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Investigating Rare Diseases in Search of a Common Cure

By Thaddeus Schug
August 2010

John Gallin, M.D., director of the NIH Clinical Center
In one of his many accomplishments as director of the NIH Clinical Center Gallin pioneered development of the Undiagnosed Diseases Program, which is a trans-NIH initiative focusing on the most puzzling medical cases referred to the NIH Clinical Center in Bethesda, Md., by physicians across the nation. (Photo courtesy of Steve McCaw)

Darryl Zeldin, M.D., left, and John Gallin, M.D.
Zeldin, left, and Gallin hope to team together to share resources. "I hope that we can combine what is going on here at NIEHS and what is going on in Bethesda to strengthen our overall clinical programs," Gallin told the audience. (Photo courtesy of Steve McCaw)

Hong Li, Ph.D., (left) and Kevin Gerrish, Ph.D.
Research Fellow Hong Li, Ph.D., (left) and Technical Laboratory Manager Kevin Gerrish, Ph.D., were among those in a near capacity audience for the Clinical Director's Seminar series held in Rodbell Auditorium. (Photo courtesy of Steve McCaw)

the NIH Clinical Center
According to Gallin, the NIH Clinical Center covers 35 acres on the 302-acre NIH campus in Bethesda. (Photo courtesy of Steve McCaw)

"NIEHS has undergone a remarkable transition with the development of its clinical program and it is very reassuring to see that you have clearly put it together right," stated John Gallin, M.D. ( Exit NIEHS, director of the NIH Clinical Center since 1994. Gallin visited NIEHS July 15, to tour the new NIEHS Clinical Research Unit and deliver a presentation as part of the Clinical Director's Seminar Series, hosted by NIEHS Acting Clinical Director Darryl Zeldin, M.D.

Gallin, a prominent clinician and researcher of rare diseases, spoke on "The Pipeline of Clinical Research: Spotlight on Rare Diseases." His seminar offered attendees an overview of the clinical program in Bethesda and new insight into the larger public health potential of research into diseases that affect a very small portion of the population.

As Gallin explained, the Clinical Center serves the needs of 17 NIH institutes and is the largest clinical research hospital in the world. Gallin oversaw the design and construction of a new research hospital for the Clinical Center, the Mark O. Hatfield Clinical Research Center, which opened its doors in 2005. He also literally wrote the book and curriculum for clinical research training at NIH, "Principles and Practice of Clinical Research." ( Exit NIEHSSince its inception in 1996, the NIH Clinical Training Program has trained over 19,000 clinical fellows and research investigators.

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Opening the Pipeline for Drug Development

The NIH Clinical Center currently hosts approximately 1,500 clinical research studies, about half of which are clinical trials in phase I or phase II of development. Much of the Clinical Center's work focuses on rare diseases that the medical industry considers too risky for drug development.

According to Gallin, as few as 1 in 200,000 patients in the United States may have rare or undiscovered illnesses - but they account for about half of NIH's patients. A central focus of the center is to investigate the possibility that new or existing drugs and protocols that are effective in treating patients with rare diseases could also be used to combat more common illnesses.

NIH has upgraded its drug development and manufacturing facility to "help move ideas from the laboratory bench to the patient faster and more effectively," said Gallin.  "Our hope would be that we could pass the baton on to industry after we get over that so-called valley of death - the gap between when the basic research is finished and when industry sees enough potential in a drug candidate to warrant starting a development program," he added.

Researching a Rare Immune Disorder

Gallin's primary research interest is a rare hereditary immune disorder called chronic granulomatous disease (CGD). Patients with this disease have mutations in oxidase enzymes (NOX) contained in cells of the immune system.  These defects make it difficult to create reactive oxygen compounds that phagocytes use to kill ingested pathogens. This defect leads to the formation of granulomata in many organs. Gallin's laboratory discovered the genetic basis for several forms of CGD and conducted pioneering research that has reduced life-threatening bacterial and fungal infections in CGD patients.

According to Gallin, CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year. Most people with CGD are diagnosed in childhood, usually before age 5. Early diagnosis is important since these people can be placed on antibiotics to ward off infections before they occur.

Gallin's discoveries of the defective genes within CGD patients has led to identification of several NOX isoforms in more common diseases. "It turns out that NOX proteins are found in many tissues of the body, and they are aligned with many inflammatory disease states, such as atherosclerosis, ischemia, and heart disease," he explained. These findings support Gallin's vision of investigating rare diseases in search of a common cure.

(Thaddeus Schug, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction and a regular contributor to the Environmental Factor.)

Rare Disease Research Leads to Big Discovery

As young clinical fellows at NIH from 1968 to 1970, Michael Brown, M.D., and Joseph Goldstein, M.D., were fascinated by patients displaying a hereditary condition that caused excessive levels of cholesterol to build up in their blood. The disease produced severe atherosclerosis, leading to heart attacks in early childhood. The condition is very rare - affecting one in a million people - so the chance that they would see cases like this in any other clinical setting was extremely small.

Brown and Goldstein decided to build a research program with a mission to determine how genes control cholesterol levels in the blood, and why some people have almost no cholesterol and others have dangerously high levels. Brown later said, "If we hadn't seen those patients at NIH, we would have never known about this illness and we would never have worked on the problem."

In their later collaborations on the studies of familial hypercholesterolemia at the University of Texas Southwestern Medical School, they made use of serum samples gathered many years earlier at NIH. In 1985 Brown and Goldstein won the Lasker Award and the Nobel Prize ( Exit NIEHS for their discovery of mechanisms regulating cholesterol metabolism, laying the foundation for interventions to control cholesterol levels and help prevent the onset of cardiovascular disease for millions of patients.

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