Download A submission to the 2016 National Research Infrastructure

2016 National Research Infrastructure Roadmap
Capability Issues Paper
Name
Organisation
Question 1:
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)
National NMR Network Australia
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)
ii)
iii)
iv)
Research excellence
Opportunities for exploratory research, innovation and proof-of-concept
Translation of outcomes, methodologies and IP to enhance the socio-economic benefit
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 solidstate 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
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?


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.
Question 19: Are there any international research infrastructure collaborations or emerging
projects that Australia should engage in over the next ten years and beyond?
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?
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.
Question 22: Are there any international research infrastructure collaborations or emerging
projects that Australia should engage in over the next ten years and beyond?
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.
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?
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 25: Are there any international research infrastructure collaborations or emerging
projects that Australia should engage in over the next ten years and beyond?
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 28: Are there any international research infrastructure collaborations or emerging
projects that Australia should engage in over the next ten years and beyond?
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?
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.
Question 31: Are there any international research infrastructure collaborations or emerging
projects that Australia should engage in over the next ten years and beyond?
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?
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.
Question 34: Are there any international research infrastructure collaborations or emerging
projects that Australia should engage in over the next ten years and beyond?
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?
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 threedimensional 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 Xnucleus (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.
Safe guarding Australia from disease:
These centres of excellence could focus in
Malaria
complementary areas of application and would
dramatically enhance Australia’s profile in
Malaria remains one of the most widespread
infectious diseases in the world today with over
metabolism research. The facilities would provide
300 million cases resulting in severe morbidity
additional capability for existing metabolomics
on the order of 1-2 million deaths. The most
services and research initiatives including
lethal of the parasites responsible is
Plasmodium falciparum which has developed
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
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.
16
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
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
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.
17
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
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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