2016 national research infrastructure roadmap capability issues … · 2016-11-08 · 2016 national...

2016 National Research Infrastructure Roadmap Capability Issues Paper

Name NNNA steering committee on behalf of NNNA Prof Ian Brereton (UQ) Prof Caroline Rae (UNSW) Prof Gottfried Otting (ANU) Prof Paul Gooley (UMelb) Prof Glenn King (UQ)

Organisation National NMR Network Australia

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

The capability focus areas identified effectively cover most research sectors that contribute to the

National Science and Research Priorities and underpin the National Innovation and Science Agenda.

However, the range of key platform technologies currently supported by NCRIS that enable major

research programs across the capabilities is too narrow. Identifying new areas of research

infrastructure that are currently lacking as national facilities is an important consideration for

enhancement of Australia’s future research and development outcomes.

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, provides a mechanism for open access,

minimises duplication, facilitates fundamental and applied research in the public and industry

sectors, and allows strategic planning for growth and renewal. The governance framework adopted

by a national facility should be appropriate for the distributed nature of the infrastructure and

ensure that, in the event of national defunding, there are opportunities for the facilities to remain

available and operational within the research sector.

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

international facilities?

Investment in Landmark facilities with narrow reach and high operational costs should be

considered carefully in terms of the flow-on impact upon the nation’s capacity to support other

more broadly applicable technologies. Where appropriate, assistance for access to international

facilities could be considered to enable high-end research and establishment of a case for demand.

Question 4: What are the conditions or scenarios where access to international facilities should

be prioritised over developing national facilities?

Where assessment of the cost benefit and local demand for technologies is insufficient, and if local

expertise is not available to enable optimal utilisation of the technology.

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

The NCRIS experience, 2011 National Research Infrastructure Roadmap and other subsequent

research infrastructure reviews have all strongly acknowledged the essential nature of expertise

and human capital in providing effective utilisation of research technology and the development of

a local skills base through training. Critical to the success of NCRIS, both in the past and future, is

the expertise offered through Facility and Informatics Fellows. Optimising outcomes from the

utilisation of national research infrastructure is only possible if highly trained experts are available

for consultation on all aspects of experimental design, protocol development, data analysis and

interpretation and subsequent translation of outcomes. These personnel should be considered as an

essential component of research infrastructure fabric.

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

Cutting-edge research infrastructure attracts world class scientists to the country and helps retain

the brightest minds. This capability creates an environment conducive to internationally

competitive research and innovation within which training of early career researchers and RHD

students can flourish. These students will be exposed to a highly dynamic research environment

and will be influenced and mentored by world leading researchers, an ideal preparation for future

skills development in the utilisation of modern instrumentation and the ability to translate their

research to new areas.

Question 7: What responsibility should research institutions have in supporting the development

of infrastructure ready researchers and technical specialists?

Institutions provide a collegiate and nurturing environment for students and researchers, including

access to a breadth of research infrastructure from basic to advanced technology acquired for

primarily local use through infrastructure grant schemes such as LIEF. Access to high-end

infrastructure and expertise networks allows specialised training programs to be offered nationally

by host institutions.

Question 8: What principles should be applied for access to national research infrastructure, and

are there situations when these should not apply?

Access by both the academic and industry sectors should be governed by equitable merit-based

principles that encourage:

i) Research excellence

ii) Opportunities for exploratory research, innovation and proof-of-concept

iii) Translation of outcomes, methodologies and IP to enhance the socio-economic benefit

iv) Training of the next generation of researchers

The cost of access to users has to be at levels within the scope of funding by granting agencies, ARC

and NHMRC in particular. Charging models should be based on marginal cost recovery – nationally

supported operational funding is crucial in reducing access costs further.

Question 9: What should the criteria and funding arrangements for defunding or

decommissioning look like?

Cessation of funding support for national facilities should only occur once the infrastructure

concerned is out dated or superseded by another emerging technology, or is assessed to no longer

be providing adequate service or quality outcomes. Sufficient wind-down time must be

incorporated to allow adequate time for job transfer by staff.

Question 10: What financing models should the Government consider to support investment in

national research infrastructure?

The initial capital and ongoing operational funding should provide for leveraging co-contributions

from institutions and state governments to maximise opportunities for research infrastructure at

the highest possible level and to invoke true national commitment. The Government should avoid

consideration of loan financing mechanisms as experience has shown these are not sustainable in

the research market.

Central to the success of the NCRIS program to date has been the in-kind contribution of existing

facilities providing complementary technology and expertise, a training ground for progression to

higher level technology and increased capacity. Access to these facilities is open to all researcher in

line with NCRIS principles and operational costs of this contributed infrastructure should be

supported.

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

requirements?

Standard or accredited operation in research not just in analytical services but across all forms of

research practise is becoming increasingly important to ensure reproducibility and reliability. This is

especially important in the provision of research services to industry but beneficial to all research

programs. The standards implemented may vary appropriately according to the role of the facility

but consideration should be given to funding implementation of standard practises such as GLP or

ISO accreditation within national capabilities.

Question 12: Are there international or global models that represent best practice for national

research infrastructure that could be considered?

World class facilities attract international interest and global networking is crucial to fostering

international collaboration, ensuring emerging research directions can be supported, raising the

profile of Australian research and providing access to international funding schemes. Membership

of international organisations such as EMBL and the Euro-Bioimaging Consortium are examples of

initiatives that have allowed exchange of knowledge and experience and provide frameworks for

collaboration. The NCRIS model has been recognised as internationally leading in the provision of

research infrastructure.

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?

Many technologies have a natural lifecycle that ends with emerging improved or alternative

technologies. Decline in demand and reduced productivity characterise this stage and regular

strategic assessment of national facilities should be undertaken to identify underperforming

infrastructure. This is separate to the issue of the need for decommissioning for replacement or

upgrade of existing technologies which is also an important aspect of maintaining Australia’s

competitive advantage in research areas that it leads.

Question 14: Are there alternative financing options, including international models that the

Government could consider to support investment in national research

infrastructure?

See 10 above.

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?

Structural biology is correctly identified as a priority in health and medical sciences underpinning

major programs in drug discovery, but this needs to go beyond X-ray crystallography on the

Australian synchrotron and beyond electron microscopy. Specifically, structual analysis of proteins by

nuclear magnetic resonance (NMR) spectroscopy has gathered pace over the past 10 years outside

Australia. In particular, in the field of ordered phase and insoluble proteins such as integral and

peripheral membrane proteins and heterogeneous non-crystalline protein assemblies involved in

neurodegeneration and pathogenesis (eg amyloid fibres involved in Alzheimer’s disease) . Dynamic

nuclear polarization (DNP) technology now routinely delivers 20-fold enhanced sensitivity in solid-

state NMR experiments and up to 80-fold sensitivity enhancements.

NMR spectroscopy is emerging as an essential tool for metabolomics of body fluids: ‘omics’ is not

only DNA sequencing or mass spectrometry. NMR spectroscopy has emerged as a key technology

together with mass spectrometry in the study of metabolism and Metabolic Phenotyping. Support for

dedicated, integrated high-resolution NMR metabolomics facilities would spearhead NMR-based

phenotyping as a low cost, efficient and comprehensive approach to generating metabolite data at

the population level to advance metabolic understanding, medical diagnosis, therapies and

personalised medicine. Closely aligned with this technology is drug design by fragment-based

screening, which is growing in capacity in Australia and benefiting from nationally available

compound libraries proved by Compounds Australia.

The emerging interest and capability in NMR-based metabolomics in Australia demands a nationally

collaborative approach to develop an integrated and comprehensive capability that would provide

significant benefit in complementing existing services within Metabolomics Australia, impacting the

health, veterinary, agriculture and food and wine industries. In addition, a national capability would

support the Western Australian Metabolic Phenotyping Centre (WAMPC) program which is in the

early stages of delivering broad-scale capabilities in targeted and exploratory metabolic

phenotyping. WAMPC will involve national and international partners and will become a member of

the International Phenome Centre Network (IPCN), directed through Imperial College London, UK.

Question 16: Are there any international research infrastructure collaborations or emerging

projects that Australia should engage in over the next ten years and beyond?

Strategic involvement with key international institutes and research centres is important for both

the Australian NMR and wider community to develop new collaborations, share best practice and

maintain links with research frontiers. From within Australia, EMBL-Australia has the ability to

drive, expand and forge new links beyond its existing strategic alliances in Europe and beyond.

Opportunities exist to build upon existing engagement with a number of major national NMR

facilities, such as the US National Magnetic Resonance Facility at Madison, USA, and the newly

opened Francis Crick Institute in London, UK. This new medical research centre is also an

infrastructure hub for state-of-the-art technologies and houses the UK MRC National 950 MHz NMR

facility.

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?

Environment and Natural Resource Management


Environment and Natural Resource Management right? Are there any missing or

additional needed?

Metabolomic NMR is emerging for targeted and exploratory phenotyping in medicine but

is also gaining traction across biological, biochemical and bioprocessing applications of cell

growth, systems biology and the production and quality control of biopharmaceuticals.

Additionally, applications of NMR to study metabolism are emerging within key research

areas including agriculture, livestock production and environmental sciences.

Agrichemical development: Australia is playing a leading role in the development and

commercialisation of eco-friendly peptide-based bio-insecticides. Structural biology plays

an essential role in elucidating the structure and mode of action of these peptides.

However, only NMR spectroscopy is suitable for this purpose as these peptides are much

smaller than the lower mass limit for cryoelectron microscopy and they are typically not

amenable to X-ray crystallography.




for the Environment and Natural Resource Management capability area?

Advanced Physics, Chemistry, Mathematics and Materials


Advanced Physics, Chemistry, Mathematics and Materials right? Are there any

missing or additional needed?

NMR spectroscopy has, for some time, been the most powerful and versatile analytical technique in

synthetic chemistry. Beyond traditional applications, massively enhanced sensitivity achieved with

dynamic nuclear polarisation (DNP) technology allows characterisation of the surface of solid-state

catalysts, while solid-state NMR has become an important tool in battery development and NMR

spectroscopy has become critically important for characterisation of ionic liquids. The

characterisation capability of NMR spectroscopy is essential for driving the forefront of chemistry and

materials science.



The unusual breadth and variability of applications of NMR spectroscopy means that best results

can only be obtained with hands-on expertise. Data recording and sample preparation need to go

hand-in-hand, making access to overseas facilities inefficient and impractical in most cases.

However, national high-field NMR facilities (including DNP and solid-state capabilities), however,

have been successful and are already available in the UK, France, Germany, Netherlands, Italy (EU);

NHML in the USA; and many other institutions in the USA, China, Japan, Korea.


for the Advanced Physics, Chemistry, Mathematics and Materials capability area?

Understanding Cultures and Communities


Understanding Cultures and Communities right? Are there any missing or additional

needed?




for the Understanding Cultures and Communities capability area?

National Security


National Security right? Are there any missing or additional needed?




for the National Security capability area?

Underpinning Research Infrastructure


Underpinning Research Infrastructure right? Are there any missing or additional

needed?

Magnetic resonance spectroscopy is a ubiquitous enabling technology that underpins research in

the molecular and material sciences across chemistry, biochemistry and physics. The technique

provides a toolkit that allows the study of structure, function, dynamics and interaction at the

molecular level in an integrated, comprehensive approach to understanding the fundamental basis

of life, materials and matter. NMR contributes unique capabilities in structural biology,

metabolomics and smart materials development. NMR can be used to probe the interactions

between molecules, the physico-chemical properties and structure of solid materials, the

composition profile of complex chemical and biochemical mixtures and the time evolution of

biochemical and chemical processes. NMR has evolved into an essential element of the

characterisation and analytical phase of molecular-based problem solving and design, providing

insight into the molecular basis of biological function and disease, characterization of porous media

and novel functionalised nanoparticles for theranostic application; in this way NMR greatly

facilitates the development of new diagnostic tools, pharmaceuticals, catalytic materials and

agrichemicals. The technology should be considered as Underpinning Research Infrastructure.

Development of an integrated national facility providing technology and expertise to support

advanced Australian research in these areas would significantly enhance research outcomes and

innovation in this country.




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?

While there has been significant investment in both data storage and management and high

performance computing, there is a lack of integration of the two and ease of access by the research

community generally. Data curation needs to be seamless and require minimum effort by researchers

who generate it. On-line data analysis tools must be able to access stored data directly for efficient

processing.

A national NMR network would provide an open access model and provide facilities for data sharing

in particular in data processing and analysis as current expertise is too widely distributed across the

country. The potential exists to connect the existing CVL system on NECTAR with the US led NMRBox

initiative to create a virtual box with all existing NMR software.




for the Data for Research and Discoverability capability area?

Other comments

If you believe that there are issues not addressed in this Issues Paper or the associated questions,

please provide your comments under this heading noting the overall 20 page limit of submissions.

The Issues Paper does not address the imminent loss of existing research expertise and capabilities in

areas that are not currently supported by NCRIS funding. This is particularly evident in the field of

NMR spectroscopy, where overseas research centres are being expanded and upgraded at a rapid

pace and are attracting researchers from Australia. For example, there are currently nine orders from

within Europe for 1.2 GHz NMR systems (ca US$15 million), and four 1 GHz systems (ca US$10

million) have already been installed worldwide. In contrast, there is only a single 900 MHz NMR

spectrometer in Australia. Furthermore, about half of the contributions at recent international NMR

conferences are in solid-state NMR, a capability Australia must invest in significantly to gain

international competitiveness and leverage Australian expertise.

The primary reason for the difficulty to maintain international competitiveness of the Australian NMR

community lies in the expense of funding cutting-edge NMR equipment, which has become too

expensive for ARC funding schemes. Without easy access to internationally competitive equipment,

the Australian NMR community will lose the capability to attract excellent researchers, and therefore

lose critical expertise. This will impact a wide range of research fields. Aware of these threats, the

Australian NMR community has established a network of key facilities, the National NMR Network

Australia (NNNA), to develop a framework for sharing of equipment and knowledge. While this

provides a basis for national collaboration in NMR, it does not address the challenge of funding for

world-class infrastructure and expertise.

The Australian National NMR Network should be supported in a ‘hub-and-spoke approach’, where

regional spokes have access to current routine spectrometers to pump-prime and develop projects

that gain traction and research funding for subsequent support involving National Centres of

Excellence in solution-state and solid-state NMR. This model provides an efficient use of resources

whilst developing centres specialising in one or more applications such as Biological, Metabolomic,

Solid-State, Biopharmaceutical and Chemical NMR spectroscopy. The current International level of

expectation in NMR expects Centres of Excellence to operate spectrometers at 950 MHz or above,

with the new leading edge instrumentation being 1.2 GHz with cryogenic probe technology.

The following submission is presented by the Australian NMR community as a recommendation for

the establishment of a national NMR capability, comprising of existing networked infrastructure and

future investment in flagship NMR facilities.

A submission to the 2016 National Research Infrastructure

Roadmap Capability Issues Paper

Nuclear Magnetic Resonance (NMR) spectroscopy is a key enabling technology that underpins a

wealth of research in the molecular and material sciences. NMR spectroscopy provides a toolkit

that allows the study of structure, function, dynamics and interaction at the molecular level in an

integrated, comprehensive approach to understanding the fundamental basis of life, materials and

matter. The NMR phenomenon, which arises from the interaction of a nucleus with radiofrequency

energy within a strong magnetic field, produces a signal that is rich in information about three-

dimensional molecular structure, molecular motion and chemistry in solution and ordered states.

As a technology complementary in nature and capability to cryo-electron microscopy and X-ray

crystallography, NMR can probe the interactions between molecules, the physico-chemical

properties and structure of solid materials, the composition profile of complex chemical and

biochemical mixtures and the time evolution of biochemical and chemical processes. NMR has

evolved to be essential for the characterisation and analytical phase of molecular-based problem

solving and design, providing insight into the molecular basis of biological function and disease,

characterization of porous media and MRI contrast agents and in this way informs the

development of new diagnostic tools, pharmaceuticals and agrichemicals.

Inclusion of NMR spectroscopy in Australia’s next Strategic Roadmap for Research Infrastructure

as a substantial National Facility supported by significant investment is crucial to maintaining this

country’s international standing at the forefront of molecular, biomolecular and medical science,

in particular, in the following four areas of strength:

Materials science, catalysis, ordered biomolecules: transmembrane proteins, porous media,

catalytic surfaces, biomaterials, nanotechnology, diffusion

Biomolecular structure, function and dynamics: proteins, DNA and RNA, drug discovery and

screening

Metabolomics: metabolic profiling, systems biology, metabolic phenotyping, diagnostic tools,

toxicology

Advanced molecules and chemistry: chemical characterisation, smart molecules, natural

products, nanotechnology, multimodal molecular imaging probes

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NMR in Australia Today

NMR instrumentation for the analysis of molecules is ubiquitous in research institutions and the biotechnology and fine chemicals industries throughout the world. There are over 100 spectrometers currently installed in Australia with a capital value of approximately $120 million. Operating frequencies vary from the routine 300 - 600MHz to a single ultra-high field 900 MHz spectrometer. The associated capital cost of NMR instruments increases exponentially with field strength from a few hundred thousand dollars to over $20 million for a state-of-the-art 1.2 GHz system.

All extant high-end NMR facilities in Australia were funded by inter-institutional cooperative grant applications, primarily to the ARC LIEF scheme, and in the case of two major facilities at UQ and Bio21, with significant financial support from the respective State Governments. This has built a framework for an extensive array of collaborative research and infrastructure development in NMR spectroscopy. The figure below is a graphical representation of the distribution of active NMR-based research project collaborations in 2016 within 13 Australian Universities classified according to their origin from within the institution, other Australian research organisations, industry-based projects and international collaborations pertaining to the three most relevant capability areas of Health and Medical Sciences, Advanced Physics, Chemistry and Materials and

Environment and Natural Resources Management.

NNNA: Establishing a National NMR Facility

In 2009, representatives of key NMR research centres across Australia established a consortium of major and specialist NMR facilities, currently known as the National NMR Network Australia (NNNA), with a view to providing open access to existing high end instrumentation and expertise to the wider research community. The major centres at ANU, UQ, UNSW, UMelbourne and USydney contributed ultra-high field (700, 800 and 900MHz) capability together with specialist expertise and support as well as engineering personnel. Other NMR facilities that provide access to specialist capabilities are also members of the network, including Monash, UAdelaide, UWA, UWS, Deakin, QUT, JCU, Macquarie, Griffith and UTAS. In 2012, 13 key institutions executed a Memorandum of Understanding (MoU) agreeing to in-principle support for establishment of a national NMR facility. This MoU was re-affirmed and expanded in 2016 to bring the number of partners to 15. To fully harness and exploit the previous investment and the collective potential of these facilities to ensure Australia’s continuing competitiveness, it is critical that Australia develops and supports a national strategy for NMR spectroscopy.

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If Australia is to compete globally in molecular-based research in the chemical and biological sciences there must be an additional focus on taking a leadership position in the development and acquisition of new technology and expertise to operate and maintain the instrumentation and to apply the technology to leading-edge research. This can only be achieved through a coordinated national network of infrastructure, operating under a governance structure based on an unincorporated joint venture between participating institutions, and collaboration in the promotion of NMR research. The Australian NMR community has a demonstrated capacity to beneficially establish and manage a network of NMR infrastructure, including the appropriate governance, cost-sharing and cost-recovery structures.

VISION

Vision for Nuclear Magnetic Resonance in Australia

Exploit local expertise to develop international leadership in emerging technologies

Build upon international competitiveness in areas of existing strength

Drive innovative research via collaboration and development of specialist critical mass

Provide expert NMR capabilities for research and industry through openly accessible state-of-the-art NMR facilities distributed nationally as a network of complementary nodes

GOALS

The goal of NNNA is to provide state-of-the-art NMR spectroscopy for the Australian research community through a distributed network of open access specialised facilities. NNNA will operate as a nationally integrated network of nodes, contributing a range of state-of-the-art NMR instrumentation, as well as on-site expertise and specialist research facilitation enabling discovery and innovation across a broad range of the natural, physical and chemical sciences.

NNNA aims to provide:

• Access to a range of world class NMR instrumentation targeting four broad applications that underpin research in the biomedical, chemical, biochemical and material sciences;

• Complementary specialised research capabilities currently not available in Australia;

• Facilitation of user research programs via specialised expertise of dedicated professional staff;

• Development and application of novel NMR methodologies;

• Rapid exchange of new technology between international research sites and the Australian NMR community;

• A framework for enhancing international research collaboration in NMR spectroscopy through links with similar networks in Europe, Asia and the USA;

• A framework for improved education and research training in NMR science;

• Internationally competitive infrastructure to attract world-class researchers.

Timeframe

The decadal plan for the NNNA includes a five year establishment period and review.

Years 1-2: National NMR Facility is established with recruitment of key facility personnel in existing centres, procurement of metabolomics NMR equipment, planning and construction of

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flagship facility.

Years 3-5: Procurement and installation of flagship ultra-high field NMR facility – estimated lead time for 1.2 GHz is currently 5 years allowing funds savings in early years. Fully established and operational NMR metabolomics facilities.

The Future

Ultra-High Field NMR

The determination of molecular structure and function in the solid state is a rapidly growing field internationally, with the latest developments in technology allowing exciting advances in understanding how biomolecules behave in membranes and on surfaces. The attachment of catalysts to surfaces to improve catalyst separation and efficiency is of significance in the pharmaceutical and fine chemicals industries. The latest new developments in NMR spectroscopy utilizing ultra-high field (900MHz to 1.2GHz) wide bore NMR systems, with ultra-fast spinning and dynamic nuclear polarization (DNP) for signal enhancement leads to greater understanding of the structure of otherwise inaccessible proteins as well as in catalysis and next generation polymer design supporting the manufacturing industry. Physical NMR techniques including translational motion (e.g., diffusion, electrophoresis and flow) and relaxation measurements have rapidly increased in importance and Australia has played a leading role in the development of novel diffusion-based NMR to characterize microstructure of porous materials, intact blood cells and smart molecular drug delivery scaffolds. Diffusion NMR is now heavily used in a diverse range of applications from drug screening to the development of chromatographic media.

An ultra-high field NMR facility equipped with DNP would provide a unique centrepiece for a networked Australian NMR capability and re-establish an internationally competitive profile in chemical and materials characterisation.

Ultra-high Field NMR enables Transformational Research

A 2015 strategic planning workshop held in the USA on the future for ultra-high field NMR identified the following unique capabilities and transformational outcomes achievable with nationally supported research infrastructure.

i. Molecular basis of neurodegeneration

Alzheimer’s, Parkinson’s, Lewy body dementia, traumatic brain injury, and age-related vision impairments are associated with the conversion of proteins from soluble to insoluble states. UHF solution and solid-state NMR will aid the understanding and development of possible treatments for these diseases. NMR based molecular studies, both in solution and in the solid state, allow characterisation of the structure and dynamics of biomolecules, including disordered and highly dynamic proteins (IDPs), which are of central importance in neurodegenerative disorders. NMR is the only analytical method that allows study of these highly flexible biomolecules at the atomic level. The highest sensitivity and resolution afforded by high magnetic fields is required to overcome limited chemical shift dispersion and low concentration of the proteins.

ii. Energy‐related materials

Efficient, environmentally-friendly and sustainable materials for solid‐state lighting, electrochemical energy generation and storage (batteries, fuel cells, and supercapacitors), and non-precious metal automotive emission catalysts are vital to prevent depletion of natural

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resources, decrease pollution, and ultimately reduce human influence on climate change. UHF solution and solid-state NMR needs to be integrated to chemically and spatially characterise these materials.

NMR permits non-invasive, site-specific characterisation of these materials and provides unprecedented level of detail on the local structure, dynamics, and chemical transformations that occur in these systems. The dramatically enhanced sensitivity and resolution at UHF is required for detection of signals from quadrupolar nuclei and those displaced paramagnetically.

iii. Conformationally dynamic biomolecular systems systems, including low-population transient states involved in catalysis, molecular recognition and regulatory processes

A new frontier is characterisation of the structure and dynamics of minor and transient states, a capability that only NMR can provide. Spectral dispersion is critical for this technology. Direct X-nucleus (13C, 15N) detection becomes important for these kinds of systems (e.g., in per-deuterated molecules for which back-exchange of amide protons is difficult or impossible). TROSY selection (a relaxation effect optimized at 1.2GHz) is key in large and complex systems. UHF is a requirement for direct X detection because of low sensitivity of direct-X nuclear detection.

iv. Integral and peripheral membrane proteins (including receptors and transporters in signalling pathways) in native-like or native environments.

In addition to the determination of native structures, the characterization of dynamics and conformational exchange will permit the mapping of allosteric pathways, elucidation of mechanisms, and will lead to unique functional insights into critical signalling events disrupted in disease. Membrane proteins represent the majority of important drug targets, including central nervous system drugs, antimicrobials, and anti-cancer agents. These systems, because of their size and complexity, need the improved resolution and sensitivity of UHF for full characterization of their structure and dynamics in solution and in the solid state.

v. Large and/or heterogeneous non-crystalline biological assemblies

Amyloid fibres and oligomeric assemblies that are critical in Alzheimer’s and related protein deposition diseases.

Multicomponent assemblies of viral and bacterial pathogens whose properties need to be elucidated for understanding of infectious diseases.

Large nucleic acid assemblies and their alignment in the magnetic field based on magnetic susceptibility anisotropy.

These systems need UHF for increased alignment, resolution and sensitivity in order to allow thorough characterisation of their structure and dynamics.

NMR-based Metabolomics and Metabolic Phenotyping

NMR metabolomics is a robust data driven approach allowing us to classify diseases and drug treatments from biological samples. The quantitative power of NMR spectroscopy allows many metabolites to be measured simultaneously from a single sample and the “pattern” of these metabolites can be used to reveal new information about the sample population such as the response of an organism to physiological stimuli or genetic modification. The approach has been used in Australia across a wide spectrum of applications: characterisation of a malaria parasite metabolome, road transport-induced stress in sheep, laminitis in horse hoof, detection of phylloxera in grape vine, the earthworm metabolome as an indicator of soil health dietary discrimination in marsupials, detection and staging of prostate cancer, obesity and growth disorders, biomarkers for heart disease, in-born errors of metabolism, the role of γ-

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hydroxybutyrate in neurochemistry, biomarkers of chronic fatigue syndrome, and the influence of prebiotics on the gut microbiota, to name but a few.

To date the development of this capability in Australia has been localized in centres in Brisbane, Sydney and Melbourne and now in Perth via the emerging Western Australian Metabolic Phenotyping Centre (WAMPC). Data analysis and interpretation in this field requires a level of expertise not generally available within NMR centres and is a barrier to new users accessing this technology.

To harness the enormous potential of NMR-based metabolomics in Australia, comprehensive and fully integrated facilities operating under GLP and providing state-of-the-art NMR equipment, sample handling and storage and data analysis capabilities should be established in centres with existing critical mass and expertise as part of a National NMR network.

These centres of excellence could focus in complementary areas of application and would dramatically enhance Australia’s profile in metabolism research. The facilities would provide additional capability for existing metabolomics services and research initiatives including Metabolomics Australia and WAMPC.

Impact of NMR on research in Australia

NMR is an essential technology that makes significant contributions to Australian government, philanthropic and industry funded research programs aimed at advancing fundamental knowledge and discovery, and ultimately, improving the health and lifestyle of Australians. These programs are aimed at producing:

new drugs with higher efficacy and safety profiles

new diagnostic tools and prognostic indicators

new methodologies for drug discovery and

development

new NMR technologies for investigating

materials in the solid and ordered phase

new methods for controlling insect-borne

diseases such as dengue and malaria

chemical probes of biological activity

new biomaterials for drug delivery

novel polymeric materials for electrical devices

environmentally friendly insecticides

new catalysts for industrial processes

next generation energy storage technology

methods for probing porous media

novel agents for MRI and PET imaging

Safe guarding Australia from disease:

Malaria

Malaria remains one of the most widespread infectious diseases in the world today with over 300 million cases resulting in severe morbidity on the order of 1-2 million deaths. The most lethal of the parasites responsible is Plasmodium falciparum which has developed resistance to available antiparasitic drugs. There is an urgent need to develop new drug targets. NMR is being used in Australia in two ways contributing to this effort. NMR characterisation of the metabolic profile of the parasite identified over 50 compounds, informing the development of potential drug targets. NMR has also been employed to better understand the structure and function of enzymes critical to the growth of the parasite informing development of novel antimalarial drugs.

Rae and co-workers, NMR in Biomedicine: 2009, 22, 292.

Keough et al, J. Med. Chem. 2006: 49, 7479.

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Health and Medical Sciences

In the broadest sense NMR has a major role in promoting health and well-being for Australians.

Research outcomes related to these priority goals supported by NMR include:

Structure‐based drug design

Biodiscovery – mining Australia’s unique

biodiversity to produce natural drug leads

Personalised healthcare via metabolic

profiling that informs drug therapy

regimes and lifestyle management

Understanding the molecular basis of

disease

Drug discovery via high-throughput and

fragment-based screening

Advanced Physics, Chemistry Mathematics

and Materials

NMR makes significant contributions to the understanding of chemical and biological systems at the molecular level and is fundamental for characterisation of synthetic compounds in organic, inorganic, biological and medicinal chemistry.

Novel Technologies

Characterisation by NMR is a crucial step for development of smart molecules, molecular imaging probes and macromolecular scaffolds in nanotechnology. The technology has a fundamental role in structure determination for biomolecular genomics and phenomics. Australia is a world leader in the development of new diffusion-based NMR technology for the study of porous media (e.g., biological tissue, zeolites).

Advanced Materials

NMR plays an important role in structural characterisation of biomaterials, organics, nanomaterials, porous media and polymers.

Australian researchers are making significant contributions to new technology development utilizing diffusion, electrophoresis and flow in the fields of materials science and industrial chemistry. Solid-state NMR aids the development of nanomaterials, improved solar cell materials, and new battery technology to facilitate green power.

Paramagnetic NMR - a unique tool for

structure-based drug design

Fragment-based drug design presents one of the most

powerful techniques to identify small compounds that

can inhibit the activity of proteins by binding to active

sites. The success of the strategy depends on detailed

structural information - how do the fragment

molecules bind to the target protein? Companies such

as Astex Therapeutics use X-ray crystallography to do

this, but many protein crystals do not tolerate the

presence of small molecules. A NMR spectroscopic

method developed in Australia that works in solution

resolves this dilemma. Following site-specific labelling

of the target protein with a paramagnetic metal ion,

the NMR spectra of fragment molecules display

changes that contain all information necessary to

determine where and how strongly they bind, and

what orientation and structure they assume in their

bound state. The structural information allows

construction of a more tightly binding lead compound

from the known binding modes of the fragments.

Otting et al,, J Am Chem Soc, 2006: 128, 12910-12916

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These programs have important application in aspects of the petroleum industry, battery technology, transport in biological tissue and drug delivery.

Environment and Natural Resource Management

Sustainable use of Australia’s biodiversity NMR aids the biodiscovery approach to development of novel agrichemicals and pesticides; NMR is used to monitor the fate and transport of persistent organic pollutants. Protecting Australia from invasive diseases and pests

Australia is playing a leading role in the development and commercialisation of eco-friendly peptide-based bioinsecticides. Structural biology plays an essential role in elucidating the structure and mode of action of these peptides. However, only NMR spectroscopy is suitable for this purpose as these peptides are much smaller than the lower mass limit for cryoelectron microscopy and they are typically not amenable to X-ray crystallography.

NMR is utilized to determine the structure and basis of action of naturally occurring toxins with potential as agrichemicals;

Metabolomic and structural approaches have been employed as part of the drug discovery process for infectious disease such as malaria;

In the detection of chemical patterns for control of pathogens and pests, NMR is used to determine the metabolic profile of organisms;

NMR metabolomics has application in food security and quality control, for example, in the beer, wine and fruit juice industries.

Mining our natural biodiversity:

Plant Cyclotides

The cyclotides are a family of plant-derived proteins that were discovered

by Australian structural biologists to be cyclic in structure, previously

thought to be very rare in nature, and have a diverse range of biological

activities, including uterotonic, anti-HIV, antimicrobial, and insecticidal

activities; the latter suggests their natural function lies in plant defence.

Individual plants express suites of 10–100 cyclotides. Cyclotides

comprise ~30 amino acids, contain a head-to-tail cyclised backbone, and

incorporate three disulfide bonds arranged in a cysteine knot topology.

The combination of a knotted and strongly braced structure with a

circular backbone renders the cyclotides impervious to enzymatic

breakdown and makes them exceptionally stable. NMR spectroscopy

played a crucial role in the structural characterisation of these potentially

important natural products, understanding their evolutionary

relationships and their applications in drug design.

Craik, Toxicon 2010: 56, 1092-1102 ; Science 2006: 311, 1563-1564

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