Early in Andrew Campbell’s career as a pediatrician, he developed an interest in caring for children with chronic illnesses. “Once I began the work, I also became focused on children who were experiencing health care disparities, which led to an interest in sickle cell anemia—a disease that’s been neglected in terms of research. Eventually, the work became a passion for me, so I now run a clinic for children with sickle cell,” says Campbell, an MD and director of the Pediatric Comprehensive Hemoglobinopathy Program at the University of Michigan.

This story is part of a series highlighting the research accomplishments of Robert Wood Johnson Foundation (RWJF) grantees from the Human Capital Portfolio.

Campbell, who is also a 2005-2009 Robert Wood Johnson Foundation (RWJF) Harold Amos Medical Faculty Development Program Scholar, is a member of a small, elite group of researchers across the country who are investigating new ways to treat—or cure—sickle cell anemia, a disease that affects approximately 100,000 Americans. One out of every 500 African American babies will be born with the disease and the life expectancy for a sickle cell patient is less than 50 years.

“The current treatment for sickle cell is Hydroxyurea, a chemotherapy drug that stimulates fetal hemoglobin,” Campbell says. “While it works well and has been shown to decrease complications and improve the survival rates of sickle cell patients, it’s not well-tolerated by every patient and it causes side effects such as nausea, hair loss, suppressed white blood cell counts and increased susceptibility to infection.”

The Path to Better Treatment

Working with the guidance of his Harold Amos program mentor, Griffin Rodgers, MD, director of the National Institute of Diabetes, Digestive and Kidney Diseases and his research mentor, James Douglas Engel, PhD, chair of the department of Cell and Developmental Biology at the University of Michigan, Campbell and his team began to search for more effective, less toxic ways to increase the amount of fetal hemoglobin in sickle cell patients.

“We are all born with 99 percent fetal hemoglobin,” Campbell explains, “but by the time we are 6 months old, the body begins to replace fetal hemoglobin with healthy, adult hemoglobin. In a person with sickle cell, however, the adult hemoglobin is not healthy, as it can sickle. Fetal hemoglobin does not sickle and it prevents sickling in the remaining blood cells. If you have high fetal hemoglobin, you will have a much lower rate of complications from sickle cell. A high rate could also extend a sickle cell patient’s lifespan. We don’t truly understand why it works, but we know it works.”

“In our research, we discovered two proteins, TR2/TR4, that can stimulate fetal hemoglobin in mouse models,” Campbell says. His team’s study, “Forced TR2/TR4 Expression in Sickle Cell Disease Mice Confers Enhanced Fetal Hemoglobin Synthesis and Alleviated Disease Phenotypes,” published in the October 2011 issue of the Proceedings of the National Academy of Sciences (PNAS), revealed that genetic manipulation of the TR2/TR4 proteins increased fetal hemoglobin levels (from 7.6 percent to 18.6 percent) and lowered levels of inflammation and liver damage in sickle cell mice.

“The finding is very significant because we have found a way to stimulate fetal hemoglobin production genetically. This is one of the first discoveries of how to turn on fetal hemoglobin in a way that decreased sickle cell complications in the mouse model,” Campbell explains. “The study is pre-clinical, but if we can find a way to manipulate the TR2/TR4 in humans, that’s really the Holy Grail, because it may prove to be a promising new treatment for the disease.”

Next Steps

“The TR2/TR4 project was supported, in part, by the National Heart Lung and Blood Institute, but because of the protected time provided by my Harold Amos award, I was able to initiate collaborations with other researchers around the country,” Campbell says. “Together, we are trying to further induce fetal hemoglobin in mouse models and look for other compounds that may help. I’m also looking at the inflammatory pathways of sickle cell. Advances in how to increase levels of fetal hemoglobin may also help people with another hematologic condition called beta thalassemia major, a blood disorder characterized by a significant reduction or absence of the production of adult beta-globin, resulting in lifelong anemia and the need for ongoing blood transfusions to sustain life.”

“I do want to emphasize the fact that participating in the Robert Wood Johnson Foundation Harold Amos Medical Faculty Development Program was so important because of the advice I received on conducting research and building my career,” Campbell adds. “It was critical to helping me shape my research questions and gather data in ways that ensured our findings would be solid. The program truly gives young investigators the committed time, supportive mentors and financial assistance needed to advance during a critical time in a physician/scientist’s academic development.”

The RWJF Harold Amos Medical Faculty Development Program was created to make it possible for scientists, physicians and dentists from historically disadvantaged backgrounds to advance to senior positions in academic medicine. The four-year, AMFDP supports biomedical, clinical, dental and health services/epidemiology research. Awards are offered to physicians and dentists who are not only committed to building careers in academic medicine and dentistry, but who hope to serve as role models for other students and faculty members from disadvantaged backgrounds.