FEATURE MISSION IMPERATIVE DENIS NOBLE is President of the International Union of Physiological Sciences and Professor Emeritus at Oxford University. Noble was one of the first researchers to use computers to look at physiology and his work led to a working mathematical model of key molecular components in the heart that generate cardiac rhythm. He shared some of his thoughts on systems biology on a recent visit to Heidelberg to give a lecture at the Print Media Academy entitled The music of life: the principles of systems biology. Biologists need a heavy dose of humility. This was one of Denis Noble’s messages delivered towards the end of a talk given at the Print Media Academy in Heidelberg, Germany, on 28 February. Noble was talk- ing about systems biology but the reference was to the human genome project. “The problem with sequencing the human genome was that we overpromised. There is no question that we had to do it but the hyperbole went a bit far. Systems biologists should take note.” According to Noble, we need a holistic approach to study the complex systems that make up life. Systems biology has many definitions but the goal is to map, understand, and model the whole network of interactions that shape biology, all the way from molecules up to cells and the whole organism. “Such a project is enormous. It’s almost mission impossible but I would call it mission imperative.” Noble put the scale of the adventure into perspective. “The human genome project was about finding the parts and we found around 25000 of them. But the number of ways of putting those parts or genes together is vastly greater than the total number of fundamental particles in the universe, so it will take a long time to work it all out.” It turns out there are 1070000 ways of putting the parts together but a mere 1080 atoms in the universe. Noble’s own work, which goes back many years, has focused on build- ing a reliable computer model for the human heart. He was one of the first researchers to use computers to look at physiology and his research led to a working mathematical model of some of the key components in the heart that generate cardiac rhythm. The model integrated channels, carriers, receptors, substrates, and other key components of cells. The breakthrough was that it successfully reproduced the oscillation of the cardiac pacemaker. In his talk, Noble emphasized that cardiac rhythm is a property of the system and there is no genetic program that directly makes it perform its function. “Sometimes we drink too much from the reductionist agenda. It is not correct to ask which gene leads to cardiac rhythm. It is a property of the higher-level components that make up the system,” commented Noble. Noble’s lifelong research interests have progressed into the Physiome project, a worldwide, public domain effort to provide a computational frame- work for understanding physiology in humans and other organisms. The task is to develop integrative models at all levels of biological organisation, from genes to the whole organism via gene regulatory networks, protein pathways, integrative cell function, and tissue and the relations between structure and function in whole organs. “This is incredibly ambitious,” said Noble “but we can see systems biology finding its feet. It is possible to unite theoretical approaches like computer modeling with practical research in ways that have outcomes. Our work with computer modeling is proving useful in drug development.” Discoveries are emerging and applications are attracting the interest of pharmaceutical companies. Noble’s research in systems biology has helped with the study of two drugs for the treatment of angina. “For Ivabradine, we identified the drug target and showed that the drug could be a safe health intervention to slow the beating of the heart,” remarked Noble. “For Ranolazine, we have revealed valuable information on the safety of the drug that would have been missed by looking at two specific effects in isolation.” Noble has been heavily involved in the activities of the International Union of Physiological Sciences, and he is currently in his second term as President. When asked about the value of physiology in the era of personal- ized medicine and individual diagnostics he remarked: “It is totally neces- sary if we define physiology as the study of function.” His advice to early- stage researchers: “Take some risks.” The talk, which was open to the general public, was organized by the European Molecular Biology Laboratory, Deutsches Krebsforschungszentrum, Ruprecht-Karls-Universität Heidelberg, and the UniversitätsKlinikum Heidelberg. The Manfred Lautenschläger Stiftung provided financial support for the lecture. ©2012 EMBO EMBOencounters | Summer 2012 | communications@embo.org 9 © Denis Noble