Microscope Based Technologies from Clinical Application to Cell Biology: A Themed Issue in Memory of Prof. Kevin C. Gatter and Prof. David Y. Mason

Dear Colleagues,

Born in 1941, David Mason trained in medicine at Oxford first, and then in London. A haematologist by training, he dedicated his professional life to the development of techniques to produce monoclonal antibodies suitable for diagnostic work.

Kevin Gatter was born ten years later in 1951 and obtained is medical degree from Oxford. Kevin was an histopathologist and closely worked with David in their quest for developing diagnostic reagents for the diagnosis of tumours.

Since the invention of the microscope, a new branch of medicine had developed, histopathology, which revolutionised the diagnosis of disease and the practice of medicine. For the first time, it was possible to actually see under the microscope the human tissue and the abnormalities caused by disease. It became possible to distinguish whether a lesion was due to an infection or to a tumour, and the main different types of tumours could be, in many cases, identified. However, strong limitations remained. As new treatments for tumours where developed, it emerged quickly that each different type of tumour required a specific treatment, as a simple histological examination would not always achieve a firm diagnosis. This race between advancement of treatments, requiring a more precise characterization of the lesion and improved characterization of the tumours, leading to identification of new type requiring a new type of treatment, is still going on.

Immunostaining started to be explored in the 1940s when antisera against infective agents were conjugated with fluorescent labels. In the 1960s, the use of enzymatic labels of far higher sensitivity were introduced which allowed to use this novel techniques with ordinary optical microscopes. The introduction by David Mason of the of the Alkaline-Phosphates anti Alkaline-Phosphate (APAAP) technique brought an increase in sensitivity and standardization. However, the big challenge was to achieve production of specific and reproducible reagents which could be suitable for both accurate research studies and, more importantly, the possibility of a safe use in clinical practice. Trainee histopathologists and haematopathologists in the early 1980s would still rely on morphology as just a very few antisera for diagnostic use were available; most notably, antibodies for light chains.

The main reason for this lack of reagents was that they were produced by injecting rather crude antigens, such as an entire cell, in animals and bleeding them, obtaining polyclonal antisera of variable quality and specificity according to the batch. David Mason and Kevin Gatter changed all this by exploiting two innovations. The first was the development by Kohler and Milstein of the techniques to produce monoclonal antibodies which allowed unlimited production of the same antibody of precise specificity. Oddly, this invention was, at the time, deemed as not very useful and the MRC, famously, did not patent it. Still, quite rightly, Kohler and Milstein went on to win the Nobel prize for it. The second has been the development of molecular biology allowing the production of very purified antigens to be used for immunization, from recombinant proteins to peptides.

Exploiting these innovations, Mason and Gatter demonstrated that diagnostically useful monoclonal antibodies could be produced and provided the histopathologists with reagents able to quickly and cheaply identify antigens in tissue. Specifically, their strategy of screening candidate antibody clones against tissue sections rather than immunising antigens yielded histopathologically useful reagents. Both clinical practice and research are now unthinkable without immunohistochemistry and it is taken for granted that oncology patients will have a very extensive and precise characterization of their tumour to guide the treatment.

All this before David and Kevin did not exist.

The main aim of this issue is to provide an update on the different arrays of microscopy techniques that have been developing since the establishment of immunohistochemistry and their impact in the biomedical research and clinical work. From automatic image analysis and its application in interpreting histology slides to live-cell imaging and their use in biology or techniques like fluorescence resonance energy transfer (FRET) which visualize molecular events.

Prof. Dr. Francesco Pezzella
Dr. Kingsley Micklem
Guest Editors

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• microscopy
• pathology
• imaging
• image analysis
• cell biology