Vignette: Sir Archibald Edward Garrod

Allan Gaw looks at the career of the clinician credited with the discovery of inborn errors of metabolism

"TOO learned to be confident." This was how one colleague remembered the physician-scientist Archibald Garrod, who was responsible for laying some of the most important groundwork for the revolution in molecular pathology that would transform medicine in the 20th century.

Having been born into an eminent medical family in 1857, it would have been surprising if Garrod had not found acclaim in his profession. But rather than clinical practice, it was the science underpinning medicine and our understanding of disease that consumed him for most of his life.

Some said Garrod preferred his test tubes to his patients and that his bedside manner was geared towards the study of his patients’ urine rather than their ailments. Others, however, remark on a “deep sense of the dignity and importance” he had for his profession. Certainly from the beginning he was marked out as an exceptional clinician destined to rise through the ranks of the London medical establishment. Doubtless it was his industry and his meticulous care and attention to detail that made him both an accomplished doctor and a successful scientist.

His father, Sir Alfred Baring Garrod, had been responsible for finding the link between uric acid and gout, and perhaps Garrod inherited his fascination with the chemical basis of disease. Initially, like his father, Garrod also studied diseases of the joints. Soon, however, he turned his attentions to other conditions.

Without access to the sophisticated laboratory investigations that we today take for granted, Garrod had to find a way to study the complex metabolic processes that control normal function and often determine disease. Garrod’s strategy was to study readily accessible metabolic products that he could easily visualise: urinary pigments. This approach apparently began in 1892 with his discovery of an unusually coloured urine in a patient with a neurological disorder. Over the next five years, he completed a body of largely descriptive work on a series of other pigments, but in 1897 it was his study of the condition alkaptonuria that would take his understanding to a new level.

We now know that this is a rare inherited metabolic disease due to a deficiency of a functioning enzyme controlling the breakdown of the amino acids phenylalanine and tyrosine. This roadblock in their metabolism leads to a build-up of the immediate precursor, homogentisic acid. Although normally virtually absent from the body, in alkaptonuria this intermediary accumulates in the blood, connective tissues and of course the urine where it is easily detected when it reacts with oxygen in the air, turning the urine black.

In the 1890s this condition was thought to be the result of infection, but Garrod’s careful study of a number of cases led him to think it may be "a familial affair". In 1899 he published his findings highlighting his hypothesis that it would be commoner in first cousin marriages. An advocate of Mendel’s work, William Bateson suggested that this pattern of inheritance would be consistent with a recessive trait, and Garrod concurred. This important link between defects in the biochemical pathways that control metabolism on the one hand and faults in our genes on the other laid the foundation for all future developments in molecular genetics.

A few years later he demonstrated that two other conditions, cystinuria and albinism, were also the result of recessive metabolic defects. In 1908 he delivered the prestigious Croonian Lectures of the Royal College of Physicians which he entitled, 'Inborn Errors of Metabolism', thus coining a term that we still use today.

Garrod was elected Fellow of the Royal Society in 1910, knighted in 1918 and was nominated Regius Professor of Medicine at the University of Oxford in 1920. But it was not all honours. The First World War claimed all three of Garrod’s sons — two in action and one from influenza shortly after the armistice. His only surviving child, his daughter Dorothy, would go on to become an eminent archaeologist and indeed would become the first woman to hold an Oxbridge chair.

That same colleague who questioned Garrod’s confidence also said of him that although he was "universally respected and liked", he was also "too gentle and honest to demand attention". Nevertheless, more than a century after he coined the phrase, ‘Inborn Errors of Metabolism,’ it is clear that while Garrod the man may not have demanded attention, his work and its legacy does.

Dr Allan Gaw is a writer and educator in Glasgow

SOURCES

  • Obituary Notices of Fellows of the Royal Society, 1936
  • Historic Hospitals Admission Records Project, 2010
  • DNA Learning Center, 2011