The sum of all parts Systems biology at UCD
It’s usually easier to understand a situation when you get a wider perspective on it. A bit like stepping back and seeing the entire wood rather than an individual tree: the workings of the entire forest can seem vast, but they make more sense.
It’s the same in biology. For decades, scientists have been zooming in closer on biochemical entities in cells, focusing on single genes, proteins or other molecules. But in recent years the field of ‘systems biology’ has been taking a broader view and using mathematical modelling to try and understand and the complexity of biological processes and predict how we might control them. The result? New avenues of understanding that are changing the way people think about how to design and use therapeutic drugs.
Shown above: Image of cell adhesion molecules on neurons in culture was taken by Dr Mark Pickering, UCD School of School of Biomolecular & Biomedical Science and UCD Conway Insitute, as part of the 2009 UCD Images of Research competition
Professor Walter Kolch and his colleagues at UCD Conway Institute of Biomolecular & Biomedical Research have been examining important processes relating to various questions in cell growth, cancer and how stem cells repair tissues.
They recently published a number of papers in high-impact scientific journals detailing their findings – including a discovery about how breast cancer cells interpret signals to grow, which was published in Cell.
So what is systems biology, and why is it widening horizons? “There are probably as many definitions of systems biology as there are people that you ask, but I think it can be described by the aims and that is to use mathematical and computational methods to understand biology,” says Professor Kolch, director of Systems Biology Ireland (SBI), a Science Foundation Ireland -funded CSET that was launched last year.
“Over the last decades we have been very successful in cataloguing all the parts and components, we know all the genes, we know the proteins. But it’s like having a telephone book where you know all the people but you don’t know how they interact.”
Getting a handle on those thousands of interactions requires more than the human brain can handle. Enter computers, mathematics and even nano-engineering, which combine to help us see the bigger picture and a more systems-based understanding that takes greater complexity into account.
And complexity is the name of the game: it’s emerging that even within the same tissue – or cancerous growth – not all cells act the same way, which can cause problems if you are treating a tumour with a drug and some cells stubbornly resist. “If you treat a tumour which consists of several billions of cells, not all cells will respond to the drug in the same way,” says Professor Kolch.
“Many of them will die but some won’t because they will respond in a different way.” Devising models and experiments in systems biology goes back to the basic hypothesis, he explains, which needs to be tight because maths is precise.
Through a blend of mathematical algorithms, computer modelling and lab experiments, including using tiny ‘nano-devices’ to measure the responses of individual cells, the researchers bring the questions through a number of iterations – does the model stack up with the experiment and if not why not? – until the pieces of jigsaw start to come together.
The approach has seen the SBI group figure out how biochemical signals that appear quite similar on the face of it can have markedly different effects on whether and how cancer cells grow. “The take home message is that biological differences can be specified by small changes in dynamic behaviour of the networks, and this is only possible to find out using the systems biology approach,” explains Professor Kolch.
“With experimentation you would need to be very lucky to hit the right one, or else you would have to do an enormous amount of experiments.” They have also developed and tested a model which challenges the thinking that a small number of ‘master genes’ control cell growth and development.
Instead their findings suggest that rather than a select bunch of puppeteer genes pulling the strings, multiple genes have an input, and this more distributed control means a biological system like a cell is able to compensate if one gene gets knocked down because others can still kick in.
This shift in understanding is an important consideration for drug design, according to Kolch, who argues that the trend towards developing drugs that act highly specifically on or in the cell is misguided, because biochemical systems can compensate.
“The [drugs] which are clinically successful are the dirty ones that hit many targets,” he says. Instead, systems biology can help design better combinations of therapies by highlighting the points in a biochemical network that the drugs need to hit in order to be effective, says Professor Kolch, who believes the field will also help explore how we can get the most from therapies by giving them at the optimum time of day too.
Stem cells are also getting the systems biology treatment, with SBI researchers working with Remedi at NUI Galway to identify the processes by which adult stem cells find and repair tissues.
Timing is an important issue here too, stresses Professor Kolch, and the researchers are looking to optimise drug treatments to help support the regenerative properties of stem cells that could be used to help heal heart and joint tissues.
SBI researchers are working with a number industry partners, including AztraZeneca, Servier, Ark Therapeutics, Hewlett-Packard and Siemens, and Professor Kolch believes solutions developed for the systems biology approach can cross over into other fields, such as managing enormous amounts of data on the web.
And while the more immediate impact of the approach will probably be felt in drug design and development, systems biology stands to inform in many other areas of medicine too, notes Professor Kolch.
“More long-term goals are using these models to design clinical trials in silico or predict toxicity effects or drug interactions,” he says. “They are feasible but they are still far off because we need to build up more data and also in this iterative process, you need the time to go through the iterations.”
Cancer genetics
Mining genes for clues about cancer, Systems Biology Ireland is a Science Foundation Ireland-funded centre based at UCD with partners in National University of Ireland, Galway. SBI is leading a €12 million EU –wide project to explore genetic mutations that lead to the development of cancer cells, with a particular focus on understanding childhood cancers.
The project, which sees collaboration between basic and clinical research groups across Europe, will use computational and mathematical tools to mine genetic data to unravel some of the complex processes that underpin cancer development at a cellular level. T he initiative is funded under the EU 7th Framework Programme for Research (FP7).