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Perspectives |
Riethoven, 5561TP 22 The Netherlands
Elsewhere in this issue of Clinical Chemistry, Lequin (1) tells the story of how, in the late 1960s, enzyme immunoassay (EIA)/ELISA was conceived and how the technology subsequently found wide application in biomedical analysis. When we started the project at Organon, we certainly did not have the vision that it would lay the foundation for billions of future laboratory analyses. The main reason for starting the project was that Organon’s management liked the success of the immunochemical pregnancy tests that had been introduced some years before (based on inhibition of hemagglutination or latex agglutination), but felt that the cumbersome and time-consuming test procedures formed a threat to continued success. A simple dip-and-read strip giving a color change seemed a more secure basis for future success. Thus, Anton Schuurs’ proposal to explore the potential of enzymes linked to antigens or antibodies for immunochemical reactions with a colorimetric endpoint found approval. Of course, we used the pregnancy hormone human chorionic gonadotropin (hCG) as the model analyte for our exploration. However, Schuurs was not blind to further applications, as the final sentence of his research proposal read: "in my view any success (of the exploratory project) could open a new field of immunodiagnosis".
We could show at a relatively early stage that the technology worked, at least in principle (2)(3), but we failed to develop an EIA-based dip-and-read pregnancy color test, in spite of much effort. Compressing the many necessary reagents on a strip and standardizing the procedure in the matrix presented too many technologic problems to be solved at that time. In fact, pregnancy color tests were developed only after the simpler sol particle immunoassay (SPIA) technology, also developed by the Organon group, became available (4). Instead, we turned to other applications in endocrinology—aiming at direct competition with RIA—and in infectious disease, primarily in hepatitis B testing, a field that had been exploding since the discovery of Australia antigen (HbsAg) a few years earlier and the subsequent identification of the hepatitis B virus.
In the meantime, we had become aware of the ELISA studies by Engvall and Perlmann and their follow-up by many groups. The most interesting applications were initiated in the fields of bacteriology/parasitology/virology, in particular by the groups of Alister Voller and Dennis Bidwell in London and Joost Ruitenberg at the Dutch State Institute of Public Health. They realized that the simplicity of EIA/ELISA compared very favorably with the cumbersome technology that was used in the field at that time (immunofluorescence, hemagglutination inhibition, and complement fixation) and quickly developed a wide range of tests for various microorganisms. These gained almost immediate acceptance and greatly helped in making reliable infectious disease testing accessible for general biomedical laboratories and for third-world countries. Until then, such testing had been limited to only a small number of highly specialized laboratories. Voller and Bidwell also initiated the use of 96-well microplates for performing EIA/ELISA, which sparked the first wave of immunoassay automation. We at Organon readily adopted this assay format for our hepatitis B and additional blood donor screening tests.
The adoption of EIA/ELISA in fields such as endocrinology and oncology, in which RIA already had gained a strong foothold, was much slower than in infectious disease testing. The precision and sensitivity of EIA/ELISA methods lagged behind those of the well-developed RIA methods, and laboratories that were equipped for and accustomed to working with radioactivity did not see advantages in changing to nonisotopic methods. Automation changed all this. Whereas automation of methods involving radioisotopes created many problems in containment and waste treatment and disposal, EIA/ELISA offered opportunities for fully automated random-access immunoassay systems, which diagnostics manufacturers fully exploited in the 1980s. This led to more reliable testing at lower cost and facilitated the move of immunochemistry from specialized radioisotope departments into the general chemistry laboratory; EIA/ELISA thus also found its way into areas other than infectious disease testing.
The patent situation, or rather the way in which Organon management dealt with it, has been a decisive factor in the success of the EIA/ELISA technology. When several competing companies approached Organon in the mid-1970s requesting to be licensed under the Organon patents, the management decided after lengthy discussion not to monopolize the technology, for which the broad applicability in laboratory medicine was becoming increasingly clear, but instead to make it available to any company prepared to meet the licensing conditions. That these conditions were reasonable is illustrated by the eventual number of more than 100 licensees. I believe that this approach has been beneficial to laboratory medicine. One cannot help but wonder what the effects would have been if other companies had adopted a similar licensing policy for more recent important technologies.
Looking back, I continue to be amazed about what came out of our (too) early attempt to develop a simple pregnancy color test!
References
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