Experts See New Ways to Solve Lupus Puzzle: Systems Biology

There’s a whole new way of looking at human lupus, and it’s not through the standard-issue laboratory microscope.

It’s through the lens of exciting new technologies that enable scientists to probe vast sets of data and generate comprehensive models more akin to what actually happens in the lupus immune system than was ever possible to illustrate before.

The four experts who told researchers and families about these new “systems biology” approaches at the LRI scientific conference last week had their audience riveted. William E. Paul, MD, chief of the Laboratory of Immunology at NIAID-NIH, and chair of the LRI’s Scientific Advisory Board, introduced the theme at the annual LRI meeting:

“Systems biology recognizes that individual humans and experimental animals are comprised of a complex set of interacting elements, and that to truly understand the biology of a whole organism in health and disease, we need to understand the how these individual elements interact in a quantitative way.”

By appreciating the body’s dynamic and massive interacting web of connections, systems biology not only produces far more realistic pictures of what happens in human lupus—it opens up a whole new spectrum of possibilities for stopping the damage.

Ronald N. Germain, MD, PhD (pictured above, R), head of the Lymphocyte Biology Section in the Laboratory of Immunology and director of the new program in Systems Immunology and Infectious Disease Modeling at NIH-NIAID, explained how the recent explosion in the power of imaging technology could be harnessed to show “real time” moving pictures of the immune system in its normal state as well as in models of lupus and other diseases.

He also showed how scientists can combine this new experimental insight with advances in computer simulation to eventually develop an ability to predict immune behavior.

Until recently, the best that scientists had to describe interactions in the immune system were static images (snapshots in time) or cartoons-those diagrams of action and reaction that many of us remember from biology textbooks. They also lacked quantitative mathematical models of how biological systems carried out their functions.

“The older technologies gave us knowledge, but not understanding,” he explained. “They didn't provide us the power to predict what would happen in a dynamic immune system that includes time and space and quantity.”

The latest imaging and computational technologies put scientists in the driver’s seat, with an early stage capacity to simulate the behavior of biological systems of substantial complexity and actually make predictions about what happens in the immune system-from what goes wrong to response to therapies and more.

David Botstein, MD, director of Leis-Sigler Institute for Integrative Genomics at Princeton University, sees a day coming soon in which the information from the sequencing of the entire human genome produces answers on which genes are actually involved in diseases such as lupus.

Think of our genetic map as a railroad system, directed the renowned geneticist and pioneer of the Human Genome Project. For years we have been looking at it on such a basic level—at how a locomotive moves along the track and how it starts and how it stops. But now “we can get into control room down underneath…where you can see the connections about which trains go where.”

Forest M. White, PhD, associate professor at the Massachusetts Institute of Technology and a biological engineer, is busy using new technologies to nudge the static model we currently have of the human cell and it circuitry to a more realistic one with dynamic, fluid wiring.

By figuring out how information flows through human cells, his laboratory aims to discover “what cells really care about.” The answers to this question will have implications for all kinds of illnesses, including lupus, in which cells end up making “bad choices.”

Virginia Pascual, MD, (pictured above) a pediatric rheumatologist and associate investigator at the Baylor Institute for Immunology Research, graphically described the application of one of these systems approaches to human lupus and showed the great insights that could be achieved. One example: description of the so-called “interferon signature” with, in some cases, as little as 1 milliliter of blood.

“Provocative and inspiring,” concluded moderator David S. Pisetsky, MD, PhD, of Duke University Medical Center and an LRI Novel Research Task Force co-chair—a sentiment echoed by dozens of LRI researchers.