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2416 Lequin: Historical Note on EIA/ELISA
using enzyme labels was met with skepticism and incre- tion and myogenic cells from nonmuscle tissues for mus-
dulity. How could so bulky and large a molecule as an cle cell replacement (21 ).
enzyme be attached to an antigen or antibody without During the late 1960s and early 1970s, many RIA test
sterically hindering the immunochemical reaction be- systems were essentially “home-brew” methods devel-
tween antigen and antibody? This objection on principle oped by individual researchers who could not keep pace
was nullified by carefully planned and executed experi- (particularly financially) with the possibilities and facili-
ments to demonstrate the feasibility of enzyme assays. ties of commercial manufacturers such as Boehringer-
Initial results were encouraging, and later the resounding Mannheim (Germany), Abbott (United States), and Or-
success of the enzyme-(linked) immunoassay technique ganon Teknika (The Netherlands), to name only a few.
proved all skeptics wrong. Commercialization of EIA/ELISA test kits had started.
How did Perlmann and Schuurs each invent a method Solid-phase techniques (8, 22 ) were used in the develop-
that others found inconceivable? These two principal ment of microtiter plates (96 wells) in which either an
References
1. Yalow RS, Berson SA. Immunoassay of endogenous plasma
insulin in man. Clin Invest 1960;39:1157–75.
2. Nobel Prize home page. http://nobelprize.org/medicine/
laureates/1977/index.html (accessed June 2005).
Fig. 3. Estimates of the number of articles published per 5-year period 3. Ekins RP. The estimation of thyroxine in human plasma by an
from 1960 to 2005. electrophoretic technique. Clin Chim Acta 1960;5:453–9.
The search was done in February 2005 in PubMed/National Library of Medicine, 4. Miles LEM, Hales CN. Labelled antibodies and immunological
NIH, with the search terms: enzyme-immunoassay, enzyme-linked immunosor- assay systems. Nature 1968;219:186 –9.
bent assay (EIA/ELISA combined), and RIA. (Ordinate), number of articles in
5. Avrameas S, Uriel J. Méthode de marquage d’antigènes et
which the keywords are quoted. (Abscissa), 5-year periods from 1960 to 2005.
⽧, combined EIA/ELISA; f, RIA. [Note: I do not pretend that the numbers in this d’anticorps avec des enzymes et son application en immunodiffu-
figure are precise; the trends, however, are evident.] sion. C R Acad Sci Hebd Seances Acad Sci D 1966;262:2543–5.
2418 Lequin: Historical Note on EIA/ELISA
6. Avrameas S. Coupling of enzymes to proteins with glutaraldehyde. 17. Engvall E. Quantitative enzyme immunoassay (ELISA) in microbi-
Immunochemistry 1969;6:43–52. ology. Med Biol 1977;55:193–200.
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electron microscopic localization of tissue antigens. J Cell Biol Detection of trophoblastic tumour activity by pregnancy-specific
1967;33:307–18. 1 glycoprotein. Int J Cancer 1978;21:265–7.
8. Wide L, Porath J. Radioimmunoassay of proteins with the use of 19. Sipponen P, Ruoslahti E, Vuento M, Engvall E, Stenman U. CEA
Sephadex-coupled antibodies. Biochem Biophys Acta 1966;30: and CEA-like activity in gastric cancer. Acta Hepatogastroenterol
257– 60. (Stuttg) 1976;13:276 –9.
9. Engvall E, Perlmann P. Enzyme-linked immunosorbent assay 20. Uotila M, Ruoslathi E, Envall E. Two-site sandwich enzyme immu-
(ELISA). Quantitative assay of immunoglobulin G. Immunochemis- noassay with monoclonal antibodies to human alphafetoprotein.
try 1971;8:871– 4. J Immunol Methods 1981;42:11–5.
10. van Weemen BK, Schuurs AHWM. Immunoassay using antigen- 21. Engvall E, Wewer UM. The new frontier in muscular dystrophy
enzyme conjugates. FEBS Letts 1971;15:232– 6. research: booster genes. FASEB J 2003;17:1579 – 84.
11. US Patent 762120. United States Patent and Trademark Office