Small is beautiful but smaller is the aim: review of a life of research.

Background and origins of research of Adam Curtis. One persisting theme has been the pursuit of different landscapes at different scales to discover the routes to explain how the body is built. His research life fell in a fortunate period during which techniques and concepts for investigating structure have improved year by year. His most fortunate encounter was with Michael Abercrombie and his views on the social behaviour of cells, aims for quantitation, and statistical testing. Adam worked in various environments--in turn Geology as an undergraduate, Biophysics Ph.D. in a Genetics department and various departments in turn from anatomy via zoology to Cell Biology. Adam started his Ph.D. work in cell adhesion, studying cell movement, trapping and reaggregation phenomena, having an early start from the physico-chemical viewpoint. He made quantitative measurements of cell adhesion by kinetic methods. Interference reflection microscopy (IRM) and related optical interference techniques were brought into the field of biology by him. In turn this led with Chris Wilkinson, a long term colleague, to the use of micro- and nanofabrication for biological research. Polscope and photoelastic measurements were introduced to biology recently in his laboratory. One long term theme has been to map the adhesion of cells to substrates to discover contact areas. Early data came from IRM and then TIRF (Total Internal Reflection Fluorescence Microscopy) and then from Forster Resonance Energy Microscopy (FRET). Another important theme was the time scale that needed to be measured--very short indeed in suspension. This was very difficult and has only become possible very recently but hydrodynamic calculation shows it must be very short. The attractions of the Derjagin-Landau-Verwey-Overbeek theory (DLVO theory) are that they explain many features of biological adhesion. The main test of this theory depends upon the energy of the adhesion at various different separation distances between cell and cell or cell and substrate. Problems with cell adhesion molecules are discussed. Contact guidance of cells by oriented structures and Paul Weiss--Tests with grating replicas suggested that topographic rather than biochemical explanations were applicable. It became clearer later that this was an area of research waiting for microfabrication. Albert Harris influenced me considerably to start thinking about mechanical forces produced by cells. Pulling at cells showed effects on the cytoskeleton and on cell cycle time. Such thoughts led to a microfabricated device for tendon repair. Recent photoelastic measurements with the Polscope have allowed much more detailed analysis of the forces between cells. The interesting results on microfabricated devices led to work on nanostructures. Results led the Glasgow group to consider dimensions of structures and how cells could sense such small objects and questions about why order and size may be important. Differential protein adsorption onto surfaces seems to provide defective explanations of the effects. The results will be discussed in terms of very recent theories of cell interaction and cell signals and possible future developments will be outlined.