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Integrated Structural Biology Infrastructure

Final Report Summary - INSTRUCT (Integrated structural biology infrastructure)

Aims of INSTRUCT
INSTRUCT will provide researchers with access to state-of-the-art structural biology technologies and expertise. By driving innovation at the boundary between technologies, it will stimulate and facilitate research that integrates an understanding of biological structure with cellular function and tackles challenging questions that are otherwise not easily addressed. Equipment at the cutting-edge of structural biology is increasingly expensive to build and maintain and no European country possesses such equipment and expertise in all structural biology technologies. INSTRUCT will enable its members to access this equipment and expertise through a dynamic, sustainable, infrastructure distributed across Europe.

- What will INSTRUCT consist of?
- Member States (MS) directing scientific strategy through representation on the INSTRUCT council.
- A dynamic distributed infrastructure of centres of excellence open to external users, driving technical innovation, and changing over time as technologies and scientific opportunities evolve.
- A streamlined central INSTRUCT hub for coordination and management.

- What will INSTRUCT deliver?
Over the first five years INSTRUCT will:
- provide peer-reviewed access, with coordinated funding, to state-of-the-art structural biology infrastructures and expertise for researchers in academia and industry, expanding the portfolio to encompass major providers of access to structural biology infrastructures (including nuclear magnetic resonance (NMR), synchrotrons, sample preparation, electron microscopy, and new technologies);
- develop a forward-looking think-tank able to formulate a coordinated European strategy for structural biology and to advise MS on their structural biology infrastructure;
- accelerate the development of integrated approaches that bridge the gap between molecular and cellular structure / function studies;
- stimulate the development of innovative technologies by European companies and their effective uptake by both academic and industrial researchers in Europe;
- develop new approaches, harmonised protocols and standards for systems to integrate structural information across technical platforms and to optimise interactions with other European activities;
- provide training in advanced and integrative structural biology techniques to researchers to facilitate the rapid exploitation of new scientific and technological opportunities.

Beyond five years, there will be further expansion of the portfolio of technologies and training programmes, and a wider geographic spread of centres across Europe. INSTRUCT will be making significant contributions to innovations in the field, with a number of technological developments in the pipeline, new collaborations underway, and increasing numbers of European publications in integrative structural biology seeding new technologies and translational research to meet the grand challenges facing Europe today. INSTRUCT will have become a major strategic voice for integrative structural biology across Europe, and a number of MS will have joined forces through INSTRUCT to tackle one or more projects that are so demanding (scientifically or economically) that joint efforts are necessary. INSTRUCT offers economic gains through new marketable technologies, new drug and vaccine development, and improved health.

What will INSTRUCT cost?
There is substantial investment across Europe in INSTRUCT centres (current total running cost across all core and associate centres is approximately 20 million per annum). During the first five years, INSTRUCT will coordinate funding for pan-European access to these infrastructures (likely to exceed 10 million per annum). The future development of INSTRUCT will require increased investment in both infrastructure and coordination activities, agreed in consultation with funders and other stakeholders.

Project context and objectives:

INSTRUCT recognises that we are now at a turning point in the impact of structural studies on biology, as sample production technologies mature and key core techniques become increasingly powerful, but escalate in cost. In addition the focus is increasingly on integration of methods, which will, in some instances imply increased co-localisation. To maintain the momentum in Europe, INSTRUCT aims to establish a series of structures including core centres and associated centres which will provide infrastructure for integrated structural biology with a firm pan-European dimension and stimulate the community across Europe to define national access communities of users.

Aims of the three-year preparatory phase (PP):

1. Scientific aims:
a. To define the scientific programme for the operations phase suitable to drive the development of infrastructure and integration of this with the needs of the biomedical community. This will be focused on systems of biomedical importance, likely immunological, neurological and cancer related proteins and pathogens and to identify the challenges of evolving from molecular structural biology to cellular structural biology.
b. To fully define the appropriate composition of core and associate centres to provide an optimum European infrastructure. Criteria: (i) scientific excellence, (ii) scientific coverage, (iii) strong record in technology and methods development, (iv) commitment to collaborative infrastructure, (v) biomedical engagement, (vi) national commitment.
c. To establish the correct balance of infrastructure provision required to permit existing and developing technologies to mesh effectively across different levels of resolution, from the molecular to the cellular and ultimately the whole organism scale, thus providing a dynamic picture of key biological processes. Criteria: (i) likely interdisciplinary impact of technologies, (ii) European leadership in each area.
d. To establish a plan to enter rapidly the operations phase of INSTRUCT whilst the construction phase runs alongside. Criteria: (i) key core technologies available at the end of the PP, (ii) integrative technologies developed in parallel.
e. To establish the scientific goals and objectives of the construction and operations phase of INSTRUCT, so that the impact and success of the infrastructure may be judged.

2. Organisational aims:
a. To convert the management structure of the PP into one suitable for the operations phase.
b. To establish a balance of national and pan-European activity within INSTRUCT that will ensure that the major centres can be supported by national funding mechanisms for their contribution to national scientific excellence and infrastructure whilst building a viable business plan that allows Pan-European access. This will require a model whereby stakeholders in all MS can input into the strategic planning process of INSTRUCT. This will require a robust governance model.
c. To establish a governance model and translate this into an operational, legally robust form, with as broad a take-up as possible, by the end of the PP. This model should establish mechanisms ensuring that INSTRUCT is responsive to the needs of the users.
d. To establish the access modalities for the national communities, on the principle that the infrastructure should be as open as possible, with access on the basis of scientific appropriateness and excellence, within the broad restrictions of reasonable juste retour to the stakeholders.
e. To cost the activity properly, to establish a cost-benefit justification of the investment (joint organisational / scientific activity) and obtain sign-up from MS.

Project results:

During the three years of the PP the INSTRUCT consortium worked into establishing the required infrastructure to provide researchers with access to state-of-the-art structural biology technologies and expertise. The original structure of INSTRUCT has therefore been revised for greater inclusivity and to broaden the opportunities for membership, through the addition of affiliated centres.

Core centres will provide access to up to 20 % of specific state-of-the-art integrative structural biology technologies (for non-nationals), and access to expertise in their use and application.

Associate centres will provide expertise and technologies that are complementary to that provided by the core centres and essential for the development of integrative structural biology, for example in protein production, mass spectrometry, software development. National affiliated centres will provide access to, and expertise in, excellent structural biology technologies that European MS may not otherwise have access to. These may be stand-alone technologies.

Member countries are those that have agreed to join INSTRUCT, including countries with centres. Other member countries will have the ability to submit research and development (R&D) proposals and apply for access, and to benefit from training programmes offered by INSTRUCT.

Instruct centres: technology platforms, conceptual pathway, and evaluation

Specialist technology platforms
Early estimates for the estimated number of INSTRUCT users / projects per year that can be accommodated by core centres are:

Conceptual pathway through INSTRUCT
An example of a conceptual pathway by which an academic user of INSTRUCT infrastructure might navigate the facilities and the support available for an integrative project is shown below. The process is summarised in the following steps. There will be flexibility in the process to accommodate experimental revisions, new technology availability and troubleshooting. Engagement with INSTRUCT centres during the preparation of grant applications to national funders for substantive funding will provide valuable expert input.

Step process:
1. user submits proposal to coordinating office, declare if part of awarded grant;
2. coordinating office sends for peer review and prioritisation to peer review committee (prioritisation only, if already peer reviewed). Reject or proceed to next step;
3. coordinating office sends approved proposals to members of operations committee (one member per centre) to optimise proposed technologies / approaches;
4. operations committee may liaise with user to optimise project design and finalise plans;
5. coordinating office liaises with user and appropriate centres to coordinate access, coordinating office may also manage I3 funding for access;
6. user accesses first technology at an INSTRUCT centre e.g. protein production to crystallisation;
7. user progresses through the recommended stages e.g. crystal structure using synchrotron, computational analysis, other structural approaches;
8. structure / function analysis achieved and data deposited. Publication.

Evaluation
Existing instruct centres will be validated periodically and proposed new centres will need to be assessed. The process must be transparent, fair, and have the confidence of the scientific community.

Evaluation of centres
It is proposed that, in future, existing centres and applications for new associate or core centres are evaluated against specific criteria by a validation committee established by the INSTRUCT council with advice from the international scientific advisory board. Centres would provide a business case that sets out their strategic fit with INSTRUCT goals. The validation committee would assess the business cases against the criteria. The case for existing centres to continue as INSTRUCT centres, and their contribution to the goals of INSTRUCT, would be reviewed every five years, with a mid-term light-touch review to identify and address any issues such as difficulties with provision of access.

Validation of current core centres
In recognition that there has not been an open selection process for the core centres participating in the preliminary phase of INSTRUCT, it is proposed that there is a validation of the current core centres.

Criteria for national affiliated centres
INSTRUCT national affiliated centres will:
- be centres of excellence within the context of their host country;
- provide some, not necessarily all, of the core INSTRUCT technologies;
- show evidence of an intention to move towards integrated structural biology approaches;
- offer access to their facilities to national, and possibly non-national, users;
- be capable of, and willing to organise training programmes in collaboration with INSTRUCT;
- be willing to participate in the transfer of relevant new technologies to / from INSTRUCT;

Operational, legal and governance structures

Operational structure of INSTRUCT
Discussions with MS have highlighted a strong demand for INSTRUCT to help with the provision of technology, expertise and training that is both integrative and single-technology-focused, and of extremely high quality, particularly including access to technologies and expertise that are at the cutting-edge within Europe or globally.

The uptake of integrative technologies by some MS may depend on their being able to access other high-quality structural biology technologies (e.g. technologies such as synchrotrons that may not be available in those MS). This broader access may be an essential foundation for those MS to be able to utilise more integrative technologies later on.

Core centres will provide trans-national access to up to 20 % of specific state-of-the-art structural biology technologies, and to expertise in their use and application. Core centres generally offer a range of structural biology / structural cell biology technologies, often with a focus on integrative approaches, within a multi-disciplinary environment. This gives the possibility of access to a 'pipeline' of related technologies. Platforms available will include: specialised sample preparation methodologies; biophysical methods for characterisation of complexes, high throughput techniques and data collection.