ireland, Conan Wang, Reena Halai, Kathryn Greenwood, Ivana Saska Human GPCR receptor bound to novel Craik group photo 2007. anti-infl ammatory antagonist.

42 Division of Chemical & Structural Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Chemical & Structural Biology 43 Structural Biology of Membrane Bugs & Drugs: Rational Proteins, Macromolecular Development of Novel Antibiotics Assemblies & Viruses & Environmentally Friendly Insecticides

Ben Hankamer Glenn King

Determining the structures of membrane proteins, also being used to develop new bio-fuel production KEY PUBLICATIONS Research in my laboratory is aimed at the RESEARCH PROJECTS Robson, S.A., and King, G.F. (2006). Domain architecture and structure of the bacterial cell division macromolecular assemblies and viruses is one systems within the Solar Bio-fuels consortium. Hankamer, B.D., Elderkin, S.L., Buck, M., and Nield, development of novel pharmaceutical agents • Developing novel antibiotics targeted against protein DivIB. Proceedings of the National Academy of of the great challenges of cell and structural J. (2004). Organization of the AAA(+) adaptor protein and environmentally friendly insecticides. Gram-positive pathogens The Solar Bio-fuels consortium (www. Sciences USA 103: 6700–6705. biology. Using advanced high-resolution cryo- PspA is an oligomeric ring. Journal of Biological Approximately half of the group is studying solarbiofuels.org), co-directed by Ben Hankamer, • Investigating the architecture and function of the electron microscopes it is now possible to capture Chemistry 279: 8862-8866. bacterial cytokinesis or signalling by bacterial Rowland, S.L., Burkholder, W.F., Cunningham, K.A., has brought together an international team of bacterial cell division machinery atomic-resolution information of biological histidine kinases in order to provide a molecular Maciejewski, M.W., Grossman, A.D., and King, G.F. specialists to develop high-effi ciency second- Iwata, M., Imamura, H., Stambouli, E., Ikeda, C., macromolecules. However, as the captured understanding of these key biological processes (2004). Structure and mechanism of Sda, an inhibitor generation bio-fuel production systems using Tamakoshi, M., Nagata, K., Makyio, H., Hankamer, B., • Using tarantula toxins to characterise ion channels images are inherently ‘noisy’, this information involved in sensing pain of the histidine kinases that regulate initiation of microalgae. This represents a rapidly expanding Barber, J., Yoshida, M., Yokoyama, K., and Iwata, S. and to establish a platform for the development must be recovered by aligning many copies of the sporulation in Bacillus subtilis. Molecular Cell 13: area of biotechnology of global signifi cance. (2004). Crystal structure of a central stalk subunit C of novel antimicrobial agents. The remainder protein (10 000 – 1 000 000 individual molecules) • Developing environmentally friendly insecticides 689–701. Our specialisation is the structural biology and and reversible association/dissociation of vacuole- of the group is focused on developing novel based on spider-venom peptides either computationally (by single particle biochemistry of the photosynthetic machinery, type ATPase. Proceedings of the National Academy of antinociceptive agents and environmentally Szeto, T.H., Rowland, S.L., Rothfi eld, L.I., and King, analysis), or biochemically (via crystallography). Science USA 101: 59-64. friendly insecticides by harnessing the remarkable G.F. (2002). Membrane localization of MinD is which drives the fi rst step of converting solar KEY PUBLICATIONS TM chemical diversity encoded in the venoms mediated by a C-terminal motif that is conserved As part of the IMB’s Visible Cell project we energy into chemical energy (fuels). Consequently Kruse, O., Rupprecht, J., Bader, K., Thomas-Hall, S., Gorbatyuk, V.Y., Nosworthy, N.J., Robson, S.A., Bains, across eubacteria, archaea, and chloroplasts. have established a powerful single particle its optimisation offers signifi cant downstream Schenk, P., Finazzi, G., and Hankamer, B. (2005). of spiders. Most research projects are highly N.P.S., Maciejewski, M.W., dos Remedios, C.G., and Proceedings of the National Academy of Sciences analysis pipeline, as well as new biotechnologies benefi ts for all bio-fuel production systems Improved photobiological H-2 production in engineered interdisciplinary and the experimental techniques King, G.F. (2006). Mapping the phosphoinositide- USA 99: 15693–15698. for template assisted 2D crystal production. (bio-ethanol, bio-diesel, BTL diesel, bio-H and green algal cells. Journal of Biological Chemistry 280: employed range from molecular biology through 2 binding site on chick cofi lin explains how PIP2 The single particle process involves merging bio-methane). With colleagues, we are now taking 34170-34177. protein chemistry to structure determination using regulates the cofi lin-actin interaction. Molecular Cell large numbers of 2D projection images of the ‘Visible Cell’ approach to develop a 3D atlas of NMR spectroscopy and X-ray crystallography. Mussgnug, J., Thomas-Hall, S., Rupprecht, J., Foo, 24: 511–522. randomly oriented molecules to calculate the photosynthetic machinery within the cellular Research in the lab is currently funded by three A., Klassen, V., McDowall, A., Schenk, P., Kruse, O., 3D reconstructions. Our current benchmark context. This 3D atlas will assist in the fi ne-tuning and Hankamer, B. (2007). Engineering photosynthetic ARC and four NHMRC research grants. resolution is ~10 Å at which individual α-helices of the light capture and conversion processes of light capture: Impacts on improved solar energy to are visualised, and we are actively developing photosynthesis, just as a manual is required to tune biomass conversion. Plant Biotechnology Journal 5: processes to improve this further. In parallel we the engine of a car. 802-814. are developing detergent-resistant 2D templates Woolford, D., Ericksson, G., Rothnagel, R., Muller, D., that chelate Ni at the surface, to facilitate the RESEARCH PROJECTS Landsberg, M., Pantelic, R., McDowall, A., Pailthorpe, systematic production of 2D crystals of tethered • High-Resolution Single Particle Analysis: Biology, B., Young, P., Hankamer, B., and Banks, J. (2007). His-tagged membrane proteins. Using these twin Physics and software development Swarm(PS): Rapid, semi-automated single particle approaches we are studying a wide range of selection software. Journal of Structural Biology 157: TM important membrane proteins (e.g. photosynthetic • The Visible Cell Project: Resolving the 3D 174-188. membrane protein complexes, ATPases, structure of the macromolecular assemblies Pantelic, R., Ericksson, G., Hamilton, N., and mechanosensitive channels), macromolecular • Template mediated 2D crystallisation: Towards Hankamer, B. (2007). Bilateral Edge Filter: assemblies (AAA ATPases and related proteins, streamlined membrane protein crystallisation ferritin) and icosahedral viruses. These structures Photometrically weighted, discontinuity based edge detection. Journal of Structural Biology 160: 93-102. provide fundamental new insights into many • Second-generation micro-algal bio-fuel systems: Development of bio-fuels systems for bio-H , bio- fascinating molecular machines and feed into 2 diesel and BTL-diesel production that are coupled Structure of the Sda antikinase. Australian funnel-web spider with venom dripping the Visible CellTM project. These technologies are from fang tips. to CO2 sequestration

LAB MEMBERS LAB MEMBERS Research Offi cers: Dr Michael Landsberg, Senior Research Offi cers: Dr Susan L. Rowland, PhD students: Margaret Gentz, Kimberly Wadsworth Rosalba Rothnagel Dr Mehdi Mobli Undergraduate Interns: Elizabeth Bast, PhD Students: Radosav Pantelic, Evan Stephens, Research Offi cer: Dr David Wilson Tomas Miljenovic, Darshani Rapasinghe Matthew Timmins, Drew Ringsmuth, Erin Ahern, Winnie Waudo Research Assistants: Lindsey Long, Natalie Saez

MSc Students: Alizeé Malnoë Honours Students: Emily Knauth, Lysha Lim, Robert Burnside, Anabelle Lindley, David Floyd (4th year biotech)

Structure of the ß domain of the bacterial cell division protein DivIB.

44 Division of Chemical & Structural Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Chemical & Structural Biology 45 Molecular Pharmacology Protein Structure of Venom Peptides & Drug Design

Richard Lewis Jenny Martin

My research focuses on the discovery and • Studying interactions of conotoxins at nicotinic Ekberg, J., Jayamanne, A., Vaughan, C.W., Aslan, S., Our group is driven by the need to understand the the lab, resulting in the conversion of DsbG into a Hiniker, A., Ren, G., Heras, B., Zheng, Y., Laurinec, S., characterisation of venom peptides, especially the acetylcholine receptors, and calcium and sodium Thomas, L., Mould, J., Drinkwater, R., Baker, M.D., role of proteins in disease and to develop novel DsbC-like protein by using single residue variations Jobson, R.W., Stuckey, J., Martin, J.L., and Bardwell, conotoxins produced by the predatory cone snail. channels (NHMRC) Abrahamsen, B., Wood, J.N., Adams, D.J., Christie, chemicals to modify the functions of disease- (Hiniker et al., PNAS 2007). We also determined J.C.A. (2007). Laboratory evolution of one disulfi de M.J., and Lewis, R.J. (2006). µO-conotoxin MrVIB isomerase to resemble another. Proceedings of the These highly structured peptides (mini-proteins) • Identifying novel anti-cancer agents from marine causing proteins. We use a range of biochemical the structure and evaluated the function of a act at ion channels, G-protein coupled receptors selectively blocks Nav1.8 sensory neuron specifi c and biophysical techniques to investigate the DsbA enzyme from a Gram-positive organism, National Academy of Sciences USA 104: 11670- biodiversity (ARC) 11675. (Open access) and monoamine transporters found in the sodium channels and chronic pain without motor structure, function and interactions of proteins, with S. aureus DsbA (Heras et al., accepted in J Biol defi cits. Proceedings of the National Academy of membranes of most cells, especially cells of the • Identifying and characterising novel sodium a particular emphasis on high-throughput protein Chem) showing that S. aureus DsbA catalysescatalyses Hu, S-H., Latham, C.F., Gee, C.L., James, D.E., Sciences USA 103: 17030-17035. nervous system. Conopeptides make exquisite channel toxins in squid and octopus (ARC) crystallography and structure-based approaches disulfi de transfer in a manner different to that of and Martin, J.L. (2007). Structure of the Munc18c/ molecular tools, with some being developed as • Discovering and characterising novel bioactives Nielsen, C.K., Lewis, R.J., Alewood, D., Drinkwater, R., for inhibitor design. Not surprisingly, our research E. coli DsbA. WeWe are nownow focusing our attentionattention Syntaxin4 N-peptide complex defi nes universal novel treatments for diseases including chronic using high-content screening Palant, E., Patterson, M., Yaksh, T.L., McCumber, D., this year has been enhanced enormously through on developing inhibitors of DsbA as potential features of the N-peptide binding mode of SM pain. A major focus of the group is to discover and Smith, M.T. (2005). Anti-allodynic effi cacy of the the ARC LIEF-funded upgrade of the UQ ROCX antibacterial agents. proteins. Proceedings of the National Academy of • Developing venomic approaches to unravel the Sciences USA 104: 8773-8778. new protein targets and develop peptides able χ-conopeptide, Xen2174, in rats with neuropathic Facility (see Deputy Director’s report on page 7). peptide diversity of cone snail venoms to act at these targets to reduce pain sensation. pain. Pain 118: 112-124. Gruber, C., Cemazar, M., Heras, B., Martin, J.L., and A major outcome over the past year or so has been RESEARCH PROJECTS This research involves the assay-guided Lewis, R.J., and Garcia, M.L. (2003). Therapeutic Craik, D.J. (2006). Protein disulfi de isomerase: The the tremendous advance in our understanding • Studying the structure, function and interactions of isolation of venom peptides, peptide synthesis, KEY PUBLICATIONS potential of venom peptides. Nature Reviews Drug structure of oxidative folding. Trends in Biochemical of the regulation of SNARE proteins involved in SNARE proteins associated with insulin action tissue pharmacology, radioligand binding and Dutertre, S., Ulens, C., Büttner, R., Fish, A., van Elk, Discovery 2: 790-802. Sciences 31: 455-464. insulin-stimulated traffi cking of the GLUT4 glucose electrophysiological studies, peptide structure R., Kendel, Y., Hopping, G., Alewood, P.F., Schroeder, • Studying the structure, function and inhibition of Sharpe, I.A., Gehrmann, J., Loughnan, M.L., Thomas, transporter. This process, which is critical to the Latham, C.F., Lopez, J.A., Gee, C.L., Hu, S-H., elucidation by NMR, receptor mutagenesis, C., Nicke, A., Smit, A.B., Sixma, T.K., and Lewis, R.J. redox folding factors involved in disease L., Adams, D.A., Atkins, A., Palant, E., Craik, D.J., Westbury, E., Blair, D., Armishaw, C., Alewood, P.F., modelling, and fi nally co-crystal structures (2007). AChBP-targeted -conotoxin correlates regulation of blood glucose levels, is affected in α Adams, D.F., Alewood, P.F., and Lewis, R.J. (2001). • Investigating novel infl ammation drug targets using Bryant, N.J., James, D.E., and Martin, J.L. (2006). and docking simulations of the peptide target distinct binding orientations with nAChR subtype Type II Diabetes. Our recent results, in collaboration Two new classes of conopeptides inhibit the high-throughput structure approaches Molecular dissection of the Munc18c/Syntaxin4 interaction. Xenome Ltd is developing an analogue selectivity. EMBO Journal 26: 3858-3867. α1 with Professor David James (Garvan Institute), adrenoceptor and noradrenaline transporter. interaction: Implications for regulation of membrane (Xen2174) of -MrIA for chronic neuropathic, show that the Munc18c protein binds to a short • Studying the structure, function and inhibition of traffi cking. Traffi c 7: 1408-1419. χ Paczkowski, F.A., Sharpe, I.A., Dutertre, S., and Nature Neuroscience 4: 902-907. postsurgical and cancer pain. High-content N-terminal peptide of the SNARE syntaxin4 transferase enzymes involved in disease Lewis, R.J. (2007). χ-Conopeptide and tricyclic protein, and that this interaction stimulates SNARE screening approaches introduced into the lab in antidepressant interactions at the norepinephrine ternary complex formation thereby promoting 2007 (using a BD Pathway 855) are expanding the transporter defi ne a new transporter model. KEY PUBLICATIONS array of targets through which venom peptides vesicle fusion (Latham et al., Traffi c 2006). We Journal of Biological Chemistry 282: 17837-17844. Forwood, J.K., Thakur, A.S., Guncar, G., Marfori, act. Finally, I am developing new methods for then determined the structure of the Munc18c: M., Mouradov, D., Meng, W., Robinson, J., Huber, Sx4 peptide complex showing that the N-peptide detection of the ciguatera toxins that contaminate T., Kellie, S., Martin, J.L., Hume, D.A., and Kobe, B. interaction is evolutionarily conserved in almost all Queensland seafood. (2007). Structural basis for recruitment of tandem SNARE systems (Hu et al., PNAS 2007). We are now The novel analgesic -MrIA interacts with residues hotdog domains in acyl-CoA thioesterase7 and its χ addressing other SNARE systems and complexes to RESEARCH PROJECTS in the mouth of NET to non-competitively inhibit role in infl ammation. Proceedings of the National norepinephrine transport. NET modeled from the unravel the molecular mechanism(s) behind these Academy of Sciences USA 104: 10382-10387. • Discovering conopeptides that modify pain Leu transporter with residues affecting binding are complicated interactions. pathways (NHMRC) labelled (from Paczkowski et al. J Biol Chem. 282, Heras, B., Kurz, M., Shouldice, S., and Martin, J.L. 17837-17844 (2007)). Our long-running interest in bacterial redox folding (2007). The Name’s Bond ..... Disulfi de Bond. Current • Determining sites of conotoxin action at the factors led to a collaboration with Jim Bardwell (U Opinion in Structural Biology 17: 691-698. α -adrenoceptor and noradrenaline transporter 1 Michigan) on the evolution of protein function in (NHMRC)

LAB MEMBERS LAB MEMBERS

Research Offi cers: Dr Fil Paczkowski, Isolation and characterization of Senior Research Offi cers: Dr Begoña Heras, Research Assistants: Kevin Chen, Russell Jarrott, Dr Lotten Ragnarsson-McGrath, Dr Marion Loughnan, α-conotoxin TxIA. (Top Left) AChBP Dr Shu-Hong Hu Patricia Walden Dr Aijun Yang, Dr Nira Gamage, Dr Natalie Lumsden screening for -conotoxins in venoms α Dr Nathan Cowieson (Australian of 30 species of Australian cone snails. Research Offi cers: PhD Students: Mareike Kurz, Nyssa Drinkwater, Research Assistants: Dianne Alewood, Jodie Major, (Bottom Left) LC-MS profi le of the Synchrotron Research Fellow), Dr Gordon King (SRC Michelle Christie Asa Anderson, Thea Monks, Alexis Barrett, crude venom of Conus textile revealing Crystallisation Offi cer), Dr Gautier Robin, Dr Stephen Honours Student: Natalie Saez Kim Hanchard, Jasmine Davis TxIA. (Top Right) Saturation binding Shouldice (UQ Postdoctoral Fellow) experiments revealed a competitive PhD Students: Marco Inserra, Christine Yan, Undergraduate Student: Rachel Effeney interaction of TxIA with Ls-AChBP. (Bottom UQ ROCX X-ray Lab Manager: Karl Byriel Claudia Zampata Right) Displacement of 125I-Bgtx from MSc Student: Nausad Shaikh Ls-AChBP by α-conotoxins TxIA, PnIA and analogues (from Dutertre et al., Honours Student: Chau Phan EMBO J 26:3858-3867 (2007)).

46 Division of Chemical & Structural Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Division of Chemical & Structural Biology 47 Combinatorial Chemistry Modelling & Visualising & Molecular Design Cellular Processes

Mark Smythe Kevin Burrage

Our research focuses on advancing drug design • Developing in vitro and cell-based assays for ß-turns are important topological motifs for biological This group works on developing simulations and • Modelling the effects of transcriptional and MacNamara, S., Burrage, K., and Sidje, R.B. and synthetic organic chemistry to discover novel screening arrays of compounds recognition of proteins and peptides. Nine clusters visualisation methodologies for understanding translational delays in a variety of genetic (2007). Stochastic analysis of the VEGF receptor represent the topology of the side chain scaffold biologically active molecules. We apply these the behaviour of complex cellular processes both regulatory settings including Hes1 in mouse, response curve, in T.D. Pham and X. Zhou, editors, architecture of the vast majority of ß-turns. and Her1/7 in somite formation in zebrafi sh COMPUTATIONAL MODELS FOR LIFE SCIENCES– new drug design and discovery methodologies to KEY PUBLICATIONS on the plasma membrane and at the genetic discover drugs to treat unmet medical needs. regulatory level. The simulation models take into CMLS ‘07: 2007 International Symposium on Horton, D.A., Severinsen, R., Kofod-Hansen, M., • Developing models for quorum sensing that Computational Models of Life Sciences, pp. 238-247, account stochastic effects, while the visualisation describe bi-modal populations effects better than Using a combination of mathematics, software Bourne, G.T., and Smythe, M.L. (2005). A versatile AIP Conference Proceedings Volume 952, 2007. focuses on two or three-dimensional display. previous deterministic models development, drug design and combinatorial synthetic approach to peptidyl privileged structures ISBN 978-0-7354-0466-3. chemistry, we are developing new approaches using a safety catch linker. Journal of Combinatorial In microscopic systems formed by living cells, • Developing spatial models that capture complex Chemistry 7: 421-435. Marquez-Lago, T., and Burrage, K. (2007). Binomial to identify biologically active molecules. Such the small numbers of reactant molecules can chemical kinetics within the cell tau-leap spatial stochastic simulation algorithm for arrays of molecules are focused towards Horton, D.A., Bourne, G.T., and Smythe, M.L. (2003). result in dynamic behaviour that is discrete applications in chemical kinetics. Journal of Chemical modulating therapeutic targets. Thus, projects are The Combinatorial Synthesis of Bicyclic Privileged and stochastic rather than continuous and KEY PUBLICATIONS Physics 127: 1. multidisciplinary and focused on achieving medical Structures or Privileged Substructures. Chemical deterministic. Our research introduces new MacNamara, S., Burrage, K., and Sidje, R.B. (2008). Nicolau Jr., D.V., Burrage, K., Nicolau, D.V., and Maini, outcomes. Reviews 103: 893-930. classes of discrete stochastic methods that Multiscale modeling of chemical kinetics via the P.K. (2007). Pomitaxis: computing with Bacterial Meutermans, W.D.F., Bourne, G.T., Golding, S.W., more accurately and effectively refl ect the master equation. SIAM Journal: Multiscale Modelling Chemotaxis. Biosystems In print. RESEARCH PROJECTS Horton, D.A., Campitelli, M.R., Craik, D., Scanlon, M., underlying cellular models. and Simulation 6: 1146-1168. and Smythe, M.L. (2003). Diffi cult Macrocyclisations: • Modulating hematopoietic prostaglandin D2 The ß-turns within each of the nine clusters are We are also focusing on some new methods for New Strategies for Synthesising Highly Strained Cyclic Burrage, K., Hancock, J., Leier, A., and Nicolau Jr., synthase for allergic disease superimposed onto the cluster’s mean structure. D.V. (2007). Modelling and simulation techniques for Tetrapeptides. Organic Letters 5: 2711-2714. both large-scale kinetics and spatial methods that The colouring schemes are: N: blue, O: red, H: white, Membrane Biology. Briefi ngs in Bioinformatics • Studying antagonists of Myb for treatment of more faithfully capture complex kinetics within Bourne, G.T., Golding, S.W., McGeary, R.P., C: green and Cß: yellow. 8: 234-244. leukaemia the cell. Meutermans, W.D.F., Jones, A., Marshall, G.R., MacNamara, S., Burrage, K., and Sidje, R.B. (2007). • Designing SHP-1 inhibitors to boost Alewood, P.F., and Smythe, M.L. (2001). The An improved fi nite state projection algorithm for the haematopoiesis Development and Application of a Novel Safety- RESEARCH PROJECTS numerical solution of the chemical master equation Catch Linker for BOC-Based Assembly of Libraries • Developing new Monte-Carlo Simulation with applications. ANZIAM Journal 48: C413–C435. • Developing antipathogenic compounds to treat of Cyclic Peptides. Journal of Organic Chemistry 66: techniques in conjunction with the group of John microbial infections 7706-7713. Hancock and researchers at Oxford University MacNamara, S., Burrage, K., and Sidje, R.B. (2007). (Dan Nicolau Jr.) that allow us to model the • Exploiting biologically relevant scaffolds Meutermans, W.D.F., Golding, S. W., Bourne, G.T., Numerical methods for the chemical master equation behaviour of lipid rafts and to investigate the and applications to stochastic models or receptor • Developing new computational algorithms and Miranda, L.P., Dooley, M.J., Alewood, P.F., and A rectangular discretisation of the space occupied by the effects of anomalous diffusion oligomerisation, Proceedings of the 6th International cell colony. This discretisation is used to effi ciently locate strategies for sampling biologically relevant Smythe, M.L. (1999). Synthesis of diffi cult cyclic Congress on Industrial and Applied Mathematics, nearest neighbours, done by querying neighbouring chemistries peptides by inclusion of a novel photolabile auxiliary in a ring contraction strategy. Journal of the American Zürich, 2007. volumes as opposed to querying the entire colony itself. • Developing a synthetic process for the Chemical Society 121: 9790-9796. In collaboration with Mr David Woolford. combinatorial synthesis of biologically relevant compounds

Superimposition of the mean LAB MEMBERS LAB MEMBERS structures of the nine clusters. Senior Research Offi cers: Dr Craig Murphy, Senior Research Offi cer: Dr Roger Sidje The superimposition is based on Dr Greg Bourne the three atoms Ca1, Ca2 and Research Offi cers: Dr Andre Leier, Ca3. The colour code for each Research Offi cer: Dr Rena Hirani, Dr Peter Bain, Dr Tatiana Marquez Lago, Dr Jiangning Song, cluster is: 1-magenta, 2-red, Dr Gerald Hartig Dr Shoaib Sehgal 3-yellow, 4-green, 5-orange, 6-dark blue, 7-white, 8-light Research Assistants: Jill Turner, Jaimee Duncan, PhD Students: Shev MacNamara, Alhadi Bustamam, blue and 9-grey. Angelika Christ, Christie Bentley Farah Abdullah, Duncan Mortimer

PhD Students: Christina Kulis, Matt Daley

SGI Origin supercomputer.

48 Division of Chemical & Structural Biology Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Joint Appointments at the IMB 49 Computational Molecular Dynamics Neuroscience of Biomolecular Systems

Geoff Goodhill Alan Mark

Understanding how trillions of nerve cells form RESEARCH PROJECTS Rosoff, W.J., McAllister, R.G., Esrick, M.A., Goodhill, The group, with members based both at The but little is known in regard to the mechanism by Leontiadou, H., Mark, A.E., and Marrink, S.J. (2006). G.J., and Urbach, J.S. (2005). Generating controlled Antimicrobial peptides in action. Journal of the networks that allow us to sense, interact with • Using in vitro assays to examine the response University of Queensland (UQ) and the University of which the binding of a molecule to an extracellular molecular gradients in 3D gels. Biotechnology and American Chemical Society 128: 12156-12161. and think about the world around us is one of the of nerve fi bres to molecular gradients Groningen, The Netherlands, (RUG), concentrates receptor transfers a signal across the cell membrane Bioengineering 91: 754-759. major scientifi c challenges of the 21st century. on modelling the structural and dynamic properties or how changes in the environment can activate Fan, H., Mark, A.E., Zhu, J., and Honig, B. (2005). • Building theoretical/computational models for the Quantitative models of brain development and Xu, J., Rosoff, W.J., Urbach, J.S., and Goodhill, G.J. of biopolymers such as proteins, nucleic acids certain surface receptors. We are, for example, Comparative study of generalized Born models: chemotaxis of nerve fi bres, particularly those based function will give us a better understanding of how (2005). Adaptation is not required to explain the and lipid aggregates. In particular, we use investigating the mechanism by which low pH triggers Protein dynamics. Proceedings of the National on Bayes-optimality principles to treat brain disorders, recover after brain injury, long-term response of axons to molecular gradients. computer simulations to understand and predict the activation of the Dengue E protein, which plays a Academy of Sciences USA 102: 6760-6764. and build smarter computers. Ultimately such • Building theoretical/computational models to Development 132: 4545-4552. the macroscopic (experimentally observable) critical role in the entry of the virus into cells. Marrink, S.J., de Vries, A.H., and Mark, A.E. (2004). models will inform the centuries-old question of understand how genetic and environmental factors behaviour of complex biomolecular systems based Carreira-Perpinan, M.A., and Goodhill, G.J. (2004). 3. Lipid aggregates and membrane-protein Coarse grained model for semiquantitative lipid how our genes and our environment interact to combine to shape brain structure, particularly in on the interactions between atoms. We develop The infl uence of lateral connections on the structure interactions: Cell membranes are the archetypal simulations. Journal of Physical Chemistry B 108: make each of us a unique individual. the visual system the software, atomic force fi elds and theoretical of cortical maps. Journal of Neurophysiology self-organised supramolecular structure. Membrane 750-760. • Modelling sensorimotor control and mechanisms 92: 2947-2959. models needed to address a range of fundamental We use theoretical, computational and protein complexes also represent a new frontier in Oostenbrink, C., Villa, A., Mark, A.E., and van of spatial navigation questions, such as: How do proteins fold? Why, in structural biology. Using simulations, we are able to Gunsteren, W.F. (2004). A biomolecular force fi eld experimental techniques to investigate the Goodhill, G.J., Gu, M., and Urbach, J.S. (2004). Alzheimer’s Disease, BSE and some forms of Type Predicting axonal response to molecular gradients directly investigate how bilayers and vesicles form. based on the free enthalpy of hydration and solvation: specifi c problem of how biological nervous II diabetes do specifi c proteins misfold, forming KEY PUBLICATIONS with a computational model of fi lopodial dynamics. We are also investigating the assembly of functional The GROMOS force-fi eld parameter sets 53A5 systems become wired up during development. destructive amyloid aggregates? How do cell Neural Computation 16: 2221-2243. structures such as the assembly of anti-microbial and 53A6. Journal of Computational Chemistry 25: A question we are particularly interested in is Mortimer, D., Fothergill, T., Pujic, Z., Richards, L.J., surface receptors transmit a signal through the peptides into transmembrane pores. This in turn 1656-1676. how growing axons fi nd their targets by detecting and Goodhill, G.J. (2008). Growth Cone Chemotaxis. Rosoff, W.J., Urbach, J.S., Esrick, M., McAllister, cell membrane? Why does one drug molecule bind Trends in Neuroscience 56: 301-311. is being used to understand the mechanism by molecular gradients. Using a combination of novel R.G., Richards, L.J., and Goodhill, G.J. (2004). A new better than another? which larger complexes form in heterogeneous experimental assays and theoretical models Giacomantonio, C.E., and Goodhill, G.J. (2007). chemotaxis assay shows the extreme sensitivity of 1. Protein and peptide folding: Understanding environments. based on Bayes-optimal signal processing, The effect of angioscotomas on map structure in axons to molecular gradients. Nature Neuroscience we are probing the astonishing abilities of axons primary visual cortex. Journal of Neuroscience 27: 7: 678-682. how proteins fold is one of the grand challenges of modern biology. It is also a critical test of our to extract directional information from noisy 4935-4946. Goodhill, G.J. (2003). A theoretical model of axon RESEARCH PROJECTS ability to accurately predict interactions in protein receptor binding signals. guidance by the Robo code. Neural Computation • Understanding protein and peptide folding Goodhill, G.J. (2007). Contributions of theoretical systems. Currently, it is not possible to directly modelling to the understanding of neural map 15: 549-564. Another main question we are interested in is how simulate the folding of proteins in atomic detail. • Simulating membrane-protein interactions development. Neuron 56: 301-311. the statistical structure of our visual environment Carreira-Perpinan, M.A., and Goodhill, G.J. (2002). Dramatic progress has, however, been made in • Modelling the nucleation and growth of amyloid infl uences the development of the mammalian Carreira-Perpinan, M.A., Lister, R., and Goodhill, G.J. Are visual cortex maps optimized for coverage? the de novo folding of small peptides and the Neural Computation 14: 1545-1560. fi brils visual system. Using computational models for (2005). A computational model for the development refi nement of some proteins. Research on folding is how neural activity affects connection strengths of multiple maps in primary visual cortex. Cerebral conducted at multiple levels. Small model systems • Atomically Atomically simulasimulatingting self-organisaself-organisationtion in between neurons, we are examining how the Cortex 15: 1222-1233. are used to refi ne force fi elds and simulation biomolecular systems map-like representations of visual features, Goodhill, G.J., and Xu, J. (2005). The development techniques. Designed peptides are used to help such as orientation selectivity, are formed in the of retinotectal maps: a review of models based on understand how peptides switch between soluble KEY PUBLICATIONS developing visual cortex. The lab is also involved in molecular gradients. Network: Computation in Neural and amyloidogenic forms. Periole, X., and Mark, A.E. (2007). Convergence and A simulation of the spontaneous binding of Equinatoxin collaborative projects investigating sensorimotor Systems 16: 5-34. sampling effi ciency in replica exchange simulations of II (a pore forming toxin from the European sea anemone, 2. Cell surface receptors: These receptors play a feedback and control, and mechanisms of spatial peptide folding in explicit solvent. Journal of Chemical Actinia equina, L) to the interface between raft forming navigation in bees, rats and robots. vital role in cellular communication, and traffi cking, Physics 126: 014903. sphingomyeline and DPPC phospholipids.

LAB MEMBERS LAB MEMBERS Senior Research Offi cer: Dr William Rosoff Research Offi cers: Dr David Poger(UQ), Dr Itamar Kass (UQ), Dr Aldo Rampioni (RUG), Research Offi cers: Dr Zuc Pujic, Dr David Smith, Dr Semen Yesylevskyy (RUG), Dr Alpesh Malde (UQ), Dr Julia Feldner Dr Maria Ratajczak (UQ) Clare Giacomantonio Research Assistant: Administration: Chantel Potter (UQ) Duncan Mortimer, Jonathan Hunt PhD Students: PhD Students: Matthew Breeze (UQ), Ajinkya Joshi (UQ), Daniela Mueller (RUG), Ying Xue (RUG), Magdelena Siwko (RUG), Jelger Risselada (RUG)

Orientation preferences of a small patch of visual The initial and fi nial confi gurations from a 200 ns simulation of the folding of an SH3 domain from a proposed folding cortex simulated using a self-organising algorithm intermediate. The fi nial structure differs from the experimental structure by only 0.18 nm backbone RMSD within based on Hebbian learning. experimental uncertainty.

50 Joint Appointments at the IMB Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 Joint Appointments at the IMB 51 Applied Statistics AFFILIATE APPOINTMENTS & Bioinformatics

Geoffrey McLachlan

My research in applied statistics is in the related RESEARCH PROJECTS Ng, S.K., McLachlan, G.J., Wang, K., Ben-Tovim, L., The purpose of affi liate appointments is to foster ASSOCIATE PROFESSOR STEVE BARKER ASSOCIATE PROFESSOR STUART KELLIE and Ng, S.W. (2006). A mixture model with random- fi elds of classifi cation, cluster and discriminant • Statistical modelling via fi nite mixture models, collaborations in teaching, research and related School of Molecular and Microbial Sciences School of Molecular and Microbial Sciences effects components for clustering correlated gene- analyses, data mining, image analysis, intelligent including methods for the detection of differentially activities between the Institute for Molecular expression profi les. Bioinformatics 22: 1745-1752 systems, machine learning, neural networks, and expressed genes in different treatment classes or Bioscience (IMB) and Schools at The University PROFESSOR MATT BROWN PROFESSOR BOSTJAN KOBE pattern recognition, and in the fi eld of statistical in time-course studies Ben-Tovim Jones, L., Ng, S.K., Ambroise, C., Monico, of Queensland. Affi liate appointees to the IMB inference. The focus in the latter fi eld has been K., Khan, N., and McLachlan, G.J. (2005). Use of contribute through active involvement with relevant Diamantina Institute for Cancer, Immunology School of Molecular and Microbial Sciences • Analysing Analysing the stastatisticstistics of microarramicroarrayy gene- on the theory and applications of fi nite mixture microarray data via model-based classifi cation IMB Groups, facilities or research programs and and Metabolic Medicine expression data for the development of disease in the study and prediction of survival from lung models and on estimation via the E(expectation)- diagnostics through joint supervision of research higher ASSOCIATE PROFESSOR FRED MEUNIER M(maximization) algorithm. cancer. In Methods of Microarray Data Analysis IV JS degree students. Affi liate appointees contribute PROFESSOR IAN FRAZER Queensland Brain Institute • Developing diagnostic methods for cancer, using Shoemaker & SM Lin (Eds.) New York: Springer, pp. to the intellectual life of the Institute through I am also actively involved in the fi eld of multiple molecular indices in conjunction with 163-173. Diamantina Institute for Cancer, Immunology attendance at IMB seminars, Divisional meetings and Metabolic Medicine bioinformatics with the focus on the development clinical factors ASSOCIATE PROFESSOR JOE ROTHNAGEL McLachlan, G.J., Do, K-A., and Ambroise, C. (2004). and IMB Group Leader retreats. Salary for affi liate of methods and software for the analysis of data Analysing Microarray Gene Expression Data. Hoboken, appointees is paid by the relevant University of School of Molecular and Microbial Sciences from high-throughput genomics projects, with PROFESSOR TOM GONDA KEY PUBLICATIONS New Jersey: Wiley. Queensland School. particular emphasis on gene-expression profi les. Baek, J., Son, Y.S., and McLachlan, G.J. (2007). Diamantina Institute for Cancer, Immunology The limitations of conventional methods of cancer Ambroise, C., and McLachlan, G.J. (2002). Selection PROFESSOR ISTVAN TOTH Segmentation and intensity estimation of and Metabolic Medicine classifi cation and diagnosis based on the site and bias in gene extraction on the basis of microarray School of Molecular and Microbial Sciences microarray images using a gamma-t mixture model. appearance of the tumour or organ are well-known. gene expression data. Proceedings of the National Bioinformatics 23: 458-465. Academy of Sciences USA 99: 6562-6566. PROFESSOR PETER GRESSHOFF With microarrays allowing genome-scale measures ASSOCIATE PROFESSOR PAUL YOUNG of gene expression, attention has turned to using Do, K.-A., McLachlan, G.J., Bean, R.W., and Wen, McLachlan, G.J., Bean, R.W., and Peel, D. (2002). Centre for Integrative Legume Research School of Molecular and Microbial Sciences differences in the activity of the gene expressions S. (2007). Application of gene shaving and mixture A mixture model-based approach to the clustering models to cluster microarray gene expression data. (gene profi ling) to classify and diagnose tumours. of microarray expression data. Bioinformatics 18: PROFESSOR WAYNE HALL Cancer Informatics 2: 1-19. 413-422. However, the complexity of tumours makes it likely School of Population Health that a diagnostic test will be based on marker McLachlan, G.J., Chevelu, J., and Zhu, J. (2007). profi les rather than individual markers. But the Correcting for selection bias via cross-validation PROFESSOR JANE HUNTER identifi cation of relevant subsets of the genes has in the classifi cation of microarray data. In Beyond its challenges, because typically thousands of Parametrics in Interdisciplinary Research: A School of Information Technology and Electrical Festschrift to P.K. Sen, N. Balakrishnan, E. Pena, and gene expression levels are available from only tens Engineering M.J. Silvapulle (Eds.). IMS Lecture Notes-Monograph of patients. It means that off-the-shelf methods Series, Hayward, California, pp. 383-395. of statistical analysis cannot be implemented, at least not without serious modifi cations. Thus, there McLachlan, G.J., Bean, R.W., and Ben-Tovim Jones, is a need for new methodologies to be able to L. (2006). A simple implementation of a normal process thousands of genes with the aim of fi nding mixture approach to differential gene expression in multiclass microarrays. Bioinformatics 22: 1608- those genes that are biologically heterogeneous 1615. (Top Row) Associate Professor Steve Barker, Professor Matt Brown, Professor Ian Frazer, Professor Tom Gonda, and therefore potential markers for cancer type, Professor Peter Gresshoff, Professor Wayne Hall and Professor Jane Hunter. treatment therapies, or clinical outcomes. (Bottom Row) Associate Professor Stuart Kellie, Professor Bostjan Kobe, Associate Professor Fred Meunier, Associate Professor Joe Rothnagel, Professor Istvan Toth and Associate Professor Paul Young.

LAB MEMBERS Research Offi cers: Dr Ian Wood, Lloyd Flack PhD Students: Justin Zhu, Katrina Monico

Books that Professor McLachlan has edited or to which he has contributed.

52 Joint Appointments at the IMB Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 AFFILIATE APPOINTMENTS 53 IMBcom POSTGRADUATE RESEARCH

It has been yet another exciting year for the IMB Rehan Villani with her presentation, “Hedgehog Australia Pty Ltd to Emma Redhead from Dr Tim IMBcom Pty Ltd is The University of Queensland’s IMBcom has had a historical strategic focus on The IMB has a commitment to the training of Postgraduate Program, with 37 new students Signalling: Balancing Skin Turnover and Skin Bailey’s group. Emma, whose honours project company for commercialisation of the IP arising developing new companies. During the fi rst fi ve high-quality graduate students in the molecular joining the program throughout the year. Nearly Cancer”. Rehan has not yet had the opportunity focused on developing a discriminative algorithm from the research of the IMB. It is responsible years, IMBcom has seen the establishment of 11 biosciences and aspires to provide a more holistic one third of these were from overseas (from to use her $1500 prize but is intending to put it for detecting motifs in DNA and protein sequences, for protection and development of the IMB’s new biotechnology companies, two in conjunction training with the inclusion of commercial and countries as diverse as Germany, USA, UK, Brazil, to good use in the fi rst half of 2008. continued in the Bailey lab as a research assistant intellectual property portfolio. Established with UniQuest. These companies have raised ethical dimensions. IMBcom has supported this Singapore, Indonesia, Thailand and Malaysia) and, for much of 2007 before travelling overseas. • The Olympus Life Science Research in 2000, IMBcom has a skilled, independent more than $40 million through private sector objective through the provision of workshops interestingly, slightly over one third commenced Amgen Australia has been presenting our honours Postgraduate Travel Award, as per last year, Board of Directors and operates as a separate investment, $16 million in federal and state throughout the training period. These “bootcamps”, their degree in the middle of the year, rather students with this award for over a decade and we attracted a number of visually as well as commercial entity, but with a charter of service to government commercial grants and currently or BioBusiness Retreats, incorporate elements of than at the more traditional January – March are thrilled by their continued support of our young scientifi cally stunning entries, which took the the University’s commercialisation objectives. The employ or contract over 60 individuals in R&D career preparation, understanding and working start date. We also had another solid year for researchers. form of still images or videos. Unlike last year company has nineteen employees who provide the and commercialisation. These spinouts have gone in a commercial environment, and working in completions, with more than 20 IMB students however, where an IMB-based team narrowed IMB also continued the Undergraduate Research necessary skills and support to IMB researchers in on to develop strategic relationships in their own teams to produce outcomes. The training engages receiving their PhD degrees (for a full list see Table the entries to the three fi nalists, this year the Scholarship Scheme (URSS) in 2007, giving 21 commercialising the results of their discoveries. right with many other Australian and international experienced professionals from the pharmaceutical, 1 page 56) and a further seven submitting their biotechnology and pharmaceutical companies, and biotechnology, investment and research industries. Olympus selection team saw all entries and third-year students the opportunity to work in a IMBcom uses a model of cooperative integration theses for examination in 2007. We currently have have encouraged the growth and establishment of The training has provided one of the building selected a winner and two runners-up from laboratory within one of our divisions for eight with the discovery activities of the research labs. approximately 130 research higher degree (RHD) service providers, adding to the fabric and critical blocks of the commercial culture emerging in the the total pool. The winner was Samantha hours per week during semester. Additionally, IMBcom staff are involved from the early stages students enrolled through the IMB and are hoping mass of the industry in Queensland. The companies IMB. These programs have provided commercial, Murphy (Parton lab), with her video titled more than a dozen third-year students completed with the planning and delivery of ways to add this number will grow slightly throughout 2008. continue to mature under their own management project and team management skills to over 240 “Characterisation of lipid droplet metabolism in mini-research projects as part of the “Introduction value to the emergent innovations. The company once substantial fi rst round investment is raised. individuals to date, some of whom have adopted Not only are our students growing in numbers, adipocyte cells (Phat and Fusogenic)”, while the to Research” module of their respective degrees, manages the IMB’s Intellectual Property as One of the companies developed in partnership careers in the industry, being placed in Queensland they are continuing to produce high-quality runners-up were Natalie Butterfi eld (Wicking 14 summer students undertook projects in custodians, developers, and drivers, resulting in with Uniquest, Xenome, has now moved to become biotechnology companies and IMBcom itself. The research outcomes. Half of our 2006 graduates, lab) and Andrew Noske (Marsh lab), who both 2007/2008 and several Advanced Studies students licences, contracts and the formation of start-up completely independent of the University, and the IMBcom model is now widely imitated by other or 12 of 24, were nominated for consideration for received gifts from Olympus. Interestingly, completed research projects as part of their companies to take discovery to products and funds generated for the IMB and IMBcom are being organisations that recognise that the preservation the Dean’s List for 2006, with Ben Clark (Capon Natalie was runner-up last year too, suggesting program. We also continued our involvement with services into markets. used to provide the “proof-of-concept” funds for of value in intellectual property is the key to lab), Alistair Forrest (Grimmond lab), Markus Kerr not only that Natalie continues to produce great the Advanced Studies Program lunchtime seminar future IP and product development. building assets upon which industry develops. (Teasdale lab) and Matthew Kirkham (Parton work but also that the selection procedures are series coordinated by Ms Robyn Evans from the lab) being successful. A snapshot of some of our robust. Sam intends to use her $1000 travel BACS Faculty at UQ. Once again, we hosted many IMBcom provides assistance to Queensland and students’ other achievements can be seen in money to attend a conference in 2008. All international students, primarily from Germany, Commonwealth government departments and Table 2 (page 56). recipients were presented with their awards Sweden and France but also from India, Singapore, agencies with respect to biotechnology industry by Mr Kieren McHugh and Mr Paul Pearce from Denmark, USA and the Netherlands, who joined This year saw the continuation of two specialist development, and is well regarded as an effective Olympus at the IMB Molecular Genetics and IMB for several months as occupational trainees, awards, initiated in 2006 for our IMB RHD advocate for Queensland’s consistent promotion of Development Divisional Forum. undertaking overseas research placements as part students, through generous sponsorship by leading the Smart Queensland agenda. IMBcom showcases of their degree requirements within their home companies in the fi eld of life science. Once again, we greatly appreciate the generous not only the IMB and the University to industry institutions. We also welcomed a number of year support of the IMB graduate program by both and investment, but Queensland as an industry • The Roche Award for Postgraduate Career 10, 11 and 12 students from schools throughout Olympus and Roche and hope these awards destination. Development (RAPCD) yet again attracted a Queensland to undertake a brief period of work continue. For more information regarding the very high standard of entries for the selection experience within research laboratories. instigation of these awards, please see the 2006 panel to consider. The three fi nalists, Andrew annual report. Our IMB student association (SIMBA) had yet Noske (Marsh lab), Michael Tallack (Perkins lab) another very productive year, ushering in a and Rehani Villani (Wainwright lab), gave a Our honours cohort was smaller than usual for 2007 new Executive in May comprising Adam Costin 15-minute oral presentation to a second and, as with our RHD students, was distributed (President), Josefi ne Sprenger (Vice President), selection panel, which included Dr Andreas such that nearly half the students commenced Andrew Noske (Secretary) Elaine Haase (Treasurer), Goertz and Ms Susan Matthews from Roche. their honours study mid-year. We had 19 students Alex Combes (SIMBAlize editor-in-chief) and Tom The presentations were wonderful, refl ecting commencing in February, seven students who Whitington (Webmaster). This Executive continued both the talent of our students and the diversity carried over from July 2006 and seven others who with the vibrancy of the last, better promoting of the IMB’s research approaches, and the commenced in July 2007. The Amgen Award for the SIMBA website among the general IMB judging panel spent much time deliberating. the most outstanding honours student at the IMB community, continuing the fi ne tradition of the The ultimate winner, announced by Dr Goertz at in 2006 was presented in August by Ms Bronwyn bimonthly electronic student journal, SIMBAlize, the Institute-wide Friday Seminar Series, was Shanahan and Ms Jo McNaughton from AMGEN

54 IMBcom Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 POSTGRADUATE RESEARCH 55 POSTGRADUATE RESEARCH

and organising a host of social events and the year, the IMB Early Career Researcher (ECR) for some of our postdocs and more senior PhD Bayer, Dr Mathias Francois, Dr Andrew Brooks, Dr (as it replaced the “Introduction to Bio-Business” of our potential students, who, until this year, were bonding exercises. This included the inaugural Committee also provided useful information students to present their research to the Institute. Allison Pettit, and PhD students Evan Stephens and Workshop) and IMBcom’s three-day “BioBusiness tied to an October deadline, requiring many to IMB/AIBN combined trivia night, which proved very sessions and a mentoring breakfast, as well as During 2007 the members of the ECR committee Simon Wilkins. Retreat” for the third-years, which was held in establish PhD projects while trying to complete successful in bringing students and staff from continuing to coordinate the Institute-wide Monday included postdocs Dr Terje Svingen, Dr Dagmar June at the Grand Pacifi c, Caloundra. Once again, their honours thesis. For a full list of scholarship The ECR committee ran several information the two research institutes together. Throughout Midday Meetings, which provided an ideal venue Wilhelm, Dr Karen McCue, Dr Michael Hanzal- feedback from the retreat was extremely positive, outcomes for 2007/2008, please see Table 3. There sessions in conjunction with the Graduate with students really enjoying the mentoring has also been a change to the way the University Program this year, including a set of two one-hour sessions, the networking opportunities and career handles international student costs, which may TABLE 1: PhD CONFERRALS FOR 2007 scientifi c writing workshops in March, conducted advice. We reinitiated our basic statistics course have implications for fee-waiver opportunities in by Dr Joan Leach, who is part of the science Last Name First Name Group Degree Thesis Title Where are they now? with Carl Sherwood, the eight-week sessions the future. communication program at UQ. These sessions Allen Tamara Muscat PhD Regulation of PPARg Activity by Novel Modulators Baker Heart Research Institute, Melbourne, Australia proving so popular that we ran them in both were very well received and will be expanded in The IMB has been very fortunate to have Professor semesters, as well as conducting a three-day Barry Daniel Craik PhD Structural and Dynamic Studies of Cyclotides and their Queensland Institute of Medical Research, the future. Another information session in October, Rob Capon continue in his role as the IMB Precursors Brisbane, Australia specialist workshop on the program R, conducted (coordinated largely by Evan Stephens from the Postgraduate Coordinator and once again serve by Professor John Maindonald from the Australian Constantin Myrna Hume PhD Transcriptional Regulation of the c-fms Promotor by the Travelling ECR committee and funded by the Postgraduate as the IMB representative on the UQ Postgraduate ETS Family of transcription Factors National University. Program), was conducted by Dr Hugh Kearns Committee of the Academic Board throughout the Dave Richa Sweet PhD Functional Characterisation of the Role of Protein Tyrosine Institute for Molecular Bioscience (Wainwright group), from Flinders University. The morning session, The year has also been a time of change for the year. Through his ongoing dedication and vigilance Phosphatase CD148 in Macrophages Brisbane, Australia covering, “The 7 Secrets of Highly Successful PhD UQ Graduate School, with the RHD offi ces initiating to all aspects of the Graduate Program, Rob is Davis Melissa Teasdale PhD Defi ning the Membrane Organisation of Institute for Molecular Bioscience (Ragan group), Eukaryotic Proteins Brisbane, Australia Students”, was complemented by an afternoon a number of changes in practice that are set to continuing to drive the IMB Postgraduate Program session discussing, “Defeating self-sabotage”, both continue in 2008 and 2009. The most important forward in a proactive and positive way to help Garcia Castro Alexander Ragan PhD Developing Ontologies in the Biological Domain Institute for Infocomm Research, Singapore of which were well received and provided food for change for this year was the deregulation of the deliver to our students the best overall research Gardiner Melissa Perkins PhD Determining the role of klf4 in zebrafi sh development Queensland Brain Institute, Brisbane, Australia thought for our student body. Australian Postgraduate Award and UQ Research training possible. Gruber Christian Craik PhD Plant Cyclotides: Evolution, Biosynthesis and Vienna Medical University, Austria Scholarships schemes such that, as of October Application of Circular Cystine Knot Mini-Proteins In addition to these information sessions, the Cystine Knot Mini-Proteins 2007, domestic students have been able to apply Postgraduate Program continued to run its for a scholarship at any time throughout the year, Hamwood Tamarind Hume PhD The Structural Basis of CSF-1:CSF-1R Interactions CBio Pty Ltd, Brisbane, Australia regular set of workshops designed to assist with their scholarship application being linked Helwani Falak Yap PhD Cortactin regulates actin cytoskeletal dynamics at Mater Medical Research Institute, Brisbane, Australia students in overall career development. These E-cadherin Adhesive Contacts to the application for enrolment into the RHD included IMBcom’s “Biobusiness Day Out” in program. This has proved benefi cial for a number Imperial Julita Alewood PhD Novel peptides from Conus planorbis, Terebra subulata, University of Utah, Salt Lake City, Utah, USA November, which was compulsory for fi rst-years and Hastula hectica Ireland David Craik PhD Structure-Activity Relationships in Biotechnology: UniQuest Pty Ltd., The University of Queensland, Scientifi c and Business Perspectives Brisbane, Australia Joseph Shannon Stow PhD The Exocytic and Endocytic Traffi cking of E-cadherin Patient Safety Offi cer, Emerald Hospital, Table 2: Non-IMB Awards received by PhD Students in 2007 TABLE 3: Scholarships Obtained in 2007 for in Epithelial Cells Queensland, Australia Funding in 2008 Recipient Award Kay Jason Stow PhD Intracellular Cytokine traffi cking and Phagocytosis Hospital for Sick Children, Toronto, Canada 7 Australian Postgraduate Awards/UQRS (2 in Macrophages Natalie Butterfi eld (Wicking lab) Finalist, Oral Abstract presentation, Australian Society of Medical Research additional scholarships obtained early 2008) Loughnan Marion Lewis/ PhD Discovery and Characterisation of Conopeptide Institute for Molecular Bioscience (Lewis group), Postgraduate Student Conference Alewood antagonists of nAChRs Brisbane, Australia 1 Endeavour International Postgraduate Ming Kang Chang (Sweet lab) Third Prize, Oral Abstract presentation, Australian Society of Medical Research Scholarships/UQRS Lovelace Erica Craik PhD The Structure, Activity and Engineering of Two Fred Hutchinson Cancer Research Center, Seattle, USA Research Postgraduate Student Conference Disulfi de-bonded Conotoxins 3 UQ International Research Awards/UQRS Alex Combes (Koopman lab) Winner, Invitrogen Molecular Probes Photo Competition Palmer James Wainwright PhD Characterisation of the Host Immune response in Cystic Institute for Molecular Bioscience (Wainwright lab), Most Outstanding Individual Presenter, GSK Biopitch, IMBcom Biobusiness 1 Endeavour Postgraduate Research Fibrosis Mice Brisbane, Australia Retreat Scholarship Pippal Jyotsna Muscat PhD The Role of PPAR-alpha In Lipid and Carbohydrate Prince Henry’s Institute of Medical Research, Metabolism of Skeletal Muscle Cells Melbourne, Australia Melissa Gardiner (Perkins lab) UQ Graduate School Research Travel Award 1 Endeavour Turkey Postgraduate Award Ratnayake Ranjala Capon PhD Chemistry and Bioactivity Studies of Australian National Cancer Institute, Frederick, USA Dhiraj Hans (Fairlie lab) Gates Foundation Global Health Series Travel Award 2 ANZ Trustees PhD Scholarships in Medical Microorganisms Research Jason Kay (Stow lab) $1000 Travel Grant, Keystone Symposia macrophage conference Ren Gang Munn PhD Interactions between PCH proteins Hof1p and Vrp1p Institute for Molecular Bioscience (Yap lab), 1 The Cancer Council Queensland (‘John (Albert) in regulation of cell division and membrane transport Brisbane, Australia Tim Mercer (Mattick lab) UQ Graduate School Research Travel Award Earnshaw Scholar’) Saska Ivana Craik PhD Biosynthesis of Circular Proteins in Plants Institute for Molecular Bioscience (Craik lab), Philip Nguyencong (Craik lab) UQ Graduate School Research Travel Award Brisbane, Australia 3 AusAID Scholarships (2 from transferred students) Woolford David Hankamer PhD Advanced Algorithms, Software and Applications Baylor College of Medicine, Houston, USA Amber Stephens (Munn lab) UQ Graduate School Research Travel Award in Single Particle Analysis Rehan Villani (Wainwright lab) Poster Prize, Australian Society of Medical Research Postgraduate Student 2 Home Government scholarships Wu Andy Cassady PhD Invitro and In vivo Characterisation of Celllular School of Biomedical Sciences, The University of Conference Chiu Ku Responses to PHBV and Hydroxyapatite/PHBV Queensland, Brisbane, Australia Composites as Bone Biomaterials. Simon Wilkins (Perkins lab) UQ Graduate School Research Travel Award

56 POSTGRADUATE RESEARCH Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 POSTGRADUATE RESEARCH 57 VISITING SPEAKERS

DR KIRILL ALEXANDROV ASSOCIATE PROFESSOR SAM EL-OSTA PROFESSOR GARY HALLIDAY DR PHILIP KIM PROFESSOR DAGMAR RINGE PROFESSOR BRIAN STORRIE Department of Physical Biochemistry, Max-Planck- Baker Heart Research Institute Melanoma and Skin Cancer Research Institute, Department of Molecular Biophysics Rosenstiel Basic Medical Sciences Research University of Arkansas for Medical Sciences, Institute for Molecular Physiology, Germany “Transient hyperglycemia induces vascular epigenetic University of Sydney and Biochemistry, Yale University, USA Center, Braindeis University, Massachusetts, USA Little Rock, USA “Development of new tools and approaches for the changes that cause persistent increased gene “Ultraviolet radiation-induced skin cancer: the “Jumping Scales: How 3D structures and Molecular “Mechanism of control of gene expression: the “Rab6 regulates both ZW10/RINT-1- and conserved analysis of GTPase controlled molecular machines” expression during subsequent normoglycemia” outcome of immunosuppression and gene mutations” Genetics Meet in Protein Networks” diphtheria toxin repressor” oligomeric Golgi complex-dependent Golgi traffi cking and homeostasis” PROFESSOR ALAN W. BELL DR MATTHIAS ERNST ASSOCIATE PROFESSOR STUART HOOPER PROFESSOR MARTIN LAVIN PROFESSOR JEFF ROSEN PROFESSOR JILL TREWHELLA Chairman, Department of Animal Science, Ludwig Institute for Cancer Research, Monash University Queensland Institute of Medical Research Baylor College of Medicine, Houston, Texas, USA Cornell University, New York, USA Royal Melbourne Hospital “Imaging Lung Aeration at Birth” “ATM activation and downstream signalling protection “Stem/progenitor cells in the etiology and treatment School of Molecular and Microbial Sciences, “The fetal origins hypothesis: evidence and “Using reverse genetics to dissect mechanisms against cancer and neurodegeneration” of breast cancer” University of Sydney maintaining epithelial homeostasis in the gut” implications for performance and health of livestock PROFESSOR JONATHON HOWARD “Protein-protein interactions in signalling pathways: species” DR LARS LEICHERT PROFESSOR ROB SAINT what we can learn from solution scattering methods” Max Planck Institute of Molecular Cell Biology, DR ALEX FRANZUSOFF Dresden, Germany Department of Molecular, Cellular and Director, ARC Special Research Centre for the PROFESSOR MAXWELL R. BENNETT AO PROFESSOR GISOU VAN DER GOOT GlobeImmune, Colorado, USA “From single motor proteins to cellular motility” Developmental Biology, University of Michigan, USA Molecular Genetics of Development, Australian Director, Brain & Mind Research Institute, “Sheep in wolf’s clothing – engineering yeast for use “Global Identifi cation of Redox-Regulated Proteins” National University Global Health Institute, Ecole Polytechnique University of Sydney in cancer and viral immunotherapy” Federale de Lausanne, Switzerland DR MICHAEL HUCKA “A versatile Rho GPTase signalling pathway in cell “Astrocyte and microglia signalling in the brain” DR GREG MUNDY division and migration” “Anthrax toxin: from entry to cell death” PROFESSOR RUDI GLOCKSHUBER Co-director, Biological Network Modelling Center, The Beckmann Institute, California Institute of Director, Center for Bone Biology, Vanderbilt PROFESSOR MARGARET BRIMBLE PROFESSOR RICK SHINE PROFESSOR GREG VERDINE Institute of Molecular Biology and Biophysics, Technology, USA University Medical Centre, Nashville, Zurich, Switzerland Department of Chemistry and Maurice Wilkins “SBML, BioModels Database, MIRIAM and SBO: Tennessee, USA School of Biological Sciences, University of Sydney Department of Chemistry and Chemical Biology Centre for Molecular Biodiscovery, “Assembly of type 1 pili in Escherichia coli ” infrastructure for computational systems biology” “New Concepts of the Vicious Cycle of Breast Cancer “Mr Toad comes to Darwin: an evolutionary and Department of Molecular and Cellular Biology, University of Auckland, New Zealand Metastasis to Bone” perspective on the cane toad invasion” Harvard University, USA “Medicinal Chemistry: An Academic Discipline or a DR ERICA A. GOLEMIS PROFESSOR DAVID HUME “The search for damaged bases in the genome” Commercial Reality?” ASSOCIATE PROFESSOR OSAMU MARUYAMA PROFESSOR EVAN SIMPSON Fox Chase Cancer Center, Philadelphia, Edinburgh Bioscience Research Centre, Scotland Pennsylvania, USA Kyushu University, Japan Director, Prince Henry’s Institute DR CHRIS L. WALLER PROFESSOR KEVIN BURRAGE “The Biology of Macrophages” “HEF1/NEDD9, a scaffold for metastasis” “ParScope: Predicting Transcription Factor Binding of Medical Research Director, World Wide Chemistry Informatics, Director, Advanced Computational Modelling Sites through Parsimonious Composite Patterns” “Sex, fat and cancer” Pfi zer Global Research and Development, USA PROFESSOR PETER HUNTER Centre, The University of Queensland PROFESSOR THOMAS GOODWIN “Challenges, strategies and solutions for drug Director, Bioengineering Institute, “Is mathematical modelling and simulation of any PROFESSOR ROBERT MURPHY PROFESSOR MANDYAM SRINIVASAN discovery data integration at Pfi zer” practical use in the life sciences?” Department of Chemistry, Hendrix College, University of Auckland, New Zealand and Professor, Arkansas, USA Oxford University Carnegie Mellon University, USA Queensland Brain Institute “Automated Interpretation of Subcellular Patterns DR ANTONY COOPER “Utilisation of green extraction techniques for “Cardiac modelling: From ion channels and protein “Smart computers in small brains: vision, navigation, pheromones in elephants, maned wolves and pathways to integrative cell, tissue and organ in Microscopic Images: Bioimage Informatics for perception and cognition in honey bees” Garvan Institute ring-tailed lemurs” function” Systems Biology” “Misfolded proteins and disease: Insights into DR DANIELA STOCK Parkinson’s Disease and ALS from model systems” PROFESSOR JENNY GRAVES DR MANDAR NAIK PROFESSOR NANCY JENKINS Victor Chang Cardiac Research Institute Research School of Biological Sciences, Institute of Molecular and Cell Biology, Singapore Institute of Biomedical Sciences, “Structure and function of proton translocating ASSOCIATE PROFESSOR PETER CURRIE Academia Sinica, Taipei, Taiwan Australian National University “Harnessing transposons for cancer gene discovery” ATPases” Developmental Biology Laboratory Head, “Weird animal genomes and the evolution of sex” “Roles of structure and structural dynamics in Victor Chang Cardiac Research Institute antibody recognition of allergen proteins” HUGH KEARNS “Zebrafi sh models of skeletal muscle development PROFESSOR JEAN GRUENBERG and regeneration” Flinders University PROFESSOR BRENT REYNOLDS Department of Biochemistry, University of Geneva, “The Seven Secrets of Highly Successful PhD Queensland Brain Institute Switzerland Students” and “Defeating Self-Sabotage” “Membrane dynamics in the endosomal pathway” “Targeting CNS cancer cell lines”

58 VISITING SPEAKERS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 VISITING SPEAKERS 59 COLLABORATIVE RESEARCH PARTNERSHIPS

Further underlining the Institute’s commitment locate the general regions where the genes reside. transformed into structure and function in the to research excellence, IMB Group Leaders The mutagen used to create the mutants leaves a mammalian cell. Perspectives and technologies collaborate extensively with partners both within particular genetic fi ngerprint that can be discerned of mathematics, statistics, high-performance Australia and internationally. The IMB is a core by sequencing candidate genes, thus identifying the computation, information technology, genomics and partner and participant in many research centres gene responsible for the trait under consideration. This high-throughput experimental phenomic biology are is a very powerful approach to biology which enables focused on representing the mammalian cell as a around the country, including three Major National gene function to be elucidated based upon the high- complex system of molecular networks, and building Research Facilities (MNRFs) and two Cooperative throughput analysis of phenotypes (“phenomics”). a common modeling and visualisation environment Research Centres (CRCs). to simulate its development and behaviour. Although directed in the fi rst instance towards understanding These programs are integral to building Australia’s ARC CENTRE OF EXCELLENCE IN human health and development, the Centre’s national and international research capabilities. BIOTECHNOLOGY AND DEVELOPMENT technologies and output are generally applicable They aim to create the scale and focus necessary The ARC Centre of Excellence in Biotechnology and to biotechnology, while building critical mass in to maintain and develop Australia’s world-class Development (CBD) was established in 2003 to focus advanced bioinformatics is vital to Australia’s standing in priority areas through highly innovative on the biology of male germ cells – embryonic stem international competitiveness in bio-based industries. research that addresses challenging and signifi cant cells that eventually produce sperm cells in men. A In 2007, the Centre was upgraded to a Centre of problems. CRCs and COEs make vital contributions review of the Centre in 2007 confi rmed its status as Excellence, which will result in a further $3.3 million to Australia’s research landscape and produce a Centre of Excellence, and extended its funding for in funding from 2008. outcomes with economic, social and cultural a further three years. The Centre will receive $6.42 million from 2008. Collaborating institutions include benefi ts to the country. Involvement in these CRC FOR CHRONIC INFLAMMATORY DISEASES ventures refl ects very highly on the participating the IMB, the Universities of Queensland, Melbourne, and Newcastle, Monash University and the Australian The IMB is a core participant in the CRC for researchers, indicating the immense value of their National University. Unlike many other types of Chronic Infl ammatory Diseases (CRC-CID), whose work in both scientifi c and commercial terms. stem cells, germ cells represent a truly “blank partners are Monash University, The University of slate” that can develop into any tissue in the body. Melbourne and AstraZeneca. The major objective ARC SPECIAL RESEARCH CENTRE FOR Understanding their specifi cation and programming of the CRC is to discover new molecular targets FUNCTIONAL AND APPLIED GENOMICS is central to contemporary efforts to harness stem involved in the pathogenesis of chronic infl ammatory cell technologies. Since male fertility depends on lung and joint disease and use this information The ARC Special Research Centre for Functional generating sperm cells in vast numbers, and since to develop novel treatments for these disorders. and Applied Genomics provides and develops genetic and environmental factors commonly disturb The CRC is using gene microarrays, proteomics, rate-limiting technologies that enable world- the quantity and quality of sperm produced, the cell-based assays and genetically modifi ed animal class research in the fi eld of genomics. An research will further impact on understanding and models of disease to understand how macrophages integrated network of core technologies, including possible treatment of infertility, a distressing condition cause chronic infl ammation. The CRC is structured computational biology, structural biology, proteomics, that represents a massive healthcare burden in to facilitate the entire drug discovery cycle: primary an animal transgenics service, as well as a Australia and worldwide. Disorders of germ cells target identifi cation using functional genomic and microarray facility, have been established. The future are often accompanied by testicular cancer, and so proteomic approaches, target validation in disease of the SRC will see the coordinated application the potential medical signifi cance of this research models and human tissues, high-throughput cell- of these technologies to provide meaningful is twofold. It has become increasingly clear that based assay development, lead target screening, description of biological systems such as mammalian manipulating the quantity and/or quality of germ generation of therapeutic and research antibodies, cells, from the structure, location and function of cells, particularly male germ cells, presents powerful and the development of macrophage-targeted drug individual proteins to the control networks that opportunities in the pest management arena, and delivery strategies. allow the system to respond to its environment in in other biotechnological pursuits such as the development, differentiation and disease. management of endangered wildlife species.

AUSTRALIAN PHENOMICS FACILITY ARC CENTRE OF EXCELLENCE IN The Australian Phenomics Facility (APF) is based at BIOINFORMATICS the John Curtin School for Medical Research and is The ARC Centre in Bioinformatics, with headquarters a Major National Research Facility (MNRF) formed at IMB, brings Australian and overseas researchers by support from the IMB, the Australian National together into interdisciplinary programs designed University and the Garvan Institute for Medical to explore how information in the genome is Research. The APF is based around the use of mouse genetics to discover novel genes that infl uence traits of medical relevance. Large populations of mice are exposed to a mutagen, traits are identifi ed and selected and then genetic mapping is used to

60 COLLABORATIVE RESEARCH PARTNERSHIPS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 COLLABORATIVE RESEARCH PARTNERSHIPS 61 COLLABORATIVE RESEARCH PARTNERSHIPS

AUSTRALASIAN INVASIVE ANIMALS CRC AUSTRALIAN STEM CELL CENTRE genotyping, microarraying, agricultural genomic QUEENSLAND FACILITY FOR ADVANCED NETWORK FOR PANCREATIC ORGAN DONORS services and other resources for the genetic and The Australian Stem Cell Centre (ASCC) is a national BIOINFORMATICS (QFAB) WITH DIABETES (NPOD) Australasian Invasive Animals CRC is a venture aiming physical mapping of chromosomes, mutation research and funding facility set up by the ARC, The QFAB was established in 2006 with a $1.9 million nPod is an initiative of the Juvenile Diabetes to counteract the impact of invasive animals through detection and associated bioinformatic analysis. Victorian Department of Industry, Innovation and Queensland State Government grant and is based at Research Foundation (JDRF) and brings together the development and application of new technologies It serves several hundred research groups across Regional Development, and the Federal Department the IMB. It is rapidly becoming a leader in supporting Organ Procurement Organisations, academic and integrating approaches across agencies and all states and territories of Australia from nodes at of Education, Science and Training through a linked the bioinformatics requirements of research-intensive institutions and leading diabetes researchers from jurisdictions. It is the fi rst time that research, industry, The University of Queensland, the Walter and Eliza MNRF. The ASCC is primarily based at Monash universities, institutions and companies, beyond the across Europe and America. The only Australian node environmental, commercial and government agencies Hall Institute of Medical Research in Melbourne, University, but through the guidance of the Scientifi c capability of any single organisation in Australia or the is at the IMB in the laboratory of Dr Brad Marsh, have combined to create and apply solutions for and the Waite Campus of the University of Adelaide. invasive animal threats, which cost Australasia at least Management Advisory Committee (SMAC) and a Asia-Pacifi c region. It provides the bioinformatics, ICT, who in addition to his research also chairs the $720 million per annum. This unique partnership will process of due diligence, the ASCC funds research research biology and clinical community with secure Communications & Awareness Subcommittee. nPod deliver the means to deal with existing high-profi le which falls within its core expertise platform areas ACRF DYNAMIC IMAGING FACILITY access to data and the tools to effi ciently deliver aims to improve the procurement of pancreatic tissue invasive animal pests as well as those that have the or its therapeutic focus areas. The IMB has very close FOR CANCER BIOLOGY relevant solutions. Its projects cover: programmatic specifi cally from patients and donors at high risk of links with the ASCC. Professor Melissa Little was access to large data sets and tools, data integration developing type 1 diabetes. It is the fi rst trial of its potential to cause catastrophic impacts in the future. This facility was launched in August 2005 with the seconded to the Centre in 2007 as its Chief Scientifi c and workfl ow technology for biological and health kind anywhere in the world and it is hoped that it will Professor Peter Koopman from the IMB currently aid of a grant from the Australian Cancer Research Offi cer, where she will be responsible for developing data, mirror site for genome browsers, annotation improve our understanding of the onset and progress serves on the advisory board for the Daughterless Foundation (ACRF). It is the only one of its kind strategy, scientifi c review and management. She will pipelines and workfl ows for biological and health of type 1 diabetes. Carp Program of the AIACRC. This program, based in Australia and the laboratory at the IMB houses also develop a Queensland division of the ASCC data, genotype/phenotype linkages, analysis and at CSIRO fi sheries in Hobart, uses innovative two technologically advanced microscope systems based at UQ. Associate Professor Andrew Perkins, visualisation of biological data and building and technologies with a view to skewing the sex ratios of that will enable cutting-edge research into cancer Dr Sean Grimmond and Dr Rohan Teasdale hold a joint using web-based tools. wild populations of the common carp, one of the most biology. IMB researchers are now able to make live grant in the therapeutic platform of “haematological widespread threats to indigenous fi sh species in our movies and track the movements and behaviour of disorders”. The aim of this project is to harvest the larger waterways. Professor Koopman’s laboratory is breast cancer cells with a higher resolution, greater immense potential of embryonic stem cells to provide also expanding this program, under the auspices of capability and more quickly than ever before. The new a novel supply of haematopoietic stem cells (HSCs) the CRC, to develop a similar management strategy facility also allows researchers to optically dissect for bone marrow transplantation, as well as other for the cane toad, currently ecological public enemy cancerous and non-cancerous cells and reconstruct blood products. Dr Sean Grimmond also holds a number one in Queensland. them in 3D, revealing much greater detail about their joint project grant with Professor Martin Pera of the inner workings. Researchers can also now examine a ASCC in the core platform technology of “embryonic vast range of proteins at the same time and examine AUSTRALIAN MICROSCOPY stem cell technology”. Dr Grimmond’s international their dynamics in live cells over time. & MICROANALYSIS RESEARCH FACILITY expertise in expression profi ling is employed to try to The Advanced Cryo-Electron Microscopy Laboratory dissect the genetic hierarchies involved in human ES – the Queensland node of the Australian Microscopy cell differentiation. In addition, the Renal Regeneration RIKEN Consortium and Nephrogenix, which are both based & Microanalysis Research Facility – is housed in RIKEN is the Institute for Physical and Chemical at two hubs – the IMB and Monash University – have a purpose-built facility at IMB. This MNRF was Sciences of the Japanese Science and Technology very close links with the ASCC through a research formed as a collaboration between the Universities Agency, and a major site of genomics research in memorandum of understanding. An eventual core aim of Queensland, Western Australia, Melbourne, New Japan. Professor John Mattick has a visiting scientist of the RRC is to employ embryonic and adult stem cell South Wales and Sydney. The facility, which includes appointment at RIKEN. The RIKEN Genome Sciences technologies to deliver cells with therapeutic potential a 300kV Technai microscope, is currently the only Centre is based at Yokohama and Wako, in the Tokyo to patients with end-stage renal failure. one in Australia or New Zealand capable of collecting area. In the late 1990s, RIKEN established a program and processing atomic resolution images at low aimed at elucidating the complete transcriptional temperature, as well as undertaking a 3D electron AUSTRALIAN GENOME RESEARCH FACILITY output of the mouse. More recently, the program has microscope (EM) tomography of organelles, cells and shifted focus towards the elucidation of transcriptional The Australian Genome Research Facility (AGRF) is tissues at both ambient and low temperature. Only control networks. Both activities have involved the an MNRF of the Commonwealth Government and was a handful of international (and no other Australian) establishment of large international consortia, fi rstly established in 1996 through an MNRF application laboratories can offer researchers equivalent state- the FANTOM consortium (Functional Annotation of led by Professor John Mattick, who served as the of-the-art research tools for high-resolution 3D Mouse), and more recently the Genome Network inaugural director until 2002, and Board Member structure studies of cells and molecules. The AMMRF consortium. The consortium has previously published until 2004. Professor Brandon Wainwright currently is a successor to the Nanostructural Analysis Network a comprehensive analysis of the human and mouse serves on the AGRF Board. The AGRF is a state-of- Organisation (NANO). transcriptomes, resulting in a series of papers in the-art facility for the collection of molecular genetic Nature Genetics, PLoS Genetics, PLoS Computational information covering large-scale DNA sequencing, Biology, Genome Biology and Genomics.

62 COLLABORATIVE RESEARCH PARTNERSHIPS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 COLLABORATIVE RESEARCH PARTNERSHIPS 63 COMMUNITY ENGAGEMENT IMB STAFF & STUDENTS

The IMB has a mission not just to perform excellent IMB TOURS the IMB stall offered information about the Institute as well as an activity in the form of extracting DNA research, but also to engage with the community The Institute welcomes enquiries from interested from strawberries. Over 100 people participated in and make them aware of us and what we do. parties who would like to tour the facility. A tour the extraction. We achieve this through a number of avenues. allows people to view some of our world-leading equipment and laboratories, and hear about our The DNA extraction also took a starring role at a research, postgraduate and commercialisation IMB WEBSITE www.imb.uq.edu.au much larger public event: the Royal Brisbane Show, Daniel Abankwa John Abbenante Kalyani Abondi Shaffi naz Abdrahman John Abramyan Zoe Ackerman Bronwyn Adams Azita Ahadizadeh Erin Ahern activities. In 2007, the IMB played host to groups of or the ‘Ekka’, as it is colloquially known. The IMB was Research Offi cer Senior Research PhD Student Honours Student PhD Student Mail Clerk Marketing and PhD Student PhD Student The IMB website is the main source of detailed Offi cer Communications school students, international university students and part of a larger UQ display, and again, the strawberry Offi cer information for community members interested in staff, politicians, dignitaries and researchers. DNA extraction was well received with around 2000 the IMB. It describes the research of each group, people taking part over three days. This was also employment and postgraduate opportunities, an opportunity to disseminate information about the commercialisation, news, conferences and more. SCIENTISTS IN SCHOOLS Institute to those who were interested. It also houses all of the publications of the IMB in Just as school groups visit the IMB, so too do electronic form, so these can be accessed from IMB researchers visit schools, in the form of the UQ held its Open Day in August, with nearly 15 000 anywhere in the world. It is the top site for people Scientists in Schools program. This allows individual people attending. The day was not just for prospective Scott Aldridge Dianne Alewood Paul Alewood Kylie Alexander Charlotta Alvarmo Paulo Amaral Asa Anderson Daphne Anderson Melanie Andrews Finance Offi cer Research Manager Group Leader PhD Student Masters Student PhD Student Research Assistant Receptionist PhD Student searching the term ‘molecular bioscience’ in Google, researchers with a passion for communication and students, but also for any community member who indicating that it is a valuable resource for those education to be paired with a school teacher. The wanted to take a closer look at the university. Within interested in this area of research. program is fl exible, allowing the scientist and teacher the IMB, PhD students hosted tours of the Institute to decide on the interaction that best suits both their and there were displays from individual research needs. Three IMB scientists – Dr Brad Marsh, Karin groups. Kassahn and Adi Idris – participated in the program in 2007, lending their expertise to four schools. IMB OUTPUT

Isye Arieshanti Nicholas Ariotti Marjan Askarian-Amiri Anzari Atic Rajith Aturaliya Tim Bailey Amanda Bain Peter Bain Walter Balansa The IMB’s quarterly newsletter allows community MPhil Student Research Assistant Research Offi cer Undergraduate Student PhD Student Group Leader Honours Student Research Offi cer PhD Student PUBLIC EVENTS members to receive regular updates on the research The IMB played a role in several public events in of the IMB. It is written so non-scientists can Brisbane during 2007. The Bridge Fun Day, held understand it, and is available on the IMB website in February, celebrated the opening of the Eleanor under “About the IMB”. To subscribe to IMB output Schonell Bridge linking the University’s St Lucia and receive either a hard or an electronic copy every campus with the southern side of the Brisbane River. three months, please visit the IMB website and follow The Fun Day was held on the banks of the river, and the “Subscribe to IMB News” link on the front page. Johanna Barclay Jeremy Barker Chris Barnett Alexis Barrett Grant Barry Elizabeth Bast Michele Bastiani Denis Bauer Kimberley Beaumont Research Offi cer CEO of QFAB Infrastructure Manager Research Assistant PhD Student Undergraduate Student PhD Student PhD Student PhD Student

Derek Benson Christie Bentley Graeme Bethel Annemiek Beverdam Renee Beyer Emmanuelle Billon Rachael Birks Jade Blakeney Mikael Bodén Computer Systems Research Assistant Senior Research Research Offi cer PhD Student MSc Student Desktop Support Team PhD Student Senior Research Fellow Offi cer Assistant Leader

Melissa Bourboulas Greg Bourne Josephine Bowles Stephen Bradford Jill Bradley Andrew Brooks Darren Brown Melissa Brown Catherine Browne Research Assistant Senior Research Senior Research PhD Student Floor Manager Research Offi cer Research Assistant PhD Student Senior Research Offi cer Offi cer Offi cer

64 COMMUNITY ENGAGEMENT Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB STAFF & STUDENTS 65 IMB STAFF & STUDENTS

Stephen Bruce Matthew Bryant Carol Burnton Rachel Burow Kevin Burrage Pamela Burrage Allan Burrows Natalie Butterfi eld Carmen Buttery Kristian Dalle Matt Daley Norelle Daly Aline Dantas Aaron Darling Kim Dastlik Richa Dave Tara Davidson Jasmine Davis Research Offi cer Floor Manager Honours Student Research Assistant Group Leader (Joint Senior Research Research Assistant PhD Student Research Assistant Undergraduate Student PhD Student Research Offi cer Research Offi cer Research Offi cer Research Offi cer Research Offi cer Research Assistant Research Assistant Appointment) Offi cer

Karl Byriel Oliver Cairncross Marie Campbell Rob Capon Amanda Carozzi Brendan Carter Laura Cascales Ian Cassady Masa Cemazar Melissa Davis Claire Debats Zoltan Dekan Christian de Marco Nicole den Elzen Marion Desclozeaux Marcel Dinger Ross Dixon Cedric Dooms Professional Offi cer Computer Systems Glassware Attendant Group Leader Postgraduate Computer Systems PhD Student Senior Research Research Offi cer Research Offi cer Research Assistant Research Assistant Computer Systems Research Offi cer Research Offi cer Research Offi cer Floor Manager Research Offi cer Offi cer Administrative Offi cer Offi cer Offi cer Offi cer

Natasha Chaduhary Angeline Chan Cheong Xin Chan Ming Chang Bruce Chau Kallayanee Kevin Chen Simon Chen Han Chiu Nyssa Drinkwater Russell Driver Mileta Duggleby Jaimee Duncan Jasmyn Dunn Tom Durek Rachel Effeney Alysha Elliot Tammy Ellis MPhil Student Honours Student Research Offi cer PhD Student Undergraduate Student Chawengsaksophak Research Assistant Undergraduate Student Research Assistant PhD Student PhD Student Purchasing Offi cer Research Assistant Research Assistant Research Offi cer Undergraduate Student Honours Student Senior Research Research Offi cer Offi cer

Kwang-Jin Cho JooYoung Choi Angelika Christ Michelle Christie Ya-Mi Chuang Michael Clark Richard Clark Nicole Cloonan Barb Clyde Mohammed El-Nagger Natalie Eriksson Andres Estéban- Calvin Evans Katherine Ewen Henk Faber David Fairlie Diana Farkas Geoff Faulkner PhD Student Masters Student Research Assistant PhD Student Undergraduate Student PhD Student Research Offi cer Research Offi cer Human Resource PhD Student Research Assistant Marcos Computer Systems PhD Student Technical Offi cer Group Leader PhD Student PhD Student Consultant Honours Student Offi cer

Nadine Coleman Brett Collins Alexander Combes Lena Constantin Anthony Cook Elaine Costelloe Adam Costin Adam Cotterell Nathan Cowieson Barbara Feenstra Allen Feng Manuel Fernandez J. Lynn Fink Rebecca Fitzsimmons Jack Flanagan David Floyd Michelle Foley Frank Fontaine Administrative Assistant Senior Research Fellow PhD Student PhD Student Research Offi cer Research Offi cer PhD Student Research Assistant Research Offi cer Offi ce Manager Research Assistant Research Offi cer Research Offi cer Research Assistant Research Offi cer Honours Student Grants Offi cer Research Offi cer

David Craik Robyn Craik Matthew Crampton Simon Cridland Larry Croft Adam Crompton Stephen Cronau Lisa Crowther Glyn Cumner Alex Foo Alistair Forrest Elizabeth Fowler Mathias Francois Leith Fremlin Martin Frith Janette Galea Nira Gamage Valerie Garceau Group Leader Purchasing Offi cer Research Offi cer PhD Student Research Offi cer Honours Student Research Assistant PhD Student Purchasing Offi cer PhD Student Research Offi cer Senior Research Research Offi cer PhD Student Research Offi cer Research Assistant Research Offi cer Research Assistant Offi cer

66 IMB STAFF & STUDENTS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB STAFF & STUDENTS 67 IMB STAFF & STUDENTS

Alex Garcia Patricia Garcia Brooke Gardiner Melissa Gardiner Angela Gardner Katrina Garner-Moore Margaret Gentz Kylie Georgas Thierry Gilbert Brett Hosking Gail Howard Mark Howes Shu-Hong Hu Crystal Yen-Hua Huang Tania Hudspith Kerry Inder Jess Ineson Marco Inserra PhD Student Undergraduate Student Research Offi cer PhD Student Finance Manager Purchasing Offi cer PhD Student Research Assistant Research Offi cer Research Offi cer Receptionist PhD Student Senior Research PhD Student Event Coordinator Research Offi cer Research Assistant PhD Student Offi cer

Felicia Goh Jaclyn Goh Caraine Gomez Milena Gongora Andrew Goodall Geoff Goodhill Dominique Gorse Jennifer Greder Kathryn Greenwood David Ireland Kate Irvine Ingrid Jakobsen Russell Jarrott Angela Jeanes Jonas Jensen Jean Jin Helene Johanson Karen Jones PhD Student Research Assistant Human Resource Research Assistant PhD Student Group Leader (Joint Technical Manager, Principal Administration PhD Student PhD Student Research Offi cer Research Offi cer Research Assistant PhD Student Research Assistant Research Offi cer PhD Student Glassware Attendant Offi cer Appointment) QFAB Offi cer

Aliesha Griffi n Sean Grimmond Rowan Gronlund Christian Gruber Sunithi Gunasekara Praveer Gupta Raj Gupta Adi Haji Idris Elaine Haase Chol Hee Jung Quentin Kaas Seetha Karunaratne Karin Kassahn Jason Kay Greg Kelly Linda Kerr Markus Kerr Janelle Keys Research Assistant Group Leader IT Support Manager PhD Student PhD Student MPhil Student Research Offi cer PhD Student PhD Student PhD Student Research Offi cer Senior Research Research Offi cer PhD Student Research Assistant Research Assistant Research Offi cer Senior Research Assistant Offi cer

Reena Halai Maria Halili Rhonda Hall Nick Hamilton Luke Hammond Kim Hanchard John Hancock Rachel Hancock Ben Hankamer Tatiana Khromykh Glenn King Gordon King Andrew Kinghorn Genevieve Kinna Wayne Kirby Luke Kirkwood Emily Knauth Deon Knight PhD Student PhD Student Research Assistant Senior Research PhD Student Research Assistant Deputy Director Research Assistant Group Leader Research Assistant Group Leader Research Offi cer Undergraduate Student PhD Student Technical Offi cer PhD Student Honours Student Research Assistant Offi cer (Research) & Group Leader

Dhiraj Hans David Hansen Martin Hansen Michael Hanzal-Bayer Lani Hardy Gerald Hartig John Hawkins Andrew Hayes Begoña Heras Gabriel Kolle Peter Koopman Darren Korbie Jeremy Kroes Lars Kuerschner Christina Kulis Jakov Kulis Krzystof Kurowski Mareike Kurz PhD Student Technical Manager, Research Offi cer Research Offi cer Research Assistant Research Offi cer Research Offi cer Research Offi cer Research Offi cer Research Offi cer Group Leader PhD Student Workshop Assistant Research Offi cer PhD Student Research Assistant Research Offi cer PhD Student QFAB Manager

Michelle Hill Rena Hirani Ondrej Hlinka Uda Ho Huy Hoang Samantha Hodgson John Holland Caroline Hopkins Gene Hopping Larisa Labzin Michael Landsberg Annette Lane Ian Lane Jane Lattin Patrick Lau Angela Lawton Giang Le Huong Le Research Offi cer Research Offi cer Computer Systems PhD Student Research Offi cer Research Assistant Senior Research PhD Student Research Offi cer Honours Student Research Offi cer Research Assistant Floor Manager PhD Student Research Offi cer Senior Research Research Offi cer Honours Student Offi cer Offi cer Assistant

68 IMB STAFF & STUDENTS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB STAFF & STUDENTS 69 IMB STAFF & STUDENTS

Emmanuelle Leiseur Richard Lewis Paul Leo Gary Leong Joan Li Lysha Lim Wen Lim Melissa Little Xin Liu Vicki Metzis Ann-Marie Michalski Tomas Miljenovic Medhi Mobli Linda Molloy Thea Monks Rod Morales Garry Morgan Isabel Morrow Research Assistant Group Leader Senior Research Senior Research Research Offi cer Honours Student Honours Student Group Leader Research Offi cer Research Assistant Masters Student Research Assistant Senior Research Glassware Attendant Research Assistant PhD Student Research Assistant Research Offi cer Offi cer Offi cer Offi cer

Harriet Lo James Lo Lindsey Long Dorothy Loos Reik Löser Marion Loughnan Erica Lovelace Paul Lovelock Regine Pei Low Cody Mudgway Arief Mulyadi Teresa Munchow Alan Munn Craig Murphy Samantha Murphy George Muscat Markus Muttenthaler Stephen Myers Research Offi cer Honours Student Research Assistant Research Assistant Research Offi cer Research Offi cer Research Offi cer Floor Manager Honours Student Executive Secretary Research Assistant Research Assistant Group Leader Senior Research PhD Student Group Leader PhD Student Research Offi cer Offi cer

Andrew Lucke Robert Luetterforst Natalie Lumsden Tricia Lusby Michael Lusis Praveen Madala Madhavi Maddugoda Stefan Maetschke Jodie Major Josh Mylne Satu Nakhuri Charles Nelson Michelle Newman Christine Neyt Philip Nguyencong Dan Nicolau Jr. Susan Nixon Suzanne Norwood Research Assistant Research Assistant Research Offi cer Research Assistant PhD Student PhD Student Research Offi cer Research Offi cer Research Assistant Research Offi cer PhD Student Safety Offi cer Floor Manager Research Offi cer PhD Student Masters Student Research Offi cer Research Offi cer

Igor Makunin Jessica Malcolm Alizeé Malnoë Tony Manderson Sabine Mangold Efstratios Manolis Kerry Manton Nelson Marques Brad Marsh Andrew Noske Ehsan Nourbakhsh Harald Oey Carolin Offenhauser Robert Oldham Julie Osborne Dmitry Ovchinnikov Fil Paczkowski James Palmer Research Offi cer Honours Student MSc Student Research Offi cer PhD Student Store Manager Research Offi cer Computer Systems Group Leader PhD Student Research Offi cer Research Offi cer PhD Student Finance Offi cer Administrative Assistant Research Offi cer Research Offi cer Research Offi cer Offi cer

Mhairi Marshall Nick Martel Jenny Martin Sally Martin Ute Marx John Mattick Erin Maylin Emily McCallum Timothy McComb Timothy Pan Radosav Pantelic Ajay Panwar Rob Parton Darren Paul Michael Pearen Hanneke Peeters John Pell David Pennisi Research Assistant Research Assistant Group Leader Senior Research Research Offi cer Group Leader Research Assistant Research Assistant Research Offi cer Research Assistant PhD Student Masters Student Group Leader Microscopy and Laser PhD Student Undergraduate Student Technical Offi cer Research Offi cer Offi cer Safety Offi cer

Ailsa McCormack Karen McCue Crystal McGirr Greg McHugh Robert McLachlan Tim McPhee Jeremy Mead Nicholas Meadows Tim Mercer Andrew Perkins Allison Pettit Chau Phan Michael Pheasant Andrew Piggott Barry Pitt Sarah Plowman Juan Carlos Polanco Aaron Poth Research Assistant PhD Student Research Assistant Workshop Manager PhD Student Research Offi cer Store Assistant Research Offi cer PhD Student Group Leader Research Offi cer Honours Student Research Offi cer Research Offi cer Store Manager Research Offi cer PhD Student Research Assistant

70 IMB STAFF & STUDENTS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB STAFF & STUDENTS 71 IMB STAFF & STUDENTS

Neelima Pottekkat Imre Radacs Fiona Rae Chikako Ragan Mark Ragan Liza-Jane Raggatt Lotten Ragnarrson- Suryaprakash Raichur Sathiya Ramakrishnan Yogendra Singh Rachel Slade Darren Smit Aaron Smith Erin Smith Jen Smith Mark Smith Michael Smutny Mark Smythe Sidharthan Infrastructure Support Research Offi cer Research Assistant Group Leader Research Offi cer McGrath PhD Student PhD Student Senior Research Undergraduate Student Research Assistant Research Offi cer Human Resource PhD Student Finance Offi cer Research Offi cer Group Leader Research Offi cer Offi cer Research Offi cer Offi cer Offi cer

Darshani Rapasinghe Lachlan Rash Lance Rathbone Ranjala Ratnayake Emma Redhead Esther Reefman Robert Reid Gang Ren Stewart Rice Giulia Solda Cassy Spiller Josefi ne Sprenger James Springfi eld Kate Stacey Stefan Stanley Samantha Stehbens Stuart Stephen Amber Stephens Undergraduate Student Research Offi cer Database Manager Research Offi cer Research Assistant Research Offi cer Senior Research PhD Student Technical Offi cer Research Offi cer PhD Student PhD Student Microscopy/Digital Senior Research PhD Student PhD Student PhD Student PhD Student Offi cer Imaging Offi cer Offi cer

Tobias Richter Andrew Ringsmuth Vera Ripoll Raju Ritesh Don Roberts Tara Roberts Alan Robertson Gautier Robin Jodie Robinson Evan Stephens Anita Steptoe Martin Stoermer Jennifer Stow Caroline Sturm Rick Sturm Jacky Suen Tim Sullivan Terje Svingen Research Offi cer PhD Student Research Offi cer PhD Student PhD Student Research Offi cer Honours Student Research Offi cer Research Offi cer PhD Student Senior Research Research Offi cer Group Leader Research Assistant Group Leader PhD Student Research Assistant Research Offi cer Assistant

Jonathon Robson Rosalba Rothnagel Susan Rowland Ian Ross Sandrine Roy Ke-lin Ru Caitlin Rudorfer Gloria Ruiz Gómez Bree Rumballe Matt Sweet Jan Szubert Ryan Taft Prascilla Tagore Michael Tallack Chia-Chia Tan Ian Taylor Rohan Teasdale Rathi Thiagarjan PhD Student Research Assistant Senior Research Senior Research Research Offi cer Senior Research Undergraduate Student Research Offi cer Research Assistant Group Leader MSc Student PhD Student Research Assistant PhD Student Research Assistant Deputy Director (Sys- Group Leader Masters Student Offi cer Offi cer Assistant tems & Administration)

Natalie Saez Daniele Sangermani Ivana Saska Nicole Schieber Horst Schirra Kate Schroder Conor Scully Nausad Shaikh Muhammad Shoaib Rachel Thijssen Amy Thurber Matthew Timmins Anne Tobin Liam Town Angela Trieu Vy Truong Kathryn Tunny Ronda Turk Research Assistant PhD Student PhD Student Research Assistant Research Offi cer Research Offi cer Research Offi cer Masters Student Seghal Undergraduate Student Research Assistant PhD Student Floor Manager PhD Student PhD Student Research Assistant Research Assistant Receptionist Research Offi cer

Desla Shand Daniel Shaw Nick Shepherd Chang Jin Shin Stephen Shouldice Cas Simons Shane Simonsen Fiona Simpson Ranee Singh Jill Turner Desmond Tutt Larissa Upward Parimala Vajjhala Lang Valentine Peter van der Heide Rebekka van Kampen Wendy van Zuylen Juliana Venturato Administrative Assistant PhD Student Research Offi cer PhD Student Research Offi cer PhD Student Research Assistant Senior Research PhD Student Research Assistant Research Assistant Honours Student Research Offi cer Computer Systems PhD Student Administrative Assistant PhD Student Research Assistant Offi cer Offi cer

72 IMB STAFF & STUDENTS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMB STAFF & STUDENTS 73 IMB STAFF & STUDENTS IMBcom STAFF

Suzie Verma Andrea Vernal Rehan Villani Nicola Waddell Kimberly Wadsworth Brandon Wainwright Patricia Walden Logan Walker Piers Walser Catherine Benham Lisa Black Kellie Broderick Leah Creed Noi Inthasan Peter Isdale Zachary King Christine Lane Andrew Leech Senior Research Research Offi cer PhD Student Research Offi cer PhD Student Director & Group Research Assistant Research Offi cer Research Offi cer Administrative Assistant Team Assistant Manager, Infrastructure Legal Counsel & IP & Operations Chief Executive Offi cer Commercialisation Grants Consultant IP Associate Assistant Leader & Education Company Secretary Support Assessment Offi cer

Dawn Walsh Bo Wang Conan Wang Jack Wang Mary Wang Shivangi Wani Mike Waters Winnie Waudo Jane Weber Bridget Maher Emma McComb Jodie McNab Chris Price Lyn Rosen Amanda Smith Karen Soxsmith Olivia Teed Erin Wansbrough Central Sterilising PhD Student PhD Student PhD Student Research Offi cer Research Assistant Group Leader PhD Student Research Assistant Commercialisation IP Associate Company Accountant VP of Commercial Executive Assistant Manager, Intellectual Systems Support IP Support and Business Development Facility Manager Assessment Offi cer Development Property Marketing Manager

Jan Westerman Nicole Wheatley Tom Whitington Carol Wicking Dagmar Wilhelm Lorine Wilkinson Ben Wilson Danielle Wilson David Wilson Simon Wilkins Research Offi cer Masters Student PhD Student Group Leader Research Offi cer Research Offi cer Research Offi cer PhD Student Research Offi cer Commercial Intelligence Analyst

Lanna Wong Simon Wong David Wood Andy Wu Fiona Wylie Christine Yan Aijun Yang Alpha Yap Greg Young Manager, ARC Centre Research Offi cer Computer Systems PhD Student Research Offi cer PhD Student Research Offi cer Group Leader Lab Manager of Excellence in Bioin- Offi cer formatics

Tiffany Young Zheng Yuan Poh Yuen Chin Ernie Yulyaningsih Claudia Zampata Boris Zhang Hua Zhang Shane Zhang Research Assistant Senior Research Undergraduate Student Research Assistant PhD Student Research Offi cer Research Offi cer Research Assistant Offi cer

74 IMB STAFF & STUDENTS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 IMBcom STAFF 75 FINANCIAL STATEMENTS STATEMENT OF OPERATING INCOME & EXPENDITURE Year Ended 31 December 2007

INCOME: NOTE 2003 2004 2005 2006 2007 University of Queensland (Operating Grant) 1 8,122,858 6,877,099 7,225,765 10,767,311 11,087,942 University of Queensland Research Grants 277,337 228,999 334,500 252,252 300,436 State Government 8,500,000 10,000,000 10,425,000 10,175,000 11,127,168 SRC Grant (Australian Research Council) 1,005,151 1,117,038 1,137,436 1,159,047 1,182,516 Australian Research Council 2 3,218,103 4,261,849 4,744,519 5,218,279 6,010,239 Arthritis Foundation of Australia 0 0 14,950 0 0 Australian Cancer Research Foundation 0 600,000 600,000 0 0 Australian Nuclear Science & Technology Organisation 0 0 85,355 78,757 230,492 Australian Stem Cell Centre 0 306,219 161,691 159,780 467,335 Cancer Council South Australia 30,500 30,500 0 0 0 Clive and Vera Ramaciotti Foundation 0 0 0 0 60,000 Community Health + Tuberculosis Australia 0 0 0 49,000 0 CRC for Discovery of Genes for Common Human Diseases 48,946 0 0 0 0 CRC for Chronic Infl ammatory Diseases 968,800 1,261,017 1,367,457 1,326,058 1,462,776 CRC for Pest Animal Control 0 0 0 122,210 0 Dairy Australia 0 338,779 203,765 167,644 700,321 Department Industry Science & Resources 0 0 0 0 200,000 Department of Primary Industries 0 0 0 0 50,000 Diabetes Australia Research Trust 0 0 0 45,000 0 Human Frontiers Science Program 146,291 138,057 0 0 81,783 The John Trivett Foundation 0 0 0 0 267,817 Juvenile Diabetes Foundation International 0 151,732 177,814 178,634 147,708 The Murdoch Institute 0 0 0 0 347,527 National Institute of Health (US) 1,049,548 1,475,684 1,132,358 1,176,642 969,415 National Health and Medical Research Council 2 6,761,404 6,438,350 9,819,880 7,888,967 11,054,142 National Heart Foundation 42,735 50,000 50,000 0 0 New Zealand Dept Science & Technology 0 0 0 0 81,392 Novartis 641,790 0 0 0 0 Post Graduate Scholarships 73,467 91,968 140,237 261,263 305,255 QIMR 60,575 0 0 0 0 Queensland Cancer Fund 72,590 140,000 215,100 148,700 312,000 Wellcome Trust 204,763 180,706 150,311 0 0 Commercial Income 1,517,449 1,473,905 1,856,012 2,018,054 4,880,234 Cross-Institutional contributions to LIEF or Facilities 122,500 192,800 60,000 509,472 188,000 University of Newcastle (re ARC Centre) 127,727 127,893 47,727 252,562 128,218 QBP recoveries 331,594 312,979 316,211 386,092 371,257 Shared Grants 105,845 128,764 262,062 234,685 4,000 Conference Income 55,275 25,501 73,032 66,615 184,340 QBPStore 0 44,021 247,890 276,819 314,057 Wesley Research Institute 0 0 0 20,000 93,645 Miscellaneous Income 392,822 355,652 416,707 399,887 357,293 TOTAL INCOME: 33,878,069 36,349,512 41,265,778 43,338,729 52,967,307 Funds brought forward from previous year 3 7,545,101 6,746,999 6,557,150 9,050,612 11,441,270 TOTAL FUNDS AVAILABLE 41,423,170 43,096,511 47,822,929 52,389,341 64,408,577 EXPENDITURE: Salaries – Research 12,238,779 16,195,354 18,430,158 20,110,376 22,878,237 – Administration 1,365,120 1,243,375 1,343,782 1,205,466 1,349,056 – Infrastructure 1,735,158 2,131,608 2,383,622 2,673,620 2,368,795 Research Services 6,938,972 7,667,863 9,976,365 10,995,871 13,099,865 Education Programs 4 484,360 418,784 375,177 358,445 332,919 Administration 5 519,046 383,224 379,317 529,612 521,743 Infrastructure 6 1,568,251 1,772,942 1,287,442 1,295,139 1,862,212 Capital Equipment 7 8,649,700 5,521,066 3,389,715 2,569,801 5,156,825 IMBcom 1,176,785 1,205,144 1,206,738 1,209,741 1,197,920 TOTAL EXPENDITURE: 34,676,171 36,539,360 38,772,316 40,948,071 48,767,573 Funds carried forward: 8 6,746,999 6,557,150 9,050,612 11,441,270 15,641,004

76 FINANCIAL STATEMENTS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 FINANCIAL STATEMENTS 77 EXPLANATORY NOTES TO STATEMENT OF INCOME GLOSSARY OF TERMS & EXPENDITURE

1/ A) IN-KIND CONTRIBUTIONS 5/ ADMINISTRATION Actin A protein, along with myosin, responsible for BRET Bioluminescence Resonance Energy Transfer. A Cytokines Small proteins released by cells that affect muscle contraction. cell-based assay allowing the direct study of complex the behaviour of other cells. Figure does not include the following salaries for joint appointments paid by other Annual Report 23,138 protein-protein interactions in living cells. departments: Marketing 48,438 Adipose Fat or fatty tissue. Cytokinesis The point in somatic cell division where Department Percentage Personnel Recruitment and Training 61,671 BSE Bovine spongiform encephalopathy. Commonly the cytoplasm splits, as opposed to the splitting of the Agonist A molecule that interacts with a receptor, known as mad cow disease. nucleus, which occurs fi rst. K. Burrage Mathematics 80 Visiting Scientists/Seminars 22,963 triggering a cellular response. G. McLachlan Mathematics 80 Fees 58,262 Cadherin A class of transmembrane protein, which Cytoplasm All of the contents of a cell, excepting the Allele One of a number of possible versions of a gene. ensures cells adhere to one another within a tissue. nucleus. G. Goodhill QBI/Maths 80 Quinquennial Review 0 Each person inherits two alleles per gene, one from A. Mark SMMS 80 Entertaining 41,006 each parent. Carbohydrate An organic molecule of carbon, Cytoskeleton The protein framework of a cell. Photocopying 121,274 hydrogen and oxygen. They are a major source of A toxin harmful to cells. Amyloid An abnormal protein deposit associated with energy for the body. Cytotoxin B) GROSS INCOME & CORPORATE SERVICES CHARGE Postage and Freight 627 tissue degeneration, such as Alzheimer’s. De novo Not previously present. The 2006 Annual Report, for the fi rst time, showed University of Queensland Printing & stationery 44,804 Caveolae A small pocket extending from the outside Analogue A characteristic or structure that evolved Operating Grant Income as a gross amount and Corporate Services charge shown Telephone 63,388 to the inside of a cell. Sites of uptake and expulsion of The process whereby specialised separately in different organisms but shares a similar Dedifferentiation separately under expenditure. For 2007 we have reverted back to the previous materials into and out of the cell. cells revert back to being multipotent, where they can Travel Expenses 19,265 form or function. method for better direct comparison. 2006 fi gures have been adjusted accordingly produce cells of any type. Board Fees 16,907 Chelate An organic molecule that has bonded to a and now show the nett. Angiogenesis Formation of new blood vessels. Total Administration 521,743 metal to form a ring-shaped structure. Deterministic Something that is predictable, not A molecule that blocks a chemical from random, given known initial conditions. The opposite of Antagonist Chemotaxis Movement of a cell or organism 2/ FELLOWSHIP/PROJECTS FROM GOVERNMENT AGENCIES binding to its receptor. stochastic. 6/ INFRASTRUCTURE stimulated by a chemical. Australian Research Council Building Maintenance 120,116 Antibody A protein produced in response to an antigen Diabetes A disease that occurs when the body cannot Projects 3,240,483 Chromatin The complex of DNA and proteins that form produce or cannot use insulin, which regulates blood Rental -Storage 11,400 to fi ght foreign substances. a chromosome. Fellowships 1,254,964 sugar levels. Safety Equipment 42,932 Antigen A molecule that triggers an immune response 4,495,447 Chromatography A method of separating chemical An organic molecule formed by combining two Laundry 5,584 in the body. compounds into their base constituents by transporting Dimer National Health and Medical Research Council smaller molecules. Minor Equipment & Furniture 19,164 Antinociceptive Counters the effect of anything the compound in liquid form through a porous Projects 8,496,269 Equipment Maintenance 234,652 caused by, or in response to, pain. substance. The different rates of absorbency of the DNA Deoxyribonucleic acid. The chemical chain that Fellowships 2,522,033 Animals 318,674 constituents mean that as they pass through the carries the genetic instructions for making a living 11,018,302 Assay Qualitative or quantitative analyses of a substance they will separate. organism. Computer Services 680,584 substance performed in order to determine its Glass washing and replacement 56,670 components. Chronic Obstructive Pulmonary Disease A Drosophila A genus of fl ies commonly known as fruit 3/ FUNDS CARRIED FORWARD TO 2007 Reticulated gases, RO water & dry ice 137,123 general term for degenerative lung diseases including fl ies. Drosophila melanogaster is often used in genetic Atherosclerosis The process whereby arteries harden emphysema and cystic fi brosis. University of Queensland Operating Grant 5,896,159 and developmental research as a model organism. Cost Recovery -9,326 and narrow over time. University of Queensland Research Grants 99,749 Stores 244,638 Clathrin The protein that largely forms the vesicle EGFR Epidermal growth factor receptor. Autoimmune Any condition where the immune system Post Graduate Scholarships 46,913 Total Infrastructure 1,862,212 responsible for transportation of proteins into and out does not distinguish between foreign substances and of the cell. Electrolyte The dissolved form of a mineral, capable State Government 3,060,830 the body’s own cells, causing it to attack normal tissue. of conducting an electrical current. Helps regulate the SRC Grant (44,721) 7/ CAPITAL EQUIPMENT Combinatorial Chemistry Methods used to proper balance of body fl uids. Axons The neurons that conduct electrical impulses in synthesise numerous, related chemical compounds. Scientifi c Equipment 4,786,617 Fellowships (as approved by funding bodies) 94,671 the nervous system. Endocrine Relating to hormones, and the glands that Overseas Grants funded mid year 25,962 Minor Equipment 370,209 Conotoxin A group of toxic peptides isolated from the produce them, that are secreted directly into the blood Total Capital Equipment 5,156,825 Bioinformatics The collection, organisation and venom of the marine cone snail. or lymph system. Contract Research 2,201,249 analysis of large amounts of biological data using Project Grants (as approved by funding bodies) 60,458 networks of computers and databases. CREB Factors that bind to specifi c DNA sequences and 8/ FUNDS CARRIED FORWARD TO 2008 alter the transcription of certain genes. 11,441,270 University of Queensland Operating Grant 7,468,461# Biopolymer Any polymer found in nature, eg. DNA, proteins. Cryo-electron microscope A microscope that uses University of Queensland Research Grants 53,647 4/ EDUCATION PROGRAMS frozen samples in order to decrease distortion and Post Graduate Scholarships 84,768 Bioscience Any of the branches of science dealing increase resolution. Postgraduate scholarships 279,180 with the structure and behaviour of living organisms. State Government 3,036,824# Postgraduate recruitment & training 53,739 Crystallography The use of X-rays to determine the SRC Grant (292,297) Biosynthesis The production of chemical compounds structure of crystallised molecules. Total Education Services 332,919 Fellowships (as approved by funding bodies) 541,148 in living organisms. Overseas Grants funded mid year 294,675 Biotechnology Any technology that uses biological Contract Research 2,639,402 systems or living organisms to make or modify products # Of this, $1.4m is the carry forward on IMB Group Leader core accounts, or processes. $1m relates to oustanding 2007 equipment commitments Project Grants (as approved by funding bodies) 1,814,376 15,641,004

78 FINANCIAL STATEMENTS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 GLOSSARY OF TERMS 79 GLOSSARY OF TERMS

Endocytosis Uptake of material into a cell. Haemoglobin A protein in red blood cells that carries Lentivirus A virus with a long period between infection Mutagenesis The process of intentionally creating Phosphatase An enzyme that removes a molecule Soleus A muscle in the back of the calf of the leg. oxygen around the body. and symptoms appearing. This period of latency mutations in an organism’s DNA. containing phosphorous acid from a nucleic acid or Endosome An organelle involved in protein traffi cking. enables the virus to be used for delivering genetic protein. Somatic Refers to any of the non-reproductive parts Haplotype A group of closely linked alleles that are Mutant A gene or an organism that has experienced a of the body, also used to mean a condition that is A protein produced by living organisms that information into a cell. Enzyme generally inherited as a unit. mutation (a change in its genetic sequence). Phosphoregulators All mouse protein kinase and non-inherited. catalyses chemical reactions of other substances Lipid Any of a group of heterogeneous fat or fat-like phosphatase genes. without being altered itself by the reactions. Helminths Parasitic worms that often carry disease. compounds that are insoluble in water. Myosin A protein, along with actin, responsible for Spectroscopy The study of the interaction between muscle contraction. Phosphorylation The process whereby a phosphate matter and radiation (eg. light). A type of microscopy using a very Pertaining to anything that affects or Epifl uorescence Hematopoietic Locus The location of a gene on a chromosome. group (phosphate and oxygen) is added to a chemical bright light source. This light is used to energise the triggers the formation of blood cells. Myostatin A growth factor that limits muscle tissue compound. Splicing The process where introns are removed from sample into re-emitting light (or “fl uorescing”) at various Lymphatic Pertaining to the circulatory network of growth. an RNA molecule. A type of amino acid, which binds to form wavelengths, which allows researchers to produce an Histidine vessels that produce and store the cells that fi ght PKA Protein Kinase A. image of the sample. proteins. Histidine is found in proteins involved in the infection. Nanovesicles Small, dense vesicles. Stochastic A process that is governed by random repair and growth of tissue. Polymorphism The existence of multiple forms of a chance. Colloquially known as roundworms. Epigenomic Pertaining to the biochemical reactions Lysosome An organelle capable of digesting Nematode gene or DNA sequence. Histology The study of the microscopic structure of Synthase A class of enzyme that triggers a synthesis that regulate gene expression. microorganisms and cellular debris. A nerve cell. tissues. Neuron Primordia The earliest stage of an organ’s process. Epithelium Membranous cellular tissue that covers the Macrophage A large cell that engulfs and absorbs Pain from nerves themselves, as opposed development. Homeodomain A protein motif in a homeobox (a Neuropathic Teleosts A class of bony vertebrate fi sh. internal and external surfaces of the body. waste material, harmful microbes or other foreign to injured or diseased body parts. highly-conserved DNA sequence) found in genes that Pronuclear injection The injection of DNA into the bodies in the bloodstream and tissues. A cell that has four sets of chromosomes, Epitope The site on the surface of a foreign substance regulate embryo development. nucleus of an unfertilised egg. Tetraploid NMR Nuclear Magnetic Resonance. A spectroscopic two from each parent. Usually, an organism only has that triggers the production of antibodies, and to which Macropinocytosis The formation of fl uid-fi lled technique that analyses the disruptions to a high these antibodies bind. Homeostasis A condition where the body uses macropinosomes – large heterogeneous, dynamic Prostaglandin Any of a group of compounds derived two sets of chromosomes, with one coming from each negative feedback processes to maintain its systems at magnetic fi eld to elucidate the chemical structure and from fatty acids with a variety of actions and effects parent. vesicles. molecular dynamics of a sample. ERK A messenger kinase belonging to the MAPK family. a constant equilibrium. on cells. Thalassaemia An inherited disease where adult red MAPK Mitogen-Activated Protein Kinase. A kinase that A molecule consisting of a chain of Erythropoiesis The development of mature red blood Homodimerize The joining of two identical subunits Nucleic Acid Protease Any enzyme that causes the interior peptide blood cells are not able to produce haemoglobin. responds to extracellular stimuli and regulates activities organic molecules that are sequenced with one another cells. to form a dimer, as opposed to heterodimerize, which such as mitosis and gene expression. bonds of a protein to split. would involve the joining of two non-identical subunits. to create genetic information. Tomography The process of creating a series of Etiology The cause, or the study of the cause, of Protein A large molecule composed of one or more detailed pictures of areas inside the body, created by a Meiosis The process by which cells divide to produce Nucleus A large, membrane-bound, usually spherical disease. Hormone A chemical secreted by one part of the body eggs and sperm. chains of amino acids in a specifi c order. Proteins are computer linked to an X-ray machine. that has a specifi c regulatory effect on other cells or structure within a living cell, containing the cell’s required for the structure, function and regulation of Fluorescent-Activated Cell Sorting. A method of hereditary meaterial and controlling its metabolism, The formation of RNA from a DNA FACS tissues. Melanin A pigment that gives the skin, eyes and hair the body’s cells, tissues and organs, and each protein Transcription sorting a heterogeneous group of cells using the light their colour and protects them from UV rays. growth and reproduction. has a unique function. Examples are hormones and template. scattering and fl uorescent characteristics of each cell. Immunoprecipitation The process whereby an A discrete subcellular structure with a antibodies. All of the messenger RNA transcribed antigen is formed in a solution using a specifi c antibody. Melanocytes Cells that produce melanin. Organelle Transcriptome A sequence of DNA involved in producing a specialised function. from genes within a given genome. Factor Proteome The complete set of proteins being polypeptide chain. In silico A process that has been simulated on a Mesenchyme Cells that have developed into expressed at any one time by a cell, tissue or organism. computer. connective tissue, blood vessels and lymphatic tissue. Orthologous Any gene found in more than one species Transgenic An organism that has a transferred gene Fluorescence Resonance Energy Transfer. A that can be traced back to the same common ancestor. (transgene) incorporated into the chromosome of all FRET Radioligand A radioactive substance injected into method of quantifying molecular dynamics such as In situ In its natural place. Mesoderm The middle layer of cells in the early tissue that binds to receptors and allows researchers to its cells. protein-protein interactions. embryo. Osteoclast A large, multinuclear cell involved with the In vitro A process occurring in an artifi cial environment absorption and removal of bone. study its behaviour. Transposon A DNA sequence capable of moving from Considered the basic unit of heredity, a gene is that would normally occur in an organism. A chemical involved in or produced during one location in the genome to another. Gene Metabolites Redox A reduction/oxidation reaction, where the a region of DNA that encodes all of the information to metabolism. Osteolytic Causing the breakdown of bone. In vivo A process occurring within an organism. oxidation number of an atom changes. Triglycerides A compound that is the major make a protein. Two genetic sequences that have the Metabolomic Relating to all of the metabolites in a Paralogous component in animal fats. A generalised response to foreign same evolutionary ancestor and arose through gene Retromer complex A protein complex that is involved Genome All DNA contained in an organism or cell. Innate immunity sample at any given time. substances with which one is born; it is not associated duplication. in the transport of proteins to the Golgi. Urogenital Pertaining to the reproductive and urinary The study of genes and their function. with a specifi c antigen. Migration of cancer cells from their original organs. Genomics Metastasis RNA A chemical similar to a single strand of DNA, site to other parts of the body. Pathogen A disease-causing organism. Globin The compound in red blood cells that binds to Insulin A hormone that regulates sugar concentration except that RNA contains ribose instead of deoxyribose Vascular Pertaining to anything related to or containing A change in function caused by a oxygen. in the blood. Microarray A technique for studying how large Pathophysiology and uracil instead of thymine. RNA delivers DNA’s conductive vessels, eg. blood vessels. numbers of genes interact and how a cell’s regulatory disease or condition. message to the site of protein synthesis. Glucose A six-carbon sugar that is a major energy Introns The non-coding regions of a gene. network controls vast amount of genes simultaneously. Vesicle A closed membrane shell. source for the body. Peptide A compound of two or more amino acids. RNAi RNA interference. Occurs when a double- Islet of Langerhans Clusters of cells in the pancreas stranded RNA molecule is introduced into a cell, Zinc fi nger A DNA-binding protein domain in which the MiRNA MicroRNAs, RNA molecules around 20 Phagocytosis The process by which cells engulf Gram-positive Bacteria that have a single cell wall; that secrete insulin. triggering the degradation of specifi c messenger RNA, zinc ion is crucial. nucleotides long that regulate gene expression. material in order to destroy or digest it. many species are pathogenic. and silencing the expression of target genes. Kinase An enzyme that catalyses the transfer of a Mitosis The process where a non-reproductive cell Pharming Farming genetically modifi ed animals and GTPase A large family of enzymes that can bind phosphate group from a donor to a target molecule. Rnomics The study of functional RNAs at the genomic divides to become two identical cells. plants to produce drugs. and break down GTP, a type of nucleotide. GTPase is level. A family of transcription factors involved in a number of processes, including translation, Kruppel-like factor Morphogenesis The process where cells differentiate homologous to the Drosophila Kruppel protein. Phenotype The characteristics of an organism transport, signal transduction and cell division. into different structures. resulting from the interaction between its genotype and its environment.

80 GLOSSARY OF TERMS Institute for Molecular Bioscience • Annual Report 2007 Institute for Molecular Bioscience • Annual Report 2007 GLOSSARY OF TERMS 81 2007 PUBLICATIONS

DIVISION OF GENOMICS 6 Carninci, P., Sandelin, A., Lenhard, B., Katayama, 11 Guipponi, M., Toh, M.Y., Tan, J., Park, D., Hanson, 19 Lieu, Z.Z., Derby, M.C., Teasdale, R.D., Hart, C., DIVISION OF MOLECULAR GENETICS AND 42 Kennedy, C.L., Koopman, P., Mishina, Y., and AND COMPUTATIONAL BIOLOGY S., Shimokawa, K., Ponjavic, J., Semple, C.A., K., Ballana, E., Kwong, D., Cannon, P.Z., Wu, Q., Gunn, P., and Gleeson, P.A. (2007). The Golgin, DEVELOPMENT O’Bryan, M.K. (2007). Sox8 and Sertoli Cell Taylor, M.S., Engstrom, G.P.G., Frith, M.C., Gout, A., Delorenzi, M., Speed, T.P., Smith, R.J., GCC88, Is Required for Effi cient Retrograde function. Annals of the New York Academy of 1 Andersson, J.O., Sjogren, A.M., Horner, D.S., Forrest, A.R., Alkema, W.B., Tan, S.L., Plessy, C., Dahl, H.H., Petersen, M., Teasdale, R.D., Estivill, X., Transport of Cargo from the Early Endosomes to the 32 Beaumont, K.A., Shekar, S.L., Newton, R.A., James, Sciences 1120: 104-113. Murphy, C.A., Dyal, P.L., Svard, S.G., Logsdon Jr., Kodzius, R., Ravasi, T., Kasukawa, T., Fukuda, S., Park, W.J., and Scott, H.S. (2007). An integrated Trans-Golgi Network. Molecular Biology of the Cell M.R., Stow, J.L., Duffy, D.L., and Sturm, R.A. (2007). J.M., Ragan, M.A., Hirt, R.P., and Roger, A.J. (2007). Kanamori-Katayama, M., Kitazume, Y., Kawaji, genetic and functional analysis of the role of type 18: 4979-4991. Receptor function, dominant negative activity and 43 Keys, J.R., Tallack, M.R., Hodge, D.J., Cridland, A genomic survey of the fi sh parasite Spironucleus H., Kai, C., Nakamura, M., Konno, H., Nakano, K., II transmembrane serine proteases (TMPRSSs) in phenotype correlations for MC1R variant alleles. S.O., David, R., and Perkins, A.C. (2007). Genomic salmonicida indicatesindicates genomic plasticity among Mottagui-Tabar, S., Arner, P., Chesi, A., Gustincich, hearing loss. Human Mutation 29: 130-141. 20 Makunin, I.V., Pheasant, M., Simons, C., and Human Molecular Genetics 16: 2249-2260. organisation and regulation of murine alpha diplomonads and signifi cant lateral gene transfer in S., Persichetti, F., Suzuki, H., Grimmond, S.M., Mattick, J.S. (2007). Orthologous microRNA genes haemoglobin stabilising protein by erythroid eukaryote genome evolution. BMC Genomics 8: 51. 12 Gupta, S., Stamatoyannopoulos, J.A., Bailey, T.L., are located in cancer-associated genomic regions in 33 Bennetts, J.S., Rendtorff, N.D., Simpson, F., Kruppel-like factor. British Journal of Haematology Wells, C.A., Orlando, V., Wahlestedt, C., Liu, E.T., Tranebjaerg, L., and Wicking, C. (2007). The coding Harbers, M., Kawai, J., Bajic, V.B., Hume, D.A., and and Noble, W.S. (2007). Quantifying similarity human and mouse. PLoS One 11: e1113. 136: 150-157. 2 Baek, J., Son, Y.S., and McLachlan, G.J. (2007). between motifs. Genome Biology 8: R24. region of TP53INP2, a gene expressed in the Segmentation and intensity estimation of Hayashizaki, Y. (2007). Corrigendum: Genome-wide 21 Marquez-Lago, T.T., and Burrage, K. (2007). developing nervous system, is not altered in a family 44 Little, M.H., Brennan, J., Georgas, K., Davies, microarray images using a gamma-t mixture model. analysis of mammalian promoter architecture and 13 Hamilton, N.A., Kerr, M.C., and Teasdale, R.D. Binomial tau-leap spatial stochastic simulation with autosomal recessive non-progressive infantile J.A., Davidson, D.R., Baldock, R.A., Beverdam, evolution. Nature Genetics : 1174. Bioinformatics 23: 458-465. 39 (2007). Unit 4.16 Analyzing Real-Time Video algorithm for applications in chemical kinetics. ataxia on chromosome 20q11-q13. Developmental A., Bertram, J.F., Capel, B., Chiu, H.S., Clements, Microscopy: The Dynamics and Geometry of Journal of Chemical Physics 127: 104101. Dynamics 236: 843-852. 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113 Yap, A.S., Crampton, M.S., and Hardin, J. (2007). 124 Chandrashekaran, I.R., Yao, S., Wang, C.C., Bansal, 136 Dekan, Z., Paczkowski, F.A., Lewis, R.J., and 145 Gruber, C.W., Cemazar, M., Anderson, M.A., and 157 Landsberg, M.J., and Hankamer, B. (2007). 165 Monk, P.N., Scola, A-M., Madala, P.K., and Fairlie, Making and breaking contacts: the cellular biology P.S., Alewood, P.F., Forbes, B.E., Wallace, J.C., Alewood, P.F. (2007). Synthesis and in vitro Craik, D.J. (2007). Insecticidal plant cyclotides and Symmetry: A guide to its application in 2D electron D.P. (2007). Function, Structure and Therapeutic of cadherin regulation. Current Opinion in Cell Bach, L.A., and Norton, R.S. (2007). The N-terminal biological activity of cyclic lipophilic -conotoxin related cystine knot toxins. Toxicon 49: 561-575. crystallography. Journal of Structural Biology Potential of Complement C5a Receptors. 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