By Dorothy Crawford
On 24 February 1964 a young research virologist at the Middlesex Hospital in London peered at the screen of an electron microscope and saw a new virus. It turned out to be a human cancer virus – the first ever discovered. That young virologist was Tony Epstein, now Sir Anthony Epstein, and the virus was named Epstein-Barr virus, or EBV, after him and his research assistant Yvonne Barr.
On seeing the virus Epstein’s excitement was unbounded. In his own words:
‘I was so amazed and euphoric that I was terrified that the specimen would burn up under the electron beam. So I switched the microscope off and walked round the block without a coat in the snow. When I had calmed down I came back and took pictures.’
The cancerous tumour from which EBV was isolated was Burkitt Lymphoma, named after Denis Burkitt, the Irish surgeon who first described it. Burkitt was working in Uganda in 1957 when he saw a small boy with swellings on both sides of his upper and lower jaw so large that they had dislodged his teeth and grossly distorted his facial features. Burkitt was mystified and when lab tests were inconclusive he decided that it was ‘another of the curiosities that one had become accustomed to seeing from time to time in Africa.’
But then, while visiting another hospital a few weeks later, Burkitt saw another child with exactly the same type of facial swellings. Now he knew that this was more than a curiosity and he immediately started to investigate. By delving into hospital records, sending questionnaires to other hospitals and missions and travelling throughout Sub-Saharan Africa, Burkitt uncovered the tumour’s fascinating demography. This was the story he told for the first time outside Africa when giving a lecture at the Middlesex Hospital while on leave in the United Kingdom in 1961.With Epstein in the audience, Burkitt described a unique childhood tumour with a distribution that mirrored that of well-known mosquito-transmitted diseases like yellow fever. He therefore suggested that the tumour might also be spread by an insect vector.
As the story unfolded Epstein realised that Burkitt Lymphoma could well be caused by a virus. At the time he was working on viruses that cause tumours in laboratory animals; viruses that most experts dismissed as having no relevance to human tumours. Indeed, these same experts thought the idea of a human tumour virus was entirely fanciful. Nevertheless Epstein was galvanised into action.
Within a short time Burkitt Lymphoma samples were winging their way from Kampala in Uganda to Epstein’s lab in London. But try as he might Epstein could not find a virus in the tumour cells. It took almost three years of frustration before the breakthrough came.
On a cold Friday in December 1963 a Burkitt Lymphoma sample was expected from Kampala. But Heathrow airport was fogbound and the plane carrying this valuable cargo was diverted to Manchester. When the sample eventually arrived in the lab in late afternoon the transport fluid appeared cloudy – a sure sign of bacterial contamination. However, Epstein examined it under a light microscope and saw not bacteria but tumour cells floating free in the fluid. With little hope of salvaging anything useful Epstein put the cells into a culture flask and headed home for the weekend.
These were the first cells of this type that ever grew in culture. In fact they grew and grew until by February 1964 there were enough to examine under the electron microscope. And on the 24th of that month, after three years of hard work, the eureka moment arrived – a new virus!
But when Epstein and Barr published their exciting findings back in 1964 they were met with scepticism – the onus was on them to prove that EBV did indeed cause cancer. As it turned out this was not an easy task and it took many years and several technical advances before the doubters were convinced.
Now, exactly 50 years after its discovery, we know that EBV infection is very common. The virus usually infects young children without causing illness, although infection later in life may result in glandular fever (also called infectious mono). Once inside the body EBV lodges there for life as a harmless infection. Presently over 90% of the world’s adult population are unknowingly carrying the virus. However, EBV is also associated with several different types of cancer, including nasopharyngeal carcinoma, lymphoma in those with immune defects such as transplant recipients and HIV carriers, around 50% of Hodgkin lymphoma cases, a proportion of gastric cancers as well as African Burkitt Lymphoma. The total number of new cases of EBV-associated cancers worldwide is estimated at around 200,000 annually.
The obvious questions to ask are how and why EBV, generally a harmless virus, causes cancer in a few unfortunate people? Over the years researchers have found that a complex chain of events is required to transform a normal cell into a cancer cell. For Burkitt Lymphoma, EBV is one such event and another is recurrent malaria infection, the latter accounting for the geographical restriction first noted by Burkitt in the 1950s. For the other EBV-associated cancers several specific environmental and genetic factors need to coincide before a cancer cell evolves, thus making the tumours much rarer than the virus infection itself. The exact nature of these cancer-promoting factors is still the subject of intense study by hundreds of EBV researchers around the world.
Dorothy H. Crawford has been Assistant Principal for Public Understanding of Medicine at the University of Edinburgh since 2007. Her books include The Invisible Enemy (OUP, 2000), Deadly Companions (OUP, 2007), Viruses: A Very Short Introduction (OUP, 2011), and Virus Hunt (OUP, 2013). Her latest book is Cancer Virus: The Story of Epstein-Barr Virus. She was elected a Fellow of both the Royal Society of Edinburgh and the Academy of Medical Sciences in 2001, and awarded an OBE for services to medicine and higher education in 2005. She has written several articles for the OUPblog.
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Image credit: Epstein-Barr virus (EBV). National Cancer Institute. Public domain via Wikimedia Commons.