Stanley Falkow Research Articles

Stanley Falkow. 24 January 1934—5 May 2018

Our understanding of infectious disease and disease-causing organisms has been broadly shaped by two revolutions. The first was the advent of clinical microbiology of the nineteenth and early twentieth centuries, which saw the isolation, identification and classification of disease-causing organisms. In the middle of the twentieth century, the emerging field of molecular biology transformed our understanding of genes and their regulation. Starting in 1960, Stanley Falkow fused clinical microbiology with molecular biology, founding the new discipline of molecular microbial pathogenesis. Over the next half century, he led and shaped this new discipline, revolutionizing our understanding of how pathogenic bacteria cause disease and become resistant to antibiotics.

From the beginning to the present state of molecular microbial pathogenesis-A tribute to Pascale Cossart.

The universe of Molecular Microbial Pathogenesis is filled with many female and male stars. But there are two particularly bright shining supernovae-like stars: the late Stanley Falkow and the very lively and creative Pascale Cossart. These two outstanding luminaries, surrounded by numerous planets, do not only belong to different scientific generations but their splendor also comes from very different scientific concepts. Stanley Falkow, often referred to as the 'Father of Molecular Microbial Pathogenesis', made many groundbreaking contributions to this field by addressing almost all important bacterial pathogens. Pascale Cossart, who could be called in analogy the 'Queen of Modern Molecular Microbial Pathogenesis' by combining the Microbiology and Cell Biology, concentrates in her similarly impressive scientific work essentially on a single bacterial species which she studied and still studies in great depth: the facultative intracellular bacterial pathogen Listeria monocytogenes-and the vast majority of her most prominent publications deals with this pathogen in almost all facets. It is certainly not an exaggeration to say that she together with her co-workers and collaborators developed this model bacterium into a paradigm among the intracellular bacterial pathogens.

Coagulase-Negative Staphylococci Pathogenomics.

Coagulase-negative Staphylococci (CoNS) are skin commensal bacteria. Besides their role in maintaining homeostasis, CoNS have emerged as major pathogens in nosocomial settings. Several studies have investigated the molecular basis for this emergence and identified multiple putative virulence factors with regards to Staphylococcus aureus pathogenicity. In the last decade, numerous CoNS whole-genome sequences have been released, leading to the identification of numerous putative virulence factors. Koch’s postulates and the molecular rendition of these postulates, established by Stanley Falkow in 1988, do not explain the microbial pathogenicity of CoNS. However, whole-genome sequence data has shed new light on CoNS pathogenicity. In this review, we analyzed the contribution of genomics in defining CoNS virulence, focusing on the most frequent and pathogenic CoNS species: S. epidermidis, S. haemolyticus, S. saprophyticus, S. capitis, and S. lugdunensis.

Antimicrobial resistance and the role of vaccines

> Stanley Falkow (Fig. 1) dedicated his life’s work to the study of bacteria and infectious disease. He was a leader in the discovery of the mechanisms of antibiotic resistance and among the first to recognize and raise the alarm about the problem of multidrug resistance. The articles of this Special Feature on Antimicrobial Resistance and the Role of Vaccines are dedicated to his memory (Box 1). Fig. 1. Stanley Falkow, January 24, 1934–May 5, 2018, a pioneer in the fight to understand and address AMR. Image courtesy of Manuel R. Amieva (photographer). Box 1 #### Dedication This Special Feature on Antimicrobial Resistance and the Role of Vaccines is dedicated to the memory of microbiologist Stanley Falkow. Professor Falkow was a pioneer in understanding how bacteria cause disease and discovered how antibiotic resistance spreads among bacteria. In 1964, Falkow was the first to physically isolate a distinct band of DNA comprising the episome (plasmid) with the genetic material coding for antibiotic resistance in a cesium chloride gradient. As early as 1975, he wrote a book entitled Infectious Multiple Drug Resistance (17) and noted that while “we owe to chemotherapy [antibiotics] the debt of reducing the high mortality rate of many bacterial infections [and to hygiene and vaccines the debt of preventing them], in helping to solve some of the problems of infectious diseases, chemotherapy created some problems of its own.” The “problems” Falkow refers to were, of course, the multidrug-resistant bacterial strains generated as a natural consequence of the drugs’ use. Falkow received numerous honors in recognition of his work, including election to the National Academy of Sciences in 1984, the Royal Society in Britain in 2007, and presentation of the National Medal of Science in 2014. Stanley Falkow died at his home in Portola Valley, California, on May 5, 2018, at the age of 84. … [↵][1]1To whom correspondence should be addressed. Email: rino.r.rappuoli{at}gsk.com. [1]: #xref-corresp-1-1

The Importance of Role Models in Research.

The Importance of Role Models in Research.

A genomic safe haven for mutant complementation in Cryptococcus neoformans.

Just as Koch’s postulates formed the foundation of early infectious disease study, Stanley Falkow’s molecular Koch’s postulates define best practice in determining whether a specific gene contributes to virulence of a pathogen. Fundamentally, these molecular postulates state that if a gene is involved in virulence, its removal will compromise virulence. Likewise, its reintroduction should restore virulence to the mutant. These approaches are widely employed in Cryptococcus neoformans, where gene deletion via biolistic transformation is a well-established technique. However, the complementation of these mutants is less straightforward. Currently, one of three approaches will be taken: the gene is reintroduced at the original locus, the gene is reintroduced into a random site in the genome, or the mutant is not complemented at all. Depending on which approach is utilized, the mutant may be complemented but other genes are potentially disrupted in the process. To counter the drawbacks of the current approaches to complementation we have created a new tool to assist in this key step in the study of a gene’s role in virulence. We have identified and characterized a small gene-free region in the C. neoformans genome dubbed the “safe haven”, and constructed a plasmid vector that targets DNA constructs to this preselected site. The plasmid vector integrates with high frequency, effectively complementing a mutant strain without disrupting adjacent genes. qRT-PCR of the flanking genes on either side of the safe haven site following integration of the targeting vector revealed no changes in their expression, and no secondary phenotypes were observed in a range of phenotypic assays including an intranasal murine infection model. Combined, these data confirm that we have successfully created a much-needed molecular resource for the Cryptococcus community, enabling the reliable fulfillment of the molecular Koch’s postulates.

Dr. Ehrlich and Dr. Atomic: Beauty vs. Horror in Science

Dr. Ehrlich and Dr. Atomic: Beauty <i>vs.</i> Horror in Science

Lasker-Koshland Award to 21st Century Microbe Master

The 2008 Lasker-Koshland Award will be presented to Stanley Falkow, one of the legendary figures in the history of microbiology research. Falkow's many contributions remade the way we think about bacterial pathogens, antibiotic resistance, and infectious disease.

Did Bacterial Sensing of Host Environments Evolve from Sensing within Microbial Communities?

Bacteria sense and respond to their environment, enabling adaptation to diverse niches, including multicellular eukaryotes. In this issue of Cell Host & Microbe, Torres et al. describe how the bacterium Staphylococcus aureus responds to heme as a molecular marker of the mammalian host environment. It is likely that mechanisms for sensing such markers evolved from systems that recognized cues present in microbial communities before the emergence of eukaryotes.

Cellular Microbiology in the 21st Century

Dr Finlay is a Professor in the Michael Smith Laboratories, and the Departments of Biochemistry and Molecular Biology, and Microbiology and Immunology at the University of British Columbia (UBC), Canada. He obtained a BSc (Honors) in Biochemistry at the University of Alberta, Canada, where he also studied for his PhD (1986) in Biochemistry under Dr William Paranchych, studying F-like plasmid conjugation. His postdoctoral studies were performed with Dr Stanley Falkow at the Department of Medical Microbiology and Immunology at Stanford University School of Medicine, CA, USA, where he studied Salmonella invasion into host cells. In 1989, he joined UBC as an Assistant Professor in the Biotechnology Laboratory. Dr Finlay's research interests are focused on host-pathogen interactions, at the molecular level. By combining cell biology with microbiology, he has been at the forefront of the emerging field known as Cellular Microbiology, making several fundamental discoveries in this field, and publishing over 250 papers. His laboratory studies cover several pathogenic bacteria, with Salmonella and pathogenic Eschericia coli interactions with host cells being the primary focus. He is well recognized internationally for his work, and has won several prestigious awards including the E.W.R. Steacie Prize, the CSM Fisher Scientific Award, five Howard Hughes International Research Scholar Awards, BC Biotech Innovation Award, the Michael Smith Health Research Prize, the IDSA Squibb award, the Jacob Biely Prize, he is an MRC Scientist, a CIHR Distinguished Investigator, a Fellow of the Royal Society of Canada and the Canadian Academy of Health Sciences and is the UBC Peter Wall Distinguished Professor. He is a cofounder of Inimex Pharmaceuticals, Inc., and Director of the SARS Accelerated Vaccine Initiative. He also serves on several editorial and advisory boards, and is a strong supporter of communicating science to the public.

Structural Biology of Bacterial Pathogenesis

Research into the pathogenesis of microbial infections has a long and fruitful history, rich with elucidation of mechanisms that have resulted in better treatments and new strategies for vaccine development. Stanley Falkow's investigations into the intimate relationships between bacteria and host cells followed his comment that, microbe is trying to make a living. Structural Biology of Bacterial Pathogenesis, by Gabriel Waksman, Michael Caparon, and Scott Hultgren, is a state-of-the-art treatise describing the known molecular mechanisms by which bacterial pathogens actively probe, sense, and respond to their environment through 2-component systems and through sigma and anti-sigma factors. In addition, the authors describe in great detail the recognition of host receptors by pili and the pilus biogenesis by chaperon-user pathways. The chapter on the role of sortases on surface expression of surface proteins among gram-positive bacteria is comprehensive and well written. Four excellent chapters describe 6 secretion systems among bacterial pathogens and elucidate the specific mechanisms by which bacterial pathogens usurp intracellular mechanisms of the host cell. This book is enjoyable to read, is extensively referenced, and has 52 superb structural models in full color, based in part on x-ray crystallography. Unfortunately, these plates are all in 1 section and require the reader to page back and forth from specific chapters to the core color plates. This book is not a compendium of bacterial toxins and virulence factors but rather a selection of molecular mechanisms of host-parasite interaction. This is a unique book that will be a valuable asset for researchers in the field of pathogenesis, graduate students, faculty who teach microbial pathogenesis, biotech companies, and pharmaceutical companies involved in antimicrobial drug or vaccine development. The sophisticated molecular mechanisms that pathogenic bacteria have developed through their evolution with the human host, as described in this book, are credible evidence that our adversaries, the microbes, are doing better than just making a living.

The Acetobacteraceae: Extending the Spectrum of Human Pathogens

The Acetobacteraceae: Extending the Spectrum of Human Pathogens

Stratégies pour la recherche de gènes de virulence chez les bactéries pathogènes

One of the recent preoccupations of medical microbiology has been to characterise the mechanisms of virulence of bacterial pathogens at the molecular level. One hundred years after Koch, Stanley Falkow proposed a new, molecular version of Koch’s postulates to define a virulence gene: (a) the gene confers a certain phenotype to the studied bacteria, (b) inactivation of the gene abolishes the phenotype, (c) reintroduction of the gene restores the wild type to the mutant. Although this strategy, based upon mutagenesis and the use of experimental models, allows the identification of many genes, it is not comprehensive. Other methods can be used to complete the identification of virulence factors such as differential expression, either at the level of transcription (transcriptome) or at the level of protein expression (proteome). All these techniques are now supported by the data from complete genome sequencing projects. The pool of information obtained from these approaches allows the definition of the ‘virulome’, which is the assembly of factors a pathogen requires for virulence. Understanding the virulome will open the way to the development of new strategies for vaccination or the development of new generation of antimicrobials.

Helicobacter breaks down junctions

![Graphic][1] H. pylori (Hp) opens up cell junctions to a black dye (arrowhead). Amieva/AAASBacteria can break apart cell junctions that link neighboring stomach cells, based on the work of Manuel Amieva, Roger Vogelmann, Stanley Falkow (Stanford University, Stanford, CA), and

Rita Colwell: sea change at the NSF

Rita Colwell: sea change at the NSF

Just Lookin' for a Home

P ity the bacteria that find themselves in the human gut. They must adjust to high temperature and acidity, not to mention competition from other bacteria for food and space. Bile salts bathe them in a powerful detergent. The constant downward squeeze of peristalsis threatens to dislodge them. Many bacteria survive these conditions through sheer tenacity. Adhering tightly to the intestinal lining, they feed and reproduce, developing colonies that cling to inner surfaces of their human hosts like bits of wet tissue paper. Other bacteria make use of the adverse conditions to spur their growth. Some bacteria, such as varieties of the common bacteria Salmonella and Shigella, however, have broken through the barrier posed by the gut. They've found new homes, either by staying within intestinal wall cells or by slipping through those cells to reach quieter niches in other tissues. bacteria that thrive on the surface of the intestines do no harm to their human hosts. Those that penetrate cells, says Stanford University School of Medicine bacteriologist Stanley Falkow, often become pathogens-microorganisms that cause disease. From the bacterial point of view, Falkow says, pathogenicity is simply another facet of their extraordinary versatility. It's survival. It's how the bacteria make a living. From the human point of view, however, this pathogenicity can mean sickness and death. Bacteria often injure cells directly or fan the immune system into a powerful inflammation that does more harm than good. Accordingly, the aim of medical scientists has long centered on wiping out pathogens after a person has become ill. as more bacteria become resistant to antibiotics, a subtler approach might be better. Most of medicine looks at the product of bacterial invasion, at the disease, Falkow says. But disease may be the last thing we want to study; it comes after all the interesting stuff happens. The interesting stuff, according to Falkow, includes how bacteria attach to and enter the cells and how they survive

5310654 Method for determining virulence of yersinia: Ralph R Isberg, Virginia Miller, Stanley Falkow assigned to The Board of Trustees of the Leland Stanford Junior University

5310654 Method for determining virulence of yersinia: Ralph R Isberg, Virginia Miller, Stanley Falkow assigned to The Board of Trustees of the Leland Stanford Junior University

Bacterium-host cell interactions in Monterey

he first Bristol-Myers Squibb Symposium on infectious dis- ease research, entitled 'The Cell and Molecular Biology of Bacterial-Host Cell Interactions', was held in February 1993 in Monterey, CA, USA. Microbiol- ogists studying host-parasite inter- actions gathered with cell biologists studying phagocytes and endo- cytosis to share information and ideas on the interaction of micro- organisms with the host cell. The meeting, organized by Stanley Falkow (Stanford University School of Medicine, USA), featured sem- inars in the morning and exten- sive poster and discussion sessions in the afternoon. This report, rather than being comprehensive, will summarize two themes that emerged from the seminars. Identification of microbial genes expressed

Capsule loss by Haemophilus influenzae type b results in enhanced adherence to and entry into human cells.

Journal Article Capsule Loss by Haemophilus influenzae Type b Results in Enhanced Adherence to and Entry into Human Cells Get access Joseph W. St. Geme, III, Joseph W. St. Geme, III Department of Microbiology and Immunology, Stanford University, Stanford, California Search for other works by this author on: Oxford Academic PubMed Google Scholar Stanley Falkow Stanley Falkow Department of Microbiology and Immunology, Stanford University, Stanford, California Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 165, Issue Supplement_1, June 1992, Pages S117–S118, https://doi.org/10.1093/infdis/165-Supplement_1-S117 Published: 01 June 1992

Reply

Journal Article Reply Get access Denise Monack, Denise Monack Departmentof Microbiology and Immunology, Stanford University School of Medicine, Stanford, California Search for other works by this author on: Oxford Academic PubMed Google Scholar Stanley Falkow Stanley Falkow Departmentof Microbiology and Immunology, Stanford University School of Medicine, Stanford, California Reprints andcorrespondence: Dr. Stanley Falkow, Department of Microbiology, Stanford University School of Medicine, Stanford, CA 94305. Search for other works by this author on: Oxford Academic PubMed Google Scholar The Journal of Infectious Diseases, Volume 161, Issue 3, March 1990, Pages 582–583, https://doi.org/10.1093/infdis/161.3.582 Published: 01 March 1990