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Revolutionizing Rheumatology Research through Genomics

Revolutionizing Rheumatology Research through Genomics

Hospital for Special Surgery

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Founded in 1863, just two months before the Battle of Gettysburg in a Second Avenue brownstone, New York City's Hospital for Special Surgery (HSS) is the oldest orthopedic hospital in the United States. Its first chief surgeon, James A. Knight, was a believer in "expectant treatment," which recommended clean air, exercise, and sunshine as the best medicine. Although medical techniques have changed with the advent of germ theory, antiseptic surgery, and the advances of 20th century orthopedic science, the hospital that Knight founded remains just as committed to improving the lives of its patients as it was 150 years ago.

HSS is today known as one of the preeminent musculoskeletal hospitals in the world, ranked first in orthopedics and fourth in rheumatology in U.S. News & World Report "Best Hospitals" 2013-14. To continue making strides in the treatment of rheumatoid arthritis (RA) and lupus, this year the hospital has established the David Z. Rosensweig Genomics Research Center, endowed by a $5.6 million grant from The Tow Foundation.

"At HSS, all laboratory research is conducted with the goal of improving outcomes for patients," says Chief Scientific Officer Steven R. Goldring, Richard L. Menschel Research Chair. "This is the mission of the new Genomics Center as well."

Although genomics research has implications for many fields of medical research, its effect on autoimmune diseases such as RA and systemic lupus erythematosus has the potential to be truly groundbreaking. There are certain cytokines—tumor necrosis factor and interleukin 6, for instance—which are associated with RA. Better understanding that relationship has already led to dramatic improvement in the treatment of RA. The goal of the Center is to apply the new and powerful technologies of genomics research to identify more effective therapies for the treatment of RA, lupus, and the related disabling rheumatic diseases. Lionel B. Ivashkiv, director of the Genomics Center and David H. Koch Chair in Arthritis and Tissue Degeneration Research, has been with HSS for 21 years, and has seen remarkable advances in rheumatology research that have led to the development of "cutting edge, state-of-the-art molecular-based therapies."

"When I was a resident and decided to go into rheumatology," he said in an interview in April, "people looked at me and said, ‘Why do you want to do that? They don't understand anything and they can't even help their patients.' And I thought it was an opportunity to have an impact. Fifteen years later, there has been a quantum leap in both the understanding of the disease mechanisms and importantly in the development and application of new and effective therapies."

"The big surprise is that [so-called ‘junk DNA'] is really linked to diseases."

Few of these new therapies have been as potentially revolutionary as the advances offered by genomic research. Epigenetic and genomic studies have shown that the genetic risk for autoimmune diseases like RA comes from an unlikely source: genetic sequences formerly known as "junk DNA." The existence of these sequences has been known for decades, but because they do not code for proteins they were assumed to be non-functioning. "It turns out that what they do is regulate how genes are expressed, and they also mediate the response to environmental cues," says Ivashkiv. "And the big surprise is that they are linked to diseases. So that the state-of-the-art understanding is that genetic susceptibility to diseases, including autoimmune diseases, is linked more to these regulatory regions… rather than to the traditional genes themselves."

Scientists in Ivashkiv's lab have discovered new mechanisms that regulate autoimmune-associated genes and identified new genes that encode "non­coding RNAs," which he hopes to use to develop very specific therapies designed to treat the inflammation that makes life with RA so difficult. Today, patients are prescribed drugs on a trial-and-error basis, testing one after the other in a painful, and often expensive, process. Ivashkiv predicts that in the next decade, improved therapies and so-called personalized medicine will eliminate that guesswork.

"We'd like to be able to select the best drug right from the get-go," he says.

The David Z. Rosensweig Genomics Center at HSS was first proposed because of the sheer complexity of genomic research, which by its very nature requires an interdisciplinary approach. HSS is an associate founding member of the New York Genome Center (NYGC), where it will share research and resources with other local institutions. Partnership with the NYGC and the Advanced Bioinformatics Core at Weill Cornell Medical College will enable genomics research at HSS.

For all those institutions involved in the NYGC, personalized medicine is one of the chief goals. If the NYGC, with significant contributions from the new HSS Genomics Center, can help make personalized medical treatment routine, it could have life-changing effects, not just for sufferers of RA and lupus, but for sick people everywhere.

"That is a very complex undertaking," says Ivashkiv, "but we think that would also have a very big impact on improving patients' lives."

Photo: HSS Chief Scientific Officer Steven R. Goldring, Richard L. Menschel Research Chair, performs an experiment in his lab.