Introduction

Darwin’s Illness

Charles Darwin suffered from a persistent, debilitating illness for most of his adult life with a wide range of bizarre symptoms.[1] Attacks of nausea and vomiting were his most distressing complaint but he also experienced headaches, abdominal pains, ‘lumbago’, palpitations and chest pain, numbness and tingling in the fingers, sweating, heat and cold sensitivity, flushing and swelling of his face and extremities, eczema, recurrent boils, attacks of acute anxiety, a sensation of dying and hysterical crying. His abdominal symptoms were associated with much flatulence with the noisy expulsion of pungent gas both ‘upwards and downwards’. In addition to all of this he also suffered from episodes of severe lethargy when he was virtually confined to his sofa.

Apart from these major symptoms Darwin also occasionally vomited blood, he developed dental decay and skin pigmentation. The sea-sickness he experienced during the entire five year voyage of HMS Beagle was also part of his illness.[2] Apart from these very many troublesome symptoms Darwin also had mild dyslexia;[3] his sister habitually would correct his spelling [4] and like most dyslexics he had difficulty learning language – Greek and Latin when at school and German in later life. With the dyslexia there is a frequent association of amusica – tone deafness, and Darwin was tone deaf.[5]

Darwin’s symptoms were certainly unusual but they had several even more unusual features:

= His illness was episodic and attacks were brought on by stressful events, even very minor stresses or pleasurable events such as the visits of friends. Perhaps the first of these attacks was after he attended two concerts in the one day, in Birmingham in 1829, when: ‘It knocked me up most dreadfully, & I will never attempt again to go to two things on the one day’.[6] Again in 1862, writing to Thomas Rivers (an expert on roses), he said: ‘… but I suffer severely from an ailment of a very peculiar kind, which prevents me from all mental excitement, which is always followed by spasmodic sickness, & I do not think I could stand conversation with you, which to me would be so full of enjoyment’.[7] In the same year three of his former shipmates from the Beagle came to visit him. ‘Two days ago three officers of the Beagle came here to dinner; I took every possible precaution, but it made me very ill with violent shaking and vomiting till early morning; & Could not even wish them goodbye next morning.’[8] Darwin declined a visit from the brother, John King of a former shipmate, Phillip Gidley King: ‘I grieve to say that my health is so indifferent, I cannot stand seeing at present anyone here. Twice lately I could not resist seeing old friends (once was when Wickham & Co came here) and the excitement made me so ill afterwards, that I have been advised not to do so again. I am well enough in the mornings and when I keep quiet.’[9]

= The vomiting occurred several hours after meals (not immediately, like bulimia), so that he vomited bilious fluid, not food. He may certainly have suffered from fluid and salt depletion but not from starvation – he seldom lost much weight.[10]

= His major symptoms had a reciprocal relationship to his eczema and to his ‘lumbago’ or ‘rheumatism’(fibromyalgia). He noted that when either of these conditions was bad his other symptoms improved. In a letter to Hooker in January 1864 he described how for five months he ‘had done nothing but be sick’. In the same letter he mentions how he ‘suddenly had a slight attack of rheumatism in my back & I instantly became almost well & so wonderfully strong that I walked to the Hothouse, which must be more than 100 yards’.[11]

= He obtained relief, at least initially, from hydrotherapy, ‘the Water-Cure’: ‘The Water Cure is assuredly a grand discovery & how sorry I am I did not hear of it, or rather that I was not somehow compelled to try it some five or six years ago.’[12]

Previous Diagnoses

More than 40 diagnoses for this illness have been proposed, a list beginning from when Darwin first showed symptoms of his ailment until the present day.[1] Many of these diagnoses can be dismissed as they were for conditions that are no longer recognised (‘aggravated dyspepsia’, ‘suppressed gout’) or for conditions that exist only in the realm of alternate medicine (‘pyroluria’, ‘candida overload’). Other suggested diagnoses that relate to his five-year voyage with the Beagle may also be crossed from the list as Darwin had definite symptoms before he sailed. These include exotic infections such as Chagas Disease,[13] malaria and brucellosis. The sickness that Darwin experienced at Valparaiso in 1834, during the voyage, was a separate illness, probably typhoid.[14] It was not the cause of his lifetime illness, as was suggested by Huxley.[15] The various gastrointestinal conditions that have been put forward as the cause of his illness (biliary disease, Crohn’s disease,[16] peptic ulceration) might explain some of Darwin’s symptoms but by no means all. Psychological or psychogenic suggested causes of his illness abound. None other than Sir George Pickering, Professor of Medicine in Oxford from 1956 until 1968, eloquently described Darwin’s illness as ‘polymorphous symptomatology’, but then he wrongly concluded that Darwin’s illness was psychogenic in nature: ‘The case for a psychoneurosis is first that the symptoms suggest it, and, taken in their entirety, they fit nothing else.’[14]

Darwin certainly had some of the conditions that have been proposed as the essential cause of his ailment such as multiple allergies,[3] panic attacks,[17] and other psychiatric symptoms but these were all an integral part of his illness, not the cause.

Other conditions such as dental decay and vomiting blood may be regarded as complications of his disorder; dental decay is seen in other chronic vomiting conditions such as bulimia and the hematemesis is a consequence of bruising or tearing of the lower oesophageal sphincter from forceful expulsion of gastric contents. His eczema has been reliably diagnosed as atopic dermatitis[18] but this diagnosis does not account for his other gastrointestinal and nervous symptoms. Patients with atopic dermatitis harbour staphylococci (Staph. pyogenes) in their skin both in the lesions and in apparently normal skin areas with the result that may develop recurrent staphylococcal skin abscesses (or boils).[19] His skin pigmentation was not the result of arsenical poisoning, as has been suggested,[20] but was a physiological response to increased ACTH and concomitant melanocyte stimulating hormone (MSH) secretion following salt and fluid loss.

Darwin’s mother died when Charles was eight; she appears to have had a similar illness having been dipped into the icy Irish Sea as a child ‘to cure her pukes and boils’. As an adult she was unable to ride in a carriage without being ill, had hyperemesis with her pregnancies and died at the relatively early age of 52 years with abdominal pains.[21]

Her younger brother Tom, Charles’ maternal uncle suffered severe headaches, abdominal pains and was confined to his cabin with seasickness on his one voyage to the West Indies, a journey taken in an attempt to improve his health.[22] He died with opium overdosage at the young age of 34.

Darwin’s Diagnosis

Darwin suffered from the Cyclical (or Cyclic) Vomiting Syndrome (CVS),[23] a little known but well described condition, first recognised in children, but one which may produce symptoms for the first time in early adult life.[24] The disorder may be related to mitochondrial dysfunction. Mitochondria in the human are entirely maternally inherited – the ovum contains many hundreds of mitochondria and the few mitochondria present in sperm are lost in the fertilized ovum. Where there is a maternal history of the disorder, as there was in the Darwin family, it is probable that the dysfunction is due to an inherited mitochondrial DNA (mtDNA) abnormality.[25]

An inherited mitochondrial disorder not only fully explains Darwin’s illness, it also explains the illness in Darwin’s mother and in his uncle Tom.

Mitochondria provide most of the energy for cellular function, producing ATP (adenosine triphosphate) from ADP (adenosine diphosphate), glucose and oxygen.[26] Regardless of the particular enzyme abnormality the end result is much the same – decreased ATP production. Mitochondria split during cell division and pass randomly to the daughter cells so that the proportion of normal to abnormal mitochondria may vary widely in subsequent cell generations (heteroplasmy). Variations early in embryogenesis lead to considerable heteroplasmy in different organs or tissues. As a result of this patients with the same mtDNA abnormality may have very different symptoms or may have no apparent symptoms at all. (These patients may have susceptibility to some drugs such as streptomycin, suffer post-viral chronic fatigue, have hyperemesis when pregnant, or have minor complaints such as the restless legs syndrome or increased susceptibility to motion sickness – but this is speculation.)

Patients diagnosed as having CVS also vary with their symptoms. Some have only occasional episodes of nausea and vomiting, others are severely incapacitated with additional symptoms of headaches, abdominal pain and severe lethargy. There may be coalescence of episodes with nausea and vomiting lasting for weeks or months.[24] Others experience noxious flatulence, symptoms of fibromyalgia, and suffer from eczema. Panic episodes may occur at the beginning or during an attack; some patients have panic episodes at times when they have no other symptoms. Some experience severe motion sickness to the extent that they cannot watch television with rapidly changing or moving scenes; one mother reported that she was unable to watch her children on a swing in the playground. Many have heat or cold intolerance and find great difficulty in finding a comfortable temperature.

Attacks may be brought on by stressful events, particularly positive stresses such as the anticipation of a holiday. Attacks are more common at Christmas and in America at Thanksgiving. Like Darwin, many patients experience relief from water exposure and spend long hours under a shower during attacks.[27]

Pathophysiological Ruminations

Many of the symptoms of Darwin’s illness and those of patients who have CVS today, such as the headache, fatigue, muscle pain and palpitations, may be explained by the concept of mitochondrial failure – the mitochondria in cells that have high energy requirements (such as neurones, cardiac and skeletal muscle cells) are simply failing to meet the energy requirements of those cells. When glycolysis is inadequate ATP is produced along with lactic acid by anaerobic metabolism, a much less efficient mechanism and the lactic acidosis resulting may be responsible for some symptoms. A further mechanism is the conversion of two molecules of ADP to one of ATP and one of AMP (adenosine monophosphate). AMP is catabolized and the ADP is not immediately regenerated so that reserves of the source of ATP are lost, providing a mechanism for persistent fatigue.

Other symptoms, such as the vomiting, flatulence, abdominal pain, heat and cold intolerance may originate from cells of the neuroendocrine system. This system has two components, a central in the brain, and a peripheral, with cells in various endocrine organs including the islets of the pancreas and in the epithelium of the gut and bronchi. The system has a long evolutionary history, evolving before the nervous system with which it is closely associated.[28] The cells of this system are characterised by possessing neurosecretory granules, complex granules containing the secretory product of the cell that have a high osmolality and are highly acidic.[29] They also contain a high concentration of ATP that maintains the stability of the granule, reducing osmotic pressure by linking the secretory molecules and reducing acidity by acting as a buffering agent. If ATP is deficient the granules are likely to be unstable and hormone secretion variable or inadequate.

Numerous differing peptide hormones are present in the granules of different cells including insulin, its antagonist glucagon, secretory agents such as gastrin, a pain perceptor, substance P and a general inhibitory agent, somatostatin. Briefly, if secretion of an activator is adequate but an antagonist, such as somatostatin, is deficient, then symptoms will result.

The effectiveness of the ‘water cure’ in Darwin’s case may have had two different but not incompatible mechanisms. Firstly, it may have provided reflex vagal stimulation and by this means reduced his abdominal symptoms.[30] The vagus, or 10th cranial nerve, is a complex nerve with sensory, motor and autonomic components, again with a long evolutionary history. It is stimulated by water on the face or body and its autonomic function, among other effects, relaxes the antral region of the stomach.

Secondly, there may have been psychological factors involved. We know that Darwin’s episodes of sickness were brought on by minor stress, even by pleasurable events. The water cure, particularly at the beginning, was carried out in resorts where, apart from the excruciating treatments, there was very little stimulation. Darwin sought this treatment when he was persistently ill when dissecting and classifying barnacles (Cirripedia). Darwin wrote to his friend and mentor, John Henslow: ‘One of the most singular effects of the treatment is that it includes in most people and eminently in my case, the most complete stagnation of mind. I have ceased to think even of barnacles.[31]

Apart from his numerous symptoms, symptoms all of which occur today in patients with CVS,[27] Darwin had several other, rather sinister symptoms. He had several episodes of transient paralysis and memory loss, greatly worrying his family.[32] They could reasonably be described as ‘stroke- like’ episodes. These are characteristic of the MELAS syndrome; MELAS is another disorder known to regularly associated with mitochondrial dysfunction; MELAS is an acronym for Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes. Lactic acid was unknown in Darwin’s time and was certainly not measured but, given Darwin’s other symptoms, it would surely have been elevated during his periods of illness. Other symptoms are muscle weakness, muscle pain, headaches and vomiting – all of which Darwin certainly had. The MELAS syndrome has been shown to be associated with a mitochondrial gene mutation designated A3243G mutation; the same mutation has been shown to be present in some cases of CVS.[33] As Darwin had evidence of both the CVS and MELAS syndromes it is a reasonable guess that he in fact had the A3243G mutation.

Epilogue

The name Cyclical Vomiting Syndrome is not an attractive name; like the disorder that may have the same background aetiology, the Chronic Fatigue Syndrome, it is not a name that immediately attracts great sympathy for the sufferers. Furthermore it is not a name that will attract research funding, and research into this group of conditions is badly needed. Importantly also it emphasises only one aspect, albeit the principle aspect of the disease, the vomiting, and the other abdominal, nervous and psychological features of the disorder are not suggested in the title. Another term that has been proposed, ‘Mitochondrial Cytopathy’, appears too vague and is possibly inaccurate as it suggests that the cell cytosol is disordered rather than the function of one type of organelle in that cytoplasm.

A new term, ‘Intermittent Mitochondrial Failure’ (IMF) is suggested. This assumes that the causation is always in these organelles, which may not be correct, but is sufficiently broad to take in the whole range of symptoms that may occur with this group of disorders. Intermittent Mitochondrial Failure could be linked with ‘Persistent (or Permanent) Mitochondrial Failure’ (PMF) to encompass coalescent episodes of CVS, chronic conditions such as unrelenting and chronic fatigue and the severe mitochondrial disorders of childhood. As an acronym, IMF is more likely to attract attention and sympathy; a disorder termed ‘IMF’ should also draw in research funding.

Regardless of the name, Darwin would be pleased with the diagnosis. A mitochondrial disorder does not explain his wife’s illnesses or the illnesses of his children but it does provide an explanation for almost all of his own symptoms. His seasickness and recurrent boils are explained, and even, if somewhat tenuously, we now know why Darwin had difficulty in learning German. If the diagnosis is accepted, 150 years from the first symptoms of an illness to a correct identification may be something of a record.

1. Colp, R., Jr, Darwin’s Illness. 2008, Gainesville: University Press of Florida.

2. Darwin, C., Voyage of the Beagle. 1839, London: Henry Colburn.

3. Smith, F., Charles Darwin. J Hist Biol, 1990. 23(3): p. 443-59.

4. Darwin, S.E. (1835) Letter 288 — Darwin, S. E. to Darwin, C. R.,. Darwin Correspondence Project Database. http://www.darwinproject.ac.uk/entry-288/ (letter no. 288; accessed 8 December 2010).

5. Barlow, N., The autobiography of Charles Darwin 1809-1882, with original omissions restored. 1958, London: Collins.

6. Darwin, C.R. (1829) Letter 73 — Darwin, C. R. to Fox, W. D. Darwin Correspondence Project Database. http://www.darwinproject.ac.uk/entry-73/ (letter no. 73; accessed 29 September 2010)

7. Darwin, C.R. (1862) Letter 3879 — Darwin, C. R. to Rivers, Thomas. Darwin Correspondence Project Database. http://www.darwinproject.ac.uk/entry-3879 (letter no. 3879; accessed 12 April 2011).

8. Darwin, C.R. (1862) Letter 3779 — Darwin, C. R. to Lubbock, John. Darwin Correspondence Project Database. http://www.darwinproject.ac.uk/entry-3779 (letter no. 3779; accessed 12 April 2011).

9. Darwin, C.R. (1862) Letter 3809 — Darwin, C. R. to King, P. G. Darwin Correspondence Project Database. http://www.darwinproject.ac.uk/entry-3809 (letter no. 3809; accessed 12 April 2011).

10. Darwin, E.W. and H. Litchfield, Emma Darwin : a century of family letters, 1792-1896. London, John Murray. 1915, Biodiversity Heritage Library /www.archive.org/details/emmadarwincentur02litc (accessed16 February 2011).

11. Darwin, C.R. (1864) Letter 4397 — Darwin, C. R. to Hooker, J. D. Darwin Correspondence Project Database. http://www.darwinproject.ac.uk/entry-4397/ (letter no. 4397; accessed 8 December 2010).

12. Darwin, C.R. (1849) Letter 1249 — Darwin, C. R. to Fox, W. D. Darwin Correspondence Project Database. http://www.darwinproject.ac.uk/entry-1249/ (letter no. 1249; accessed 8 December 2010).

13. Adler, S., Darwin’s Illness. Nature, 1959. 184(Oct 10): p. 1102-1103.

14. Pickering, G., Creative Malady. 1974, New York: Oxford University Press.

15. Huxley, T.H., Obituary notice: Charles Robert Darwin. . Proceedings of the Royal Society of London, 1888. 44(269): p. 1-25.

16. Orrego, F. and C. Quintana, Darwin’s illness: a final diagnosis. Notes Rec R Soc Lond, 2007. 61(1): p. 23-9.

17. Barloon, T.J. and R. Noyes, Jr., Charles Darwin and panic disorder. JAMA, 1997. 277(2): p. 138-41.

18. Sauer, G.C., Charles Darwin consults a dermatologist. Int J Dermatol, 2000. 39(6): p. 474-8.

19. Aly, R., H.I. Maibach, and H.R. Shinefield, Microbial flora of atopic dermatitis. Arch Dermatol, 1977. 113(6): p. 780-2.

20. Winslow, J.H., Darwin’s Victorian Malady. Evidence for its Medically Induced Origin. Memoirs of the American Philosophical Society. Vol. 88. 1971, Philadelphia: American Philosophical Society.

21. Healey, E., Emma Darwin: The Inspirational Wife of a Genius. 2001, London: Headline Book Publishing.

22. Wedgwood, B. and H. Wedgwood, The Wedgwood Circle 1730-1897. 1980, London: Macmillan Publishing Co.

23. Hayman, J.A., Darwin’s illness revisited. BMJ, 2009. 339: p. b4968.

24. Fleisher, D.R., et al., Cyclic Vomiting Syndrome in 41 adults: the illness, the patients, and problems of management. BMC Med, 2005. 3: p. 20.

25. Boles, R.G., K. Adams, and B.U. Li, Maternal inheritance in cyclic vomiting syndrome. Am J Med Genet A, 2005. 133A(1): p. 71-7.

26. Cohen, B.H. and D.R. Gold, Mitochondrial cytopathy in adults: what we know so far. Cleve Clin J Med, 2001. 68(7): p. 625-6, 629-42.

27. Cyclic Vomiting Association (2010) Forums. http://cvsa.websitetoolbox.com/.

28. Hartenstein, V., The neuroendocrine system of invertebrates: a developmental and evolutionary perspective. J Endocrinol, 2006. 190(3): p. 555-70.

29. Payne, C.M., Phylogenetic considerations of neurosecretory granule contents: role of nucleotides and basic hormone/transmitter packaging mechanisms. Arch Histol Cytol, 1989. 52 Suppl: p. 277-92.

30. Andrews, P.L. and T. Scratcherd, The gastric motility patterns induced by direct and reflex excitation of the vagus nerves in the anaesthetized ferret. J Physiol, 1980. 302: p. 363-78.

31. Darwin, C.R. (1849) Letter 1241 — Darwin, C. R. to Henslow, J. S. Darwin Correspondence Project Database. http://www.darwinproject.ac.uk/entry-1241/ (letter no. 1241; accessed 9 December 2010)

32. Jones, H.B. (1867) Letter 5639 — Jones, H. B. to Darwin, Emma. Darwin Correspondence Project Database. http://www.darwinproject.ac.uk/entry-5639/ (letter no. 5639; accessed 9 December 2010)

33. Salpietro, C.D., et al., A mitochondrial DNA mutation (A3243G mtDNA) in a family with cyclic vomiting. Eur J Pediatr, 2003. 162(10): p. 727-8.