Profile of Richard P. Novick

Bacteria are infinitely versatile, occupying every imaginable ecological niche, from miles-deep ice cores to fuming hot springs to high-pressure cauldrons of the deep. Much of their versatility results from a remarkable ability to exchange genetic material between relatives as well as total biological strangers. To do this, they use “mobile genetic elements” (MGEs), which carry from one to several hundred specialization genes and maintain the ability to self-replicate and transfer themselves from one bacterium to another. Although MGEs have helped bacteria diversify, they are also responsible for virtually all lethal bacterial toxins, for most resistance to antibiotics, and for much of the ability of bacteria to attach to body surfaces.

Richard Novick, Professor of Microbiology and Medicine at New York University (NYU, New York, NY), has made critical discoveries about MGEs in staphylococci. In his Inaugural Article published in this issue, Novick, who was elected to the National Academy of Sciences in 2006, details the mechanism of replication of a fascinating member of the MGE family (1).

Reluctant Biologist

Born and raised in New York City, Novick developed a love of nature during weekends and summers at his family's second home in Westport, Connecticut. “I became an outdoor biologist very early,” says Novick. “My mom would have a fit when she wanted to take a bath, only to find a frog or an eel in the bathtub.” However, he did not realize that biology was his calling until much later. In high school, he focused more on the “hard” sciences, such as mathematics, physics, and chemistry. “In those days, a very long time ago, biology was counting flies and photographing ferns,” he quips. “I didn't even take the course in high school because it was for sissies.” His perspective changed as an undergraduate at Yale (New Haven, CT). “I took a very inspiring biology course with Norman Giles, which focused on genetics and evolution,” he recalls. “From that, I developed an interest in the human mind, resulting in a major in psychology.” Novick got his first taste of serious research when he worked on a senior thesis project with biopsychologist Frank Beach, titled “Reward value of aggression in mice.” “As I remember with some satisfaction, a mouse, most likely male, would learn to perform some task in order to gain access to another mouse, which it would then attack,” says Novick.

Richard Novick

Despite a growing interest in biology and research, after graduating from Yale in 1954, Novick entered medical school at NYU, still unsure of a career goal. “Although I went to medical school because of its rough ballpark focus on science,” he says, “I still did not quite understand that my calling was research rather than medical practice.” After his first year of medical school, Novick entered the laboratory of Charles Gilvarg, with whom he would work for two summers on basic bacterial biochemistry. As his interest in research became clearer, Novick considered leaving medical school to pursue a doctorate at The Rockefeller University (New York, NY). He did not do it. Instead, he took advantage of a newly established “Honors Program” at NYU that allowed medical students to take a year off to conduct research. Novick spent his year in the laboratory of Werner Maas, where he studied genetic regulation of the arginine biosynthetic pathway in Escherichia coli. The experience “initiated a lifelong interest in gene regulation,” Novick says.

Rather than giving up on medicine entirely, Novick completed his medical degree in 1959. “Then I did a series of what I call ‘yo-yo’ bounces, back and forth between clinical medicine and basic science and couldn't quite decide which way to go,” he says. In his first clinical bounce, Novick went to Yale–New Haven Medical Center for an internship under the direction of Yale's head of medicine, Paul Beeson. Beeson's research on endocarditis and infectious disease inspired Novick and piqued a lifelong interest in how microbes cause disease.

Then, in 1960, Novick crossed the Atlantic to the National Institute for Medical Research in London for a postdoctoral fellowship, working with microbial biochemist Martin Pollock. During his two years in London, the threads of interest in bacterial genetics and regulation, plus infectious diseases, combined into a career-determining focus on the genetics and biology of the staphylococci. Pollock had put him to work on β-lactamase, a bacterial enzyme responsible for staphylococcal resistance to β-lactam antibiotics, the penicillins and cephalosporins. Researchers had just synthesized a new penicillin drug, called methicillin. Pollock wanted Novick to test whether he could get the β-lactamase gene in Staphylococcus to mutate to become resistant to methicillin. “This was ethically slightly dubious; one might think twice about encouraging resistance to a critically important new antibiotic,” Novick says. “In the course of those experiments, which failed by the way, I discovered that the β-lactamase gene in staph was carried by a plasmid,” he says (2).

Joshua Lederberg discovered plasmids, arguably the most important and widespread class of MGEs, in the late 1940s, determining that they were the mediators of bacterial conjugation (mating) in E. coli. However, at the time of Novick's discovery, they were still poorly understood and had been identified in only a handful of bacterial species. “This was the first plasmid discovered in Gram-positive bacteria,” says Novick. “It was a discovery that was instrumental in the development of my career.”

Before recognition of the plasmid's biological significance, clinicians assumed that conventional mutations caused clinical antibiotic resistance, Novick recalls. “I was taught in medical school that two antibiotics should always be used in treatment since the probability of simultaneous mutations causing resistance to both was vanishingly small.” However, adds Novick, “a remarkable observation by the late Tsutomo Watanabe that the dysentery bacillus could become resistant to three or four antibiotics simultaneously during treatment with only one, and that acquisition of a plasmid was responsible, radically changed this view and led to the realization that plasmids were a major source of antibiotic resistance in bacteria.”

This finding was ample encouragement for Novick to pursue the study of plasmids and antibiotic resistance in staphylococci during his time in Pollock's laboratory. He developed a number of tools for the study of staphylococcal genetics, including a highly sensitive assay for β-lactamase (3), which enabled him to demonstrate that, contrary to the prevailing view, staphylococcal β-lactamase could hydrolyze (and inactivate) methicillin, albeit slowly (4). He also began assembling a collection of staphylococcal strains, which now exceeds 10,000 and is a worldwide resource.

After one last clinical “bounce,” this time an internal medicine residency at Vanderbilt University Hospital (Nashville, TN) from 1962 to 1963, Novick returned to New York, to the laboratory of Rollin Hotchkiss at The Rockefeller University. “That experience led to basic science as the final resting place for my career choice,” says Novick. “As I had my own money (a National Foundation Postdoctoral Fellowship), [Hotchkiss] let me do what I wanted.” So Novick went back to work on the staphylococcal plasmid system that he had discovered in London. At Rockefeller, Novick first encountered a type of “small-minded scientific hostility,” which he calls “E. coli chauvinism.” At the time, E. coli was the darling of bacterial genetics research. “Many who worked on E. coli saw little point in studying anything else,” Novick says. “Even colleagues I knew well and greatly respected would not acknowledge anything novel in our work unless it had been confirmed with E. coli. Then they would quote the E. coli results and not bother referring to ours. That has been a thorn in my side throughout my career.”

Probing Plasmids

After completing the fellowship with Hotchkiss in 1965, Novick began his independent research career at New York's Public Health Research Institute (PHRI), a private, nonprofit institute founded by the city to provide a venue for basic research on infectious diseases connected to the city health department. At PHRI, Novick discovered that, in addition to antibiotic resistance, plasmids also carried genes for resistance to toxic inorganic ions including cadmium, arsenate, arsenite, and lead, which could help the bacteria survive in a polluted environment (5). He also demonstrated the in vivo transmission of plasmid-encoded antibiotic resistance among staphylococcal strains in infected mouse kidneys (6) and began a series of studies of plasmid replication and its control.

The theory at the time was that a plasmid had to be attached to the cell membrane to replicate. If this was true, it would mean that the host cell controlled plasmid replication. Researchers also thought then that the plasmid was an accessory to the bacterial genome, merely the provider of useful gene functions that were not encoded in the chromosomes. However, Novick's studies suggested otherwise. “As we went along, we began to realize that the plasmid has a life of its own,” he says. Although it could enable gene transfer, only the plasmid itself was transferred. And if the bacteria were, for example, faced with an antibiotic, the plasmid could avoid the fate of its host by transferring to a resistant bacterium.

Moreover, contrary to the prevailing view, all plasmids control their own replication by a negative feedback mechanism. Indeed, there were plasmid mutations causing the plasmid to escape its own regulation and kill its host bacterium. “In other words, although the plasmid genes were clearly useful for the host, the plasmid was beating its own drum as an independent, self-perpetuating element that lived within the bacterium,” explains Novick. “We think of it as the simplest endosymbiont.”

In a 1980 Scientific American article (7), Novick detailed this thesis, which echoed the “selfish DNA” concept just put forth by Richard Dawkins in his book, “The Selfish Gene.” These principles were affirmed by Novick's work on a small tetracycline-resistance plasmid (pT181), which demonstrated that plasmids regulate their own replication (8). He then identified a plasmid-encoded protein responsible for initiating plasmid replication (9) and demonstrated that an anti-sense RNA molecule (10) controls replication by attenuating production of the initiator protein (11). This protein limited the rate of plasmid replication. Novick's studies also led him to suspect that this regulation could work only if the protein were inactivated after use, a hypothesis later confirmed by Avi Rasooly, a postdoctoral fellow in Novick's laboratory (12).

In parallel with its plasmid studies, the Novick laboratory cloned the plasmid-encoded gene for lysostaphin, an enzyme that effectively degrades the staphylococcal cell wall (13). Lysostaphin's ability to lyse staphylococci made it a useful reagent for laboratories researching the bacteria. It also suggested that the enzyme could be used to treat staphylococcal infections. Indeed, Mead Johnson initiated the development of lysostaphin as a therapeutic agent in the 1960s but quickly dropped it for fear that it could spark an immunological reaction, says Novick. “I didn't agree with their dropping it,” he says. “We thought it could be used therapeutically even if allergenic. It was, mole-for-mole, 100-fold more effective than penicillin for curing an infection in mice (his unpublished data).” “It's never really gotten a fair trial,” he adds. In addition, given the growing threat of methicillin-resistant Staphylococcus aureus (MRSA), Novick maintains that lysostaphin could provide a much-needed therapy. Even if it could be used only once per patient, “it could save the patient's life,” he says.

Investigating Virulence

Despite the “E. coli chauvinism” that Novick experienced early in his career, it turned out to be an opportune time to work on staphylococci. During the late 1970s and early 1980s, “toxic shock syndrome,” a life-threatening condition caused by a staphylococcal toxin, came to the forefront. Novick's laboratory, working in collaboration with tampon manufacturers, cloned the genes for toxic shock syndrome toxin-1, TSST-1 (14) and enterotoxin A, which could also cause toxic shock (15).

Novick returned to the NYU School of Medicine as Professor of Medicine and Microbiology in 1993, where he continued his studies on toxic shock and discovered an important new MGE associated with the syndrome. “We found that the TSST-1 gene was present in some strains but not others … and discovered that those lacking the gene also lacked 15 kb of flanking DNA,” Novick explains. “This suggested that the 15-kb segment was a specific genetic element inserted in the bacterial chromosome, perhaps a transposon.” It turned out not to be a transposon but a newly discovered type of genetic element called a pathogenicity island. This “island” was a segment of DNA in the bacterial chromosome associated with pathogenesis and was not present in nonpathogenic strains of the same species.

In 1998, Novick and colleagues showed that the TSST-1 gene was carried by a bacteriophage-related pathogenicity island, called SaPI1 (16), the first pathogenicity island identified in a Gram-positive species and the first shown to be mobile (17). “These islands, more selfish DNA, are related to the bacteriophage in certain very special ways,” Novick explains. “They commandeer bacteriophage functions to their own ends. They get themselves excised and replicated. They then remodel the phage capsid to fit their smaller genome and get packaged into the remodeled capsids for transfer. It's very cool.” Additionally, although they are like plasmids in that they possess a replicon, enabling their autonomous replication, says Novick, unlike plasmids, they are extremely unstable and cannot segregate to daughter cells. Instead, they rely on a coinfecting phage for encapsidation and release as infectious particles.

In his Inaugural Article, Novick and colleagues report the identification of the SaPI1 replication origin and replication initiation protein, detailing the mechanism by which it replicates and suggesting a mechanism for its instability (1). Understanding how this staphylococcal pathogenicity island moves between pathogenic strains of bacteria underscored the profound significance of MGEs in bacteria and led Novick to the realization that all of the bacterial toxin genes responsible for simple toxinoses (such as toxic shock syndrome, anthrax, tetanus, botulism, and diphtheria) are carried by such elements.

The outdoor biologist, Richard Novick, with his wife, Barbara, and a few of his favorite fungi.

Novick's studies of the genetics of toxic shock syndrome also led him to the discovery of the genetic system used by the staphylococci to control its virulence. This is agr, a signal transduction system autoactivated by a unique thiolactone peptide (18–20). “Activation by this peptide leads to the synthesis of a remarkable regulatory RNA molecule that controls the synthesis of a wide variety of virulence factors and is responsible for a switch during growth from an adherent state to an aggressive, toxin-producing mode,” explains Novick. The agr system is required for pathogenesis and is conserved throughout the staphylococci. However, variants of the system have evolved whose peptides cross-inhibit activation of the system and can be used to block an experimental infection. Novick's laboratory is busy working on the therapeutic potential of these peptides, he says.

Political Passion

Novick's expertise in bacterial genetics not only provided for a successful research career and election to the National Academy of Sciences, it also led him more than once into the political arena. In the early 1970s, Novick joined other scientists concerned about biological warfare and the misuse of science for military and commercial purposes in an organization called “Science for the People.” He campaigned against U.S. chemical and biological warfare programs, and, in a controversial move, he presented Edward Teller, the “father of the hydrogen bomb,” with the “Dr. Strangelove” award from the organization. In another public show of defiance, Novick and a group of colleagues resigned en masse from the Council for Agricultural Science and Technology (CAST), a committee composed of scientists and representatives from agribusiness and pharmaceutical companies assembled to evaluate the use of antibiotics in feed. “I and a well respected group of colleagues served on this committee for a while, until we realized that we were being used in order to legitimize the use of antibiotics in feed,” he says. “They were trying to discredit the concern people had for antibiotics in feed.”

Novick is less politically active now. He is exploring several other talents, including reviewing nonfiction science books for The Times Literary Supplement (London). In addition, he returns often to the woods surrounding his Connecticut home to gather mushrooms, skeletons, and interesting wood to shape with his lathe. “I like the idea of getting an ugly, misshapen piece of wood and turning it into a beautiful vase,” says Novick. The reluctant biologist who once thought biology was “for sissies” now uses its treasures as his palette.