Exploring a novel approach to understanding a common autoimmune disease

6/4/2012

Frederic Chedin was the victim of some cruel news on April 1.

“An email from the Hartwell Foundation came, and unfortunately you weren’t funded,” his wife told him over the phone.

The associate professor in the Department of Molecular and Cellular Biology, who had taken his two daughters on a bike ride to stop himself from clicking “get mail” every two minutes, says his heart fell.

“April Fool’s!” she exclaimed.

And with that, Chedin learned that he was among 12 scientists selected to receive Individual Biomedical Research Awards from The Hartwell Foundation, which grants awards to individuals for innovative and cutting-edge biomedical applied research that potentially benefits children. The awards provide $100,000 of direct support each per year for three years.

Chedin will use the funds to explore a novel approach to understanding a common autoimmune disease, Systemic Lupus Erythematosus, in which the body's immune system attacks itself including making antibodies against DNA.

“I hope to get a firm handle on the molecular events that trigger an autoimmune reaction in AGS and, by extension, in lupus,” Chedin says. “It is this kind of basic science discovery that will provide the fuel for developing diagnostic tests and, hopefully, therapies.”

Chedin says that, despite the fact that lupus affects millions of people, very few drugs are currently available for combating it.

“Last year was the first time in 56 years that the FDA approved a new drug for Lupus treatment!” he says. “I hope that our work will start reversing this trend and contribute to helping patients who cope with these diseases.”

His study will focus on epigenetic changes in our genes that may trigger autoimmune disease.

At any time, most of our DNA is "silenced," or switched off by a chemical modification, except at a few specific sites called CG islands, which serve as epigenetic “on” switches for our genes. This is advantageous for several reasons including the fact that it helps to silence vast portions of “junk” DNA sequences, which can act like retroviruses when active.

Chedin's lab has been studying how these CG islands are protected from silencing in some people. He thinks that too little suppression might reawaken normally silent regions of DNA and trigger SLE.

“Junk DNA sequences resemble retroviruses and could greatly harm us if they were able to express themselves,” Chedin says. “One idea behind autoimmunity is that a deficit of silencing enables retroelements to reawaken and that this, in turn, triggers a response by our immune system.”

He will test his hypothesis by focusing on Aicardi-Goutières syndrome, a severe autoimmune disorder and mimic of early onset SLE that affects infants and in most cases leads to premature death by age 10-15.

Chedin says that he chose AGS as his study subject because it is both genetically well defined—thereby lending itself to study—and acts on the body in the same way as lupus.

“Both Lupus and AGS trigger a strong Interferon alpha response which is a molecular hallmark of a particular type of autoimmune reaction. Both are systemic disorders in that they affect multiple organs in the body,” he says. “However, AGS is a childhood disorder in that it is diagnosed at birth. In that, it is closest to early-onset lupus.”

Understanding the biological mechanisms that underlie AGS will generate critical insights into how the innate immune system can be triggered and eventually, if successful, to the development of new diagnostic tests and therapies for children affected with early onset SLE and related autoimmune diseases.

College of Biological Sciences Dean James Hildreth praised Chedin’s previous research establishing the connection between gene silencing and autoimmunity. "Fred's genetics discovery is a tremendous advancement, not just for lupus research, but also for AIDS, cancer and other diseases.”

To obtain lab samples of the genes that lead to this incredibly rare disease, Chedin is collaborating with one of the world’s foremost experts on AGS, Dr. Yanick Crow from the University of Manchester in Britain.

“Through the last 10 years, Dr. Crow has identified all the AGS genes using samples collected from numerous families,” Chedin says. “We are currently culturing cells from AGS patients obtained from him and testing the hypothesis that these cells show a deficit of epigenetic silencing leading to a reactivation of junk retroelements.”

His team is also working with Dr. Eric Gershwin, UC Davis’ chief of the Division of Clinical Immunology and a renowned expert on autoimmune disorders. They are collaborating on the study’s implications for Lupus.

Chedin says the $100,000 annual award will fund a postdoctoral fellow position and enable him to purchase new genomics technologies.

“These methodologies are critical in obtaining a bird's eye view of what is happening throughout the entire human genome and not just a few genes,” Chedin says. “Our understanding of autoimmunity has been hampered by a lack of such genome-wide studies. While developing such approaches is still costly, I am optimistic that it will enable us to see the entire iceberg and not just its tip.”