Julian Downward obtained his bachelor’s degree in Natural Sciences from Cambridge University and then studied for his Ph.D. in the laboratory of Michael Waterfield at the Imperial Cancer Research Fund in London, where he established in 1984 a link between a retroviral oncogene (v-erbB) and a cellular growth regulatory protein, the EGF receptor, establishing the cellular function of an oncogene for only the second time and leading to an ISI “citation classic” publication. In 1986, he moved to Robert Weinberg’s laboratory at the Whitehead Institute at the Massachusetts Institute of Technology in Cambridge, MA, where he began work on the role of RAS proteins in human cancer. In 1989 he started his own lab at the Imperial Cancer Research Fund, subsequently Cancer Research UK London Research Institute, where he remained until moving to the Francis Crick Institute in 2015. His lab has provided critical insights into the molecular mechanisms of function and regulation of oncogenic proteins of the RAS family and the importance of their mutational activation in human tumours.
In 1990 his lab provided the first demonstration that the activation state of the RAS protein, as assessed by the ratio of bound GTP relative to GDP, is normally regulated in response to extracellular factors, in that case the activation of the T cell antigen receptor. In 1993 he established the mechanism of activation of RAS by growth factors, showing that it involved the assembly of a complex of autophosphorylated receptor tyrosine kinase (e.g. EGF receptor), adaptor protein (Grb2) and guanine nucleotide exchange factor (Sos). The same year he showed that GTP-bound RAS binds to and activates the Raf kinase, which controls the MAP kinase pathway, and a year later identified a second RAS effector family in phosphoinositide 3-kinase, a critical regulator of cell survival, proliferation and metabolism. Recently his lab has shown that the ability of RAS to interact with PI 3-kinase is absolutely essential for the formation of tumours in two different mouse cancer models, lung cancer driven by sporadic activation of endogenous KRAS and skin cancer driven by carcinogen induced mutation of endogenous HRAS, suggesting that targeting of the RAS-PI 3-kinase interaction may have therapeutic potential.
Other work from his lab has established that transformation by RAS requires interaction with multiple effectors, which contribute differentially to cell cycle progression, cytoskeletal regulation, and apoptosis, and that cell-matrix interaction activates the PI 3-kinase pathway, allowing anchorage-independent growth of transformed cells.
Julian has a long held interest in functional genomics, coordinating a number of programmes in this area, including most recently setting up a high throughput screening facility for RNA interference and other cell based screens. These have revealed the identities of novel proteins important in the resistance of tumour cells to cytotoxic agents, determinants of resistance of lung cancer cells to EGF receptor targeted therapies and also genes whose inactivation is synthetically lethal with expression of an activated RAS oncogene.
Julian was Associate Director of the Cancer Research UK London Research Institute from 2005-2015 and is now Associate Research Director of the Francis Crick Institute. He was elected to the membership of the European Molecular Biology Organisation in 1995 and in 2005 was made a Fellow of the Royal Society, the UK’s national academy of sciences. He was made a Fellow of the Academy of Medical Sciences in 2009 and an honorary fellow of the Royal College of Physicians in 2012. He belongs to the Editorial Boards of the journals Cell, Science, Molecular Cell and PLOS Biology among others.