|Fig 1. Archibald Edward Garrod. Crop of image in Obituary Notices of Fellows of the Royal Society, 1932–1954. Wellcome Collection. CC BY 4.0.|
It is given to very few to invent a new class of diseases and to even fewer one that has survived subsequent scrutiny.
Archibald Garrod, KCMG DM LLD FRCP FRS (1857–1936) (Fig 1), was born in London into an unusually talented family. He was the fourth son of Sir Alfred Baring Garrod, MD FRS (1819–1907), an eminent physician known for his work on arthritis, who in 1848 showed and measured the excess of uric acid in the blood of gouty patients. His son Archibald later delighted in recalling that this was the first quantitative biochemical investigation made on the living human body. His brother, Alfred Henry Garrod (1846–1879), also qualified in medicine and became Fullerian Professor of Physiology at the Royal Institution, subeditor of the journal Nature, and FRS. Aged only thirty-three, he died of phthisis.
Archibald Garrod attended Marlborough School and Christ Church College, Oxford. He was placed in the First Class of the Natural Sciences School in 1880 and then read medicine at St. Bartholomew’s Hospital (Barts) where he qualified. His exceptional abilities were quickly recognized.1 After junior appointments, he became assistant physician in 1903 and full physician at Barts in 1912. He was appointed physician at Great Ormond Street Hospital in 1899. Chemical pathology was a major interest throughout his life. But soon, World War 1 took him to Malta as consulting physician to the Armed Forces; he saw the patients evacuated from Gallipoli and Salonika. For his distinguished service he was appointed KCMG in 1919.
On return to Barts he was appointed the first director of the new medical unit, but one year later was invited to succeed Sir William Osler as Regius Professor of Physic at Oxford in October 1920, a post he held until retirement at the age of seventy.
His earliest publications were clinical, dealing with rheumatism, rheumatoid arthritis, and kindred conditions. He published many papers and books on diverse subjects, which included An Introduction to the Use of the Laryngoscope (1886) and A Treatise on Rheumatism and Rheumatoid Arthritis (1890).2 In 1913 with Frederick E. Batten and Hugh Thursfield, he published Diseases of Children, by Various Authors. However, reflecting his principal interest, he explored the changes in metabolism that induced disease and took a special interest in urinary pigments. This began with the original studies in 1892 of hematoporphyria, and of urobilin with F. Gowland Hopkins.
His interest turned to the urinary pigments in five new cases of alkaptonuria,3 first mentioned by Marcet in 1823 and more fully by Bodecker in 1859. Alkaptonuria became the prototype of the inborn errors of metabolism, which Garrod investigated; he eventually collated forty instances from the literature.4 It was his experience with alkaptonuria that led him to wonder, speculate, and write so lucidly about what he called “chemical mal-formations,” or “inborn errors of metabolism.”1
In alkaptonuria, homogentisic acid derived from tyrosine and phenylalanine is excreted in the urine and deposited in cartilage (ochronosis). When oxidized, it turns brownish black. In The Inborn Errors of Metabolism, he wrote:
Of inborn errors of metabolism alkaptonuria is that of which we know most, and from the study of which most has been learnt. In early life … attracts attention because an infant stains its clothing or the urine has a peculiar appearance. As the years go on the cartilages become blackened, giving a blue tint to the hollows of the ears, brown marks develop on the conjunctivae, and there is a great tendency to osteo-arthritic and osseous lesions.
He observed that freshly passed urine of an alkaptonuric seldom shows any abnormality of tint, but soon begins to darken in contact with air. At that time, alkaptonuria was supposed to be caused by an infecting organism in the intestines, which converted tyrosine into homogentisic acid. Garrod speculated it might be a “sport” or an alternative mode of metabolism peculiar to the individual, which might be familial.5 His hypothesis of a hereditary, metabolic error seemed proved when in 1897, a mother arrived at the Great Ormond Street Hospital with an infant and a nappy (diaper) stained black, whose older sibling had been diagnosed as an alkaptonuric, described from birth, “diaper by diaper.” In the mother’s next child there was also deep diaper staining after fifty-two hours in the air.6 Garrod said:
alkaptonuria could be described as a ‘freak’ of metabolism, a chemical abnormality more or less analogous to a structural malformation.
He considered alkaptonuria an individual variation from normal metabolism with a familial distribution: “Individual cases of any particular disease… are not exactly alike…; they resemble rather the drawings made from the same model by individual members of a drawing class.” He rightly predicted such disorders would be likely to occur in first cousin marriages. Bateson and Punnett then confirmed its Mendelian recessive inheritance.
Inborn errors of metabolism
|Fig 2. Inborn Errors of Metabolism. Croonian Lectures.|
By 1903 he had shown that albinism, pentosuria, and cystinuria were also inborn metabolic errors. In 1908, he gave the Croonian Lectures of the Royal College of Physicians with the title “Inborn Errors of Metabolism,” where he crystallized his original ideas:
The conception of metabolism in block is giving place to that of metabolism in compartments. The view is daily gaining ground that each successive step in the building up and breaking down, not merely of proteins, carbohydrates, and fats in general, but even of individual fractions of proteins and of individual sugars, is the work of special enzymes set apart for each particular purpose.7
This was a wholly new concept. It initiated the study of genetic diseases and established Garrod’s reputation as the founder of modern genetics. The lectures8 later published in his book (Fig 2) were dedicated to Frederick Gowland Hopkins (Nobel laureate with Christiaan Eijkman for discovering vitamins) and are considered a milestone in biochemistry. Garrod described the biochemical individuality of humans and how metabolic errors and resultant diseases are caused by a deficiency in or absence of particular enzymes. It led to the one gene–one enzyme hypothesis of Beadle and Tatum in 1941.9 A second edition appeared in 1923, which added congenital steatorrhea and hematoporphyria congenita.
Gowland Hopkins observed that his work on these departures from the normal chemical rhythm of the human body constituted a most important contribution to medical and biological science. Garrod gave the Bradshaw and Croonian lectures and the Harveian oration to the Royal College of Physicians, the latter titled “The debt of science to medicine.”
Inborn errors of metabolism are now defined as a group of (individually rare but collectively about 1 in 2,500 births) disorders, which result from deficiency of a single enzyme in a metabolic pathway. Most are inherited in an autosomal recessive manner and involve abnormalities in enzymes and transport proteins. The Metabolic Basis of Inherited Disease by Stanbury and colleagues (1960) provided a comprehensive review.
The major subgroups include disorders of amino acid metabolism, disorders of carbohydrate metabolism, lyosomal storage defects, peroxisomal disorders, and mitochondrial disorders. The clinical signs, biochemical and genetic tests, and management are diverse, depending on the specific defect and tissues affected.10,11 George Beadle in his 1958 Nobel Prize lecture called attention to the originality and significance of Garrod’s work: “We had rediscovered what Garrod had seen so clearly so many years before. By now we knew of his work and were aware that we had added little if anything new in principle.”
Despite his penchant for experimental investigation, Garrod was said to be first and foremost a clinician. He wrote: “It is in the ward rather than in the laboratory that the importance of inborn factors is to be appreciated.”12 He was elected Fellow of the Royal Society in 1910. His father had become a Fellow in 1858 as had his eldest brother Alfred Henry Garrod in 1876. It must be rare indeed in the history of the Royal Society for a father and two sons to attain to its Fellowship.1
In 1886, Archibald Garrod married Laura Elisabeth, eldest daughter of Sir Thomas Smith (Surgeon Extraordinary to Queen Victoria). They had three sons and a daughter, Dorothy A. E. Garrod, an archaeologist and a Fellow of Newnham College, Cambridge. He was grievously affected by the loss of his sons killed in the war. After retirement he lived in Suffolk before he moved to Cambridge to be with his daughter. He died there on 28 March 1936 at her home in Huntingdon Road.
- Hopkins FG. Obituary, Archibald Edward Garrod 1857-1936. Royal Society. https://catalogues.royalsociety.org/CalmView/Record.aspx?src=CalmView.Persons&id=NA7976.
- Piro A, Tagarelli A, Tagarelli G, Lagonia P, Quattrone A. Archibald Edward Garrod: the physician father of biochemistry. Metabolism Clinical and Experimental 2009;58:427-37.
- Garrod AE. A contribution to the study of alkaptonuria. Med.-Chir. Trans 1899;82:369-94.
- Garrod AE. 1902. The Incidence of Alkaptonuria: A Study in Chemical Individuality. Lancet 1902;2:1616-20.
- Garrod AE. About alkaptonuria. Lancet 1901;2:1484-6.
- Knox WE. Sir Archibald Garrod’s “Inborn Errors of Metabolism” II. Alkaptonuria. American Journal of Human Genetics 1958;10:95-124.
- Garrod AE. Inborn Errors of Metabolism. London: Frowde, Hodder & Stoughton, 1909.
- Garrod AE. Croonian Lecture I Alkaptonuria. Lancet 1908;2:73-9.
- Beadle GW, Tatum EL. Genetic Control of Biochemical Reactions in Neurospora. Proc Nat Acad Sciences 1941;27;499-506.
- Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998;102(6):E69.
- Online Mendelian Inheritance in Man (OMIM): An Online Catalog of Human Genes and Genetic Disorders. https://www.omim.org.
- Garrod AE. The Inborn Factors in Disease: An Essay. Oxford University Press: Oxford, UK, 1931.
JMS PEARCE is a retired neurologist and author with a particular interest in the history of medicine and science.