Biophysics in Great Britain and Ireland

The subject of Biophysics—the application of physical science to our understanding of biological processes at both molecular and macroscopic levels, has extensive roots in Great Britain and Ireland and is represented by an active Biophysical Society (BBS) which serves laboratories, institutions and Industry across both countries. The next biennial meeting will be in Glasgow and celebrates 65 years of activity.

The origins of Biophysics can be traced back to the 19th and early twentieth centuries, with pioneering work that sought to apply physical principles to biological phenomena, building on the great physical discoveries of pioneering Irish scientists such as John Tyndall and G.G. Stokes, and British researchers including Michael Faraday, James Clark Maxwell, J.J. Thomson and Lord Rayleigh. Early applications often focused on areas such as the physical properties and thermodynamics of biological molecules in studies of diffusion and viscosity; here in this issue, D.P Mulvihill and M.A. Geeves give a contemporary approach to high pressure effects on biomolecules. The scattering and interaction of electromagnetic radiation by biomolecules is fundamental to the origins of spectroscopy, and at a macroscopic level with microscopy leading to determinations of the physiology of nerve conduction and muscle contraction from studies by A.L. Hodgkin and R.D. Keynes (Hodgkin and Keynes 1955).

Following further pioneering work of the Bragg father and son partnership (Fig. 1) in the early part of the twentieth century (see, for example Hughes 2008 & references cited therein), a key period was the discovery in the middle part of the twentieth century of the double helix in DNA by J.D. Watson and F.H.C. Crick at Cambridge (Watson & Crick 1953), utilising the earlier discovery of hydrogen bonds in DNA by J.M. Gulland, D.O. Jordan and J.M. Creeth at Nottingham (Creeth et al. 1947—see also Harding et al. 2018 on Creeth’s particular contribution). Much of this advance was founded on the pioneering x-ray work initially by W. Astbury and Florence Bell at Leeds, and then crucially by Rosalind Franklin, M.H.C. Wilkins and R. Gosling at Kings College London (see Watson et al. 2012 for a review of this earlier work). Other important structural molecular biology followed: the structure of penicillin – solved by Dorothy (Crowfoot) Hodgkin (Fig. 2) and coworkers at Oxford (see Hodgkin 1946), the structures of myoglobin (J. Kendrew; a founding member and former secretary of the British Biophysical Society in 1960 – Kendrew et al. 1958), of haemoglobin (M. Perutz and co-workers – Perutz et al. 1960) and of lysozyme (D.C. Phillips and coworkers – Blake et al. 1965) (Fig. 3). The discovery of the structure of insulin by the Hodgkin’ team in 1969 has proved crucial in the treatment of diabetes (Adams et al. 1969). Here, contemporary issues with these structural methods are discussed by A. Brink and coworkers (Brink et al. 2025).

Fig. 1.

Lawrence and William Bragg who received the Nobel Prize in 1915 “…for their services in the analysis of crystal structure by means of X-rays"

Fig. 2.

Dorothy Hodgkin, who was awarded the Nobel Prize in 1994 “for her determinations by X-ray techniques of the structures of important biochemical substances”

Fig. 3.

The team (left to right: David Koenig, Colin Blake, Louise Johnson, Tony North, David Phillips and V.R. Singh) led by David Phillips that resolved the structure and mechanism of lysozyme in 1965. Courtesy of the Royal Institution

In addition to crystallography, other areas of biophysics have flourished. Optical microscopy (R. D. Preston) was used to give molecular structural details of plant cell wall structure (Preston 1974). Further developments in microscopy resulted in electron microscopy, which advanced investigations of biomembranes and gave insights into multimolecular complexes including cells, viruses and bacteria. Microscopy has seen very significant developments at the single molecule level, and recent advances and uses are discussed by Kongari et al. (2025).

Model membrane systems devised by A. Bangham (1968) in the 1960s, are still very actively studied in research today, and one of the aims is to construct an artificial cell: a contemporary use of these systems is presented by Fletcher and colleagues here (Fletcher et al. 2025). Similarly, the exquisite molecular selectivity of membranes and their proteins has been exploited in nanopores, a technology devised by Hagan Bayley and brought to device usage (Bayley 2015). The highly controversial notion of lipid-protein interactions was addressed by D. Chapman, J. Metcalfe and P. F. Knowles in the 1970s/1980s. The drive to study biomolecules in situ, here in membranes, was realized by the use of electron diffraction and then cryo-electron microscopy to give the structure of membrane proteins in their natural membrane environments, with bacteriorhodopsin (R. Henderson) and the nicotinic acetyl-choline receptor (N. Unwin) (Fig. 4) - being early examples (Unwin and Henderson 1975). The interplay between protein complexes, specifically in the electron transport chain, was constructed from successive molecular structures and biochemical studies by J. Walker (Walker 1992), and the rediscovery of cubic phase forming lipids has revolutionized membrane protein crystallization (Caffrey 2003). In all of this structural work, molecular graphics permits the direct observation and analysis of biomolecules, with Britain leading the world in the developments in this area through the pioneering work and vision of A.C.T. North at Leeds (North 1989).

Fig. 4.

Nigel Unwin and Richard Henderson (left to right) sitting on the steps of the original entrance to the MRC Laboratory of Molecular Biology, Cambridge in the 1990s

Unlike in crystallography and cryo-environments, where molecular rigidity is a pre-requisite for structure determinations (as discussed by A. Brink and colleagues here), it was quickly realized at the time that such macromolecular assemblies were dynamic and covered a wide range of timescales. The increase in our understanding of the interaction of electromagnetic radiation with biomolecules then led to the development of a range of spectroscopic methods for giving greater insight into this dynamic nature in biology, such as Nuclear Magnetic Resonance (NMR) spectroscopy (including solid-state NMR) and Electron Paramagnetic Resonance (EPR) spectroscopy. This was alongside parallel developments in scattering methods (light, x-ray, electrons, neutrons), and macromolecular hydrodynamics (analytical ultracentrifugation and viscometry). Much of the spectroscopic developments utilized a strength in the UK of high-field magnet technology (R. Richards, Oxford Instruments; Magnex), and included the exploitation of NMR visible nuclei (¹H, ³¹P) for MRI development, metabolic monitoring and related technologies by P. Mansfield (Mansfield 2013) and G. K. Radda (Radda 1990). Recent developments in ESR and NMR are discussed by C.E. Skinner and colleagues in this issue.

The development of the wide range of physical and physico-chemical techniques to study biomolecules, driven by a need to answer specific biological questions, are continuing to provide powerful insights into the dynamics, interactions, and conformational changes of biomolecules in solution, complementing structural information obtained from crystallography. Ways of addressing complex macromolecular assemblies and interaction in a variety of situations is addressed by several contributors including Laura Mijangos and colleagues, Charlotte Hunter and colleagues, Eve Dawson and colleagues, T. Ng and colleagues, and N.M. Mockler and P.B. Crowley. Particularly strong in Ireland has been Food Biophysics, building on a historical strength in agricultural and food sciences: biophysical studies relating to food structure, material properties of biological tissues, and the interaction of biological systems with their environments, and helping provide the platform for the growth of glycobiology and glycan biotechnology with come spectacular modern finds.

The establishment of the British Biophysical Society in 1960 (see https://britishbiophysics.org for a brief history), which despite its name has served both Great Britain and Ireland and has played a vital role in promoting biophysical research, organizing conferences, and fostering collaborations among biophysicists locally, nationally and internationally—the BBS was a founding society member of both the International Union of Pure and Applied Biophysics (IUPAB) and the European Biophysical Societies’ Association (EBSA). This society, along with others, has helped to define and advance the field within Great Britain and Ireland and beyond, as well as to encourage and reward the community through awards and prizes, such as the John Kendrew Thesis Prize, Elspeth Garman Public Understanding Prize and the prestigious Sosei-Heptares Prize.

This present volume showcases a snapshot of British and Irish Biophysics and has brought together reviews from a representative spectrum of scientists from well-established biophysicists to Early-Career researchers. In the first paper (Naney at el, 2025) Christo Naney, Emmanuel Saridakis and Naomi Chayen review the latest in protein crystallisation strategies using “pore” technologies to address the problem of stubborn non-crystallizers and getting them to produce diffraction quality crystals, thereby supplementing existing (and inefficient) trial and error strategies. “High throughput” until now has generally been “low output”. Synergistic diffusion-absorption effects with these narrow pores facilitates an increase in concentration to a level sufficient for crystal nucleation.

This is followed by Brink et al. (2025) where Alice Brink, John Helliwell and Francois Jacobs raise the important question of whether structures of macromolecules – largely proteins – obtained for example, using cryogenic conditions to minimise radiation damage need to relate better to relevant physiological temperature conditions, an important requirement also for the understanding of protein–ligand interactions in the development of new therapeutic drugs. They review the techniques that can be used to adapt or provide structures to these conditions (including for thermophiles).

The theme of macromolecular interactions – and relevance to drug discovery is continued in the next paper by Charlotte Hunter, Ehmke Pohl and Stefanie Freitag-Pohl (Hunter et al. 2025). They consider high throughput Spectral Shift technologies for the rapid assessment of inter-molecular interactions, and in particular the “Nanotemper’s Dianthus platform” allowing high throughput, immobilisation free analysis, and review the fluorescent labelling strategies involved as well as future applications for drug discovery and optimisation.

Ever since the method for routinely sequencing proteins was developed by Sanger, attempts have been made to predict local and full structures of proteins. The advance of artificial intelligence (AI) technologies with AlphaFold has greatly increased the accuracy by which this can be done and in the next paper Caitlin Skinner, Bethany Hayes and Rivka Isaacson review how this has led to a resurgence of magnetic resonance techniques (Skinner et al. 2025), including membrane proteins, and how both nuclear magnetic resonance (NMR) spectroscopy and electron paramagnetic resonance (EPR) spectroscopy are well placed to benefit from this post-AlphaFold landscape.

The study of membrane transporter proteins has also benefited from the development of advanced optical microscopy methods for in situ single molecule studies and these advances are reviewed by Shannan Foylan, Gail McConnell and Gwyn Gould (Foylan et al. 2025). Recent advances allow for non-invasive analysis of the native organisation of transporter molecules in the plasma membrane, and the elucidation of new regulatory mechanisms with the potential for a wide range of applications.

There is currently great interest in the delivery of monoclonal antibody formulations subcutaneously – coping with the issue of the high viscosity of elevated/ high concentration formulations is not easy and in the next paper Laura Mijangos, and coworkers extensively consider the advances, critical for example for cancer therapies, Issues of biophysical instability and thermodynamic/hydrodynamic non- ideality become relevant in these high-concentration monoclonal antibody product (HcmAP) formulations. Excipients such as salts, amino acids (particularly Arg-HCl) show improved viscosity formulations but can impact on stability and so the route to finding optimal formulations is ongoing (Mijangos et al. 2025).

Considering further the progress in the use of biophysical methods for the study of membrane related phenomena Daniel Mulvihill and Michael Geeves review how rapid changes in hydrostatic pressure (HP) can be used for perturbing protein and membrane structures as a probe for correlating the function of purified proteins with their measured activity in living cells. HP methods can be applied and removed in less than a second and is transmitted through a cell at the speed of sound. The review focuses on moderate HP (< 200 atmospheres) where safety issues are not as significant as with previously used methods with higher pressures (Mulhivill and Geeves, 2025).

Cancer therapies are also benefitting from advances in the use of biomolecular assemblies in gene regulation, and these are reviewed in the following paper by Eve Dixon, Karolina Stanczy and Yolanda Markaki. The interplay between biomolecular assemblies (BAs), namely protein–protein interactions and the different forms of chromatin are essential for obtaining diffusible regulatory proteins at specific genomic regions for precise gene regulation. Issues of molecular crowding, phase separation, concentration variations and liquid–liquid condensation are crucial. Advances in super-resolution microscopy and single molecule technologies are proving particularly useful (Dixon et al. 2025).

The theme of advances in the study of biomolecular assemblies is continued in the paper of Niamh Mockler and Peter Crowley who consider the important advances in the use of modular protein frameworks and supramolecular “synthons” in the design of functional assemblies. Polymorph searching, “molecular tectonics”, supramolecular synthons and other crystal engineering concepts are being adapted and utilised and these are reviewed. Mix and match approaches with modular frameworks are considered along with the numerous established methodologies in protein assembly and crystallization (Mockler and Crowley 2025).

Being able to measure the forces between molecules inside cells is important in understanding cellular processes, including those involved with changing shape, growth, movement and division and in the next paper Abhinav Kongari and Maxim Molodtsov review the use of magnetic tweezers for this purpose, building on the advances in other force spectroscopic tools which have previously focused on purified components outside cells. Kongari and Molodtsov (2025) focus on advances in instrument design for generating and controlling magnetic gradients at the single cell scale, and also the production of magnetic biofunctionalized particles for targeting specific structures.

This is then followed by a review by Mads Gabrielsen and coworkers on the use of small molecules to stabilize proteins systems (Tchiakam et al. 2025). This is very relevant across a wide range of biomolecular assemblies important for example in the design of high concentration antibodies and other therapeutic systems (Mijangos et al. 2025), and for the stabilisation of nanoparticles for gene therapy and RNA vaccination technologies.

Marcus Fletcher, Yuval Elani, Ulrich Keyser and Ran Tivony then consider the usefulness of giant unilamellar vesicles (GUV) as a model system for studying ion transport. Regulation of ionic gradients across membranes is employed by cells to control energy storage, bioelectrical signalling and for driving transport mechanisms. Reconstituting single ion transport pathways is proving invaluable for accurate elucidation of ionic permeabilities and channel conductivity and newly established methods using GUV are reviewed (Fletcher et al. 2025).

The theme of biomolecular assemblies or “condensates” is continued by Tin Long Chris Ng, Luisa Capalbo and Janet Kumita who review the use of microscopic methods for studying biomolecular condensates within and around cells. They emphasize the importance of cell-based studies in a molecular crowded environment to reinforce measurements made in the controlled environments possible with in vitro studies. Specific labelling technologies such as FRAP (fluorescence recovery after photobleaching), FLIM (fluorescence lifetime imaging microscopy) and Flicker microscopy are reviewed alongside the label-free method of Brillouin Light Scattering (BLS) to help decipher the cellular biophysics of cellular condensates/ assemblies (Ng et al. (2025).

Zuzana Coculova and Richard Berry (Coculova and Berry 2025) re-emphasize the importance of relating biophysical structures and interactions to physiological conditions in their paper which considers the vision of a perfusion system for the functional study of membrane proteins in relation to transmembrane chemical and electrical potential. It reviews the earlier pioneering work of Leptihn and coworkers who developed the “droplet-on-hydrogel” bilayer technique (sandwiching a < 1 mm water droplet) which enables high-resolution total internal reflectance microscopy. This can then be adapted to give an electronically controlled perfusion system for following mechanisms of energy transport.

Alongside all these exciting and innovative developments by biophysical laboratories in Great Britain and Ireland has been a recognition of the need to maximize the potential usefulness of these developments to communities both locally and internationally. It is therefore fitting that for the penultimate review of this volume by Jack Shepherd and Mark Leake, invention, innovation and commercial possibilities are considered and strategic recommendations are given concerning future resourcing (Shepherd and Leake 2025). The analysis of the interactions between biological macromolecules and ligands has been at the core of Biophysics over the last century. It is therefore highly appropriate that the final review in this special issue celebrating Biophysics in Great Britain and Ireland by Simon Poole, Brionna McGorman and Andrew Kellett (City of Dublin University) with Christine Cardin (University of Reading) shows how a combination of crystallographic, spectroscopic and other biophysical methods with biomolecular assays is continuing to enhance our understanding of small molecule interactions with DNA, with far reaching consequences in drug delivery and biomedicine (Poole et al. 2025).

Stephen Harding and Anthony Watts.

Universities of Nottingham & Oxford, August 2025.