Fischetti’s studies have shown that when small amounts of phage lysins are given to infected mice, the disease-causing bacteria die rapidly. For example, Fischetti and his collaborators have shown that the phage enzyme Cpl-1 can cure mice with fatal pneumococcal pneumonia and completely reverse lung tissue damage when given 24 hours after infection. Similar results were seen in mice with life-threatening infections by antibiotic-resistant S. aureus by treating them with a lysin engineered specifically for staphylococci. A recent successful phase II clinical trial involved patients with methicillin-resistant S. aureus, or MRSA, a common infection that doesn’t respond to conventional antibiotics. Results revealed that, among patients whose infection had spread to the blood, the positive response rate to treatment was 40 percent higher when a lysin-based drug called Exebacase was given together with antibiotics, compared to when antibiotics were administered alone. On follow-up, patients treated with lysin and antibiotics left the hospital sooner (6 vs 10 days) and had fewer relapses that resulted in re-admission to hospital (8% vs 15.4%) than patients treated with antibiotics alone. This lysin technology has now progressed to phase 3 clinical trials and is the first antibiotic alternative to successfully achieve this final milestone. Like antibiotics, lysins may be developed to most disease bacteria.

The lab also developed novel immunotherapies inspired by lysins. The Fischetti lab fused a portion of the S. aureus-specific lysins to immune molecules called antibodies, generating so-called “lysibodies” with the capacity to tag all staphylococci for destruction by human immune cells. Lysibodies may also be used to boost the immune response of Staphylococcus-infected patients. In mouse models, lysibodies were shown to protect the animals from infection by MRSA staphylococci. Since all attempts to develop vaccines to protect against staphylococcal infections have so far failed, lysibodies may be used passively in pre-surgical patients to protect them from hospital-associated S. aureus infections, particularly MRSA.

Fischetti is a faculty member in the David Rockefeller Graduate Program, and the Tri-Institutional M.D.-Ph.D. Program.

Education

• B.S. in bacteriology, 1962 , Wagner College

• M.S. in microbiology, 1967 , Long Island University

• Ph.D. in microbiology, 1970 , New York University

Postdoc

• The Rockefeller University, 1970–1972

• Albert Einstein College of Medicine, 1972–1973

Positions

• Assistant Professor, 1973–1978

• Associate Professor, 1978–1990

• Professor, 1990–

• The Rockefeller University

Awards

• NIH MERIT Award, 1987, 1997

Honorary Societies

• National Academy of Inventors

Selected Publications

• Raz, A. et al. Isolation of phage lysins that effectively kill Pseudomonas aeruginosa in mouse models of lung and skin infections. Antimicrob. Agents Chemother. 63, e00024-19 (2019).

• Heselpoth, R.D. et al. Lysocins: bioengineered antimicrobials that deliver lysins across the outer membrane of gram-negative bacteria. Antimicrob. Agents Chemother. 63, e00342-19 (2019).

• Raz, A. et al. Lysibodies are IgG Fc fusions with lysin binding domains targeting Staphylococcus aureus wall carbohydrates for effective phagocytosis. Proc. Nat. Acad. Sci. U.S.A. 114, 4781–4786 (2017).

• Lood, R. et al. Novel phage lysin capable of killing the multidrug resistant gram-negative bacterium Acinetobacter baumannii in a mouse bacteremia model. Antimicrob. Agents Chemother. 59, 1983–1991 (2015).

• Gilmer, D.B. et al. Novel bacteriophage lysin with broad lytic activity protects against mixed infection by Streptococcus pyogenes and methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 57, 2743–2750 (2013).

Twenty-five years later, Fischetti looked up at that hotel room window, as he walked into the Paris Opera House on the red carpet. The occasion was the 100th anniversary of the Pasteur Institute, one of the world's great scientific research centers focused on infectious diseases, and Fischetti was an honored guest. Over the years, the optimistic pronouncements of Macfarlane Burnet and others had not proven true. The fight against infectious diseases had not ended; if anything, it had become even more intense. Fischetti had become something of a general himself: a leader in the ongoing war against harmful bacterial infections.

In fact, in many ways, Vincent Fischetti '62 H'10 is changing the nature of the war itself, opening new fronts in the fight against man's smallest and deadliest enemies.

Total Immersion

When you step off of a charmless stretch of York Avenue in Manhattan onto the campus of Rockefeller University, it feels like you are entering an enchanted garden. Behind an ornate wrought-iron fence, you glimpse tree-lined paths, brick facades, and a geodesic dome, like a giant white egg laid in the greenery.

This wondrous place has been Vince Fischetti's professional home ever since he first came to work here in August 1962, and was immediately immersed into the struggle to understand and outwit the microbial world.

Postdoctoral researcher June Wang displays a petri dish with a streptococcus bacterium colony, sitting on agar gel that contains human blood.

Rockefeller University is not what most people think of when they hear the word “university.” It has no undergraduate students; it awards only Ph.D.s, and it is structured around laboratories — more than 70 of them at this point, all focused on different aspects of biological and biomedical research.

To the young Vince Fischetti, this place was, indeed, a microbiologist's paradise. As a young boy, growing up in West Hempstead, Long Island, he had spent many happy hours engrossed in his microscope, watching things move in the water he took from a pond near his home, and teaching himself how to preserve the microscopic creatures on slides.

But young Vince was not just a nerdy bookworm — he started mowing lawns on his father's work crews at age 10, and he also showed a gift for athletics. He was small but quick and strong, and he excelled in high school as a sprinter and a halfback. That took him away from the microscope for a while — but when it came time to go to college, he was steered by science.

Turning down college football scholarships (at 140 pounds, he says, “I knew I would have gotten killed”), he chose Wagner College and enrolled as a pre-dental student. When he took his first microbiology course, though, he was smitten. “This is what I love to do,” he thought, peering through microscopes and studying those tiny worlds. He declared a major in bacteriology and public health, the highly unusual undergraduate program founded by Edythe Kershaw and Natale Colosi just a few years prior, and never looked back.

‘This is what I love to do,’ he thought, peering through microscopes.

His roommate, Ted Caccia '62, remembers Fischetti studying in their room every night, while Caccia was out playing intramural basketball. They both belonged to Delta Nu fraternity, as did Frank Catalfumo '62, a fellow bacteriology major and boyhood friend of Fischetti's.

“He was a very organized studier,” says Catalfumo. “He took magnificent notes. I would study for exams the night before. Vinnie would be sleeping, and I'd review his notes.”

Catalfumo, now a successful plastic surgeon in Florida, tried to persuade Fischetti to go to medical school with him — to no avail. Fischetti knew that his calling was in the laboratory. In December of his senior year, he attended a seminar on virology at Rockefeller University and afterward wrote to all of the speakers to ask if they had openings in their labs. His letter was forwarded to Maclyn McCarty, head of the Laboratory of Bacterial Pathogenesis and Immunology.

With this connection, Vince Fischetti had found his place. One member of the McCarty lab, John Zabriskie, needed an assistant. A physician-scientist, he was interested in understanding the microbial chain of events that triggers scarlet fever. Every morning, Zabriskie met with Fischetti to discuss what needed to be done in the lab that day. Then Zabriskie went to the hospital to work with patients, leaving his assistant to figure things out mostly on his own.

“I cannot believe they pay me for this,” Fischetti thought. “I was in the lab doing experiments, being on my own, making decisions. … I was like a pig in shit. That's when you love what you're doing, you're immersed in it.”

A Perennial Problem

Coincidentally, it was one grandfather's tragic experience with scarlet fever that inspired the founding of Rockefeller University itself.

In January 1901, a young boy fell ill with scarlet fever. He died days later. Neither the disease nor its outcome were unusual in those days. But this boy's grandfather was John D. Rockefeller Sr., one of the wealthiest men ever to walk this earth. Later that year, pushed by this family tragedy, he founded the Rockefeller Institute for Medical Research. It was the first of its kind in the United States.

‘If you understand what’s happening during those earliest events [of infection], hopefully you can stop it. Then you prevent infection, rather than waiting for the infection to happen, and then treating the infection.’

At that time, no one even knew what caused scarlet fever, much less how to treat it. Today in the United States and other developed nations, scarlet fever is easily treatable by a course of antibiotics. The groundwork for this medical triumph was laid by a woman whose black-and-white photo hangs in Vince Fischetti's office: Rebecca Lancefield.

“She's called 'The Mother of Streptococci,'” Fischetti says. Lancefield discovered that certain streptococcus bacteria, Streptococcus pyogenes or group A, were the culprit behind not only scarlet fever, but also other common diseases such as strep throat. Because of her work, therapies and tests were developed that enable doctors to quickly detect and treat strep throat, making its potentially lethal complications, like scarlet fever and rheumatic fever, almost unknown in developed countries today.

But, Fischetti points out, the solution is not perfect. Strep throat and its more dangerous relatives are the only common childhood diseases for which there is no vaccine. Outbreaks of rheumatic fever still occur periodically in the United States. And in the developing world, where rapid strep detection and antibiotic treatment are not available, rheumatic fever is still a significant public health problem. Every year, rheumatic fever outbreaks leave surviving victims with permanent heart damage, unable to work.

That's only one of the problems that has impelled Fischetti's work. While the antibiotics developed over the past century have markedly improved human health, infectious bacteria have evolved along with them, developing new defenses against attack. Antibacterial resistant strains have multiplied, especially in hospitals, outpacing scientists' ability to develop new drugs. Biological terrorism, such as the anthrax attacks of the fall of 2001, have raised new concerns and needs for protection.

Plenty of work for microbiologists like Vincent Fischetti.

A Virulent Cast of Characters

On every front of the war against infectious disease, Fischetti is developing tactics that have never been tried before.

Primarily, his tactic is prevention — rather than developing treatments for infections, he is focusing on how to prevent infection from happening at all. And preventing infection requires understanding how bacteria work — really understanding how bacteria work.

“This whole lab has always been interested in understanding the very earliest events in infection,” Fischetti says. “Because if you understand what's happening during those earliest events, hopefully you can stop it. Then you prevent infection, rather than waiting for the infection to happen, and then treating the infection.”

His first project at Rockefeller University, the scarlet fever study with John Zabriskie, introduced him to key microbial characters that have loomed large in his work ever since. They knew that group A streptococci released a toxin that caused scarlet fever. But what was it in the bacteria that produced the toxin? Zabriskie had a suspect: bacteriophages (also known as phages), a type of virus that attacks bacteria. With Fischetti's help, he proved he was right. “It was a major finding at the time,” says Fischetti.

While working full-time on this project, Fischetti earned his master's in microbiology at Long Island University. It took him four years to finish, working on it at night. Then, his Rockefeller mentors told him, “That's nice, but if you really want to advance in this field, you need a doctorate.”

“So,” Fischetti says, “I applied for Ph.D. programs.” He already knew exactly what he wanted to study: bacteriophages. He was accepted by New York University, and continued working in the lab at Rockefeller University. His study of the phage enzyme called lysin, which allows a phage to burst open the bacterium it has infected and release its progeny into the environment, was published in the Journal of Experimental Medicine in 1971.

Meanwhile, he had become a postdoctoral researcher at Rockefeller and started to work on another project: Defining the structure of the M protein, a molecule on the surface of group A streptococci. The long, thin strands of M protein all over the bacteria's surface make them look like fuzzy little tennis balls. This “fuzz” surrounding the bacteria is what makes strep infectious to humans, defusing our immune system's defenses and allowing the bacteria to become active.

Over decades of work, Fischetti became the first scientist to clone the gene of the M protein, the first to determine its structure, and the first to completely characterize any surface protein on this class of bacterium. He also became convinced that the M protein was the most promising target for developing his holy grail: a strep vaccine.

In fact, Science magazine published one of his approaches for an M-protein-based strep vaccine in 1989. He tested it and found it effective in mice. But so far, no pharmaceutical company has stepped forward to fund its development for human use. There are multiple reasons for this lack of interest, with the financial calculus standing at the top of the list. Nevertheless, Fischetti has confidence that one day, the strep vaccine will be made. Rheumatic fever is a significant problem in developing countries, he says, and he is working with the World Health Organization to solve this public health concern.

A Eureka Moment

Meanwhile, his work on bacteriophages and the enzyme lysin was far from forgotten. One day about 10 years ago, he says, he was having a phone conversation with a colleague. “We were just talking about lysins in general, and things like that,” he recalls. Because he was working on his strep vaccine at the time, he had mice infected with strep throat for one of his vaccine studies. The conversation about lysins, though, gave him a different idea.

The function of lysins, after all, is to burst open bacteria, killing them. And that's exactly the goal of antibiotics: to kill bacteria. If it works for phages, Fischetti suddenly realized, might it not work for him?

He went back to the strep throat-infected mice and added lysin to their oral cavities. He waited about an hour, then swabbed the mice's throats and tested the results: They were clean. No more strep. No more infection.

“It was a eureka moment, no question about it,” he says with a grin. “And that was what really started this whole process of using lysins as a therapeutic.”

The novelty of this approach to bacteria-busting also struck the U.S. patent office, which issued him a patent in record time. Since then, he has accumulated about 40 patents for lysins and other treatments targeted at different organisms.

This specificity speaks to one of the benefits of the lysin technology: As opposed to conventional antibiotics, which can kill everything in their path — including bacteria that are essential to human health — lysins target specific bacteria: only group A streptococcus, or only pneumococcus, or only Bacillus anthracis (which causes anthrax), which are all bacteria against which lysin has been shown to be effective.

Fischetti’s lysin treatments use ‘nature against nature,’ he says. ‘It’s always the best way.’

Furthermore, lysin acts very fast, killing bacteria within seconds of contact. And to top it all off, Fischetti's lab has shown that bacteria will not be able to easily develop resistance to lysin-based drugs, as they do to conventional antibiotics. For a billion years before any other life appeared on earth, bacteria and phages, the source of lysin, evolved in tandem with one another, learning to exploit each other's strengths and weaknesses. A phage actually drills into a bacterium to reproduce, and then produces lysin to get back out, exploding its host in the process. Therefore, Fischetti was able to follow phages to bacteria's Achilles heels: Molecular targets that are consistently and unavoidably lethal to bacteria. In other words, he's using “nature against nature,” he says. “It's always the best way.”

A startup biotech company, Contrafect, has licensed the technology to produce a lysin drug to treat staph, skin, and soft tissue infections; the first stage of human trials is expected to begin next spring. And many other uses for lysin are under development, ranging from an agent that can decontaminate an environment of anthrax spores without using harsh chemicals, to a lysin drug that could treat battlefield wounds infected with MRSA (methicillin-resistant Staphylococcus aureus).

Defensive Measures

Vince Fischetti became an assistant professor at Rockefeller in 1973, an associate professor 1978, and a full professor in 1990. He served for 10 years as editor-in-chief of a major scientific journal, Infection and Immunity, and he has published well over 200 papers and book chapters. Under his leadership for the past two decades, the Laboratory of Bacterial Pathogenesis and Immunology — the most historic lab at Rockefeller University — shows no sign of losing its vitality, relevance, and productivity.

The lysin technology, especially with its applications to anthrax, is the most attention-grabbing development in the Fischetti lab right now, but it's far from the only promising project underway.

Visiting his laboratory on the eighth floor of the Bronk Building at Rockefeller University, you'll find lab benches crammed with equipment and petri dishes; old filing cabinets and handwritten signs (“If you spill buffer over counter can u please clean it up”); and graduate students and postdocs who are dressed, like college students anywhere, in T-shirts and jeans.

It doesn't look imposing, but Vince Fischetti and his longtime lab tech, Clara Wetzel Eastby '69, who has worked with him ever since she graduated from Wagner with a bachelor's in bacteriology, make sure that everything runs with razor-sharp precision. This team has a feel for microbes that is unparalleled; you could even say that it's in the blood — literally.

"You need a feel for the cell work," says Clara Wetzel Eastby '69. "Other people can look at the same cells, and not see what I'm seeing."

At one of those crowded benches, postdoctoral researcher June Wang picks up a petri dish. Its contents are a translucent rosy color, irregularly speckled with clear circles. Inside each circle is one tiny dot. That, Wang says, is a streptococcus bacterium colony, sitting on agar gel that contains human blood. Each colony ruptured the red blood cells around it, creating the cleared zones.

“This is Vince's blood, actually,” she says.

“She bled me yesterday,” he adds with a shrug. He points out a second dish, which has the same rosy color, but no clear circles. “I have antibodies to this strep, because I've been working with it for so long.”

Fischetti's antibodies are the envy of many an ill person. These scouts of the bloodstream latch onto harmful bacteria, so that the white blood cells, or phagocytes, recognize them as enemies and, as Fischetti says, “gobble up the organisms.” The difference between the two dishes was that the first had been kept still, and the second one rotated. That motion allowed the phagocytes to “find” the bacteria and eliminate them.

Wang's experiment on her boss's blood is a preparatory stage for her work on developing an antibody therapy for staph infections. “They're really nasty bugs,” Fischetti says, noting that about 700,000 people are hospitalized each year in the US with staph infections, and about 20 percent of those infections are lethal. While Fischetti's lysin technology has the potential to clear up staph much faster than current treatments, the antibody approach would help susceptible patients stave off infection in the first place.

In the meanwhile, his best advice to keep yourself healthy is simple: drink a lot of water. “Drinking water is healthy, and it makes you go to the bathroom,” he says. “You go to the bathroom, you wash your hands. That's your best protection. Unless someone sneezes on you. There's nothing you can do about that.”

No matter how complicated life gets for Fischetti — traveling from New York to Boston to Nevada to Italy to give lectures, writing and revising major papers, advising and managing dozens of graduate students and postdocs, raising millions of dollars in grant money — in a way, it's still the playground it always was.

“I always look at it as climbing Mount Everest,” he says. “Every time you get a result, you see something no one's ever seen before. And that's what keeps me excited, is a finding that is new, and a finding that no one has ever discovered before.” A finding that just may, one day, save your life.