History of the Study of Genetic Disease From the Greeks to Garrod

As already stated, the idea that the features of parents could be transmitted to their offspring was ap plied very early in human history in the domestication of animals. Some of the knowledge of "good inheritance," the transmission of favorable features, undoubtedly came from observations of "bad inheritance." Thus, for some 10,000 years we have been aware to a greater or lesser degree that certain malformations and diseases are hereditary, if not genetic. However, only from the written records of ancestors can we reliably assess the state of their awareness regarding heredity.

Early History

By the time of the Greeks, ample evidence already existed that people were cognizant of heredity, both good and bad. Moreover, many Greek scholars speculated as to the mechanism of heredity. Nearly all of them had a theory of vertical transmission, but the theory promoted by Hippocrates survived until the Renaissance. Writing in the fourth century B.C., Hippocrates put forth the idea that each organ and tissue produced, in its turn, a specific component of semen. This composite semen was then transmitted to the woman through coitus, whereupon it incubated to become a human baby. This, of course, included the good and the bad:

... of the semen, however, I assert that it is secreted by the whole body - by the solid as well as by the smooth parts, and by the entire humid matters of the body. .. . The semen is produced by the whole body, healthy by healthy parts, sick by sick parts. Hence when as a rule, baldheaded beget baldheaded, blue-eyed beget blue-eyed, and squinting, squinting; and when for other maladies, the same law prevails, what should hinder that longheaded are begotten by longheaded. (Hippocrates in Vogel and Motulsky 1979)

Note that in this single passage Hippocrates accounts for the inheritance not only of desirable traits but of the abnormal and undesirable as well, and by the same mechanism. So powerful was the idea of heredity among the Greeks that many scholars felt the need to warn against unfavorable unions. Thus did the sixth-century B.C. scholar Theognis lament:

We seek well bred rams and sheep and horses and one wishes to breed from these. Yet a good man is willing to marry an evil wife, if she bring him wealth: nor does a woman refuse to marry an evil husband who is rich. For men reverence money, and the good marry the evil, and the evil the good. Wealth has confounded the race. (Theognis in Roper 1913)

Clearly, Theognis believed that marriage for the sake of money would cause the race to sink into mediocrity and greed.

The traits commented on by the Greeks when dis cussing heredity were usually abstract qualities such as good and evil or desirable normal characteristics such as eye color, strength, speed, and beauty. Of course, they also took notice of the shocking and fantastic, gross malformations, or severe illness. Em-pedocles suggested in the fifth century B.C. that the cause of monsters, as grossly malformed infants came to be called, was an excess or deficit of semen. Many other writers held similar views, which presumably became part of the hereditary theory of Hippocrates. The treatment of infants with abnormalities was roughly the same everywhere in the ancient world. They either were left to die or were killed outright. Often, the mother suffered the same fate as her offspring. The practice of destroying abnormal infants was advocated by Hippocrates, Plato, Aristotle, and virtually all others whose works on the subject have survived. Yet the practice was not universal, as evidenced by the mummy of an anencephalic (20650) infant at Hermopolis. The archaeological evidence suggests that this baby, who would have been stillborn or died shortly after birth, was an object of worship (Glenister 1964).

The physical, mechanistic interpretation of the causes of birth defects was modified by the somewhat more mystical Roman frame of mind. In the first century A.D., Pliny the Elder wrote that mental impressions resulting from gazing on likenesses of the gods during pregnancy were sufficient to produce monsters. Indeed, the root of the word monster is the Latin word monere, "to warn." Thus, such children were regarded as warnings from the gods transmitted to pregnant women. J. W. Ballantyne (1902) related the circumstances of a black queen of ancient Ethiopia who presented her husband, the black king, with a white child. It was concluded that the queen had gazed on a white statue of the goddess Andromeda during the early stages of her pregnancy. The description of the white infant, however, leads one to suspect that it was an albino (20310), particularly given the propensity for royalty to marry close relatives.

The decline of reason that marked the Middle Ages was reflected in interpretations of the birth of malformed infants. T. W. Glenister (1964) notes that such children were called "Devil's brats" and were generally believed to have been conceived in a union with Satan. As was the case with any perceived deviation from piety, the fate of both infant and mother was quickly and ruthlessly determined. Late in the Middle Ages, however, the rise of astrology sometimes made for surprising outcomes. For example, when in the beginning of the thirteenth century a deformed calf said to be half human in its appearance was born, the cowherd was immediately accused of having committed an unnatural act, the punishment for which was burning at the stake (Glenister 1964). Fortunately for the cowherd it was pointed out that a particular conjunction of the planets had recently occurred, a conjunction that was often the cause of oddities of nature. The cowherd's life was spared.

As the Renaissance dawned, reason returned to the writing of discourses on heredity and failed heredity. Scholarly works of the classical era were rediscovered, and the development of a science of heredity was once again underway. A curious episode occurred a few years after the death of Leonardo da Vinci in 1519. A half-brother of Leonardo conducted an experiment in an attempt to produce a second Leonardo. The half-brother, Bartolommeo, who was 45 years younger than the great artist and scholar, tried to recreate the exact circumstances of Leonardo's birth. Leonardo was the illegitimate son of Fiero, a notary of Vinci, and a peasant girl of the same city named Caterina. Bartolommeo, a notary by trade, moved to Vinci, whereupon he sought out a peasant girl much like Caterina. He found one and married her, and she bore him a son, whom they named Piero. One author notes the following:

Bartolommeo had scarcely known his brother whose spiritual heir he had wanted thus to produce and, by all accounts, he almost did. The boy looked liked Leonardo, and was brought up with all the encouragement to follow his footsteps. Pierino da Vinci, this experiment in heredity, became an artist and, especially, a sculptor of some talent. He died young. (Ritchie-Calder in Plomin et al. 1980)

As the foregoing passage indicates, the Rennaisance saw a revival of the principles of heredity. The writings of Hippocrates and Aristotle were translated and amplified by medical scholars such as Fabricius ab Aquapendente and his pupil William Harvey. In addition, there was a growing interest in rare and unusual medical cases. Weeks before his death in 1657, William Harvey wrote a letter of reply to a Dutch physician's inquiry about an unusual case in which he counseled, "Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path" (in Garrod 1928).

For Harvey and others, rare pathology was not a source of revulsion or the workings of Satan but, rather, a subject demanding study and understanding. In 1882, Sir James Paget made a similar appeal on behalf of the study of rare disorders: "We ought not to set them aside with ideal thoughts and idle words about 'curiosities' or 'chances.' Not one of them is without meaning; not one that might not become the beginning of excellent knowledge." He went on to speak of new diseases that "are due mainly to morbid conditions changing and combining in transmission from parents to offspring."

The debt owed to scholars such as Harvey was acknowledged in the twentieth century, when medical genetics was coming into full bloom. Archibald Garrod, the father of human biochemical genetics, of whom we will hear more, paid homage to his intellectual ancestor: "It is rather, as Harvey saw so clearly, because we find in rare diseases the keys to note a few dark places of physiology and pathology, that I recommend them to you as objects of study" (Garrod 1928).

The Forgotten Origins of Medical Genetics With the Enlightenment the floodgates to inquiry were opened for medical scientists and progress was made on nearly all fronts in understanding pathology. However, in spite of eloquent writings on heredity in general and on rare cases in particular, few references to specific genetic diseases were made before the twentieth century. Yet among those few instances are to be found brilliant insights.

Between 1745 and 1757 the French natural philosopher Pierre Louis Moreau de Maupertuis conducted studies on the heredity of Polydactyly (the condition of having more than the normal number of fingers and/or toes; 26345). Maupertuis published a four-generation pedigree of Polydactyly and commented, "That peculiarity of the supernumerary digits is found in the human species, extends to the entire breeds [races]; and there one sees that it is equally transmitted by the fathers and by the mothers" (Glass 1947).

He based his theory of heredity on these studies and suggested that particles of inheritance were paired in the "semens" of the father and the mother and that "there could be . . . arrangements so tenacious that from the first generation they dominate" (Glass 1947). This led him to suggest that hereditary pathologies were accidental products of the semen. In other words, he correctly predicted genes, dominance, and mutation. In addition, he estimated the probability of Polydactyly at 1 per 20,000 by his own survey and noted that the chance of a joint occurrence of an affected parent and an affected offspring was 1 per 400,000,000 and that of an affected grandparent, parent, and offspring in sequence was 1 per

8,000,000,000,000 if the disorder was not hereditary. This made the probability of his four-generation family being chance so small as to be immediately dismissed. Here, then, was also the first use of statistics in a study of heredity.

Various sex-linked, or X-linked, disorders such as color blindness (30370) and hemophilia (30670) were accurately described in the late eighteenth and early nineteenth centuries. A German physician and professor of medicine, Christian F. Nasse, presented in 1820 a detailed pedigree of X-linked, recessive hemophilia and noted:

All reports on families, in which a hereditary tendency toward bleeding was found, are in agreement that bleeders are persons of male sex only in every case... . The women from those families transmit this tendency from their fathers to their children, even when they are married to husbands from other families who are not afflicted with this tendency. This tendency never manifests itself in women. (Vogel and Motulsky 1979)

Perhaps the most remarkable instance before the work of Gregor Johann Mendel (which although published in 1866 had to await rediscovery until the beginning of the twentieth century) was an 1814 publication by British physician Joseph Adams (Motulsky 1959). In this study, the author drew a distinction between familial diseases, which he considered to be confined to a single generation, and hereditary diseases, which he noted were passed on from generation to generation. Moreover, Adams defined congenital disorders as ones appearing at birth and regarded them to be more likely familial than hereditary. He observed that familial inherited diseases were often very severe, so much so that subsequent transmission from the affected individual was ruled out by early death. These conditions increased among the offspring because of mating between close relatives and were often to be seen in isolated districts where inbreeding was common. Clearly, from a modern perspective, Adams's familial diseases were what we term recessive and his hereditary diseases were what we term dominant.

Adams also concluded that hereditary diseases (in the modern sense) were not always to be found at birth but might have later ages of onset, that correlations existed among family members with regard to the clinical features of a hereditary disease, and that hereditary diseases might be treatable. Adams hinted at the phenomenon of mutation when he remarked that a severe disease would last only a single generation were it not for the fact that normal parents occasionally produced offspring in whom the disease originated. Finally, he called for the establishment of hereditary disease registers that could be used for the study of these diseases: "That to lessen anxiety, as well as from a regard to the moral principle, family peculiarities, instead of being carefully concealed, should be accurately traced and faithfully recorded" (Adams 1814, in Motulsky 1959).

The Impact of Mendelism

The story of the discovery of the basic hereditary laws of segregation and independent assortment by the Austrian monk Mendel and of their subsequent independent rediscovery by Carl Correns, Hugo de Vries, and Erich von Tschermak some 35 years later has been told many times (e.g., Olby 1966; Stern and Sherwood 1966). Mendel, conducting experiments in hybridization with the common garden pea, Pisum sativum, in his garden at the Augustinian monastery in Brno, Czechoslovakia, demonstrated that alternative hereditary "characters" for a single trait segregated from one another each generation and that the characters for multiple traits assorted independently in each generation. Moreover, the observed distribution of characters for multiple traits followed a precise mathematical formulation - a binomial series. Mendel reported his results to the Natural Science Association of Brno in 1865. His written report was published the following year, but almost no attention was paid to it until 1899.

By that time, however, numerous investigators were pursuing experiments in heredity, and many of them had chosen simple plants as their experimental systems. Professor Hugo de Vries, a Dutch botanist, studying hybridization, came upon a reprint of Mendel's report, where he found the solution to the problems he had been working on. Thus, while he had independently derived his own formulation of the law of segregation, he reported the Mendelian results as well and stressed their importance in a 1900 publication (Olby 1966). At the same time, both the German botanist Correns and the Austrian botanist von Tschermak independently discovered the Mendelian laws and recognized their significance. All three published translations of Mendel's paper and commented on the laws therein. That these papers opened the new field of genetics and put it on a sound analytic footing from the outset is undeniable. However, as we will see, the translation by de Vries had an almost immediate impact on the study of human genetic disease.

The English biologist William Bateson was also interested in plant hybridization. However, his inter est stemmed from the fact that, as an ardent advocate of evolution, he was unable to reconcile his belief that hereditary variation was discontinuous with the Darwinian model of evolution through selection on continuous variation. Bateson thus had spent years searching for a mechanism for discontinuous traits (Carlson 1966). Then in 1900 he read de Vries's account of Mendel's experiments. As E. A. Carlson (1966) notes, Bateson called the moment when he recognized the importance of Mendel's work "one of the half dozen most emotional moments of his life." In Mendel's work, Bateson believed he had found the mechanism for discontinuous variation for which he had searched. Shortly after this time, Bateson mistakenly championed Mendelism as an alternative to Darwinism, a position that haunted him the rest of his life (Sturtevant 1966). In 1901, however, Bateson, as we shall see, made an almost offhand comment that turned out to be a fundamental contribution to the study of human genetic diseases.

In 1897 Sir Archibald E. Garrod, a member of the staff of London's St. Bartholemew's Hospital, came upon and was intrigued by a case of alkaptonuria (20350). Alkaptonuria is a nonfatal disorder, present at birth, that is characterized by the excretion of homogentisic acid in the urine, which turns the urine dark upon standing. The disorder is often accompanied in later years by arthritis and a black pigmentation of cartilage and collagenous tissues. At the time that Garrod was diagnosing his first case of alkaptonuria it was believed that the condition was infectious and that the excretion of homogentisic acid was the result of bacterial action in the intestine. Garrod, however, refused to accept this view, believing instead that the condition was a form of abnormal metabolism (Harris 1963). He published this theory in 1899 along with the contention that the error of metabolism was congenital (Garrod 1899.

Less than a year later Garrod made what would prove to be his crucial observation. He noted that, among four families in which all alkaptonuric offspring had two unaffected parents, three of the parental pairs were first cousins. In 1901 he wrote in the Lancet:

The children of first cousins form so small a section of the community, and the number of alkaptonuric persons is so very small, that the association in no less than three out of four families can hardly be ascribed to chance, and further evidence bearing upon this point would be of great interest.

This circumstance would hardly have surprised Garrod's fellow countryman and physician Joseph

Adams, who, it should be remembered, had made a similar observation about inbreeding nearly 90 years earlier. William Bateson read the paper and discussed its conclusions with Garrod. Bateson recognized that the pathology was discontinuous, all or none, affected or normal. Moreover, the high incidence of consanguinity and the characteristic familial pattern of normal, consanguinous parents having affected offspring were precisely what would be expected were the abnormality determined by a rare, recessive Mendelian character. Bateson commented on the case in a footnote in a 1902 report to the Evolution Committee of the Royal Society with E. R. Saunders:

Now there may be other accounts possible, but we note that the mating of first cousins gives exactly the conditions most likely to enable a rare and usually unseen recessive character to show itself. .. first cousins will frequently be bearers of similar gametes, which may in such unions meet each other, and thus lead to the manifestation of the peculiar recessive characters in the zygote.

In Bateson's interpretation of the situation, Garrod saw the solution to the problem of alkaptonuria. Garrod published the landmark paper "The Incidence of Alkaptonuria: A Study in Chemical Individuality" in 1902, adding further clinical data and incorporating the hereditary mechanism proposed by Bateson. Therein he reported on nine families of alkaptonuries and noted:

It will be noticed that among the families of parents who do not themselves exhibit the anomaly a proportion corresponding to 60 per cent are the offspring of marriages of first cousins.

However, he continued:

There is no reason to suppose that mere consanguinity of parents can originate such a condition as alkaptonuria in their offspring, and we must, rather seek an explanation in some peculiarity of the parents, which may remain latent for generations, but which has the best chance of asserting itself in the offspring of the union of two members of a family in which it is transmitted.

Garrod (1902) suggested that the laws of heredity discovered by Mendel and relayed to him by Bateson offered an explanation of the disorder as an example of a Mendelian recessive character and, thus, there seems to be little room for doubt that the peculiarities of the incidence of alkaptonuria and of conditions which appear in a similar way are best explained by supposing that... a peculiarity of the gametes of both parents is necessary.

Here Garrod had already gone beyond alkaptonuria to include the possibility of other disorders sharing the same hereditary mechanism. Indeed, Garrod did go on to study cystinuria (22010), albinism (20310), and pentosuria (26080) and to put them all in the same class with alkaptonuria.

In 1908 Garrod delivered the Croonian Lectures to the Royal College of Physicians. To these lectures, and to the four disorders on which they were based, Garrod gave the name "Inborn Errors of Metabolism." The impact of Mendelism was fully felt by then, and there were few who doubted that these and other diseases were due to Mendelian characters. Garrod then went on to the next stage of the study of inborn errors, by noting in the case of alkaptonuria that we may further conceive that the splitting of the benzene ring in normal metabolism is the work of a special enzyme, that in congenital alkaptonuria this enzyme is wanting, whilst in disease its working may be partially or even completely inhibited.

He was suggesting that the pathology of inborn errors of metabolism consisted of a blockade at some point in the normal pathway and that this blockade was caused by the congenital deficiency or absence of a specific enzyme (Harris 1963). The truth of his insight is evidenced by the metabolic pathways shown in Figure III.1.2. Clearly, Garrod believed that these deficiencies were transmitted as Mendelian characters, or determinants, and that the study of the families, particularly those in which inbreeding was known or suspected, was crucial to obtaining new insights into old disease entities.

The principal tenet of inborn errors of metabolism, that transmitted enzymic defects cause disease, eventually led to the "one gene-one enzyme" hypothesis (Beadle 1945) and to the theory of gene action. In 1950 G. W. Beadle called Garrod the "father of chemical genetics" (Harris 1963).



DIETARY PROTEIN [i)~f- tyrosines-hydroxylase / (a) / ™


(a) \ / tyrosine peroxidase


phenylalanine-4-hydroxylase IB)

tyrosine transaminase


4-hydroxyphenylpyruv1c acid hydroxylase


homogentisic acid oxygenase


maleylacetoacetic acid isomerase


Figure III. 1.2. A representation of metabolic pathways involving the amino acid tyrosine. These pathways are linked to no fewer than six genetic diseases of the type envisioned by Garrod. (A) A defect in the gene coding for phenylalanine-4-hydroxylase results in the recessive disorder phenylketonuria (26160). (B) A defect in the gene coding for tyrosine transaminase results in the rare disease tyrosinosis (27680), whereas a defect at the next step involving 4-hydroxyphenylpyruvic acid hydroxylase leads to the much more serious disorder ty-rosinemia (27660). (C) The metabolic lesion suggested by Garrod for alkaptonuria is in fact a defect in the gene coding for homogentisic acid oxygenase. (D) A form of goitrous cretinism (27470) is caused when there is a lesion involving the enzyme tyrosine peroxidase. (E) Another of Garrod's original defects, albinism, arises when the gene for tyrosine-3-hydroxylase is defective. To date, more than 500 such disorders are known to exist in humans. Some are vanishingly rare, but others, such as phenylketonuria, are quite common (From McKusick 1986).

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