Stanley Falkow (1934-2018) Microbe Hunter Who Uncovered How Bacteria Cause Disease

COMMENT OBITUARY Stanley Falkow (1934-2018) Microbe hunter who uncovered how bacteria cause disease.

tanley Falkow discovered the molecular Another of Falkow’s heroes, Robert Koch, mechanisms through which bacteria established a set of guidelines in the 1880s cause disease and how to disarm them. (Koch’s postulates) to define when a microbe SBut he always described himself as being “on is responsible for an infection. Falkow the side of the microbes”. extended this idea in the 1980s, developing Falkow, who died on 5 May, began his the ‘molecular Koch’s postulates’. These career in the late 1950s, when DNA was first describe how one could define virulence at recognized as the stuff of life, and bacteria the molecular level — for example by inactiv were thought to be good model systems for ating specific genes to render a microbe studying it. By the 1960s, he had worked out harmless, or transferring a gene for adhesion how to extract and isolate the extrachromo- or invasion to an innocuous bacterium to NEWS SERVICE CHUCK PAINTER/STANFORD somal packets of bacterial DNA that we now improve its ability to interact with host cells. call plasmids, and found that these carry His lab elucidated the mechanisms of disease information from one microbe to another. of many bacteria (and even yeasts), including This showed how bacteria can acquire the major gut pathogens such as Salmonella and ability to survive on a new food source or pathogenic Escherichia coli, along with bac- become resistant to an antibiotic. teria that cause skin, urinary-tract and sexu- He made the ominous observation that ally transmitted infections, whooping cough, even harmless bacteria could serve as a pneumonia, sepsis, and even stomach cancer. source of resistance genes for pathogens. Falkow came to think of the “pathogenic Falkow understood the public-health signifi- lifestyle” as being not about causing disease, cance of this, predicted the rise of multidrug- but rather about subtly manipulating a host. resistant bacteria and campaigned against with his heroes from this book. He became best friends with his prey. Over the overuse of antibiotics. His discoveries of Microbe Hunters begins with Antonie van time, he spoke more and more about the the molecular nature of antibiotic resistance Leeuwenhoek, who, in the 1670s, was the potential beneficial attributes of bacteria that won him the 2008 Lasker–Koshland Special first to craft glass lenses so powerful that he live on and in our body, foreseeing the study Achievement Award in Medical Science. was able to visualize microscopic organisms. of the human microbiome. The question that framed Falkow’s career When Falkow read this, he had to have a Despite his fame, Falkow often said that his was: what is a pathogen? Specifically, what microscope. He found a Gilbert Company greatest achievements were those of his stu- makes some microbes disease agents, while Hall of Science microscope on the shelves of dents. One of his most important gifts was his others are innocuous or even beneficial? He the local toy shop (he could not afford it, but ability to infect these students with the same hypothesized that bacteria have genes coding in the end, the shop owner gave it to Falkow). sense of awe that he had when he first peered for specialized ‘virulence factors’ — the trans- Through this, Falkow witnessed the darting into a microscope. More than 120 scientists, ferable, molecular equivalents of claws, fangs, shadows of bacteria growing in the spoilt including some of today’s most prominent toxins, fur and camouflage — that allow path- milk that he kept under his bed. microbiologists, were trained in Falkow’s labo- ogenic bacteria to attack, hide and survive in Falkow’s love of microscopy continued ratory. Despite his illness, he was still teaching extreme environments. He spent his life iden- throughout his career, which started with at Stanford last semester, and video-calling tifying the genes and molecules behind these a PhD in 1961 from Brown University in into classroom discussions and lab meetings. abilities. He discovered, for example, that Providence, Rhode Island. He learnt elec- For pragmatists interested in tools for con- some bacteria decorate their surfaces with tron microscopy and, in the 1970s, at the quering the microbial world, Falkow’s vision molecules designed to adhere to host cells, University of Washington School of Medi- provided the technical framework by which and even fool the host into allowing bacteria cine in Seattle, used it to visualize resistance to define potential targets for vaccines and to invade. Others have molecular needles that genes that had hopped on to plasmids. In the methods to identify, fingerprint and follow disarm white blood cells by injecting proteins 1980s at the Rocky Mountain Laboratories in the evolution of pathogens through molecular that stop the cells moving, or prevent them Montana and at Stanford University School epidemiology. For pure biologists, this same from sounding the alarm. of Medicine in California, where he chaired vision provided the foundation for under- Falkow was born the son of Jewish immi- the department of microbiology and immu- standing the natural history of pathogenic grants in Albany, New York, on 24 January nology, he made micrographs of Yersinia and and mutualistic microbes. For those of us who 1934 at the peak of the Great Depression. He Salmonella bacteria invading the intestine. had the good fortune to know him, he left a was a terrible student, especially in mathe- He was the first to make movies with a bounty of stories and examples of his generos- matics and science, but loved to read. When videomicroscope to show how Salmonella ity of spirit as a scientist and a mentor. ■ he was 11, he found in the local library the invade gut epithelial cells by causing a literal book Microbe Hunters by Paul de Kruif. splash of cytoskeleton and membrane at the Manuel R. Amieva is an associate professor Written for lay audiences in 1926, it describes cell surface. He adapted diverse methods of Pediatric Infectious Diseases and of the personalities and adventures of some of of painting and tagging molecules inside Microbiology & Immunology at Stanford the most important figures in microbiology. bacteria and host cells to follow their fate University School of Medicine; he was one of Falkow devoured it and decided to become a during infection, and even to find bacterial Falkow’s last postdoctoral fellows. microbe hunter. His life was a conversation genes that turn on only when inside cells. e-mail: [email protected]