When Isabelle Holdaway developed a serious bacterial infection after a lung transplant, she had few options for treatment. The infection spread throughout her body and was resistant to antibiotics. However, she made an amazing recovery thanks to genetically engineered viruses that killed the bacteria.

Isabelle Holdaway's Story

Isabelle Holdaway was 15 years old when she had a lung transplant because of cystic fibrosis. Since organ transplantation requires patients to take medications that suppress their immune systems, Holdaway was susceptible to infections. Doctors believe she already had the Mycobacterium abscessus bacteria in her system because it's common among patients with cystic fibrosis.

The immunosuppressant drugs allowed the bacteria to grow out of control in her body. She developed a serious infection in her chest, liver, torso and other parts of the body. The infection was resistant to antibiotics, so doctors at Great Ormond Street Hospital in the U.K. sent her home for palliative care with little hope for recovery.

Holdaway's mother researched treatment options online and discovered phage therapy. Phages are viruses that can kill bacteria, and researchers have been experimenting with them for many years. Holdaway received an experimental phage treatment that saved her life.

How Phages Kill Bacteria

Bacteriophages or phages are viruses that can kill bacteria. Although they have different shapes and sizes, phages tend to have either DNA or RNA. Discovered in the 1900s, phages helped treat bacterial infections such as cholera. However, penicillin's discovery in 1928 shifted the focus away from phages as antibiotics became popular.

Since phages are viruses, they can't reproduce without infecting a host. Bacteriophages tend to follow two general processes for infecting bacteria: the lytic cycle and the lysogenic cycle. In the lytic cycle, the phages infect bacteria, take over the cells and use them to make more phages until the cells lyse, or burst.

In the lysogenic cycle, the phages infect bacteria, insert their DNA into the bacteria's genetic information, and the cells include the DNA during cell division. This piece of phage DNA is called the prophage. It can become active and make phages, which would start the lytic cycle.

However, it's important to note that phages are very specific. This means that each type infects a different type of bacteria. A single phage may only work on one species of bacteria and not others.

The Phages That Saved a Teenager

After Holdaway's mother became aware of phage therapy, the doctors at Great Ormond Street Hospital connected with Rebekah Dedrick and Graham Hatfull at the University of Pittsburgh who had a collection of phages. The Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) program, which is an undergraduate research course, helped put together the collection. Many phages were discovered by simply digging in the soil.

The researchers at the University of Pittsburgh had the phages for experimentation, but they did not know which ones would actually kill the Mycobacterium abscessus bacteria that infected Holdaway. They spent weeks growing bacteria and treating it with different phages. In 2018, a bacteriophage they called Muddy killed bacteria in a petri dish.

Although Muddy was an important find, researchers knew that bacteria could become resistant to phages, too. They wanted to find multiple phages capable of using the lytic cycle to treat the teenager's infection. Months later, they found the phages ZoeJ and BPs could also affect the bacteria. The team had to genetically modify ZoeJ and BPs to make them lytic instead of lysogenic. They created a drug cocktail of these three phages for Holdaway.

Phage Treatment

The researchers at the University of Pittsburgh shipped their phage cocktail to Great Ormond Street Hospital in London. By this point, Holdaway's infection had continued to spread, and she had a 1% chance of survival. Doctors at the hospital gave her an IV of the phages and used some in a salve, which they applied to her skin.

Holdaway was able to leave the hospital after nine days. The wounds on her wrist went away, her skin improved and her liver was better. She continues to receive phage therapy today. Doctors noted that she had "almost no side effects" from the phages. However, researchers hesitate to call it a complete cure at this time.

Although others have been treated with phage therapy in the past, what makes Holdaway's case unique is the use of genetically engineered bacteriophages. Researchers deleted a gene in the phages and didn't add any new ones.

Future of Phage Therapy

Scientists want to see large clinical studies before supporting phage therapy as an effective treatment for bacterial infections. Anecdotal cases like Holdaway's provide hope but aren't enough for phages to be sold at your local pharmacy anytime soon.

Researchers also warn that phage therapy is highly specific. The phages that killed the infection in Holdaway's body didn't work for a patient with a different strain of the bacteria. Despite the interest, phage libraries are still relatively small compared to the ones that exist for bacteria. In order for them to become an accepted treatment, a lot more research will have to happen.

Phages vs. Antibiotics

One thing that gives phage researchers hope is the growing interest in their field because of intensifying antibiotic resistance around the world. Infections that used to be treated with one antibiotic are now becoming resistant to multiple drugs. However, phages aren't easy to use as a treatment and come with multiple challenges. For instance, it takes time to isolate and find the right phage that can kill each type of bacteria.