October 1, 2006 (Vol. 26, No. 17)

The Institute for Systems Biology Takes Advantage of a Cross-disciplinary Approach

For the last half century, biological researchers have looked at one gene and its related protein in isolation from others. Although the take-home message from this approach is that biology and medicine are complex, “we still don’t understand deep principles,” says Leroy Hood, M.D., Ph.D., president and co-founder of the nonprofit Institute for Systems Biology (ISB; www.systemsbiology.com) in Seattle.

Dr. Hood defines systems biology as the science of discovering, modeling, understanding, and ultimately engineering at the molecular level the dynamic relationships among biological molecules that define living organisms. A “system” can be any particular aspect of an organism’s behavior that a researcher wants to consider as interrelated. Whatever the chosen system, researchers define its fundamental elements and the interrelated biological networks and their dynamics. Not only do they look at the networks directly that encode the particular system of interest, but they also see how all the networks interact. “Through an integration of these factors, we come to understand the system’s properties,” Dr. Hood explains.

Fourteen years ago Dr. Hood headed the department of molecular biotechnology at the University of Washington, funded by Bill Gates. That endeavor, the first cross-disciplinary department in the world, integrated physical, biological, and computational scientists in the field of interdisciplinary biology.

“We learned each other’s language and created the fundamental framework used at ISB,” says Dr. Hood. Now ISB uses this cross-disciplinary environment to focus on selected biological and medical problems. Designed along academic lines, ISB develops new technologies and computational tools to promote systems biology, trains young scientists, and spins off intellectual property and startup companies.

Several scientific themes are emphasized at ISB. One focuses on microorganisms, such as yeast and halobacterium, as model organisms to drive the development of new quantitative technologies. “We’re putting the major effort into microfluidics and nanotechnology devices for making in vitro measurements,” says Dr. Hood.

The microbial experiments also help to drive the development of computational tools for analyzing large amounts of data. “We’re pushing the frontiers of computational and mathematical techniques,” Dr. Hood adds. Innate immunity, such as the responses of toll-like receptors to foreign microbes, form another research focus at ISB. Yet another focus is the application of systems biology to medicine and human diseases, particularly prostate cancer and prion diseases.

The project with halobacterium illustrates how a systems biology approach unlocks biological mysteries. Just seven years ago, little was known about halobacterium, a microbe that gives the Great Salt Lake and Dead Sea their yellow-orange color. ISB scientists sequenced the entire genome of halobacterium, then generated detailed information sets about its genomics, proteomics, and biological circuitry.

Halobacterium thrives in high salt concentrations, withstands high levels of radioactivity, and efficiently converts sunlight into energy. The microbe is ideally suited to be genetically engineered to solve bioremediation problems or create biologically energetic compounds.


The completion of the Human Genome Project gave a deeper understanding of the molecular basis of disease and medicine. However, in order for personalized medicine to live up to its promise, tools must be created to sequence billions of strands of DNA simultaneously. In collaboration with Helicos Biosciences (www.helicosbio.com), ISB researchers are working to apply techniques to speed the sequencing of single-stranded DNA and make it less expensive.

A high-throughput, single molecule sequencer developed at Helicos analyzes DNA or RNA without amplification. ISB is applying this single molecule sequencing technology to study gene expression in prostate cancer. “In eight to ten years we may be doing this for personalized medicine,” Dr. Hood projects.

ISB researchers are also looking at ways to precisely quantitate thousands of proteins in a droplet of blood or body fluids to obtain molecular fingerprints of individuals so that physicians will be able to prescribe drugs tailored to an individual’s genetic makeup. This requires the integration of microfluidics and nanotechnology platforms to make in vivo imaging probes to interrogate key information nodes in biological networks.

“We want to visualize disease at the molecular level,” Dr. Hood says. To advance this work, a group called the Nanosystems Biological Alliance was set up that unites scientists at ISB, the University of California Los Angeles, Stanford University, and the California Institute of Technology.

A partnership with GenoLogics Life Sciences Software (www.genologics.com) allows ISB’s Trans Proteomic Pipeline (TPP) to be launched on GenoLogics’ ProteusLIMS platform. TPP is a set of free, open-source programs that run in a series to form a pipeline. The integration of TPP and ProteusLIMS supports the automatic statistical validation of protein search results and calculated quantitation information.

Ruedi Aebersold, a co-founder of ISB, pioneered the development of TPP and other leading-edge computational proteomic tools. The collaboration with GenoLogics “makes all this software available to the world in a user-friendly format,” says Dr. Hood.

Future Trends

Systems biology will change the way that biotechnology and pharmaceutical companies think about research, predicts Dr. Hood, and transform healthcare in the next 10 to 15 years. A systems approach lends itself to pioneering new diagnostics, inventing new strategies for identifying drug targets, and assessing adverse reactions of potential new drugs. Through a systems biology approach, drug companies may even be able to design drugs to prevent, rather than just treat, illnesses.

Nonetheless, systems biology remains an “enormously immature field,” says Dr. Hood. Among the challenges facing systems biology researchers is the need for better tools to gather and analyze global data sets. Informational molecules, such as proteins, RNA, and DNA, must be monitored dynamically as they change over time during development or physiological responses. Computational tools must integrate all this data.

“The techniques we use today for analyzing three or four proteins are totally inadequate,” says Dr. Hood. New types of mathematics are required to process the billions of units of information coming from the genomics and proteomics techniques of the future.

This new scientific specialty also needs more trained scientists. “Not many people understand systems biology,” says Dr. Hood. Molecular biologists who look at three to ten genes may claim to be doing systems biology, “but it’s not the globally driven, integrative approach that lies at the heart of systems biology.”

Biology is undergoing a paradigm shift and moving toward a systems approach that will dominate biology in the 21st century. “The importance of pioneering and teaching this new field cannot be overstressed. That’s what ISB is all about,” Dr. Hood says.

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