Engineered Viruses to the Rescue?

As the stakes rise in our war against antibiotic-resistant pathogens, medical researchers are seeing new hope in souping up a century-old viral weapon with cutting-edge synthetic biology. With a June 2023 World Economic Forum report highlighting so-called “designer” bacteriophages—genetically engineered versions of the viruses that are bacteria’s natural predators—as one of the year’s most promising disruptive technologies, government funding and new startups are pushing to make that prediction a reality. The field holds promise not only for human medicine but also for tackling bacterial diseases in the plants and animals we rely on. Beyond that, possible applications could be deployed anywhere bacteria cause problems, such as in food processing, environmental remediation, and wastewater treatment.

Bacteriophages, or phages, first came to light in the 1920s as a treatment for bacterial infections but fell out of favor 20 years later with the advent of penicillin and other antibiotics. Phage re­search and use was kept alive primarily in Soviet-bloc countries, and Georgia in particular, home to the 100-year-old Eliava Institute of Bacteriophages, Micro­biology, and Virology. Highly specific bacteria killers, phages are harmless to any other organism, including human cells. Each strain of these viruses may target only a handful, or even just a single strain, of a particular bacteria species; pinpointing the correct phage version—out of a pool made up of the most abundant organism on the planet—to use for any given patient is akin to finding the proverbial needle in a haystack. Antibiotics, on the other hand, are broad-spectrum weapons that were welcomed as quicker, easier-to-use cures. But the simplicity of antibiotic treatment has since become its downfall, with overuse resulting in the rise of “superbugs,” bacteria that shrug off many, and sometimes all, of our available antibiotics. That resistance to our drug arsenal is now considered one of the top global health threats as pathogens evolve resistance faster than resear­chers can develop new, more effective antibiotics. Without effective alternatives, the World Health Organi­zation estimates that antibiotic-resistant infections could overtake cancer and heart disease as the world’s leading cause of death by 2050, killing as many as 10 million people each year.

The renewed focus on phages is only about a decade old, as the pipeline of new antibiotics dried up, and work is moving beyond a focus on “natural” phages collected from the environment. Kept in phage libraries at research institutions around the world, these wild-type phages are studied to determine their target bacteria and other characteristics. Phages can’t replicate on their own but require bacterial hosts—and not just any bacteria will do. They zero in on a specific receptor on their targets that matches a binding protein that phages carry in their tails, much like a key designed for a particular lock. Once that lock is open, the phages favored for therapeutic use inject their genetic material inside bacteria cells, where they produce numerous copies that ultimately burst open the host’s cell walls, killing that bacterium, and sending the progeny out to continue the cycle in new hosts.

Exactly how many different phage strains exist is unknown, but their abu­ndance is staggering. According to Ste­ffanie Strathdee, codirector of the Center for Innovative Phage Applica­tions and Therapeutics at the University of Cal­ifornia, San Diego, a single drop of water can contain trillions of phages. One of the bigger phage libraries, at the University of Pittsburgh, has identified 23,000 strains. New finds regularly added to the collection there and at other libraries are building a vital resource for creating the right therapeutic cocktails to match the bacteria causing patients’ infec­tions. These mixtures of several complementary phages provide better results against problematic infections than any single phage strain, helping to ensure that any bacteria that develop resistance to one phage won’t escape the other killers. So far, most contemporary evidence favoring phage treatment is essentially anecdotal, the result of individualized “compassionate use” cocktails administered when antibiotics have failed. This collection of data points is compelling but doesn’t carry the same confidence as controlled clinical trials, given that each case presents a different set of bacteria and phage strains.

Some clinical trials are in their early stages, however, including a phage cocktail from Israeli company BiomX designed to attack persistent antibiotic-resistant Pseudomonas aeruginosa (PsA) infections in cystic fibrosis patients. But it’s the pairing of phages with genetic engineering and other synthetic biology technologies that may provide the necessary leap forward. Work in labs around the world is taking natural phages and tinkering with their genome to broaden their target range to additional strains of such bacteria as Escherichia coli (E. coli) and PsA. Their aim is to create more standardized weapons to replace the one-off concoctions that are now necessary. BiomX’s cocktail, nebulized to do its work inside the lungs, incorporates phages with the broadest possible target range chosen from a forced evolution program that taps into gene sequencing and machine learning. Another clinical trial, with a cocktail of engineered phages designed by North Carolina–based Locus Biosciences Inc., is underway to test its efficacy against the E. coli bacteria that cause 80 percent of urinary tract infections. Other research focuses on improving phages’ ability to break down bio­films that shield bacteria, and on boosting phages’ deadliness to ensure fewer of their bacterial prey escape. Phico Therapeutics Ltd.’s app­roach uses engineered phages to hijack their targets’ DNA and turn it against them, for­cing the bacteria to produce proteins that prevent the pathogens from reproducing or feeding themselves. The UK company has completed a Phase 1 clinical trial of a version against Staphy­lococcus aureus, and has versions under development tailored to E. coli, PsA, and Klebsi­ella pneumoniae.

Researchers are also delving deeper into the mechanisms that help both phages and bacteria survive and thrive. The CRISPR-Cas gene-editing tool stems from a defense that bacteria employ to inactivate phages by snipping out sections of their DNA. Conferring that same ability to phages to use against their bacterial prey could make them even more precise and deadly weapons. Elsewhere, understanding fundamental phage systems and traits is helping gene engineering go beyond simply tinkering to the assembly of entirely new, fully functioning phage genomes from DNA fragments. That could be key to reaching a practical production level for widespread phage use. To get there, biofou­ndries, including the US Department of Energy–funded Phage Foundry project, are being established to harness automation and machine learning to speed up and expand the work of synthesizing and engineering phages.

Adding to the impetus for creating designer phages through gene editing and other types of synthetic biology is a profit motive. Simply put, phages collected from the environment and used without modification can’t receive the same patent protection as any chemical pharmaceutical developed in the lab, but precedents exist to patent engineered organisms. Apart from any hurdles to patenting these new phages on their own, products that incorporate engineered phages, such as wound dressings or implants with infection-fighting coatings, are more likely to sail through the process.

Farther down the road is the prospect of using phages for more than just killing bacterial pathogens, but to also serve as delivery vehicles for therapeutic molecules, gene therapy, and diagnostic tools. With an added gene for luminescence, phages could be deployed to hunt down a specific pathogen and light up when it latches on to its target, speeding up the tests needed to determine the cause of an infection. Engineering could steer phages to attack tumor cells or replace defective genes at the root of some genetic disorders. As our ability to design and create new, beneficial phages ramps up, the future looks promising for not only wins in the fight against drug-resistant infections, but other medical breakthroughs as well.

 

Innovation Flashback

May 8, 1886—An Atlanta drugstore sells the first glass of Coca-Cola for a nickel at its soda fountain, pairing carbonated water with a syrup invented by pharmacist John Stith Pemberton. Pemberton intended his syrup, originally produced with coca leaves and kola nuts, for use as a patent medicine, and it was marketed in the area as a temperance alternative after local legislation prohibited alcohol sales. In its first year, daily sales of the drink averaged nine glasses, but by the late 20th century, Coke dominated the global soft drink market, and now comes in sugar-free and caffeine-free varieties, as well as a range of flavors. Although the exact formula remains a trade secret, the original coca leaves—common at the time in tonics along with caffeine-rich kola nuts—have long since been replaced by cocaine-free “spent” versions.

May 14, 1796—Edward Jenner administers the first smallpox inoculation to an 8-year-old boy, using infectious material from a dairymaid who had contracted the related but mild cowpox virus. Jenner’s experiment offered significant improvement over the existing practice of variolation, which inserted live smallpox scabs into the skin in hopes of conferring immunity without passing on the infection. At the time, smallpox killed roughly 400,000 Europeans a year, and left a third of the survivors blind; introduced by European explorers and colonists into the Americas where the population had no previous experience with the disease, smallpox proved devastating. After the cowpox inoculation, Jenner’s young subject developed a mild fever, but recovered in time for the experiment’s second stage: an inoculation with material from a smallpox lesion that demonstrated the boy’s newfound immunity. Although decades passed before variolation fell completely out of favor, Jenner is now considered one of the founders of immunology. Today, despite unproven fears of vaccines, vaccination—the term stemming from the Latin word for cow—is a standard protection against many diseases. After a vigorous global vaccination campaign, the World Health Organization in May 1980 declared smallpox completely eradicated, finally fulfilling a prediction Jenner had made less than 200 years earlier.

May 22, 1990—Microsoft releases Windows 3.0, a groundbreaking version of its operating system that launches the company to market dominance. New features included a graphical user interface that introduced clickable icons, as well as an improved file management system, better memory management, and even Solitaire—all a major leap over Microsoft’s MS-DOS command line-based system. Windows PCs now offered similar, or better, features to previous market leader Apple Macintosh at a significantly lower cost. First-year sales totaled 4 million Windows copies, a figure that had climbed past 10 million copies by the time Windows 3.1 came out in 1992. That same market dominance, however, ultimately brought Microsoft under fire and government scrutiny for anticompetitive practices that led to a 1994 settlement in which the company agreed to stop bundling separate software packages with its operating system.

May 23, 1930—The US Congress enacts the Plant Patent Act, allowing breeders to patent new plant varieties, and bypassing the requirement for an industrial patent to describe the invention well enough that others could reproduce it—an impossibility with plants, even with a complete DNA sequence. This new type of patent applied only to new and distinct varieties of asexually produced plants, and several such patents were awarded posthumously to renowned horticulturist Luther Burbank. Today, the US Patent and Trademark Office issues more than 1,000 plant patents each year, helping to protect this aspect of horticultural innovation. The 1930 legislation was cited as a precedent 50 years later, in a US Supreme Court case on whether other living organisms could be patented. On June 16, 1980, a 5–4 court majority ruled in Diamond v. Chakrabarty that genetically engineered bacteria able to break down crude oil qualified for patent protection. Ananda Mohan Chakrabarty and his employer, General Electric, intended the newly developed microorganism for use in treating oil spills. Their victory is considered a turning point for the biotechnology industry, allowing it to profit from research investments, and clearing the way for numerous examples of synthetic biology now found in industry, farms, hospitals, and medical research.

June 26, 1974—A pack of Wrigley’s gum with a printed barcode is scanned at an Ohio grocery store checkout, marking the first use of the newly developed Uniform Product Code for speedier sales as well as inventory control. The store had been outfitted the night before with the necessary scanners and computers, while staff affixed barcodes to every item on the shelves. Inventors Norman Woodland and Bernard Silver patented the initial barcode concept, using a bull’s-eye pattern, in 1952, but it took the development of lasers, optical scanners, and minicomputers to bring it to stores everywhere the reimagined barcodes with their now-familiar parallel lines whose sequences of different widths and spacing represent data. Today, barcodes are ubiquitous, with uses ranging from managing patient care in hospitals to tracking rental cars and mail. The latest innovations include the two-dimensional quick-response (QR) codes that provide even more detailed information when read by our smartphones.

Renee Stern, Contributing Writer
Renton, Washington
[email protected]

Disclosure Statement

No potential conflict of interest was reported by the author(s).