All systems go
Even ten years ago, systems biology was regarded by many researchers as more science fiction than science, but now it has become an indispensable part of the biologist’s toolkit, and Scotland’s ‘digital laboratories’ are leading the way – with a little help from international colleagues……
Rainer Breitling started thinking about systems biology in the early 1980s, long before the science was officially invented, when he imagined using computers to ‘simulate’ living organisms. If you can generate spectacular patterns like fractals, he thought, then why not model complex biological functions? At that time, he was still at school in Germany, but thanks to IBM (his father’s employers), Breitling was one of the first of a new generation to grow up with PCs at home, and already saw computers as the ‘digital laboratories’ of the future. At that time, most biologists would have laughed at the idea. But soon they’ll wonder how they ever managed without it – and Breitling has found his vocation.
In January 2010, Dr Breitling will take up a new position as SULSA Professor of Systems Biology (now a well-established science), based in the Faculty of Biomedical & Life Sciences at the University of Glasgow. He will not only benefit from newly-acquired computer resources in Glasgow – including a Sun 200 processor system in the Systems Biology Centre, plus GRID access via the eScience centre – but also a collaborative cluster of fellow researchers in Scotland. Breitling will also maintain his close links with his colleagues in the Netherlands, where he is currently Assistant Professor at the Bioinformatics Centre of the University of Gröningen, sharing his computer resources with astronomers and astrophysicists, whose radio telescopes generate similarly huge streams of data.
“I find this parallel between the study of the macrocosm (the universe) and the microcosm inside the cell/body highly intriguing,” says Breitling. “Both are very complex systems with an amazing number of components and we are only beginning to understand how they work – there are still surprising amounts of ‘dark matter’ in both of them.”
Like a number of SULSA researchers, Breitling brings an international flavour to the project. “That’s part of the fun of science,” says Breitling, whose own career has taken him from Germany to Scotland, California and the Netherlands, and from biochemistry via bioinformatics to systems biology.
“Systems biology brings together scientists from every direction; for example, engineers, statisticians and computer scientists, as well as biologists. Our challenge is to get all these people to speak the same language, and bridge the gap between experimentalists and informatics.” Breitling says that he is still “emotionally attached” to biochemistry, but also looks forward to his new job in Glasgow, where part of his task will be training the next generation of systems biologists, as well as pure research. Even though systems biology is still at the early stages of development, Breitling thinks the science has begun to reach critical mass, and the facilities at his disposal in Glasgow are evidence of growing academic commitment – and a reflection of the fast-growing confidence in this new field.
According to Breitling, systems biology was an “underground stream” in the 1970s and 1980s but started to gather momentum when the Human Genome Project got underway in the 1990s. By the time the Project was completed in 2003, systems biology had already emerged as a new branch of science because computational approaches had proved they could speed up advances in biology. Combined with the massive amount of information provided by the genome sequences, the special algorithms used in systems biology could now be used to “begin elucidating the molecular circuitry of living cells.”
The Human Genome Project identified about 30,000 genes, and about 100 of these genes may be involved in the development of cancer or diabetes, for instance. None of these genes works in isolation, but they rather function via complicated and very dynamic networks of interactions, which can only be analysed using computers. And the situation gets even more complex as many other factors and ‘knock-on’ effects are involved in the progress of any disease, says Breitling. With diabetes, for example, lifestyle and diet may be critical. The genetic component that people inherit may only trigger the disease in a certain percentage of people, and the big question is to identify what other factors may cause or prevent it, including other genes as well as certain types of molecules, enzymes and proteins.
Or, in Breitling’s words: “What makes a gene a critical gene? People realised the need to take the concept of systems biology to a new level. They also realised they needed an holistic approach that would provide opportunities for large-scale quantitative analysis.” And since those early days, systems biology has passed the ‘proof of principle’ test and is now producing practical results.
Breitling’s research interests include the development of innovative computational approaches for post-genomic systems biology, statistical methods for high-throughput biological experimentation, and the dynamic modelling of cellular systems. One of his specialist interests is ‘high-accuracy’ metabolomics – studying networks of metabolites or “measuring very small molecules and how they respond to perturbation.” In basic terms, metabolites are involved in biological processes like growth and development, or perform ecological functions such as defending organisms from disease. They are also biomarkers that can indicate the early signs of health problems. Breitling is also searching for new molecules which may influence biological processes, and even entire new families of signalling molecules.
As well as studying variations in genes, Breitling analyses the molecular networks associated with certain conditions – like the switches that turn on or turn off diseases or other malfunctions. Sometimes, this means identifying influential ‘hot spots’ or genetic variations which explain why diseases develop in some individuals but not in others with similar genes. Much of this work is carried out in model organisms in the laboratory. According to Breitling and other biologists, many human diseases have the same genetic origin as diseases in other species, and that is why studying plants, worms or fruit flies, for example, can lead to significant breakthroughs in understanding human diseases by discovering ‘fragilities’ at critical nodes in the regulatory circuitry of a cell.
Sometimes, “unlikely candidates” emerge from research. One metabolite may initially be associated with a particular disease or biological process – in the same way as cholesterol may indicate a cardiovascular problem – but then be discovered to influence a totally different disease, often as the result of unexpected ‘cross-talk’ in the molecular networks.
Breitling is also concerned with a concept called ‘robustness’ – the ability of living things to resist diseases despite sometimes dramatic variations in genes and environmental conditions. This involves studying the ‘feedback loops’ in the networks of genes and metabolites, which sometimes can form ‘vicious circles’ from which the organism cannot recover – for example, once someone develops advanced diabetes, the condition tends to be chronic.
Will this research lead to a cure for diseases like cancer? In Breitling’s view, the first aim is to understand the basic process, since if we know how and why problems occur, we can intervene in order to prevent them from developing. Early screening and diagnosis based on improved biomarkers and a better understanding of how they interact may indicate problems before a person ever gets ill; in this way, it may be possible to design personalised prevention strategies that would be more efficient than trying to ‘cure’ a chronic disease later on.
Breitling and his systems biology colleagues don’t ‘get their hands dirty’ in laboratory work but develop methods to interpret the large datasets generated in the experiments carried out by their research collaborators. In Breitling’s view, it makes a big difference, however, if the systems biologist has some experience in experimental science, since this makes them more sensitive not only to their colleagues but also to the data.
For Breitling, systems biology is now an integral part of the biologist’s toolkit, and can be used in a wide range of projects. For example, his work at the moment covers everything from synthetic biology (using soil bacteria to develop new antibiotics) to research into diabetes (the ‘geneticist’s nightmare’), sleeping sickness (working with parasitologists to develop new, less toxic drugs) and Parkinson’s disease (using nematode worms to mimic the human brain). He is also ‘open for business’ with respect to other topics for research. “If it’s an interesting or innovative concept, and it excites me, I’ll think about taking it on,” he explains.
Sometimes, Breitling sounds like a computer scientist, talking about biological processes in terms of data and “how information passes through the network,” but he also recognises that the key to the success of SULSA and his own future research will not only be computational power but ‘human chemistry’ – how people work together in Scotland and beyond. In his own words: “Systems biology is a social enterprise which offers fascinating opportunities for collaboration across traditional disciplines.”