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Falkow, Stanley

Stanley Falkow

Stanford University

For a 51-year career as one of the great microbe hunters of all time — he discovered the molecular nature of antibiotic resistance, revolutionized the way we think about how pathogens cause disease, and mentored more than 100 students, many of whom are now distinguished leaders in the fields of microbiology and infectious diseases.

The 2008 Lasker~Koshland Award for Special Achievement in Medical Science honors one of the great microbe hunters of all time. In his 51-year career, Stanley Falkow (Stanford University) discovered the molecular nature of antibiotic resistance and revolutionized the way we think about how pathogens cause disease. He mentored more than 100 students, many of whom are now distinguished leaders in the fields of microbiology and infectious diseases. Falkow invented and exploited new techniques to study how bacteria pass traits to one another and pioneered the use of recombinant DNA technology and other molecular methods to untangle the details by which bacteria survive and spread. He made seminal breakthroughs in understanding causative agents of numerous maladies (including diarrhea, plague, ulcers, tuberculosis, typhoid fever, food poisoning, whooping cough, urinary tract infections, and sexually transmitted diseases) and influenced important advances in public health and in medical and agricultural practices.

Passing resistance

At age 11, Falkow stumbled across a copy of The Microbe Hunters, Paul de Kruif’s book that describes the first microbiologists’ explorations. Entranced by the world in which tiny creatures from pond water and bodily fluids wriggle under microscopes and provoke devastating epidemics, Falkow decided that he wanted to emulate those pioneers.

As an undergraduate, Falkow trained in a hospital microbiology laboratory. There, he learned how to discriminate between bacteria that live peacefully in our bodies and those that cause illness. Biochemical tests pinpointed features that distinguish the microbes from one another, but Falkow’s instincts told him that additional traits dictated whether an organism would stir trouble. This hunch sparked questions that have captivated him ever since: Why do some bacteria, but not their close relatives, live harmlessly within us? What makes a pathogen a pathogen? This early immersion in medical microbiology forever tethered Falkow to the clinical world and led him into his first major research finding.

In 1959, researchers isolated from a patient with typhoid fever a version of its causative agent — Salmonella typhi — that could use the sugar lactose as food. This characteristic violated one of the conventional properties of S. typhi. Falkow was intrigued. It was as if he had seen a lion with zebra’s stripes. Furthermore, this S. typhi could transfer to other bacteria its ability to derive energy from lactose (lac+). The S. typhi observation grabbed Falkow because the germ had picked up its lac+ attribute in nature.

At the time, researchers had detailed some mechanisms by which bacteria pass characteristics to one another, but the lac+ transfer represented a different method from those that had been studied. Therefore, no one had established the molecular nature of the lac+ element.

By exploiting the fact that bacterial species contain DNA of characteristic densities and the ability of the S. typhi strain to transfer its lac+ element to distantly related bacteria, Falkow and the late Julius Marmur (Brandeis University) established in 1961 that the lac+ element was made of DNA and, crucially, that it remains distinct from the chromosome. Such elements are now called plasmids. In addition to establishing that plasmids exist, Falkow’s method broke open the ability to separate them from chromosomes, an advance that would have a dramatic impact on the entire future of molecular biology.

In this same set of experiments, Falkow showed that another ill-defined genetic element — R factor — was also a piece of DNA that resided outside the chromosome. This finding held extraordinary medical importance.

In the 1950s, clinicians had begun to notice that germs could acquire resistance to multiple antibiotics during transit through a patient’s intestinal tract, and by 1962, this phenomenon had become a global health problem. Falkow’s discovery that R factors are plasmids, like the lac+ element, provided an explanation for the observations: Each R factor carried genes that encode resistance to one or more antibiotics, and destructive microbes can pick them up from harmless bacteria that dwell in the body. Falkow subsequently found that the antibiotic resistance genes reside on genetic elements that can hop from one piece of DNA to another. Several other laboratories simultaneously detected these so-called transposable elements — or transposons. Not only could bacteria pass R factors to one another, but the antibiotic genes on these R factors could jump from plasmid to plasmid or from plasmid to chromosome.

In addition to its implications for public health and understanding the basic biology by which bacteria transmit traits to one another, Falkow’s work on lac+ and R factors helped lay the groundwork for one of the first recombinant DNA experiments, in which Herbert Boyer (University of California, San Francisco) and Stanley Cohen (Stanford University) created a hybrid molecule composed of two completely unrelated parent DNAs, one of which Falkow provided. The resulting plasmid duplicated inside a bacterial cell and its descendants. Suddenly it was possible to isolate a gene of interest from any organism, manipulate it, and re-introduce it into living cells.

Opening the bacterial toolbox

The ability to insert single genes into a bacterium of choice presented a new experimental playground for Falkow. This method provided a way to discern the function of any particular gene and thus, he could tease apart individual threads of pathogenesis.

In 1976, Falkow and his student Magdalene So used the new recombinant DNA technology to isolate the heat-stable toxin gene from a type of Escherichia coli that causes diarrhea, thus ‘cloning’ the first gene involved in bacterial virulence. He subsequently pinned down genes that encode many functions — other toxins, molecules that deflect or undermine immune attack, proteins that attach bacteria to their target host cells, and regulators that govern the activity of other virulence genes. He began increasingly to think about virulence factors not as elements that define disease-causing bacteria in the laboratory, but as elements that help bacteria in their fundamental mission to duplicate.

One cloning experiment in particular changed the course of Falkow’s work and the field. He and his postdoctoral fellow Ralph Isberg tracked down a molecule that could confer upon a normally non-invasive type of E. coli the ability to enter mammalian cells in culture dishes. When Falkow looked under the microscope at this event, he noticed that the host cells pucker at the point of bacterial contact and slurp up the E. coli carrying the invasion protein. The molecule seemed to be triggering a normal host process by which the cells usually ingest a useful particle from their surroundings.

Falkow knew then that the next frontier in studying disease-causing bacteria would involve probing interactions between host cells and bacteria rather than bacteria alone in petri dishes. His work in this arena with postdoctoral fellow B. Brett Finlay spurred a profound new approach in the field, a discipline that is now called cellular microbiology. Researchers have since found that bacteria harness multiple host talents to perform tasks that are crucial for the microbes’ duplication and spread. This ability to co-opt host cells allows the germs to gain entry, escape from compartments that would otherwise kill them, hijack molecules and direct them to propel the bacteria into adjacent cells, trigger cell-suicide mechanisms that allow the bacteria to enter their preferred areas of the body, and so on.

Since the beginning of his career, Falkow has forged new tools with which to study infectious disease. In addition to introducing the use of recombinant DNA technology in the field, he initiated the discipline of molecular epidemiology and developed a method for identifying disease-causing bacteria that cannot be grown (and thus scrutinized by conventional means) in the laboratory; he was one of the first investigators to use DNA microarrays, deploying these devices to probe pathogen and host genes that play a role in infection; and he pioneered fluorescent imaging as a means to track microbes inside host cells.

Falkow has applied his knowledge and foresight to benefit the public. For example, he predicted the spread of clinical antibiotic resistance and, in the late 1970s, urged the US Food and Drug Administration to remove antibiotics from animal feed. At the advent of the recombinant DNA era, Falkow’s views on the risks of placing new genes into bacteria were widely sought and proved highly influential in developing the guidelines that govern such experiments.

Falkow’s contributions to bacterial pathogenesis extend far beyond the walls of his own laboratory. An enormous number of researchers in the field, including many of its most illustrious members, have worked with him and he has influenced and inspired numerous other eminent investigators. Falkow is known for his wit and irreverence as well as an unmatched intuition about his miniscule study subjects. He possesses an unusual ability to ‘get inside’ a bacterium and think about the world from the microbial point of view, a perspective that he instills in all audiences. Universally considered the father of modern molecular pathogenesis, he has earned from his trainees and colleagues overflowing respect and affection.

by Evelyn Strauss

Key publications of Stanley Falkow

Falkow, S., Citarella, R.V., Wohlhieter, J.A., and Watanabe, T. (1966). The molecular nature of R-factors. J. Mol. Biol. 17, 110-116.

Heffron, F., Bedinger, P., Champoux, J.J., and Falkow, S. (1977). Deletions affecting the transposition of an antibiotic resistance gene. Proc. Natl. Acad. Sci. USA. 74, 702-706.

Dallas, W. and Falkow, S. (1979). The molecular nature of heat-labile enterotoxin (LT) of Escherichia coli. Nature. 277, 406-407.

Isberg, R.R. and Falkow, S. (1985). A single genetic locus encoded by Yersinia pseudotuberculosis permits invasion of cultured animal cells by Escherichia coli K12. Nature. 317, 262-264.

Valdivia, R.H. and Falkow, S. (1997). Fluorescence-based isolation of bacterial genes expressed within host cells. Science. 277, 2007-2011.

Falkow, S. (2008). The fortunate professor. Annu. Rev. Microbiol. 62, 1-18.

Award Presentation by Stanley Cohen

Award Presentation by Stanley CohenRecently, I re-read The Microbe Hunters, Paul De Kruif’s classic book about scientists and discoveries that provide the foundation for current knowledge about the microbial world. The book recounts medical research from Antonie van Leeuwenhoek, the 17th-century inventor of the microscope and the first person to actually see bacteria, to Louis Pasteur, Robert Koch, Paul Ehrlich, Elie Metchnikoff, and others. De Kruif’s classic was published in 1926; if updated for this century, Stanley Falkow would surely merit inclusion in the pantheon of great microbe hunters. During a scientific career that has spanned more than five decades, the magnitude and breadth of Falkow’s contributions to an understanding of how microbes cause disease and become resistant to the antibiotics used to treat infections have made him a giant among microbial biologists.

Falkow was born in 1934 during the depths of the Great Depression into a Ukranian/Polish immigrant family living in Albany, New York. In a remarkable autobiographical article published earlier this year, he described his childhood in a noisy, colorful neighborhood of tenement row houses filled with a mélange of languages, smells, and customs. Notwithstanding his claim that he was a terrible student, at age 11 Stanley decided that he wanted to be a bacteriologist, and he later began to pursue that goal in earnest. As a young Brown University graduate student carrying out PhD thesis work at Walter Reed Army Medical Center with an older microbiologist named Lou Baron, Falkow found that extrachromosomal pieces of bacterial DNA known as plasmids could transfer themselves even to bacteria that were not closely related. Falkow then helped to prove that differences in composition between the plasmid DNA and the chromosome of the new host enabled the plasmid to be detected biochemically. At that time, the problem of multi-drug antibiotic resistance, which first had been observed in the late 1950s, was becoming the focus of increasing worldwide attention, and the approaches that Stanley pioneered were quickly applied for investigations of the molecular nature of resistance plasmids.

Stanley accepted a faculty position at Georgetown University and during the next decade continued to elucidate the characteristics of resistance plasmids while also beginning studies of bacterial virulence. In 1972, at a US-Japan joint symposium on plasmids in Honolulu, Hawaii, he was present at the Waikiki beach delicatessen discussion— over corned beef and pastrami sandwiches and very cold beer — that resulted in the invention of recombinant DNA by Herb Boyer and me. Stanley’s description in an MIT oral history document helped to make that discussion public. Stanley quickly saw the potential of DNA cloning to solve key problems in both plasmid biology and pathogenesis, and he rapidly established methods in his own lab to do this.

Those were particularly heady times for scientists studying plasmids. Stanley’s lucid and prescient 1975 monograph on bacterial plasmids captured this excitement in an unparalleled way and quickly became a period classic. This burgeoning field also required a uniform nomenclature. Stanley was among the first to recognize this and was part of a group of plasmid workers that addressed the nomenclature issue. The group morphed into a committee whose report at the 1975 Asilomar Conference on Recombinant DNA provided a framework for research guidelines developed during the subsequent years of the biohazard controversy. Working with Stanley on this committee was an experience one does not easily forget; not only was his expertise about microbial disease far greater than the know-how of any of the rest of us, but he was a skillful mediator whose judgment and spirit of compromise brought together disparately thinking scientists.

Later, Stanley’s knowledge and wisdom as a member of the first NIH Recombinant DNA Advisory Committee were crucial in providing perspective in discussions about governmental regulation of research during the early days of DNA cloning. By virtue of his abilities, knowledge, and integrity, he gained respect among persons of widely differing views and was a voice for scientific reason. Although less visible than his research contributions, Falkow’s impact also on the conduct of science has also been enormous through his role as an advisor to the NIH and the Food and Drug Administration, and to companies translating the fruits of scientific discovery into new therapies.

Quite remarkably, increasing his non-lab responsibilities did not in the least slow the pace of Stanley’s scientific contributions. In early 1975, he and his collaborators provided some of the earliest molecular information about bacterial transposons. During this period, he also initiated studies of how bacterial pathogens cause disease: microbial pathogenesis.

Stanley’s laboratory was the first to clone genes that encode bacterial toxins and the molecules that enable pathogens to adhere to and be taken up by mammalian cells. The concept that pathogenic bacteria interact dynamically with the host to cause disease came largely from such work. The list could go on and on. His decades of seminal contributions toward an understanding of microbial pathogenesis have made him the undisputed father of the field. He is also renowned as a master technologist in developing and applying new approaches that address important scientific questions, and as a philosopher who is well known for his love of knowledge and his sage advice. Stanley Falkow is also an outstanding and generous mentor who has trained and/or influenced in a major way virtually all of the scientists that now populate his field.

It is not possible today for me to describe all or even nearly all of Stanley Falkow’s enormous contributions to science, but I’ve tried to convey some sense of who and what Stanley has been. No description of Stanley’s life, whether as a scientist or person, would be complete without mention of his wife, Lucy Tompkins, who has been his closest scientific collaborator and who has brought much love and joy into his life.

The selection of Stanley Falkow for this award speaks directly to the question of what it is that makes a scientist extraordinary. One ingredient is the human qualities that make a person extraordinary, scientist or otherwise — including wit, humility, kindness, and fairness. All who know Stanley know exactly what I mean. Scientific greatness also results from an ability to identify the important questions to address, to creatively design experiments and tools to answer these questions, to correctly interpret results that lead to new concepts, and to provide leadership that inspires awe and respect. During a lifetime of accomplishment, Stanley has epitomized these qualities, and the field of microbiology would not be the same if not for a man and scientist named Stanley Falkow.

Acceptance remarks by Stanley Falkow

Stanley Falkow

Nature Medicine Essay

Acceptance remarks, 2008 Lasker Awards Ceremony

When I was a boy, I looked out into the star-filled sky one night and was awestruck by its beauty. I had just learned in school about how distant these points of light were and the idea of a universe. And I thought, “But what’s beyond that?” I believe it was at this moment that I became a scientist. A few days later, I happened on a book called Microbe Hunters and became equally enchanted by the stories of microbes and their role in disease. It dawned on me that I wanted to explore this hidden universe.

I was able to follow my dream to study microbes because of my teachers. The earliest were all women who taught in public schools. I realized later that I was the beneficiary of the discrimination that for generations led many of the brightest women to find their intellectual outlet by teaching others to be what they could not. Later my professors at the University of Maine and at Brown University taught me the basic tools of science.

My first job at the Walter Reed in 1960 introduced me to the world of epidemiology and global medicine. It was there that I learned how infectious diseases had influenced human history. Subsequently I discovered the joys of teaching. I have been a professor at three universities since then, but there has been one constant — students. The greatest compliment one can receive is when a student says that he or she wishes to work with you. It is also a moment of anxiety since these individuals have essentially put part of their lives in your hands. The language has changed. The music played in the laboratory has changed from Pete Seeger in the ’60s to what now seems to me to be random noise. Yet, thank goodness, the same palpable exuberance, excitement and passion for knowledge and the occasional joy of joint discovery remains the same.

At a time when infectious diseases were predicted to be no longer important because of the use of antibiotics, my students and I learned how bacteria were becoming quickly tolerant to these medicines. Subsequently, we uncovered tactical tricks used by microbes to infect humans. We learned that bacteria know more cell biology and immunology than possibly all previous Lasker Award winners; microbes are masters at harnessing the normal human cellular machinery for their own purposes, and they have learned to circumvent the immune system that’s designed to defeat them. The more we learned about how microorganisms persisted on and within us, the more we learned about our own biology. I believe this fundamental understanding is the key to the future development of effective vaccines and therapeutic intervention against all infectious disease.

It is not a matter of them versus us, or a war of attrition. Rather, based on cell number, each of us is more microbial than human; we carry ten times more microbial cells than cells of our own. The human body is a biological universe of many species, most of which have never been grown in the laboratory and whose role in health and disease is still a mystery. It is another new frontier and another great adventure of discovery of just the kind promoted by The Albert and Mary Lasker Foundation.

I am honored to receive this special award. Yet, you must now realize that my life in science was fueled by my teachers and mentors and reflects the shared dreams and ideas of my creative students and colleagues. I share this recognition with them. And, with my little buddies, the microbes.

Interview with Stanley Falkow