Kings and Queens

Genetic Diseases in Royal Families

Mendel

The fundamental idea of heredity—that the germ cells transmit factors which shape basic characteristics in offspring and which are invariant through the generations—was discovered by a Moravian monk working alone in an Augustinian monastery in Brunn, which is today part of the Czech Republic.

Born in 1822 to a peasant family, Gregor Mendel must have been a top student from the start, for that alone could explain his climb from such humble origins. As was often then the case for bright men without other resources, the priesthood provided the path to a scholarly life. It was his high school physics teacher, Freidrich Franz, who recommended him to the Monastery of St. Thomas, saying, "In my own branch, he is almost the best." For a time after his ordination in 1848, he worked as a substitute teacher in village church schools. Curiously, although he failed an examination for a regular teaching license, his examiners recommended that he be sent to university for further study. After concentrating in mathematics and physics at the University of Vienna (1851-1853), Mendel returned to Brunn. He sat for the teaching license examination a second time but withdrew, possibly due to illness, which caused him again to receive a failing grade. He then settled into a routine life within the monastery, punctuated by regular work as a substitute teacher. In this he must have prospered, for in 1868 he was elected abbot. It was during the decade from 1854 to 1865 that Mendel, working in a small garden within the monastery, made his world-changing discovery.

The cornerstone of modern genetics, now a towering skyscraper of knowledge, is a single paper, first read by Mendel to his colleagues at the Natural Science Society of Brunn on the evenings of February 8 and

March 8, 1865, and published in its obscure journal in 1866. The journal had a subscription list of only 120, and the paper elicited no known effort to replicate its findings, a critical process for all scientific discoveries, for nearly 35 years. Mendel himself published only one other paper on plant breeding. In 1869, he reported that working with a plant called hawkweed (Hieracium) he had been unable to demonstrate the particulate nature of the hereditary material that he had shown so convincingly in his study of garden peas (Pisum sativum).

We have no idea why Mendel began his exhaustive study of heredity, but we do know why he chose garden peas. He wanted a hardy annual plant that was easy to grow, from which insects could not gather pollen to cause cross-fertilization, and that had a well-established number of strains with obvious physical differences. Easily available to him were strains that were tall or dwarf, strains with flowers that were white or red, strains with seeds that were round or wrinkled and green or yellow. For a decade Mendel bred hundreds of pea plants, crossing strains with one sharply contrasting characteristic against those with an opposite form. His genius was to follow them through the generations. He collected the seed from each hybrid plant, isolated it from the seed of all his other plants, and sowed it separately the following year. This allowed him to observe the characters associated with particular seed from particular matings over time.

Whenever Mendel crossed a tall plant with a dwarf plant, all of the offspring were tall. However, when he crossed the hybrid plants, he found that for every three plants that were tall there was roughly one plant that seemed to revert to the size of its dwarf grandparent. When he crossed a dwarf plant with a dwarf plant, the result was always dwarf offspring. From these experiments, repeated hundreds of times, Mendel deduced that in the seed of tall pea plants there was a factor that was transmitted intact through the generations and that was dominant to some corresponding factor in dwarf pea plants. From following crosses of tall plants he deduced that, despite their tallness, all of the hybrids must contain a factor which, if present in the seed of both parents, would yield dwarf plants, and that this happened in about one-fourth of the progeny. Because the tall plants masked the presence of the factor for dwarfness, Mendel called the dwarf factor recessive. Mendel repeated his breeding studies with six other easily characterized features, including flower color, seed shape, and seed color. In each case he was able to show that one of two characteristics was dominant over the other. All the work was summarized in his 1865 paper that announced the particulate nature of heredity and the concept of dominant and recessive traits.

In the 1920s, when geneticists reexamined his original data, they found that, given the large number of plants that he had studied, Mendel's numbers fit too well with the expected 3:1 ratio! This has led to accusations of fraud by Mendel or, in the alternative, suspicions that his assistant, knowing what Mendel thought he should be finding, rigged the count to satisfy his boss. But if Mendel's work is tainted, it can only mean that he somehow deduced the theory of particulate inheritance and then sought physical evidence to support it, which is even more impressive. For, unlike most scientific advances, there is no evidence that his discovery was guided by the work of others. There is simply no published literature on particulate inheritance remotely close to Mendel's work until his findings were rediscovered independently in 1900 by three botanists, an event that launched modern genetics.

After its rediscovery, the theory of particulate inheritance was investigated widely across many species, especially by animal breeders. The word "gene" was first used to describe a unitary, invariant, hereditary characteristic in 1906. By 1910 Mendelism, as it was often called, had refuted the notion of blending (that inherited characteristics represented a smooth mix of two sets of ingredients) that had dominated biological thinking in the second half of the 19th century.

Naturally, there was great interest in the application of Mendel's findings to humans. In the United States, Charles Davenport, Director of the Station for Experimental Evolution at Cold Spring Harbor, New York, was among the first and most forceful to apply the new theory of inheritance to humans. He and his contemporaries did this by compiling pedigrees. What Mendel had done by following the transmission of factors through generations, they did retrospectively. They looked for families with distinguishing features and tried to trace the features back through the generations. This was no easy task. Medical records were sparse, photography had only been available for about two generations, and they had little knowledge of what physical characteristics might reflect the underlying presence of single, dominantly acting genes.

Dominant Genes

In 1905, W. C. Farrabee, an American anatomist, reported the first example of dominant inheritance in humans—a large family in which about one-half of the members were born with brachydactyly (unusually short fingers). Of the descendants of a single affected woman born over four generations, 36 had the family hand. In 1917, Edward Drinkwater, an English pathologist, wrote up an astonishing confirmation of dominant inheritance in humans. He had examined a man with unusually short fingers due to a fusion of the first and second finger bones. The man, who reported that his father and grandfather had the same condition, was a lineal descendant of the first Earl of Shrewsbury, who was born in 1390. During repairs of the family burial vault, it was necessary to open the first earl's tomb, giving Drinkwater the opportunity to look at the skeleton. The long-dead earl also had markedly short finger bones, proving that this rare dominant gene had been present in the family for 14 generations!

Even better than earls for the early study of human genetics are kings and queens. Until about 1800, any unusual physical characteristics or odd medical problems were far more likely to be noted and recorded in these individuals and their families than in virtually anyone else in their era. Perhaps the earliest evidence of genetic disorders, as well as of the dangers inherent in incest, was discovered in the tombs of the pharaohs of Egypt. For centuries those dynasties practiced brother-sister and other close marriages. Because the pharaohs were considered to be gods, it was believed that no persons outside their blood line were a suitable match. Early in the 20th century, when European archaeologists opened royal tombs along the Nile, they found that many skeletons from the pharaonic lines showed evidence of congenital malformations, most likely, given the inbreeding, due to the effects of two recessive genes.

The most famous example of a dominant phenotype (the word, phe-notype, refers to a discernible physical trait shaped by an underlying gene or genes), the result of one or many genes interacting with the environment, certainly the one most commonly used in genetic textbooks, has been provided by the Hapsburgs, the family that ruled the land that is now Austria from 1278 until the end of World War I. The ancient family name seems to have originated from the Habichtsburg or Hawk's castle, a small castle now in ruins in northern Switzerland, which was erected in 1020. With but one exception, Hapsburgs sat on the throne of the Holy Roman Empire from 1438 until it was abolished in 1806.

In the 15th century, a Bohemian princess married into the Hapsburg family, bringing with her a dominant gene that strongly influences the shape of the face. Perhaps the earliest evidence of the phenotype is a medallion showing the profile of Maximilian I (1459-1519). His distinct, narrow lower jaw and protruding lower lip are seen over and over through the generations. The Hapsburg face is unusually long, and the mouth tends to be partially open, an unattractive look, but one that court artists were apparently not directed to soften. Portraits of Emperor Charles V (1500-1558) and Archduke Albrecht (1817-1895) clearly show the distinctive face. The gene does not seem to have had any other effects; it certainly did not prevent its carriers from ruling the Austro-Hungarian Empire with iron fists for centuries.

George III

George III, the British king who lost the colonies, was often severely incapacitated by a dominant genetic disease, a rare disorder that is well understood today, but which was a complete mystery in the late 18th century. George III ascended the throne at the age of 22 when his father died suddenly on October 25, 1760. At the new king's side was John Stuart, the third Earl of Bute, a Scotsman who had risen to power during the 1740s as a favorite of Princess Augusta, the wife of the Prince of Wales, and the new king's mother. In the years immediately before his coronation, young George had been constantly under Bute's wing, and for years after, he viewed the political world through Bute's lens. In the early years of his reign, George's illness would give Bute tremendous power.

By all contemporary accounts, George III worked hard at learning to carry the mantle of kingship, but in the winter of 1765 he developed a strange malady that incapacitated him for the better part of three months. It was a second and much more severe attack of the same illness that had first come on after a cold in 1762. The symptoms were complex and baffling. At various times the king suffered from constipation, colic, chest pains, stomach cramps, skin lesions, an alarmingly fast pulse, profuse sweating, rapid and sometimes gibberish speech, swelling of the joints, loss of taste, gross irritability, hallucinations, delusions, and delirium. He also on numerous occasions passed urine which when left standing in a chamber pot was reported variously to turn crimson, purple, or the color of port wine. At times it was thought that he was near death. As his queen had not given birth to an heir, the illness of 1765 caused great political consternation, and led to the passage in May of a Regency Act, a law that laid out the succession to a king dying without issue.

The medical history, taken together with other contemporaneous records, clinches the diagnosis. George III suffered from acute intermittent porphyria, one of a group of six different disorders, each of which arises from a genetic defect in one of the six enzymes that are collectively responsible through a series of coordinated biochemical reactions for making a molecule called heme. Heme forms the core of hemoglobin, the molecule in red blood cells that carries oxygen from our lungs to our remotest cells. It is crucial to the respiratory cycle of cells. It is also the pigment that gives blood its color. Our bodies are constantly reprocessing old red blood cells, which are used up by the millions each minute. Cells in the liver normally use the breakdown products of hemoglobin to manufacture new heme.

People with the form of porphyria known as acute intermittent por-phyria have a block at the beginning of this recycling pathway. Curiously, some people with the defective gene never become ill, whereas others become severely incapacitated. That is, the disease sometimes appears to skip generations. This strongly suggests an important role for environmental factors in triggering the illness. Scientists today think that symptoms arise when a chemical known as 8-aminolevulinic acid, which derives from the breakdown of hemoglobin, begins to accumulate. 8-Aminolevulinic acid is extremely toxic to the nervous system. An excess level was almost certainly the direct cause of the madness of King George III. One environmental factor that increases the risk of illness (probably by increasing levels of this chemical) in those who are born with the mutation is drinking alcohol. This is a particularly unfortunate fact, as brandy was one of the treatments ordered for the king when he suffered his attacks.

Although these different forms of porphyria each strike fewer than about 1 in 10,000 persons, the illnesses are well known. This may be due to the folklore that arose over the centuries in several isolated European villages where there were families burdened with a slightly different form of the disorder called congenital erythropoetic porphyria. Unlike the disease that incapacitated George III in his adult years, people with this disorder are affected from birth. They are extremely sensitive to sunlight, which blisters their skin. Over the years their skin and nails become brownish red due to the deposition of unmetabolized heme pigments, and they make blood-red urine. Because of the photosensitivity, affected persons, who also suffer psychiatric problems, naturally choose a nocturnal existence. One can easily see how, as the collective folk experience accumulated over the centuries, villagers could use their observations of these unfortunate individuals to create tales about vampires and werewolves.

Acute intermittent porphyria is known for the wide variability in the way it affects different people in the same family and even for its unpredictable expression in a single affected person. This was surely the case for the British royal family. The disorder is dominant, and it has been traced back from George III as far as Mary Queen of Scots, his grandmother six generations removed. Many biographers have described her behavior, especially her hopelessly foolish plot to murder her cousin, Elizabeth I, which led to her execution in 1587, as the work of a deranged mind. It is well established that Mary's son, James I, had acute intermittent porphyria, for there are records of him passing purple urine (the color is caused by the presence in the urine of unmetabolized iron-containing pigments). Yet, he does not seem to have been severely impaired. Nor were George III's great-grandfather (George I), grandfather (George II), or father (Frederick, Prince of Wales). George I lived to be 67 and was in relatively good health, and George II, who was also in good health, died suddenly of a heart attack at 77. Frederick, who died before his father, was taken suddenly at 44 by a lung infection (he was autopsied). Thus, a disease gene that had been traveling in the British royal family for at least eight generations had not caused really severe disease until it expressed itself in George III.

The diagnosis of George III was made, albeit somewhat late, in 1966 when two British physicians, Macalpine and Hunter, published the results of their detailed analysis of the many records kept concerning George's illness in the British Medical Journal. They report that during the worst bout of illness, which lasted for several months in 1788-1789, the king was committed against his will to a private asylum under the complete control of John Willis, a "mad doctor," a forerunner of today's psychiatrists. Willis, who, when the king was uncontrollable, sometimes constrained him with a straitjacket, and who placed too much faith in purgatives, generally used more benign techniques to calm and quiet his royal patient. Much time was spent in taking the king for country walks with his attendants, for example. We cannot know if these interventions helped, but they were far preferable to the treatments provided by the court physicians. The king, who had been periodically insane and sometimes near death since the attack started on June 11, 1788, began to convalesce rapidly in mid-February of 1789. During this eight-month period, one of the royal physicians, who closely followed his course, compiled some 40 volumes of handwritten notes, probably the largest medical record of the century.

George III was not again severely ill until 1801. During this attack, records show, he was clearly mentally impaired. He was unable to concentrate, often cried uncontrollably, engaged in many perseverative behaviors such as rolling handkerchiefs, and complained that he could not recognize himself in a mirror. Despite the best efforts of his physicians, who bled him and ordered that he drink brandy each night, he recovered. The king suffered yet another severe attack in 1804, but he again miraculously recovered. Unfortunately, his mind deteriorated and in 1810 he was adjudged to be permanently insane.

Despite being periodically ravished by his bizarre disease, George III lived to be 82, the longest reigning British monarch, save for Victoria. His last major attack of acute intermittent porphyria occurred in 1811. Interestingly, during his attacks of 1804, 1811, and when George III was dying in 1820, his oldest son, the Prince of Wales, with whom he had never gotten along, was also violently ill. In 1811, there was genuine concern that both men would die within days of each other. The Prince of Wales almost certainly also had acute intermittent porphyria, although in him it ran a less severe course.

Given the state of 18th-century medicine, it is hardly surprising that George III's physicians were of little help during any of the five major and many minor attacks that he suffered over the course of 50 years. The best of the royal physicians, realizing how little they knew, observed the course of the illness carefully and tried to protect the king by isolating him in a quiet rural setting when the illness exploded. The worst of them, especially during the major attacks, harmed him further with repeated bloodletting and worthless remedies such as drinking mare's milk.

There must have been countless occasions when his judgment was impaired by the effects of porphyria that George III was nevertheless either making decisions of great political importance or letting others exercise his authority. Of special interest is the impact of his extended illness in 1765 on the deteriorating relations with the North American colonies. We certainly cannot attribute the course of events that led to the Revolutionary War as being deeply affected by his illness, but George III may have for a time perceived his faraway subjects to be more intransigent than they really were, a perception that could not have helped hopes for reconciliation.

X-Linked Genes

Mendel definitively described two of the three classic modes by which genes that travel through generations affect us—dominant and recessive (see Chapter 3). It would be another 50 years before the scientific basis for the third mode, sex-linked or X-linked inheritance, was clearly grasped. In humans the genes are arranged on 23 pairs of chromosomes, 22 pairs of autosomes and a pair of sex chromosomes. Women have two X chromosomes and men have one X and one Y chromosome. The Y chromosome transmits the gene that determines maleness, but compared to the much larger X chromosome, it has relatively few genes. The consequences of this for the two sexes are immense. If a girl inherits an X chromosome with a potentially harmful recessive gene, it is almost certain that the comparable gene on her other X chromosome will protect her from it. If a boy inherits an X chromosome with a harmful gene, there is no corresponding gene on his Y chromosome to counter its effects, and he will become ill.

Nearly two millennia separate the earliest record of humanity's practical understanding of X-linked disease genes from the scientific understanding of how they operate. By the 2nd century A.D., the Talmud had rules regarding the ritual circumcision of boys in families in which death had occurred as a result of excessive bleeding following the operation. The rules forbade the circumcision of later-born sons of a woman who had lost two boys from uncontrollable bleeding. In addition, it admonished that the sons of her sisters should not be circumcised. Yet, half-brothers of the dead sons, if sired by the same father and a different mother, were to be circumcised. Clearly, those who wrote these rules realized that there was a hereditary risk of bleeding that was carried by and passed through the mother. Further elaboration did not come until about 1820, when a German physician recognized that daughters of men with bleeding diseases, although themselves unaffected, could pass the disease on to their sons.

Only about 1910, as geneticists studied the inheritance of certain traits in animal breeding and as others began to map the location of genes on the chromosomes of fruit flies, did it become clear that the Talmudic observations could be explained by positing that a gene that affects how blood clots must be located on the X chromosome.

During the mid-19th century, as scientists were beginning to grasp the idea of sex-linked inheritance, another long-lived British monarch, Queen Victoria, was born with what is almost certainly the most famous mutation in history. Today the remnants of Europe's royal families include many persons with hemophilia. By reconstructing the pedigrees, it is readily apparent that all affected persons are descendants of Victoria, and that none of her ancestors were affected. Thus, either the egg from her mother or the sperm cell from her father must have carried within it a new mutation in the gene that codes for a protein essential to blood clotting that is known as factor VIII (the name dates from a time when scientists were working out the complex pathway by which blood clots, but before they had identified the enzymes that did the work). Victoria was a silent carrier who could not know the risk she posed to her children and grandchildren.

Hemophilia is the most common of the serious clotting disorders, affecting about 1 in 10,000 persons. As is true with most genetic disorders, the severity of the disease depends on which of the hundreds of different possible mutations are in the gene of the particular patient. The reason that there can be hundreds of different mutations is that the DNA sequence that codes for a protein typically is composed of thousands of chemical units called bases. A change in even one base can give rise to a defective protein. Depending on how much damage is done by the mutation, some people are at risk for serious bleeding only after major injury, some bleed severely in response to minor injuries, and some—the most severely affected—bleed spontaneously, especially into their joints, which in the past caused serious skeletal problems. Until the development of factor VIII therapy, the periodic transfusions of donor plasma enriched for the needed protein, children with severe mutations usually died.

The great progress with factor VIII therapy had a tragic setback in the 1980s when some children, especially in France where the blood supply was not sufficiently monitored, became infected with HIV and died of AIDS. Today, thanks to the tools of genetic engineering, we use bacterial factories to make vast amounts of pure factor VIII. The treatments pose little risk of an allergic reaction and no risk of HIV infection. Today, even children with severe hemophilia can be greatly helped by such therapy.

Unquestionably, the most famous recipient of Victoria's new and, unfortunately, severe mutation was her great grandson, Alexis, heir to the throne of Russia. Victoria passed the chromosome with this mutation to her daughter, Alice, who silently passed it on to her daughter, who grew up to marry Czar Nicholas II of Russia. When the empress discovered that Alexis had severe hemophilia and realized that contemporary medicine had little to offer him, she turned elsewhere for help. She came under the influence of Rasputin, a monk with allegedly mystical healing powers, and soon placed Alexis under his care. The boy seemed to improve, perhaps because Rasputin successfully used hypnosis to help him avoid even minor trauma. Impressed with Rasputin's work, the empress manipulated the tsar to heed the monk's advice on an ever-widening array of matters. For a short time, he was among the most influential persons in Russian politics. The decadence and corruption that Rasputin encouraged during his brief flirtation with power almost certainly helped to weaken the tsar's hold on his nation as it spiraled into revolution. It is intriguing to speculate how the course of modern European history might have differed had Victoria not been born with a mutation in her factor VIII gene.

The mutations that cause acute intermittent porphyria or hemophilia or Marfan syndrome (see Chapter 1) provide some of the most dramatic examples of the influence of a single mutation on the body. The knowledge of the impact of a few disease genes in the history of a few famous families helped formulate concepts that led to the much deeper understanding of gene action that we have today. Classic Mendelian disorders are the great peaks in the landscape of genetics, the landmarks that the early explorers could set their sights and their hopes on as they marched along. But the interaction of gene pairs, the biochemical dance of dominance and recessiveness, is by no means limited to genetic disorders. It is played out trillions of times, usually in extremely subtle ways, in our cells from the moment of conception until death. Today, as we shall see, molecular biologists can ask far more subtle questions about that minuet.

Henri de Toulouse-Lautrec. (© Georges Beaute.)

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