H i s t o r y
We've discovered the secret of life.
Though he was only forty-five in 1902, Archibald Garrod was already a pillar of the British medical establishment. He was the son of a knighted professor, the famous Sir Alfred Baring Garrod, whose treatise on that most quintessential of upper-class afflictions, gout, was reckoned a triumph of medical research. His own career was effortlessly distinguished and in due course the inevitable knighthood (for medical work in Malta during the First World War) would be followed by one of the most glittering prizes of all: the Regius professorship of medicine at Oxford in succession to the great Sir William Osier.
You can just picture him, can you not? The sort of crusty and ceremonious Edwardian who stood in the way of scientific progress, stiff in collar, stiff in lip and stiff in mind. You would be wrong.
In that year, 1902, Archibald Garrod risked a conjecture that would reveal him to be a man far ahead of his time and somebody who had all but unknowingly put his finger on the answer to the greatest H I S T O R Y 3 9
biological mystery of all time: what is a gene? Indeed, so brilliant was his understanding of the gene that he would be long dead before anybody got the point of what he was saying: that a gene was a recipe for a single chemical. What is more, he thought he had found one.
In his work at St Bartholomew's Hospital and Great Ormond Street in London, Garrod had come across a number of patients with a rare and not very serious disease, known as alkaptonuria.
Among other more uncomfortable symptoms such as arthritis, their urine and the ear wax turned reddish or inky black on exposure to the air, depending on what they had been eating. In 1901, the parents of one of these patients, a little boy, had a fifth child who also had the affliction. That set Garrod to thinking about whether the problem ran in families. He noticed that the two children's parents were first cousins. So he went back and re- examined the other cases: three of the four families were first-cousin marriages, and of the seventeen alkaptonuria cases he saw, eight were second cousins of each other. But the affliction was not simply passed on from parent to child. Most sufferers had normal children, but the disease could reappear later in their descendants. Luckily, Garrod was abreast of the latest biological thinking. His friend William Bateson was one
This gave Garrod an idea. Perhaps, he thought, the reason that the disease only appeared in those with a double inheritance was because something was missing. Being well versed not only in genetics but also in chemistry, he knew that the black urine and ear wax was caused by a build-up of a substance called homogentisate.
Homogentisate might be a normal product of the body's chemistry set, but one that was in most people then broken down and disposed of. The reason for the build-up, Garrod supposed, was because the 4 0 G E N O M E
catalyst that was meant to be breaking down the homogentisate was not working. That catalyst, he thought, must be an enzyme made of protein, and must be the sole product of an inherited factor (or gene, as we would now say). In the afflicted people, the gene produced a defective enzyme; in the carriers this did not matter because the gene inherited from the other parent could compensate.
Thus was born Garrod's bold hypothesis of the 'inborn errors of metabolism', with its far-reaching assumption that genes were there to produce chemical catalysts, one gene to each highly specialised catalyst. Perhaps that was what genes were: devices for making proteins. 'Inborn errors of metabolism', Garrod wrote, 'are due to the failure of a step in the metabolic sequence due to loss or malfunction of an enzyme.' Since enzymes are made of protein, they must be the 'seat of chemical individuality'. Garrod's book, published in 1909, was widely and positively reviewed, but his reviewers comprehensively missed the point. They thought he was talking about rare diseases, not something fundamental to all life. The Garrod theory lay neglected for thirty-five years and had to be rediscovered afresh.
By then, genetics was exploding with new ideas and Garrod had been dead for a decade.1
We now know that the main purpose of genes is to store the recipe for making proteins. It is proteins that do almost every chemical, structural and regulatory thing that is done in the body: they generate energy, fight infection, digest food, form hair, carry oxygen and so on and on. Every single protein in the body is made from a gene by a translation of the genetic code. The same is not quite true in reverse: there are genes, which are never translated into protein, such as the ribosomal-RNA gene
Garrod's contemporaries may have missed his point, but at least they honoured him. The same could not be said of the man on whose shoulders he stood, Gregor Mendel. You could hardly imagine a H I S T O R Y 4 1
more different background from Garrod's than Mendel's. Christened Johann Mendel, he was born in the tiny village of Heinzendorf (now Hynoice) in Northern Moravia in 1822. His father, Anton, was a smallholder who paid his rent in work for his landlord; his health and livelihood were shattered by a falling tree when Johann was sixteen and doing well at the grammar school in Troppau. Anton sold the farm to his son-in-law so he could afford the fees for his son at school and then at university in Olmiitz. But
Back to Brunn he went, a thirty-one-year-old nonentity, fit only for monastic life. He was good at mathematics and chess playing, had a decent head for figures and possessed a cheerful disposition.
He was also a passionate gardener, having learnt from his father how to graft and breed fruit trees. It is here, in the folk knowledge
So Father Mendel, aged thirty-four, started a series of experiments on peas in the monastery gardens that were
