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The Future of Complex Disease


Nestled between a world-renowned department of biology and an equally established university hospital, the Institute for Genomics and Systems Biology at the University of Chicago has the best of both worlds. A collaboration between the university and Argonne National Laboratory, the DOE's premier supercomputing hotspot some 40 miles west of Chicago, the institute is poised to lead the way for translational science and metagenomics research.

"The Institute for Genomics and Systems Biology basically started out with the challenge in mind of translating the vast amount of data that's being produced on genome structure and genome variation into more practical understanding of complex biological processes, especially things having to do with human disease," says director Kevin White, who first had the idea of starting a large-scale collaborative effort of this sort while at Yale.

Armed with a $1 million grant from the Chicago Biomedical Consortium, one of the first things White did was set up a large-scale cellular screening center at the University of Chicago. He then formed collaborations with other local schools, including Northwestern University and the University of Illinois in Chicago. While the number of fellows at the IGSB now totals 70, they're not solely restricted to University of Chicago faculty, and White plans to hire six more faculty members during the next several years. Next year, the group will move into the newly built Gwen and Jules Knapp Center for Biomedical Discovery, a 330,760-square-foot research space that will house departments of medicine and pediatrics, as well as the Ludwig Center for Metastasis Research.

White says the main factors that mattered when making the decision to set up shop in Chicago included "the history of collaborative research at the University of Chicago, combined with the world-class clinical and basic science research, [and the] structure of having both under one divisional leader, one dean." He adds, "It's a small enough school that you can actually know a large proportion of the scientists … and interact with them, and big enough that it's still a world-class research institution."

Translation in mind

Recently, White, who runs a lab consisting of 80 percent experimental and 20 percent computational work, published research in which his team used genome-scale assays and data to build network models of breast cancer. From these, they discovered a histone variant that is associated with disease progression. With the help of medicinal chemists working at the University of Illinois, White and his team identified several candidate compounds that inhibit cancer cells. "Our view of genomics and systems biology is to go from having global pictures of the state of the genome to having pictures of the molecular networks that act in the cells, to making predictions about which parts of those networks are actually important for complex diseases," White says. "And so, for us, that's the future of understanding complex diseases."

Going from basic research to clinical application is the goal, says White. Because it's often difficult to get people talking outside their specific domain, the physical integration of researchers with doctors "allows us to expose physician-scientists to new basic discoveries and expose the basic research scientists to the important clinical problems that doctors wish they had the answers to," he says.

In addition, White has established joint seminar series and various workshops that help bridge the divide. Sharing common resources, he believes, is especially important to getting scientists and clinicians working together.

Research director Imogen Hurley manages the cellular screening core and the high-throughput genome analysis core at Argonne. She sees the close proximity to the hospital as a driving factor in making the institute a standout translational research center. "The medical center, the clinical scientists, the basic scientists, we're all within a few blocks, and it shouldn't make a difference, but it does," she says.

The CSC, as it's called, can screen more than 250,000 reactions per day, perform RNAi screening of the entire genome three times a day, and screen hundreds of thousands of chemical compounds. The facility is fully operational at all hours, every day, and even has remote monitoring capabilities. "If an error occurs during the middle of the night the robot will actually contact [the researchers]," Hurley says. By going online, they can see what's happening via installed cameras, and "if it's just that a plate's slightly in the wrong position, then they can make adjustments remotely."

Over at Argonne, the high-throughput genome analysis core takes advantage of existing computing infrastructure, including one of the largest civilian supercomputers in the world. The center has two Illumina Genome Analyzers and one 454 sequencer. The core also has the capacity to scan up to 800 microarrays per week.

Hurley says the leadership chose to set up the genome analysis core at Argonne not only because of the existing computational power, but also because of the computer science expertise there. One example of this is the metagenomics pipeline, and "this is one of the strengths of the partnership between the U of C and Argonne," she says.

Metagenomics in gear

One of the main thrusts at Argonne right now is the push for metagenomics — sequencing and annotating large numbers of genomes within a community, such as water, soil, or the human gut. At this point, Argonne is helping lead the field, having recently published a method that automates the processing and annotation of complete, or nearly complete, archaeal and bacterial genomes. To date, the RAST (for Rapid Annotations using Subsystems Technology) server has been used to annotate more than 1,800 genomes since the beta version was launched in February 2007. In addition, a user is presented with an initial metabolic reconstruction; this is especially useful to clinicians hoping to gain insight into protein function in a metagenome.

"Metagenomics is well beyond where genomics ever has been," in terms of computational analyses, says Folker Meyer, a computational biologist who is the associate director of IGSB at Argonne. Even with Argonne's supercomputing heft, "we have to reinvent everything," he says, including most analysis algorithms.

In trying to push scientists to change the way they do biological research, Argonne encourages IGSB scientists to use metagenomics data more routinely, and to link metagenomics with protein structure and function. One way they've gotten scientists to warm up to all this data is by having a series of regular workshops and working in close collaboration with the researchers who submit a sample to be sequenced and annotated. Through interactions with core personnel, scientists get more hands-on training and feedback, which in turn helps them shift gears. "It's a very involved thing. It's not like the detached model that we have when we're doing bioinformatics," Meyer says. And getting biologists comfortable with using high-throughput genomics is not necessarily easy. "It requires a lot of changes in your attitude toward data, data availability, all these things that are new to biologists."

Institute for Genomics and Systems Biology

Chicago, Ill.
Director: Kevin White
Host: University of Chicago
Began: Established in 2006
Staff: 70 faculty fellows, with plans for more in the coming years
Funding: $40 million from the University of Chicago
Research themes: Translational research, especially for common cancers; metagenomics
Core facilities: Two core facilities: the cellular screening center at the University of Chicago, which runs high-throughput cell-based assays, RNAi screens, and small molecule screens; and the high-throughput genome analysis core at Argonne National Laboratory, which runs next-gen sequencing and metagenomic analysis
Expansion plans: Will move into 330,760-square-foot Knapp Center for Biomedical Discovery in 2009