Wellcome Centre for Integrative Parasitology

In the early 20th century a controversy raged within the international medical and scientific community. Point of contention: the endorsement of the discoverer of the causal agent of sleeping sickness, a deadly illness that was decimating the indigenous population in Sub-Saharan Africa. Ultimately, Scottish pathologist and microbiologist David Bruce went down in history as the man who identified the protozoan parasite Trypanosoma brucei as the cause of the disease. However, Bruce’s priority claim was fiercely disputed by a man who, for many, was the true discoverer of the cause: Italian physician Aldo Castellani. Just as other battles for credit on who discovered the modality of malaria transmission or, more recently, on who first identified the HIV virus, the controversy fueled fierce international competition and patriotic disputes.

PART ONE - A mysterious disease ravages Uganda

The journey from London to Uganda took several weeks. The comforts of the large steamer cruising from Marseille to Aden soon made way for a far more cramped sailing trip to the port city of Mombasa, in the company of four hundred Arabian goats. From here, the members of the first British Sleeping Sickness Commission reached the heart of Africa in just a few days by means of the newly constructed Uganda Railway, which ran along the route that had previously been a three to four months' arduous trek undertaken by so many missionaries, explorers and slave traders. After arriving in Kisumu, on the north-east shore of Lake Victoria (then called Lake Nyanza), the group embarked on a further three-day steamboat trip across the lake to their final destination, Entebbe, the British headquarters of the Uganda Protectorate.

East African Protectorate and Uganda 1898

Dr Robert Unwin Moffat, Principal Medical Officer, and Colonel James Hayes Sadler, the colonial Commissioner and Consul General, were waiting for them at the pier. It was July 1902. The new arrivals were served food at the Consul’s house, the only tin-roofed building with glass windows among grass-roofed huts. Moffat had witnessed the building’s erection, along with the rest of Entebbe, when the town was established as the administrative capital in 1894. Nephew of the great Scottish explorer David Livingstone, Moffat had spent most of his life under African skies, first as the Medical Officer to the company building the Uganda Railway and then as Medical Officer of Uganda.

The conversation soon focused on the mysterious, dreadful disease, sleeping sickness (also called “negro lethargy”), that was decimating the local population on the shore and islands of Lake Victoria. The disease had an insidious onset and sufferers presented with weakness, frontal headache, drowsiness, glandular enlargement and an irregular fever. Over time they became unable to walk or speak properly. Their bodies became bloated and puffy and they developed the typical "moon face" due to oedema. After suffering for approximately five to six months, the urge to sleep became overwhelming. Mental disorders and emaciation ensued, and victims eventually slipped into a coma and died.

Sleeping sickness was a life sentence, but no one knew its cause. Wildly differing hypotheses circulated. Some thought the disease originated from emotional distress connected with slavery; others proposed sunstroke, whilst others suspected an extreme manifestation of beriberi or food poisoning. Some, influenced by the germ theory of disease and the recent discoveries of the causes of tuberculosis and malaria, suggested it was linked to an infection with some microorganism.

By the time the first Sleeping Sickness Commission arrived, tens of thousands had already succumbed in the Busoga province, where the disease had been first recognised only the previous year. An astonishingly rapid spread! As David Bruce later wrote “in a short time [sleeping sickness] reduced a populous and richly cultivated country to a depopulated wilderness”[1].

The matter was extremely serious, as the outbreak compromised the availability of African labour and was threatening the habitability of the area. The economic consequences of the disease were clearly a concern for the British Empire, while perhaps the humanitarian impact was less considered. Moreover, there was widespread fear that the infection could spread to other colonial territories, particularly to India, the "Jewel in the Crown", with catastrophic consequences. Indeed, many believed sleeping sickness to be communicable and contagious between people and the creation of isolation hospitals offered the only available solution to colonial health authorities.

Sleeping sickness was, however, nothing new to Africans who had lived with it for centuries. The Atlantic slave trade and colonial rule had already demonstrated its deadly effects to Europeans too. However, prior to the early 20^th century, the disease had only been known in some areas of West and Central Africa (mainly the Congo basin) and epidemics on the scale of the one seen in Uganda had never been recorded. It was actually not just Britain's dominions that were witnessing the disease’s rapid spread. All colonial powers in East and Central Africa – the Portuguese, French, German and Belgian governments – had to contain outbreaks during the first part of the 20^th century[2].

What European powers failed to recognise, at least initially, was that the epidemics were triggered by colonial rule itself. Increases in trade, coercive movement of indigenous people, agricultural shifts and ecological disasters such as drought and famine, all served to escalate the risk of the disease by increasing the likelihood of human contact with what we now know to be its vector, the tsetse fly.

Soon enough the need to discover the nature and cause of sleeping sickness became a matter of economic, political as well as scientific concern. National prestige and supremacy too were at stake. Hence, the colonial overlords of affected territories each sent expeditions to study the matter. Between 1901 and 1914 as many as seventeen scientific and government commissions were launched to carry out field work in Africa. One of the earliest efforts was the first Sleeping Sickness Commission, dispatched by the Malaria Committee of the Royal Society in London. Its mission was to study the Ugandan outbreak, identify the causal organism and understand its transmission. This basic knowledge was essential if control measures could be put into place. After all, the discovery by Ronald Ross in 1897 that malaria was transmitted in birds by mosquitoes, and its confirmation in humans by the Italian Giovanni Battista Grassi in 1899, had allowed unprecedented action to be taken towards stopping the transmission of the Empire’s most dangerous foe.

The First Sleeping Sickness Commission

By May 1902 the members of the British mission had been appointed. The Royal Society had found it near-impossible to put together a team of highly experienced investigators. Instead, it was a small commission of relatively young (and some believed, ill-prepared) scientists who were dispatched to Uganda. The commission was led by George Carmichael Low, a Scottish parasitologist from the London School of Tropical Medicine. The school had been recently established by Patrick Manson, who suggested Low himself. Low was a physician, who had participated in both Manson’s malaria studies in Italy and in his work on filarial worms in the Caribbean. He had been able to demonstrate that human infection with filariae occurred via mosquito bites and not by ingestion of mosquito-contaminated water. Low also proved that Europeans could avoid malaria by sleeping in mosquito-proof houses, as he did himself for three months in the notoriously Plasmodium vivax-endemic Roman Campagna.

Cuthbert Christy, an epidemiologist, was to lead the mission’s fieldwork. Although born in England, Christy, like Low, had studied at the University of Edinburgh where he had developed a keen interest in zoology. He was a skilled naturalist who had travelled to both South America and Northern Nigeria and had worked on plague in India. Unfortunately for the commission, Christy was endowed with a belligerent and arrogant personality, which caused his relationship with Low to deteriorate rapidly. According to one report, finding a label on their carriage in the train from Mombasa that stated “Dr. Low and party”, was enough for the enraged Christy to pick a fist fight with Low[3]. They barely spoke or saw each other for the remainder of their stay in Uganda and Christy spent most of his time trekking across the Protectorate.

In the field - Sleeping Sickness Commission

The third and final member of the expedition was an obscure Italian bacteriologist. Like Low, he was from Manson’s London School, which he had joined only a few months earlier. His name was Aldo Castellani. Castellani was a cultured man, born in 1874 into a wealthy Florentine family. Against the will of his father, who wanted him to work in his vineyards, he went on to study medicine in Florence. After qualifying, he furthered his microbiology training at Bonn University under the famous professor Walther Kruse. In 1901 he left Bonn for London. A few months after his arrival he was offered an opportunity he could not refuse. Manson needed a third person to join Low and Christy, and asked for a volunteer for the mission at the end of one of his lectures. Many were interested. In order to select a volunteer, Manson set a competitive examination that the young Italian graduate won.

Castellani later wrote in his autobiography “I had always wanted to go to the Tropics, and I thought my chance had come”[4].

Federica Giordani

[1] Bruce D. Sleeping Sickness in Uganda. J R Army Med Corps 1904, 3:17-41

[2] Headrick D R. Sleeping sickness epidemics and colonial responses in East and Central Africa, 1900-1940. PLoS Negl Trop Dis 2014, 8:e2772

[3] Lumsden W H R. Some episodes in the history of African trypanosomiasis. Proc Roy Soc Med 1974, 67:789-96

[4] Castellani A. Microbes, men and monarchs: a doctor's life in many lands; the autobiography of Aldo Castellani. Gollancz, London, 1960, p. 29

*Image of Aldo Castellani from National Portrait Gallery, London. by Bassano Ltd
whole-plate film negative, 3 September 1935. NPG Academic License.

Sir David Bruce Image from London School of Hygiene & Tropical Medicine (CC BY 4.0).

Sleeping Sickness Commission - image from Wellcome Collection (CC BY 4.0)

The first British Sleeping Sickness Commission has arrived at the Uganda Protectorate with the aim to discover the cause of sleeping sickness, a deadly, mysterious disease that is decimating the local population. However, the three members of the commission will experience personality clashes and make incorrect hypotheses, until the day a corkscrew shaped parasite is discovered.

PART TWO

Barking up the wrong tree – Filaria worms and streptococci

Each member of the sleeping sickness commission had been assigned a specific task. Low and Christy were to research Manson’s hypothesis, which postulated a microfilarial worm was the responsible agent. Filaria perstans (now known as the harmless Mansonella perstans) had been discovered in 1891 by Manson himself in the blood of a West African sleeping sickness patient hospitalised in London. At the outset of the Ugandan outbreak the blood-worms were subsequently found in other individuals affected by the disease, seemingly supporting Manson's hypothesis.

Christy parted from his two colleagues immediately after reaching Kisumu, to undertake the first of his three journeys aimed at mapping the geographical distribution of sleeping sickness and Filaria perstans. He travelled alternately by foot and canoe into German East Africa (modern day Tanzania) to the east, and to the Congo Free State to the west, taking blood slides from people in every village he passed. He ended up stopping in Entebbe only for short rests in between his excursions.

In the most affected districts of the Busoga region Christy witnessed at first hand the misery inflicted by sleeping sickness. He described people walking only with the aid of friends or walking sticks or lying prostrated in the doorways of their huts. He found corpses along the way, empty huts and abandoned plantations. He described how locals, fearing contagion, abandoned the sick to their fate. Many villages had lost up to two-thirds of their inhabitants and half of those left behind had the disease[1].

During his investigations Christy noted that the areas where sleeping sickness thrived were wooded, tsetse fly-infested regions along the border of the lake and on the islands. However, further from the lake, the number of sleeping sickness cases dwindled - although Filaria perstans remained common in blood. This important observation allowed Christy to rule out Manson's original hypothesis: filarial worms most likely were not the cause of sleeping sickness.

In the meantime, Low and Castellani had stayed in Entebbe in a small laboratory set up in a native hut where they studied samples from local patients. Their workplace comprised a room divided in two by mats: half occupied by the microscope and the kerosene-operated incubator, while the other half was used for the preparation of culture media. The laboratory was connected to another hut, where they had established a hospital with separate wards for women and men. The hospital provided subjects and specimens for study, but little more than that. None of the patients who were admitted could be saved.

Low's data, together with those collected by Christy, further demonstrated that Manson’s worms were only randomly found in sleeping sickness cases leading the commission to discard the filarial theory. A disappointed Low left Uganda before the end of the mission, only six months after his arrival. He left orders for Christy to do the same once he returned from his latest wanderings in the field. Low went on to spend the rest of his career in London, working at the London School of Tropical Medicine and as a physician at the Hospital for Tropical Diseases[2]. Christy returned to Africa for a number of expeditions. He eventually died there, gored by a buffalo in the Belgian Congo in 1932.

Castellani’s expedition lasted longer and had more profound consequences. His original assignment had been to work on a possible bacterial origin of sleeping sickness. Pasteurian bacteriology was, by this time, a mature discipline and represented the classical paradigm for the study of germs in experimental medicine. Tropical Medicine was also rapidly expanding and the charismatic Manson, one of its major protagonists in Britain, was able to persuade the government of its value to the Empire.

At the same time as the British Commission was working in Uganda, another expedition, led by the Portuguese in Angola, was also looking for the underlying cause of sleeping sickness. Their work suggested that a diplo-streptococcal bacillus, named the “hypnococcus”, isolated from blood and cerebrospinal fluid of sleeping sickness patients, was playing a role[3]. Castellani, a trained bacteriologist, was aware of the results from the Portuguese sleeping sickness mission. After much painstaking work, the Italian also isolated streptococci from cerebrospinal fluid and cardiac blood of post-mortem sleeping sickness cases, as well as from a number of living patients with advanced disease. However, Castellani was convinced that his bacilli differed from those reported by the Portuguese and claimed to have discovered the real cause of the disease.

In October 1902 Low wrote a report to the Royal Society: “I have the honour to inform you with great satisfaction that Dr. Castellani has found a germ to be the cause of sleeping sickness. […] I have therefore proposed to Dr. Castellani that he should write a preliminary report on the organism for transmission home to the Royal Society [...] and I trust that the Society will at once see its way to publishing this note in the leading medical papers in England…”[4].

Castellani’s report was received coldly in London, where members of the Society considered his conclusion premature and dismissed the claims of this inexperienced, impudent foreigner. The decision was not to publish the preliminary note and to give Castellani six more months to confirm his results. Offended by the rejection, Castellani went on to publish his note in the Lancet in March 1903 without the approval of the Royal Society[5]. The mistrust sparked by the incident was soon to resurface in a series of events that followed.

A corkscrew shaped parasite

The bacillus hypothesis was destined to be short lived. During his investigations, Castellani had also found something other than bacteria in sleeping sickness patients. On the 12th November 1902, microscopical examination of the overlaying liquid (the “supernatant”) from a centrifuged sample of cerebrospinal fluid taken from a patient by lumbar puncture revealed a motile trypanosome. While this was the first time a trypanosome had been found in humans in East Africa, similar parasites had previously been observed in human blood in Western Africa in May 1901 by colonial service surgeon Robert Michael Forde working in The Gambia[6].

While treating a feverish master of the government steamer on the River Gambia, Forde had seen many motile, worm-like bodies in a fresh sample of his blood. The microorganisms had been subsequently identified by Joseph Everett Dutton, a young parasitologist from the newly founded Liverpool School of Tropical Medicine, who had named the species Trypanosoma gambiense (now T. brucei gambiense, a subspecies causing the chronic form of sleeping sickness in West and Central Africa)[7]. The febrile illness caused by these parasites in West Africa became known as “trypanosoma fever”, and was considered then a mild infection, completely unrelated to sleeping sickness, the dreadful “negro lethargy”.

Prior to this discovery, trypanosomes had only been known to live in the bloodstream of animals and had been linked to the animal diseases surra, affecting horses and camels in India, and nagana, affecting cattle in Southern Africa. The name “trypanosoma” had been given to these flagellated microorganisms in 1843 by David Gruby, who wanted to reflect their corkscrew shape (“trupanon” in Greek means auger).

Dr Alexander Maxwell-Adams, another doctor working in the Gambia, had been asked for his views by Forde and wrote down his thoughts on the case. His notes reveal just how close he got to solving the puzzle. Maxwell-Adams proposed that transmission to men could occur through the bites of insects in much the same way as malaria was transmitted by mosquitoes. He recognised that the disease could also affect Europeans (contrary to the common view at the time that considered white people to be immune to the disease) and even wondered whether the trypanosome had any relation to sleeping sickness, suggesting that trypanosoma fever and sleeping sickness may be two phases of the same disease. He wrote: "Though the symptoms of the two diseases are different might they not be different stages of the same process -the first stage of the parasite circulating freely in the blood, in the second stage accumulating in the brain tissue, and so causing somnolency through local anaemia?"[8].

His intuition was ultimately correct, but his work was only published at the end of March 1903, by which time the Sleeping Sickness Commission was already hot on the tracks of the trypanosome.

The Second Sleeping Sickness Commission

By the middle of March 1903, working alone in his small laboratory, Castellani had found Trypanosoma parasites in the cerebrospinal fluid and in blood of some of the patients he was studying. Although these microorganisms were similar to those identified by Dutton in trypanosoma fever patients, he believed they belonged to a different species altogether, which he later named Trypanosoma ugandense.

However Castellani’s time in Africa was quickly running out and his research would soon be handed over to others. The Royal Society, dissatisfied with the lack of progress and aiming to probe more deeply into the streptococcus hypothesis, had dispatched a Second Commission.

This new commission included two renowned investigators: pathologists David Nunes Nabarro and Col. David Bruce. Nabarro was a London-born son of a merchant who had undertaken a successful career as a surgeon. He was described as a modest and retiring person, beloved by his colleagues. His role in Uganda was to work on the clinical aspects of sleeping sickness. Bruce, conversely, was a Scottish army doctor with a taste for whisky and penchant for boxing. He had already made a name for himself by identifying the bacterium that caused Malta fever (Brucella). Perhaps more notably, he had discovered that trypanosomes were the cause of nagana disease in cattle (named Trypanosoma brucei after him), and found that transmission occurred via the tsetse fly. His wife, Lady Mary Elizabeth Bruce, accompanied him, acting as his laboratory assistant as was often the case.

Colonel David Bruce

Castellani had been informed that a new commission was on its way and he was instructed to communicate his work to Bruce and to follow his instructions. However, the Italian was still trying to publish his streptococcus note and was increasingly irate with the Royal Society’s conduct. Offended and lacking enthusiasm for the new commission, Castellani was evasive in his dealings with Bruce, even obstructive. Bruce, annoyed with the Italian’s lack of cooperation, complained to London that little work had been done in the preceding few months[9].

The Second Commission’s arrival in Entebbe, on 16 March 1903, was preceded by another dubious occurrence. Feeling under immense pressure, Castellani shared his findings regarding the trypanosome, allegedly under a “bond of secrecy”, with Moffatt and Clement John Baker, a Medical Officer in Entebbe⁹. Castellani’s revelation occurred after Baker had also seen trypanosomes in the blood of a feverish patient on 12 March 1903. While he had been examining a fresh blood film for possible malaria parasites he had seen “an elongated, actively motile body”[10] which he identified as a trypanosome, a diagnosis confirmed by Moffatt and Castellani. Other similar cases followed, but, incredibly, the connection with sleeping sickness remained elusive. The presence of trypanosoma fever among sleeping sickness patients had been shown and yet, possibly blinded by the desire to prove his original streptococcal hypothesis, Castellani refused to connect the two.

Castellani did eventually tell Bruce about his discovery of the trypanosome and the centrifugation method he had developed to isolate it from cerebrospinal fluid. Though ever secretive and conspiratorial, Castellani insisted that Bruce keep the revelation from Nabarro and allow the two men to work independently until the Italian’s departure; conditions Bruce accepted. The Italian also asked to stay in Entebbe for a few more weeks, during which time he and Bruce worked tirelessly seeking more evidence for the presence of trypanosomes in sleeping sickness patients. Trypanosomes were identified in 70% of cases, but never in controls. The streptococcus theory received further blows as other experiments failed to prove it.

Following his departure from Uganda (on the 6th April 1903), Castellani published his findings as sole author, seizing credit for the discovery[11]. In his account he suggested that trypanosomes were the causal organism of sleeping sickness but couldn’t quite bring himself to admit the streptococcal theory had been completely wrong, leaving open the possibility of germs having a secondary role in the pathogenesis of the disease.

He concluded his paper with the following statement: “I would suggest as a working hypothesis on which to base further investigation that sleeping sickness is due to the species of trypanosoma I have found in the cerebro-spinal fluid of the patients in this disease and that at least in the last stages there is a concomitant streptococcus infection which plays a certain part in the course of the disease”¹¹.

FEDERICA GIORDANI

[1] Christy C. Sleeping sickness. Journal of the Royal African Society, 1903, 3:1-11

[2] Cook G C. George Carmichael Low FRCP: twelfth President of the Society and underrated pioneer of tropical medicine. Trans R Soc Trop Med Hyg 1993, 87:355-60

[3] Amaral I. Bacteria or parasite? The controversy over the etiology of sleeping sickness and the Portuguese participation, 1898-1904. Hist Cienc Saude Manguinhos, 2012 19:1275-300

[4] Boyd J. Sleeping sickness. The Castellani-Bruce controversy. Notes Rec R Soc Lond 1973, 28:93-110

[5] Castellani A. The etiology of sleeping sickness (preliminary note). Lancet 161:1903 723-25

[6] Steverding D. The history of African trypanosomiasis. Parasit Vectors 2008, 1:3-10

[7] Dutton J E. Preliminary note upon a trypanosome occurring in the blood of a man. Thompson Yates Lab Rep 1902, 4:455-68

[8] Maxwell-Adams A. Trypanosomiasis and its cause. B M J 1903, 1:721-722

[9] Boyd J. Sleeping sickness. The Castellani-Bruce controversy. Notes Rec R Soc Lond 1973, 28:93-110

[10] Baker C J. Three cases of trypanosoma in man in Entebbe, Uganda. Br Med J 1903, 30:1254-6

[11] Castellani A. On the discovery of a species of trypanosoma in the cerebro-spinal fluid of cases of sleeping sickness. Lancet 1903, 161:1735-1736

*Image of the First Sleeping Sickness Commission from the Wellcome Collection (CC BY 4.0)

Trypanosomes have finally been found in the blood and cerebrospinal fluid of sleeping sickness patients, but the discovery is soon to become the subject of an international dispute where science and politics intersect.

PART THREE

The dispute

That Castellani was the first to discover trypanosomes in the cerebrospinal fluid of patients suffering from sleeping sickness was beyond all doubt. He was also instrumental in developing the diagnostic method that would allow researchers to isolate and identify trypanosomes in the cerebrospinal fluid of sleeping sickness patients. However, whether he was the first to grasp the link between the presence of these parasites and the origin of the disease, as he always asserted, became a matter of ferocious contention in the years that followed.

The Italian found himself on the wrong end of the might of the British establishment, caught in between rivalries of personalities and scientific institutions. The London School of Tropical Medicine and Royal Army Medical Corps developed an unhealthy competition which compromised the various commissions sent to Africa in the years that followed. European politics would also impact Castellani’s future reputation. As he went on to become an international figure, serving as Mussolini’s physician and as a medical officer during Italy’s wars in Ethiopia and North Africa[1]^,[2], he offered detractors ammunition to besmirch his name.

Dr Aldo Castellani in his lab

The Castellani-Bruce controversy became public after the publication of Report No. 4 (November 1903) from the Sleeping Sickness Commission, co-authored by Bruce. The report stated that “At the time of the arrival of the second commission he [Castellani] did not consider that the trypanosome had any causal relationship to the disease but thought it was an accidental contaminant like Filaria perstans. When he reported his observations to Lt.-Col. Bruce the latter was much struck by the discovery and urged Dr. Castellani to pursue this point during his few remaining days in Entebbe”[3].

Although Nabarro appeared in the author list of the Report, he later made his support for Castellani clear on several occasions, for “having first connected [the trypanosome] with the etiology of sleeping sickness”[4].

Opposing factions at the Royal Society sided with either of the two contenders, but the home player, Bruce, had more support. Most agreed with the view of the Royal Society, minimising Castellani’s contribution and maintaining that he “failed to appreciate the etiological significance of his finding, until it was brought home to him by Lieut.-Colonel later Colonel Sir David Bruce”[5]. Baker and Moffatt concurred that when Castellani had told them about his discovery of the trypanosome he still believed his streptococcal theory to be true. That he had remained silent during the months prior to Bruce’s arrival, and the fact that he leaked the news to others before communicating it to the Royal Society, helped to further discredit Castellani’s position.

The dispute between Castellani and his advocates versus Bruce’s supporters went on for years, often appearing in the press. Reams were written, yet the two camps were never able to reconcile the conflicting versions of events. This was a controversy which, as J N P Davies wrote, was "largely irrelevant and founded [...] on personal jealousies and departmental rivalries which had little to do with the sleeping sickness investigations"[6].

After Castellani’s departure from Uganda, it took Bruce and Nabarro just a few months to collect solid evidence that Trypanosoma gambiense (Castellani's T. ugandense) caused sleeping sickness. More recently, some authors have challenged this identification, arguing that the causative species of the Ugandan epidemic was not Trypanosoma gambiense imported from the Congo, but more likely T. brucei rhodesiense, a more virulent form transmitted to humans from an animal reservoir[7]. T. b. rhodesiense was, and is, endemic in Uganda and East Africa, and it has been argued that socio-economic and environmental disruption caused by colonialism could have exacerbated the disease.

Samples of biting flies were collected from across the Protectorate and sent to Entebbe, revealing a remarkable overlap in the geographical distribution of sleeping sickness and the presence of tsetse flies. Further experiments demonstrated that flies that had fed on diseased humans could transmit Trypanosoma parasites to monkeys. The vector had been identified as the blood-sucking tsetse fly Glossina palpalis that thrived in forests along the shore of lake Victoria. This preliminary groundwork made it very easy for Bruce to reach his conclusions. Davies remarked “As far as David Bruce is concerned - in his first 24 hours in Uganda he was shown a case of trypanosome fever and saw slides of the parasite, was handed a collection of biting flies amongst which he recognised a tsetse fly and heard of the discovery of trypanosomes in the C.S.F. [cerebrospinal fluid] of five cases of sleeping sickness. Rarely can the investigator of the cause of an obscure disease be handed quite so much immediately relevant information in so short a time at the outset of his investigations and one did not have to be a microbiologist of genius, or even a Fellow of the Royal Society to realize that here were immediate leads to be followed up”[8].

Tsetse fly - the vector for sleeping sickness and nagana

It finally became clear that trypanosoma fever and sleeping sickness were in fact two different names for the same disease, which manifested itself in two sequential stages, just as Maxwell-Adams had suggested. It became clear that fever and the presence of parasites in the blood occurred during the first stage, while parasites in the brain (and cerebrospinal fluid) accompanied by somnolence, apathy and wasting characterised the second stage.

Bruce continued his studies on sleeping sickness in Uganda for several more years. Castellani instead pursued other interests and went on to become one of the most important medical figures of the first half of the 20^th century. He is remembered chiefly for his contributions to tropical dermatology and microbiology rather than for his role in the discovery of the cause of sleeping sickness. A contribution that, along with some of the other investigators involved (such as Baker, Nabarro, and Dutton), failed to get the recognition it deserved.

The discovery of the pathogen and vector of sleeping sickness was immediately acknowledged by most investigators working in the field and it enabled measures to halt the spread of the disease to be implemented[9]. Unfortunately, it was too late for the 200,000-300,000 people believed to have died in Uganda during the epidemic that swept the region from 1896 to 1906. Further west, in the Congo basin, another half a million are believed to have died.

Incisive and radical control measures implemented in Uganda did start to slow transmission of the disease. Entire villages, for example, were forcibly evacuated from tsetse-infected areas; tsetse-harbouring bushes were cleared; indigenous people were tested for infection and, if positive, locked up in sleeping-sickness camps. In the years that followed, the microbiologist Robert Koch and the chemist Paul Ehrlich started experiments that led to the development of the first drugs capable of treating the disease⁹.

Prior to the First World War research on sleeping sickness became top of the list of pan-African priorities, receiving the largest share of funds spent for infectious diseases. Efforts continued until midway through the century, with coordination of research that helped to create the first organisational infrastructures that linked disease control in Africa and Europe.

International cooperation among scientists accelerated progress towards control of the disease and by the end of the Colonial Era in the 1960s sleeping sickness was close to elimination. Nevertheless, that was not the end of the disease. Control programs were abandoned in post-colonial nations and the disease resurged, becoming the “neglected tropical disease” it is today, afflicting the poorest communities in Sub-Saharan Africa, and attracting little by way of health investment. New devastating epidemics arose during the second half of the 20^th century, prompting renewed international efforts. Today, more than a hundred years from the discovery of its cause, sleeping sickness is once again under control and on track for elimination. Hopefully this time there will be no grounds for complacency.

FEDERICA GIORDANI

Read more about the WCIP's research into sleeping sickness, and take a look at our comic: Sleeping sickness - the fight against a nightmarish disease.

[1] Binazzi M. Italian memoirs of Aldo Castellani. Int J Dermatol 1991, 30:741-745

[2] Seeliger H P, Seefried L. Aldo Castellani – an appraisal to his life and oeuvre. Mycoses 1989, 32:391-7

[3] Bruce D, Nabarro D, Greig E D W. Reports of the Sleeping Sickness Commission of the Royal Society (no. IV). 1903

[4] Nabarro D. The discoverer of the cause of sleeping sickness. Br Med J 1917, 2:374-375

[5] Boyd J. Sleeping sickness. The Castellani-Bruce controversy. Notes Rec R Soc Lond 1973, 28:93-110

[6] Davies J N P. Informed speculation on the cause of sleeping sickness 1898-1903. Med Hist 1968, 12:200-4

[7] Fèvre E M, Coleman P G, Welburn S C, Maudlin I. Reanalysing the 1900-1920 sleeping sickness epidemic in Uganda. Emerg Infect Dis 2004, 10:567-73

[8] Davies J N P. Informed speculation on the cause of sleeping sickness 1898-1903. Med Hist 1968, 12:200-4

[9] Headrick D R. Sleeping sickness epidemics and colonial responses in East and Central Africa, 1900-1940. PLoS Negl Trop Dis 2014, 8:e2772

*Image of Also Castellini from Alchetron Social Encyclopedia (CC BY-SA).
Tsetse Fly image by Dan Salaman, Wellcome Images (CC BY-NC 4.0)