When Andrey Shaw was in medical school, he struggled to understand the kidney and its afflictions. So when he set up his lab at the Washington University School of Medicine in St. Louis, he had no intention of delving into the finer points of kidney function. Ironically, that's exactly where his studies of immune cell signaling led him. Today, Shaw is poised to unravel the key molecular events that cause some forms of kidney disease.
An immunologist, Shaw set up his lab to study how interactions between two types of immune cells, antigen-presenting cells and T cells, form a structure he called the immunological synapse. He and his colleagues were working on the hypothesis that the special arrangement of proteins at the surface between the two cells could influence cell signaling. As he delved deeper, he wanted to know how this rearrangement came about.
His research revealed that a protein called CD2AP is critical for stabilizing the interaction between the two immune cells. The next step was to genetically engineer mice that lacked CD2AP so they could study the protein's function. But the mice died of kidney failure at six weeks of age. It turned out that CD2AP is found in podocytes, specialized cells in the kidney with tentacle-like extensions that help form the barrier through which blood is filtered to make urine. Although the cells were discovered more than thirty years ago, Shaw said, “it is still not exactly clear what the podocyte is doing.”
Today, podocytes are the focus of Shaw's research, and his lab is searching for genetic defects that can compromise the cells' function in human patients. They have already found that mutations that produce CD2AP protein deficiency can cause disease but hypothesize that many other genes may be involved.
“Our big goal is to identify as many of these genes and their role in susceptibility to renal failure as possible,” Shaw said. “It's interesting because we weren't looking to do research on the kidney. But trying to understand what CD2AP was doing in the kidney evolved into an opportunity to understand the genetic basis of many common kidney diseases.”
Shaw, a music major who trained as a classical pianist at Columbia College, was first exposed to the lab after he had completed medical school and was doing a pathology residency at Yale University School of Medicine. “Within a week or two weeks of working in a lab, it felt like a perfect fit. It was creative and felt very similar to music. There was a lot of hard work, a lot of repetitive tasks, but it was very rewarding. I was surprised to find research to be a creative, exploratory place.”
His early lab experience also taught him that science is more about what is unknown than about memorizing facts. “Being a good scientist is finding out you're wrong—a lot. Being wrong and having experiments fail continuously is hard.”
But research is a great opportunity, he said, to attack the frustration he experienced in medical school with the kidney. “I was astonished to find out how little we knew about how the kidney worked” and what goes wrong to cause disease.