How Phage Therapy & CRISPR-Cas May Help Defeat Infectious Bacteria

by Tyler Zlupko, MBS 2020, GCSoM
mentor: Jennifer Boardman, PhD

The use of traditional antibiotics is becoming outdated. Many bacteria are starting to build up a tolerance to many of the drugs that we normally used to treat them. There are millions of antibiotic-resistant bacteria infections that occur in the United States alone each year, causing tens of thousands of deaths annually. This threat of antibiotic resistance in bacteria is dangerous to the environment, food production and livestock, and our wellbeing. In addition to the danger that resistant bacteria pose to our health, these infections can be incredibly costly. For instance, the total health care costs from bacteria-related infections exceeds $55 Billion each year in the United States alone. So, if traditional antibiotics are becoming ineffective, and the resistant bacteria are posing a serious danger and financial cost to society, what new techniques are scientists using to fight these microbes?

A technique that is being explored in the scientific community is phage therapy, which is a method that uses bacteriophages to kill bacteria. Bacteriophages are viruses that have developed over millions of years to specifically target and often destroy bacteria. Bacteriophages that kill bacteria are deemed “lytic,” which means that the virus creates copies of itself within the bacteria until the bacteria bursts and dies. Some bacteriophages do not directly kill bacteria, but rather they insert their DNA into the bacteria, and this DNA may become part of the bacterial genome - these bacteriophages are termed “temperate.”

Importantly, bacteria have developed a defense mechanism against foreign invaders like bacteriophages. They have a protective system called CRISPR-Cas that identifies foreign DNA that the bacteria comes into contact with, and it will save pieces of that DNA in a molecular “memory bank.” Thus, when the bacteria comes into contact with that foreign DNA again, the CRISPR-Cas system will identify the DNA as foreign, releasing signals to destroy the invader DNA. In this regard, the CRISPR-Cas system is the bacteria’s adaptive immune system.

Interestingly, scientists have enough understanding of how this CRISPR-Cas defense system works in bacteria that they are able to exploit it to their own advantage. One of the ways that they do this is by customizing CRISPR-Cas systems, inserting them into bacteriophage genomes, and then introducing the genetically modified bacteriophages to the bacteria. Using this method, researchers have identified a way to alter antibiotic resistant bacteria so that they are susceptible again to traditional antibiotic drugs.

For example, researchers might introduce a bacteriophage to the bacteria that contains similar proteins as the bacteria but a modified antibiotic resistance gene. The bacteria also contain these antibiotic resistance genes and can become programmed to eliminate their own antibiotic resistance genes. This decreases the bacteria’s ability to defend itself from destruction by antibiotics. In this regard, the bacteria will target their own defenses against traditional drugs, and the bacteria will become susceptible again to normal antibiotics.

Other researchers have shown that CRISPR-Cas editing can increase the range of bacteria that bacteriophages can infect, and that this bacterial defense system can be used to modify bacteriophages so that they may work alongside antibiotics to more effectively kill bacteria. In addition, other scientists have been working to modify CRISPR-Cas systems outside of bacteriophages, and they have been able to engineer effective methods that limit the growth of antibiotic resistant bacteria.

Whereas, the prospects of CRISPR-Cas phage therapy are promising, the scientific community still has a long way to go. First, phage therapy in general is not a widely accepted or used method in Western medicine. This could be because the idea of treating infections by ingesting bacteriophage viruses is not palatable for many people. Another drawback is that controlling the amount of bacteriophage viruses delivered during treatment can be hard as they love to keep replicating themselves, sometimes too much so. Lastly, skeptics ponder whether or not bacteria will always find new ways of defending themselves against treatments we throw their way. So it is possible that bacteria could become resistant to phage therapy methods down the road.

Either way, CRISPR-Cas phage therapy represents a new and modern approach to deal with antibiotic resistance, something that has been greatly needed for some time. With hope, these methods will lead to even more discoveries that help humans fight off harmful bacteria, and lead to a safer and more healthy society.