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Systems Biology in Action


When it launched in 2005, the Ottawa Institute of Systems Biology laid the groundwork for a new trend — similar systems biology institutes have popped up recently in Toronto, Montreal, and Vancouver. Located at the University of Ottawa and funded by a range of Canadian granting bodies, the OISB aims to develop and apply systems biology to the study of human diseases. According to Director and CSO Daniel Figeys, research at the institute spans both basic research, such as studies of gene expression regulation in chromatin remodeling, and more translational work, including looking at diseases of the brain like Alzheimer's, Parkinson's, and stroke. In addition, OISB focuses on technology development in proteomics, lipidomics, and high-throughput screening in model organisms as well as on developing bioinformatics approaches to integrating data analysis.

The current staff at the institute includes 14 core members and nearly 25 associate members whose labs span a diverse range of research — from chromatin assembly and remodeling to gut microbial genomics to gene expression regulation in muscle development and more. The scientists employ a host of systems biology tools, such as gene expression arrays, ChIP-chip, RNAi, and sequencing. The institute is still recruiting and expects to ramp up to some 200 staff and students when it reaches capacity.

Though OISB received ample startup funds and moved into a new building last August, getting going wasn't an easy task. "It's not necessarily easy to do that because you have to have the right elements that line up," Figeys says. "You have to have a very strong local support. In our case it was done very quickly, but it's pretty rare."

Focus on research

Alain Stintzi came to OISB three years ago, and his primary research focuses on using systems biology techniques to study interactions between bacteria and their human hosts. One particular species he studies is Campylobacter jejuni, a food-borne microbe that colonizes the human gastrointestinal tract and causes diarrhea. He not only looks at gene expression changes due to environmental stimuli in the human gut, but also the community of gut microbes and how it reacts to invasion. "We are trying to identify at the genome level the genes from the microbe that are important to colonize the gastrointestinal tract," Stintzi says, adding that they employ microarrays, proteomics, and bioinformatics techniques to do so.

In coming to the institute, he's been able to expand his systems biology toolbox from gene expression using microarrays to "using more, different approaches" like proteomics and crystallography. "Being part of the institute actually helps bridge these different technologies together," Stintzi says.

Being in the same building on the same floor holds a definite advantage for collaboration, he says. One of the biggest pluses is that he can discuss experimental design with people who know about the technology. Taking a sample to a core lab is nice, but talking to someone about the experiment's design is arguably the key to doing better science. "The main difference is that you talk with someone who actually will give input on the experimental approach and the experimental design," he says. "It's not only the technology, but it's the scientific input that comes with it. So we have access to the technology, but [we] also have access to the knowledge. And in my mind, this is what is actually more important."

Technology focus

A major push at the institute is technology development. In addition to directing the center, Figeys is the project leader for developing the "proteomic reactor." His team recently introduced a prototype of the reactor, which reduces and simplifies handling of proteomes, greatly reduces the volume of reactions down to nanoliter amounts, and shortens the time for processing samples.

In phase one of development, he and his group have created a capillary-based reactor and a processing fluidic station linked to mass spec and capillary electrophoresis systems. Phase two will port the processing system to a chip. In essence, the reactor will be able to quickly prepare complex samples like plasma, and samples with very few cells for mass spec and other proteomic analysis. "Basically, it allows you to do protein biochemistry on a very small scale," Figeys says, adding that "all of our proteomic samples now will go through the proteomic reactor." Further funding from Genome Canada and the province of Ontario will allow Figeys to develop even more effective reactors to handle post-translational modifications.

One area where the reactor has already been useful is in studying protein-protein interactions. In contrast to conventional approaches for mapping protein-protein interactions, using the reactor lets Figeys and his colleagues purify the protein complex while it's bound to DNA and allows them to visualize what surrounds the complex. They are also largely focused on studying lipid metabolites, especially in the brains of patients with Alzheimer's and Parkinson's diseases. "We can go into very specific regions of the brain, extract some material, and look at the lipid concentration in that region of the brain," Figeys says. "What we've been observing is that there are some very significant changes in lipid composition in the human and mouse brain" as these diseases progress.

Biofx on board

The institute's emphasis on bioinformatics development drew native Texan David Bickel from a job in industry to OISB in 2007. He's working on developing methods to analyze gene expression and ¬genome-wide association data, with an eye toward protein and metabolomic expression data as well as integrated analysis. "My lab focuses on developing new methods for more reliable analyses of the data, so that the data can be more accurately interpreted," Bickel says. The challenge of looking at gene expression data is figuring out what to focus on, and his team is trying to address the level of expression. In GWAS, "the data analysis methods are lagging behind [those] for gene expression analysis," Bickel says, so he's applying his statistical methods to advancing these as well.

Bickel says that it's easy to form collaborative partnerships at OISB, and he is involved in two. One involves analyzing lipid expression data using statistical concepts from his gene expression analyses, while the other looks at gene expression ¬changes in muscle differentiation. He says that institute-organized retreats and symposia help him stay in touch with colleagues. "When I interviewed, I saw potential collaborations here that looked like they would be interesting, and the focus was on the data integration and that was something I wanted to continue doing," Bickel says.

He foresees the integration of different data types as being particularly important and hopes to soon focus on developing methods to analyze different data simultaneously. "Right now, work is mostly focused within each data type and once that's mastered, people will start moving toward working on methods for the integration and using [Bayesian] probability theory," Bickel says.

Ottawa Institute of Systems Biology

Ottawa, Ontario
Director: Daniel Figeys
Established: 2005
Facility: In August 2008, the OISB moved into a new, 23,000-square-foot building where the institute occupies one floor in one wing.
Staff: 14 core members and almost 25 associate members; a total of 100 people
Funding: OISB's startup funding included $11.3 million from the University of Ottawa's medical faculty and $7 million in grants.
Focus: The institute focuses on basic and translational research in diseases of the brain, technology development, and bioinformatics.
Core labs: OISB has shared facilities for ChIP-chip, gene expression, mass spectrometry, microscopy, X-ray crystallography, robotics, proteomics, and flow cytometry.