In the late 1980s, when cloning a gene "was like landing on the moon," M.D./Ph.D. student Brendan Lee cloned the genes for two connective tissue diseases—Marfan syndrome and osteogenesis imperfecta. Then he was faced with a decision: continue with this promising research, or finish his M.D. degree.

Lee decided to earn his M.D. because he was interested in studying the genetics of connective tissue diseases and extending the reach of this research to patients' lives. Because connective tissue diseases are often diagnosed in childhood, he completed a pediatric residency and a fellowship in genetics at Baylor College of Medicine. By then, Lee had clarified his desire to work both at the bedside and bench—to "wear both hats."

Lee's research strategy has four parts: First, gain clinical insights about genetic diseases from patients. Second, discover gene mutations that cause these genetic diseases. Third, generate and test hypotheses about gene function in mammalian models that derive from a combination of clinical and molecular insights. Fourth, return to patients and discern how all of this information might affect diagnosis, therapy, and management.

Lee focuses on the effects of gene mutations on organ and skeletal development. In 2006, Lee and colleagues pinpointed the gene responsible for a previously unidentified form of osteogenesis imperfecta, or brittle bone disease. This gene, called CTRAP (cartilage-associated protein), is mutated in about 15 percent of cases. Although most forms of brittle bone disease are inherited in a dominant fashion, this form is inherited in a recessive fashion. Affected children receive one copy of the mutated gene from each parent.

Now, both children and potential parents can be tested for the mutation. Because brittle bone disease is sometimes mistaken for child abuse, Lee's gene discovery helps the legal and social services systems, as well as the medical one.

This form of brittle bone disease differs from other forms in another important way. Normally, collagen fibers are created and then modified to provide support to bone, skin, ligaments, and other connective tissues. In most forms of brittle bone disease, a gene mutation leads to the creation of an abnormal collagen protein. In the form of disease that Lee discovered, the proteins produced are normal, but they can't undergo one of the biochemical modifications needed to make a functional collagen fiber.

That's because the mutation in CRTAP affects a "helper protein" for one of the biochemical modifications. The mutated CRTAP protein can't do its job, and the resulting collagen is not shaped properly.

To find out more about CRTAP, Lee created transgenic mice that lacked the gene. He showed that they could create collagen normally, but could not modify it to make it useful. Lee's next step was to complete a genetic study of two families with an unusual form of osteogenesis imperfecta to see if CRTAP was responsible. It was: mutations in CRTAP were causing their bone disease.

Now, he is studying the role of CRTAP and its related protein family members in other tissues of the body to see if similar defects may lie behind other connective tissue disorders.

Lee is also interested in disorders of metabolism, or energy regulation. Although the genetic changes he finds are often straightforward, they can cause multiple symptoms that don't always seem to have a common explanation. "We have been applying genetic tools to try to understand what these simple errors of metabolism can teach us about complex disease," Lee says.

He is studying people with urea-cycle disorders, who cannot remove nitrogen from their blood. "They can die from eating high-protein foods, such as meat," Lee says. Lee is focusing on interactions between the body's urea cycle and the pathways of nitric oxide (NO), an important molecule that regulates blood flow, among other processes. He believes NO could be used therapeutically, but he first needs to know more about the molecule. "We have to know when high levels of NO are good and when they are bad, and how to manipulate them."

Lee also is exploring how gene therapy might help treat some of these disorders. In animal models, he has used gene therapy to cure different inborn errors of metabolism like urea-cycle disorders and bilirubin-clearance disorders. Now, he's trying to translate that knowledge into therapies for people. The main hurdle is the human immune system, which reacts to the virus carrying the gene.

Despite all of these research directions, Lee is committed to making a difference in patients' lives by continuing to translate each of these discoveries back to patient care. "One of the great privileges of being a physician-scientist is the ability listen to patients' stories. These stories continually give us the scientific leads and motivation to continue to focus on each of these problems." He is ready to shift gears tomorrow if an exciting avenue presents itself. "The next patient who walks in the door could take you in a completely new direction that you never expected," he says.