Yale's innovative Investigative Medicine Program awards a PhD degree in investigative medicine to physicians training in either laboratory- or clinically-based patient-oriented research. The IMP has been expanded under the Clinical and Translational Science Award (CTSA) to include scholars in nursing, public health, biomedical engineering, and the biological and biomedical sciences. IMP also serves as a vehicle for integrating student training; many other individuals (medical, nursing, and graduate students; residents; international scholars; and clinical fellows and junior faculty members, some of whom are YCCI Scholars) take courses offered by the IMP each year.
Exploring Rare Mutations to Understand Kidney Disease
Throughout his medical career, Mathieu Lemaire, MSc, MDCM, has been fascinated by genomic science and renal physiology. Those two interests led him to Yale's Investigative Medicine Program and the lab of Richard Lifton, MD, PhD. The idea of combining doctoral training in translational research with his medical training appeals to him because it allows him to study diseases in his own patients, moving from the bedside to the bench and back to the bedside.
Trained as a pediatric nephrologist, Lemaire is uniquely positioned to diagnose and treat such serious but rare inherited kidney conditions as Dent's disease, which is characterized by defective functioning of the proximal renal tubules. Children with the disease are unable to absorb such critical components needed for proper growth and bone health as salts, amino acids, and proteins. Two genes are implicated in Dent's disease–CLCN5 and OCRL—but while studying the literature on the disease, Lemaire noticed that a number of the patients in published cohorts didn't have a mutation in either gene.
It turned out that about 30 percent of these patients lacked the mutations. This finding suggests that there may be unknown disease-causing genes implicated in this disease. In his IMP thesis project, Lemaire is using whole-exome capture to study the DNA of approximately 80 unrelated patients from the United States, Europe, and Asia without CLCN5 or OCRL-1 mutations. He hopes to find a set of patients that have not only a similar phenotype, but also mutations in the same gene. Although the work is more challenging than he anticipated, it has been worthwhile—he has found a handful of convincing novel candidate genes.
Elucidating the underlying genetic basis of Dent's disease may prove helpful in terms of treatment, but its usefulness goes beyond this rare disease. This approach has the potential to shed light on the pathophysiology of the proximal renal tubules, as well as other rare diseases that affect nephron segments and are commonly seen in pediatric nephrology. Lemaire is also working on a genomic project on essential hypertension, which has wider implications for the health of the general public. "It's a nice complement to work on both common and rare diseases," he said.
Lemaire was drawn to the Investigative Medicine Program in 2009 because of its structure and collaborative nature. "For most people, doing clinical work doesn't give you the confidence to be a functional scientist," he said. He finds that regular meetings with his committee members who are experts in their fields adds value to his training, as does the IMP curriculum, which includes courses in grant writing and other aspects of clinical and translational research. What may be most appealing, however, are the skills he's acquiring that will allow him to help his young patients. "To know the underlying cause of a disease, even if there's not a cure, is incredibly reassuring for a family," he said.