Six new Group Leaders partnering with EMBL Australia and other news from the Imaging Centre of Excellence

ARC Centre of Excellence for Advanced Molecular Imaging, Bulletins

Posted on behalf of James Whisstock, Director Imaging CoE

The Centre is collaborating with EMBL Australia to expand the highly successful EMBL Australia Group Leader program at UNSW and Monash. The program offers a five-year funded position, extended to a maximum of nine years subject to an external review.

Two new five-year EMBL Australia Group Leaders working in light microscopy and single molecule science will be recruited to UNSW.  The new Group Leaders will benefit from close linkages to the UNSW node of the Centre led by Chief Investigator Kat Gaus and with her new single molecule imaging centre.

At Monash University a further four new EMBL Australia Group Leader opportunities are being created.  Two of these researchers will be in protein crystallography and electron microscopy and will have natural synergy with the structural and cell biology directions of the Imaging Centre. A further two Group Leaders will be recruited in regenerative medicine and based at ARMI, the Australian Regenerative Medicine Institute. 

Altogether this represents a new funding commitment of $21 million to the EMBL Australia Group Leader program and will represent a major opportunity to recruit new talent to our shores.  An international recruitment drive is being developed, and the formal advertisements for the positions will be released through EMBL Australia in the coming couple of weeks.

In further good news many congratulations to Kat Gaus and Steve Lee who have been nominated for this year’s Eureka Prizes. Kat is the Centre’s Deputy Director and has been nominated for the Eureka Prize for Excellence in Interdisciplinary Scientific Research with colleagues from the University of New South Wales, Professor Justin Gooding and Dr Peter Reece.

Steve Lee, an Associate Investigator from the Australian National University in Canberra, has been nominated with colleague Dr Tri Phan from the Garvan Institute of Medical Research in Sydney for the Eureka Prize for Innovative Use of Technology. You can read more about Kat and Steve and their nominations in this month’s newsletter. The Eureka prizes will be announced on Wednesday 10 September.

Finally, I would like to highlight the launch of the Centre on Tuesday 15 October by Professor Aidan Byrne, CEO of the Australian Research Council. I hope you will be able to join us for the celebrations.

In this newsletter we:

Please feel free to share this newsletter with interested colleagues, and do of course let me know if you do not want to receive future issues.

James Whisstock
Director, Australian Research Council Centre of Excellence in Advanced Molecular Imaging
Professor, Department of Biochemistry and Molecular Biology, Monash University

Generating images of biological molecules in a flash

Chief Investigator Harry Quiney, an Associate Professor at the University of Melbourne, is a theoretical physicist. His contributions to the field have recently been recognised by his appointment to an assessment panel that allocates time to users on the world’s most powerful X-ray laser, the Linac Coherent Light Source (LCLS) at the SLAC National Accelerator Center at Stanford University in California.

What do such things have to with the Centre of Excellence for Advanced Molecular Imaging? A whole lot, as it turns out. Just as the development of synchrotrons provided sources of X-rays powerful and numerous enough to unravel the complex structures of proteins via crystallography, the recent development of X-ray free-electron lasers—a billion times more powerful—holds forth the prospect of analysing not just crystals, but individual molecules. At present there are only two free-electron lasers in the world, at the LCLS and in Japan.

But between blasting biological molecules with the most powerful of man-made X-rays and calculating their structures lies a vast amount of as yet unknown physics describing the details of the interaction. That is where Harry Quiney and his research group will be working. They hope to develop the computational algorithms which will turn mountains of data from X-ray free-electron lasers into meaningful images.

When X-rays interact with the atoms in a crystal, they are diffracted—their straight-line paths are deflected. Measurements of the angle through which the X-rays are diffracted can be used to determine the distribution of atoms in a crystal and the structure of the molecules from which the crystal is built.

But, says Harry, everything is a trade-off. Crystals are useful because their structure of regularly repeating units amplifies the X-ray diffraction signal. Unfortunately, not all molecules of biological interest can be made into crystals which give useful information.

One way of getting around this is to boost the signal by increasing the number of X-rays hitting molecules. And that’s what a free-electron laser can do. Increasing the brightness of the X-ray beam in this way allows researchers to make sense out of smaller sections of crystals or potentially even out of large numbers of independent molecules.

But there’s a barrier to all this. When you start hitting individual molecules with a beam of X-rays one billion times the power of a synchrotron the molecules blow up. They are, as Harry describes them, “rather delicate creatures”. There is a solution—work fast enough to get the information you need before destroying the molecule. Free-electron laser pulses last only femtoseconds, that is quadrillionths of a second. The hope is that in that tiny window of time, enough data can be collected before the molecules explode.

“Almost no research has been done so far into the intense interactions between X-rays and matter at this level,” Harry says. “It’s an entirely new regime, which introduces fundamental physics questions. That’s what motivates me.” He and his group will be constructing mathematical models to guide the experiments of the La Trobe University chief investigators, experimental physicists Keith Nugent and Brian Abbey, and to make sense of the data they produce.

Harry brings a vast amount of experience to the development of these models. He has an MSc in Theoretical Chemistry from Monash, a DPhil in Physical Sciences from Oxford, and has studied the structure of atoms and molecules, the quantum nature of materials, chemical bonding and the interaction between light and matter. And he is hoping that what he finds about the interaction between X-rays and matter in the extreme environment of free-electron laser beams in his studies with the Centre will lead to a great deal more than just protein structures.

Bringing cell biology to order

As a trained physicist Katharina Gaus—the Deputy Director of the Imaging Centre of Excellence and head of its University of New South Wales (UNSW) node—makes a very good biologist.

Kat is professor and NHMRC senior research fellow in the Faculty of Medicine at UNSW, and was the driving force behind establishing the University’s Biomedical Imaging Facility.  She has been collaborating with the renowned German manufacturer of optical systems, Carl Zeiss AG in developing a super-resolution fluorescence microscope, which can image molecules in living cells. That’s one way in which she brings her physics to biology, but there’s much more to it than that.

She now heads a laboratory in which physicists and biologists interact on a daily basis. They are interested in solving questions to do with the membrane structure, signalling and interaction. In particular, Kat is investigating how T cells, the workhorses of the immune system, make decisions which ultimately affect our health and well-being.

Although she was always interested in biology “at the level of zoology and botany, it was way too messy for me. There were too many details”. So at secondary school, and as an undergraduate in Germany, Kat studied mathematics and physics. “I liked the clarity and logic. That really appealed to me.”

Then she took time out from her studies at the University of Heidelberg to study at Cambridge in the UK, and found a way to apply her physics rigour to biology—through biotechnology. She ended up doing her PhD in biotechnology at Cambridge studying cellular interactions. It was technology based. She developed an instrument, the Biacore, which measures the affinity between receptors and the molecular sequences or ligands that bind to them. It is still commercially available, and used in laboratories around the world.

In 2001, she came to work at the Heart Research Institute in Sydney as a fully fledged cell biologist. Since 2002, Kat has been at the Centre for Vascular Research at UNSW, and since 2008 her work has been increasingly centred around the super-resolution fluorescence microscope. “It is a game-changing technology,” she says, that allows researchers to observe the interactions of molecules in a living cell.

Before its advent, images at the molecular level called for technologies such as electron microscopy which demand killing, staining and embedding cells. Light microscopy, which can be undertaken on living cells, hits a barrier at about 250 nanometres (millionths of a millimetre), about the same dimension as the wavelength of light. At that distance, two points are no longer distinguishable from each other.

Super-resolution works around this barrier by attaching fluorescent tags to individual molecules that flicker on and off. By taking a series of about 20,000 images of the same cell, and resolving it into one, a picture of the cell can be constructed molecule by molecule. These images can also reveal the interaction and activity of molecules within the cell.

At present, Kat is working on how T cells make decisions on actions such as moving, secreting the signalling compounds known as cytokines or committing suicide. It is all encoded, she says, in the patterns of molecular interactions in the cell—how they interact, when they interact and for how long. She suggests that, like computers, the behaviour of T cells is based on a set of logical rules—algorithms, if you like—and that the whole spectrum can start to be unravelled by observing the activity of one molecule involved in one process.

The members of her group have already begun to move along that path by studying how cell signalling begins. They have been observing the behaviour of the T cell protein Lck which initiates signalling. They found Lck exists in two states—closed, when it clusters together, and open, when it leaves the cluster. The probability of initiating signalling increases as the rate of interchange between these two states increases.

The emergence of such a probability relationship at the heart of a key biological activity like decision-making in the immune system brings together physics and biology in a very real manner.

Kat and colleagues from the University of New South Wales, Justin Gooding and Peter Reece, have been nominated for the Eureka Prize for Excellence in Interdisciplinary Scientific Research. The citation is for their work in developing “an optical device that can monitor the activity of a single living cell, with wide-ranging applications in drug discovery, toxin detection and personalised medicine”.

What this means in practice is that they have developed a silicon-based surface that can capture the versatile immune cells known as macrophages, and then monitor in real time their release of enzymes which break down proteins, an action which is central to their function. The activity of macrophages constitutes an early warning for many degenerative diseases including cancer. The device may well be able to be used to test anticancer drugs and therapeutics related to the immune response, to diagnose disease, and to detect pathogens, toxins and poisons.

The Eureka Prizes will be announced on Wednesday 10 September.

Peering inside the body’s living tissue

Turning a smartphone into a mobile microscope may not seem to have much to do with puzzling out the workings of the immune system, but Imaging Centre of Excellence Associate Investigator Steve Lee is bringing the two together.

Steve is a lecturer at the Research School of Engineering of the Australian National University (ANU). His primary research interest is in developing miniature optical devices that deliver magnified images of cells to biologists from deep inside living tissues.

Before leaving the University of New South Wales for ANU, Steve discussed with Kat Gaus developing high resolution intravital microendoscopes for imaging immune system cells in living organs, such as lymph nodes and the spleen. Now, Steve is working in the Centre with Chief Investigators Kat Gaus and Bill Heath to bring those ideas to reality.

At present, commercial microscope technologies are rarely implanted and their operations are limited to only a millimetre or two beneath the surface of an organ.

Recently, Steve invented a way of making inexpensive high resolution lenses, with the collaboration of Tri Phan from the Garvan Institute of Medical Research. Their innovation has been nominated for the Eureka Prize for Innovative Use of Technology. They have developed a do-it-yourself high performance lens for mobile phones which can magnify by up to 160 times. The lens, which can turn your average smart phone into a mobile microscope, can be generated on the spot in about 15 minutes using a polymer mix and a standard kitchen oven, all for less than $2 – see the video. The images the lens produces can be printed or sent for further analysis via the Web.

Steve proposes using similar lens fabrication technology to make even higher powered lenses able to be implanted inside tissues and organs. Once the lens is in place, he will feed in an optical fibre connection to relay images out of the body. The system will use adaptive optics to correct any residual image distortions.  Steve thinks the combined technologies could resolve images to around a thousandth of a millimetre, small enough to pick out the larger subcellular structures, such as mitochondria.

So what do he and his colleagues hope to observe? “It’s difficult enough to achieve our goal. And because we haven’t done it yet, it’s kind of hard to predict what we are going to see. We have to get the optics and the resolution right first. Once we have the capability, we will be at the stage where we can decide what questions to ask.”

Penetrating deeply into the organs of the body should open up a whole new frontier of knowledge.

Low dose, but high resolution X-ray imaging

Two Chief Investigators, Keith Nugent and Brian Abbey of La Trobe University, and Partner Investigator Andrew Peele of the Australian Synchrotron are among the senior authors of a paper published this month in Ultramicroscopy. The first author was Australian Synchrotron Associate Investigator Michael Jones.

The researchers from Melbourne and the US used a red blood cell infected with a malaria parasite to demonstrate the effectiveness and utility under low radiation of phase-diverse X-ray coherent diffractive imaging. With this microscopic technique, they were able to form their image with high sensitivity and resolution, while employing X-ray doses significantly lower than any other so far reported. And they could generate two dimensional images quickly without having to fix or freeze tissue.

Read the abstract.

PhD top-up scholarships in biology, chemistry and physics

Help us transform immunology and microscopy
Apply now for $5000 top-up scholarships in biology, chemistry and physics

  • UNSW
  • The University of Queensland
  • La Trobe University
  • The University of Melbourne
  • Monash University

Over 40 top-up scholarships between 2014 and 2020.

The Centre aims to provide an unprecedented understanding of how immunity works and to pioneer the next generation of imaging at the atomic, molecular, cellular and whole animal levels.

The Centre’s PhD program offers:

  • biology, chemistry and physics projects
  • exceptional interdisciplinary projects
  • work across multiple nodes, including with our international partners in Germany and the UK
  • training and use of state-of-the-art research infrastructure.

Apply or contact

Taking the Centre’s message to the world

July to August is conference season in the Northern Hemisphere which means the past month has been a busy time for presentations by members of the Imaging Centre of Excellence. And there are several scheduled for September.

Chief Investigator Kat Gaus and Associate Investigators Richard Berry and Michelle Dunstone all gave papers at the 2014 International Biophysics Conference in Brisbane early in August. Kat outlined her studies observing single molecules, and puzzling out the molecular role in the decision-making of immune T cells. She will do it all again at the 4th Single Molecule Localisation Microscopy Symposium at Kings College, London on 28 August. Richard spoke about the work on immunoevasins, viral molecules which mimic and subvert the immune system. And Michelle talked about molecules such as perforin, which form pores in cell membranes.

She and Centre Director James Whisstock will have more to say about perforins in September, James at a seminar at the Centre’s partner institution, the University of Warwick in the UK and Michelle at the 8th Asia Oceania Forum for Synchrotron Radiation Research in Hsinchu, Taiwan. She is also proposing a new model of pore formation to a conference in Trento, Italy on 30 August.

Meanwhile, Jerome Le Nours, a research fellow in Chief Investigator Jamie Rossjohn’s laboratory, was in Montreal in early August at the International Union of Crystallography conference (IUCr 2014) talking about the recognition of CD1d-lipid antigen by T cell receptors.

He was joined at that conference by Stephen Scally, a PhD student from the Rossjohn laboratory, who gave a paper describing the molecular basis for the association between the HLA-DRB1 allele and rheumatoid arthritis. Stephen gave a repeat performance at the Scripps Research Institute in San Diego later on in the month, and will be doing it all again at the ComBio 2014 conference in Canberra in late September.

In the middle of August, chief investigator Brian Abbey told the Joint Institute for Laboratory Astrophysics in Colorado about the Centre’s free electron X-ray laser work.

Chief Investigator Harry Quiney spoke to VCE students about the particle and wave properties of light at The University of Melbourne in early August.

About the Centre

The goals of the Centre are to build Australia’s knowledge, capabilities and capacity in advanced molecular imaging and immunology by:

  • undertaking large scale, transformative, interdisciplinary and collaborative research
  • developing innovative imaging technologies, products and IP
  • establishing a centre that will link national and international networks of universities, research infrastructure and industry
  • attracting and mentoring early and mid-career interdisciplinary researchers, and
  • establishing a strong, nationwide, outreach program, with a focus on communicating our scientific discoveries to key stakeholders and the general public.

The ARC Centre of Excellence in Advanced Molecular Imaging is funded by the Australian Research Council and administered by Monash University. The Centre brings together teams from:

Collaborating Organisations: La Trobe University, The University of Melbourne, The University of New South Wales, The University of Queensland.

Partner Organisations: Australian Nuclear Science and Technology Organisation, Australian Synchrotron, Carl Zeiss Pty Ltd, Deutsches Elektronen-Synchrotron, Germany, Leica Microsystems Pty Ltd, University of Warwick, UK.