Beryl Thyer Memorial Africa Trust: supporting African children that suffer from Burkitt lymphoma cancer

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Burkitt

Denis Parsons Burkitt was born on 11th February 1911 in Enniskillen , Ireland. Denis was not a bright lad at school. At age 18 he entered the Engineering faculty of Trinity College Dublin, and showed no talent or promise there either; so much so that one of his professors wrote to Burkitt’s father advising the young man be removed from the course, there being little likelihood that he would obtain the degree. Ironical indeed that half a century later the same university conferred their highest award on him – Honorary Fellowship of Trinity College

Burkitt’s subsequent years in medical school were happier. He was always within the top set each year, and won the coveted Hudson Prize and silver medal. His main interest after graduation was surgery, and there his problems began – for he was unable to secure a surgical post. It was likely that he was turned down on the grounds that he had but one eye. This was the result of a boyhood argument at school. A fight with stone-throwing ensued, and Denis’s glasses were smashed, with shards of glass entering his right eye. It had to be removed, and for the rest of his life he wore a glass eye on the right.

The war helped him, for he was accepted into the Army Medical Corps in 1941 and joined a troopship for Mombassa – his first taste of Africa. After the war the Colonial Service finally accepted him in 1946, sending him to Kampala, Uganda as a general surgeon. Burkitt never claimed to be other than a `bush surgeon’. Everything else that he subsequently observed and achieved was, he said, `his hobby’. It could be argued that Burkitt observed more with his one eye than most of us do with both.

Burkitt had observed the curious tumour in the faces of children for a number of years before submitting his first paper about them. New to him however, was to see a child with four tumours of the face – upper and lower jaws on both sides simultaneously. A few weeks later he saw another identical case himself.

Burkitt’s clinical simplicity, astute observations, epidemiological reasoning, and significant research in the absence of modern technology – carry messages for all who care for cases of Burkitt’s lymphoma (BL) – and indeed for any rare, neglected or obscure disease – especially insofar as they affect children in the tropics.

He described 38 cases of his own seen over 7 years. He reported Lilongwe (Malawi) as having 2 or 3 cases per year, and a Tanzanian hospital as receiving 6 patients in three months. Burkitt noted that the disease also occurred in Kenya and Nigeria. To these we can now add all countries in Africa lying between 12º N and 12º S of the equator. He originally suspected that the maxilla and mandible were solitary primary sites, but was puzzled – after having reviewed the case mentioned above, with Hugh Trowell in 1957 (rather poignantly this child’s name was ‘Africa’) – about the children with initial lesions seen in the jaws on both sides; four sites simultaneously. He later recognised that lesions could first appear below the diaphragm and subsequently appear in the jaw. Hence the question of a primary site with distant spread presented a problem. This anticipated later thinking that BL is to be regarded as a systemic disease, ie capable of appearing in any site at which cells of the lymphoid series can be found.

As to treatment, Burkitt soon recognized that surgery was not appropriate, and that since radiotherapy was not available, chemotherapy was the only option. With nitrogen mustard (military designation HN-2; designed for warfare, but never used; precursor of cyclophosphamide) he recorded cure in some cases. He thus anticipated chemotherapy as the likely treatment of choice.

As to the cause of the tumour – ‘by far the commonest tumour of childhood in Mulago Hospital, Uganda’ – he at that time made no predictions. One can however almost see his scientific, epidemiological and tenacious mind working on the problem half a century ago, and he was to address the question of causation most directly and persuasively a few years later. What became very clear was that this tumour was hugely aggressive, rapidly growing, and invariably fatal within weeks or a few months.

Twenty six years later we read of subsequent progress, as described in his oration upon receiving the Charles Stewart Mott Award – a private philanthropic society based in Michigan, USA, in 1982.

Starting in 1958 Burkitt distributed a questionnaire and conducted personal interviews over a vast swathe of sub-Saharan and southern Africa (research grant: £25 [$75]), seeking information from distant colleagues as to the incidence of BL in their region. He received over 300 replies. This was followed by the epic `Tumour Tour’ (research grant: £250 [$700]) in which he and two colleagues travelled 10 000 miles (16 000 km) in a second-hand Ford pick-up truck, visiting sixty hospitals in ten weeks. From this he mapped out the areas and altitudes at which BL occurred and did not occur. So it was, that with simple logic he came to several conclusions which still hold firm today: BL does not occur in significant numbers where malaria is absent, but that in malarious areas the disease can be found in black, Asian and European children, and it is far less common in children with sickle cell disease. BL does not occur in malarious areas if successful antimalarial interventions were in place there. BL does not occur over 3000 ft (923m) elevation at 1000 miles (1666km) south of the equator, (even in nearby low-lying areas of intense malaria transmission) nor over 5 000 ft (1 515 metres) at the equator. The significance of the altitude data was provided by a virologist friend and colleague A J Haddow, who suggested that altitude might imply a temperature gradient and barrier. BL seeming not to occur where the average temperature was less than 60ºF (15ºC). It was then realized that a rainfall pattern also emerged; the disease not being found in regions where annual precipitation was less than 20 inches (45cm). Both observations fitted very well with the suspicion of the involvement of malaria and the mosquito. The tumour was found to be virtually restricted to river valleys, lake shores and regions near the sea coast. These facts held true for all other areas of the world where intense malaria transmission remains a problem – notably some areas of Papua New Guinea, and the Amazon basin. Never before had a malignant tumour been related to ambient temperature or annual rainfall, or altitude above sea level, or malaria and its vector.

Anthony Epstein, a virologist, had been wondering about viruses as being implicated in the causation of human cancer, as they were known to be in certain animal cancers; Burkitt had wondered about this too. Thus the meeting of the two men at a lecture given by Burkitt at Middlesex Hospital in 1961 was mutually agreeable. Epstein asked for tissue from BL cases, Burkitt agreed. It was not long before Epstein and colleagues discovered a herpes-like virus within lymphoid cells in BL cases. This was where the virus – to become known as Epstein-Barr Virus (EBV) – was first seen. A few years later Epstein and his colleagues at the Bland Sutton laboratory, Middlesex Hospital, London, learned how to maintain BL cells in vitro from a case in Uganda – who would die very soon after the tissue was flown to London. It therefore now appeared, on epidemiological grounds, that both malaria and EBV might be responsible for BL. Ninetyfive percent of endemic BL tumours have subsequently been shown to contain EBV.

It is also recognized however, that whereas in the temperate zones of the world EBV is found in adolescents, in Africa it is found early in life – often before age one year Along with the early onset of malaria, EBV infection is thus still widely agreed to be a candidate in the causation of BL.

However, since intense malaria and EBV infection are clearly both common in children in sub-Saharan Africa, and since BL is – on the same scale – a comparatively rare disease – there must be yet more to be considered in the causation of BL. Burkitt himself wondered about the relevance of other insect-borne diseases in Africa, of which there are many. Research continues.

In 1966 Burkitt left Africa to take up a post at the Medical Research Council, London.

He died on 23 March 1993. His family maintains funds, which they give to the Royal Society of Tropical Medicine and Hygiene, London, for doctors performing research in the developing word. The award is known as the Denis Burkitt Fellowship. Both Professor Peter Hesseling and Dr Peter McCormick have received this award.

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