The Evolution of Immunoassay As Seen Through the Journal Clinical Chemistry (Aacc 50th Years Anniversary Retrospective‪)‬

A brief historical review shows that the first reference in the Journal to an immunologically based method was in 1962 [in a method for lipoproteins using an immunoprecipitation technique (1)]. In 1962 and 1963, there were two references to enzyme-mediated methods (again the first in the Journal) for glucose and oxalate! In 1965 came the first reference to a competitive protein binding method for thyroxine (2), which was also automated (!). In contrast, in 1966 there was a reference to the effect of ultrasound on isoenzymes! In 1968 came the second reference to an immunologically based assay, this time for growth hormone (3), as well as, in contrast, the use of nuclear magnetic resonance for studying low molecular weight constituents! I mention these other landmark papers because enzyme-mediated and protein-binding assays reflect other examples of biorecognition systems that have also matured with great success (particularly in the case of enzymes) as well as other analytical concepts that in the 1960s may have been considered ahead of their time, in relation to what has been achieved in laboratory medicine. In 1969, papers on immunoassay began to blossom, with more publications on the assessment of thyroid status, the issues of sensitivity in relation to quantification of low concentration proteins in cerebrospinal fluid, and reagent quality control. These early papers should be placed chronologically in the context of the publication on the radioimmunoassay of insulin by Yalow and Berson (4) in 1959 and the measurement of thyroxine by Ekins about that time. Thus, in the first 15 years of the Journal, there were approximately 10 papers on immunologically based assays or their utilization; in 1997 there were in excess of 100 papers in which immunoassay methods were utilized (35% of the total number of papers published). Looking at the Editor's perspective on the 30 most cited papers in the Journal (Clin Chem 1998;44:698-9), I find 4 that involve immunoassay; they carry important messages. The abstracts of the first three are shown as Figs. 1-3. The contribution by Rodbard (5) on data handling provides a detailed treatment of an aspect of immunoassay that lives in the shadow of the huge developments in basic knowledge of the antigen-antibody reaction and reagent technology (Fig. 1); the discussion has been continued over many years by Rodbard and colleagues as well as other contributors. In the field of reagent technology, the paper by Del Villano et al. (6) was one of the first in which an antibody was used to characterize a marker, in this instance the tumor marker CA 19-9 (Fig. 2); antibodies have been used to characterize specific antigen moieties on many occasions since, including prostate-specific antigen and nicked human chorionic gonadotropin. The paper by Nussbaum et al. (7) illustrated the clinical benefits of using two monoclonal antibodies against unique epitopes to quantify the whole molecule of parathyroid hormone (Fig. 3).