Over the next 20 years he served on the attending staff of several hospitals in London: Marylebone General Dispensary, West London Hospital, St. Bartholomew's Hospital,
Great Ormond Street Hospital for Children, and Alexandra Hospital for Children with
hip dysplasia. In 1892, he was appointed assistant physician at the Great Ormand Street Hospital. Dronamraju writes, “He was interested in studies of normal and pathological urine, especially in differences of their coloration. It is of interest that his interest in butterflies and flowers in childhood was also related to color differences and biological variation, and it may well have helped to sharpen his perception in this regard.”
Alkaptonuria and inborn errors of metabolism Garrod is best known for his scientific study of inborn errors of metabolism. He developed an increasing interest in chemical pathology, and investigated
urine chemistry as a reflection of systemic
metabolism and disease. This research, combined with the new understanding of
Mendelian inheritance, evolved from an investigation of a few families with an obscure and not very dangerous disease (
alkaptonuria) to the realization that a whole territory of mysterious diseases might be understood as inherited disorders of metabolism. In the 1890s he collaborated with Frederick Gowland Hopkins, a well-known and respected London physician and biochemist who studied the concept of how vitamins, then known as “accessory factors”, effect dietary health of patients. Under Hopkins's influence and led by his own childhood fascination with color variations, he took particular notice of how the color of urine changed. In 1897, a mother arrived at the Great Ormand Street Hospital with an infant and a diaper stained brownish-black. Dr. Garrod recorded the family history of the baby and kept tabs on the newborn's growth over the years. He quickly began seeking other patients with the same disorder and found forty cases and read up on the disorder, the first instance of which was noted in 1822. Alkaptonuria is a rare familial disease of organic acid metabolism that is best known for the darkening of urine from yellow to brown to black after it is exposed to the air. In later life, individuals with this disease develop
arthritis characterized by deposition of brown pigment in
joint cartilage and
connective tissue. Garrod studied the recurrence patterns in several families, realized it followed an
autosomal recessive pattern of inheritance, and postulated that it was caused by a mutation in a gene encoding an enzyme involved in the metabolism of a class of compounds called
alkapton. He published
The Incidence of Alkaptonuria: a Study in Chemical Individuality in 1902. Over the next decade he developed an understanding of the possible nature of inherited diseases of metabolism. He described the nature of recessive inheritance of most enzyme defects. In 1908, the core of this work was presented as the
Croonian Lectures to the
Royal College of Physicians, entitled Inborn Errors of Metabolism and published the following year. Garrod expanded his metabolic studies to cover
cystinuria,
pentosuria, and
albinism. These three inborn errors, along with alkaptonuria are collectively called
Garrod's tetrad. In 1923 he summarized these studies in an expanded edition of his best known work. == Honours ==