History and genetic diseases

How hereditary diseases changed our history—from ancient Egypt and the House of Habsburg to the House of Romanov

Introduction

Whether in the East or the West, humankind has taken a keen interest in heredity and genetic diseases from ancient to modern times. A typical example of this is the theory of heredity and hereditary disease discussed by renowned scholars such as Hippocrates and Aristotle of ancient Greece from the West. Meanwhile, in the East, an ancient Indian medical book called Charaka Samhita, written around 300 AD, was the first paper to argue that the traits of offspring are inherited from their parents, and it went on to suggest that these traits were being passed on over generations through heredity. Additionally, around the ninth century, the African–Arab writer Al-Jahiz wrote a book called Kitab al-Hayawan (The Book of Animals), which stated that the natural environment influences to have new characteristics for the survival of living things, and such affected creatures pass on their newly generated characteristics to their offspring over time. Furthermore, Albucasis, an Arab–Andalusian physician in AD 1,000, who is called as the father of modern surgery, first described the genetic nature of hemophilia in his medical book based on the study results of a family history from the Iberian Peninsula.

As such, even before the first modern genetics and research in genetic disease by Gregor Mendel progressed, humankind attempted an extensive scientific approach to genetic disease transmitted through heredity regardless of period, region, or culture throughout the world. This indicates that humankind has been interested in the transmission and new manifestation of genetic diseases that occurred through ‘marriage’ and ‘birth’.

Considering the premodern period had its limitations in that writing ability, the publication and preservation of records, and receiving professional diagnosis by a doctor (a result of the social milieu) were not equally accessible to all classes of society, genetic diseases that occurred through ‘marriage’ and ‘birth’ not simplistically examined and recorded in ordinary families of the era. Rather, in many cases, the discussions were centered on the families that ruled over a kingdom and the manifestation and symptoms of genetic diseases in them were well recorded in history. Consequently, genetic diseases manifested in them not only affected the realm they governed but also were among the key factors impacting the pathway of world history from time to time.

Historically, even the royal family that ruled over a kingdom or even an empire could not have any control over the manifestation of genetic diseases, but now humankind lives in a world where the prediction and prevention of genetic disease and the management of genetic disease diagnosis are inevitably possible through genetic testing and carrier screening. For this topic of “History and Genetic Diseases’ ‘ posted on 3billion Blog, we will discuss how genetic diseases that existed regardless of era and culture left their footprints in history through ‘marriage’ and ‘birth’ within powerful royal families and to discuss what implications it has left for us.

Ancient Egypt—the inbreeding of Pharaohs

The pharaohs of ancient Egypt were considered sons of gods and were not expected to marry ordinary people. Therefore, the pharaohs passed on their lineage through inbreeding from generation to generation. Indeed, if one looks at the lineage of the pharaohs, there are not only overwhelming cases of marriages between brothers and sisters but also marriages between parents and children are recorded in history.

Akhenaten of the eighteenth dynasty of ancient Egypt is well known as a religious reformative pharaoh, who worshiped a single God called Aton, contradictory to the existing pluralistic Egyptian belief. Further, when looking at the extant statues depicting Akhenaten, he is depicted as having a pointed jaw, a very skinny constitution, and yet a bulging belly. Indeed, Akhenaten was known to have married his eldest daughter, Meritaten, and in his later years, he married his third daughter, Ankhesenpaaten, as his queen. Tutankhamun, who is famously known to us for the Tutankhamun mask, is known to be a child of Akhenaten and one of his own siblings. Based on archaeological findings on the mummy autopsy of Tutankhamun, research revealed that he was born with a congenital disability in his legs, causing mobility problems and speech disorders due to cleft lips and a cleft palate. Several other Egyptian pharaoh mummies that still survive today have been reported with various malformations, such as Froehlich syndrome*, caused by extensive inbreeding within the royal families.

What is Froehlich syndrome?
Rare childhood metabolic disorder characterized by obesity, growth retardation, and retarded development of the genital organs – Definition quoted from Britannica

This ancient Egyptian tradition of inbreeding continued until the very last Egyptian pharaohs, the Ptolemaic royal family. The historically infamous queen Cleopatra married her 10-year-old brother, Ptolemy XIII at the age of 18. Although the marriage did not produce any child between them, it can be said to be a very typical case of incest between the brothers and sisters in the royal family until the very last pharaonic dynasty of Egypt.

Thus, in the ancient Egyptian royal family, marriages and births between relatives were extremely common as a means to prevent the influx of external powers and to maintain their family power. The tradition of inbreeding was passed down from generation to generation to maintain power within the dynasty even if there was a change in the ruling family on the throne.

The Premodern European Context—the Habsburgs

The Habsburg family, which started as a small, humble lordship in Switzerland and Alsace in the tenth century, produced their first Holy Roman Emperor Rudolf I in 1273. By the sixteenth century, the family had risen to prominence as a dominant European royal family, which ruled both the Holy Roman Empire and Spain.

During the process of abdication of Charles V in the mid-sixteenth century, to rule the expanded empire, the Habsburg dynasty was divided into the Spanish and Austrian Habsburgs. Charles V’s son Philip II inherited Spain, Naples, and Sicily, and Charles V’s younger brother, Ferdinand I, inherited the throne of the Holy Roman Empire. All of them eventually suffered from a genetic disease called “Habsburg-Unterlippe,” which means born with a particularly long, protruding lower jaw through inbreeding that persisted and was passed on throughout the family.

The Habsburg-Unterlippe, also known as the “Habsburg Jaw,” started with and was passed down from Maximilian I of the Holy Roman Empire to King Charles II of Spain over more than six centuries. Due to the Habsburg Jaw, most of the sufferers were not able to chew food properly because the upper and lower sides of their jaws did not fit, and records indicate that they had difficulty articulating. Therefore, Charles V avoided face-to-face work, and instead introduced a new working system to receive and process all work in documents. Of the many members of the Habsburgs, the one who suffered the most from the Habsburg Jaw was Charles II, the very last king of the Habsburgs of Spain and son of Philip II. He was born with a naturally weak body, with a hunchback, he had a mental illness, and he could not even chew food properly because he had the worst jaw problem inherited from his ancestors. It is said that his upper and lower teeth did not meet at all, so he was drooling all the time. In addition to this, he was widely known as sexually disabled, and he became bald in his early- to mid-30s.

Because of this, it was difficult for him to properly rule the realm, but the critical part of the time was that the condition of the king born this way was seen as a sign that a demon had taken possession of the king’s body and that the king was a victim of black magic. Therefore, the news of the exorcism performed to defeat the demon in his body eventually spread all over Europe, giving Charles II the nickname “bewitched” in historical records.

After Charles II, who suffered from a severe genetic disease, the Spanish Habsburgs left no more living descendants; therefore, the Spanish throne was passed to the French Bourbon family. In addition, as the era of kings with genetic diseases that were filled with turbulence to take care of national affairs passed, Spain’s heyday which was widely considered as the Spanish Armada (invincible fleet), was slowly coming to an end, leaving its splendid glory behind.

The Russian Context—the Romanovs

Queen Victoria of Great Britain (1819–1901) was believed to be a carrier of hemophilia caused by a variant, and as her descendants extensively married royal families in neighboring countries, hemophilia eventually spread to other royal families in Europe. Queen Victoria’s granddaughter, Alexandra, also a carrier of hemophilia, met and fell in love with the then 16-year-old Crown Prince Nikolai from Russia when he attended the wedding of Alexandra’s sister. Despite opposition from the Russian royal family, she married Crown Prince Nikolai (who later became Emperor Nicholas II) of the Russian Romanov dynasty. Eventually, she gave birth to Prince Alexei, a hemophiliac himself, just like his mother and her ancestors.

At that time, there was no cure for hemophilia, and for this reason, the Empress was greatly concerned for her only son, Crown Prince Alexei. Meanwhile, a mysterious monk from Siberia called Rasputin set out to cure Alexei’s disease. What he performed was mild hemostasis, but miraculously, every time he performed the procedure, Alexei regained both psychological and physical stability. This treatment eventually allowed Rasputin to gain a title of nobility coupled with deep trust from the imperial Romanovs.

Rasputin used and manipulated this favorable situation extensively, which led to various instances of corruption and sexual scandals, causing enormous turbulence in Russian politics. This abuse of power even led the pro-imperial aristocrats to turn their backs on the emperor, who invested great trust and power in Rasputin. In the end, Rasputin was murdered by Russian aristocrats; however, only a year after his death, the Russian Revolution erupted due to dissatisfaction with the weak emperor and his family. The revolution led to the abdication of the emperor, and in 1918, a year after his abdication, the emperor and his family were executed; thus, the Romanov dynasty was seen off, permanently expunged from Russian politics.

Over the years, some people have claimed to be the emperor’s fourth daughter, Anastasia, by claiming that they miraculously escaped from the slaughter scene, but DNA testing of the remains of the emperor’s family, exhumed in the 1990s, and the testimony of nobles from the Romanov line revealed that those claims were false.

Conclusion

As seen from the brief coverage of the topic “History and genetic disease,” genetic diseases have existed together with us, and around the world, for much longer than we might have thought. As seen in each example, hereditary diseases can be said to be a natural part of our human history over time, where genetic diseases have manifested through ‘marriage’ and ‘birth’ regardless of historical and geographical differences. Not only the family itself but also the hereditary diseases that have emerged have often influenced major changes in history.

Before genetic diseases were studied using modern scientific approaches, genetic diseases were dismissively addressed as a way of fighting against “the devil’s magic” or “God’s curse.” Nowadays, we live in a world where, through various methods, such as prenatal carrier screening and NIPT(non-invasive prenatal testing), it is possible to prevent the onset of serious genetic diseases in advance. Indeed, as for a genetic disease that has already manifested, an accurate diagnosis is possible through Whole Exome Sequencing (WES) or Whole Genome Sequencing (WGS), and extensive research on genetic diseases is being conducted continuously to reduce the pain that patients suffer.

Although it is true that the vague but abstract concept related to genetic diseases has indeed existed historically, the backdrop against which genetic diseases occur has changed over time, and the causes of many genetic diseases have been scientifically elucidated. Indeed, when the main cause of hereditary diseases in the past was, most likely caused by marriages between close relatives, the frequency and context of the occurrence of hereditary diseases in modern times are significantly different from those of the past largely because marriage between close relatives is prohibited in most cultures in the modern world.

In addition, modern scientific research has revealed that the cause of genetic diseases is not always necessarily transmitted from parents but is transmitted probabilistically according to various biological combinations. “De Novo’, that is, genetic diseases caused by completely new variants, and not from parents, have been newly revealed as well. Because of these scientific and technological developments, coupled with modern scientific approaches, humankind has been able to cope with genetic diseases wisely in contrast to the perceptions in the past.

We live in a world where genetic diseases that existed historically are not feared or regarded as a curse from God thanks to modern medicine and advances in science and technology, and genetic diseases can be managed and treated through any nearby medical staff. Genetic diseases are no longer obscure and simply unlucky for humankind, and although they do exist among us, they are predictable and treatable.

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