What has changed is the recognition that many issues in biology, biotechnology and medicine can be translated into problems of direct interest to physicists and physical scientists who want to understand the principles governing the structure and dynamics of molecules in solution; energy transfer; thermodynamics; biological motility; population dynamics, cell differentiation and signalling; mechanisms of molecular recognition; biomechanics and rheology; nonlinear phenomena and modelling of complex interacting systems.

The characterization of molecular structure, the measurement of molecular properties and the observation of molecular behaviour present enormous challenges and rewards for the physical and life sciences. A wide range of biophysical techniques are therefore undergoing constant development to better study molecules in solution, in cells and in complex, artificially structured environments.

This endeavour has been advanced significantly by the lowering of the conceptual and cultural barriers that traditionally separated physics from the life sciences. Some of the most exciting approaches provide detailed images of cells, subcellular structures and even individual molecules. Among the ultimate objectives is the capability to observe directly the biological behaviour and physical properties of single protein or DNA molecules within living cells and to determine how the structure and behaviour of single molecules influence biological function.

See the light

Biophotonics is an emerging cross-disciplinary field where physics-led photonics meets biology. It is the science and technology of generating and exploiting light to detect, image and control biological processes. These processes occur on lengthscales as small as a single molecule and extend up to many cells and tissues. Biophotonics is a fast-moving area that's driven by advances in laser science, detector technology and the increasing scope of biologically inspired problems in physics.

Among the many examples of areas where physicists are engaging deeply with biological problems is that of optical trapping using so-called laser tweezers. The capability to use laser light to trap and manipulate biological material without mechanical contact has opened a host of new opportunities for direct experimental contact with the realm of single biomolecules and for exploration of heterogeneity among "identical" molecules within a population.

Similarly powerful is the prospect of manipulation of single cells or subcellular constituents. This emerging capability has the potential to provide fundamentally new information about biological processes. Laser tweezers allow the 3D trapping of small dielectric particles in a tightly focused laser beam. Trapped particles can be manipulated simply by moving the position of the laser focus. In biophotonics, this phenomenon can be used for single-molecule manipulation - for example, by chemically tethering a single DNA molecule to a small perspex bead. The bead is then trapped in the laser tweezers, thereby permitting direct manipulation of a single DNA molecule.

At a larger scale, living cells can also be trapped directly, since many of the internal cell structures behave optically as small dielectric particles. Such structures can be trapped in the laser focus, so trapping the whole cell and allowing the direct, non-contact manipulation of cells. The simple laser tweezers can be extended in a range of directions to give, for example, tweezer arrays to trap many particles or cells into clusters. Alternatively, calibration of the trap forces yields an analytical force-measurement tool capable of applying known forces to trapped materials for the direct measurement of physical properties. This technique is non-invasive and can be combined with other advanced optical imaging techniques, such as fluorescence or confocal imaging, to form a combined manipulation and imaging system.

At the molecular scale, a synthesis of leading-edge research expertise in DNA nanotechnology (combining genomics, microarray technology, electrochemistry and microelectronics) is being pioneered at the University of Edinburgh, UK, to create a biophotonics-based platform technology. The technology is based on the idea of using biomolecules switching between two configurations to mimic transistor-like behaviour.

As a specific illustration, the research programme has explored the characteristics of DNA Holliday Junctions as ion-controlled nanoscale switches. Ion-induced switching in solutions of DNA Holliday junctions has been detected optically using fluorescence resonance-energy transfer (FRET). The FRET technique is based on the idea that two different fluorescent molecules (a donor and an acceptor) brought close together (within a few nanometres) can exchange energy and modify the colour of the fluorescence emission. Relative changes in the donor and acceptor emission spectra can be related to their separation. FRET can therefore be used as a nanoscale optical ruler with wide-ranging applications in protein and nucleic acid structure determination.

Heavy-duty computing

Another area where physics is likely to have a major impact in the life sciences is very-large-scale computer simulation. Initiatives like the IBM Blue Gene project are dedicated to exploring the frontiers of supercomputing, with specific motivation drawn from the need to simulate biological processes such as protein folding and self-assembly. Understanding the principles and processes by which proteins in aqueous solutions assemble from amino acid chains into biologically functional 3D structures is recognized as one of the major challenges spanning the physical and life sciences.

In addition to fundamental interest in the factors surrounding this process, protein misfolding events are also attributed to diseases such as cystic fibrosis, CreutzfeldtJakob disorder and Alzheimer's. Consequently, the long-term impact of advances in this area also reaches into medicine and may have future ramifications for protein and peptide design. The basic molecular-scale issues that underlie folding and other related "self-organization" phenomena can be grouped under the following themes:

Hydration structure: How are the water molecules organized around the polar, non-polar and peptide groups of complex biomoleclues? How is this organization influenced by externally controllable conditions, such as temperature and pressure?

Molecular flexibility: How flexible are the bonds of complex molecules that define overall macromolecular shape? And how is this flexibility affected by hydration structure and other environmental factors, such as pressure and temperature?

Ionic (Hofmeister) effects: How does the presence of simple inorganic ions influence hydration structure and flexibility?

One thing is certain: the outlook for physics reaching ever further into the biological domain looks set to pick up speed as its practitioners continue to find more motivation from biological molecules and their organization into not only complex but functional objects.