By Dorothy Crawford
Chance is a fine thing, especially when it leads to a major new discovery. Remarkably, this often seems to be the case with scientific discoveries, at least in my field – tumour virology. We now know that around 20% of cancers are caused by microbes but without chance this figure might be substantially lower.
The first human tumour virus was discovered in 1964 by Anthony Epstein and Yvonne Barr at the Middlesex Hospital in London with the virus being named Epstein-Barr virus (EBV) after its discoverers. The identification of EBV and the later unravelling of the diseases it causes undoubtedly depended on a series of chance events, but this does not devalue the work of the scientists involved who were all astute enough to recognise the chance they had been given and make the most of it.
The EBV story began with Denis Burkitt (1911-1993), a British doctor who, describing himself as ‘a simple bush surgeon’, went to work in Uganda in the 1950s. In 1957 he saw a five year-old boy with multiple jaw tumours in Mulago Hospital in Kampala and a few weeks later he saw a similar case. He was sufficiently puzzled to search through the hospital records for other cases. Surprisingly, he found that jaw tumours were a common cause of childhood death in Kampala, and, realising that he had stumbled on a ‘new’ type of cancer (now called Burkitt’s lymphoma, BL), he applied for a grant of £250 to investigate further. On receiving the money he bought a second-hand station wagon and set off on his ‘long safari’ to investigate the distribution of BL in Africa. He mapped the geographical range of the tumour to areas of high temperature and rain fall but low altitude; identical to that of non-seasonable, all-year-round malaria. On this basis Burkitt suggested that BL, like malaria, was caused by an infectious agent that was spread by mosquitoes. We now know that he was right in the former but wrong in the latter prediction.
During a spell of leave back in the UK, Burkitt gave a lecture about his discoveries at the Middlesex Hospital, London. Epstein was in the audience and the resultant meeting between him and Burkitt heralded the discovery of the first human tumour virus.
At the time Epstein was working on what he called ‘the unfashionable subject of chicken tumour viruses’ since the idea of viruses causing human cancers was ‘considered eccentric or even cranky’. But listening to Burkitt’s lecture, Epstein was so sure that BL must be caused by a virus that he persuaded Burkitt to send him tumour samples from BL patients.
Epstein and his co-workers spent two years searching for a virus in BL material, but without success. Most would have given up but they persisted and when the ‘eureka’ moment finally came it was down to chance. A tumour sample was delayed in transit and arrived late on a Friday afternoon apparently contaminated with bacteria. Epstein debated whether to chuck it in the bin but eventually put the tumour cells (lymphocytes) into a culture. Tended by Epstein’s research student, Yvonne Barr, the cells thrived and when Epstein examined them under the electron microscope he saw the virus. As it turned out the cell culture step was essential for visualising the virus in the cells.
EBV was soon identified as a new herpes virus but antibody tests showed that it was not restricted to BL patients but infected over 90% of the adult population world wide. With no idea what disease(s) EBV might cause, Epstein sent the virus to Gertrude and Werner Henle, husband and wife virologists in Philadelphia, USA. There a laboratory technician was given the task of screening for antibodies in different human populations. She tested her own serum and finding it negative used it as a control in all further tests. She then developed glandular fever (also called infectious mononucleosis) and when she returned to work she found she was EBV antibody positive so identifying EBV as the cause of glandular fever.
In 1966 yet another chance observation was made, again while screening a panel of blood samples. Unusually high EBV antibodies were detected in blood from people with nasopharyngeal carcinoma (NPC), the commonest tumour in men in Southern China. This further link between EBV and cancer was met with disbelief because NPC is a tumour of epithelial cells rather than lymphocytes, but to everyone’s surprise, just as in BL, the virus is present and active in all NPC cells. This revelation opened a whole new field of research investigating the mystery of how EBV interacts with epithelial cells to cause the tumour.
Serendipity, chance, accident, coincidence, even fate or destiny; call it what you will, it certainly plays a part in discoveries of all kinds. But although chance, including being in the right place at the right time, is part of it, more important is seizing the opportunity, realising its potential and exploiting it.
Professor Dorothy Crawford took the Robert Irvine Chair of Medical Microbiology at the University of Edinburgh in 1997, headed the school of Biomedical Sciences from 2004-2007, and was appointed Assistant Principal for Public Understanding of Medicine in 2007. Crawford recently published Viruses: A Very Short Introduction. She has also previously published two books on microbes for a general audience, The Invisible Enemy and Deadly Companions. Crawford 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.