From Cell Signalling to Human Health
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Babraham Institute From cell signalling to human health Co-ordination of cell activities through inositol Living cells are complex systems of molecules that work together to maintain life Inositol lipids are found in the membranes that enclose cells, in addition to and respond to ever-changing conditions. Cell signalling systems exist to detect forming structures changes in their abundance act as signals to alter gene activity, lipid signalling systems these changes and initiate appropriate responses within the cell. They do this by metabolism and other behaviours within a cell. Amongst other things, the balance Fundamental cell biology research at the Babraham Institute is laying controlling the activity of a small number of key ‘signal transduction’ proteins, of these lipids acts as a key control mechanism for cell growth, division and survival. the groundwork for new treatments for cancers, chronic inflammation which in turn regulate a cascade of further events. These include affecting the Disruption of inositol lipid signalling can lead to a range of illnesses including and other diseases all caused by defects in the mechanism that activity of other proteins, metabolic changes and altered gene expression. Together immunodeficiencies and cancers. transmits signals within cells. By working with companies on the these co-ordinate complex cell behaviour, such as growth and development. Babraham Research Campus, in the local Cambridge area and beyond, the Institute is ensuring a rapid development pathway from discovery Signalling research at the Babraham Institute has focused on systems that involve research to biotechnology, drug development and clinical application. regulating the abundance of a group of molecules called ‘inositol lipids’ inside cells. Liposomes Research overview: lipid signalling All cells receive a constant stream of information 1960 1964 Liposomes are microscopic 1979 1983 1993 1994 from their surroundings in the form of chemical Rex Dawson’s pioneering Rex Dawson discovers spheres made up of a double Michael Berridge, working Robin Irvine, working initially The Institute of Animal BBSRC forms from the messages. These messages are mainly received layer of lipids surrounding work at the Institute on that cells can split lipid in the ARC-affiliated unit in with Rex Dawson and then Physiology is renamed to the merger of the AFRC with at the surface of the cell and trigger specific a water-based centre. This purifying and studying PIP2 molecules in the the Department of Zoology leading his own laboratory Babraham Institute to reflect bioscience aspects of the signal responses inside the cell. is a simplified version of the metabolism of membrane into a water- living cells, which are mostly (Cambridge), provides at the Institute, joins forces a new approach and scientific Science and Engineering One of these responses is to activate an enzyme membrane lipids leads to soluble chemical called water surrounded by a lipid evidence that hormone- with Michael Berridge to vision. The Babraham Institute Research Council. called phospholipase C (PLC), which converts the identification of ‘tri- inositol trisphosphate membrane. Lipids are a group stimulated metabolism bring together previous would become focused on an inositol lipid called PIP2 into IP3 and 2 of molecules that include phosphoinositide’ . This (IP3) and membrane- of inositol lipids regulate research. They demonstrate fundamental biology with a diacylglycerol (DG). The rise in IP3 stimulates the fats and oils, there are many inositol lipid has become bound diacylglycerol (DG). the levels of calcium inside that IP3, which is produced focus on lifelong health and release of calcium inside the cell and this then different lipids in biology with 5 carries the signal to other systems. known as ‘PIP2’. The enzyme responsible a wide range of roles. Lipids cells . This is one of the first from PIP2 by PLC (shown in the biology of ageing. This for this is now called form membrane structures, are examples of inositol lipid 1964), can travel into cells would include a shift away Another response to signals from outside the cell Phospholipase C (PLC)3. effective energy stores and play metabolism controlling and cause calcium release from agricultural research and is to activate PI3 kinase (PI3K) enzymes. PI3K a part in cell signalling. other cell behaviours. (seen in 1979) from internal the use of larger animals. attaches an extra phosphate group to PIP2 to stores6. This defines the ‘PLC’ make a new inositol lipid in the membrane called The structural similarities PIP3. The increase in PIP3 activates another between liposomes and cells signalling pathway as a protein called PKB, initiating a series of events mean they can be used to critical link that allows many that help co-ordinate cell growth. deliver drugs or genes into cells. different signals received on Liposomes are able to fuse with the surface of cells to control Mistakes in PI3Ks can have a wide range of the surface of cells, releasing 7 effects. These changes can contribute to various their contents inside the cell. internal activities . cancers as well as other diseases including They can even be targeted to immunodeficiencies – where the body is less able specific parts of the body to to fight infections. more effectively deliver drugs where they are needed. 1948 1964 1965 1983 1991/92 1994 1996 Babraham Hall & estate Having joined the Institute Gerald Weissman is a visiting The Agricultural Research Len Stephens and Phill Hawkins join Len Stephens and Phill Collaborations between Institute scientists purchased by the Agricultural in 1952 to study the researcher at the Institute. Council becomes the Robin Irvine’s group and go on to show Hawkins find PI3K activity in and Onyx Pharmaceuticals leads to the Research Council (ARC) at membranes that surround He suggests the alternative Agricultural and Food that enzymes called PI3-kinases (PI3Ks) white blood cells and identify discovery of how PIP3 regulates protein the suggestion of founding living cells, Alec Bangham name ‘liposomes’ for Alec Research Council chemically modify PIP2 to form a new an enzyme called PI3Kgamma. kinase B (PKB, also called AKT) . This Director Professor Ivan De provides the first evidence Bangham’s ‘Banghasomes’. signalling molecule called PIP3. (PI3Ks This attracts the attention of turns out to be a key signalling pathway Burgh Daly to establish the that cell membranes are Bangham’s work with feature in over 31,000 publications pharmaceutical companies, that allows growth factors outside cells newly-funded Institute of made of double layers of Institute colleagues Jeff between 1991 and end 2017)8. including GSK. They hope to regulate cell growth and survival. Animal Physiology (IAP). The lipid molecules. His work Watkins and Malcolm to draw on the Institute’s The pathway has since been shown to Institute has a mission to shows that lipids in water Standish would lay the “At the time, researchers knew very little discoveries to develop new play a role in many human cancers. The improve agricultural animal can organise themselves foundations of liposome about the PI3-kinase enzymes, except drug therapies. Over 25 years collaboration with Onyx generates several health and productivity into membranes like those research worldwide (Over that they were associated with several later, GSK still support work by patents around the genetics, composition following World War II1. The around a cell; he calls these 55,000 publications up to proteins implicated in cancer. We knew Stephens and Hawkins. and function of PI3K enzymes. initial study of lipids at the structures ‘Banghasomes’. end 2017)4. that PI3-kinase enzymes modified a family Institute contributed to our of inositol lipids, which had been studied “In many cancers, there is a random fundamental understanding at the Babraham Institute since the 1960s, mutation in PI3-kinase, which switches it of cells, their specialisation but we didn’t know what these lipids were permanently on. PIP3 is constantly being and capacity to form or what role they played in the cell.” Dr made, and the signalling pathway cannot different structures. Phill Hawkins, Group Leader, Babraham be switched off as it normally would. Institute, talking about joining the PI(3,4)P2 in mouse tissue In the presence of too much activating Institute in the late 80s. Image: Anna Kielkowska & Tamara Chessa signal, things go wrong. One of those things, because PI3-kinase controls cell growth, is that the cells grow too much, and this is one of the hallmarks of the early stages of cancer.” Dr Len Stephens, Head of the Signalling Programme and Associate Director, Babraham Institute. A mouse cell – nucleus in blue, actin filaments in green Image: Barzan Sadiq 1998 2008 2013 2017 2002 Autophagosomes are a kind 2011 2012 2014 The Institute ceases A collaboration between The Institute develops an The Institute launches Klaus Okkenhaug at the Idelalisib (Zydelig) The Wakelam group and the of cellular ‘dustbin’ used to research with direct Martin Turner, A BBSRC-funded innovative new approach a collaboration with Institute, in collaboration with is licensed for use in Institute’s Bioinformatics recycle cell components and agricultural relevance. Group Leader at the Institute, to measure the levels of Karus Therapeutics to researchers at the University treating chronic lymphoid facility become part of the their malfunction is thought and US-based Icos Corporation PIP3 in cells and biopsies investigate the use of of Cambridge, discovers a leukaemia (CLL). Around international LIPID MAPS to be at the heart of several results in a PI3K delta knock- leading to a collaboration PI3K inhibitors in treating new human genetic disease 3,700 cases of CLL are consortium as part of a new age-related diseases, such out mouse model. These mice with GSK on clinical trials14. inflammatory diseases such responsible for increased diagnosed in the UK round of four years of funding as neurodegeneration. lack the PI3K delta protein, so as rheumatoid arthritis. Our susceptibility to lung infections.