A Guide to the History of Clinical ChemistryLarry J. Kricka1* and John Savory2

BACKGROUND: This review was written as part of the cel-ebration of the International Year of Chemistry 2011.

CONTENT: In this review we provide a chronicle of thehistory of clinical chemistry, with a focus on NorthAmerica. We outline major methodological advancesand trace the development of professional societies andjournals dedicated to clinical chemistry. This reviewalso serves as a guide to reference materials for thoseinterested in the history of clinical chemistry. The var-ious resources available, in sound recordings, videos,moving images, image and document archives, muse-ums, and websites dedicated to diagnostic companytimelines, are surveyed.

SUMMARY: These resources provide a map of how themedical subspecialty of clinical chemistry arrived at itspresent state. This information will undoubtedly helpvisionaries to determine in which direction clinicalchemistry will move in the future.© 2011 American Association for Clinical Chemistry

The International Year of Chemistry 2011, designatedby the United Nations General Assembly, has the goalof increasing public awareness of chemistry in meetingworld needs, increasing the interest of young people inchemistry, generating enthusiasm for the creative fu-ture of chemistry, and celebrating the 100th anniver-sary of Madam Curie’s Nobel Prize. Clinical chemistrymost certainly must be featured in such an initiativebecause it plays a key role in the diagnosis and treat-ment of the sick and in the maintenance of healththrough preventative medicine. Clinical chemistry alsohas a direct link to the contributions of Marie Curiethrough the development of the technique of RIA(which led to Roslyn Yalow’s Nobel Prize). This tech-nique has revolutionized endocrinology and has led toremarkable contributions to other subspecialties (suchas toxicology and cardiology).

To write this review we have delved into the ar-chives of clinical chemistry to provide a guide to refer-ence materials, with a focus on North America, to helpthose interested in the history of clinical chemistry.These archival materials provide a map of how thismedical subspecialty arrived at its present state, infor-mation that will undoubtedly help visionaries to deter-mine the direction in which clinical chemistry willmove in the future.

Clinical chemistry is the term most commonlyused around the world to define the field, althoughclinical biochemistry and chemical pathology are alsowidely used. Because chemistry is the foundation of thescience that underlies biochemistry and pathophysiol-ogy, it is appropriate to use the term clinical chemistry.To reach the level of sophistication that defines presentday clinical chemistry, major advances in analyticalchemistry, biochemistry, and pathophysiology havebeen necessary. Clinical chemistry is that branch ofmedical science that involves the analysis of biologicalmaterials, usually body fluids, to provide diagnostic in-formation on the state of the human body. Veterinaryclinical chemistry is a branch of clinical chemistry ap-plied to animals. The production of accurate, precise,and timely results, and the interpretation of these re-sults and assessment of margins of error, are key ele-ments in clinical chemistry and are the most importantskills of the clinical chemist.

Chronicle of the History of Clinical Chemistry

This discipline, which could originally be practiced insmall laboratories in which relatively few manual testswere performed, now requires highly automated and in-tegrated laboratories that perform millions of tests eachyear (Fig. 1). There is a body of literature, albeit not exten-sive, in which the history of clinical chemistry is chroni-cled. Table 1 lists the most significant general reviews ofthe field, most of which chronicle the development ofclinical chemistry from its beginnings in antiquity (1–11).

Johannes Buttner has contributed several articlesand books based on research of the roots of clinicalchemistry, with a primary focus on clinical chemistryin Germany (3– 6 ). These texts include History of Clin-ical Chemistry (5 ), edited by Buttner, which exploresthe origins of clinical chemistry. The most ambitiouspublication on the history of clinical chemistry is abook by Louis Rosenfeld, Four Centuries of Clinical

1 Department of Pathology and Laboratory Medicine, University of PennsylvaniaMedical Center, Philadelphia, PA; 2 Department of Pathology, University ofVirginia, Charlottesville, VA.

* Address correspondence to this author at: Department of Pathology andLaboratory Medicine, 3400 Spruce St., Philadelphia, PA 19104-4283. Fax 215-662-7529; e-mail kricka@mail.med.upenn.edu.

Received March 18, 2011; accepted March 29, 2011.Previously published online at DOI: 10.1373/clinchem.2011.165233

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Chemistry (9 ), which describes the development ofknowledge of analytical chemistry and biochemistryand the emergence of clinical chemistry. Contributionsbeginning in the 16th century and leading to more re-cent times are covered. Specific assays that formed thecornerstone of the clinical chemistry laboratory in the1960s are described, such as glucose, urea, creatinine,electrolytes, cholesterol, some basic enzymes, total pro-tein, and albumin/globulin. Of course, the contribu-

tions and impact of Donald Dexter Van Slyke, StanleyBenedict, and Otto Folin are prominently featured, asis the introduction of analysis by color comparison andthe Duboscq colorimeter, invented by Jules Duboscq in1870. Rosenfeld’s extensive publication was precededin 1973 by an article by Wendell Caraway, a practicingclinical chemist in Michigan who graced the clinicalchemistry scene in the post–World War II era. Carawaywas the president of AACC from 1965 to 1966 and was

Fig. 1. The clinical chemistry laboratory then and now.

(A), Then: Otto Folin in the biochemistry laboratory at McLean Hospital, Boston, MA in 1905 (http://en.wikipedia.org/wiki/File:1905_Otto_Folin_in_biochemistry_lab_at_McLean_Hospital_byAHFolsom_Harvard.png). (B), Now: the Autolab in the Depart-ment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, in 2011.

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a pioneer in chronicling the history of clinical chemis-try. His landmark papers (1, 2 ) are concise and presenta fascinating exploration of the origins of the field.

Major technological milestones that have contrib-uted to the present day clinical chemistry laboratoryare listed in Table 2 (2, 12–23 ). The analytical balancehas been known since antiquity because the accurateweighing of gold and other precious materials was vi-tally important in ancient civilizations and contributed

to the development of trade and accumulation ofwealth. Spectrophotometry, a development that datesback more than a century, has, in all of its forms, cer-tainly contributed the most to the process of perform-ing basic measurements in the routine clinical chemis-try laboratory. Previously known as colorimetry, thismethod was used for most of the early clinical chemis-try assays such as urea, creatinine, uric acid, glucose,total protein, and albumin. Chemical reactions be-

Table 1. General history of clinical chemistry.

Title Year Reference

Scientific Development of Clinical Chemistry to 1948 1979 Caraway (1 )

Major Developments in Clinical Chemistry Instrumentation 1981 Caraway (2 )

Emergence of Clinical Chemistry in the 19th Century: Presuppositions andConsequences

1982 Hickel (3 )

From Medicinal Chemistry to Biochemistry: The Making of a BiomedicalDiscipline

1982 Kohler (4 )

History of Clinical Chemistry 1983 Buttner (5 )

Roots of Clinical Chemistry 1987 Buttner and Habrich (6 )

Clinical Chemistry as Scientific Discipline: Historical Perspectives 1994 Buttner (7 )

Laboratory Instrumentation in Clinical Biochemistry: A Historical Perspective 1997 Olukoga et al. (8 )

Four Centuries of Clinical Chemistry 1999 Rosenfeld (9 )

A Golden Age of Clinical Chemistry 2000 Rosenfeld (10 )

Clinical Chemistry since 1800: Growth and Development 2002 Rosenfeld (11 )

Table 2. Milestones in the application of instrumental techniques to clinical chemistry.

Instrument/technique Developer Year Reference

Analytical balance for urinalysis Bang IC 1913 Caraway (2 )

Duboscq colorimeter for the measurementof creatinine in urine

Folin O 1904 Caraway (2 )

Beckman DU spectrophotometer Cary AH and Beckman AO 1941 Caraway (2 )

Atomic spectroscopy

Flame photometry Hald P 1947 Hald (12 )

Atomic absorption Zettner A 1964 Zettner and Seligson (13 )

Gasometric analysis Haldane JS 1912 Caraway (2 )

Electrochemical techniques Hober R 1900 Caraway (2 )

Proficiency testing Sunderman FW Sr 1945 Sunderman (14 )

Zone electrophoresis Cremer HD and Tiselius A 1950 Cremer and Tiselius (15 )

Durrum EL 1950 Durrum (16 )

RIA Berson SA and Yalow RS 1959 Berson and Yalow (17 )

Monoclonal antibodies Schwaber J 1973 Schwaber and Cohen (18 )

Automation Skeggs LT 1957 Skeggs (19 )

Computers Sunderman FW Jr. et al. 1968 Sunderman (20 ), Sunderman et al. (21 )

Point-of-care testing/dry reagent technology Free AH et al. 1957 Free et al. (22 )

PCR Mullis K 1983 Mullis et al. (23 )

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tween the analyte and a reagent that possessed somedegree of specificity were used with a final colorimetricmeasurement and calculated against a standard curve.Most reactions were relatively insensitive and requiredrelatively high volumes of sample that would lead toprotein precipitation. Hence, protein-free filtrateswere usually required and resulted in time-consumingmeasurements. The introduction of enzymes as re-agents and the use of measurement in the ultravioletwavelength range led to increased sensitivity, decreasedsample volume, and simpler analytical procedures.Urease, which converts urea to ammonium ion, wasused as early as 1914 (24 ). The modern clinical chem-istry laboratory now uses a wide variety of photometrictechniques, including fluorescence, fluorescence po-larization, nephelometry, chemiluminescence, phos-phorescence, and electrochemiluminescence. It is withsome hesitation that we include the technique of gas-ometry into this list of important breakthroughs intechnology. Gasometric techniques were doomed toextinction from their first use because they were socumbersome and fraught with mercury-related envi-ronmental problems; however, the use of such meth-ods led to a basic understanding of blood gases andacid– base balance. There is no question that the inven-tion of the continuous-flow autoanalyzer changed thecharacter of clinical chemistry testing so that minutesrather than hours (or days) were needed to complete ananalysis, and personnel were then free to developemerging subspecialties such as toxicology, endocri-nology, and later, molecular diagnostics. Other inno-vative approaches to automation were also introduced,including the centrifugal analyzer developed by Nor-man Anderson in 1968 (25 ). This instrument was thefirst clinical analyzer to incorporate a computer. Thefinal autoanalyzer, the SMAC (Sequential Multiple An-alyzer with Computer), introduced in 1974, also had abuilt-in computer. An instrument known as the RobotChemist, which was introduced by the Research Spe-cialties Company in 1959, used conventional cuvetteswith automatic pipetting and mixing, but the mechan-ical complexity of the instrument made it impractical.One of us (J. Savory) worked with both the first auto-analyzer and the Robot Chemist and can attest to theabove statement. Eventually automated pipetting wasperfected and it is now the approach of choice for au-tomation in clinical chemistry laboratories, thanksmainly to the introduction of the Beckman Astra in1978. As early as 1949, Örjan Ouchterlony used anti-bodies as reagents for immunodiffusion methods (26 ),but the major breakthrough was with the application ofRIA, which was developed by Solomon Berson and Ro-salyn Yalow and for which Yalow was awarded the No-bel Prize. The introduction of this method made avail-able for the first time highly specific and sensitive

methods for measurement of a wide variety of hor-mones, proteins, and drugs. This technique replacedother bioassays for pregnancy, including follicle-stimulating hormone, and indirect hormone tests such as17-ketosteroids. Many immunoassay techniques are usedin clinical chemistry laboratories and are reviewed in Ta-ble 3 (27). Other than the invention of RIA, the mostimportant development in immunoassay techniques wasthe ability to produce monoclonal antibodies, which haveserved as immensely important reagents with a large vari-ety of applications. Controversy exists as to who first pro-duced monoclonal antibodies in the laboratory, but thisachievement is often ascribed to Jerrold Schwaber (18).Other important milestones in clinical chemistry and ac-counts of their histories are listed in Table 2 and Table 3(27–37), respectively. These milestones include the intro-duction of computers to handle the massive amounts ofdata produced by the modern clinical chemistry labora-tory; the development of dry reagent technology, whichhas revolutionized point-of-care and self-testing; profi-ciency testing to improve quality; and, of course, PCR,which has brought molecular diagnostics into the fore-front of diagnostic testing.

As clinical chemistry developed as a medical sub-specialty in different parts of the world, professionalsocieties and journals were founded to represent andcater to the professional needs of clinical chemists.There are historical accounts of clinical chemistry inBritain (38, 39 ), France (39 ), Austria (40 ), the US(41 ), and Scotland (42 ).

Histories have also been written of 2 importantearly US clinical chemistry laboratories, the WilliamPepper Laboratory of Clinical Medicine of the Univer-sity of Pennsylvania (Fig. 2), (43 ) and the Children’sHospital of Columbus, Ohio (44 ). In addition, the his-tory of the journal Clinical Chemistry has been summa-rized by its long-time editor J. Stanton King (45 ).

Table 3. Histories of key techniques andtechnologies in clinical chemistry.

Technique Reference

Filter paper electrophoresis Martin and Franglen (28 )

Clinical enzymology Buttner (29 )

Urinalysis White (30 )

Blood gas analysis Severinghaus and Astrup (31 ),

Breathnach (32 )

Dry chemistry (Eastman Kodak) Kaiser (40 )

Lipid and lipoprotein testing Sunderman (41 )

Enzyme immunoassay/ELISA Simpson (42 ), Young et al (43 )

Molecular (DNA/RNA)diagnostics

Meites (44 )

Immunoassay Wu (27 )

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One of the most fascinating aspects of the study ofthe history of clinical chemistry is the lives of those whofounded the field. Otto Folin was one of the pillars ofthe field of clinical chemistry, and his life and work arecaptured in Samuel Meites’ biography of Folin (46 ).Biographies of other key figures include those of HenryBence Jones (47 ) and Joachim Kohn (developer of cel-luose acetate electrophoresis) (48 ).

The first professional organizations dedicated toclinical chemistry sprang up in the 1940s, beginningwith the AACC in the US in 1948 (49 ). This was fol-lowed by the founding of national societies for clinical

chemistry in many countries (e.g., the Association forClinical Biochemistry in the UK in 1953) (50 ) and alsoan international body, initially known as the Interna-tional Association of Clinical Biochemists (1952) thatsubsequently became the IFCC (International Federa-tion of Clinical Chemistry) in 1953 (51 ).

Museums of Clinical Chemistry

The size and weight of some of the larger clinical chem-istry analyzers has no doubt posed a barrier to theirretention for exhibition in museum collections. Never-

Fig. 2. (A), William Pepper Laboratory of Clinical Medicine, Hospital of the University of Pennsylvania, circa 1925,(built 1894–1897, Cope and Stewardson, architects, demolished in 1928) (©courtesy of the University of Pennsyl-vania Archives); (B), the terra cotta frieze from the north face of the William Pepper Laboratory of Clinical Medicinenow displayed on the seventh floor of the Maloney building at the Hospital of the University of Pennsylvania.

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theless, several museums have exhibits related to thehistory of clinical chemistry that contain analyzers ofdifferent types. The Chemical Heritage Foundation(CHF) (52 ) has a number of clinical chemistry analyz-ers on display, such as a Technicon AutoAnalyzer Sam-pler Unit, in their permanent exhibition in Philadel-phia, “Making Modernity.” The AACC also has a smallexhibit of historic instruments at its office in Washing-ton, DC, which includes a Klett Photoelectric Color-imeter, a Folin-Wu Sugar Tube, a Technicon Auto-Analyzer System, and a Beckman Model DUSpectrophotometer (53 ). The Beckman Coulter Heri-tage Center and Caltech’s Science Museum’s BeckmanRoom Exhibit (54 ) feature exhibits relating to the workof Arnold O. Beckman and the analyzers produced bythe Beckman company. In addition, several companieshave virtual museums in the form of illustrated onlineinteractive timelines and histories, e.g., BeckmanCoulter (55 ), Ortho Clinical Diagnostics (56 ), AbbottLaboratories (57 ), Roche (58 ), Instrumentation Labo-ratory (59 ), and Olympus (60 ).

Sound Recording, Video, Movie, Image, andDocument Archives

Various archives of surviving photographs, movingimages and oral histories, and collections of artifactsand memorabilia, make it possible to trace the growthof clinical chemistry from its origins in small one-roomlaboratories with a few staff performing a very limitedmenu of manual tests to large modern laboratorieswith large staffs overseeing an extensive menu of highlyautomated tests.

The Science Museum in London, UK, has a web-site, Brought to Life, which explores the history of medi-cine. It includes images of early instrumentation (e.g., aureometer from the 1800s), urine test kits (e.g., theClearblue One Step Pregnancy test kit, England, 1988),and biographies of famous clinical chemists [e.g.,Leonard Skeggs (1918 –2002)] (61 ). Getty Images (62 )also provides numerous images relating to home test-ing (e.g., pregnancy and diabetes testing).

The Wellcome Images: 2000 Years of HumanCulture archive at the Wellcome Library, also lo-cated in London (63 ), contains numerous imagesrelating to test strips (e.g., pregnancy tests, urinetests) and glucose meters. A detailed and illustratedhistory of pregnancy testing can be found on theNIH archive (64 ). This source contains images oftest devices and early advertisements for over-the-counter pregnancy tests.

The Wellcome Moving Image and Sound Collection(a collection of moving images on 20th-century health-care and medicine) contains what may be the earliestmovie of a hospital laboratory, shot around 1932 at the

Royal Hospital Sheffield (Sheffield, UK) (65). It shows aclinical chemist performing a glucose test. This imageprovides a graphic illustration of the changes in labora-tory safety standards between now and then: he is mouth-pipetting and not wearing gloves! (Fig. 3). Despite thelong and concurrent histories of the clinical laboratoryand movie/video cameras, there are relatively few otherexamples of movies or videos showing the content andworkings of early clinical laboratories. Another notableexample is the movie taken by Peter Wilding in 1966 at theclinical chemistry laboratory of the Los Angeles GeneralHospital, California (66). This archive also has video re-cordings of lectures on RIA by John Landon at the Uni-versity of London in 1972.

In addition, the Nobel Prize website contains linksto a video lecture (“RIA: Tool for Biomedical Investi-gation and Clinical Medicine”) presented by RosalynYalow (1977 Nobel Prize in Physiology or Medicine) atthe 1978 Nobel Laureate Meeting in Lindau, Austria(67 ). There are now available numerous grand roundsvideo archives and live audio and synchronized Pow-erPoint presentations of more recent lectures by fa-mous clinical chemists, and these provide a historicalrecord of the state of knowledge and thinking at a par-ticular point in time.

Notably, the Smithsonian Institution Archives(Oral Histories in Medicine and the Health Sciences)has a number of oral and video histories of relevance toclinical chemistry, including histories of DNA se-quencing and PCR (68 ).

A more extensive collection of interviews withprominent clinical chemists is to be found on theOral Histories section of the CHF website (69 ). Inaddition the CHF website includes images of clinicalanalyzers such as the circa 1975 YSI (Yellow SpringsInstrument) Blood Glucose Analyzer, Model 23A(70 ), and the Photovolt Hemoglobin and GlucoseMeter (71 ).

The Images from the History of Medicine website pro-vides access to images in the collections of the History ofMedicine Division of the US National Library of Medi-cine (72). This collection contains images of clinicalchemists (e.g., Donald S. Fredrickson), chemistry labora-tories of various military and university hospitals (e.g.,University of Virginia Hospital in 1929, the chemistry lab-oratory in the laboratory of pathology at St. Elizabeth’sHospital Blackburn, UK, circa 1910), and posters for cho-lesterol testing and for the National Medical LaboratoryWeek. One of the latest image archive initiatives has beenthe AACC History Division Analyzer Archive. The objec-tive of this project is to collect images of the full scope ofclinical laboratory analyzers (including chemistry, immu-noassay, hematology, and other areas) and associated au-tomation equipment (73).

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The advent of YouTube in 1985 has provided asource for numerous contemporary videos of clinical lab-oratories, commercial diagnostic tests, and the testing thatis performed. These films will provide future historianswith a wealth of historical data on clinical chemistry fromthe end of the second millennium onwards. A notableentry on YouTube is the introductory video for the 45thannual meeting of the AACC in New York, NY, in 1993,which documents the contribution of the NortheasternUS to the development of clinical chemistry (74).

Whither Clinical Chemistry?

At the AACC National Meeting in 1984, one of us (J.S.)presented the National Lectureship Lecture, which wasentitled “On Such a Full Sea Are We Now Afloat,” a quo-tation from Shakespeare’s Julius Caesar. The year, 1984,was a time of some despondency by clinical chemists be-cause the exciting early times of method development inthe hospital laboratory had been virtually taken over bycommercial manufacturers of instruments and reagents.The purpose of the lecture was to point out the goldenfuture of the field, with the introduction of molecular di-agnostics, the applications of robotics, and the routine useof mass spectrometry in the clinical chemistry laboratory

of the future. Now, some 27 years later, these predictionshave come to pass.

As we conclude this present history we are cau-tiously offering our predictions for the next quartercentury. We expect that as the cost of healthcare con-tinues to spiral almost out of control, major develop-ments in technology related to clinical chemistry willbe made to reduce these costs. More point-of-care test-ing linked to telemedicine will be introduced to de-crease the number of hospital visits for patients withchronic conditions and hence reduce overall healthcarecosts. We will mimic the electronics industry and seemore technology convergence and cost reduction forhandheld devices. Emphasis will continue to be placedon more specific markers for disease and testing for apatient’s vulnerability to acquiring an illness. Cancerand heart disease will continue to be targeted, but therewill be an intense initiative to develop early markers forneurodegenerative disorders. Despite a great deal ofresearch into the pathogenesis of Alzheimer and Par-kinson disease, little progress at the early detection andtreatment has been made. This will change and we an-ticipate that the clinical chemistry laboratory will playan important role.

Fig. 3. A hospital biochemist performing a blood glucose test at the Royal Hospital Sheffield, UK, circa 1932 [framegrabbed from Hospital Laboratory, Skinner and Watson (65)].©Reproduced with permission from the Wellcome Library, London.

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As members of the clinical chemistry fraternity wecan take great pride in our heritage and look forward tothe future with considerable optimism.

Author Contributions: All authors confirmed they have contributed tothe intellectual content of this paper and have met the following 3 re-

quirements: (a) significant contributions to the conception and design,acquisition of data, or analysis and interpretation of data; (b) draftingor revising the article for intellectual content; and (c) final approval ofthe published article.

Authors’ Disclosures or Potential Conflicts of Interest: No authorsdeclared any potential conflicts of interest.

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ReviewInternational Year of Chemistry 2011

1126 Clinical Chemistry 57:8 (2011)