In the battle against antibiotic resistance in animal agriculture, researchers from Washington and New York states are hoping to help pave the way for U.S. approval of a promising biological therapy that has the potential to not only treat sick cows, but also save human lives threatened by infectious diseases that no longer respond to antibiotics.
The “weapons” in this battle — bacteriophages, or phages for short — are microscopic beings that live everywhere on Earth — inside of us, on our skin, in the soil, inside and on the outside of plants and animals, and even in the ocean. This summer, researchers in the United States and Australia reported that humans have 10 trillion or so bacteria in their gastrointestinal tracts and more than 10 times that amount of bacteriophages residing and “working” there.
Bacteriophages — so named when they were first discovered because they appear to eat bacteria — are naturally occurring viruses that can infect and kill bacteria. That’s important because it’s different forms of bacteria that cause dread diseases such as typhoid, leprosy, cholera, TB and meningitis, as well as foodborne illnesses such as E. coli, Listeria and Campylobacter.
Bacteriophages were discovered in 1915 by British bacteriologist Frederick Twort, and independently 2 years later by Canadian Felix d’Herelle, at the Pasteur Institute in Paris.
Their first medical success was realized in 1919 when they were used to treat severe cases of bacterial dysentery, which would otherwise have been a fatal infection, in 4 children in Paris. All of the children recovered.
The way phages work is nothing short of amazing. They typically have hollow heads, where their DNA or RNA is stored. At the other end of their tiny beings they sport tails that could be compared to tunnels. The tips of these tails can “dock” onto molecules on the surface of the specific bacteria they’re targeting.
With that mission accomplished, they begin shooting their viral DNA through their tails into the targeted cell. Once inside, the DNA takes over and starts directing the production of progeny phages — often more than a hundred in a mere 30 minutes. These “young phage-warriors” then burst out of the host cell, killing it in the process, and eagerly head off in search of more bacteria to infect and kill.
Yet as powerful as phages are against bacteria, they’re nontoxic to mammals and the environment. That’s because they require the specialized form of cellular machinery found only in bacteria to multiply. Another plus is that no genetic engineering is required. There’s no need for that, say scientists, simply because bacteriophages are so plentiful that it’s not difficult to combine them into cocktails that can be highly effective against bacteria.
This is not pie-in-the-sky science fiction. Before the advent of antibiotics, phage therapy was used with varying degrees of success against a range of bacterial diseases.
But with the advent of “miracle” antibiotics during World War II, interest in phage therapy plummeted. One of the main reasons for that downward spiral is based on how bacteriophages work. In contrast to antibiotics, which can be effective against a wide range of different bacteria, bacteriophages target specific bacteria. That means the bacteriophage that works against a specific bacteria needs to be isolated, which in earlier times was far more challenging than it is today.
Then, too, technologies that are now available, such as the electron microscope and computers, weren’t available during the early stages of phage research. In fact, until the electron microscope was invented in 1940, these bacteriophages couldn’t even be seen as anything but a clear spot under a regular microscope.
“In a flash, I had understood: what caused my clear spots was in fact an invisible microbe … a virus parasitic on bacteria,” D’Herelle wrote while he was investigating an outbreak of dysentery in Paris.
Fast forward to the present, where an increasing number of bacteria strains — often referred to as “super bugs” — are becoming resistant to antibiotics typically used against them. The fear of seeing human medical science being hurled back into a pre-antibiotic era is ever present.
This is not an overblown fear. In a letter last November to the presidents of the United States and the European Union, the Infectious Disease Society of America described antibiotic resistance as one of the world’s greatest health threats.
The IDSA has collected patient stories describing how antibiotic resistance has affected them and their loved ones, some of whom died for the lack of an effective antibiotic to treat the disease they had contracted.
A report done by a task force co-chaired by the Centers for Disease Control and Prevention, the Food and Drug Administration, and the National Institutes of Health, warned that “the world may soon be faced with previously treatable diseases that have again become untreatable, as in the pre-antibiotic era.”
With thousands of people dying each year from bacterial diseases that have grown resistant to antibiotics, interest in alternatives to antibiotics has propelled bacteriophages back onto the medical stage. Some scientists say their time has come — once again.
But because they aren’t approved for human use by the FDA, much of the research is directed toward animal agriculture. The hope is that successes there will serve as an “end run” around FDA and prompt the agency to move forward on policies and regulations pertaining to phage therapy in human health.
In Washington and New York states, researchers are working on developing bacteriophage “cocktails” that will be able to treat some serious dairy cattle diseases — postpartum uterine infections caused primarily by E. coli, and Salmonella-related diarrhea in calves — that are typically treated by antibiotics in their severe stages. They have achieved success in the laboratory and now want to see how effective these “cocktails” will be when used on cows.
According to information on a Cornell website, researchers Rodrigo Carvalho Bicalho, Peter Frazier, and Thorsten Joachims will isolate and evaluate new bacteriophages and develop mathematical models to optimize a phage cocktail.
“In short, the right match has to be made,” said computer scientist Joachims. “We are using genetic data about phages and bacteria to predict which phage will effectively treat which bacterium.”
The study, which will be conducted along with researchers Mike Paros, Elizabeth Kutter and Andrew Brabban, all of The Evergreen State College in Washington state, as well as researchers from Washington State University, will culminate in a clinical trial on 900 dairy cows.
One of the goals of the research project is to come up with an economic model for evaluating the cost-effective
ness of phage therapy for commercial dairy farms.
But more than that, the research promises to harness the antibacterial power of bacteriophages, replacing antibiotics for the treatment of common bovine diseases — and may eventually lead to phage therapies for human diseases, according to the Cornell website.
Bicalho, one of the project’s research scientists, refers to the growing interest in bacteriophage research as “a renaissance.”
“We’re coming out of the dark ages,” he told Food Safety News. “More and more people are becoming interested in it because of the rise of antibiotics resistance. It’s on people’s minds. Everyone who goes into surgery is worried about it.” As he works on this research project, he has his eye on the future. “My major objective is to prove it works in animals,” Bicalho said. “But my biggest hope is that it will help open the world’s eyes to this as an alternative to antibiotics for humans.”
Phage biologist Elizabeth Kutter, who has been doing research on bacteriophages at The Evergreen State College for about 40 years, agrees, saying that ever since her first visit to Tbilisi, in the former Soviet Republic of Georgia, in 1990, where she saw phages being used therapeutically for humans, she has had a “very strong sense that eventually this was going to be the wave of the future.”
To share some history about Tbilisi, even after the Western world embraced antibiotics, bacteriophage therapy was used broadly in the Soviet Union, particularly in the Republic of Georgia, which has been the global center of phage-therapy expertise for more than 80 years.
According to the Phage Therapy Center’s website, the Tbilisi center provides an effective treatment solution for patients who have bacterial infections that don’t respond to conventional antibiotic therapies.
Also, according to the website, although the center does not anticipate that phages will replace antibiotics as the first-line, general antibacterial therapy in major Western countries, it does see a promising role for phages in situations where antibiotics alone are not sufficient.
The center is currently accepting patients with diabetic foot ulcers, urinary infections, tropic ulcers, bed sores, sinusitus, and osteomyelitis — including those with infections that are drug-resistant.
Kutter has her own success stories to share about phage therapy at Tbilisi. One involves a musician who was facing amputation of his foot in 2001 due to a serious infection that just wouldn’t respond to antibiotics. His doctors told him that without amputation, he would be dead within a year. Thanks to phage therapy he received at Tbilisi, he didn’t have to have his foot amputated and was able to resume activities such as playing his bass in bands and playing with his kids.
In the conclusion of the story she wrote about the musician, Kutter says that “hopefully there will be more routine mechanisms in place before long for others to follow in his footsteps — and eventually phage therapy will be available around the world for all who need it so desperately.”
Kutter can tick off a list of advances that phage therapy has made in agriculture in this country.
A good example is OmniLytics, a Utah-based company whose website proclaims: “Bacteriophage: The Good Virus.”
On the food-safety front, the company has been granted a federal “no objection” for a bacteriophage product that when applied as a mist, wash or spray on live animals can reduce Salmonella before the animals are slaughtered. Another product used in the same way can reduce E.coli O157:H7 before the animals are slaughtered.
The company’s AgriPhage product line gives organic vegetable growers the opportunity to use what the company describes as “a natural, safe, effective bacteria-control solution.”
That benefit translates into worker safety as well. The Environmental Protection Agency has approved a label amendment for the AgriPhage products that reduces to zero the amount of time before workers can re-enter the fields after the products are applied to crops. That’s in contrast with the substantial time intervals required when pesticides are used.
The AgriPhage products also eliminate the need for workers to wear personal protective equipment.
Another company success is the use of bacteriophages to protect tomato plants from tomato spot, a disease that has developed resistance to widely used antibiotic and chemical sprays.
Intralytix, a Baltimore-based company, offers another example of advances being made in phage therapy. It says one of its products reduces or eliminates Listeria contamination when sprayed on ready-to-eat foods. And it says another product is highly effective in reducing E. coli O157:H7 contamination of various foods, among them ground beef, fruits, and vegetables.
According to the company, both of these products are 100 percent natural, contain no preservatives or any known, potentially allergenic substances.
Intralytix says it has also developed and licensed bacteriophage-based animal health-care products effective against two bacterial diseases and has two human therapeutic products in various stages of production. One of the company’s prototype phage preparations for treating infected wounds was recently used during a human clinical trial in Lubbock, TX, with an outcome the company describes as “very favorable.”
On the academic scene, a new book published by The American Society for Microbiology, “Bacteriophages in the Control of Food- and Waterborne Pathogens,” looks at the use of bacteriophages in detecting and controlling foodborne bacteria pathogens – both in the production of plants and animals and in food processing. (Kutter wrote the introduction.)
Meanwhile, medical tourism has kicked into gear on a global scale, with patients suffering from chronic, drug-resistant or difficult-to-treat infections heading for the Phage Therapy Center in Tbilisi. There’s even a lab in New York that tests patients’ samples and sends the results to the center ahead of time so the appropriate treatment can be decided upon in advance.
Other countries are taking note. Kutter said that people in China are importing bacteriophage products from Tbilisi. And phage conferences were held last year in such far-flung places as Paris, Australia, and Bogota, Columbia.
Trials have also taken place in Brussels and London.
“It’s exciting to see things like this happen in other countries,” Kutter said, adding that it’s unfortunate that the United States is one of the last countries to be going forward on phage therapy in human health.
Kutter said the biggest hurdle is money.
“Everything costs so much when you’re trying to get to the position where FDA is willing to look at it,” she said.
But cost may also be on the side of bacteriophage therapy. Although bacteria may develop resistance to phages, it is far easier to find new phages that will work against the problem bacteria than develop new antibiotics.
Generally, it only takes several weeks to find new phages for an emerging strain of resistant bacteria compared with the 7 to 12 years it takes to discover and develop a new antibiotic and get it approved by the FDA.
Even so, Kutter said phage therapy is not the panacea. “It generally needs to be used in conjunction with good surgical techniques, antibiotics to deal with secondary in
fectious agents not targeted by the phage cocktail, and other therapies,” she said.
Black and white bacteriophage images courtesy of Cornell University.