A person's risk of heart disease can't be blamed solely on eating too many cheeseburgers and other foods high in saturated fat. Genetic makeup also plays a powerful role. Helen Hobbs has discovered new genes and variations within genes that account for individual differences in blood levels of low-density lipoprotein, the "bad" cholesterol. High LDL cholesterol is a major risk factor for heart disease and heart attack because it contributes to the buildup of plaque that can clog artery walls. By identifying the genes that influence cholesterol levels and exploring their function, Hobbs's studies are laying the groundwork for the development of new cholesterol-lowering drugs.
Hobbs was chief resident at UT Southwestern Medical Center in Dallas and well on her way to becoming a practicing endocrinologist when she decided to give research a try. Her mentor, Donald Seldin, then the school's head of medicine, was convinced that Hobbs possessed the natural curiosity and the drive to flourish in a research environment, even though she had no experience at the bench, and that she would not be fulfilled in her work without the challenge of new discovery. "He knew all my strengths, but more importantly, he knew all my weaknesses, and he felt strongly that I should do this," Hobbs recalls. Seldin arranged for her to work as a postdoctoral fellow in the laboratory of two well-established investigators—Michael Brown and Joseph Goldstein—who later won a Nobel Prize for discovering the cell-surface receptor for LDL cholesterol and demonstrating its role in cholesterol metabolism.
Hobbs initially struggled in the laboratory. She much preferred the faster pace of clinical medicine and was easily frustrated by her own technical mistakes. "Patience is not my virtue. It took me a long time to adjust to the slow pace of laboratory science," Hobbs says. But once she started to get results, Hobbs relished the thrill of scientific discovery. When she joined the Brown-Goldstein laboratory, the pair was trying to understand how mutations in the LDL-receptor gene affect the receptor's function. One of Hobbs's first research successes was finding a mutation in this gene that alters its ability to bind LDL cholesterol. Today, she admits, "I am able to delight more in the slower process of telling a scientific story with my work. Ironically, the observations I have made with the greatest potential for clinical impact came from studies driven by scientific curiosity rather than thoughts of developing new therapies."
Since setting up her own laboratory at UT Southwestern in the late 1980s, Hobbs has discovered genetic defects that cause very high and very low blood levels of cholesterol and studied the faulty proteins that underlie these disorders. This information may help determine how the body normally regulates cholesterol by removing it from the bloodstream and shuttling it to the liver, where it is broken down in the bile. In 2001, she identified a genetic defect that causes a rare type of high-cholesterol disorder, autosomal-recessive hypercholesterolemia. People with the disease have normal-functioning LDL receptors but can't remove LDL cholesterol from the bloodstream. She and her colleagues also discovered two genes, ABCG5 and ABCG8, that play key roles in maintaining the proper balance of sterols in the body, including plant-based sitosterol and animal-based cholesterol. Mutations in either gene can lead to a buildup of cholesterol in the blood.
In addition to her laboratory work, Hobbs runs the Dallas Heart Study, aimed at uncovering the risk factors for heart disease and at finding new treatments. Initiated in 1999, the study includes taking blood samples and performing detailed heart imaging studies in 3,000 Dallas County residents (about half of them African American). Based on data already collected, Hobbs recently identified two beneficial genetic mutations linked to low levels of LDL cholesterol. The gene alterations were found almost exclusively among African Americans, even though as a group they have a higher risk of heart disease. One out of 50 African Americans in the study had either of the mutations, which increase the amount of cholesterol the liver removes from the body.
Hobbs sees patients in the clinic. Most have very high or low levels of cholesterol, and sometimes their symptoms lead to the identification of a new disorder that becomes the focus of her work in the laboratory. Recently, Hobbs saw a patient whose LDL cholesterol level skyrocketed after he went on the low-carb Atkins diet. She found abnormalities not only in the patient's cholesterol metabolism but also in the metabolism of other family members, and she is now trying to pinpoint this defect.