Epidemics of infectious disease are frightening and potentially devastating events. Perhaps the deadliest in modern recorded history was the influenza pandemic of 1918, a global phenomenon that infected up to half a billion people and killed tens of millions. While these numbers underscore the lethal potential of a transmissible agent, they also show that even the potent influenza virus of 1918 did not kill everyone with whom it came into contact. The pandemic dramatically illustrates a scientific question that Jean-Laurent Casanova, M.D., Ph.D., confronts every day: why do some people exposed to a microorganism (microbe) become very sick, while others experience only mild illness or remain unharmed?

The germ theory of disease, the idea that some illnesses can be caused by microorganisms (pathogens), revolutionized medicine the 19th century. Soon after scientists began chasing germs, however, they discovered that asymptomatic infections—which show no symptoms and signs—are more common than clinically significant infections accompanied by identifiable symptoms. In his research, Dr. Casanova studies rare instances where a given microbe causes clinically significant infections only in a very small number of people. They are usually children. Using genome sequencing, computational analysis, and other approaches, the Casanova lab has shown that these individuals harbor variants in their genes that disable their immune responses against specific microorganisms. Dr. Casanova’s groundbreaking discoveries suggest a surprising alternative to the time-honored germ theory. According to his model, understanding and treating infectious illnesses is not just about identifying and combating bacteria, viruses, or fungi. Instead, he searches for genetic lesions, known as hereditary anomalies, which are often critical to understanding how one child might be more, or less, susceptible to microbial infection.

Dr. Casanova is a Howard Hughes Medical Institute investigator, a member of the National Academy of Sciences and National Academy of Medicine, and professor and head of the St. Giles Laboratory of Human Genetics of Infectious Diseases at The Rockefeller University. He has identified many single-gene mutations that compromise the immunity of otherwise healthy children and young adults, rendering them vulnerable to specific infectious diseases. Dr. Casanova’s work lends support not only to the controversial idea that an error in a single gene is enough to dramatically alter an individual’s risk for infectious disease, but also to the notion that humans have sets of genes that are pathogen-specific. Though his research focuses on the causes of rare pediatric infections, the work is shedding light on factors that contribute to more common infectious diseases that occur across age groups.