Garrod, Archibald Edward
GARROD, ARCHIBALD EDWARD
(b. London, England, 25 November 1857; d. Cambridge, England, 28 March 1936)
medicine, medical chemistry, genetics.
Garrod was the fourth and youngest son of Sir Alfred Baring Garrod, physician to King’s College Hospital, and his wife, Elisabeth Ann Colchester. In 1848 his father, deeply interested in chemistry, discovered that in patients suffering from gout, the blood contains an elevated concentration of uric acid, an observation that enabled him to distinguish gout from rheumatoid arthritis.
Garrod was educated at Marlborough, whence he went to Christ Church, Oxford. In 1880 he was graduated B.A., with first-class honors in natural science, and began to study medicine at St. Bar tholomew’s Hospital, London. Four years later he received the M.R.C.S. diploma of the Royal College of Surgeons and was graduated M.B. at Oxford. In 1886 he proceeded to the Oxford M.D. degree, and the same, year married Laura Elisabeth Smith, daughter of Sir Thomas Smith, baronet, surgeon to St. Bartholomew’s Hospital.
After receiving his medical qualification in 1884, Garrod remained at St. Bartholomew’s Hospital, first as a house physician (1884–1887) and then as casualty physician, assistant demonstrator in practical medicine, medical registrar, demonstrator of morbid anatomy, and lecturer on chemical pathology. While engaged in the daily work of a medical school teacher and the care of patients in the hospital, Garrod also pursued research. In 1886 he published his first book, a manual on the use of the laryn goscope, and in 1888 became a member of the Royal College of Physicians of London. In 1890 Garrod published a work on rheumatism and rheumatoid arthritis, diseases on which he had already written several papers pointing out the close connection among rheumatic fever, chorea, and endocarditis. Garrod argued that rheumatoid arthritis was essen tially a disease of the joints and should be distinguished clearly from rheumatism, which he viewed as a single, specific disease that might manifest itself as rheumatic fever, rheumatic heart disease, or chorea. In 1891 he was elected a fellow of the Royal College of Physicians.
In his studies of rheumatic diseases, Garrod began in the 1890’s to investigate both normal and abnormal pigments in the urine for the purpose of detecting changes in metabolism induced by disease. In 1892 he found an unusually colored urine in a patient suffering from chorea and showed that it was caused by the pigment urohematoporphyrin.1 He worked out methods for the separation of the pigment and showed that it was present in small amounts in normal urine.2 In 1896 Garrod began, in collaboration with the biochemist Frederick Gowland Hopkins, to study the urinary pigment urobilin, describing its spectroscopic properties.3
In addition to his posts at St. Bartholomew’s Hospital, Garrod served on the visiting staffs of the West London Hospital and of the Hospital for Sick Children in Great Ormond Street. In 1897, at the Hospital fro Sick Children, Garrod examined a three month-old boy. Thomas P., brought to the outpatient department because his urine was staining his diapers a deep reddish-brown. Garrod recognized the phe nomenon as alkaptonuria, a condition described in 1822 by Alexandre Marcet and named in 1858 by the pharmaceutical chemist Carl Heinrich Detlev Bodeker.4 In 1891 Michajl Volkov and Eugen Bau mann found that the pigment in alkaptonuric urine was a derivative of the amino acid tyrosine, and they named it homogentisic acid.5 From his study of Thomas P., Garrod developed an improved method for the extraction of homogentisic acid from the urine.6 He went on to determine the levels of homogentisic acid in four other patients with al kaptonuria. Thesecond patient, a boy of fourteen, had a brother with alkaptonuria.
In 1899 Garrod drew together data on thirty-nine cases of alkaptonuria, either recorded in the literature or observed by himself or other London physicians.7 He noted the tendency of the anomaly to occur among siblings, but at that time he knew of no instance of the transmission of alkaptonuria from one generation to another.
In March 1901 a fifth child born to the parents of Garrod’s former patient Thomas P. proved to have alkaptonuria. Three of the five children in the family were alkaptonuric, and several months later Garrod thought to ask the mother whether she and her husband were related. He learned that they were first cousins: their mothers were sisters. When Garrod inquired about other families possessing one or more children with alkaptonuria, he found that in each instance the parents were first cousins.
In accordance with the germ theory of disease, then strongly in the ascendant. Garrod had first thought that alkaptonuria must result from an in testinal infection by some organism that converted tyrosine to homogentisic acid. But one afternoon, as he was walking home from the hospital, thinking about the question, it occurred to him that alkap tonuria might result from some error in the metab olism more or less comparable with a structural malformation. It should not be considered a disease, but simply an alternative course of metabolism, in herited and harmless.8
Garrod saw, too, that Mendel’s laws of inheritance, presented to English readers by the biologist William Bateson in his book Mendel’s Principles of Heredity (1902), provided an explanation of the puzzling phe nomenon of alkaptonuria. The mating of first cousins created the conditions that enabled a rare, recessive character to appear. Garrod found that some twelve alkaptonuric children, described by himself and others, all resulting from the marriages of first cous ins, had a total of thirty-six normal siblingsm-a ratio of three normal children to one alkaptonuric in fam ilies containing alkaptonuries. Such a perfect 3: 1 Mendelian ratio showed that alkaptonuria was in herited as a simple Mendelian recessive factor.
To reinforce his view that alkaptonuria was simply an alternative mode of metabolism. Garrod studied such similar familial anomalies as albinism and cys tinuria. Like alkaptonurics, albinos tended to be the offspring of marriages of first cousins. Garrod suggested that in addition to the known anomalies he had studied, others might exist still unrecognized. Just as no two individuals of a species were exactly identical in bodily structure, neither might their in ternal chemistry be exactly the same.
In June 1908 Garrod delivered the Croonian Lec tures before the Royal College of Physicians of London on the various metabolic anomalies he had studied and published them as a book entitled Inborn Errors of Metabolism. By 1908 he was able to suggest that the anomaly in alkaptonuria derived from the lack of a specific enzyme that catalyzed a specific chemical change within living tissue. The lack of such an enzyme would result in the accumulation of an intermediate substance that would then be excreted. The metabolic error in alkaptonuria was an inability to break down the aromatic portion of the molecules of phenylalanine and tyrosine. Since the inborn error was inherited and caused by a specific Mendelian factor (in modern parlance, a gene), Garrod was introducing a link between a specific enzyme and a specific gene. He thus fore-saw the one gene–one enzyme hypothesis that in the 1940’s would be developed so effectively by George Wells Beadle and Edward L. Tatum in their study of the fungus Neurospora, and that has been central to the development of theories of gene action.
From a historical standpoint, Garrod’s work rep resents a convergence of clinical medicine and med ical chemistry with the new science of genetics that developed so rapidly after 1900. In England during the 1890’s the presuppositions of both medical chemistry and clinical medicine were undergoing subtle but profound change under the influence of Charles Darwin’s theory of natural selection, an influence especially great upon Garrod and Hopkins. In Garrod’s work, clinical medicine and medical chemistry joined with genetics to produce the concept of inborn errors of metabolismm-a concept containing the views that metabolism consisted of a series of chemical reactions and intermediate substances and that the production of the enzyme catalyzing each metabolic reaction was governed by a specific in herited factor.
In recognition of his contributions to science, Garrod was elected a fellow of the Royal Society in 1910. In 1912 he was appointed a full physician to St. Bartholomew’s Hospital. Following the out break of World War I in 1914, Garrod joined the staff of the First London General Hospital at Cam berwell. In 1915 he was promoted to temporary colonel in the Army Medical Service and went to Malta, where he remained until 1919 as consulting physician to the Mediterranean forces. In 1918 he was knighted. Two of Garrod’s three sons were killed in action during the war, and one died of influenza after the armistice. In 1919 Garrod returned to St. Bartholomew’s Hospital as director of a new medical unit that included a clinical laboratory close to hospital wards.
In 1920 Garrod succeeded Sir William Osler as Regius professor of medicine at Oxford University. At Oxford he worked to develop clinical investi gation. He emphasized that in disease the clinician saw unique phenomena, experiments of nature, that he alone could study. For that reason the clinician needed at hand his own laboratories for the scientific study of the problems that arose in the care of patients.
A tall, handsome man of distinguished appearance and kindly manner, Garrod taught medical students to think biochemically. He was also a supremely effective bedside clinician who could elicit the signs and symptoms of disease with great skill and sim plicity. In 1923 he brought out a second edition of Inborn Errors of Metabolism, in which he added discussions of two more inherited anomalies, ste atorrhea and hematoporphyria. In 1924 Garrod de livered the Harveian Oration to the Royal College of Physicians, “The debt of Science to Medicine,” in which he pointed out the many contributions of clinical observation to the growth of medical science.
Garrod remained at Oxford until his retirement in 1927, at the age of seventy. After living for a short time at their country house at Woodbridge in Suffolk, Sir Archibald and Lady Garrod moved to Cambridge, where their daughter, the archaeologist Dorothy A. E. Garrod, was a fellow of Newnham College. Garrod died at his house in Cambridge.
NOTES
1. A. E. Garrod, “On the Presence of Urohaematoporphyrin in the Urine of Chorea and Articular Rheumatism,” in Lancet (1892), 1 793.
2. A. Garrod. “Haematoporphyrin in Normal Urine,” in Journal of Physiology, 17 (1894), 349–352.
3. A. Garrod and F. Gowland Hopkins, “On Urobilin,” ibid., 20 (1896), 112–144, and 22 (1897–1898), 451–464.
4. lsqbCarl Heinrich Detlevrsqb Boedeker, “Uumlber das Alcapton: ein neuer Beitrag zur Frage: Welche Stoffe des Harns koumlnnen Kupferreduction bewirkenquest” in Zeitschrift fuumlr rationale Med izin. 7 (1859), 130–145
5. M. Volkov lsqbWolkowrsqb and E. Baumann, “Uumlber das Wesen der Alkaptonuria,” in Zeitschrift fuumlr physiologische chemie, 15 (1891), 228–285.
6. A Garrod, “Alkaptonuria: A Simple Method for the Extraction of Homogentisic Acid from the Urine.” in Journal of Phys iology. 23 (1898–1899). 512–514.
7. Archibald E. Garrod, “A Contribution to the Study of Al kaptonuria,” in Medico-Chirurgical Transactions published by the Royal Medical and Chirurgical Society of London. 82 (1899), 367–391.
8. Archibald E. Garrod. “About Alkaptonuria,” ibid., 85 (1902), 69–77: and “The Incidence of Alkaptonuria: A Study in Chemical Individuality,” in Lancet (1902), 2 1616–1620.
BIBLIOGRAPHY
1. Original Works. In addition to about 100 papers published in various medical and scientific journals, Garrod published the following books: An Introduction to the Use of the laryngoscope (London, 1886); A Treatise on Rheumatism and Rheumatoid Arthritis (London, 1890); A Handbook of Medical Pathology for the Use of Students in the Museum of St. Bartholomew’s Hospital (London, 1894); Inborn Errors of Metabolism (London, 1909; 2nd ed., 1923): The Debt of Science to Medicine… (Oxford, 1924): and The Inborn Factors in Disease… (Oxford, 1931).
Among his many articles in journals the more significant include: “On the Relation of Chorea to Rheumatism, with Observations of Eighty Cases of chorea,” in Medico Chirurgical Transactions, 72 (1889), 145–163; “On the Occurrence and Detection of Haematoporphyrin in the Urine,” in Journal of Physiology, 13 (1892), 598–620; “Concerning Cystinuria,” in Journal of Physiology, 34 (1906), 217–223, with W. H. Hurtley; “The Croonian Lectures on the Inborn Errors of Metabolism,” in Lancet (1908), 2, 1–7, 73–79, 142–148, 214–220: “Congenital Family Steatorrhea,” in Quarterly Journal of Medicine, 6 (1912–1913), 242–258: “Medicine from the Chemical Standpoint,” in British Medical Journal (1914). 2, 228–235; “On Congenital Porphyrinuria, Associated with Hydro Aestivale and Pink Teeth,” in Quarterly Journal of Med icine, 15 (1921–1922), 319–330, with L. Mackey; and “The Lessons of Rare Maladies,” in Lancet (1928), 1, 1055–1059.
II. Secondary Literature. There is no biography of Garrod. Obituaries include “Sir Archibald Garrod,” in British Medical Journal (1936), 1, 731–736; and “Sir Ar chibald Edward Garrod,” in Lancet (1936), 1, 807–809. See also F. G. Hopkins, “Archibald Edward Garrod, 1857–1936,” in Obituary Notices of Fellows of the Royal Society of London, 2 (1936–1939), 225–228.
Leonard G. Wilson