PROFILE

Profile of Richard P. Novick acteria are infinitely versatile, occupying every imaginable ecological niche, from miles- B 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 sev- eral 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 bacte- rial toxins, for most resistance to antibi- otics, and for much of the ability of bacteria to attach to body surfaces. Richard Novick, Professor of Microbi- ology and Medicine at New York Uni- versity (NYU, New York, NY), has Richard Novick made critical discoveries about MGEs in staphylococci. In his Inaugural Article published in this issue, Novick, who was other mouse, which it would then at- head of medicine, Paul Beeson. Beeson’s elected to the National Academy of Sci- tack,’’ says Novick. research on endocarditis and infectious ences in 2006, details the mechanism of Despite a growing interest in biology disease inspired Novick and piqued a replication of a fascinating member of and research, after graduating from lifelong interest in how microbes cause the MGE family (1). Yale in 1954, Novick entered medical disease. school at NYU, still unsure of a career Then, in 1960, Novick crossed the Reluctant Biologist goal. ‘‘Although I went to medical Atlantic to the National Institute for Medical Research in London for a post- Born and raised in New York City, Nov- school because of its rough ballpark fo- doctoral fellowship, working with micro- ick developed a love of nature during cus on science,’’ he says, ‘‘I still did not bial biochemist Martin Pollock. During weekends and summers at his family’s quite understand that my calling was research rather than medical practice.’’ his two years in London, the threads of second home in Westport, Connecticut. interest in bacterial genetics and regula- ‘‘I became an outdoor biologist very After his first year of medical school, Novick entered the laboratory of tion, plus infectious diseases, combined early,’’ says Novick. ‘‘My mom would Charles Gilvarg, with whom he would into a career-determining focus on the have a fit when she wanted to take a work for two summers on basic bacterial genetics and biology of the staphylo- bath, only to find a frog or an eel in the biochemistry. As his interest in research cocci. Pollock had put him to work on bathtub.’’ However, he did not realize became clearer, Novick considered leav- ␤-lactamase, a bacterial enzyme respon- that biology was his calling until much ing medical school to pursue a doctorate sible for staphylococcal resistance to ␤ later. In high school, he focused more at The (New -lactam , the and on the ‘‘hard’’ sciences, such as mathe- York, NY). He did not do it. Instead, he cephalosporins. Researchers had just matics, physics, and chemistry. ‘‘In those took advantage of a newly established synthesized a new drug, days, a very long time ago, biology was ‘‘Honors Program’’ at NYU that allowed called methicillin. Pollock wanted Nov- ␤ counting flies and photographing ferns,’’ medical students to take a year off to ick to test whether he could get the - he quips. ‘‘I didn’t even take the course conduct research. Novick spent his year lactamase gene in Staphylococcus to in high school because it was for sis- in the laboratory of Werner Maas, mutate to become resistant to methicil- sies.’’ His perspective changed as an un- where he studied genetic regulation of lin. ‘‘This was ethically slightly dubious; dergraduate at Yale (New Haven, CT). the arginine biosynthetic pathway in one might think twice about encourag- ‘‘I took a very inspiring biology course Escherichia coli. The experience ‘‘initi- ing resistance to a critically important with Norman Giles, which focused on ated a lifelong interest in gene regula- new ,’’ Novick says. ‘‘In the genetics and evolution,’’ he recalls. tion,’’ Novick says. course of those experiments, which ‘‘From that, I developed an interest in failed by the way, I discovered that the Rather than giving up on medicine ␤ the human mind, resulting in a major in entirely, Novick completed his medical -lactamase gene in staph was carried psychology.’’ Novick got his first taste of degree in 1959. ‘‘Then I did a series of by a plasmid,’’ he says (2). Joshua Lederberg discovered plas- serious research when he worked on a what I call ‘yo-yo’ bounces, back and mids, arguably the most important and senior thesis project with biopsychologist forth between clinical medicine and ba- Frank Beach, titled ‘‘Reward value of sic science and couldn’t quite decide aggression in mice.’’ ‘‘As I remember which way to go,’’ he says. In his first This is a Profile of a recently elected member of the National with some satisfaction, a mouse, most clinical bounce, Novick went to Yale– Academy of Sciences to accompany the member’s Inaugural likely male, would learn to perform New Haven Medical Center for an in- Article on page 14182. some task in order to gain access to an- ternship under the direction of Yale’s © 2007 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0707438104 PNAS ͉ September 4, 2007 ͉ vol. 104 ͉ no. 36 ͉ 14179–14181 Downloaded by guest on September 29, 2021 widespread class of MGEs, in the late spected would not acknowledge anything mids regulate their own replication (8). 1940s, determining that they were the novel in our work unless it had been He then identified a plasmid-encoded mediators of bacterial conjugation (mat- confirmed with E. coli. Then they would protein responsible for initiating plasmid ing) in E. coli. However, at the time of quote the E. coli results and not bother replication (9) and demonstrated that an Novick’s discovery, they were still poorly referring to ours. That has been a thorn anti-sense RNA molecule (10) controls understood and had been identified in in my side throughout my career.’’ replication by attenuating production of only a handful of bacterial species. ‘‘This the initiator protein (11). This protein was the first plasmid discovered in Probing Plasmids limited the rate of plasmid replication. Gram-positive bacteria,’’ says Novick. After completing the fellowship with Novick’s studies also led him to suspect ‘‘It was a discovery that was instrumen- Hotchkiss in 1965, Novick began his inde- that this regulation could work only if tal in the development of my career.’’ pendent research career at New York’s the protein were inactivated after use, Before recognition of the plasmid’s bio- Public Health Research Institute (PHRI), a hypothesis later confirmed by Avi Ra- logical significance, clinicians assumed a private, nonprofit institute founded by sooly, a postdoctoral fellow in Novick’s that conventional mutations caused clini- the city to provide a venue for basic re- laboratory (12). cal antibiotic resistance, Novick recalls. ‘‘I search on infectious diseases connected to In parallel with its plasmid studies, was taught in medical school that two the city health department. At PHRI, the Novick laboratory cloned the plas- antibiotics should always be used in treat- Novick discovered that, in addition to an- mid-encoded gene for lysostaphin, an ment since the probability of simultaneous tibiotic resistance, plasmids also carried enzyme that effectively degrades the mutations causing resistance to both was genes for resistance to toxic inorganic ions staphylococcal cell wall (13). Lyso- vanishingly small.’’ However, adds Novick, including cadmium, arsenate, arsenite, and staphin’s ability to lyse staphylococci ‘‘a remarkable observation by the late lead, which could help the bacteria sur- made it a useful reagent for laboratories Tsutomo Watanabe that the dysentery vive in a polluted environment (5). He researching the bacteria. It also sug- bacillus could become resistant to three also demonstrated the in vivo transmission gested that the enzyme could be used to or four antibiotics simultaneously during of plasmid-encoded antibiotic resistance treat staphylococcal infections. Indeed, treatment with only one, and that acquisi- among staphylococcal strains in infected Mead Johnson initiated the develop- tion of a plasmid was responsible, radically mouse kidneys (6) and began a series of ment of lysostaphin as a therapeutic changed this view and led to the realiza- studies of plasmid replication and its agent in the 1960s but quickly dropped tion that plasmids were a major source of control. it for fear that it could spark an immu- antibiotic resistance in bacteria.’’ The theory at the time was that a nological reaction, says Novick. ‘‘I didn’t This finding was ample encourage- plasmid had to be attached to the cell agree with their dropping it,’’ he says. ment for Novick to pursue the study of membrane to replicate. If this was true, ‘‘We thought it could be used therapeu- plasmids and antibiotic resistance in it would mean that the host cell con- tically even if allergenic. It was, mole- staphylococci during his time in Pol- trolled plasmid replication. Researchers for-mole, 100-fold more effective than lock’s laboratory. He developed a also thought then that the plasmid was penicillin for curing an infection in mice number of tools for the study of staphy- an accessory to the bacterial genome, (his unpublished data).’’ ‘‘It’s never lococcal genetics, including a highly sen- merely the provider of useful gene func- really gotten a fair trial,’’ he adds. In sitive assay for ␤-lactamase (3), which tions that were not encoded in the chro- addition, given the growing threat of enabled him to demonstrate that, con- mosomes. However, Novick’s studies methicillin-resistant Staphylococcus trary to the prevailing view, staphylococ- suggested otherwise. ‘‘As we went along, aureus (MRSA), Novick maintains that cal ␤-lactamase could hydrolyze (and we began to realize that the plasmid has lysostaphin could provide a much- inactivate) methicillin, albeit slowly (4). a life of its own,’’ he says. Although it needed therapy. Even if it could be He also began assembling a collection could enable gene transfer, only the used only once per patient, ‘‘it could of staphylococcal strains, which now plasmid itself was transferred. And if save the patient’s life,’’ he says. exceeds 10,000 and is a worldwide the bacteria were, for example, faced resource. with an antibiotic, the plasmid could Investigating Virulence After one last clinical ‘‘bounce,’’ this avoid the fate of its host by transferring Despite the ‘‘E. coli chauvinism’’ that time an internal medicine residency at to a resistant bacterium. Novick experienced early in his career, Vanderbilt University Hospital (Nash- Moreover, contrary to the prevailing it turned out to be an opportune time to ville, TN) from 1962 to 1963, Novick view, all plasmids control their own repli- work on staphylococci. During the late returned to New York, to the laboratory cation by a negative feedback mechanism. 1970s and early 1980s, ‘‘toxic shock syn- of Rollin Hotchkiss at The Rockefeller Indeed, there were plasmid mutations drome,’’ a life-threatening condition University. ‘‘That experience led to ba- causing the plasmid to escape its own reg- caused by a staphylococcal toxin, came sic science as the final resting place for ulation and kill its host bacterium. ‘‘In to the forefront. Novick’s laboratory, my career choice,’’ says Novick. ‘‘As I other words, although the plasmid genes working in collaboration with tampon had my own money (a National Founda- were clearly useful for the host, the plas- manufacturers, cloned the genes for tion Postdoctoral Fellowship), [Hotch- mid was beating its own drum as an inde- toxic shock syndrome toxin-1, TSST-1 kiss] let me do what I wanted.’’ So pendent, self-perpetuating element that (14) and enterotoxin A, which could Novick went back to work on the staph- lived within the bacterium,’’ explains also cause toxic shock (15). ylococcal plasmid system that he had Novick. ‘‘We think of it as the simplest Novick returned to the NYU School discovered in London. At Rockefeller, endosymbiont.’’ of Medicine as Professor of Medicine Novick first encountered a type of In a 1980 Scientific American article and Microbiology in 1993, where he ‘‘small-minded scientific hostility,’’ which (7), Novick detailed this thesis, which continued his studies on toxic shock and he calls ‘‘E. coli chauvinism.’’ At the echoed the ‘‘selfish DNA’’ concept just discovered an important new MGE as- time, E. coli was the darling of bacterial put forth by Richard Dawkins in his sociated with the syndrome. ‘‘We found genetics research. ‘‘Many who worked book, ‘‘The Selfish Gene.’’ These princi- that the TSST-1 gene was present in on E. coli saw little point in studying ples were affirmed by Novick’s work on some strains but not others...anddis- anything else,’’ Novick says. ‘‘Even col- a small tetracycline-resistance plasmid covered that those lacking the gene also leagues I knew well and greatly re- (pT181), which demonstrated that plas- lacked 15 kb of flanking DNA,’’ Novick

14180 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0707438104 Marino Downloaded by guest on September 29, 2021 explains. ‘‘This suggested that the 15-kb Political Passion segment was a specific genetic element Novick’s expertise in bacterial genetics not inserted in the bacterial chromosome, only provided for a successful research perhaps a transposon.’’ It turned out career and election to the National Acad- not to be a transposon but a newly dis- emy of Sciences, it also led him more than covered type of genetic element called once into the political arena. In the early a pathogenicity island. This ‘‘island’’ 1970s, Novick joined other scientists con- was a segment of DNA in the bacterial cerned about biological warfare and the chromosome associated with pathogene- misuse of science for military and com- sis and was not present in nonpatho- mercial purposes in an organization called genic strains of the same species. ‘‘Science for the People.’’ He campaigned In 1998, Novick and colleagues showed against U.S. chemical and biological war- that the TSST-1 gene was carried by fare programs, and, in a controversial a bacteriophage-related pathogenicity is- move, he presented Edward Teller, the land, called SaPI1 (16), the first pathoge- ‘‘father of the hydrogen bomb,’’ with the nicity island identified in a Gram-positive ‘‘Dr. Strangelove’’ award from the organi- species and the first shown to be mobile zation. In another public show of defi- (17). ‘‘These islands, more selfish DNA, ance, Novick and a group of colleagues are related to the bacteriophage in certain The outdoor biologist, Richard Novick, with his resigned en masse from the Council for very special ways,’’ Novick explains. ‘‘They wife, Barbara, and a few of his favorite fungi. Agricultural Science and Technology commandeer bacteriophage functions to (CAST), a committee composed of scien- tists and representatives from agribusiness their own ends. They get themselves ex- drome, anthrax, tetanus, botulism, and and pharmaceutical companies assembled cised and replicated. They then remodel diphtheria) are carried by such elements. the phage capsid to fit their smaller ge- to evaluate the use of antibiotics in feed. Novick’s studies of the genetics of ‘‘I and a well respected group of col- nome and get packaged into the remod- toxic shock syndrome also led him to eled capsids for transfer. It’s very cool.’’ leagues served on this committee for a the discovery of the genetic system used Additionally, although they are like plas- while, until we realized that we were being by the staphylococci to control its viru- mids in that they possess a replicon, en- used in order to legitimize the use of anti- lence. This is agr, a signal transduction abling their autonomous replication, says biotics in feed,’’ he says. ‘‘They were try- system autoactivated by a unique thio- Novick, unlike plasmids, they are ex- ing to discredit the concern people had tremely unstable and cannot segregate to lactone peptide (18–20). ‘‘Activation by for antibiotics in feed.’’ daughter cells. Instead, they rely on this peptide leads to the synthesis of a Novick is less politically active now. He a coinfecting phage for encapsidation remarkable regulatory RNA molecule is exploring several other talents, includ- and release as infectious particles. that controls the synthesis of a wide va- ing reviewing nonfiction science books for In his Inaugural Article, Novick and riety of virulence factors and is respon- The Times Literary Supplement (London). colleagues report the identification of the sible for a switch during growth from an In addition, he returns often to the woods SaPI1 replication origin and replication adherent state to an aggressive, toxin- surrounding his Connecticut home to initiation protein, detailing the mechanism producing mode,’’ explains Novick. The gather mushrooms, skeletons, and inter- by which it replicates and suggesting a agr system is required for pathogenesis esting wood to shape with his lathe. ‘‘I mechanism for its instability (1). Under- and is conserved throughout the staphy- like the idea of getting an ugly, misshapen standing how this staphylococcal pathoge- lococci. However, variants of the system piece of wood and turning it into a beauti- nicity island moves between pathogenic have evolved whose peptides cross- ful vase,’’ says Novick. The reluctant biol- strains of bacteria underscored the pro- inhibit activation of the system and can ogist who once thought biology was ‘‘for sissies’’ now uses its treasures as his found significance of MGEs in bacteria be used to block an experimental infec- palette. and led Novick to the realization that all tion. Novick’s laboratory is busy working of the bacterial toxin genes responsible for on the therapeutic potential of these Melissa Marino, Freelance Science simple toxinoses (such as toxic shock syn- peptides, he says. Writer

1. Ubeda C, Barry P, Penades JR, Novick RP (2007) 10. Kumar CC, Novick RP (1985) Proc Natl Acad Sci 16. Lindsay JA, Ruzin A, Ross HF, Kurepina N, Proc Natl Acad Sci USA 104:14182-14188. USA 82:638–640. Novick RP (1998) Mol Microbiol 29:527– 2. Novick RP (1963) J Gen Microbiol 33:121–136. 11. Novick RP, Iordanescu S, Projan SJ, Kornblum J, 543. 3. Novick RP (1962) Biochem J 83:236–240. Edelman I (1989) Cell 59:395–404. 17. Novick RP, Schlievert P, Ruzin A (2001) Microb 4. Novick RP (1962) Biochem J 83:229–235. 12. Rasooly A, Novick RP (1993) Science 262:1048–1050. Infect 3:585–594. 5. Novick RP, Roth C (1968) J Bacteriol 95:1335– 13. Recsei P, Gruss A, Novick RP (1987) Proc Natl 18. Ji G, Beavis RC, Novick RP (1995) Proc Natl Acad 1342. Acad Sci USA 84:1127–1131. Sci USA 92:12055–12059. 6. Novick RP, Morse SI (1967) J Exp Med 125:45–61. 14. Kreiswirth BN, Lo¨fdahl S, Betley MJ, O’Reilly M, 19. Novick RP, Ross HF, Projan SJ, Kornblum J, 7. Novick RP (1980) Sci Am 243(6):102–107. Schlievert PM, Bergdoll MS, Novick RP (1983) Kreiswirth B, Moghazeh S (1993) EMBO J 8. Carleton S, Projan SJ, Highlander SK, Moghazeh Nature 305:709–712. 12:3967–3975. S, Novick RP (1984) EMBO J 3:2407–2414. 15. Betley MJ, Lofdahl S, Kreiswirth BN, Bergdoll 20. Mayville P, Ji G, Beavis R, Yang H-M, Goger M, 9. Khan SA, Carleton SM, Novick RP (1981) Proc MS, Novick RP (1984) Proc Natl Acad Sci USA Novick RP, Muir TW (1999) Proc Natl Acad Sci Natl Acad Sci USA 78:4902–4906. 81:5179–5183. USA 96:1218–1223.

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