Charles Darwin’s Mysterious Illness
This week’s article focuses initially, and unusually, on a notable individual, not a biological question. It will, however, end up with biology and some current issues in medicine that are of serious interest today. A friend and I are currently writing a book on this subject, hence it has been much on my mind in the last several years.
The individual in question is Charles Darwin. Many books have been written about him and everyone knows who he was: the father of evolutionary biology. As a famous scientist, he is right up there with Isaac Newton and Albert Einstein. But how much is known about him as a man with his own personal history? Some will know that he was a wealthy Victorian gentleman and that he lived in the countryside not too far from London, as a country squire.
Did you know, however, that he was ill for most of his lifetime? Indeed, he was chronically ill – not constantly or continuously but chronically -- for about 45 years. Yet it did not stop him from producing a remarkable body of work that reshaped biology. The illness was peculiar, with multiple and seemingly unconnected symptoms, and it was a mystery both during his lifetime and long afterwards. Its nature, however, may be coming into focus now, as will be described in this article. We begin, however, with the history of this strange illness.
A crucial point is that Darwin started life as a healthy and vigorous person, first in his childhood and teenage years, then as a young adult in his early to mid-20s. He was into outdoor activities in a big way as a youngster and, later, as an undergraduate. Soon after graduating (from Cambridge University in 1831), he set sail on a globe-girdling voyage on The Beagle, a ship in the Royal Navy, a journey that stretched into a nearly five years’ long expedition. Its principal aim was to map the coast of South America. Charles Darwin was initially brought on board as a gentleman companion for the captain but became the ship’s naturalist. It was a physically demanding job – Darwin spent a large part of his time on land exploring by foot and on horseback, in South America and Australia and various islands along the way. He was not only up to those demands but well-liked by both the officers and crew and had the reputation of being one of the fittest men on board.
It was only after returning to England that his health problems began in earnest, dating apparently from the first month he settled in London, in March of 1837. He spent five years in that city, in poor health, before retiring to the English village of Downe, where he spent the rest of his life. His symptoms involved: his heart, his digestive system (especially regular bouts of vomiting), chronic fatigue, migraine headaches, periodic eczema, occasional breathing problems, muscle pains (fibromyalgia) and more. By September of that year, he turned down the secretaryship of the Geological Society of Great Britain. It was an honour to be offered this position, especially to someone his age (he was only 28), and he declined it with regret. He felt, however, that he had to conserve his energies to complete all the follow-up work from the expedition. From that point onwards, he was never really well and often quite ill, though there were brief periods of relative recovery.
That, at least, is the story generally recounted about his health: that he was a young man in good health until he was 27-28 and after that a semi-invalid, for the next 45 years, though with brief periods of relief. This picture, however, leaves out certain signs of ill-health he experienced in his late teens and then, more dramatically, during the voyage of The Beagle. The latter included a period of heart “palpitations” just before The Beagle left Portsmouth at the start of her voyage, brief bouts of eczema on his lips and hands, and some strange problems in body temperature regulation (now labeled as “dysautonomia”, a condition of his peripheral nervous system). Most strikingly, there was his endless seasickness during the voyage. Of course, sea sickness is normal amongst people who are new to ocean voyaging but usually people get their “sea legs”, becoming used to the movements of the ship and experiencing much less motion sickness. In contrast, Darwin never adjusted and reported to his relatives that it was just as bad toward the end of the voyage as at the beginning.
Evidently, Darwin had a delicate constitution, and a proneness to certain symptoms, even in his time of basically good health in his teens and early 20s. There was quite probably already a predisposition to the serious illness that began in his late 20s. In this timing, his ill-health was already unusual. Apart from infections (either bacterial or viruses) or illness due to poisoning or accidents, all of which can strike at any time of life, serious illnesses tend to cluster either in childhood or old age. Darwin’s illness, in contrast, started in-between those periods, a category known today as an “adult-onset illness”.
Medical knowledge at the time, the mid-19th century, was neither up to recognizing or dealing with Darwin’s condition although his doctors did what they could. Often a proposed therapy would have a temporary ameliorative effect but that was all. At the time of Darwin’s death in April, 1882, there was no better understanding of his illness than there had been at its apparent onset in 1837. The concept of “chronic illness” did not exist then; indeed little was known of human biology at the time. (“Germ”-mediated diseases were understood from the 1850s onwards but little else.)
Yet, Darwin’s illness has had a strange after-life: it has been the subject of much speculation by historians, medical people, psychologists and biologists. Indeed, it generated its own small academic cottage industry, with approximately 40 to 60 hypotheses published. (It is hard to be precise about the number because some have been labeled as new while actually being variants of previously published ideas.) This seems an excessive number and in one sense it must be, because presumably only one or two, at most, can be right but it is not surprising. With Darwin’s body long gone in decay and interred in Westminster Abbey, there is no way to test most of these ideas, and with no idea ruled out, there is no bar toward forming new hypotheses.
Many published in the 20th century focused on Darwin’s psychology and essentially claimed that his illness was the product of a disturbed psyche in some sense. It is unquestionably true that various forms of stress could bring on bouts of illness or make his suffering worse but they were almost certainly not the primary “cause” of his illness. Rather, stress can trigger the onset of symptoms in a person already physiologically predisposed to illness and this seems almost certainly to apply to Darwin’s case. This thought and the probability that Darwin’s illness was an adult-onset disease suggest an underlying genetic predisposition. If so, there might well have been signs of similar illness amongst Darwin’s relatives, perhaps his siblings, maybe one of his parents or grandparents or still earlier relatives.
My friend John Hayman, a pathologist from Australia, decided to look at Darwin’s family tree with this in mind. He found that none of Darwin’s relatives showed his exact condition but many showed overlapping symptoms, including the chronic fatigue, severe headaches, and muscle pain. It is the distribution of these ill relatives in the family tree that is striking: they are all on his mother’s side of the family. The individuals who showed the strongest resemblance in symptoms included his mother, her mother, an uncle, and Darwin’s brother, Erasmus. Erasmus’ condition was like a mild version of Charles’ condition while that of his uncle Tom, who died young, had a much closer version (though missing one of Darwin’s key symptoms, the repeated or “cyclic” vomiting).
There is one, and only one, genetic element that is inherited maternally, which could cause this pattern of matrilineal inheritance. That is the small circular DNA molecule possessed by the mitochondrion, the tiny organelle that supplies energy – and a lot more – to the cell. (See no. 8 in this series.) A matrilineal inheritance for any disease condition indicates that there is a genetic variant in the chromosome of many of the mitochondria of that individual, one that would cause sub-optimal mitochondrial performance. If there is a degree of mitochondrial dysfunction in a tissue or an organ, there can well be health problems in the form of one or more disease symptoms. The more tissues and organs affected by such a mutation, the worse the condition will be.
Such mutations were known in fungi from the 1960s onwards but were only discovered in humans in the 1980s. Within 10 years of the first publication, there were about half a dozen of these mitochondrial genetic disease states known. They are now well characterized but a signal feature is the variability in the severity and range of the symptoms. That variability is a function of the nature of the genetic variant itself – with some creating a lot more dysfunction than others – and of the proportion of mutant to normal (wild-type) chromosomes in the mitochondria of the different tissues and organs of the body, which can vary a great deal.
Altogether, there are now eight major mitochondrial genetic disease syndromes in humans. When very severe, they can be lethal either in infancy or early childhood but in their less harmful forms, they can allow survival well into adulthood. Even in those cases, however, the suffering of the affected individuals can be strong. Darwin’s symptoms do not closely match any of the known mitochondrial genetic syndromes yet that is not a serious problem for this interpretation. The reason is that the symptoms produced by this kind of genetic defect are very much a quantitative reflection of the proportion of mutant to wild-type mitochondrial chromosomes, the tissues affected, and several other factors we will not go into here. We are proposing that Darwin suffered from what is known as a “non-syndromic mitochondrial disorder”. By their very nature, these conditions are heterogeneous and do not conform to particular set types.
In principal, and in contrast to most of the other proposals for the nature of Darwin’s illness, this idea is testable. All it would take is a sample of Darwin’s mitochondrial chromosomes. These should be obtainable from either Darwin’s bones or those of his mother, grandmother, or brother (or possibly his books.) Obtaining those samples is, in principle, possible though difficult; the barriers are legal and bureaucratic, not technical. The idea predicts that Darwin’s mitochondrial DNA will reveal that it contains a genetic variant, atypical for healthy humans, and in sufficient numbers to cause disease. The current state of DNA sequencing is adequate to this challenge.
The study of human mitochondrial genetic diseases is now about 40 years old and began about a century after Darwin’s death. If our hypothesis is correct, then the subject of Darwin’s death already has a contemporary relevance. Yet the tie-in to mitochondrial biology has a further connection to contemporary medicine.
The most crippling of Darwin’s symptoms, in terms of his daily ability to work was his chronic fatigue, which typically limited his working day to two to three hours for most of his life. That aspect of his illness bears a striking resemblance to two other disease conditions today that affect many millions of people and which are now receiving much attention from medical researchers. These are chronic fatigue syndrome itself, now designated “myalgic encephalitis/chronic fatigue syndrome” or ME/CFS, and “long COVID”, the condition that follows a bout of COVID-19 infection about 10-30% of the time. These two states are increasingly regarded by clinicians as essentially the same, though set off by different factors. Other conditions, such as Lyme disease, also feature chronic fatigue. One could label such states as “diseases of fatigue”. They have different initiating factors but end up in chronic fatigue.
The periods of exhaustion they feature can go on for weeks to months, without significant let-up. Such periods of prolonged fatigue can be set off by relatively short periods of exertion or exercise, which, in normal people, might require only 10 minutes to an hour of rest to recover from. This phenomenon has a name, “post-exertional malaise” or PEM. Darwin suffered from PEM too, even during the expedition, in South America and Australia, though at that time, his recovery took place after a few days, not weeks or months. Increasing evidence implicates the mitochondria in these conditions, in a particular long-lasting dysfunctional state known as “mitochondrial allostasis”.
We will return to mitochondrial dysfunction as a common feature in many diseases, in a later article in this newsletter.
Supplementary Reading
The most extensive account of Darwin’s illness and the various ideas about it, with emphasis on the mitochondrial hypothesis described above, is the book by John Hayman and myself. However, it will probably not be out for at least a year. Some other sources are available and may be of interest.
Hayman, J.A. (2013). Charles Darwin’s mitochondria. GENETICS 194: 21-25.
A short and early account of the mitochondrial hypothesis of Darwin’s illness.Buchanan, R.D. (2021). Syndrome du jour: the historiography and moral implications of diagnosing Darwin. Studies in History and Philosophy of Science, Part A 90. 86-101
A well-written and witty account of the many hypotheses of Darwin’s illness and how they often reflected aspects of the time in which they were written.
Gorman, G.S. et al. (2016). Mitochondrial diseases. Nature Reviews Disease Primers. Doi: 10.1038/nrdp.2016/80
An older but thorough and useful review of the known mitochondrial genetic disorders.