Friday January 18 2008
Olivia and Isabella Murphy
Many national newspapers reported today on the story of Isabella and Olivia, four-year-old identical twins who have “unlocked the secret of leukaemia”. The papers describe how one twin was diagnosed with leukaemia and underwent chemotherapy, whereas the other twin did not develop the disease. Their unique situation of being identical twins who've had the same environment since they were conceived gave researchers an unprecedented opportunity to investigate the causes of leukaemia.
When researchers compared their bone marrow, they found that both girls had pre-leukaematic stem cells (which carry a genetic defect). However, Olivia (the twin who developed leukaemia) also carried a second mutation – a missing gene – that switched pre-leukaemia cells into full-blown leukaemia.
The Times reported that "the discovery will enable doctors to screen young leukaemia patients to establish the severity of their illness and spare some of the harrowing side effects of aggressive chemotherapy”.
The research behind these stories is an investigation of identical twins and a further laboratory study in mice that was inspired by the differences between them.
The causes of acute lymphoblastic leukaemia (the most common childhood form) remain largely unknown. There has been a previous suggestion of some genetic link (with slightly increased risk in children with Down's syndrome, for example), in addition to theories about risks from radiation, drugs or infections. The study gives new insight into the mechanisms involved in the development of leukaemia in children, and opens up a new area for further study. Doctors and researchers will be particularly interested in the findings that pre-leukaemia cells could be used to screen for the disease and that further mutations appear to be needed to switch these on.
Until further research is done, it is unclear what strategies could be followed to prevent conversion to the full-blown disease, or whether this knowledge might have any influence upon the treatment of childhood leukaemia.
Where did the story come from?
Dr Dengli Hong and colleagues from the University of Oxford, Great Ormond Street Hospital, the Institute of Child Health, the Institute of Cancer Research and centres in Italy and Japan carried out the research. The study was funded by grants from the Leukaemia Research Fund, the Medical Research Council, and EuroCSC. The study was published in the peer-reviewed medical journal Science.
What kind of scientific study was this?
One popular theory for the cause of human cancers is that they are a result of “cancer stem cells” which spread the cancer. In this twin study, both twins were predisposed to leukaemia because they carried pre-leukaemic cells. The researchers suggested that these pre-leukaemic cells crossed from one twin to the other during development because of their shared placenta. They investigated whether this was possible by seeing whether this type of cell would grow and divide when transplanted from one individual to another (in this case a mouse).
Acute lymphoblastic leukaemia (the most common cancer in children) may result from one or more mutations while the stem cells of the foetuses are developing in the uterus. A common mutation is believed to be involved in the type of leukaemia that Olivia had, when two genes fuse to form the TEL-AML1 fusion gene.
In the case of the twins, it is believed that this mutation occurred in one of them, resulting in pre-leukaemia cells that spread to the second twin through their shared placenta. As only one twin went on to develop the disease, the researchers analysed bone marrow samples from the twin with leukaemia and blood samples from the healthy twin to see the differences between them.
In another part of their investigation, the researchers used mice to explore whether the pre-leukaemia cells could have moved from one twin to the other and what effect this would have had on the healthy twin’s cells. To do this, the researchers transplanted human cells with the TEL-AML1 mutation into mice to see whether the pre-leukaemia cells would be able to spread.
What were the results of the study?
Tests on the bone marrow of the twin with leukaemia showed pre-leukaemia cells in her bone marrow. For ethical reasons, the researchers did not take bone marrow samples from the healthy twin, and so the presence of pre-leukaemia cells was detected through blood tests.
Although the researchers found that both twins carried pre-leukaemia cells, the twin with leukaemia also had a second mutation (loss of the normal TEL gene).
The researchers showed that transplanting human cells with TEL-AML1 mutation into mice resulted in pre-leukaemia cells that could grow and divide. These pre-leukaemic cells were also able to survive and grow and multiply when transplanted into the bones of other mice.
What interpretations did the researchers draw from these results?
The research highlights that a mutation can lead to pre-leukaemia cells that are capable of self-replicating.
What does the NHS Knowledge Service make of this study?
This study has provided more information about the molecular mechanisms involved in the development of leukaemia. The experience of identical twin girls, who initially shared the same genetic make-up and shared the same placenta in the uterus, has given researchers a unique opportunity.
Identifying precursors to the disease gives doctors and scientists the hope that in future it will be possible to screen children for leukaemia. These findings will hopefully lead to developments in the field of prevention and treatment.
The Guardian reported that doctors believe that the pre-leukematic cells developed in one twin around about the first month of pregnancy and “spread to the other in the womb”. A second mutation, which may have been triggered by a chance infection, may have “switched on” the disease. These are currently theories that have not been tested. The researchers did not set out to confirm whether the second mutation found in the twin with leukaemia was responsible for conversion of pre-leukaemia to leukaemia.
These findings are likely to initiate interest in further research with implications for leukaemia screening.
Sir Muir Gray adds...
What would we do without twin studies? This type of opportunity offers the chance of distinguishing between the effects of nature and nurture.