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An Integrated Approach
CHORI at the Forefront of Sickle Cell Disease and Thalassemia Research

"Our mission here is really to have patient outcome related research, to focus on re-search that directly relates to the best approaches to disease prob-lems. It's a special vision of Children's, to integrate clinical and basic scientists in a common goal."

The cutting edge research conducted through CHORI’s Center for Sickle Cell Disease and Thalassemia has been highlighted recently in Current Molecular Medicine (Curr Mol Med) and the New England Journal of Medicine (NEJM). The December issue of Curr Mol Biol, edited by Elliot Vichinsky, MD, CHORI scientist and chief of the division of Hematology/ Oncology at CHRCO, along with Griffin P. Rogers, the deputy director of the National Institute of Diabetes and Digestive and Kidney Diseases, is a pointed review of the current state of sickle cell disease and thalassemia research.

“The review focuses on the major pathophysiological discoveries in the area of sickle cell disease and thalassemia. There has been an explosion of new data in this area, looking not just at biologic changes, but at global biologic mechanisms, genetic modifiers and the impact of oxidative damage on nitric oxide regulation,” says Dr. Vichinsky of the issue, which he was invited to edit as a result of his more than 20 year commitment to the best in translational research in the field of sickle cell disease and thalassemia.

The Curr Mol Med issue not only features Dr. Vichinsky as editor, but many CHORI scientists as well, all of whom are at the forefront of this research field. CHORI's Frans Kuypers, PhD, Claudia Morris, MD, Sylvia T. Singer, MD, and Mark Walters, MD all provide the latest insight into sickle cell and thalassemia research, covering topics ranging from nitric oxide and arginine dysregulation to advances in bone marrow transplant for hemoglobinopathies.

"CHORI is so highly represented in this issue because we have a unique program that actual integrates very basic research with clinical and translational research," says Dr. Vichinsky. "There aren't many programs that take such an integrated approach to the disease."

In fact, most research programs that investigate hemoglobinopathies have strength either in one basic subject area of a disease, or in the kind of research conducted on a disease, such as a focus only on the biological aspects or only on the clinical aspects. There is rarely the opportunity for an integrated research model around one disease.

"Children's has a very unique partnership between basic and clinical scientists that has enabled them to synergistically address different problems together," Dr. Vichinsky explains. "That's an unusual relationship. Our mission here is really to have patient outcome-related research, to focus on research that directly relates to the best approaches to disease problems. It's a special vision of Children's, to integrate clinical and basic scientists in a common goal."

That special vision and integration has resulted in decades of ground-breaking research, which the reviews in Curr Mol Biol showcase. But as the NEJM publication illustrates, that integration has also resulted in greater paradigmatic shifts in current researching thinking.
"The NEJM publication represents the integration of epidemiology, pathophysiology, and new therapeutic approaches, all working together to understand the biology of how hemolysis, or the breakdown of red blood cells, affects acute chest syndrome, the leading cause of premature death in sickle cell disease."
"It really pulls together a fundamentally new paradigm for the disease," says Dr. Vichinsky.

The old paradigm in which sickle cell disease has been understood is that sickle cells cause red blood cells to sickle, making the red blood cells sticky and rigid, mechanistically causing functional problems. The new paradigm, however, put forth by Dr. Vichinksy and his colleague Mark T. Gladwin, MD, in the NEJM article – and based on the innovative integration between basic and clinical researchers at CHORI – is much more complex, integrating a more biologic mechanism.

“The sickle cell mutation essentially creates a storm of biological changes that affect multiple physiologic mechanisms,” Dr. Vichinsky explains.

"Greater hemolysis and nitric oxide deficiencies that then cause enormous changes related to cell adhesion, thrombosis and organ function. The basic key is that nitric oxide deficiencies are the main mechanism of sickle cell disease, while all other aspects are secondary," says Dr. Vichinsky.
"It's a fundamental expansion of our understanding of the mutation's impact on the whole system," says Dr. Vichinsky.

With this fundamental expansion, CHORI has paved the way for a whole new avenue of sickle cell disease and thalassemia research. If these latest publications are any indication, CHORI will continue to lead the field with its outcome-oriented integration of basic and clinical research.

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