Submission to 2016 National Research Infrastructure ... · in national research infrastructure? NIF has only been able to deliver a national capability through significant co-contributions

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Name Prof Graham Galloway Title/role Director of Operations Organisation National Imaging Facility

Questions

Question 1: Are there other capability areas that should be considered?

No, but it is not clear that multi-disciplinary infrastructure has been fully recognised. As identified in the 2011 Roadmap, the Characterisation capabilities, including imaging, are enabling technologies, which contribute to most of the other capability areas. Much of the commentary about imaging was addressed by the Advanced Physics, Chemistry, Mathematics and Materials capability, whilst the Health and Medical Science group concentrated on one aspect of imaging, which although important, is not the whole picture. Characterisation, in all its forms needs to be recognised for its place in many of the capability areas and contribution to many of the Focus areas.

Question 2: Are these governance characteristics appropriate and are there other factors that should be considered for optimal governance for national research infrastructure.

Governance is critical to ensuring that each component of the national research infrastructure commits and acts upon the principles and ideals of NCRIS, providing a mechanism for minimising duplication of capability, for identifying gaps, and for strategic planning for growth and renewal. See Section 1

The existing NCRIS capabilities have self-organised to meet regularly, and discuss opportunities to connect to meet the needs of the research community. In the early development of NCRIS, the Characterisation capabilities were supported by an independent council, which provided direction and support to provide a coordinated approach for researchers’ needs. Parts of NIF’s vision can only be developed in collaboration with other national infrastructure. See Section 1.1, including a well-developed plan for eResearch, developed together with the existing capabilities, and is well placed to support transition from the existing multi-agent solution to an integrated eResearch capability. See Section 6

Question 3: Should national research infrastructure investment assist with access to international facilities?

Yes, where it is not cost effective in Australia, e.g. CERN.

Question 4: What are the conditions or scenarios where access to international facilities should be prioritised over developing national facilities?

In the health theme, research involving rare diseases or where there is a biohazard risk for Australia.

Question 5: Should research workforce skills be considered a research infrastructure issue?

Yes. An essential component of NIF, and one that has been identified in every survey of effectiveness of NCRIS, is the expertise offered through the

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Facility Fellows and Informatics Fellows. The collaborative nature of NIF provides a mechanism for transfer of skills between modality, technology and nodes, and ensures training of the next generation of instrument scientists in a wide range of technologies. See Section 2.2 and 8

Question 6: How can national research infrastructure assist in training and skills development?

State-of-the-art instrumentation is, by nature, complex, and rapidly evolving. A critical component of research infrastructure is to provide the practical expertise, in experimental design and data analysis, as well as the operation of sophisticated technology. See Section 8

Question 7: What responsibility should research institutions have in supporting the development of infrastructure ready researchers and technical specialists?

No institution is able to provide access to the full range of technology, and particularly the smaller ones, do not have the resources, to provide access for their students. Students from across the spectrum, through national infrastructure, can be given that opportunity. Institutions can then include theoretical aspects of new technologies within their curricula and training programs, and design research projects, in the confidence that they can get access to the technology.

Institutes should also commit to creating career pathways to scientists that commit to being a part of providing research infrastructure services. This is particularly important if the proposed NHMRC changes go ahead. These changes will make it very difficult for enabling scientists like imaging physicists, chemists and infomaticians to be funded as primary investigators. Therefore career progression metrics will need to be modified.

Question 8: What principles should be applied for access to national research infrastructure, and are there situations when these should not apply?

Access should be governed by the following 4 priorities. See Section 7.1: i. Research excellence ii. Opportunities for innovation and proof-of-concept iii. Translation to deployment of national utility iv. Training the next generation of researchers It is important that all priorities are recognised, even if that means

training takes precedence over opportunities for innovation.

Question 9: What should the criteria and funding arrangements for defunding or decommissioning look like?

Most research technology has a limited effective life. National infrastructure must be internationally competitive, and preferably world-leading. To remain so, the national research infrastructure must provide for upgrading / renewal of key infrastructure.

Question 10: What financing models should the Government consider to support investment in national research infrastructure?

NIF has only been able to deliver a national capability through significant co-contributions. In 2006 Investment plan the NCRIS provided $7M of a $21M project, matching funding by both state and institutional sources. In 2009 EIF, commonwealth capital contributed $40.5M to a $106M project. A further $60M of existing infrastructure has been contributed by the institutions,

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to the national capability. Host institutions are selected because of their expertise and track-record, World-class research and expertise, built on this framework and the capabilities are immediately able to cater for a broader range of applications and users, expanding their utility, and availability to the wider research community. However, funding of expert personnel to facilitate the sharing of these resources, and commensurate ongoing equipment maintenance funding, has been chronically inadequate for NIF given the past formula applied to operational infrastructure funding.

NCRIS has been hallmarked by a principle of whole-of-life costs line item, maintenance and operational funding considerations. As access is provided to all researchers at the same cost, regardless of institution, mechanisms need to be developed to ensure that operational costs of this infrastructure are supported.

Question 11: When should capabilities be expected to address standard and accreditation requirements?

Accreditation is increasingly important for research infrastructure. Recent reports that much research is not reproducible is unacceptable. A national research infrastructure must ensure it does not contribute to this deficiency in research reproducibility.

One of the reasons given for industry not engaging with academia, is the belief that any research used as background IP will need to be repeated. This is a major impediment to innovation at the boundary of industry and the academic sector. This can be largely mitigated by implementing industry standard processes that are ensured through proper documentation and industry accepted accreditation, GLP or ISO9000, will significantly shorten the time between discovery and innovation.

Question 12: Are there international or global models that represent best practice for national research infrastructure that could be considered?

As identified at the recent GlobalBioImaging symposium, the NCRIS initiative, and in particular, NIF and AMMRF, are being held up as the model for collaborative infrastructure, which EuroBioImaging would like to emulate. That is not to say that we have everything running perfectly, and a future investment plan must resource improvement in the areas of utilisation, quality control and universal access of meritorious researchers to world-leading imaging infrastructure and training of students and Early Career Researchers (ECR).

Question 13: In considering whole of life investment including decommissioning or defunding for national research infrastructure are there examples domestic or international that should be examined?

As an example of what hasn’t worked, the Canadian decision to instantly cut funding to national research capabilities, such as the National Ultrahigh-field NMR Facility for Solids and National Research Council Canada Institute for Biodiagnostics, resulted in a major vacuum for researchers across Canada. Many highly experienced and professional researchers found themselves unemployed, and either left Canada or left science.

Question 14: Are there alternative financing options, including international models that the Government could consider to support investment in national research infrastructure?

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Health and Medical Sciences

Question 15: Are the identified emerging directions and research infrastructure capabilities for Health and Medical Sciences right? Are there any missing or additional needed?

National Research Infrastructure needs to be aligned to strategic directions of ARC and NHMRC, and in particular ensure that the infrastructure needed for large scale projects to be funded by the Medical Research Future Fund, is available. See Section 3.6

NIF agrees with the EWG about the need for further development of radiotracer capability, something that NIF has already recognised. The additional material, provided as a separate attachment, includes a document prepared by the Australian radiochemistry and molecular imaging community, which addresses the issues raised by the EWG in detail. See Section 3.2 for a summary of the planned response to this need.

Increasingly, biomedical research requires robust quality control and if results are to be used as part of large clinical trials or regulatory approvals, GLP accreditation. NIF has plans to jointly develop this capability across all nodes, particularly those contributing to large cohort and phase 2 and 3 clinical trials.

Closely related to imaging is the emerging field of theranostics. Some of the infrastructure proposed to satisfy radiotracer development, would also be needed in theranostics. This includes toxicology, dosimetry, and PET and SPECT imaging to confirm delivery to target, as well as identifying accumulation in non-target areas and excretion paths. See Section 5.1

In considering imaging, temporal processing was not identified by the EWG. This is important when considering cognitive processing and its impact within psychiatric and neurological disorders. New technologies, including EXPLORER (section 9.1) and Atomic Clock Imaging (section 9.2) are able to increase the temporal resolution needed for modern imaging research.

Question 16: Are there any international research infrastructure collaborations or emerging projects that Australia should engage in over the next ten years and beyond?

NIF, through a Memorandum of Understanding with EuroBioImaging, signed in Brussels in 2014, and as a partner in the Horizon 2020 Global BioImaging project has initiated strong engagement with the international community, and is recognised by our international colleagues as being leaders in collaborative infrastructure. Increased engagement will lead to improved delivery of services, through collective development and sharing of expertise, increased international collaboration, and evolving opportunities for sharing of data, and engagement in the international Big Data revolution.

International projects, in which Australia is engaged, include ENIGMA, and ADNI. Other projects would be the Human Connectome Project (USA) and the Human Brain Project (EU).

Researchers at different nodes of the NIF capability study different aspects of prenatal injury and placental deficiencies – preclampsia at WSU, injury in pre-term lambs at UWA, hypoxia porcine models of prenatal damage at UQ, and MRI images of the beating sheep fetal heart to assess myocardial

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viability after an infarct at LARIF. A modest investment in coordinating capability across the NIF network, would make Australia a strong partner in projects such as the NIH Human Placenta Project.

Question 17: Is there anything else that needs to be included or considered in the 2016 Roadmap for the Health and Medical Sciences capability area?

The strength of NIF is the network of capability, expertise and capacity. This ensures a research environment that covers the range of medical themes; oncology, neuroscience and mental health, cardiovascular, musculo-skeletal and biomaterials, as well as the capacity to support multi-centre trials. The opportunity to translate from small-animal pre-clinical to large animal pre-clinical to human, is fundamental to the vision and mission of NIF.

NIF was identified in the 2011 Roadmap as an enabling technology, providing essential technology in the following areas:

i. identifying phenomic changes as a result of genetic changes ii. investigating prodromal changes before the onset of clinical disease

and providing earliest markers of disease iii. assessing efficacy of novel therapies, and recognising unexpected

side effects iv. translating research from animal models to human studies

Multi-modal imaging, in all its forms, both preclinical and human has become a key tool in health and medical sciences. However, if Australia is to maintain its position as a world-leader, in a 10-year plan, there needs to be provision for investment in newly developing capability and further capacity. Imaging technology continues to evolve, and NIF will need to upgrade or replace existing equipment, if Australian researchers are to be internationally competitive. The issues paper has correctly identified the importance of molecular imaging, however there are other imaging domains equally important that require further investment.

NIF is constantly reviewing the inventory required to ensure world-leading equipment is available to the wider research community, in a geographically sensitive way. Some key regions are underrepresented (e.g. no clinical research imaging in WA), or unrepresented (ACT and NT).

Some technologies, that play an essential role in translational research are underrepresented, for example, there are only two pre-clinical SPECT scanners within the NIF infrastructure.

NIF has established centres of excellence with multimodal imaging and associated infrastructure to support the whole research endeavour. Some of these centres are missing key pieces of imaging equipment (e.g. the Large Animal Research and Imaging Facility does not have PET. See Section 3.4 for an example of how this contributes to Australia’s biomedical position of leadership).

Whole body PET is an emerging transformative technology. NIF is of the opinion that Australia should do something bold and transformative in this space by joining the international PET EXPLORER consortium.

The Medical Research Future Fund has been established to address the big health issues facing Australian society. These are not problems that can be addressed by a single institution and are going to need the expertise

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and resources of biomedical researchers, clinicians and hospitals and industry. Section 3.6

Environment and Natural Resource Management

Question 18: Are the identified emerging directions and research infrastructure capabilities for Environment and Natural Resource Management right? Are there any missing or additional needed?

Whilst the medical importance of MRI has long been understood the application of MRI to industry and agriculture is almost untapped. Working in concert with agricultural and industrial researchers, the infrastructure and expertise in NIF has enormous potential to drive and increase the competitiveness of Australian Industry (e.g., imaging of process and electrochemistry) and Agriculture (e.g., root imaging to better understand plant growth in various soils, salt transport in engineered phenotypes and plant phenomics need more focussed attention). Section 4.3


Question 20: Is there anything else that needs to be included or considered in the 2016 Roadmap for the Environment and Natural Resource Management capability area?

Advanced Physics, Chemistry, Mathematics and Materials

Question 21: Are the identified emerging directions and research infrastructure capabilities for Advanced Physics, Chemistry, Mathematics and Materials right? Are there any missing or additional needed?

If Australia is to maintain its position as a world-leader, in a 10-year plan, there needs to be provision for investment in newly developing capability and further capacity. Imaging technology continues to evolve, and NIF will need to upgrade or replace existing equipment, if Australian researchers are to be internationally competitive. See Section 9

As identified in Section 3.5, development of existing capability, will increase its value, resulting in a much greater return on investment. Imaging infrastructure is delivering new opportunities in non-traditional fields, such as agriculture, materials and environment. To maximise this opportunity, there needs to be investment in developing new acquisition sequences and optimising profiles. This requires experts in physics, chemistry, maths and image processing.

New technologies are continually adding to the capability. Magnetic Particle Imaging is not yet available in Australia, and will contribute to development of nanoparticles as novel multifunction contrast agents and carriers of theranostics.


EXPLORER whole-body PET technology is a new innovation, and Australia has the opportunity to join an international consortium in its

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development to ensure that the temporal domain and whole of organism approaches are adopted early in Australia (section 9.1)

Question 23: Is there anything else that needs to be included or considered in the 2016 Roadmap for the Advanced Physics, Chemistry, Mathematics and Materials capability area?

Imaging does not operate in isolation, but needs to be part of an ecosystem. Added to the equipment is the need for a range of architectural and organisational features, barrier facilities, etc. See Section 2

Understanding Cultures and Communities

Question 24: Are the identified emerging directions and research infrastructure capabilities for Understanding Cultures and Communities right? Are there any missing or additional needed?


Question 26: Is there anything else that needs to be included or considered in the 2016 Roadmap for the Understanding Cultures and Communities capability area?

National Security

Question 27: Are the identified emerging directions and research infrastructure capabilities for National Security right? Are there any missing or additional needed?


Question 29: Is there anything else that needs to be included or considered in the 2016 Roadmap for the National Security capability area?

Underpinning Research Infrastructure

Question 30: Are the identified emerging directions and research infrastructure capabilities for Underpinning Research Infrastructure right? Are there any missing or additional needed?


Question 32: Is there anything else that needs to be included or considered in the 2016 Roadmap for the Underpinning Research Infrastructure capability area?

Data for Research and Discoverability

Question 33: Are the identified emerging directions and research infrastructure capabilities for Data for Research and Discoverability right? Are there any missing or additional needed?

Data must be connected to compute.

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Researchers will be greatly encouraged to store their data in repositories, if it facilitates the short-term research experiments. The long-term benefits of properly curated and discoverable data come as an ancillary benefit.

Effective use of resources is to connect data storage to where it needs to be. Section 6


Australia should continue its role as a member of the International Neuroinformatics Coordinating Facility (INCF). Existing international imaging projects, in which Australia is engaged, include ENIGMA, the BigBrainProject, and the Human Connectome. A potential international project in which Australia could be a foundation partner would be extending ELIXIR to link imaging data with genetic data. The question to answer is not “Are there projects?” that is plainly YES. It is impossible to deterministically guess what is beyond the horizon, but it is critical that Australia’s data systems are responsible to and capable of engaging from day 1.

Question 35: Is there anything else that needs to be included or considered in the 2016 Roadmap for the Data for Research and Discoverability capability area?

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Other comments

National Imaging Facility – a new future

Executive Summary National Imaging Facility (NIF) is a world-leading imaging capability that embraces

state-of-the-art imaging infrastructure empowered by highly specialized expertise. NIF currently has 10 nodes across Australia and operates with a Governing Board to set strategic direction, and an Operations Committee to develop the most effective ways of meeting the needs of the national research community. Australian Nuclear Science and Technology Organization (ANSTO) is an integral and equal partner, providing a national focus to the development of a network of cyclotrons, and supporting an integrated system for development of novel tracers and the effective supply of radiotracers to the research community.

Through 2006, 2008, 2011 and now 2016, NIF has consistently reviewed and updated its role and place in the Australian and world-wide research infrastructure frameworks.

1) It must provide researchers with reliable, state-of-the-art technology, with expertise to ensure world’s best, reproducible data, to solve their problems.

2) It must ensure that industry has access to the tools to drive the biotech and advanced manufacturing industries, and grow the economy into the future.

3) It must be closer to the “clinical translation” interface, including delivering a national competency in radiotracer development, production and delivery.

4) It must create the environment for high quality translation by establishing national accreditation, trusted quality control and assurance, and advanced data management.

5) It must lead in developing and implementing the most effective imaging technologies, in diverse environments and ensure the expertise exists for first class research.

6) It must identify iconic new investments that constitute a new direction, and ensure Australia remains at the cutting edge: EXPLORER whole body PET, personalised medicine through theranostics.

7) It will deliver a continuum of imaging capability from molecule, through small and large animal models to human trials and clinical practice.

8) It will develop imaging capability to inform responses to nationally important questions about food supply, best environmental practices and improved industrial processes.

9) It will ensure that the next generation is trained to respond to a rapidly changing environment with the skills and the courage to go in new directions.

10) It will build on strong international linkages, to make them deeper and wider.

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1. Vision

Imaging is undoubtedly driven by biomedical applications, which incentivise the vendors in the development of sophisticated commercial products. However, we should not lose sight of the opportunity for its use in other domains. Indeed, the 2011 Roadmap identified imaging as an enabling technology. As a national capability, NIF is in a position to provide infrastructure to what may be considered minority fields, which on their own would be unable to support this level of imaging capability, but nonetheless address significant research questions for the future of Australia. The following diagram identifies the breadth of the influence of NIF and the many national capabilities with which NIF is engaged.

“A national network of advanced imaging capability to deliver innovation and growth”

To fulfil the national needs of the broad research communities (universities, institutes, or industry) that NIF serves, the vision of NIF is to evolve into a user-focused theme-based capability where each theme integrates a well-developed plan with interdisciplinary practices to simplify the interface between NIF and communities, support new developments, and facilitate outcomes from which the Australian economy benefits. NIF is well known for its role in biomedical research and is increasingly important in materials science and advanced manufacturing. There are opportunities for NIF to purposefully develop new research directions in agriculture, ecology and anthropology. Therefore, the future NIF themes, as shown in the above diagram, include Health, Environment & Agriculture, and Materials.

1.1 Intercapability engagement NIF’s vision supports the concept of a co-ordinating body, which facilitates inter-

capability discussion and drives collaboration. NIF is well placed to engage with other national research capabilities, such as BioPlatforms Australia (BPA), Australian Phenomics Network (APN), Therapeutic Innovation Australia (TIA), and Australian Microscopy and Microanalysis Facility (AMMRF) in Health Theme, Australian Plant Phenomics Network (APPN) in Agriculture, Atlas of Living Australia (ALA) and AMMRF in Environment, Australian NanoFabrication Facility (ANFF) in Advanced Manufacturing and CSIRO in Materials theme. NIF also does and will continue to drive the domain specific eResearch agenda, collaborating with Research Data Services, Australian National Data Services and NeCTAR to co-develop tools that benefit all researchers using imaging capability. A testament to this, has been the co-development of the Characterisation Virtual Laboratory, together with AMMRF, and more recently tools for automated dataflow, from instrument to

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repository, capturing the necessary meta-data to make the data useful over a longer timeframe, and develop a Trusted Data Repository. This leads not only to efficiencies, but importantly, the opportunity to develop stronger linkages between multi-scalar data. NIF has committed to developing a joint informatics capability with AMMRF to ensuring that data can be readily shared and analysed and utilisation of eResearch tools is maximised.

2. Infrastructure is more than equipment

NIF defines its capability by four major components:

2.1 Technology Imaging infrastructure is strategically located throughout Australia to ensure

researchers have access to the imaging required for their research. This is particularly the case for research involving live samples; human, animal or plant, where transport of samples is not always possible, either because of fragility, cost or regulatory concerns. Using a collaborative approach, a range of different research environments is available, based on the expertise and applications at each location.

2.2 Expertise As important as the instruments is the human capital that provides highly specialized

expertise to different research communities. National Research Infrastructure is able to attract leading expertise in the technology and application of sophisticated equipment. NIF Fellows are amongst the most experienced in the world in their area of expertise. NIF will continue to hold regular workshops for the Facility and Informatics Fellows to exchange experience, learn about complementary technologies and develop new skills around facility management, support for users and expectation management, and data management.

2.3 Diverse environments Research requirements extend beyond a piece of equipment, often with complex

environmental requirements, which together create the foundation for a capability. NIF has provided imaging equipment in a clinical environment, for use in studies with patients who require additional clinical support, as well as a campus environment, where equipment can be used in sophisticated research in conjunction with other modalities, such as MEG, EEG and TMS. Modern research requires ability to acquire and correlate data from multiple sources, and hence often there is a need to co-locate MEG with MRI or MRI with PET. Animal research has an even wider range of requitements, PC2 may be universal, but for all imaging capability to be within a Specific-Pathogen-Free (SPF) facility is not practical. Many researchers would be disenfranchised because they cannot access SPF imaging capability with genetic, behavioural or environmental animal models that they have taken years to develop. Other research requires access to surgical capability, and post-surgery recovery space. Molecular imaging requires radiation protection and monitoring systems, radiotracer dosing and measurement facilities. Often in vivo experiments then need to be validated using biodistribution measurements, which need to be performed within the decay time of the radioisotope. Imaging with radioactive tracers in longitudinal experiments also require animal accommodation while they “cool down”.

Some solutions require a large range of equipment in a single highly specialised environment. The NIF capability at the Large Animal Research and Imaging Facility (LARIF) is one such example that includes imaging capability along with specialised animal housing, operating theatres, and space for related treatments.

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2.4 Interdisciplinary practices Most research requires specific knowledge relevant to the research question. Different

sites within a coordinated network are able to specialize in particular areas, develop new capability and share it with the rest of the network. As an example, within NIF, the Florey node is a world-leader in the development of new acquisition and data technologies including Diffusion Imaging, a key technology in understanding and mapping the human connectome, and one of two big game-changers in neuroimaging in the past 10 years. The image acquisition strategies and post-processing tools are used the world-over, and will soon be incorporated into the Siemens mainstream product, testament to the fact that technology developed in Australia has been translated into standard clinical practice. To have that local expertise is of enormous value to the whole of the neuroscience community in Australia. Another example: Large animal research requires very specialised knowledge in animal care, ethics, anatomy and physiology, in addition to the imaging expertise. NIF capability at LARIF brings all that expertise under one roof.

3. Health Theme

A national collaborative network of open access facilities spanning fundamental research and pre-clinical capabilities through to clinical settings has been established. Imaging plays a strong role in translation pathway as well as reverse translation, i.e., informing future molecular and pre-clinical research using data from human & animal imaging. The future mission of NIF is to address the needs of the broader research community (hospitals, industry (SME & large), university researchers, medical research institutes, students, Public Funded Research Agencies (PFRA)) across this spectrum. The needs of researchers must drive the strategic development of NIF. This framework is essential for further incremental and major investment so as to 1) realise the benefit from prior investment, 2) establish and expand new capability and 3) ensure maximum impact of ongoing investment through maximum utilisation of infrastructure.

Translational research: a) animal to human, b) bench to bedside c) laboratory to industry. Imaging plays an important role in all of these domains, and provides important links between the stages of research. Information flows in both directions. Understanding of molecular and preclinical models are transferred through large animal models to human trials, where findings provide direction for further refinement in the laboratory.

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3.1 Molecular Multi-modality imaging is an essential driver of drug development. Morphological,

functional and molecular imaging all contribute to the discovery of potential targets and targeting molecules. Only by building laboratories that cover the full range of modalities can Australian researchers (academic and industry) address the challenges of drug discovery. Multimodality imaging provides complementary data about morphology, function and chemistry, and enables the development of multi-functional agents that target different facets of the disease process, including:

• identifying phenomic changes as a result of genetic changes • recognising prodromal changes before the onset of clinical disease and providing

earliest markers of disease • assessing efficacy of novel therapies, and recognising unexpected side effects • translating research from animal models to human

Personalised medicine requires more than a knowledge of the genome, but tools to identify gene expression within the phenome and subsequent changes due to environmental effects are critical. Imaging needs to be connected to the Australian Phenomics Network (APN), as imaging is an essential tool in identifying and understanding genetic changes in the whole animal, working alongside microscopy, histology and histochemistry. Together, these technologies provide information across the range of distance scales, from sub-cellular to whole organism. Combined with molecular imaging, morphology and histochemistry becomes functional. Working together with AMMRF, APN and BPA, NIF provides the capacity to link the gene with the final functional manifestation of biological processes and the genesis and progress of disease. This ecosystem needs to be developed deliberately and systematically, so while individual pieces of equipment may be considered commodities, the ecosystem is far from it.

3.2 Radiochemistry Plans, as enclosed to this document, are well advanced for an Investment Plan,

including human capital to address the shortage of radiochemistry capability for Australian researchers. Integral to these plans is working together with clinical and commercial radiochemistry facilities, to jointly develop an environment for development of new radiotracers, with capacity to be reliably delivered to researchers throughout Australia. The development of novel tracers exceeds normal funding mechanisms, as a result of the high cost of toxicology, dosimetry and development of synthetic pathways that can be delivered by chemistry modules in a hotcell. As a national network, NIF will develop systems that can be used by chemists and biological scientists to transform compounds known to bind to receptors into radiotracers. For some applications, NIF recommends investment in microfluidics, which could accelerate development and for low use tracers, provide production facilities. The development of new radiotracers are dependent on the ability to optimise image acquisition and access the new information. This type of research can only be done in a research environment.

NIF agrees that productivity could be improved with better integration of existing infrastructure and resources. In particular, there are a number of major cyclotron/PET facilities that are not part of NIF (primarily hospital-based facilities) which have very strong academic output and radiochemistry capability, and teaching and training track records. Similarly, commercial providers are an important player in the provision and distribution of radiotracers to sites without an on-site cyclotron and radiochemistry facility. As a first step, it’s proposed to conduct a national audit of molecular imaging facilities that spans NIF, industry and hospital based radiotracer/imaging facilities.

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NIF’s proposal to deliver systems to share radiotracers for human studies is predicated on the need to increase the number of GMP facilities. It is important to highlight that while GMP conditions are appropriate for clinical studies (particularly phase 2 and 3 trials), they are an impediment to radiotracer research and development and innovation, and not required for phase 0 and phase I trials. Thus, there continues to be a need for both GMP and non-GMP radiochemistry facilities to ensure Australia is able to respond to the full range of research opportunities in translational molecular imaging. There are costs associated with building infrastructure, which would need to be satisfied, in facilities requiring GMP, but the other significant cost is documentation and training. Upskilling of staff through funding of staff to participate in the ACPSEM training and accreditation program would partially address this need. NIF nodes would commit to sharing their documentation and facilitating exchange programs to upskill staff across the network.

The main barriers to the Australian research community taking full advantage of new and “first in country” radiotracers are (a) the high costs, some of which must be passed on to the researcher if not covered by other sources of funding and (b) a severe shortage of highly trained synthetic radiochemists. To address the issue of high tracer development costs, NIF recommends that NCRIS cover the sunk costs of radiochemistry facilities and the radiochemistry workforce which is so critical to this capability. In addition, there are several actions NIF can take to help mitigate the high cost of tracer development, including provision of nationally accessible dosimetry services, coordination of access to toxicology labs and data, coordination of imaging studies between facilities to maximise efficient utilization of radiotracer syntheses and coordination of tracer distribution between facilities. NIF also undertakes to establish and maintain a national registry of radiotracers available for animal and human use.

A further opportunity will arise for coordinated imaging and therapy programs of research at the national level should Australia proceed with the establishment of a proton and heavy ion cancer therapy facility. Such facilities require non-conventional off-line imaging (e.g. X-ray CT) for dose planning as well as experimental in-beam imaging platforms for dose verification, such as PET (using endogenously generated positron emitters) and proton CT. These experimental platforms require a sustained research effort to understand the physics and biological mechanisms of absorbed radiation dose at the cellular level and their effect on patient outcomes, particularly in the case of heavy ion therapy. Australia is well placed to tackle these challenges with its strong track records in medical physics and radiation oncology. This is a natural area for collaboration between NIF and the radiation physics/oncology communities.

3.3 Small Animal Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and natural

genetic variation (Collaborative Cross) – small and large animal models: Understanding the impact of genetics is the new frontier for medical research and new therapies, but it is necessary to test hypotheses and validate therapies first in animal models. Imaging is an essential tool to demonstrate the expression of the genetic change, to observe epigenetic effects, by which genes are switched on by their environment, and determine the benefits and timeframe of therapy, as well as potential side-effects. For this to be effective, imaging capability must be co-located with the animal breeding facilities, with appropriate Genetically Modified Organisms (GMO) control, and strict documentation capability. Going forward, it is essential that NIF more fully integrate with other national capabilities, such as APN and BPA, to provide researchers with a pipeline for research into genetic models of disease. Existing small and large animal NIF facilities are able to provide the environment and the imaging capability, although, to be internationally competitive, they will need to be kept state-of-the-art.

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The Australian pharmaceutical and biotechnology industry lacks on-shore access to a preclinical small animal molecular imaging facility with an integrated suite of imaging modalities and animal models in a GLP/ISO certified environment. A one-stop-shop offering a range of in-house animal models, multimodal imaging including MRI, PET/CT, PET/MR, ultrasound/photo-acoustics, fluorescence and X-ray, radiochemistry and immunohistological capabilities would provide these services to pharmaceutical developers avoiding the need to go off-shore for access. Other NCRIS capabilities, notably TIA, could have a significant role in establishing this capability in collaboration with NIF. Access to these capabilities in Australia would reduce drug development costs and improve efficiencies in translation programs.

3.4 Large Animal The Large Animal Research & Imaging Facility (LARIF) node of NIF has an

international reputation with researchers from around the world returning to what is seen as internationally unique. LARIF is engaged with a U.S company who wants to place Scientific Interns to fast-track integration with the way in which preclinical studies are planned and managed by the private sector. They have chosen LARIF because of the comprehensive integrated Imaging and Experimental Physiology/Surgical expertise and ISO 9001 (2015)/OECD GLP recognition. Furthermore, access to existing transgenic sheep, an interest in neurodegenerative diseases and the ability to assess neurodegeneration using imaging and large animal behaviour testing draw international researchers to Australia. To maintain that status, NIF must constantly review the infrastructure and recommend new technology and renewal of existing. And being part of NIF, LARIF can rely on the imaging expertise provided through the network. LARIF has been identified by TIA as part of the Australian Therapeutic Pipeline.

NIF is aware of a bold plan to establish a germ-free facility for large animals, to extend microbiome research from rodents to large animal models, which better reflect human biology. This is an area in which Australia would not only be world-class, but a world leader. Co-located imaging capability will be essential to such a facility.

An example of the benefits of NIF’s large animal capability is its use in the assessment of regional lung function and health. Australian-designed technology is already being trialled in lung cancer and respiratory diagnostics, for early detection and treatment outcome monitoring. The methods are even more suited to deeper-level lung disease research in medium and large animal models, from rabbits to pigs and sheep, and will provide an ideal advanced, multi-user capability that integrates perfectly with the current and expected services provided by LARIF.

3.5 Human There is much more that can be extracted from existing MRI hardware by

programming new sequences and making available advanced analysis methodology. Appropriately resourced, NIF could provide domain specific expertise in advanced analysis methodology, and application of emerging MRI sequences, increasing the value of the infrastructure.

While 3T MRI may be perceived as a backbone technology, further development of its capabilities is crucial to make the most of a widespread and successful technology. 3T MRI remains one of the most rapidly developing imaging modalities in the research setting and NIF's network of high-end 3T MRI facilities positions it to offer a network of research-ready, QA attuned systems for multi-site trials. These 3T sites also contribute internationally to stretching the frontiers of 3T MRI capability with unique expertise in diffusion MRI (Florey), spectroscopy and magnetic resonance elastography (UNSW), translation of ultra-high field

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capabilities (UQ and Florey), cognitive neuroscience (Swinburne), large animal model translation (LARIF) and multi-modality imaging including co-location with the Australian Synchrotron Imaging and Medical Beam Line (Monash). MRI is constantly evolving, different images can be obtained by re-programming the scanner. e.g. Quantitative MR fingerprinting, fast functional imaging and diffusion sequences have recently become available as research sequences and cannot be installed on hospital scanners. Furthermore, there are advanced imaging protocols that require extensive post-processing and expert analysis to utilise – the highly expert human resources that form part of the NIF infrastructure facilitate this national service, which is simply not available in hospital MRI departments.

To maintain our international leading edge and preserve our ability to participate in global research collaborations, including sharing of works-in-progress sequences for MRI (which requires up-to-date hardware), NIF will constantly review equipment needs, and recommend new technology and upgrades to and/or renewal of existing.

There is a large external user base for 3T MRI research capability in Australia that is serviced by NIF. Specialised activity is occurring at all our sites for national benefit, including developments being translated to clinical 3T MRI via industry collaborations.

The recently installed Ultra-High Field (7T) MRI, NIF flagships, supported by EIF, are far from routine clinical devices. This is not simply due to cost, but the physical principles of working at 300MHz, that make imaging far more difficult. But the rewards are great, in the increased signal-to-noise, resolution and new contrast mechanisms, which open whole new directions for research. As above however, maximal value from these instruments requires sufficient human resources and timely incremental hardware upgrades.

3.6 Infrastructure for the Medical Research Future Fund The Medical Research Future Fund has been established to address the big health

issues for the Australian society. These research programs will need integrated and connected capability, to enable translation that makes a difference in the health of people and the communities in which they live. Translation may start with animal models, involve the development or validation of new diagnostic tools, and result in the discovery, development and production of new therapies. In every step imaging is a key tool. If such studies are to be coordinated across the nation, and if they are to deliver evidence that can be used to commercialise and ultimately get regulatory approval, connectivity is not enough. For effective national studies, there needs to be QC systems, common protocols, data sharing, pooled data analysis and systems to link imaging data to other clinical and demographic data, while maintaining patient privacy, data integrity, and protection of IP.

a) Coordinated network: This will enable multi-site research, with confidence that data from all sites are comparable, with harmonised protocols and common QC procedures.

b) Accreditation The NIF Board has committed to all nodes developing QC processes and becoming accredited under GLP and NATA.

c) Connected Such a research environment does not develop organically, it needs to be deliberate, targeted and planned. Furthermore it needs to be linked to other capabilities, such as genomics, phenomics, metabolomics. It needs to be part of a development pathway, as may be delivered through the Australian Therapeutic Pipeline.

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4. Environment & Agriculture Theme

4.1 Species diversity Museums and Australia’s wildlife collections often have single specimens of organisms

that are either rare or extinct, for which detailed dissection is not an option. MRI and CT are both being used to produce cross-sectional and 3D images of the whole organism.

In a project with Atlas of Living Australia, imaging is being used to study small changes in species, as a result of changes in the environment. These could be natural climactic changes or man-made effects. These effects provide important information on the effect of industrialisation on the ecosystem and support development of policy and practices to minimise harm to the environment.

4.2 Environment: At the UWA node of NIF, the preclinical MRI is answering important questions about

desalination membrane systems and liquefied natural gas recovery, supporting the ARC Industry Transformation Training Centre for Liquefied Natural Gas Futures.

4.3 Agriculture 4.3.1 Plant phenomics: Most studies of growth in new plants is through external photography. Imaging provides an opportunity to measure the internal processes, and has been used for measuring movement of nutrients, an important factor in development of drought resistant species. Root development is of significant interest in the development of new varieties, using conventional cross-breeding or gene-editing, such as CRISPR. Imaging capability needs to be made available to plant phenomic researchers across Australia, potentially in close proximity to the Australian Plant Phenomics Facility.

4.3.2 Plant diseases and environmental effects: Imaging in agricultural research is an emerging field allowing non-destructive analysis of growth, ripening and disease processes. Existing imaging technologies have opened new avenues for plant research and play an increasingly important role in understanding plant development and disease. Imaging is being used to better observe the development and effect of parasites within fruits, or damage due to excessive rain, or rain at a critical time in growth, which has been of particular interest to the NSW Department of Primary Industries, National Wine & Grape Industry Centre who have long-term projects and collaborations with the NIF capability at Western Sydney University (WSU).

4.3.3 Path to market: For fragile fruits, such as avocados, imaging can be used to track damage to fruit from picking to serving. This has a major impact on both domestic and export markets, and findings in this type of study can be used to optimise time of picking, storage conditions and handling processes.

Materials Theme

5.1 Radiopharmaceutical Therapy and Theranostics Radiopharmaceutical Therapy uses high-energy therapeutic radiopharmaceuticals to

target and combat diseased tissue. This requires the development of new materials to target

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specific binding sites and deliver a therapeutic dose. Imaging is a key tool for monitoring the targeting and the effectiveness of radiopharmaceutical therapy.

Theranostics involves development of new therapies and building therapeutic agents into the same agents as used for diagnosis. This is where the Health and Materials themes join force. The use of diagnostic radiotracers, such as labelled Antibodies, nanoparticles and cells that also have the ability to carry a therapeutic payload is an important emerging area which we believe will become a major complement to our treatment armamentarium in cancer over the next 5-10 years. This is a highly inter-disciplinary area of research in which Australia has an excellent track record. As well as specialised radiochemistry expertise and collaborations with nanoscientists, immunologists and cell biologists, medical physics expertise is critical to ensure accurate personalised dosimetry and research into radiation effects at the sub-cellular level. The national dosimetry service NIF proposes is a critical component of this vision. Radiopharmaceutical therapy and theranostics require GMP capability. This area is ripe for academic/industry collaboration, and the earlier in the development cycle the more effective will be translation to clinical trials and practice.

5.2 Contrast Agents The NIF capability at WSU has state-of-the-art chemistry facilities, soon to include

Australia’s only fast field cycling relaxometer for characterising molecular relaxivity, and pre-clinical imaging for measuring the in vivo effect, all available to chemists from across Australia. With expertise in the synthesis and development of MRI contrast agents with probing hypoxia being a particular focus, WSU is in a position to contribute a broad theoretical and experimental expertise and act as a hub for the development of novel contrast agents and exploitation of new endogenous contrasts.

6. Data Management

NIF has, since its inception, argued for the importance of Research Data Management. In addition to discoverability and accessibility, data must be correctly credentialed, and access strictly governed by ethics and legislative considerations. NIF, through collaboration has developed tools to enable data to be transferred from “instrument to repository”, with appropriate credentials and access permissions, using AAF credentials. These tools need to be further rolled out.

Furthermore, imaging analysis tools are developing rapidly and, given the multidisciplinary nature of most imaging research, it is inappropriate to expect that all researcher disciplines, which take advantage of imaging will be able to critically evaluate and apply the most appropriate imaging analysis methods. This is where domain-specific facility and informatics expertise work together to ensure optimum outcomes for research users.

The greatest emerging need for NIF, and presumably all research involving human data is to facilitate data use and re-use within the legalities of human data storage and sharing.

NIF has collaborated with all three eResearch capabilities, building tools to improve the integration of data solutions. Whilst NIF very much values the power of the eResearch solutions, there must be more investment in domain specific knowledge, to ensure that the solutions meet the needs of different domains, and promote and provide training to the users in those domains to maximise uptake. There remains a cultural divide between researchers and the eResearch community, in that researchers are not confident in the provider’s ability to maintain and protect their data. Many researchers feel more secure, having “control” of their own data, be it a lab-based server or USB drives in their desk drawer. They are often unaware of the life of the media, or changes in technology that may render the media

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useless in 10 years. Data is also stored in an adhoc way, such that re-finding it can be very time-consuming. There needs to be far more education about data management plans, along with long-term certainty for an Australian data storage repository. We are working with ANDS and RDS to develop the Trusted Data Repository, which we believe will become the primary storage. Such trusted data environments are essential for industry uptake of capability.

7. Access

7.1 Principles Merit should be the main criterion in areas where Australia has strengths and where

new capabilities can be leveraged. Merit is defined in terms of academic output, publications, citations, academic collaborations and invitations. These are all important for basic science, and to build the reputation of the nation. National infrastructure must also address strategic needs of the nation. Requirements for the development of expertise in areas where Australia does not have a strong reputation can be a basis for access in these areas. National Infrastructure should become, to a greater degree, an incubator for introducing new technologies, or new applications for existing technologies into Australia, and provide training to develop industry prepared graduates.

7.2 Cost NIF supports the model of recovery of marginal costs from the users. But it is beyond

the capacity of the existing research funding mechanisms to meet the sunk costs of capital and maintenance and sufficient expert staff to facilitate optimum skilled use of the equipment and the acquired data. NIF is strongly of the opinion that these costs need to be met through the national infrastructure such that access costs are well within the scope of ARC and NHMRC and that postgraduate students and early career scientists are not disadvantaged.

Some consideration should be given to the provision of a limited amount of funding for proof-of-concept and pilot studies, as obtaining competitive grant funding without preliminary data is currently extremely difficult. These rates should be within the scope of internal organisation seed grants and philanthropic seed grants. Mechanisms could be developed, whereby at short notice, a limited amount of unused instrument time can be accessed at a reduced rate, for pilot studies.

Large industry users doing commercial research, with a strong potential for commercial returns, should be asked to pay whole-of-cost for access. Experience shows, in the NIF context, that such costs are beyond the reach of most small to medium enterprises and start-up. They do not yet have the cash-flow to support innovation at full-cost. Mechanisms, such as Tech Vouchers should be integral to the research infrastructure system to encourage SME engagement with the academic sector, and make use of the national research infrastructure. Australian SMEs can often take their research to places like Singapore or the Netherlands at lower cost, resulting in loss of that innovative pathway to the Australian community and economy.

8. Training

Development of further skills and maintenance of the existing are essential to a healthy research infrastructure. Whilst always key to the mission of NIF, this view was confirmed at the recent Global BioImaging (GBI) meeting in Heidelberg, where the development of the workforce was identified as the number one priority for the planning of an international collaborative imaging infrastructure. NIF is collaborating with EuroBioImaging to develop a series of courses in both collaborative infrastructure, and instrument skills development and

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has been invited to participate in the international workshops of GBI, both as instructors and participants.

In turn those fellows collaborate and train facility users to the level required to optimally perform their research using the advanced imaging equipment. RHD students across a wide range of disciplines in physics, mathematics, chemistry, advanced technology, image analysis and data modelling are key beneficiaries of the expertise within the capabilities.

In collaboration with specialty colleges, national research infrastructure can provide training to physicians, technologists, physicists, radio-chemists, informaticians, mathematicians, and research managers.

National research infrastructure can and should assist by integrating with other funding schemes that support postgraduate and ECR training, such as ARC ITTC. For example, while ARC ITTC provides the funding for PhD scholarships and postdoc fellowships, NCRIS provides the high end physical infrastructure (with a national reach) on which these people gain world class training.

The proposed national radiochemistry training scheme will leverage the training, education and accreditation program (TEAP) recently established by the Australasian College of Physical Scientists & Engineers in Medicine (ACPSEM) which provides the educational and accreditation framework for radiochemistry. Currently, there are only a small number of funded radiochemistry registrar training positions; 6 funded by Commonwealth Department of Health and 4-5 by NSW Health over the next 5 years. These numbers are too small to meet the needs of the clinical and research communities. Consideration should be given to additional training positions, funded through National Infrastructure to fill this critical infrastructure gap.

A further opportunity for training is to embed synthetic chemistry PhD students into industry partners. This will not only address the shortage of trained radiochemists, but lead to better collaboration between industry and academia.

9. Technologies of the Future

9.1 Explorer PET: Whilst current imaging infrastructure meets most researcher requirements, some of the

big challenges in metabolic disorders and psychiatry require the ability to capture radiotracer kinetics in all tissues of the body simultaneously and to answer questions on multi-organ disease and the brain-gut axis such as: How does the brain regulate nutritional state in health and pre-diabetes? How does signalling between the gut microbiota and brain affect behaviour, cognition and mood? These questions cannot be addressed with current PET/CT or PET/MRI technology which are designed for single organ imaging. There is an opportunity for Australia and NIF to take a lead in this space internationally by joining the EXPLORER consortium (http://explorer.ucdavis.edu). This consortium is developing a whole body PET system that will enable the simultaneous measurement of kinetics in all tissues of the body and it will do so at more than 40 times the sensitivity of current PET systems, enabling micro-dosing studies (<0.2 mSv effective dose). This addition to the national infrastructure would be transformative. It would leverage the excellent existing radiotracer capability while enabling researchers to answer challenging questions of national significance and opening up opportunities to study new cohorts with PET, such as paediatrics and non-patient populations (e.g. prodromal syndromes in mental health and diabetes).

http://explorer.ucdavis.edu/

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9.2 Atomic Clock imaging Atomic clocks have the most accurate temporal and frequency information available.

Modern neuroimaging has provided us with an increasing knowledge of the working human brain via MRI, MEG and PET. MEG, in particular, has been important in providing temporal characterisation, which has been important in understanding cognitive processes, especially within psychiatric and neurological disorders. Atomic magnetometry has seen rapid progress over the last decade with prototypes showing improved sensitivity in comparison to standard MEG. Such advances are important within the field as such equipment has the potential to a) be simpler and less costly to operate, b) show improved temporal characterisation and c) lead to greater insights into the working human brain.

9.3 Image guided high intensity focused ultrasound (HIFU): Image-guided high-intensity focused ultrasound is an innovative therapy that permits

targeted thermal ablation while minimising damage to surrounding tissue. Most applications to date have been in oncology in the body. MRI-guidance is essential in potential neurosurgical application, where there is considerably less margin for error. MRI guidance provides the essential depiction of anatomic detail and real-time thermometry during thermo-ablation sessions.

10. Stakeholders & Impacts

NIF contributes to increasing Australia’s attractiveness to global industries as a high-performing R&D platform. By associating technology platforms, expertise, and interdisciplinary practices in complex environments and by collaboration with other national capabilities such as AMMRF and BPA, we build a comprehensive and coherent network of capabilities dedicated to the development, characterisation and validation of complex new products in Health, Materials, and Agriculture & Environment, for:

a) Industry: Highly reliable (compliant, standardised) and flexible system of capabilities – increase attractiveness and deliver on jobs,

b) Research: Specialised world-leading imaging research precincts/nodes – increase innovation and research outcomes’ quality

c) Government: Translation of expertise to utility via national deployment of training, products or protocols, especially in Health (but also in other fields) – savings in health system

d) Education Develop next generation of researchers and attract international students (with resultant economic gains)

By developing specific complementary strengths in each node, we maintain world-class research and expertise in the field.

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Submission to 2016 National Research Infrastructure ... · in national research infrastructure? NIF has only been able to deliver a national capability through significant co-contributions