ing for these resident lysosomal proteins—the molecular biology of how this works. Over time, the efforts of multiple laboratories figured out the overall targeting pathway. “There’s a really smart protein that can recognize approximately 70 different proteins that are destined to live in the lysosome—it puts a special tag on them, and then another protein grabs the tagged proteins and sends them to their destination,” he says. When Kenneth Valenzano, PhD ’96, adjunct professor of pharmacology, was a graduate student in Dr. Lobel’s lab, he developed a method to visualize all of these tagged lysosomal proteins simultaneously. This method of visualization gave new importance to the research in 1996 when David Sleat, PhD, then a postdoctoral fellow in the lab and now an associate professor of biochemistry and molecular biology and a close collaborator with Dr. Lobel, began to look at samples associated with different human diseases and learn how the lysosomal proteins change. “Serious diseases result when an individual lacks a particular protein that lives in the lysosome,” says Dr. Lobel. “For example, Tay-Sachs disease is a deficiency in a lysosomal enzyme that normally degrades glycolipids.” With this new method of visualization, the lab’s team could start interrogating samples. One of the first was from a child who had died from a neurodegenerative disease called late infantile neuronal ceroid lipofuscinosis (LINCL)— one of the most frequently encountered of a large group of neurological diseases collectively called Batten disease. LINCL typically emerges in children around the age of 3, when they begin to have seizures. Their health fails in stages. First, they lose the ability to walk, then to see. Eventually they are bedridden. By the age of 10, one-third of the neurons in their brain have died. Dr. Lobel and Dr. Sleat discovered that a lysosomal protein that was prominent in normal samples was missing in the child who had died of this disease. After purifying the normal protein and determining its sequence, they analyzed its gene and found mutations that had caused the disease. This discovery occurred in 1997, and the work surrounding LINCL continues today. Dr. Lobel and his team worked to understand the basic properties of the missing protein, learned how to make the protein in large quantities, and developed LINCL mouse models for testing therapeutics. They began to work with a pharmaceutical company, BioMarin, to develop enzyme replacement therapy for LINCL, in which children are treated with a version of the missing protein that is made in the lab. BioMarin has sponsored clinical trials, led by a physician in Hamburg, Germany, that have shown a stabilization of the disease in treated children. On April 27, 2017, the FDA approved the first treatment for a form of Batten disease—Brineura (cerliponase alfa)— based on this research. It is the first FDA-approved treatment to slow loss of walking ability (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2, also known as tripeptidyl peptidase-1 deficiency. Dr. Lobel has also spearheaded research in Niemann-Pick disease type C (NPC)—a rare progressive genetic disorder caused by cholesterol that accumulates in the lysosome. A team of investigators at the National Institutes of Health discovered the disease gene responsible for approximately 95 percent of NPC cases. As an outgrowth of their basic research to identify the proteins that live in the lysosome, in 2000, Dr. Lobel’s group reported a second disease gene responsible for NPC. Ara Parseghian, the former head football coach at the University of Notre Dame—three of whose grandchildren were diagnosed with the disease and died in childhood—established a medical research foundation that funded Dr. Lobel’s work on NPC for 10 years, as well as work by two of his collaborators, Ann M. Stock, PhD, professor of biochemistry and molecular biology and interim director, CABM, and Judith Robert Wood Johnson I MEDICINE 27