In 2017, Jessica Sacher, now a postdoctoral research scientist, was establishing Phage Australia’s production pipeline for therapeutic bacteriophages at the Westmead Institute for Medical Research in Sydney when she received an emergency request for phage — a virus that selectively kills bacteria — to treat a person in Pittsburgh, Pennsylvania, with a deadly lung infection.
This incident made Sacher realize that, to improve access to new phage therapies, there needs to be a way to better connect medical researchers to practicing physicians.
She tells Nature why phage research is important and how Phage Directory, an initiative that she co-founded, is helping to bring the tool from the laboratory to the clinic.
What is phage therapy, and why is it useful?
Researchers are studying phages as a treatment for bacteria that are resistant to antimicrobials. This resistance arises when bacteria (and other microorganisms such as fungi) no longer respond to antimicrobial medicine, such as antibiotics. It is a growing problem — antimicrobial resistance contributed to six million deaths in 2019.
The last new class of antibiotics, daptomycin, was discovered in the late 1980s — so resistance is growing, and scientists don’t have a silver bullet. Pharmaceutical companies are not financially incentivized to develop antibiotics, which requires a costly investment with low returns. An alternative option for treating bacterial infections that are resistant to antibiotics is phage therapy. It’s gaining traction.
How is phage therapy administered?
Phages and bacteria are engaged in an evolutionary arms race. Bacteria evolve various mechanisms to evade infection by phages in the same environment. Phages evolve to get around those bacterial defences, and so could theoretically be used to destroy bacterial infections in the body. Phages can be isolated by suspending an infected sample of sewage, water, soil, or even bodily fluids in a phage-friendly buffer, before filtering away larger cells, such as bacteria. This process is called phage preparation.
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However, the idea of using phages in people is still experimental. There’s not yet a standardized protocol for quality control of phage preparation or determining how much to give a patient, which is one of the things my lab is working on.
A phage can be administered just like an antibiotic: orally, intravenously, topically or directly into the lungs through a nebulizer, depending on where the infection is.
Tell us more about the global development of phage therapy.
The use of phages to treat bacterial infection was first proposed in the late 1910s by Félix D’Herelle, a Franco-Canadian self-taught microbiologist, while he was volunteering at the Pasteur Institute in Paris. During the First and Second World Wars, phage therapy fell out of favour. Antibiotics, by contrast, could be produced at a large scale and administered conveniently, and were effective against a broad spectrum of bacteria.
Despite this, phage research continued in some countries. In Georgia and Poland, there are now medical centres dedicated to phage therapy, although it still remains a last resort medical option. In countries such as the United States and Australia, and in western Europe, phage therapy is restricted to compassionate use when patients no longer respond to any antibiotics. Belgium, the United States and Australia are emerging as leaders in bringing phage therapy into medicine.
Small to medium biotechnology start-ups around the world are also leading programmes to move phage therapy closer to the clinic. Some ideas include phage cocktails that can target multiple bacterial strains simultaneously; phages genetically modified through CRISPR for improved performance or selectivity towards pathogenic bacterial species; and screening a large library of phages and identifying those that can kill harmful bacteria.
What are the top challenges in phage therapy?
There are two major challenges in phage therapy, in my opinion. First, phage therapy does not fit the model of modern medicine: a given phage kills only a limited number of bacterial strains that typically belong to the same species. This limitation makes study recruitment and validation difficult because it’s hard to find enough people who are infected with the same strain of bacteria to test a product. Phage therapy is therefore very personalized — and very expensive.
The second big challenge is phage availability. There are many physicians who want to administer phage therapy for compassionate use, but they usually either do not have access to the infrastructure to manufacture phages or cannot produce them at a safe-to-use quality. For compassionate use, the regulation requirements for phage products are often more relaxed. However, it is still necessary to perform quality control, such as verifying that phages have low levels of endotoxins — components of the bacterial cell wall that trigger an immune response in humans, causing anaphylactic shock and even death.
How is Phage Directory helping with the challenges?
In 2017, my co-founder Jan Zheng, a user-experience designer and software developer trained in human–computer interaction at Carnegie Mellon University in Pittsburgh, and I set up Phage Directory to support physicians looking for phages. We have since developed the directory to post calls or ‘alerts’ for phages against different bacterial strains. We receive one such request a week on average, and 84% of the alerts we have sent out have received a response, such as sharing of phages or directing requestors to labs with the appropriate phage. Requests can come from anyone. They’re typically from patients, but we post alerts only when the requests come from doctors. After this, the labs and requestors will typically proceed with a materials transfer agreement, and the labs will ship the phage to the requestors.
We have had incredible success stories because of Phage Directory, such as 7-year-old Dhanvi in Sydney, whose leg amputation was prevented in 2019 thanks to 12 labs from our network offering to help provide and purify phages. However, we soon realized that this approach was not sustainable — suddenly receiving hundreds of phages for your patient brings new challenges to a treating team. We needed better ways to support physicians and researchers.
Over the past few years, we have curated a list of researchers, academic labs, companies and phage-therapy centers around the world working on phages, along with a list of their phage collections and bacterial targets. Our mission is to accelerate the study and use of phages for research and therapy.
What is your most important take-away from this experience?
My experience setting up Phage Directory helped me to understand the power of building action-oriented communities, especially for smaller research fields. There are only a few hundred labs worldwide working on phages, and this number pales in comparison with the hundreds or thousands of labs working on diseases such as cancer and diabetes — yet antimicrobial resistance is one of the top ten global public-health threats facing humanity, according to the World Health Organization. Connecting the phage community to share best practices and resources has already allowed a small group of active researchers to make an outsized impact, and continuing to leverage it will help us to achieve the clinical potential of phage therapy.