Sir Mel Greaves
Group Leader: Biology of Childhood Leukaemia
Biography
Professor Sir Melvyn (Mel) Greaves' laboratory research is now focussed on modelling the prevention of infection triggered leukaemia by manipulation of the gut microbiome early in life.
He has worked at the Institute of Cancer Research since 1984, when he joined to establish the UK’s first Leukaemia Research Fund Centre (for Cell and Molecular Biology). Earlier in his career, Professor Greaves pioneered immunological methods to differentiate between types of leukaemia, which improved understanding of the disease and allowed treatments to be better tailored to patients.
Professor Greaves and his group made a major discovery at the ICR in the 1990s and early 2000s when combined studies on identical twins with leukaemia, archived neonatal blood spots of patients and a large cohort of frozen cord bloods taken at birth identified the presence and frequency of mutations initiating leukaemia in utero.
Since 1988 he has developed evidence for the idea that common infections trigger clinical emergence of acute lymphoblatic leukaemia but only in children who carry a silent 'foetal' pre-leukaemic clone and who had a deficit of immune priming microbial exposures in infancy. Epidemiological data suggests that the latter exposures derive primarily from the gut microbiome, and this now forms the basis of Professor Greaves' team's modelling studies in mice.
With a broad educational background, Professor Greaves initially trained in zoology and immunology in the sixties at University College in London and Stockholm. He was drawn into cancer research in the mid-1970s when, as a young father, he visited a cancer ward at a London hospital and met children stricken with leukaemia. At the time, little was known about the disease, and Professor Greaves began a lifelong study – initially at the Imperial Cancer Research Fund (now the Cancer Research UK London Research Institute) – into its biology in the hope of improving patient diagnosis, treatment options and ultimately prevention.
Awards and activities
His research at the ICR has been recognised by many national and international awards including the José Carreras Award, the British Society for Haematology Gold Medal and the King Faisal International Prize for Medicine.
Professor Greaves is an Honorary Member of the Royal College of Physicians, a Fellow of the United Kingdom Academy of Medical Sciences and a Fellow of the American Association for Cancer Research. He was elected to The Royal Society in 2003. In 2015 Professor Greaves received the Cancer Research UK Lifetime Achievement Award for Cancer Research.
In 2017 Professor Greaves was awarded the prestigious Royal Medal from The Royal Society in recognition of his research, which dramatically improved our understanding of childhood leukaemia. He was honoured in the 2019 New Year Honours with a knighthood for services to children’s leukaemia research.
In 2014 Professor Greaves founded the Centre for Evolution and Cancer at the ICR. The centre is focussed on providing a new, evolutionary perspective on cancer risk, cancer clone development and drug resistance. He stepped down as Director in April 2020.
Mel is a strong supporter of science communication to the wider public. He initiated the ICR Science Writing Prize ten years ago (now named the Mel Greaves Science Writing Prize). He is the founding editor of the ICR blog ‘The Bigger Picture’. In 2015 he set up The Darwin Cancer Blog (previously hosted by Nature Publishing Group on the British Journal of Cancer site until May 2018) which aims to provide a forum for the discussion of how an evolutionary perspective is changing thinking about cancer.
He is the author of two popular science books: ‘Cancer. The Evolutionary Legacy’ (2000) translated into five languages and Braille, and ‘White Blood. Personal Journeys with Childhood Leukaemia’. In 2017 he completed a science book for teenagers (principally his own grandchildren): ‘The Making of You: The Most Incredible Journey, Ever’. Professor Greaves enjoys classical music, opera, the theatre, many sports (all too passively now) and being a grandfather.
After five decades of scientific research and publishing, Mel still enjoys the illusion that his best idea and best paper is his next one.
BSc (Hons) Zoology, University of London.
PhD, University of London.
MRCPath, Royal College of Pathologists.
FRCPath, Royal College of Pathologists.
The Paul Martini Prize, Martini Foundation, Gottingen University, Germany, 1977.
The Peter Debye Prize, University of Maastricht, The Netherlands, 1981.
Honorary MRCP, Royal College of Physicians, London, 1986.
King Faisal International Prize for Medicine, King Faisal Foundation, 1988.
Gold Medal, British Society for Haematology, 1999.
The Jose Carreras Award, European Haematology Association, 2001.
Fellow, The Royal Society, 2003.
Fellow, European Academy of Cancer Sciences, 2009.
The 29th Myron Karon Memorial Lectureship Award, Children's Hospital, Los Angeles, 2009.
The American Society of Hematology Ham-Wasserman Lecture Award, American Society of Hematology, 2009.
Lifetime Achievement Merit Award, Leukaemia & Lymphoma Research (UK), 2010.
Honorary Fellow, Clinical Genetics Society, 2013.
Fellow, The Academy of Medical Sciences, 1999.
Member, European Molecular Biology Organization, 1978.
Personal Chair of Cell Biology, University of London, 1985.
Gordon Bloom Distinguished Visiting Professorship, Harvard University Medical School, Boston, 2002.
American Society of Clinical oncology (ASCO) Pediatric Oncology Lectureship, American Society of Clinical Oncology (ASCO), 2003.
The First Herman Van den Berghe Invitation Chair, University of Leuven, Belgium, 2011.
Cancer Research UK Lifetime Achievement in Cancer Research Prize, Cancer Research UK, 2015.
2017 Royal Medal, The Royal Society, 2017.
Society of Memorial Sloan Kettering Prize, 2018.
Knighthood, HM The Queen, 2019 New Year's Honours.
Fellow of the AACR Academy, American Association for Cancer Research, 2019.
Editorial BoardsTransplantation, 1971-1975.
Journal of Immunology, 1972-1975.
European Journal of Immunology, 1971-1978.
Immunology, 1971-1978.
British Journal of Haematology, 1978-1984.
Leukemia Research, 1976-1986.
Cancer Cells, 1989-1991.
International Immunology, 1989-1996.
Expert Reviews in Molecular Medicine, 1998-2012.
Evolution and Medicine Reviews, 2008.
Journal of Adolescent and Young Adult Oncology, 2010-2013.
Leukemia, 1987-1995.
Receptors and Recognition (Review Series), 1976-1984.
Medical Advisory Board, Member, Leukaemia Research Fund, 1976-1979; 1981-1984; 1988-1991-1991.
Tumour Products Committee, Member, MRC, 1977-1984.
Scientific Committee, Member, European School of Hematology, 1986-2008.
Appointed Teachers' Committee, Member, British Postgraduate Medical Federation, 1987-1991.
Medical Advisory Committee, Member, Multiple Sclerosis Society, 1987-1998.
Sub-Committee on Radiation and Cancer, Member, UKCCCR, 1988-1988.
Leukaemia Steering Committee, Member, MRC, 1988-1988.
COMARE, Member, COMARE, 1989-1992.
UKALL Trials Working Party, Member, MRC, 1989-1989.
Scientific Advisory Group, Member, Kay Kendall Leukaemia Fund, 1991-2012.
Scientific Advisory Committee, Member, Northern California Childhood Leukemia Study, 2003-2012.
GlaxoSmithKline Prize and Lecture Committee, Member, The Royal Society, 2004-2009.
Sectional Committee 10, Member, The Royal Society, 2004-2009.
Sectional Committee 10, Chair, The Royal Society, 2007-2009.
Research Committee, Member, UK Childhood Cancer Study, 1992.
Faculty Committee, External Faculty Member, Center for Evolution and Cancer, San Francisco, California, 2011.
Related pages
Types of Publications
Journal articles
Low folate intake as well as alterations in folate metabolism as a result of polymorphisms in the enzyme methylenetetrahydrofolate reductase (MTHFR) have been associated with an increased incidence of neural tube defects, vascular disease, and some cancers. Polymorphic variants of MTHFR lead to enhanced thymidine pools and better quality DNA synthesis that could afford some protection from the development of leukemias, particularly those with translocations. We now report associations of MTHFR polymorphisms in three subgroups of pediatric leukemias: infant lymphoblastic or myeloblastic leukemias with MLL rearrangements and childhood lymphoblastic leukemias with either TEL-AML1 fusions or hyperdiploid karyotypes. Pediatric leukemia patients (n = 253 total) and healthy newborn controls (n = 200) were genotyped for MTHFR polymorphisms at nucleotides 677 (C-->T) and 1,298 (A-->C). A significant association for carriers of C677T was demonstrated for leukemias with MLL translocations (MLL+, n = 37) when compared with controls [adjusted odd ratios (OR) = 0.36 with a 95% confidence interval (CI) of 0.15-0.85; P = 0.017]. This protective effect was not evident for A1298C alleles (OR = 1.14). In contrast, associations for A1298C homozygotes (CC; OR = 0.26 with a 95% CI of 0.07--0.81) and C677T homozygotes (TT; OR = 0.49 with a 95% CI of 0.20--1.17) were observed for hyperdiploid leukemias (n = 138). No significant associations were evident for either polymorphism with TEL-AML1+ leukemias (n = 78). These differences in allelic associations may point to discrete attributes of the two alleles in their ability to alter folate and one-carbon metabolite pools and impact after DNA synthesis and methylation pathways, but should be viewed cautiously pending larger follow-up studies. The data provide evidence that molecularly defined subgroups of pediatric leukemias have different etiologies and also suggest a role of folate in the development of childhood leukemia.
Approximately 20% of childhood B-precursor acute lymphoblastic leukemia (ALL) has a TEL-AML1 fusion gene, often in association with deletions of the nonrearranged TEL allele. TEL-AML1 gene fusion appears to be an initiating event and usually occurs before birth, in utero. This subgroup of ALL generally presents with low- or medium-risk features and overall has a very good prognosis. Some patients, however, do have relapses late or after the cessation of treatment, at least on some therapeutic protocols. They usually achieve sustained second remissions. Posttreatment relapses, or even very late relapses (5-20 years after diagnosis), in childhood ALL are clonally related to the leukemic cells at diagnosis (by IGH or T-cell receptor [TCR] gene sequencing) and are considered, therefore, to represent a slow re-emergence or escape of the initial clone seen at diagnosis. Microsatellite markers and fluorescence in situ hybridization identified deletions of the unrearranged TEL allele and IGH/TCR gene rearrangements were analyzed; the results show that posttreatment relapse cells in 2 patients with TEL-AML1-positive ALL were not derived from the dominant clone present at diagnosis but were from a sibling clone. In contrast, a patient who had a relapse while on treatment with TEL-AML1 fusion had essentially the same TEL deletion, though with evidence for microsatellite instability 5(') of TEL gene deletion at diagnosis, leading to extended 5(') deletion at relapse. It is speculated that, in some patients, combination chemotherapy for childhood ALL may fail to eliminate a fetal preleukemic clone with TEL-AML1 and that a second, independent transformation event within this clone after treatment gives rise to a new leukemia masquerading as relapse. (Blood. 2001;98:558-564)
Identical infant twins with concordant leukemia were first described in 1882, and since that time many such pairs of infants and older children have been described. It has long been recognized that this situation offers a unique opportunity to identify aspects of the developmental timing, natural history, and molecular genetics of pediatric leukemia in general. We reviewed both the older literature and more recent molecular biologic studies that have uncovered the basis of concordance of leukemia. Molecular markers of clonality, including unique, genomic fusion gene sequences, have provided unequivocal evidence that twin pairs of leukemia have a common clonal origin. The only plausible basis for this, first suggested more than 40 years ago, is that following initiation of leukemia in one twin fetus, clonal progeny spread to the co-twin via vascular anastomoses within a single, monochorionic placenta. This explanation has been endorsed by the identification of clonotypic gene fusion sequences in archived neonatal blood spots of individuals who subsequently developed leukemia. These analyses of twin leukemias have thrown considerable light on the natural history of disease. They reveal a frequent prenatal origin and an early or initiating role for chromosome translocations. Further, they provide evidence for a variable and often protracted latency and the need, in childhood acute lymphoblastic leukemia (ALL)/acute myeloblastic leukemia (AML), for further postnatal exposures and/or genetic events to produce clinical disease. We argue that these insights provide a very useful framework for attempts to understand etiologic mechanisms.
Chromosome translocations are often early or initiating events in leukaemogenesis, occurring prenatally in most cases of childhood leukaemia. Although these genetic changes are necessary, they are usually not sufficient to cause leukaemia. How, when and where do translocations arise? And can these insights aid our understanding of the natural history, pathogenesis and causes of leukaemia?
Previous cell subfractionation studies have indicated that bcl-2 is an inner mitochondrial membrane protein. We have sought to determine the ultrastructural localization of bcl-2 protein in lymphoma and breast carcinoma cell lines and biopsy material known to overexpress bcl-2 using immunoelectron microscopy. To avoid the possibility of processing artifacts, samples were prepared by three different methods: progressive lowering of temperature, cryosectioning, and freeze-substitution. In all instances the labeling of bcl-2 protein was relatively weak but the distribution the same. In both lymphoma and breast carcinoma tissues, bcl-2 protein was detected on the periphery of mitochondria: little labeling of either the mitochondrial matrix or cristae could be detected. Labeling was also detected on the perinuclear membrane and throughout the cytoplasm, as also indicated by confocal microscopy. These data therefore indicate that bcl-2 protein can be detected at several intracellular sites and that at the likely functional destination, the mitochondria, there appears to be, contrary to expectations, a preferential association with the outer membrane.
Epidemiological evidence has suggested that some pediatric leukemias may be initiated in utero and, for some pairs of identical twins with concordant leukemia, this possibility has been strongly endorsed by molecular studies of clonality. Direct evidence for a prenatal origin can only be derived by prospective or retrospective detection of leukemia-specific molecular abnormalities in fetal or newborn samples. We report a PCR-based method that has been developed to scrutinize neonatal blood spots (Guthrie cards) for the presence of numerically infrequent leukemic cells at birth in individuals who subsequently developed leukemia. We demonstrate that unique or clonotypic MLL-AF4 genomic fusion sequences are present and detectable in neonatal blood spots from individuals who were diagnosed with acute lymphoblastic leukemia at ages 5 months to 2 years and, therefore, have arisen during fetal hematopoiesis in utero. This result provides unequivocal evidence for a prenatal initiation of acute leukemia in young patients. The method should be applicable to other fusion genes in children with common subtypes of leukemia and will be of value in attempts to unravel the natural history and etiology of this major subtype of pediatric cancer.