The mouse footpad model.

It may be hard, now that Mycobacterium leprae is just another entry in the large catalogue of pathogens whose DNA sequence is known and leprosy is just another treatable bacterial disease, to understand the excitement generated by the mouse footpad model when it was introduced. It is, after all, not obviously exciting: 10,000 bacilli are injected into the hind footpad of a normal mouse. This is the lowest dose that allows any organisms to be found when the footpad is homogenized and the suspension is stained and examined with a microscope. After a wait of several months, during which the mouse remains healthy and its footpad is macroscopically normal, about 1 million bacteria can be found in the footpad. There is no spread of infection to other parts of the animal, and no further increase in bacterial numbers occurs throughout its life. One needs to understand the situation at the time. The association of M. leprae with the disease leprosy had been discovered by Armauer Hansen in the nineteenth century, but it had never been possible rigorously to show that the bacterium caused the disease. The organism could not be cultivated in any laboratory medium, and no reproducible animal model was known. Metabolically M. leprae seemed almost inert, though experiments were hard to perform and interpret because the only available bacteria were obtained from human biopsies and were heavily contaminated by host tissue. Though the disease was treatable it was not curable, and there was no method, apart from laborious and doubtfully ethical human trials, to investigate any potential new drug. Study of the immunology and pathology of leprosy was frustrated by being limited to studies on people; since diagnosis of leprosy was only possible long after the original infection had occurred, the development of the infection was opaque. A number of people–scientists and clinicians–had realized that hugely increased knowledge obtained in other fields should be applied to leprosy research, to try to control this continuing global problem, but exactly how this could be done was not clear. The discovery of the mouse footpad model by Charles Shepard was characteristic of that remarkable man. Many attempts had been made to infect a variety of animals without success, always using large inocula. Shepard had the experimental skill and the patience to use minimal inocula and observe the results, and to be certain that the model was reproducible. Also characteristic was that he realized that he would be unable to exploit all the possible applications of his model, so he encouraged collaborators. A remarkable group of people assembled and, in an informal manner, shared the field. In particular, Shepard concentrated on the bacteriology of the infection, Dick Hilson and Lou Levy on its use in