What is Antibiotic-Resistance and How Phage Therapy Could Solve It
What’s the one thing most people take for granted even though they shouldn’t? Their phones? Their TV? Time?
No, no, and no. It’s medicine.
A hundred years ago, you could die from any number of horrible bacterial infections by simply cutting your hand while cooking. Millions of people died every year because of things we don’t even look twice at today. The reason for this dramatic change… antibiotics.
Despite their wonderful properties in helping people, antibiotics are becoming less and less effective every year. They’ve been used, misused, and overused to the point where bacteria have been able to develop immunity to even the strongest antibiotics. Every year 2 million people are infected with antibiotic-resistant bacteria and over 23,000 die from them. What this means is that soon, by 2050, we could return to what is essentially a pre-antibiotic world.
There is, however, a solution to this growing problem. Or rather, there are many solutions-all of which involve bacteriophages.
Antibiotics
Penicillin was created in 1928, and that year marked the beginning of the antibiotic era. Since then the number of deaths around the world has plummeted and average life expectancy has increased. Before 1936, it's estimated that 30% of deaths were due to bacterial infections.
Antibiotics each work in different ways, but they all share the same characteristic: they interfere with one of the bacteria’s vital processes. They also have to target only bacteria so that they don’t damage our cells. Penicillin, for example, is able to selectively attack bacteria by preventing them from creating cell walls. Most bacterial cell walls are made out of peptidoglycan, a macromolecule that human cells do not need. Penicillin prevents transpeptidation, which is the final step in the process. Other antibiotics target the ability of bacteria to create folic acid while others, like tetracycline, bind to the bacterium’s ribosome and prevent it from synthesizing proteins. The antibiotics that kill the bacteria, like penicillin, are called bactericidal antibiotics while those that keep them from replicating are called bacteriostatic.
Antibiotic Resistance
The first case of antibiotic resistance was in 1947, and that was before the so-called “golden age of antibiotics” from 1950–1960. Since then we’ve seen more and more bacteria become resistant to common antibiotics. In 2017, bacteria were found in a Chinese pig farm that contained a gene called mcr-1 which made them immune to colistin, an antibiotic that is used as a last resort when nothing else is working. If this stayed in pigs, then it wouldn’t be that big of a problem, but resistance to colistin has since spread to people, and in many communities, the drug is ineffective in treating more than 50% of the population.
How did this problem become so large? Well, it's simple, we brought it on ourselves. Antibiotics are sorely abused. In developing countries, where people are unable to see doctors for financial reasons, it is much simpler to get antibiotics. Even in the United States and Europe, antibiotics were overprescribed until as recently as 2010, when the creation of superbugs became a bigger concern.
Also, antibiotics are used on livestock. The dangerous side effects of colistin, including kidney failure, have been known for some time and therefore it is rarely used on humans. However, it’s almost always included in the diet of farm animals around the world. This is a controversial point to discuss, and with good reason. Without using antibiotics, it would be nearly impossible to feed the world’s growing population-a task which is becoming more and more daunting each year. The majority of people are afraid of GMOs (genetically modified organisms) and so would rather eat meat that was grown with a lot of antibiotics. On the other hand, by encouraging the usage of these drugs, we’ve inadvertently given rise to superbugs.
How does it happen?
First off, it’s worth noting that bacteria are literally some of the oldest things on the planet. Consequentially, evolution has turned them into very efficient killers that have some interesting properties. For one, bacterial cells have their DNA both in the cells’ nuclei and in small structures called plasmids. Plasmids can replicate themselves without depending on the bacteria’s chromosome. They can also be exchanged between bacteria through physical contact. This, in turn, lets the DNA of bacteria that have developed resistance to be transferred to other bacteria.
That might be the less scary way in which superbugs cand develop. In a process called transformation, bacteria can absorb pieces of DNA from their environment and integrate it either their chromosomes or their plasmids. Horizontal gene transfer like this quickly allows multiple species of bacteria to gain immunity to antibiotics.
Another thing about antibiotic resistance is that we’ve all contributed to it at some point. Every time someone doesn’t complete the whole dosage of antibiotics prescribed by the doctor because “they got better” or “the bug went away” they’re allowing some of the bacteria to survive. The same goes for people who take antibiotics because they have a cold or are feeling slightly under the weather. True, most superbugs originate in hospitals or livestock facilities, but antibiotic misuse by everyday people is a cumulative effect that can have dire consequences.
However, as with most problems, there is a solution.
Phage Therapy
A phage (shortened from bacteriophage) is a virus that targets and attacks only bacterial cells. Phages were first ‘discovered’ by Ernest Hankin in India’s Ganges and Jamuna rivers. Many of the British soldiers and Indian civilians in the area would get Asiatic cholera, but would report the disease becoming less sever when they drank water from the rivers. He noticed that something in the water had an antibacterial effect against the bacteria responsible for vibrio cholerae. At about the same time, phages were also discovered by Gameleya, a Russian bacteriologist, and later by Frederick Twort. However, the discovery is usually attributed to Felix d’Herelle. Unlike Twort, d’Herelle actively pursued his discovery and tested his treatments on soldiers suffering from dysentery.
Phages look like the textbook image of a virus. An oddly shaped ‘head’ on top of a long cylindrical body, and some spindly legs at the bottom.
The ‘head’ of the virus is called the capsid and is a shell made up of protein. Inside the capsid is the virus’s genome, which can either be DNA or RNA. Remember that viruses can’t replicate themselves on their one and so need to take control of living things. The body of the virus, sometimes also called a tail or a sheath, functions like a syringe and is used to infect a cell. The legs of the virus are more similar to human hands in that they aren’t used to move, but rather to grab onto a bacterium.
I’ll explain the process of infection in a moment, but it’s essential to know that there are two different ways in which phages replicate; the lytic and lysogenic cycles.
The Lytic Cycle:
Once a phage lands on a bacteria, it inputs its own genome into the cell and takes over its ribosomes to form more copies of itself. Proteins are created and then self-assemble to form an identical copy of the parent bacteriophage. Then, an enzyme called lysin is released and the cell wall is literally blown to pieces. The phages are released into the bloodstream ad restart this cycle.
Lysogenic Replication
Similar to lytic replication, the virus latches onto a bacteria’s cell and releases its genome into it. However, in this method, the virus does not immediately replicate itself. Instead, the phage’s genome integrates itself into that of bacteria. If external stimuli change, the virus can change to a lytic replication cycle and explode out of the cell.
Now, for obvious reasons, the lytic replication cycle is the one that scientists hope to replicate for phage therapy. There are other ways in which bacteria can be destroyed that take inspiration from this cycle, but more on that later.
How Phage Therapy works
If you remember, each type of bacteriophage targets at most a few varieties of very closely related bacteria. This means that before a disease can be treated, a phage needs to be discovered that will attack that specific kind of bacteria. There are 10³¹ phages on the planet, so it’s very likely that there exists at least type that can be used to treat each infection. The process of discovering new phages doesn’t involve overly complicated science. It’s as simple as collecting a sample of water from a bacteria-rich environment like sewage treatment plants and polluted rivers. Next, by introducing some of the bacteria that you want to destroy into the water and observing if they get destroyed you can find evidence of a bacteriophage.
Next, after all the required testing, clinical trials, etc., these phages would be isolated and grown in Petri dishes on a diet of bacteria before being injected or applied to the site of infection on a patient. After that, they’ll replicate themselves, destroy the bacteria, and once that's done, the body will naturally expel them.
(Dis-)Advantages
Phage therapy is very simple and promising, but like every other medical advance, people are divided about it.
- Pro: Even if superbugs evolve, phages will evolve right along with them and so will retain their efficiency for far longer than antibiotics. It’s also very difficult to discover a new antibiotic, but phages can be converted into a medical treatment much more easily.
- Pro: Unlike antibiotics, phages do not cause damage to the human body. The reason antibiotics like colistin are no longer used is because they can cause organ failure, but that’s impossible with bacteriophages. The name itself means ‘bacteria eaters’
- Pro: Given current circumstances, it’s perfectly normal for most people to not be too keen on getting injections of viruses as medicine. There may be no need to get injected with phages if a way to deliver lysin, the enzyme that causes bacterial cells to explode, is discovered. The added benefit of this is that bacterial cells don’t appear to be able to develop a resistance to lysin.
- Con: The immune system might be our biggest enemy in phage therapy. Because it can’t tell the difference between a bacteriophage and a harmful virus, it will quickly produce antibodies and/or expel the phages from the body. The other side of this is that it usually takes some time, between 1–2 weeks, for antibodies to be created and so the treatment might be over before your body can try to stop it.
- Con: Ironically, the same reason why phages don’t harm the body might limit their efficacy. Since they are so species-specific, it will take a lot of research(mostly the ‘search’-ing part) to find a phage that can be used to treat a new infection. This can be offset by using mixtures of multiple kinds of phages and by extensive testing.
- Con: There is very little public knowledge of this technology. Most people have no idea about bacteriophages and even fewer have heard of phage therapy. Besides that, people will naturally be hesitant to inject viruses into their bodies even if those viruses are harmless.
Where it's at right now
Bacteriophage therapy was rediscovered in the west in the 1980s when it started becoming clear that antibiotic resistance would eventually be a problem. Early in 2019, the University of California, San Diego announced that they had been given permission by the FDA to start clinical trials of phages to treat drug-resistant bacteria. This news comes after Thomas Patterson, Ph.D., a teacher at the university was treated using bacteriophages in a landmark event in 2016.
Phages have been used in former Soviet bloc countries since World War II. As a consequence, many of the research papers and advances in the field come from Russia and Georgia. In fact, Georgia is a major destination for medical tourists from around the world who want to try bacteriophages as their last resort option.
Institutions
Currently, there are a few companies and universities involved in the search for new bacteriophages and the development of treatments using them.
In the United States, UCSD is by far in the lead. Along with their announcement of clinical trials, the university created the Center for Innovative Phage Applications and Therapeutics (IPATH). IPATH is, at the time of its creation at least, the only center of its kind in the United States.
PhagoMed is a company that is attempting to treat bacterial infections that cause potentially deadly biofilms to form. The company has been able to create a cocktail of different phages called PM398 that can be used to treat the superbug MRSA (Methicillin-resistant Staphylococcus aureus). Currently, all of its treatments are in the preclinical stage with developments expected to happen in the near future.
In Georgia (the country), The Phage Therapy Center is a medical facility that treats people suffering from a variety of issues including acne, cystic fibrosis, laryngitis, and MRSA. Located in Tbilisi, the country’s capital, this center is near the top globally in phage therapy and has an 80% success rate.
🔑Takeaways
Bacteriophage therapy is a relatively new phenomenon in most of the world and odds are, if you’re reading this, you might be overwhelmed with the information presented. So, if you take anything away, it should be the following:
- Overuse of antibiotics has led to the creation of superbugs
- Bacteriophages are special viruses that target only bacterial cells while leaving human cells the way they are
- Phage therapy is using these bacteriophages in the human body to kill drug-resistant bacteria
- Phage therapy is a little ways off in the United States, but is well known and used in Eastern Europe.
Contact me
Before you go…
I hope you enjoyed reading this article! I’m a 16-year-old innovator at The Knowledge Society committed to changing the world using new technologies like AI, Gene Editing, and BCIs. If you want to learn more or are interested in talking, email me at veda.bhattaram@gmail.com
