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Stanley Falkow (1934–2018)

2018; Cell Press; Volume: 23; Issue: 6 Linguagem: Inglês

10.1016/j.chom.2018.05.014

1934-6069

Denise M. Monack,

Stanley Falkow’s intellect, creativity, and wit have impacted the way we think about antibiotic resistance, bacterial pathogens, and infectious diseases and have led to a “gestalt” of the way researchers study and view host-microbial interactions. Sadly, arguably one of the most influential microbiologists in the past 50 years passed away on May 5 after a battle with myelodysplasia syndrome. Stan was born in New York and then moved with his family to Providence, Rhode Island. He describes his passion for microbes developing after he read the book Microbe Hunters by Paul de Kruif, which led him to acquire a microscope from the toy store in exchange for his hard labor at the age of 11. Stan went to undergrad at University of Maine, where he demonstrated that supernatants from “antagonistic” strains of Proteus mirabilis induced the L-form in other Proteus strains. This resulted in his first scientific publication in 1957. The next several years were spent working full time in the clinical microbiology lab at Newport Hospital. I remember Stan speaking very fondly about this period of his career when he learned, by osmosis, the clinical and pathological consequences of infections caused by the microbes that he revered. It also played a big role in his desire to understand the underlying biology behind many of the correlations that the physicians noted between infectious disease symptoms and the microbes that caused them. Stan obtained his PhD from Brown University, where he did his dissertation research in part with C.A. Stuart and L.S. Baron at Walter Reed Army Institute of Research. He showed that a unique Salmonella typhi clinical isolate that was able to ferment lactose could transfer this phenotype at high frequency to other bacteria, including Serratia marcescens and Vibrio cholerae. These results led Stan to discover that episomal DNA, F-lac, could be transferred to other bacteria. He exploited the fact that bacterial species contain DNA of characteristic densities and nucleotide content to demonstrate that the transferable elements (R-factors) were the agents of transmissible antibiotic resistance. These findings led Stan to predict the spread of clinical antibiotic resistance, and in the late 1970s, while an Associate Professor at the University of Washington, he urged the Food and Drug Administration to ban antibiotics in animal feed. The livestock industry pushed back and the attempt failed, but Stan’s opinions and recommendations on the risks of placing new genes in bacteria influenced guidelines for modern molecular biology research. At the forefront of the use of recombinant DNA for various biotechnology applications, Stan recognized the utility of this new and powerful molecular tool to study his favorite pathogens and convince the skeptics of the time, who believed that pathogens were “degenerate forms of bacteria” and that pathogenicity was a kind of genetic adaptation for survival—one of his famous quotes is “the goal of a bacterium is to become bacteria.” Utilizing recombinant DNA techniques, Stan’s group was the first to clone and characterize enterotoxin genes from Escherichia coli isolates that cause diarrhea in humans. Shortly after this, while still at the University of Washington, Stan began to work on Yersinia pestis, the causative agent of plague, and Bordetella pertussis, the bug that causes whooping cough. He and his students made many seminal discoveries during this time—discoveries that really led to the advent of molecular pathogenesis as we know it today. For example, they discovered that genes that are critical for Yersinia virulence are contained on a plasmid. This led to the discovery of a dedicated secretion system (now called Type III system) that translocates effector proteins into mammalian cells. In addition, Stan’s lab conducted one of the first unbiased transposon mutagenesis screens to identify virulence factors in B. pertussis, leading to the identification of a histidine kinase cascade that regulates the expression of crucial virulence factors. It was during this time that Stan was recruited to Stanford University to chair the Department of Microbiology and Immunology. I first met Stan in 1984 when I interviewed for a technician’s job in his lab at Stanford. I was very young and naive and had no idea how famous Stan was. I remember complaining about having to mail out DNA probes to labs all around the world, probes that could distinguish between E. coli strains that can cause diarrhea in humans. I soon learned that diarrhea and its causal bacterial agents were subjects near and dear to Stan’s heart. In addition, I was informed about the many other important discoveries arising from his lab including, for example, the cloning of invasin from Yersinia pseudotuberculosis into E. coli to demonstrate that this factor was necessary and sufficient for entry into mammalian cells. I was very grateful and felt incredibly lucky to have the opportunity to learn from such an intelligent and creative scientist. It was a privilege to witness Stan shape the way we think about the evolution of pathogens and formulate “Molecular Koch’s Postulates,” which define criteria and guidelines to establish the role of bacterial factors in infection of hosts. This provided a paradigm to seamlessly meld traditional microbiology with the molecular revolution he helped launch. Stan was a devoted teacher, an endeavor that he took great pride in, and was honored with teaching awards over the years. I will never forget sitting in on his infectious disease lectures to the medical students. While on the subject of diarrhea, he would ask students, “What is a normal stool?” He would wait for answers and then explain that a normal stool is the size, shape, and consistency of an overripe banana. His deadpan delivery was the best part. I learned so much from his lectures and his very patient scientific conversations with me about my data or a paper I had read. As the technician I received the same amount of time and respect as any of his students and postdocs. This is when I realized that I was really lucky to be in his lab…yes, I drank the Kool Aid. Stan was one of the most humble scientists I have known. His personality and approach to his career are embodied in a quote from the Talmud that he cited in his retrospective “The Fortunate Professor”—“Much have I learned from my teachers, more from my colleagues, but most from my students.” This deep appreciation and respect for his mentees is rare. He instilled confidence in his mentees and was extremely supportive of women. He had a tremendous impact on my career. After working in his lab as a technician, working on my own research projects and publishing first author papers, he gave me a gentle push to go to graduate school and obtain my PhD. This was not an easy decision for me as I had two young kids. I remember asking Stan, “What do I do if my kid is sick and I can’t go to class?” His advice was to not worry about that; I could always talk to the instructor and make up the work. I was fortunate enough to have the support of the admissions committee in my department; they accepted me to the Microbiology and Immunology program at Stanford, and after fulfilling all requirements and research, I obtained my PhD in Stan’s lab. Over the 34 years that I knew Stan, I witnessed him influence the careers of many scientists in various ways. After his death, I have reflected on the impact he has had on my science and several interactions are at the forefront of my mind. One is walks with Stan and his dog Brandy, who often accompanied him to work, to the campus cactus garden. This was a perfect time to chat with Stan about whatever was on our minds. On one occasion I shared my concern about “missing the microarray boat” because at that time many researchers in our field were using this new tool to study various aspects of host-pathogen interactions. His sage advice was to never let technology drive my research. He said, “Just keep your focus on your most pressing biological questions, and of course you will use the latest technology if that will bring you to the answer; don’t worry.” During my reflections, I also looked through my email folder of communications with Stan. I saw many emails that contained the subject heading “You should look at this” and articles would be attached. He continued this even after he retired. After Stan retired, he continued to teach and contribute to review articles. He taught undergraduate students at Stanford the History of Infectious Disease. His lectures were impactful, and the students described his lectures as “eye opening” and “thought provoking.” He cared so much about learning new science that he continued to come to the Monack lab meetings. When Stan was not able to come to lab meetings, he started joining us via Skype. I am eternally grateful to Stan for his wisdom, sharp wit, friendship, and legacy. The legacy is shared by more than 120 mentees who trained directly with him; their mentees, whom Stan referred to as his grand students; the great grand students; and numerous colleagues who worked with him. He leaves behind his wife, Dr. Lucy Tompkins; his two daughters, Jill Brooks and Lynn Short; stepson Chris Tompkins; and four grandchildren, Megan Brooks, Shannon Brooks, Jenna Tompkins, and Joel Tompkins.Stanley FalkowView Large Image Figure ViewerDownload Hi-res image Download (PPT)