The term, complement, refers to a group or system of proteins in plasma that serves as the source of a large variety of biological activities. The first activity described that actually led to the discovery of the existence of this group of proteins was bacteriolysis. The nothing short of spectacular lysis of cholera bacilli by fresh serum of guinea pigs caused great deal of excitement and served as an explanation of why freshly drawn blood tended to remain sterile upon storage. Between 1880 and 1914 a firm foundation was laid for investigating the action of complement in the laboratories of two giants of immunology, Bordet and Ehrlich. The most important results from these studies were that 1. The cytolytic action of complement depended on the presence of an anti-cell antibody; 2. Complement was not a single substance but was comprised of several components; 3. Components had to act in a specific order; 4. Some component activity appeared to be bound in some manner to the target cell; 5. Physical-chemical properties of the components were different; 6. Complement activity was "consumed", inactivated, or "fixed" by antibody-antigen complexes, be they in solution or in an insoluble form. The last finding was used to invent the complement fixation test, a test that is even today is one of the most useful immunological tests for antibodies or antigens. Yet for the next 50 or 60 years most main-line immunologists (with very few exceptions) tended to ignore complement, or at best, to use the complement-fixation test without admitting that complement was an important constituent of plasma. Some went as far as declaring that the activity called complement was simply a physical state most likely generated as an artifact of obtaining plasma or serum and that these activities did not exist in vivo. The major problem of obtaining convincing evidence for the reality of complement was a lack of appropriate biological, chemical and physical tools to measure and quantitate its or its components' activity. The first real break occurred in Heidelberger's laboratory where it was shown that a defined and quantified antibody-antigen complex gained protein N upon mixing it with fresh serum. Controls indicated that the additional N was most likely some part of the complement system. Two of Heidelberger's young associates, Manfred M. Mayer and Abraham G. Osler became interested in complement and continued complement research after they became independent investigators. My story concerns contributions of Mayer's laboratory for it was there that the one-hit theory of immune hemolysis was developed and experimentally verified.

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