UK must get with the systems to stay in front

February 2, 2007

A merger of biology and engineering could help to realise the promise of the Human Genome Project, writes Denis Noble.

When the medical and engineering sciences come together to consider the future of healthcare in the UK, you can be sure that something important is on the horizon.

This week, the Royal Academy of Engineering and the Academy of Medical Sciences published their long-awaited report on systems biology.

Its message is very simple: the UK has to invest money and undertake reforms in higher education if it is to maintain its leading role in the biological sciences.

With huge advances in understanding at the molecular and genetic levels, we are awash with low-level data. Yet the promises of the Human Genome Project have not been realised with the frequency that had been hoped for. The reason is that, once we move from the molecular level of DNA and proteins, the higher-level interactions become exceedingly large and difficult to interpret. The human genome's 25,000 genes may sound a small number. But it is very large: there would not be enough material in the whole universe for evolution to have encountered all the possible interactions between 25,000 elements, even during the billions of years of the development of life on Earth.

Combinatorial explosion means that a fully bottom-up understanding of life will probably always elude us.

This is where systems biology and the merger of engineering and biology comes in. The study of the interactions between the components of a system - rather than the components themselves - can be pursued at all levels of biological organisation, from gene-protein networks up to the whole organism. A basic principle of engineering is central: investigate the principles of organisation at each chosen level using the tools appropriate for that level.

Detail from the lower levels is selected through the vision provided by higher-level understanding. The levels can then be connected: multi-level organisation is a key feature of the systems biology approach.

There is, however, widespread prejudice within the scientific community that the lowest, molecular level of biological explanation is superior to the rest. That view would be correct if causation in organisms acted only upwards from lower levels. But a key principle of the systems approach is that in functions involving feedbacks between different levels of organisation, there is also downward causation.

Events in organs, tissue and cells trigger events at every lower level. All levels require study if we are to succeed in understanding the functioning of the whole. This is as true in engineering as it is in medicine. If we want to know what a computer is doing, we may not need to know what all the individual components are doing. We do need to know how it has been programmed and what principles determine its behaviour.

These ideas have infused the report of the two academies. There is also a sense of urgency. Major initiatives in systems biology have already been launched in the US, Japan and elsewhere. The UK has some strengths in the field, but these need to be developed systematically if the country is to remain a major player.

Why does it matter? Consider the pharmaceutical industry, in which Britain is strong but in danger of losing research initiatives to the US. The costs of producing a new drug can exceed £500 million. Most candidate chemicals fail to make it to the clinic because of serious side-effects such as heart arrhythmia, liver metabolism or kidney failure. Such side-effects really do require systems-level understanding. They arise because a chemical designed to have the effect we want on its biological target invariably has an impact on other parts of the body.

In trying to work out these side-effects, to predict them and to overcome them, we enter the world of interactions. It is impossible, for example, to understand sudden heart death caused by a particular drug without considering how all the cells in the heart interact to produce the susceptibility to this unwanted outcome.

Fibrillations, as they are called, kill. We do not understand that by studying genes and proteins alone, even though some forms of such sudden cardiac death do have a genetic component.

Some funding agencies have already launched initiatives in systems biology.

But there is a sense that we do not yet fully understand what it really is, how it should develop, and how best to fund it.

The report makes clear proposals - £325 million needs to be invested and higher education reformed to make sure that there are enough qualified graduates and that the right working practices for systems biology research programmes are in place. If such initiatives are undertaken now, the UK still has time to grasp this exciting opportunity.

Denis Noble is professor of physiology at Oxford University.

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