Feature: Diagnosing Darwin

This feature appeared in the January/February 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.

In January last year, Dr John Hayman read a biography of Charles Darwin and became intrigued by Darwin’s almost lifelong battle with a chronic, relapsing illness. But now, Hayman, an Associate Professor in Monash University’s Department of Pathology, thinks he’s narrowed it down to a rare mitochondrial disorder inherited from his mother.

Darwin’s chronic, relapsing illness baffled not only the best physicians of his day, but also a considerable number of clinicians, medical researchers, psychologists and lay experts who have sought to make a posthumous diagnosis.

Even before he came aboard HMS Beagle just after Christmas in 1831, to take up his appointment as ship’s naturalist and companion to Captain James Fitzroy, 22-year old Darwin was exhibiting symptoms of the debilitating illness that would plague him during its epic, 58-month voyage around the world.

The symptoms included nausea and uncontrollable vomiting, heart pain and palpitations, anxiety, headaches, dizziness, visual disturbances, weakness and lethargy, accompanied by abdominal pain, “inordinate flatulence” and diarrhoea.

His ‘seasickness’ made his life a misery for much of the almost five-year voyage – and significantly, he continued to suffered episodes of sickness, headache and fatigue even when he went ashore.

Darwin’s symptoms

Many theories were proposed, but when Hayman looked in to them, he didn’t find them convincing. “All of these theories were floating around, and some were clearly preposterous,” says Hayman.

In 1959, Israeli tropical medicine specialist Saul Adler suggested Darwin had suffered from Chagas disease, an insect-borne trypanosomal disease that affects millions of people in Mexico and South America. But Hayman rapidly dismissed the idea, because Darwin was already debilitated by bouts of uncontrollable vomiting as the Beagle crossed the Bay of Biscay, three days out of Plymouth Sound.

The inner-ear disorder, Meniere’s disease, also seemed unlikely. It is characterised by severe dizziness and nausea, and tinnitus – ringing in the ears. But by all accounts, Darwin did not mention suffering from tinnitus.

Lactose intolerance could explain Darwin’s flatulence and diarrhoea, but not his other symptoms. Arsenic poisoning from Fowler’s solution, a primitive remedy he once took for his skin condition, also seemed unlikely. Hayman says there is no evidence that Darwin took large amounts of arsenic over a sustained period.

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“Several psychologists proposed that his illness was psychosomatic: he hated his father, he disliked his wife, his theory conflicted with his early religious beliefs, and his plans to pursue a career in the ministry. Reading about these ideas on the Web, it became clear to me that they were kept going by Creationists. If they could show that Darwin was psychologically unsound, it would discredit his theory of evolution. That really fired me up,” he says.

Hayman has a long-standing professional interest in migraine, and his initial thought was that Darwin’s major symptoms of vomiting and stomach pain matched up with abdominal migraine. “The more I read about his symptoms, the more they seemed to fit.”

But while reading British historian Janet Browne’s two-volume biography of Darwin, Hayman became aware of the interwoven lineages of the Darwins and Wedgwoods, two of the most prominent English familes of the 18th and 19th centuries.

Darwin’s mother, Susannah, was a daughter of Josiah Wedgwood, the celebrated founder of the famous English pottery. Darwin’s wife Emma was Josiah’s niece.

Susannah had suffered bouts of vomiting while pregnant with Charles, Emma suffered chronically with migraine, and Susannah’s brother, Tom, also suffered from migraine, abdominal pain and motion sickness throughout his life.

“It became clear to me that Susannah and her brother suffered from the same illness as Darwin,” Hayman says. “Tom used to roll around the floor in agony with his headaches and,like Darwin, he suffered severe seasickness during a voyage to the Caribbean.”

In Emma Darwin, the Inspirational Wife of a Genius, he found a detailed description Susannah’s illness, including an account of how her parents had dipped her into the icy Irish Sea in an attempt to cure her ‘pukes and boils’. Like his mother, Darwin suffered from atopic dermatitis – eczema. Hayman says eczema sufferers are susceptible to boils because their skin is very vulnerable to infection by Staphylococcus aureus, which is found in huge numbers on the skin.

Trawling the Web, Hayman found a number of personal accounts by patients who had the same vomiting symptoms and who also had eczema. In some of his numerous letters, Darwin reports that when his eczema flared up, his nausea and vomiting abated.

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Darwin’s diagnosis

Hayman became convinced that Darwin’s illness was neither psychosomatic, nor the result of an infection. He did not lose his hearing, eliminating Meniere’s disease, and Darwin’s failure to obtain relief by abstaining from eating dairy foods ruled out lactose intolerance.

The familial connection was a powerful clue that Darwin had inherited a genetic disorder from his mother. Taking all Darwin’s symptoms into account, Hayman concluded they were almost a perfect match with a rare mitochondrial disorder, cyclical vomiting syndrome (CVS).

Hayman says the obscure disorder was recognised in the English medical literature as long ago as 1802. William Heberden’s Commentaries on the History and Cure of Disease describes a stomach condition he called Ventriculi Morbi:

“One of the many disorders of the stomach is a disagreement sense of activity rising from it, which is accompanied often with pain, or a sort of anxiety worse than pain, and sickness and vomiting, a sense of weight, voraciousness in some, and loss of appetite in others, flatulence and distension of the stomach, headache, great quantities of phlegm, and a waking out of sleep with a degree of terror.”

CVS may be associated with mutations in the MTTL1 gene, which codes for the mitochondrial transfer RNA for the amino acid leucine. It impairs the mitochondrial respiratory chain that synthesises energy-rich ATP, the primary fuel for all cellular metabolism.

Hayman says ATP deficiency produces a wide variety of effects, particularly in tissues or organs with high energy requirements, like the brain, which may explain Darwin’s dizziness, headaches, visual disturbances, palpitations, sweating and overwhelming nausea and vomiting.

By impairing protein phosphorylation, ATP deficiency can dysregulate the activity of high-energy enzymes, and disrupt signalling systems, including the neuroendocrine system, which controls the release of hormones into the bloodstream in response to emotional changes.

Hayman says Darwin’s prolonged episodes of nausea and vomiting, lasting up to several weeks, were probably triggered by severe motion sickness – seasickness – but could also be brought on by anxiety or excitement, even pleasurable excitement.

He believes this could explain why Darwin became a virtual recluse in his mid-life, avoiding potentially emotional contact with all but his family and a few close friends. He did not attend the funerals of his father, or his beloved eldest daughter, Annie, who died of tuberculosis in 1851, aged 10.

Darwin’s symptoms abated as he aged – also consistent with a diagnosis of CVS. He sought and obtained a measure of relief through cold-water hydrotherapy. Hayman believes the treatment had a calming effect, via the vagus nerve, which projects from the brain to innervate the internal organs, including the intestinal tract.

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Darwin’s prognosis

Hayman sent a paper on his conclusions to Nature, then to The Lancet, but was rejected both times. During further research to improve the draft, he found further evidence supporting his diagnosis of CVS. He finally succeeded this month in getting complementary papers published in the British Medical Journal, and the Medical Journal of Australia and his CVS hypothesis made international headlines.

In his BMJ paper, Hayman rejects suggestions that Darwin suffered from hypochondriasis (imagined illnesses), neurasthenia (a condition involving fatigue, anxiety and headache), agoraphobia (a fear of open spaces) or “any other of the strange psychoanalytically derived maladies that have been proposed”.

To the contrary, he notes that latter-day CVS patients have been described as competitive, perfectionist, high-achieving, strong willed and moralistic. “Surely this is Darwin,” Hayman says.

In the BMJ paper, Hayman writes that Darwin knew nothing of genes or mutations, but was very much aware of random variations within species, the basis of his theory of natural selection, the driving mechanism of evolution. Darwin subscribed to the theory of ‘blending inheritance’, which proposed that offspring are the average of its parents’ characteristics.

If Hayman’s diagnosis is correct, there would be a great irony in Darwin’s belief in blending inheritance, because he inherited a disorder that is exclusively transmitted via the female line. After conception, the male mitochondria that powered the father’s sperm are labelled with ubiquitin inside the fertilised egg, marking them for destruction, and they make no contribution to the unique genetic admixture of the new individual.

Darwin’s own children were spared his misery, because their mitochondria came exclusively from their mother. If Emma Darwin also inherited the Wedgwood curse, as Hayman suspects, it was of a much milder form than her husband’s debilitating malady.

So perhaps, on the 200th anniversary of Darwin’s birth, the mystery surrounding his lifelong illness has finally been solved – and it hinges on the very mechanisms of inheritance that Darwin sought employ to explain the variation of species.

This feature appeared in the January/February 2010 issue of Australian Life Scientist. To subscribe to the magazine, go here.