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A brief history of and the birth of the clinical laboratory Part 1—Ancient times through the

By Darlene Berger, former MLO editor (1998-2000) Part 1 in this four-part series was originally published in July 1999.

From tasting urine to hree distinct periods in the history of are associated with three different places and, therefore, microscopy to molecular different methods of determining diagnosis: From the to the 18th century, bedside medi- testing, the sophistication of cine was prevalent; then between 1794 and 1848 came medicine; and from that time forward, laboratory Tmedicine has served as medicine’s lodestar. The laboratory’s diagnostic techniques has contribution to modern medicine has only recently been recog- come a long way and continues nized by historians as something more than the addition of another resource to medical and is now being appreciat- to develop at breakneck speed. ed as the seat of medicine, where account for what they observe in their . The history of the laboratory The first medical diagnoses made by were based on what ancient could observe with their eyes and ears, is the story of medicine’s which sometimes also included the examination of speci- mens. The ancient Greeks attributed all to disorders of from empirical to bodily fluids called humors, and during the late medieval period, doctors routinely performed uroscopy. Later, the experimental techniques and revealed not only the cellular structure of human , but also proves that the clinical lab is the organisms that disease. More sophisticated diagnostic tools and techniques—such as the for measuring the true source of medical temperature and the for measuring rate—were not in widespread use until the end of the 19th century. The clini- authority. cal laboratory would not become a standard fixture of medicine until the beginning of the . This four-part article reviews the history and development of diagnostic methods from ancient to modern times, as well as the evolution of the clinical laboratory from the late 19th century to the present.

c. 1300 Uroscopy is 1592 Galileo Galilei invents the Timeline widespread in Europe. thermometer. c. 300 BC advo- c. 1500 Physicians 1684 Anton van Leewenhoek publishes cates examination of urine to begin using urine color the first drawings of as seen under diagnose disease. charts for visual urinalysis. the microscope. AD 1267 R. Bacon experi- 1590 Hans Janssen 1714 Gabriel Fahrenheit develops the ments with optics, probably invents the compound mercury thermometer and the Fahrenheit produces first microscope. microscope. temperature scale. and Hippocrates

1 HISTORY OF THE LAB – PART 1 MLO ■ www.mlo-online.com Ancient diagnostic methods ments (earth, air, fire and water), corresponded to various In ancient and , the earliest physicians combinations of the physiologic qualities of dry, cold, hot made diagnoses and recommended treatments based pri- and moist. These combinations of physiologic characteris- marily on observation of clinical symptoms. and tics corresponded roughly to the four humors of the were also used. Physicians were able to : hot + moist = blood; hot + dry = yellow bile; describe dysfunctions of the digestive tract, heart and circu- cold + moist = ; and cold + dry = black bile. lation, the and spleen, and menstrual disturbances; Galen was known for explaining everything in light of unfortunately, this empiric medicine was reserved for roy- his theory and for having an explanation for everything. alty and the wealthy. He also described as “ of urine” and Other less-than-scientific methods of diagnosis used in noted the normal relationship between fluid intake and treating the middle and lower classes included divination urine volume. His unwavering belief in his own infallibility through ritual sacrifice to predict the outcome of illness. appealed to complacency and reverence for authority. Usually a sheep would be killed before the statue of a god. Its That dogmatism essentially brought innovation and dis- liver was examined for malformations or peculiarities; the covery in European medicine to a standstill for nearly 14 shape of the lobes and the orientation of the common duct centuries. Anything relating to , and were then used to predict the fate of the . disease was simply referred back to Galen as the final Ancient physicians also began the practice of examining authority from whom there could be no appeal. patient specimens. The oldest known test on body fluids was done on urine in ancient times (before 400 BC). Urine was Middle Ages poured on the ground and observed to see whether it attract- In medieval Europe, early Christians believed that disease ed insects. If it did, patients were diagnosed with boils. was either punishment for sin or the result of witchcraft or The ancient Greeks also saw the value in examining body possession. Diagnosis was superfluous. The basic fluids to predict disease. At around 300 BC, Hippocrates was prayer, penitence, and invocation of saints. Lay medi- promoted the use of the mind and senses as diagnostic tools, cine based diagnosis on symptoms, examination, , pal- a principle that played a large part in his reputation as the pitation, , and inspection of excreta and some- “Father of Medicine.” The central Hippocratic doctrine of times semen. Diagnosis by “water casting” (uroscopy) was humoral attributed all disease to disorders of fluids practiced, and the urine flask became the emblem of of the body. To obtain a clear picture of disease, Hippocrates medieval medicine. By AD 900, Isaac Judaeus, a Jewish advocated a diagnostic protocol that included tasting the and philosopher, had devised guidelines for the patient’s urine, listening to the , and observing use of urine as a diagnostic aid; and under the Jerusalem color and other outward appearances. Beyond that, the Code of 1090, failure to examine the urine exposed a physi- physician was to “understand the patient as an individual.” cian to public beatings. Patients carried their urine to Hippocrates related the appearance of bubbles on the surface physicians in decorative flasks cradled in wicker baskets of urine specimens to and chronic illness. He and, because urine could be shipped, diagnosis at long dis- also related certain urine sediments and blood and pus in tance was common. The first book detailing the color, den- urine to disease. The first description of hematuria, or the sity, quality and sediment found in urine was written presence of blood in urine, by Rufus of Ephesus surfaced at around this time, as well. By around AD 1300, uroscopy around AD 50 and was attributed to the failure of kidneys to became so widespread that it was at the point of near uni- properly in filtering the blood. versality in European medicine. Later (c. AD 180), Galen (AD 131–201), who is recog- Medieval medicine also included interpretation of nized as the founder of experimental physiology, created a dreams in its diagnostic repertoire. Repeated dreams of system of pathology that combined Hippocrates’ humoral floods indicated “an excess of humors that required evacua- theories with the Pythagorean theo- tion,” and dreams of flight signified “excessive evaporation ry, which held that the four ele- of humors.”

1754 1816 R. T. H. 1830 Gerardus Mulder performs introduces percussion of the chest into Laennec invents the first elemental chemical analysis medical diagnosis. the stethoscope; of proteins; J. J. Lister develops an 1770 John Hill introduces a method G. B. Amici invents achromatic microscope and introduces of obtaining specimens for microscopic the dioptric/achro- dark-field microscopy. study. matic microscope. 1836 James Marsh develops a standard 1789 de Fourcroy discovers cholesterol. 1828 British hos- test for arsenic. pitals are organized Uroscopy in an early physician’s office into clinical wards.

2 HISTORY OF THE LAB – PART 1 MLO ■ www.mlo-online.com Seventeenth century The gravimetric analysis of urine was introduced by the The medical advances of the 17th century consisted mostly of Belgian mystic, Jean Baptiste van Helmont (1577–1644). descriptive works of bodily structure and function that laid Van Helmont weighed a number of 24-hour specimens, but the groundwork for diagnostic and therapeutic discoveries was unable to draw any valuable conclusions from his mea- that followed. The status of medicine was helped along by surements. It was not until the late 17th century—when the introduction of the scientific society in Italy and by the Frederik Dekkers of Leiden, Netherlands, observed in 1694 advent of periodical literature. that urine that contained protein would form a precipitate Considered the most momentous event in when boiled with acetic acid—that urinalysis became more since Galen’s time, the discovery of the circulation of blood scientific and more valuable. The best qualitative analysis of by (1578–1657) marked the beginning of a urine at the time was pioneered by Thomas Willis period of mechanical explanations for a variety of functions (1621–1675), an English physician and proponent of chem- and processes, including digestion, metabolism, respiration istry. He was the first to notice the characteristic sweet taste and . The English proved through vivi- of diabetic urine, which established the principle for the dif- section, ligation and perfusion that the heart acts as a muscu- ferential diagnosis of diabetes mellitus and . lar pump propelling the blood throughout the body in a con- with were also getting tinuous cycle. underway with the help of a physiologist in Cornwall, The invention of the microscope opened the door to the England, named Richard Lower (1631–1691). Lower was invisible world just as Galileo’s telescope had revealed a vast the first to perform direct transfusion of blood from one ani- astronomy. The earliest microscopist was a Jesuit priest, mal to another. Other medical innovations of the time Athanasius Kircher (1602–1680) of Fulda (Germany), who included the intravenous injection of , transfusion of was probably the first to use the microscope to investigate blood, and the first attempts to use pulse rate and tempera- the causes of disease. His experiments showed how maggots ture as indicators of status. and other living creatures developed in decaying matter. Kircher’s writings included an observation that the blood of Eighteenth century patients with the contained “worms;” however, what The 18th century is regarded as the “Golden Age” of the suc- he thought to be organisms were probably pus cells and red cessful practitioner, as well as the successful quack. Use of blood corpuscles because he could not have observed (the study of the shape of the skull to predict Bacillus pestis with a 32-power microscope. mental faculties and character), magnets, and various pow- (1635–1703) later used the microscope to document the ders and potions for treatment of illness were a few of the existence of “little boxes,” or cells, in vegetables and inspired more popular scams. The advancement of medicine during the works of later histologists; but some of the greatest con- this time was more theoretical than practical. Internal medi- tributions to medical science came from Italian micro- cine was improved by new textbooks that cataloged and scopist, (1628–1694). described many new forms of disease, as well as by the intro- Malpighi, who is described as the founder of histology, duction of new drugs, such as digitalis and . The state served as physician to Pope Innocent XII and was famous of in the 18th century, however, was alarming by for his investigations of the of the chick and today’s standards. Recovery from surgical operations was the histology and physiology of the glands and viscera. His rare because of septicemia. The concept of antisepsis had not work in embryology describes the minutiae of the aortic yet been discovered, and hospitals were notorious for filth arches, the head fold, the neural groove, and the cerebral and disease well into the 19th century. and optic vesicles. One notable event that is a forerunner to the modern Uroscopy was still in widespread use and had gained pop- practice of laboratory measurement of prothrombin time, ularity as a method to diagnose “chlorosis,” or love-sick plasma thromboplastin time and other coagulation tests, was young women, and sometimes to test for chastity. Other the discovery of the cause of coagulation. An English physi- methods of urinalysis had their ologist, William Hewson (1739–1774) of Hexham, North- roots in the 17th century, as well. umberland, England, showed that when the coagulation of

1841 P. S. Denis describes the 1849 A. E. for performing accurate blood counts separation of blood proteins into Berthold demon- (hemocytometry); G. G. Stokes discovers albumins and globulins by salt strates endocrine fluorescence. precipitation. function by proving 1854 links London 1846 The optical factory of Carl that the testes are outbreak to Broad Street Pump; Jules Zeiss is founded in Jena, Germany. required in roosters Duboscq develops the first visual col- for comb growth. 1847 The American Medical orimeter based on Beer’s Law. Association is founded. 1852 K. Vierordt 1856 William Perkin prepares the first develops a method Early synthetic dye.

3 HISTORY OF THE LAB – PART 1 MLO ■ www.mlo-online.com Table Evolution of diagnostic tests as documented in textbooks of laboratory medicine

Copyright year Author, Title New tests described 1892 Sir , Hemoglobin estimation, red and counts, Textbook of Medicine parasite identification, simple urinalysis, examination of sputum for . 1898 Sir William Osler, Blood culture, agglutination test for typhoid , of Textbook of Medicine Klebs-Löffler bacillus with tests in , lumbar puncture, examination of cerebrospinal fluid in suspected , amino aciduria in . 1901 Sir William Osler, Isolation of typhoid bacilli from urine and the clotting time Textbook of Medicine in hemophilia. 1912 Sir William Osler, Tissue examination for spirochetes in syphilitic , the Wassermann Textbook of Medicine test, osmotic fragility tests, a crude form of the tolerance test. 1914 P. N. Panton Blood counts and examination of stained smears, agglutination (title N/A) reactions, the Wassermann test, parasitology, blood cultures, spectro- scopic examination, visual detection of bilirubinemia, Gmelin tests, Garrod technique for uric acid, alkalinity of blood, (basic and culture methods in use today), urinalysis (pus, red blood cells, albumin, sugar), test meals in use, fecal examinations for fat and sterocobilin, histology (frozen section and paraffin embedding). the blood is delayed, a coagulable plasma can be separated of a healthy person sounds like a cloth-covered drum. A stu- from the corpuscles and skimmed off the surface. Hewson dent of Auenbrugger’s, Jean Nicolas Corvisart, a French found that plasma contains an insoluble substance that can physician at La Charité in Paris, pioneered the accurate diag- be precipitated and removed from plasma at a temperature nosis of heart and using Auenbrugger’s chest- slightly higher than 50°C. Hewson deduced that coagulation thumping technique. Corvisart’s translation of Auen- was the formation in the plasma of a substance he called brugger’s treatise on percussion, “New Invention to Detect by “coagulable lymph,” which is now known as fibrinogen. A Percussion Hidden Diseases in the Chest,” popularized the prac- later discovery that fibrinogen is a plasma protein and that in tice of thumping on a patient’s chest. The resulting sounds coagulation it is converted into fibrin attests to the impor- are different when the lungs contain lesions or fluids than in tance of Hewson’s work. healthy people. This observation was validated by post- The clinical diagnostic methods of percussion, tempera- mortem examination. ture, and measurements were fur- James Currie (1756–1805), a Scot, was the first to use ther refined, and there were some remarkable attempts to cold baths in treatment of typhoid fever; and by employ precision instruments in diagnosis. the patient’s temperature using a thermometer, he was able Leopold Auenbrugger (1722–1809) was the first to use to adjust the temperature and frequency of the baths to percussion of the chest in diagnosis in 1754 in Vienna. This treat individual patients. It took another hundred years, method involved striking the patient’s chest while the patient however, before thermometry became a recognized feature holds his or her breath. Auenbrugger proposed that the chest in clinical diagnosis.

1859 E. Bec- 1869 Luer invents the glass 1875 Corfield establishes the first public querel invents the hypodermic syringe. health laboratory in England; Osaka, fluorescent lamp. 1871 The dry-plate photographic Japan, establishes the Imperial 1866 Voit estab- process is invented. Hygienic Laboratory. lishes the first 1872 Oscar Brefeld develops the use 1879 Karl von Linde invents the hygienic laborato- of a gelatin medium for isolation domestic refrigerator; Thomas Edison ry in Munich. of fungi in pure culture. invents the incandescent light bulb. 1886 Jaffe develops alkaline picrate Uroscopy method for the determination of creatinine;

4 HISTORY OF THE LAB – PART 1 MLO ■ www.mlo-online.com In 1707, Sir John Floyer (1649–1734) of Staffordshire, younger physicians aspired to careers in academic medical England, introduced the concept of measuring pulse rate by centers patterned after German institutions. The younger, timing pulse beats with a watch. He counted the beats per more energetic ranks had to first lobby for such facilities to minute, and tabulated the results; but his work was ignored be built; and as older doctors retired from teaching posts and because of a healthy skepticism for an old Galenic doctrine of turned over editorship of scientific journals, this opposition there being a special pulse for every disease. to the lab faded. The groundbreaking work for measuring blood pressure Medical historians also note that the 19th century was one was done by Stephen Hales (1677–1761), an English clergy- in which the rest of therapeutics lagged behind, and called it man. By fastening a long glass tube inside a horse’s , an era of . New discoveries in bacteriology Hales devised the first manometer or tonometer, which he allowed for water treatment and of milk, used to make quantitative estimates of the blood pressure, the which significantly decreased mortality rates. In addition, the capacity of the heart and the velocity of blood current. Hales’ advent of in the late 19th century reduced work was the precursor for the development of the sphygmo- the mortality from and operations and increased the manometer used today to measure arterial blood pressure. range of surgical work. Medical practitioners relied, for a Additional advances in urinalysis occurred with J.W. time, more on increased and less on drugs. Advances Tichy’s observations of sediments in the urine of febrile in public and personal hygiene had dramatically improved patients (1774); Matthew Dobson’s proof that the sweetness the practice of medicine; predictions were even made that of the urine and blood serum in diabetes is caused by sugar the of the time would eventually be reduced (1776); and the development of the test for sugar in dia- to a small fraction of its size. betic urine by Francis Home (1780). At the beginning of the century, physicians depended pri- marily on patients’ accounts of symptoms and superficial Nineteenth century observation to make diagnoses; manual examination The emergence of sophisticated diagnostic techniques and remained relatively unimportant. By the 1850s, a series of the laboratories that housed them coincides roughly with the new instruments, including the stethoscope, ophthalmoscope worldwide political, industrial and philosophical revolutions and laryngoscope, began to expand the physician’s sensory of the 19th century, which transformed societies dominated powers in clinical examination. These instruments helped by religion and aristocracy into those dominated by the doctors to move away from a reliance on the patients’ experi- industrial, commercial and professional classes. In the ence of illness and gain a more detached relationship with decades after the Civil War, American laboratories and their the appearance and sounds of the patients’ body to make champions were met with a vehement skepticism of science, diagnoses. which was viewed by some as an oppressive tool of capitalist Another wave of diagnostic tools—including the micro- values. The lay public, as well as many practitioners, saw the scope and the X-ray, chemical and bacteriological tests, and grounding of medicine in the laboratory as a removal of machines that generated data on patients’ physiological con- medical knowledge from the realm of common experience ditions, such as the spirometer and the electrocardiograph— and as a threat to . Many American physicians produced data seemingly independent of the physician’s as who went abroad to Germany and France for supplementary well as the patient’s subjective judgment. These develop- training came back to impart the ideals of European medi- ments had uncertain implications for professional autonomy: cine, as well as those of higher education for its own sake, to They further reduced dependence on the patient, but they an American society that found these beliefs threatening. increased dependence on capital equipment and formal orga- The lab itself was not seen as a threat, but rather the claims it nization of medical practice. made to authority over medical practice were assailed. The These detached added a highly persuasive empiricists and the “speculative medical experimentalists” rhetoric to the authority of medicine. They also made it pos- were for the most part divided along generational lines. The sible to move part of the diagnostic process behind the scenes older empiricists had a stake in continuing their careers inde- and away from the patient where several physicians could pendent of a medical infrastructure or system, while the have simultaneous access to the evidence. The stethoscope,

The Pasteur and Surgeons establishes and hire colleagues to perform Institute is a conjoint clinical laboratory in London; laboratory testing; New York City founded in G. S. Woodhead is the Department of Health establishes the first Paris. first director. public diagnostic bacteriology lab in 1890 The 1891 C. E. Brown-Sequard describes the U.S. under Hermann N. Biggs and Royal College “internal secretions” as produced by William H. Park; Laboratory of Hygiene of Physicians specific organs. at the of Pennsylvania is Binocular micro- opened in Philadelphia. scope with light 1892 J. Dewar invents the vacuum flask; collector c.1870 Charles and William Mayo found their

5 HISTORY OF THE LAB – PART 1 MLO ■ www.mlo-online.com A brief history of the hospital he earliest hospitals in pre-industrial societies were charitable institutions used for tending the sick as opposed to medical Tinstitutions that provided for their . Medieval hospitals were operated by religious or knightly orders in individual communities. The facility was essentially a religious house in which the personnel had united as a vocational community under a religious rule. In colonial America, almshouses were the first institutions to provide care for the sick. These facilities also had a communal character in that they provided a substitute residence for people who were homeless, poor, or sick. Founded as early as the 17th century in America, almshouses offered sanctuary to all kinds of dependent people from the elderly to the orphaned, the insane, the ill, and the debilitated. In a number of large cities, hospitals evolved from almshouses: The Philadelphia Almshouse became Philadelphia General Hospital; the New York Almshouse became Manhattan’s Bellevue Hospital; and the Baltimore County Almshouse became part of the Baltimore City Hospitals. The next rendition of the hospital was a facility that served the sick but limited its services to the poor. Not until the 19th century did hospitals serving all classes emerge. The Daughters of Charity Medical Center in New Orleans was founded in 1734, making it the oldest hospital in the United States. New York Hospital was chartered in 1717, but wasn’t opened for another 20 years, and the Massachusetts General Hospital opened in Boston in 1821. These institutions were termed “voluntary” because they were financed with donations, rather than with taxes. In Europe, hospitals figured prominently in and research, but were mostly ignored in America until the founding of Johns Hopkins. Between 1870 and 1910, however, hospitals began to play this part in the United States, as well. Before 1900, the hospital offered no special advantages over the home in terms of surgery. The that periodically swept through the wards made physicians cautious about sending patients there. Antiseptic techniques were for a short time adapted for use in patients’ homes. “Kitchen surgery” became more inconvenient for patient and surgeon alike as procedures became more demanding and more people moved into apartments. As antiseptic techniques improved, and the stigma of disease in the hospital died out, surgery was brought back into the hospital. Source: Starr P. The Social Transformation of American Medicine. New York: Basic Books Inc.; 1982. for example, could only be used by one person at a time, but started a physiologic laboratory in his own house. lab tests and X-rays enabled several doctors to view and dis- Purkinje’s work includes descriptions of the germinal vesi- cuss the results. This team approach to diagnosis strength- cle in the embryo, description and naming of protoplasm, ened the medical community’s claim to objective judgment. discovery of the sudoriferous glands of the skin and their Equipped with methods for measuring, quantifying and qual- excretory ducts, and numerous descriptions of brain, , ifying, doctors could begin to set standards of human physiol- and muscle cells. ogy, evaluate deviations, and classify individuals. When John Snow studied the great London cholera out- break in 1854, he brought it under control by tracing it to Microscopy the Broad Street Pump and eliminating access to this Many were making great strides in bacteriology, source of contaminated water. Snow’s work foreshadowed , and histology as well. Improvements in the some of the earliest successful applications of laboratory microscope allowed further exploration of the cellular and methods to public hygiene that came in the 1860s and microbial worlds in the 19th century. Johannes Evangelista 1870s with the breakthroughs in bacteriology made by Purkinje was an important Bohemian pioneer of the use of and . the microscope. In 1823, he was appointed professor of Louis Pasteur (1822–1895) discovered the anaerobic char- physiology at the University of Breslau; and a year later, he acter of the bacteria of butyric and introduced

1893 J. Elster and H. F. Geitel invent Pepper Laboratory is established at Glasgow, and London by this date. the photoelectric cell; T. W. Richards the Pennsylvania General Hospital. 1897 The first commercial clinical invents the nephelometer; Hermann M. 1896 S. Riva-Rocci invents the laboratory established in England, The Biggs establishes Diagnostic Laboratory sphygmomanometer; C. W. Purdy Association, receives in New York City. publishes Practical Urinalysis and Urinary specimens by mail. 1895 Franz Ziehl and Friedrich Neelsen Diagnosis; Ferdinand Widal develops the Source: CLMA and Garrison. Portions of introduce their modification of the agglutination test for identification of the this timeline are reprinted with permission acid-fast stain for tuberculosis; William typhoid bacillus; in Great Britain, clinical from CLMA. Roentgen discovers X-rays; William laboratories existed in Edinburgh, Leeds,

6 HISTORY OF THE LAB – PART 1 MLO ■ www.mlo-online.com n the 19th century, diagnostic tools— the concepts of aerobic and I Koch received the Nobel Prize. anaerobic bacteria around the including the microscope and These two bacteriologists year 1861. About the same were responsible for the isola- time, he discovered that the X-ray—helped provide hard tion of the organisms responsi- pellicle that is necessary in the ble for major infectious diseases formation of vinegar from wine data independent of subjective and led public health officials to consists of a rod-like microor- make more focused efforts ganism, Mycoderma aceti. In judgment and anecdote. against specific diseases. Sand 1867, the wine industry of filtration of the water supply France reported a significant gain in revenue because of was introduced in the 1890s and proved to be effective in pre- Pasteur’s discovery that the spoiling of wine by microorgan- venting typhoid. Regulation of the milk supply also cut infant isms can be prevented by partial heat mortality dramatically. Antiseptic surgery, which reduced the (Pasteurization) at a temperature of 55–60°C without any mortality from injuries and operations and increased the alteration of the taste. Later (c. 1878), an accident brought range of surgical work, represents another successful applica- about the discovery of preventive inoculation with the weak- tion of the work of these two scientists. ened form of a virus. While Pasteur was away on vacation, virulent cultures of chicken cholera became inactive; and The emergence of quantitative diagnosis when injected into animals, they were found to act as preven- and the hospital laboratory tive against a subsequent injection of a live organ- By the mid-1800s, lab tests had been introduced to detect ism. The attenuated virus could be carried through several tuberculosis, cholera, typhoid and diphtheria, but for generations and still maintain its immunizing property. In these diseases would not come until later. Physicians also 1881, Pasteur produced a against and low- began to study pulse, blood pressure, body temperature and ered the to 1% in sheep and to 0.34% in cat- other physiological indicators, even though simple, practical tle. In 1885, the was opened, and here instruments to measure these signs were not developed until Pasteur worked with several protégés for the rest of his . the end of the century. The use of precise measurements in A contemporary of Pasteur’s, Robert Koch (1843–1910), diagnosis became standard in medicine in the early 1900s. began a brilliant career and a series of discoveries with his Standardized eye tests, weight and height tables, and IQ tests report in 1876 on the complete life history and sporulation were all part of a movement to identify statistical norms of of the anthrax bacillus. His culture methods were confirmed human physiology and behavior. by Pasteur; and in 1877, Koch published his methods of fix- The first hospital lab in Britain, which was set up at ing and drying bacterial films on coverslips, of staining them Guys Hospital, was organized into clinical wards. Two of with Weigert’s aniline dyes, of staining flagella, and of pho- these wards were designated for medical student rotations tographing bacteria for identification and comparison. The and had a small laboratory attached for clinical work. By following year, he published a memoir that included an etiol- 1890, most laboratory procedures in the United States ogy of traumatic infectious disease in which the bacteria of 6 were performed by the physician with a microscope in his different kinds of surgical are described, with the home or office. In 1898, Sir William Osler, a Canadian pathological findings of each breeding true physician, professor, and one of the first well-known through many generations or in animals. In 1881, he authors in the clinical laboratory literature, established developed a method of obtaining pure cultures of organisms ward laboratories at , where rou- by spreading liquid gelatin with infusion on glass plates, tine tests were carried out by attending physicians, and forming a solid coagulum. Koch also played a role in perfect- more complex procedures and research problems were ing the method of steam sterilization. The year after that, he referred to the pathology laboratory. discovered the tubercle bacillus by other special culture and An increasing number of useful laboratory tests were dis- staining methods and formulated a rule for determining the covered in the second half the 1800s, and by the turn of the specificity of disease-causing organisms. The rule, called century, specific chemical and bacteriological tests for dis- Koch’s postulates or Koch’s law, stipulated that the specifici- ease emerged rapidly. In the 1880s, the organisms responsi- ty of a pathogenic microorganism could only be established ble for tuberculosis, cholera, typhoid and diphtheria were if: (1) it is present in all cases of the disease, (2) inoculations isolated; and by the mid-1890s, lab tests had been intro- of its pure cultures produce disease in animals, (3) from these duced to detect these diseases. The spirochete that causes cultures it can again be obtained, and (4) then it can again be was identified in 1905; the Wassermann test for propagated in pure cultures. In 1883, Koch discovered syphilis was introduced in 1906. Advances in the analysis of Cholera vibrio and recognized its routes of as urine and blood gave physicians additional diagnostic tools. drinking water, food and clothing. In 1893, he wrote an These innovations were the result of progress in basic sci- important paper on waterborne showing how they ence that made it possible to duplicate successful applica- could be prevented by proper filtration. Finally, in 1905, tions more rapidly than ever before. The earlier advances in

7 HISTORY OF THE LAB – PART 1 MLO ■ www.mlo-online.com , such as vacci- Vierordt introduced coagulation time nation, had been purely empirical dis- as an index of blood coagulative coveries and were not quickly repeated. power. Sir Almroth Edward Write, an Microbiology for the first time enabled Irish professor of pathology in physicians to link disease-causing Dublin, was the first to observe the organisms, symptoms and lesions sys- role of calcium salts in the coagulation tematically. The principles that Pasteur of blood. He also devised a coagu- demonstrated in the development of lometer to estimate coagulation time. anthrax and vaccines now provid- In 1879, (1854–1915), a ed a rational basis for developing vac- Czech cellular pathologist and cines against typhoid, cholera and chemist, was enamored with dyes and plague. developed many methods of drying and fixing blood smears using heat. Surgery Ehrlich also discovered mast cells and Surgery enjoyed tremendous gains in saw their granulations using a basic the late 1800s. Before , aniline stain. His classification of surgery required brute force and speed white blood cells into different mor- because it was important to get in and phological types (neutrophilic, out of the body as quickly as possible. basophils and oxyphilic) paved the After William T. G. Morton’s way for identifying many diseases of (1819–1868) demonstration of ether at the blood. Ehrlich also contributed to the Massachusetts General Hospital in microbiology the discovery of methyl- 1846, use of anesthesia allowed for ene blue as a bacterial stain.  slower and more careful operations. ’s (1827–1912) methods of Editor’s note: antisepsis using carbolic acid, first pub- A review of diagnostic and dis- lished in 1867, became general practice covery from ancient times to the nineteenth around 1880 and improved the previ- century establishes the emergence and pop- ously grim mortality rates for all types ularization of laboratory medicine at about of surgery. Before antiseptic tech- 1850. The advent of antiseptic surgery, as niques, the mortality rate for amputa- well as public and personal hygiene, attest tions was about 40%. Surgeons were to the benefits that other branches of medi- reluctant to penetrate the major bodily cine have enjoyed as a direct result of the cavities, and then only as a last resort. efforts of laboratory scientists during this After surgeons were able to master the period. Part 2 of this series explores the tedious procedures demanded in anti- development of modern , , they began to explore the as well as takes a retrospective look at the abdomen, chest and skull and devel- ever-changing regulatory landscape in the oped specific techniques for each area. United States. The sophistication and success of surgery blossomed in the 1890s and Bibliography early 1900s, spurred on by the develop- 1. Bettmann OL, Hench PS. A Pictorial . Springfield, IL: Charles C. Thomas; 1956. ment of X-rays in 1895. Surgeons were 2. Cahan D. The institutional revolution in German physics, able to operate earlier and more often 1865–1914. In: Historical Studies in the Physical . Vol. 15 1984: p. 1–65. for a variety of ills, including appendici- 3. CLMA Ensuring universal access to quality laboratory ser- tis, gall bladder disease and stomach vices: CLMA White Paper. Clinical Laboratory Management Review. 1994;8(3):198–240. ulcers. The growth in surgical work 4. Cunningham A, Williams P. The Laboratory Revolution in provided a means for expanding profit Medicine. Cambridge, Great Britain: Cambridge University in hospital care as well (see Sidebar, “A Press; 1992. 5. Gantzer ML. The value of urinalysis: An old method con- brief history of the hospital”). tinues to prove its worth. Clinical Laboratory News. 1998;12(1):14–16. 6. Garrison FH. History of Medicine. Philadelphia: W.B. Saunders Co.; 1929. In the later part of the century, several 7. Marti-Ibañez F. The Epic of Medicine. New York: Clarkson N. Potter, Inc.; 1962. discoveries emerged as the foundation 8. Starr P. The Social Transformation of American Medicine. of hematologic methods. In 1877, K. New York: Basic Books, Inc.; 1982.

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