Formed in 2002, the London Research Institute is based over 2 sites, and consists of 44 research groups, with 13 core technology facilities supporting the science.
Milestones
The history of the London Research Institute is the history of cancer research itself. From small beginnings as the Imperial Cancer Research Fund at the turn of the 20th century, the Institute has evolved into a vibrant, multi-disciplinary laboratory which has maintained and extended the tradition of excellence laid down by its founders. Scientists at the Institute have participated in a revolution that in a few decades has taken the world from a place where cancer was a killer disease with unknown causes and no cure, to one where much is understood of cancer’s origins, and effective treatments allow many to live with cancer, rather than die of it. There is still a long way to go, but the next generation of cancer biologists are likely to participate in the last phase of the fight, when cancer becomes at worst a chronic disease, and at best a vanquished one.
Revolutions in science occur by step changes; leaps and bounds where suddenly, the pieces of the puzzle fit together, and a new understanding is achieved. Sometimes, these leaps are taken collectively by those working at the cutting edge of the scientific community, and sometimes, by one or two remarkable people. Nineteen of the most striking pieces of research undertaken at the London Research Institute are described. Some fall into the category of cutting edge communal changes, but some are the result of exceptional people working at the right time and in the right place. Together, these milestones in research form a body of work of which the Institute and its staff can be justifiably proud.
Milestones;
Foundation of the ICRF
Birth of modern cancer research
DNA and RNA Tumour viruses
Discovery of Fibronectin
Personalized cancer medicine
Discovery of p53
Fos oncogene discovered
Insertional mutagenesis and oncogene cooperation
Growth factors and receptors can be oncogenes
Conservation of the Cell Cycle
Why can’t a woman be more like a man? The race for the male sex-determining gene
Myc causes apoptosis
The Diffley lab cracks DNA Replication
Into the nucleus: regulation of transcription
Upstream and downstream of the RAS oncoprotein
The Hedgehog signalling pathway
Steve West and Genetic recombination
Cancer Genetics
Innate immunity
Foundation of the ICRF
- 1901: Thomas Rudd, a wealthy city businessman, writes to the St James’s Gazette to propose the establishment, by national subscription, of a “klinik” devoted to cancer research and treatment.
- 1902: Public donations of £49,686 5s. 6d collected from 213 subscribers. Ernest Bashford appointed as first director of the Cancer Research Fund, patron HM The King, President, HRH The Prince of Wales. Work begins.
- 2002: Merger of the ICRF and the Cancer Research Campaign to form Cancer Research UK. The ICRF labs are rechristened the Cancer Research UK London Research Institute.
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Birth of modern cancer research
- First systematic classification of cancers undertaken.
- Major contributions to study of neoplasia. Haaland proposes that normal cells progress by stages to cancer. Foulds first to describe general rules of neoplastic progression.
- Crabtree and Cramer’s work on radiosensititvity of tumours lays foundation of radiotherapy.
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DNA and RNA Tumour viruses
- 1968: Sir Michael Stoker brings virology to ICRF.
- 1970s: ICRF becomes world-renowned centre for molecular biology.
- Basis of transcription biology and many neoplastic principles originate from this time.
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Discovery of Fibronectin
- 1973: Richard Hynes and Nancy Hogg independently discover a protein, fibronectin, which is present on normal cell surfaces, but disappears when cells become cancerous.
- 2011: An entire field has grown around this discovery. The fibronectin family, and their partners the integrin receptors, turned out to be central to cell adhesion and migration, and many other processes. Numerous steps in the progression of cancer, including invasion and metastasis, involve altered adhesive properties of cells, and novel.
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Personalized cancer medicine
- 1974: Mel Greaves realises childhood leukaemias can be classified according to their cell surface markers into different cancers of varying prognosis.
- This work revolutionized the diagnosis and treatment of childhood leukaemia. It was the first example of personalized cancer therapy - where the treatment is tailored to the patient’s disease.
- Classification of leukaemias was the first step towards understanding their molecular biology modern leukaemia research began here.
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Discovery of p53
- 1979: David Lane and Lionel Crawford show that the oncogenic viral SV40 large T antigen binds a cellular protein, dubbed p53.
- p53, the “guardian of the genome”, is mutated in around half of all human cancers.
- Restoring normal p53 activity is the holy grail of cancer therapeutics.
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Fos oncogene discovered
- 1982: Tom Curran and Natalie Teich identify the v-Fos retroviral oncoprotein and associated protein p39 (later shown to correspond to the Jun oncoprotein).
- 1982: Curran, Teich and collaborators clone and sequence the v-fos gene and show there is a cellular homologue, c-fos.
- Fos and its partner Jun were the first oncoproteins shown to directly regulate transcription, the switching on and off of genes. They are now known to participate in controlling growth, differentiation, cell death and activation of neurons. Their discovery led to the realisation that upregulation and downregulation of specific crucial target genes can cause cancer, and that all parts of the cellular machinery are vulnerable to cancer mutations.
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Insertional mutagenesis and oncogene cooperation
- 1983: Gordon Peters and Clive Dickson show MMTV causes tumours by insertional mutagenesis.
- 1986: Peters, Lee and Dickson discover first evidence of oncogene cooperation in an animal model.
- Both these discoveries form part of the conceptual foundations of our current understanding of cancer.
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Growth factors and receptors can be oncogenes
- 1983: Mike Waterfield and colleagues show that the human gene encoding Platelet Derived Growth Factor (PDGF), and the cancer-causing sis oncogene, found in a tumour virus, are closely related.
- 1984: Julian Downward discovers that another tumour virus has hijacked the human Epidermal Growth Factor Receptor (EGF-R) and converted it into the v-erb-b oncogene.
- These two discoveries showed that oncogenes can cause tumours because they encode mutationally activated components of normal cellular growth control mechanisms. The work transformed our understanding of how growth is regulated in normal cells, and what goes wrong in cancer.
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Conservation of the Cell Cycle
- 1987: ICRF Cell Cycle Control laboratory, led by Paul Nurse, shows for the first time that the cell cycle works the same way in all eukaryotic cells, a discovery with relevance for many diseases, but especially cancer.
- 2001: Paul Nurse, fellow ICRF lab head Tim Hunt, and Leland H. Hartwell are awarded the Nobel Prize in Physiology or Medicine “for their discoveries of key regulators of the cell cycle”.
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Why can’t a woman be more like a man? The race for the male sex-determining gene
- 1990: Peter Goodfellow’s lab show that the testis-determining factor, which specifies maleness, is encoded by the SRY gene.
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Myc causes apoptosis
- 1992: Gerard Evan and co-workers shows that the Myc oncogene is a double-edged sword, not only instructing cells to proliferate, but also causing programmed cell death (apoptosis).
- The balance between proliferation and apoptosis is now a universally recognised mechanism of growth control; the default pathway for all cells is death, and cancers are as rare as they are because it is hard to escape this default when things go wrong.
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The Diffley lab cracks DNA Replication
- Identification of Origin Replication Complex, responsible for initiating DNA replication in eukaryotes.
- Pre-Replication Complex discovered: it dictates one round of replication per cell cycle. 18 years on, the Pre-Replication Complex is reconstituted on DNA in a test tube from its purified component proteins.
- Cyclin dependent kinases are responsible for the tight linkage of DNA replication and the cell cycle.
- DNA damage inhibits replication initiation; this is controlled by regulated activation of just two proteins.
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Into the nucleus: regulation of transcription
- 1992: Identification of SAP, the first growth factor-regulated transcription factor
- 1993: First demonstration that the MAPK pathway can directly regulate a transcription factor.
- 1995: First demonstration that proteins involved in controlling cell shape and structure can also regulate transcription.
- 2000s: Transcription can be directly regulated by the actin cytoskeleton, and this is required for adhesion and invasiveness in cancer.
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Upstream and downstream of the RAS oncoprotein
- 1990: Julian Downward shows that signals from outside the cell can activate the RAS oncoprotein.
- 1993: Downward lab publish mechanism of regulation of Ras by growth factors.
- 1993: Ras lies upstream of the Raf mitogen activated protein kinase pathway.
- 1994: Ras also acts through other targets, notably phosphatidylinositol-3-kinase.
- This work defined how Ras is regulated by extracellular stimuli and how it works to cause normal and neoplastic cell growth.
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The Hedgehog signalling pathway
- 1993: Phil Ingham’s lab clones the zebrafish hedgehog homologue, and predicts its importance as a morphogen.
- The hedgehog signalling pathway is the key to development of the vertebrate embryo.
- The hedgehog pathway is mutated in multiple cancers; drugs to block the pathway are in clinical trials.
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Steve West and Genetic recombination
- 1994: Steve West and colleagues purify human RAD51, a protein that plays a key role in DNA double strand break repair.
- 2006: Discovery of the molecular defect associated with the neurodegenerative disorder Ataxia with Oculomotor Apraxia-1.
- 2008: Identification of GEN1, the elusive human Holliday junction resolvase that processes recombination intermediates.
- 2010: Purification and characterisation of BRCA2, the tumour suppressor protein that is defective in many individuals with inheritable breast cancers.
- These discoveries provided a direct link showing that defects in basic cellular DNA repair processes can lead to tumourigenesis and/or neurodegenerative disease. The work transformed our understanding of mechanisms of DNA repair and their importance for normal cell growth.
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Cancer Genetics
- 2007 and 2008: Tomlinson lab publishes collaborative studies identifying loci in genome associated with susceptibility to breast, colorectal and prostate cancer.
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Innate immunity
- 2004: Caetano Reis e Sousa shows viral infections are detected by dendritic cells of the innate immune system recognising mislocalised viral RNA.
- 2007: Identification of a novel signalling pathway by which dendritic cells detect fungal infections and dead cells.
- Working in a new and fast moving field, the Reis e Sousa lab has made multiple key discoveries, some of which have great promise for the development of anti-cancer therapies.
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