Taking a bold step into a new era of biology, a team of scientists from the University of California San Diego, the J. Craig Venter Institute and Yale University has been awarded $10 million by the Howard Hughes Medical Institute (HHMI) to support research on using viruses as new therapeutic agents.
The research team, which combines leading experts from several fields, will leverage the biomedical promise of viruses known as bacteriophages, or phages—including “jumbo phages” that were recently discovered to feature extraordinarily large genomes—in the fight against the rising tide of antibiotic-resistant bacterial infections.
The UC San Diego-led team’s three-year award is part of HHMI’s new $100 million Emerging Pathogens Initiative, an effort announced Jan. 26 that will fund basic research targeted at preparing for future and emerging pathogens that threaten human health.
“Jumbo phages and their ‘weird biology’ open a completely new era that we think will blow open our ability to create new therapy tools,” said Elizabeth Villa, an HHMI investigator, associate professor in the UC San Diego School of Biological Sciences and HHMI Emerging Pathogens Initiative project lead. “The goal of this project is to establish a proof of principle that these jumbo phages can be optimized into a type of personalized therapy against specific pathogens.”
The research team includes Kevin Corbett (UC San Diego), John Glass (J. Craig Venter Institute), Justin Meyer (UC San Diego), Joe Pogliano (UC San Diego), Kit Pogliano (UC San Diego), David Pride (UC San Diego) and Paul Turner (Yale University).
Phages, the most abundant organisms on Earth, for decades have been tapped as a source of therapeutic hope for various diseases. Only recently, however, have they re-emerged as a viable source for countering the growing crisis of bacterial resistance due to their unique abilities to infect and kill bacteria. While attention has historically focused on small phages, the new project will center on phages that are much larger and feature a nucleus analogous to those found in human cells. The larger size allows more room for adding genes that make them better for phage therapy. Finding the right jumbo phages will be key to the project’s efforts.
“You can’t just pick any phage off the shelf and throw it on any bacteria as we did with penicillin,” said Joe Pogliano, a professor in the UC San Diego Department of Molecular Biology and HHMI project team member. “Phage tend to be very specific. Our project’s goal is to create designer phage that have a broad host range so they can infect a large number of bacterial strains.”
The project will join experts from UC San Diego’s Center for Innovative Phage Applications and Therapeutics (IPATH), the first dedicated phage therapy center in the United States, with researchers at Yale University’s Center for Phage Biology and Therapy. Cutting-edge imaging techniques using powerful instrumentation to determine phage structures, synthetic genome technology and genome engineering to build and edit phage genomes will be featured elements of the project.
Viruses and bacteria have been engaged in a continuous struggle to outcompete each other for millions of years. As viruses become skilled at infection, bacteria evolve new defenses to counter infection, causing viruses to develop their own adaptations to work around the bacteria’s evolved defenses. This continuous “evolutionary arms race” will be the focus of the evolutionary biologists who are part of the team.
The research consortium will concentrate on a family of jumbo phage that infect Pseudomonas, a type of bacteria found in soil and water that is known to infect patients in hospital settings, and other pathogens including staph (Staphylococcus) and E. coli (Escherichia).
“We’re seeing that the pathogens that are making us sick are starting to become really resistant to the antibiotics we’ve been using for years,” said project team member David Pride, a professor and infectious disease specialist in the Department of Pathology, UC San Diego School of Medicine. “The pipeline of new and novel antibiotics that are coming along does not seem to be good enough to keep up with the resistance that’s developing over time. Our role is to find and understand phages that kill Pseudomonas and figure out how we can make them better. Let’s start to use these phages in clever ways so that antibiotics are again useful for us and we can decrease the antibiotic pressure that’s driving this crisis around the world.”
The researchers will seek to understand certain jumbo phages enough so that they can deconstruct their essential elements. The team’s expertise in genome biology will help them design and synthetically engineer jumbo phages that are skilled at infecting and killing antibiotic-resistant bacterial pathogens.
“This nimble approach will herald a new era in antibacterial therapies, in which we have both the weapons to fight both current antibiotic resistant bacterial pathogens, and the means to swiftly design and deploy new therapies as new threats emerge,” the scientists note in their project description.
Pogliano says that once they are better able to replicate and understand these jumbo phages, they will be able to take them apart, keep important components and add new components that will make them better at phage therapy.
“We’d like to build new phages that have very broad host ranges and are optimized so that the bacteria also have a much harder time to evolve resistance to them,” said Pogliano.
“The dream is to engineer a phage after we identify what we need to kill the bacteria,” said Villa. “This project brings together diverse people who are incredibly good at what they do in order to tackle an important problem. It’s really a dream team that will bring this idea from basic research all the way to pre-clinical.”
HHMI is committing $100 million to the new Emerging Pathogens Initiative to support basic research targeted at preparedness for emerging pathogens that could threaten human health in the future. Thirteen project teams involving 70 scientists from 29 institutions will collaborate on the research.
“We are optimistic that this initiative will help these scientists develop new, untested approaches that can reveal how pathogens work and how the human immune system responds to pathogen infection,” said HHMI Vice President and Chief Scientific Officer Leslie Vosshall. “With this program, we hope to gain some of the knowledge and tools we need to get a scientific head start on future epidemics.”