The Science of Integration

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Systems biology research brings differing approaches together to understand disease mechanisms

By Amber Lepage-Monette

How do you explain a scientific discipline that isn’t technically a discipline at all?

When it comes to defining systems biology, integration is a key word.

“The notion of systems biology is pretty broad,” acknowledges Daniel Figeys, director of the Ottawa Institute of Systems Biology (OISB) (Ottawa, ON).

“It covers a broad range of scientific disciplines, and which scientific discipline is involved depends on the systems of interest,” he explains. “So if you’re going to study cells and organs, it’s a bit different than studying pathways and protein complexes.”

Mads Kaern, PhD, the Canada Research Chair in systems biology and a researcher at the OISB, agrees.

“In my opinion, systems biology is an approach. It’s not a discipline per se,” he says. “It’s an approach where you try to use quantitative tools in order to analyse experimental data and to generate a hypothesis about how the system works.”

Kaern says systems biology is a growing field that can really be broken down into two classes: quantitative and qualitative.

Quantitative systems biology, which Kaern works in, is the use of quantitative models such as mathematics, to help understand research data in areas such as proteomics and genomics.

“Using the data, we can use quantitative tools to uncover what are the design principles, what makes living cells work, and why do they fail? Why, (if) the regulation fails, for example, it leads to cancer,” Kaern says.

Qualitative systems biology is looking at a cell or organism as a complete functioning system, rather than studying its individual parts.

“Some people also say (that) is called systems biology, because it considers the whole cell as being a system, or the whole organism as being a system, rather than going for the single-gene or single-protein approach,” Kaerns explains.

In this method, one can look at anything — from a human, to an organ, to a cell, to protein pathways — as an integrated system, where the whole is greater than the sum of its parts.

The common denominator throughout systems biology, however, is that it brings together researchers from various disciplines, utilizing different strengths and knowledge.

“What you want to do is bring a mathematician together with somebody who might be doing genomics and somebody who might be a clinician,” Figeys says. “Those are things that will impact the success of systems biology.”

Coming Together

Though elements of systems biology have been used in one way or another for decades, systems biology in its current form is really a new, growing field, which is clearly demonstrated in the establishment of the OISB itself.

Launched in March, the OISB has been a work in progress for the last couple of years, Figeys explains. It is housed on a floor at the University of Ottawa’s (Ottawa, ON) new faculty of medicine building.

“It’s a network as well as a facility where research activities are ongoing,” Figeys says. “We realize that to do systems biology . . . it cannot just be Ottawa, because it’s pretty intense in terms of research activity.”

One area the OISB is currently involved in is mapping protein-protein interactions in human disease.

“We want to integrate genomics, proteomics and potentially other ‘omics’ approaches that will be used to gather information on the system, and, then we’ll use bioinformatics and mathematical modelling to interpret the information and potentially construct mathematical models,” Figeys says. “Our goal is to be able to, over time, apply that to the study of given disease.”

He goes on to explain that to study systems at the level of proteins and pathways, researchers must introduce a disruption in the pathway and measure what changes occur.

“What we have to do is go in the system, basically tickle the system and see what are the changes that occur when you’re doing that, and measure that through those technologies like genomics and proteomics, and then build models on top of that based on the response that you’re seeing,” he says.

Kaern also works in genomics, trying to understand when and why genes are expressed.

From previously conducted research, it is already known that some regulatory proteins regulate other regulatory proteins. From that understanding, Kaern says his research group has been able to establish circuit diagrams of regulators regulating other regulators.

“It’s kind of the CPU (central processing unit) of the cell,” he says.

“What my group is trying to do is to understand . . . what are the programs and how do they come about based on these molecular level interactions,” Kaern says.

He adds, however, that this data poses some challenges.

“Presently . . . we don’t have the technologies and tools that allow us to just look at the diagram, which is a qualitative description,” he explains. “This is a qualitative aspect of systems biology — to establish these circuits first; then the quantitative aspect of systems biology comes in and tries to make sense of this network. In particular, what is the relationship between the architecture of the circuit, the dynamics . . . and the biological function that the program then controls.”

In looking to understand disease mechanism, Kaern’s work could eventually be translated into diagnostic tools.

“What is really important is to understand, what are the targets of the drugs, what are the side-effects of drugs, (and) can we find new, better targets within pathways associated with disease that work better than the ones we have,” he says.

Investigating the Mind

Though genomics approaches are still at work, a group of researchers operating through the National Research Council (NRC) (Ottawa, ON) are working in a slightly different vein than Figeys and Kaern, investigating systems biology in neurobiology.

Roy Walker, PhD is a neurobiologist for the NRC’s Institute for Biological Sciences (IBS) and is group leader of IBS’s neurogenomics group.

For the last three years Walker was part of the Systems Biology of Brain Cell Interactions program, which received funding through the Genomics and Health Initiative. Though the program was formally ended in March, Walker says many of the researchers involved are continuing the research in their own projects.

“We’d gotten a great deal of information by the time that program finished, and that gave us some really good ideas of where we want to go from now on,” he says. “Although the efforts are a bit smaller, we’re still going very much in that direction.”

The team specifically looked at genes and proteins associated with three neurological conditions: Alzheimer’s disease, Parkinson’s disease and stroke.

It is the sheer complexity of the brain as an organism that makes systems biology an ideal means of study, Walker says.

“It was a natural progression from our earlier studies on disease genes, using genomics tools to start thinking along the systems biology idea, because the whole concept of genomics is to look at many, many things and then think about how you’re going to integrate that knowledge into getting information on how the cell or how an organism works,” he says.

“The brain is not just about neurons,” Walker explains. “Only about 30 per cent of the cells in your brain are neurons, and the other 70 per cent are cells that also contribute to the function of the brain — whether they’re astrocytes, whether they’re endothelial cells. So they also work as an organized system. That was the overall goal — to say, OK, how do these cells interact?”

Danica Staminovic, PhD, director of the IBS neurobiology program, agrees with Walker that the brain presents an interesting challenge because of its complexity.

In her own research, Staminovic is studying the blood brain barrier and how this may contribute to disease. A protective layer of vessels and cells, the blood brain barrier acts as a regulator that controls what enters the brain.

“Blood vessels prevent things from getting into the brain,” Staminovic says. “This helps with disease, but it’s hard to deliver drugs.”

Her participation in the Brain Cell Interactions program involved studying brain endothelial cells, and the development of methods that allow researchers to model stroke. These models help the researchers analyse blood vessels and map gene and protein changes.

Within the program, researchers developed the capacity to use genomics to understand these processes, Staminovic says. Systems biology provides an understanding of the whole vascular system in relation to brain function, she adds.

She also points out that building brain models is not only key in stroke research, but will benefit other researchers as well.

“Building these types of models is essential for any disease,” Staminovic says, noting that vasculature is a key element in any neurobiological condition.

Facilitating the Integration

With such interesting research under way, systems biology is an area that, while hard to define, seems poised to flourish.

“After the completion of the sequencing projects in the 90s, it has become apparent that the complexity of organisms and cells is too high for us really to comprehend without the assistance of quantitative tools,” Kaern says.

“It’s in the same way that bioinformatics was necessary. It was necessary to use computers in order to complete the sequencing projects . . . there is no way around it because there is so much information,” he adds.

While some may feel it necessary, Figeys warns that challenges remain.

“What happens when we’re talking about systems biology, is we’re talking about really bringing sciences of different backgrounds together. We’re not inventing a new science, we’re integrating science,” he says. “But to do that, it does challenge the current academic models of scientific silos.”

Figeys points out that in bringing together researchers with varied backgrounds, funding would be better to support research teams, rather than individual researchers.

“It will have to move more toward program funding,” he says. “The community will have to recognize that if you have a mathematician on (their) own, (they) might not be able to get funding from CIHR or agencies like that. But this mathematician, as part of a program, like systems biology . . . becomes fundable.”