Imaging dynamics in biophysical/biochemical processes across the hierarchical scales (BioPro Network)

Biological tissues and organs undergo a constant state of dynamical structural and chemical changes with time, which can range from our joint tissues elastic recoil during walking to the slow tissue breakdown as we age, to the very rapid secretion and reaction of proteins by cells in response to sensed mechanical forces. Biological tissues are hierarchical in both structure and function, with protein and DNA architecture at the nano scale leading up to cells and fibrous extracellular matrices at the micron scale to organs at the largest scale. The way such organs operate in a dynamic environment cannot be inferred solely from the gene, but must take into account the processes happening at multiple levels. A classic example is how our joints deteriorate with age, which is - at the molecular level - governed by how proteins levels and composition, at one level higher how they aggregate differently into fibres with poorer elasticity, at a level higher still (microscopic) in how cells react to external loads by changing what proteins they secrete, and finally at the level of the whole organ in how the cell/tissue array becomes less resilient and breaks down with time.

A grand challenge is to understand both what this hierarchy of dynamical processes are as well as how they affect tissue functioning, growth and disease. Currently, however, physical-science and engineering methods used in the biomedical field lack the capacity to image these processes dynamically, in a condition close to the living tissue and at multiple levels simultaneously. However, this is potentially possible, due to recent advances in physical-science based high energy imaging methods at central research facilities (like synchrotrons) in specialist methods like 3D X-ray imaging, microfocus diffraction, laser-scanning methods and the use of free-electron lasers to watch molecules vibrate at speeds many orders of magnitude faster than was previously possible. The challenge is coupling these with physiologically realistic environments to enable the imaging of dynamics of biophysical/chemical processes, bridging the huge temporal and spatial scales of these processes, and finally translating these technologies first to the laboratory and then into the clinic.

In this network, we will work to make this potential a reality by bringing together leading physical-science and engineering researchers in the UK with biomedical researchers to attack the engineering and biological challenges in a team-effort. We will focus on three areas: i) developing experimental setups using these high energy methods which keep the tissue/cell/organ in a native state ii) devising methods to cross-correlate the information across techniques and iii) linking information obtained at different length scales into a unified picture. Our projects will focus on musculoskeletal degeneration at multiple scales, but we will seek to develop methods that are as widely applicable to other conditions as possible.

We will run several short-term proof of concept projects which will allow these teams to test new ideas and whether they work, and fund researchers to spend short-term visits in each other's labs which will help transfer from the physical to the biological sciences. If these results show promise, they will lead to full-scale projects where a biomedically or clinically relevant application can be developed in full. We will hold a range of activities to explore and identify challenges (sandpits and workshops) and to present and analyse the results (annual conferences). The methods and tools we develop will be made widely available to the general academic community to bring them sooner to benefit the general public. Our network, in short, will provide the key proving-ground where the most advanced high energy techniques to analyse complex matter, available only at central facilities, are adapted and made applicable to solve critical questions in the life- and medical-sciences.

Biological organs constantly undergo a hierarchical and dynamical set of structural, biochemical and biomechanical alterations which are critical to tissue functioning and growth and whose dysfunction, at multiple scales, is associated with pathologies. These range from individual protein molecules, their self-assembly into and mechanical response as fibres, cellular response to external fields, flows and forces and whole-tissue deformation under physiological loads. The integrative knowledge of these processes - and understanding how they affect tissue and organ function - is a grand challenge in bioengineering and medicine. We will build a network to utilize the latest advances in high resolution, high energy physical-science methods at central facilities which can probe complex matter at multiple scales - including X-ray tomography, X-ray scattering, cryo-EM and light-sheet imaging - to address this challenge. Specifically, we will adapt these techniques to the challenges of working with biological matter in a time-resolved manner - mimicking and modelling the physiological environment during testing, maintaining the tissues in a viable state, correlating information from multiple techniques, minimizing radiation exposure, optimizing signal analysis techniques. Using musculoskeletal degeneration (as in osteoarthritis) as an exemplar, we will enable proof-of-principle projects in these areas via pump-priming funding of multidisciplinary teams, enable researcher exchanges and target early-career researchers in learning these new methods. Via sandpits, workshops, and conferences we will develop, disseminate and document new protocols and techniques for biological process imaging in a quantitative and realistic manner. Our network will seed the development of next-generation techniques that exploit the multiscale capacity and high resolution of new imaging and spectroscopic methods, translating them to the laboratory and clinic.

Beyond academic engagement, as exemplified in the networking, training and dissemination activities, the "Ideas Factory" created by this network will fuel impact via enabling the development and translation of disruptive technologies touching life. With an initial focus on musculoskeletal degeneration, but with potential to expand the techniques to other diseases, end users will be orthopaedic surgeons, national health services as well as patients, and the timescale of the impact will be from 5-50 years. Indeed, within a time-frame of up to 15 years, we envisage the translation of technologies developed into clinical and healthcare practice as helping millions of people suffering from conditions involving musculoskeletal degeneration, including osteoporosis, osteoarthritis and reduced joint mobility.

This impact will be achieved via the following objectives:

1. Development of world-leading transformative technologies that can analyse, perturb and correlate multiscale biophysical and biochemical dynamics.
2. Work with key instrumentation and software companies to translate the technologies into wealth creation for UK industry.
3. Work with clinical end-users (surgeons, health-care organizations) and medical device companies to ensure that these technologies are absorbed by the end-users and translated into clinical practice.
4. Develop strategies for utilization by creating a Translation Roadmap, coupled with appropriate intellectual protection.

By including orthopaedic clinicians, medics and industrialists on our co-investigator team and International Advisory Committee (IAC), we will enable end-user engagement and guidance from the start of the network. The medics on this team are regular participants in meetings like the Orthopaedic Research Society, British Orthopaedic Society and American Academy of Orthopaedic Surgeons. Drawing on their experience, two translation workshops for clinicians and industrialists are planned, and we will seek to engage leading surgeons and industrialists to present their work as well as to promote the technologies coming out of the network.

Likewise, the investigators and other network members have a strong track record working with industry, and these contacts will be leveraged over the duration of the network to enable translation. We have engaged with important imaging equipment and medical industrial players for this proposal for substantial in-kind support both in expertise, network engagement, software and materials.

Based on this experience in translational research, we will formulate a Translational Roadmap one year into the lifetime of the network, to define best practice for network members. IP will be retained by the participating network members home institutions, where established IP protection routes exist.