Once upon a time, antibiotics revolutionized healthcare. Nowadays, however, their overuse and the rise of drug-resistant infections are cause for alarm.

An Evergreen Specialty Since 1973

by Meryl Lipman with Annie Ferguson ’15

T4 virus. Illustration by Benjamin Darby in Life in Our Phage World (2014) by Forest Rohwer et al.

Every year, antibiotic-resistant infections kill more than 50,000 people in Europe and the United States alone. A study commissioned in Britain suggests such infections could cause 10 million deaths a year by 2050 and some experts call that a conservative estimate. Still, the predictions have forced scientists to look beyond the antibiotic age to alternative methods of killing bacteria.

One solution that has stood on the fringes of U.S. medicine for decades, but has been a staple of Evergreen’s research program, is bacteriophage or “phage” therapy. While phages are used in several European and Asian countries to treat human maladies, as well as by some naturopaths and podiatrists in the U.S., they are approved by the FDA and USDA only for treating processed poultry and meat products.

Bacteriophage means “eater of bacteria,” and these spidery-looking viruses may be the most abundant life-form on the planet. HIV, Hepatitis C, and Ebola have given viruses a bad name, but microscopic phages are the good guys of the virology world. Each phage specializes in overtaking certain strains of bacteria—for example, staph, strep, and E. coli—which they attack and use as a host to multiply. To invade a host microbe, a phage uses proteins on its own surface to bind with proteins on the host cell, creating a passageway through which the phage can inject its genes.

Phage therapy has several advantages over antibiotics. Though bacteria develop resistance to phages, it is easier to develop a new phage than a new antibiotic (in many cases, a few weeks versus years). As bacteria evolve resistance, the relevant phages naturally evolve alongside. When a super bacterium appears, the super phage attacks it.

Betty Kutter, Evergreen’s phage sage

Faculty emerita and phage sage, Betty Kutter. Photo by Karissa Carlson ’12.

Phage has a rich history at Evergreen. Elizabeth (Betty) Kutter, who began teaching at Evergreen in 1972, has researched phage since her own college days, in 1963. Now 75, this faculty emerita has not slowed down; Kutter still oversees three to five students a year in the Evergreen Phage Lab, which she created in the college’s second year.

T4-infected bacteria. Photo by R. Bijlenga.

Kutter’s work with phage has put her—and her students—in contact with virologists, bacteriologists, wound-care practitioners, veterinarians, and specialists from around the world, from countries such as Georgia (in Eurasia) and Poland, which use phages in medical practice, to Belgium, France, and other countries working toward revitalizing the use of phage therapy.

August 2 through 7 will mark the 40th anniversary of the International Phage Biology Meeting, a worldwide event that takes place at Evergreen every other year; 2015 will be the 21st time phage scientists have met on the Olympia campus. Kutter expects 200 attendees from around the world, foremost among them scientists researching phage, as well as medical practitioners and food safety experts already using phage. Many attendees will present findings during the five-day conference. The group will forge bonds through group activities, including a welcome salmon bake put on by a Chehalis Tribe family and a day trip to Mount Rainier National Park.

The early work of the phage lab focused on phage genetics and the transition from host to phage metabolism after infection of E. coli by a specific phage called T4. Collaboration with members of the international phage community has since added new exploration, including the T4 genome project of the 1980s and 1990s, anaerobic infections, ecologically relevant simulations, and a variety of new phages.

Then-faculty member Betty Kutter, front, with students at Evergreen in 1975.

Budding scientists blossom in Evergreen’s lab

Like decades of Evergreen science students before them, today’s Evergreen student lab assistants are not relegated to washing test tubes and logging data. They do important work in the lab. Faculty member Mike Paros, D.V.M., who is researching the effects of phage therapy on bovine mastitis, said, “Our students get to be involved in a collaborative, meaningful way. When they come up with good ideas, they have autonomy and mentorship.” As one example, from Kutter’s work, Evergreen students and alumni are currently observing interactions between phages and bacteria when bacteria are in a nutrient-starved dormant or “stationary” phase.

Kutter holds vials of phage from Georgia (in Eurasia). Photo by Karissa Carlson ’12.

Daniel Bryan ’10, who studied under Kutter and is a research assistant in her lab, will present this latest work at the August conference. He plans to take the GRE and said he hopes to attend graduate school and study environmental astrobiology. He clarifies, “I am interested in what bacteria may grow on other planets, but also in very harsh environments, and what phages may be there.” During the conference, he plans to connect with a researcher who will be presenting on phages in Antarctica.

Sofia Gulyas, who graduates in 2015, has spent two years in the lab and is also planning for graduate school. She recently accompanied Kutter to London and Leicester in England to attend a conference and a professional exchange. In addition to her research, Gulyas has personal experience with phage therapy; her parents, who are Hungarian, have both used the treatment. Of her father, an amputee whose prosthetic rubs and causes cysts, she said, “The cysts went down within a week and he hasn’t had much recurrence.” Her mother used a staph phage to treat infected heel blisters after teaching in Rwanda. “Within three days, the blisters were scabbing up.”

Kutter and student Doug Bradley ’75.

While she is recognized as Evergreen’s phage pioneer, Kutter is not the only professional innovating with phage. Naturopaths, osteopaths, podiatrists, and other healthcare providers are allowed to use drugs and procedures that have been approved in other countries on a voluntary basis, in conjunction with FDA-approved therapies, when all other treatments have failed.

Alumna Satya Ambrose ’75 is one of a handful of naturopaths employing phage therapy on a voluntary, compassionate-use basis to help patients who have found no other cures. The naturopathic doctor and acupuncturist, who studied under Kutter in 1973, now uses phage at Sunnyside Collaborative Care in Happy Valley, just south of Portland, Ore. She currently applies a phage treatment to various intransigent gastrointestinal problems and has gathered significant data on phage therapy for papers she and Kutter are planning to write, including best practices. She applies other phages to wound therapy and methicillin-resistant Staphylococcus aureus (MRSA), a particularly resistant infection.

Evergreen graduate Randy Fish ’75 has had success using phage therapy for diabetic foot wounds, also on a compassionate-use basis. (See profile below.)

Phage can be used in veterinary medicine, and Paros, a large-animal veterinarian, has engaged students in experiments that put staph or E. coli bacteria and phage into raw cow’s milk. The phages were able to invade the E. coli bacteria in the milk, but not the staph. “Phage has potential,” Paros said, “but there are major obstacles. Just because it will work in a petri dish doesn’t mean it will work in an animal. Phages are very specific.”

Nurturing the phage community worldwide

Paros has ramped up his phage studies since 2012, and Kutter now devotes her time to planning, writing, and speaking about phage—including presentations in Israel, Switzerland, Germany, and China. Despite her travel schedule, Kutter says she is still available to help students when they get stuck.

Now in her 53rd year of phage studies, 43 of them at Evergreen, Kutter looks forward to hosting the upcoming conference on campus and to advancing the roles of phage in medical treatment and food safety. “Evergreen has been good to me,” Kutter said. “I see no reason to stop.”

E. coli bacteria infected by a bacteriophage, two minutes post-infection. Photo by B. Menge.

Phaging Out a Dangerous Problem

Evergreen faculty emerita Betty Kutter and a former student, podiatrist Randy Fish ’75, are on a mission to find out. Together, they’re cultivating interest—through research and education—in initiating clinical trials in the United States to determine the safety and effectiveness of using bacteria-killing phage to fight the often hard-to-treat foot infections that plague many diabetic patients. When antibiotics fail, these infections often lead to lower-limb amputations, which in turn impair the quality and length of patients’ lives. After losing their limbs to the disease, only one in five will survive for five years. In 2010, American adults underwent 73,000 diabetes-related amputations—one every seven minutes.

Podiatrist Randy Fish, D.P.M. has seen exciting results in treating diabetic patients with phage therapy. Photo by Karissa Carlson ’12.

At this point, therapeutic phage isn’t FDA approved, so it can’t be used without special permission. If trials do go forward, as Kutter and Fish hope, and prove that phage holds promise in healing these infections—as it has long done in the country of Georgia, where it is routinely prescribed—it could receive regulatory approval for clinical use in the United States. Then it would be readily accessible to patients who need it.

Fish has more than three decades of experience in clinical wound management. A graduate of Temple University School of Podiatric Medicine, he works in the wound centers at St. Joseph’s Medical Center in Tacoma and Grays Harbor Community Hospital in Aberdeen. He calls himself “a wandering minstrel going from clinic to clinic.”

A couple of years ago, he reconnected with Kutter, with whom he’d studied recombinant DNA as a senior undergraduate. It just so happened that she was seeking to collaborate with doctors interested in participating in the compassionate-care use of phage to help patients left with few other options. Fish, whose patients include diabetics suffering from difficult foot problems, was excited to get involved.

Since then, he’s treated several of these patients with a phage preparation approved and marketed in Georgia through a compassionate-use exemption. Because antibiotics hadn’t helped them, they faced amputation of toes or feet. Within days of receiving the treatment, all were on the mend. Instead of losing their toes, their wounds closed and healed. None experienced any recurrence within six months.

Fish, who lives in Tacoma, has lately been returning to the much-changed Olympia campus he graduated from 40 years ago to work again with Kutter. They’ve been presenting their work at several important scientific meetings, including the 2015 Diabetic Foot Global Conference in Los Angeles and an upcoming one held by the American Academy of Physicians in Wound Healing. The posters they exhibit at these meetings, which took top honors at two they attended last year, show the remarkable improvement of diseased toes treated with phage. Posters, said Fish, enable researchers to “get information out. They start to light the fire for people.”

“What I’m doing is just peanuts,” he said, “but it serves as the tinder so we can get the fire going.” By sparking awareness about phage as a viable treatment for diabetic foot infections, Kutter and Fish hope to generate interest in advancing it into the clinical trial stage, perhaps with funding from a federal agency. Such a development could someday save the lives and limbs of tens of thousands of Americans.