In Which Year Did Scientists Start to Experiment With Phages Again

Bacteriophages in nature

Derived from the Greek words meaning "bacteria eater," bacteriophages are abundant everywhere — on state, in h2o, within any form of life harboring their target. According to Woods Rowher, PhD, a microbial ecologist at San Diego Country Academy, and colleagues in their book Life in Our Phage World, phages cause a trillion trillion successful infections per second and destroy up to 40 percent of all bacterial cells in the body of water every day.

Thousands of varieties of phage exist, each evolved to infect only ane type or a few types of bacteria. Like other viruses, they cannot replicate by themselves, but must commandeer the reproductive mechanism of bacteria. To exercise so, they attach to a bacterium and insert their genetic material. Lytic phages then destroy the cell, splitting it open to release new viral particles, which in plow infect more leaner.

Phages as therapy

History

Phages (green) docking on a bacterium

Though the original discoverer of bacteriophages remains a matter of argue, it'due south widely accepted that in 1915, Frederick Twort, a bacteriologist from England, was the outset to suggest that information technology was a virus that was responsible for previous observations of a "gene" that killed bacteria. Two years afterwards, Felix d'Herelle, a microbiologist at the Institut Pasteur in Paris, picked up where Twort left off and get-go proposed phages as a therapy for human infections. The first known therapeutic use of phages occurred in 1919, when d'Herelle and several hospital interns ingested a phage cocktail to bank check its safety, and then gave it to a 12-year-old boy with severe dysentery. The male child'due south symptoms cleared up after a single dose and he fully recovered inside a few days. Nevertheless d'Herelle didn't publish his findings until 1931.

In the 1920s and 30s, researchers around the world continued to report and test phages for their ability to care for bacterial infections in humans. Withal, most of the results of those studies were published in non-English journals and therefore did non immediately spread to Western Europe and the U.South. In the 1940s, the pharmaceutical company Eli Lilly produced phages for man use in the U.S., and they were marketed to care for a range of bacterial infections, including in wounds and upper respiratory infections. Simply it was suspected that the phages didn't work all that well, partly since they were improperly stored or purified, and it was not recognized at the time that many phages were highly selective about the kind of bacteria they infected. Phage therapy fell out of favor in the U.South. and most of Europe with the appearance of antibiotics. Only in regions where antibiotics were not every bit easily accessed — namely what is now Russia, Poland and the Republic of Georgia — did phage therapy and commercial production continue. However, the phage studies conducted in these regions connected to be not-randomized and uncontrolled, and thus empirical information is still lacking to evidence that phage therapy was effective.

Current day

Western scientists "re-discovered" phage therapy in the 1980s. Since then, the growing threat of antibody-resistant bacterial strains has connected to further interest in phage therapy as a potential culling. In the 2000s, human experiments began again and data from the starting time phase I clinical trial in the U.S. was published in 2009. That trial tested the rubber of a cocktail of phages specific for E. coli, Staphylococcus aureus and Pseudomonas aeruginosa in 42 patients with chronic leg ulcers. Since it was a phase 1 trial, the study only analyzed safety, not clinical outcomes. No adverse events related to the phages were reported.

Some other contempo randomized, double-blinded, controlled trial took place in the Britain, where researchers tested half-dozen bacteriophages in patients with chronic ear infections caused by P. aeruginosa. The amount of leaner significantly decreased in the treated group, those patients also reported that their symptoms eased and there were no adverse events due to treatment. In 2014, researchers in Belgium launched a small-scale clinical trial to exam phage therapy in burn victims whose wounds are infected with East. coli or P. aeruginosa bacteria. The results have non withal been fully published, just there were no safety issues reported.

UC San Diego Health's Robert Schooley, MD, and Randy Taplitz, MD, administer intravenous experimental phage therapy for patient Tom Patterson in March 2016, four months after he contracted a multidrug-resistant bacterial infection in Egypt. Credit: UC San Diego Health

At Yale Academy, a bacteriophage taken from a local pond was recently used to treat a life-threatening bacterial infection in an eighty-year-quondam man's breast. That case, described in the May 26, 2016 issue of Scientific Reports, is like to the UC San Diego treatment of Tom Patterson, just only in the sense that they both used bacteriophages. Success in the Yale case appears to have relied upon the conversion of the bacteria (Pseudomonas aeruginosa) to an antibiotic-sensitive strain.

Until the 2016 example of Tom Patterson at UC San Diego Health, very few, if whatsoever, patients in the U.Due south. have received intravenous phage therapy to directly impale multi-drug resistant bacteria, particularly since the advent of antibiotics.

Benefits

Phages may help overcome the principal drawbacks to today's antibiotics. Antibiotics are broad spectrum, significant that in improver to killing the nefarious species causing infection, antibiotics too destroy many beneficial leaner making up a person's microbiome, and that tin take a variety of short- and long-term wellness effects. Leaner likewise replicate quickly and the selective pressure of antibiotics encourages the emergence of antibiotic-resistant strains.

In dissimilarity, phages are very specific about the bacteria they infect, so the collateral damage to other bacteria or human cells is minimal. Though bacteria tin can develop resistance to phage (they tin eventually shed the surface receptors that phages employ to dock and enter the cells), the gamble is low. What's more than, since there is a nearly inexhaustible supply of phages in nature, if resistance does occur, researchers can at present notice new phages that use other receptors, as they did in Tom Patterson'south case. Such an arroyo tin can be expedited with the apply of phage libraries. Finally, antibiotics have years to develop, whereas a phage cocktail can be identified and matched to a patient'south specific bacterial infection and purified inside a thing of days, making personalized phage therapy-on-demand a potential reality in the time to come.

Risks

Given that phage therapy testing to appointment has largely been observational, or conducted in small, non-randomized trials, researchers don't yet have the full motion-picture show of how it works and the potential risks. They don't notwithstanding know the extent of potential short- and long-term side effects of phage therapy. Decades of anecdotal reports from Russian federation, Poland and the Republic of Georgia, equally well every bit preclinical studies in animals, indicate that phage therapy is likely rubber for well-nigh people, at to the lowest degree when applied topically to the skin. Given the lack of controls and transparency, nonetheless, it'southward likewise possible that side furnishings have been underreported.

Septic shock is the main worry for doctors considering phage therapy. That'southward considering many types of bacterial cells release endotoxins when broken upwardly by phages, which can atomic number 82 to an overwhelming allowed response and organ failure. Withal this is too a concern for some currently bachelor antibiotics. There was no evidence of endotoxins causing septic stupor in response to phage therapy in Tom Patterson's example, and septic stupor has non been widely reported through the many decades of phage therapy in Eastern Europe.

Finally, phages are able to transfer Deoxyribonucleic acid from one bacterium to another, in a naturally and commonly occurring process known as transduction. Phage manipulation and engineered introduction could theoretically introduce new virulence factors or toxins to already pathogenic bacteria, or convert non-pathogenic leaner into pathogens. However, this issue can exist overcome by pre-selecting phages that have been advisedly screened for toxins and virulence factors — an effort that can be facilitated past using always-expanding phage libraries that several teams are currently developing around the world.

Challenges

The principal challenges to phage therapy are one) doctors demand to know exactly which bacterial strain is causing the infection and ii) they must have several phages that specifically target that strain readily bachelor, ideally from a big phage library that can exist screened for a suitable phage cocktail that matches the leaner. Compounding the latter problem, most pharmaceutical companies are reluctant to dedicate resource to phage therapy evolution and commercialization. That's because phage therapy is well-nigh 100 years onetime, making it difficult to patent and generate revenue to justify the initial development costs.

Lack of regulatory approval for phage therapy is too an issue. Phage cocktails need to be customized for each patient's infection and constantly adjusted equally the bacteria evolve and develop resistance. Regulatory agencies such as the U.s. Food and Drug Administration (FDA) currently lack streamlined review and approval mechanisms to adjust personalization and flexibility on a large scale. Future

Diagnostic innovations that take reward of genomic sequencing and mass spectrometry may before long meet the need for rapid and accurate bacterial identification. Phage therapy'southward second hurdle, the demand for readily available phages, may eventually be met in function past the U.South. Navy Medical Research Center and other teams around the world, who are currently building phage libraries.

Looking farther ahead, other technology advances may assist make phage therapy even more specific and help with the patent problem. For example, phages could eventually be engineered using CRISPR/Cas9 gene editing techniques to impale just antibody-resistant leaner. Companies then might be more likely to obtain patents on unique phage or phage cocktails, making them a commercially viable investment.

Whatsoever the futurity holds for phage therapy, almost experts agree that phage therapy will never completely supersede antibiotics. Instead, this approach may be used in combination with antibiotics, or as the concluding line of defence for patients with infections that have not responded to any other treatments. Given the alarming increment in the number of life-threatening multidrug-resistant infections in recent years, the demand for investigating the potential function of phage therapy and other alternatives to antibiotics is urgent.

For more data, run across:

Sulakvelidze et al. Bacteriophage Therapy. Antimicrob Agents Chemother. 2001 Mar; 45(3): 649–659.

Wittebole, et al. A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence. 2014 Jan 1; 5(1): 226–235.

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Source: https://health.ucsd.edu/news/topics/phage-therapy/pages/phage-101.aspx#:~:text=In%20the%202000s%2C%20human%20experiments,patients%20with%20chronic%20leg%20ulcers.

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