A Child's Life
Volume 25 Number 2
The symptoms first appear in infants or young children.
A bacterial infection takes its toll on a child; large doses of antibiotics are necessary to overcome the onslaught. Soon, another bacterial infection, or perhaps a fungal infection, appears. Intensive antibiotic treatment is repeated. Eventually, tests reveal the culprit: chronic granulomatous disease (CGD).
"CGD is an inherited disorder. A defect in an enzyme prevents white blood cells in the body from killing invading bacteria," explains Mary Dinauer, the Nora Letzter Professor of Pediatrics at the Indiana University School of Medicine.
In patients with the disease, neutrophilsphagocytic white blood cells that attack invadersmove normally to the site of a microbial (bacterial, protozoa, or fungi) invasion and do their immune system work by ingesting the microorganism. After ingestion, however, a malfunction occurs in the complex chemical reactions that ordinarily produce oxidizing agents needed to destroy the invader. In patients with the genetic defect, the enzyme that initiates the necessary oxidative burst simply fails to act.
With compromised immune systems, children with CGD endure recurring infections and antibiotic treatment, and the dreaded likelihood of a shorter life spanĊalthough thanks to modern medicine, most do reach adulthood.
"This disease is relatively uncommon," Dinauer notes. "It occurs in approximately one in 250,000 people. But studies of CGD patients have helped us to identify key subunits of the enzyme and what signals turn the enzyme on."
Building on that knowledge, Dinauer's research team has done gene targeting, breeding mice with a similar enzyme defect. That set the stage for experiments to cure the genetic defect.
"We've done gene therapy by using retrovirus, putting a normal version of the affected gene back into mouse bone marrow stem cells," Dinauer reports. The defect in host defense and inflammation has been corrected in the mice as a result of these maneuvers.
Dinauer, who is both research scientist and practicing physician, is now embarked on gene therapy for human CGD sufferers, putting a normal copy of the defective gene into their bone marrow stem cells. The hope is that the normal copy will replace the defective gene and cause white blood cells to produce the burst needed to kill invading pathogens.
"We have some very promising results in preclinical studies, and we've recently undertaken a very early (Phase 1) clinical trial with several adult subjects," she says.
An understanding of the oxidative burst mechanism in the enzyme involved in CGD may have a role beyond the treatment of CGD patients. Similar enzymes that produce oxidants have been discovered in blood vessels, the gut, and the kidney. These non-blood-cell enzymes may play a role in immunity, atherosclerosis, and signaling to cells in response to changes in the environment. "The potential to use our research on the white blood cell enzyme to cast light on other organ systems is exciting," Dinauer says.
Interested in hematology since her college days, Dinauer found early in her studies that she was attracted to both biomedical research and the practice of medicine. "I knew I enjoyed working with patients and their families," she recalls. That set of inclinations led her to enroll in a combined degree program at the University of Chicago, where she earned both a Ph.D. and an M.D. This combination places Dinauer at the forefront in current medical efforts to translate, as soon as possible, the findings of basic science research into clinical diagnosis and treatment of patients.
In addition to her research and clinical work, Dinauer has directed the Herman B Wells Center for Pediatric Research at the IU School of Medicine since the summer of 2000.
"Our main goal at the center is to provide a conducive environment for faculty to carry out state-of-the-art biomedical research that relates to childhood diseases," Dinauer explains. "We've fostered excellent research on genetic blood cell diseases and blood cell development at the center. And we have smaller but growing programs in the area of cancer biology and DNA repair; cardiac biology and development; and growth and metabolism."
The Wells Center is also developing a new program related to pediatric pulmonary disease, but research is not the center's only aim. "We're expanding our efforts to train the next generation of pediatric scientists," Dinauer says with pride. For example, the center supports Molecular Medicine in Action, a hands-on program for high school students to experience the methods Wells Center scientists use in unlocking the genetic code of diseases. It also sponsors a summer research program for college students, who intern or assist in various research laboratories at the School of Medicine.
Serving as researcher, medical doctor, and administrator, Dinauer finds time also to be an educator. She works with medical students and pediatric residents during the time she spends at the Riley Hospital for Children in the hematology/oncology ward. "I also have graduate students and post-doctoral researchers in my laboratory," she says, "so a lot of teaching is the hands-on variety, working alongside students. That's something I really enjoy."
Dinauer's own research on CGD is part of a much larger research scheme. She currently coordinates a multiproject grant related to gene therapy targeted at genetic blood diseases. Other blood-cell research teams in the Wells Center and elsewhere at the School of MedicineĊalong with the National Gene Vector Laboratory directed by Ken Cornetta, professor of genetics and microbiology/immunology at the School of MedicineĊare crucial to this collaborative effort.
Dinauer and her team are also part of a second multiproject grant, this one directed by Professor of Pediatrics David Skalnik. Faculty in pediatrics, medicine, and biology are working on the grant, which focuses on how cell-signaling molecules regulate the oxidative burst and other blood-cell functions.
"A key part of our work on this project involves studies with Simon Atkinson (IU associate professor of medicine) using the Indiana Center for Biological Microscopy," notes Dinauer. This center lends advanced imaging technology to the project, enabling research that would be impossible without such access.
Dinauer says staying abreast of the latest technology is a challenge in the medical field, but she's enthusiastic about IU's recent and exceedingly rapid progress in gene research and manipulation: "Current efforts to establish a group at IU School of Medicine in the area of genomics/proteomics and making these technologies accessible to other scientists is important to the medical research community."
She also expects great benefit from the increasingly powerful computer modeling of complex systems. "Between genomics and bioinformatics, in the future we may be able to identify variations in the function of the white-cell oxidase and related enzymes that will link to various inflammatory diseases," she says.
That prospect excites Dinauer the researcher, just as the potential of translating that knowledge into successful therapies for children encourages Dinauer the physician.
William Rozycki is a freelance writer in Bloomington, Ind.