Systems biology – seeing the bigger picture
Suppose you wanted to figure out how a community works, but you only had a map of the houses and the phone listings of the people who lived there. To get a better picture of what goes on, you would need to understand how the people interact and what those interactions mean for the wider city, country and even the world.
In a similar vein, scientists have spent decades piecing together what molecules are in biological systems, and they have looked at how small groups of molecules and cells relate to each other. But a field called ‘systems biology’ looks to take a more overarching view.
“I don’t see systems biology as a new field, but I think it is a new way to do science,” explains Prof Walter Kolch, who heads Systems Biology Ireland, a Science Foundation Ireland-funded CSET that links University College Dublin, NUI Galway, international collaborators and industry partners Siemens, Hewlett Packard, Servier, Astra Zeneca, Protagen, Agilent and Ark Therapeutics.
“What scientists have been doing so far is trying to learn and understand how things work by dismantling them and looking at the parts. What systems biology does is the opposite, we are taking the parts and piecing them together again trying to better understand how the whole thing functions – how a whole cell functions, how a whole organism functions - based on a more holistic view.”
The known catalogue of nucleic acids (including our genes), proteins and sugars in cells has grown, but these individual molecules are like the listings of individuals in the phone book, explains Prof. Kolch.
“You know all the people but, you don’t know how they interact,” he says. “What you need is an understanding of how the components interact and how they generate biological function.”
Our minds can handle analysing such interactions when there are only two or three components to consider, but bump it up to thousands of players and it goes beyond our intuition, so we need computer models to help.
Starting with a hypothesis, systems biology uses maths and computers to build a model based on what we know, and then tests that model with experiments. SBI in particular uses advanced imaging and micro-engineered devices to home in on how individual cells respond to their environments. Because it is becoming clear that even if cells might appear to be similar, they don’t all react in the same way.
“When we did classical biochemistry we crunched up millions of cells and measured something and got the average,” explains Prof. Kolch. “Now with advanced imaging methods we can look at at least some of these biochemical properties in single cells - and it turns out there’s a huge heterogeneity in a population.”
Understanding these differences is more than merely an academic exercise – it could have profound implications for how we treat diseases like cancer.
“If you treat a tumour which consists of several billions of cells, not all cells will respond to the drug in the same way,” explains Prof. Kolch. “Many of them will die, but some won’t because they will respond in a different way. These resistant cells will now keep the cancer growing.”
Tackling such major questions requires a multi-disciplinary approach, and systems biology leans on maths, computational science and engineering as well as biology itself.
“The experiments are informed by the model so you can very often guess what may be missing and it leads you to fill in the picture. Every iteration is one more piece in the jigsaw,” says Prof. Kolch, who notes that being able to predict how a system works can inform us how to derail it when needed.
“For things like drug discovery in silico, we can make predictions of which are the important targets we should hit with the drugs and possible side effects.”
The approach offers new routes to get around the dwindling pipeline of drugs emerging in the pharmaceutical industry, according to Prof. Kolch – by understanding how best to combine drugs and even the optimum timing of when people should take medications during the day, we could predict better therapeutic regimes for complex diseases like cancer.
Another focus of SBI is stem cells, which stand to have important applications in regenerative medicine because they have the potential to replenish tissues and stimulate healing.
A project between UCD’s Conway Institute and REMEDI in Galway is analysing how mesenchymal stem cells find the tissues that need fixing in the body, and also the time they take to differentiate and provide new cells of the type needed.
“We are on the verge of trying to understand what we can do with stem cells,” says Prof. Kolch. “Most of what we know is empirical, so we know by observation what the stem cells are doing, but we are looking to know how they are doing it and how we can improve it.”
