Two major grants support creation of Chicago Center for Systems Biology

The National Institute of General Medical Sciences (NIGMS), part of the National Institutes of Health, has awarded more than $15 million over five years to the University of Chicago to support a new research center--The Chicago Center for Systems Biology--to study how networks of genes work together to enable cells and organisms to respond to environmental and genetic change.

The Chicago Center for Systems Biology (CCSB) also represents a collaboration among researchers at Chicago-area universities fostered by the Chicago Biomedical Consortium (CBC), with support from The Searle Funds at The Chicago Community Trust. The CBC will provide an additional $3 million over three years to the new initiative.

One of 10 National Centers for Systems Biology and the only such center in Illinois, the CCSB will combine experimental and computational tools to study the dynamic behavior of gene networks in cells, tissues, and organisms.

Systems biology, an emerging field, is distinguished by its focus on connections between multiple levels of biological organization--from networks of molecules to whole organisms. It is a discipline, according to the NIGMS, "at the intersection of biology, mathematics, engineering, and the physical sciences."

By integrating mountains of data from multiple levels in an environmental and evolutionary context, systems biology has the potential to explain "the behavior of the system as a whole." It will help scientists understand and treat human diseases by uncovering "how genes, cells and tissues respond to natural and artificial stimuli."

This is a significant change in how biomedical research is performed. For most of the last 50 years, biologists concentrated on isolated genes and proteins. But the rapid accumulation of vast amounts of data, such as the genomes of many different organisms, is enabling scientists to study a far more complicated problem: How do multiple genes or proteins--dozens or even hundreds at once--work together as networks to regulate the basic processes of life?

To answer that question, the Chicago Center for Systems Biology will concentrate on transcriptional networks, clusters of the master genes that regulate the activity of other genes by directly turning them on or off.

"Our goal is to understand the principles that transcriptional regulatory networks share as they respond to different types of environmental and genetic variation," said Center director Kevin White, PhD, the James and Karen Frank Family Professor in the Departments of Human Genetics and of Ecology & Evolution, and Director of the Institute for Genomics & Systems Biology.

"To do that," he said, "we have brought together from around the city more than a dozen experts in genomics, developmental biology, evolutionary biology, stress and physiology, chemistry and physics, with several computational specialists who focus on network modeling, and high-performance computing."

The researchers will use increasingly complex biological models to study five core topics, beginning with studies of how a single bacterial cell turns on or off various genes in response to an environmental stress. They will also use model organisms such as yeast, worms and fruit flies to identify ancient stress-response circuits and to learn how these have evolved differently in each system.

Two more research topics involving fruit flies will look at the genetic networks that maintain both stability and flexibility for repeating anatomical patterns during development, and how gene transcription guides the decisions each cell must make as it chooses to become one of two cell types within a fly's eye.

The fifth topic will turn to mammals, such as mice, to understand the complex sets of chemical and genetic signals that guide stem cells in the bone marrow as they mature to become many different kinds of blood cells.

"Systems biology is a very exciting, young field that's bringing both old and new approaches from engineering, physics, and mathematics to the fore of understanding biology," said NIGMS's Peter Lyster, PhD, who oversees this center grant. "The White center, which focuses on a very important, discrete step of gene expression, will make great strides in uniting systems biologists across the Chicago area and revealing the organizing principles behind transcriptional properties that persist across multiple organisms and cell types."

The Chicago team was well positioned to compete for this prestigious research award. It has nationally recognized programs in evolutionary biology and genetics, a reputation for collaborative research, and the ability to combine theoretical and computational studies with laboratory investigation.

White, a pioneer in the study of gene regulation during development and evolution, came to Chicago from Yale in 2006. One of the first scientists to design genome-scale experiments and apply them to genetics and evolution, he quickly established the Institute for Genomic & Systems Biology (IGSB) at the University of Chicago and Argonne National Laboratory, which will take a leadership role in this project. White has worked with the CBC from the beginning of his time in Chicago, using a $1 million CBC Recruitment Resources Award to establish the Cellular Screening Center at IGSB.

In 2007, White also secured a $9.1 million grant from the NIH's Human Genome Research Institute to identify regulatory elements--the DNA sequences that control when and where specific genes get turned on or off--in the fruit fly genome. More recently, his team has extended this research into human cells.

The additional $3 million, the Lever Award, from the Chicago Biomedical Consortium will enable key initiatives to be developed for the benefit of not only the Center for Systems Biology but also the larger Chicago research community, including the establishment of imaging, transgenic and computational facilities.

The CBC is a partnership involving the University of Illinois at Chicago, Northwestern University, and the University of Chicago. Its mission is to stimulate collaboration among scientists at the three universities. In keeping with this mission, the CBC helped bring together the multi-institutional team of scientists who will collaborate in the Chicago Center for Systems Biology.

CBC funding will also support training the next generation of young scientists in the art of interdisciplinary research through the new Research Fellows Program in Systems Biology.

"The Chicago Center for Systems Biology provides a unique opportunity to promote interdisciplinary scientific investigation and education in Chicago," White said. "This is an ambitious project, but one with enormous potential. We propose to go beyond mapping genetic networks to develop testable computer models of the behavior of transcriptional regulatory networks during physiological stress, during cellular and organismal development, and during the evolution of species."

"These principles," he said, "are expected to reveal structure-function relationships in networks that lead to physiological and evolutionary robustness or, its complements, flexibility and change. The crux of this research is that once we understand how stability is maintained in the face of environmental or genetic change, we will then be in a position to intelligently manipulate the core cellular processes give cells their identity and that contribute to disease when they break down."