Stanley Falkow (1934–2018)

A self-described “terrible student,” Stanley Falkow loved to read, though not what his teachers assigned. In the library at age 11, he discovered the book Microbe Hunters and was captivated by tales of tiny disease-causing critters and the pursuit to uncover their secrets. That experience ignited a lifelong passion that fueled an extraordinary career. He died on 5 May at his home in Portola Valley, California. Outside Stanley's former lab at Stanford University, we hear his voice and see his smile in our minds. We remember a visionary scientist and a devoted mentor. Stanley spearheaded the development of the interrelated fields of microbial pathogenesis, molecular epidemiology, and cellular microbiology. As a graduate student in the 1960s, he unveiled a previously unknown mechanism by which unrelated bacteria share traits when he showed (with Julius Marmur of Brandeis University) that they can transfer—on extrachromosomal pieces of DNA—the ability to use lactose as food. He went on to demonstrate that similar genetic elements, now called plasmids, carry antibiotic resistance genes. These and other groundbreaking discoveries not only explained how antibiotic resistance spreads among bacteria, they also helped lay the foundation for the recombinant DNA enterprise. Soon, scientists would insert any gene of interest into a plasmid and place it in living cells to decipher the gene's function. Stanley immediately recognized this technique's potential for studying pathogenesis, and he used it to isolate, for the first time, a gene involved in bacterial virulence, one that encodes a toxin from a diarrhea-causing Escherichia coli . Years later, he created what he termed “molecular Koch's postulates,” a framework for discerning how particular genes and proteins contribute to infection and disease. The paradigm melded traditional microbiology with the molecular revolution he helped launch. Stanley predicted the spread of clinical antibiotic resistance and, in the late 1970s, he urged the U.S. Food and Drug Administration to ban antibiotics in animal feed. The livestock industry pushed back and the attempt failed, but Stanley's opinions and recommendations on the risks of placing new genes in bacteria influenced guidelines for modern molecular biology research. Stanley Falkow was born in Albany, New York, in 1934. After studying at the University of Maine and earning a doctorate from Brown University, his career path led him to Stanford University in 1981 where he remained on the faculty for the next 23 years and continued as an emeritus professor until his death. He mentored more than 120 graduate students, postdocs, and clinical fellows; his trainees are among the most prominent microbiologists in the world. His style was unusual in many ways, and his generosity shone. He frequently said that he learned more from his students than vice versa, and he prioritized their interests. His postdocs could take their projects with them when they set up their own labs, and he would focus on other topics to avoid competition. When I (E.S.) expressed a desire to learn how to study a pathogen “from the beginning,” he suggested that I start an Edwardsiella tarda project. Initial studies on this obscure pathogen likely would not break new scientific ground or yield high-profile publications, yet he recognized the potential for teaching me what I wanted to learn. ![Figure][1] PHOTO: LINDA A. CICERO/STANFORD NEWS SERVICE Stanley's wit infused many lessons and stories, as did his irreverence. When I (D.M.) began working in his lab as a technician in the mid-1980s, I was fortunate enough to sit in on his lectures to medical students. He began by telling us about the normal flora in the “warm Miami” of the colon and informed us that “normal stool is about the size, shape, and consistency of an overripe banana.” To convey modes of bacterial transmission, he used a marker on transparencies (those were the days of overhead projectors) to draw stick figures and arrows—from rats to humans, for instance. By the time he got to fecal-oral spread and sexual transmission, the students were in stitches; Stanley maintained a deadpan delivery. In informal situations, he'd illustrate the clinical symptoms caused by enteric bacterial pathogens such as Shigella by showing pictures of bloody diarrhea. He would get the expected groan or blanch and his eyes would twinkle. “Well, it may be shit to you,” he'd say, “but it's my bread and butter.” When Stanley received the Lasker-Koshland Special Achievement Award in Medical Science in 2008, he titled an associated commentary, “I never met a microbe I didn't like.” The range of bacterial pathogens he studied— Yersinia, Helicobacter, Bordetella, Salmonella, Neisseria , and Edwardsiella , to name a few—bore out this sentiment. Not only did he like them, but he identified with them. Knowing only Stanley's stature in the field, one of us (E.S.) probably benefited from this affinity. In my postdoc interview, he asked why a yeast biologist wanted to study bacterial pathogenesis. I told him that I held a long interest in microbial disease, and then I blurted out, “Also, I like pretending that I am a bacterium.” I cringed and thought, “No way did that statement make sense to him.” But Stanley got it. His proclivity to “see” things from a microbial point of view likely fueled some of his imaginative and insightful thinking. He frequently pointed out that bacteria have no malignant intent; their goal is not to make anyone sick. His dictum was, “a bacterium's goal is to become bacteria.” Stanley shaped not only the way that I (D.M.) approach science, but also how I think about my students and postdocs. Several decades ago, I had occasion to attend a meeting at a biotech company on whose scientific advisory board Stanley sat. Employees, scientific advisers, and executives were discussing finances and assets. At one point in the conversation, Stanley's face clouded. He was irritated by a comment someone had made. “Don't forget that your most important and valuable assets are sitting here at this table,” he said as he looked around at the employees. In the hallway outside his former lab at Stanford, a portrait of Stanley by a former student captures his facial asymmetry and his warm gaze. We look up and see a giant among microbe hunters, an inspiring teacher, and a beloved friend. [1]: pending:yes