The inflammatory system doesn’t get as much press as its close collaborator, the immune system. But our bodies’ inflammatory response to tissue injury, bleeding, and infection is critical to our survival.
Scientists have known the basics of how this process works for decades. Plasma proteins near the affected area set off a cascade of chemical reactions, signaling the DNA in cells that there is tissue damage or infection nearby. Proteins bind to the DNA, turning on particular genes that trigger the inflammatory response. Enzymes and other proteins then rush to the damaged area. They clot blood to stop bleeding, heal damaged cells, or fight infection. But only in the past few years have scientists been able to study in great detail the specific molecular interactions that turn on certain genes to regulate the system.
Trevor Siggers, an Arts & Sciences assistant professor of biology, is at the forefront of this wave of discovery. He is part of a new breed of biologists using highly detailed data—combined with a big-picture, systems biology approach—to peer into the intricacies of how the inflammatory system and many other living systems work. With a two-year grant from the National Institutes of Health (NIH), he studies the interaction between two proteins, NF-kB and HMGA1, which bind to each other to turn on genes that are critical in guiding the inflammatory response.
Well-functioning inflammatory systems support good health, but when they become overactive, they can cause inflammatory diseases such as arthritis and lupus. Drugs now used to treat these diseases generally turn off proteins connected with a wide range of inflammatory and immune system activities. Although these drugs have the desired effect of turning off the overactive inflammatory response, they also turn off the positive functions those proteins perform. Drugs for arthritis, for instance, tend to weaken the immune system, causing big problems for those suffering from the disease.
The goal of Siggers’s research is to discover which of the thousands of potential locations on the human genome the NF-kB and the HMGA1 proteins actually bind to. Armed with this information, drug developers would then be able to create medications that stop the proteins from turning on those genes. Drugs could be developed that would fight inflammatory diseases without the harmful side effects of current medications.
“What we’re doing provides targets [for drug makers],” says Siggers. “We’re coming closer to turning off individual genes. And we are providing systems-level analysis of the consequences of disrupting those protein complexes.”
By interfering at the level of individual gene expression, drug developers using Siggers’s data would take a more fine-tuned approach. NF-kB binds with a variety of cofactors to regulate different genes. By intervening to stop NF-kB from binding with just HMGA1, but not stopping its interactions with other cofactors, drug makers would be shutting down just those functions of NF-kB that are relevant to the disease they are trying to fight. That would mean fewer negative side effects for patients.
A protein-binding microarray is used to find which of the thousands of locations on the human genome particular proteins bind to. When these locations are pinpointed, they can be targeted by improved drugs to treat inflammatory diseases, such as arthritis and lupus.
To identify where these two proteins are binding to the DNA, Siggers and his lab team use an impressive new instrument in the biologist’s toolbox: a protein-binding microarray. The microarray resembles the thin glass slides you may have used to observe specimens under a microscope in high school biology class. The difference is that the array’s glass slide contains 100,000 tiny dots, each with a specific gene sequence infused with Siggers’s protein cofactors. By running a laser across the slide, Siggers can use a computer to look at all of the reactions and see which DNA locations glow brighter, an indication that the proteins are turning on that gene. Once he identifies these locations, he tests his results on live cells in a petri dish.
Siggers is one of only a few biologists using this specific type of microarray to study the inflammatory system. He hopes other biologists will adopt his methods so as to unlock the secrets of other immune and inflammatory system responses.
“The techniques that we pioneer hopefully will pave the way for these same sort of studies in other parts of the network,” he says. “If this approach is as fruitful as we expect, it’s a way for everyone to make connections from protein molecules to gene regulatory networks and, ultimately, to disease.”