Phage therapy is a century-old treatment largely abandoned since the invention of penicillin, writes Ben Spencer. As traditional drugs lose their power, is this the future of fighting infection?
Abigail Halstead is a master of understatement. “I’m in a bit of a pickle,” she says. The mother of three has cystic fibrosis, a chronic condition that leaves her extremely vulnerable to infection, and her doctors are running out of ways to treat her. For years they have used antibiotics to keep bacteria in her lungs and digestive system at bay. But one by one the drugs have stopped working as the bacteria evolved to resist them.
Halstead’s own immune system has rebelled too. “I’m now allergic to all the antibiotics I can have,” the 32-year-old says. “I’m a bit stuck.” With conventional medicine failing, her only hope comes from a surprising source. Her life is blighted by bacteria but her salvation may lie in a virus. A team of scientists at Yale University in the US is trying to find a highly specific treatment called a bacteriophage, or phage for short, a virus that can kill the bacteria in her lungs.
For Halstead — and by extension for her husband, John, 36, son Ben, eight, and twin daughters Freya and Eve, six — it is a final throw of the dice. Every two or three months she suffers a flare-up that results in her being rushed from her Cambridgeshire home to hospital for emergency treatment. “I’ve worked through the last remaining antibiotics,” she says. “So when I go in next time, they will have to hope they can make a combination of antibiotics work that is not so bad for me that I die.” She pauses. “It’s not a very comfortable place to be.”
It is odd to think of any virus as a positive thing. Since the early days of 2020, when Covid-19 turned our lives upside down, “the virus” has been the enemy, something to be defeated, killed, vaccinated into oblivion. Even before we had heard of Covid, viruses were synonymous with colds and flu, HIV and ebola. They are nasty little things that cause disease and misery. But scientists are waking up to the idea that not all viruses are bad. In fact the viruses that cause suffering are vastly outnumbered by viruses that could help us.
Phages are viruses that infect and kill bacteria. They are harmless to humans and trillions of them already live in each of us without our knowledge. When a phage comes into contact with a bacterium it has evolved to infect, it grabs hold and injects its genes deep inside. The genes then replicate and churn out more and more copies of the phage until they burst the host from the inside out. If you were challenged to create from scratch a drug to wipe out bacterial infections, it is hard to think of anything more efficient. Phages are biological predators, ruthless killing machines. And bacteria are their prey.
For the past two years Tom Ireland, editor of The Biologist magazine, has been investigating the potential of phages for his new book, The Good Virus. He describes these microscopic scraps of genetic material and protein as a “mind-blowing feat of bioengineering”. They are “exquisitely, beautifully evolved” and come in a “variety of shapes and sizes, with whiskers, tails, spiderlike legs and landing gear for attaching and breaking into their hosts”.
And they are everywhere: rivers, soil, our skin, the sea, even floating in the air. Last year scientists from the University of Copenhagen announced they had found 876 different types of phage just on the leaves of wheat plants. For every bacterial cell on the planet there are thought to be at least 10 phages finely tuned to combat them in what Ireland calls a “never-ending microbial war”. “Researchers estimate there may be as many as 10³¹ phages on Earth — that’s 10 with 30 zeros after it — a truly preposterous number that equates to about a trillion phages for every grain of sand on the planet,” Ireland writes. “Despite their submicroscopic individual size, there are so many phages on Earth that if they were all put end to end, they would stretch for 400,000 light years into deep space.”
I’m now allergic to all the antibiotics I can have. I’m a bit stuck.
Phages are in fact the most abundant biological entity on Earth. And yet most people have never heard of them. Part of the reason for this is that mainstream science has always been slightly suspicious of these odd little viruses. They were discovered more than a century ago by scientists in Paris and London (exactly who identified them first is still a cause of debate), and initially were hyped as a medical miracle. But even colleagues of the early phage pioneers were sceptical, viewing them as too good to be true.
When Alexander Fleming discovered penicillin in 1928, sparking the antibiotic revolution, research into phages was largely abandoned. Only in the Soviet Union — particularly in Georgia — did it continue. Even today, Ireland tells me, there’s a “lingering prejudice” about phage therapy. A decades-old idea that it is pursued merely by “cranks and commies” is only just beginning to shift among the medical professions. “It’s a bit like how Lada and Skoda cars used to be seen — as a joke,” he says. But this attitude is changing.
Antibiotics are no longer the panacea they once were. As Halstead is experiencing, these once-great drugs have their limits. She reels off those she has been prescribed: tobramycin, co-trimoxazole, meropenem, tazocin, temocillin, fosfomycin, ceftazidime. Each is now failing against the bacterial species racking her body — a particularly tricky type called Burkholderia gladioli.
As antibiotics are used and overused — sometimes for diseases against which they don’t even work — superbugs evolve to resist them. In the 20th century scientists simply developed new antibiotics to get around this. “But that pipe has run dry,” Ireland writes. “No major new class of antibiotic has been developed in the past 30 years.”
For decades scientists have been warning of a future in which bacteria will evolve to evade antibiotics. The former UK chief medical officer, Dame Sally Davies, has described this as “one of the greatest challenges facing humanity”. In 2014, a government review led by Lord O’Neill of Gatley projected that resistant superbugs would kill 10 million people a year globally by 2050. But that horror story is closer than we thought. Last year a study found that 4.95 million people had died in 2019 due to causes associated with drug-resistant bacterial infections. As Ireland writes: “The crisis threatens to return us to the pre-antibiotic age, where common illnesses, food poisoning, basic surgical procedures and even an infected cut could develop into life-changing infections, chronic disease, disfigurement and death.”
Suddenly phage therapy seems a very attractive option. Around the world companies are springing up to capitalise on what they believe could be the future of medicine. At least 15 specialist biobanks — vast repositories of phages — have been established from Canada to South Korea.
Phages are collected from sewage, from soil, from bodily samples. One girl’s life has been saved by a phage sourced from a compost heap in a South African student’s garden. A jar is all that’s needed — there are many “citizen science” projects around the world to encourage budding researchers to find their own phages. Each sample is spun in a centrifuge to remove any solid matter, and filtered to remove anything larger than a virus. They are then introduced to different types of bacteria to see how they react. If a match is found, it is purified and replicated in huge vats.
Last month Leicester University launched Britain’s first Centre for Phage Research. The Commons science and technology select committee is also conducting an inquiry into the potential of the therapy. But key challenges remain. Phages are highly specific — each will only work against certain species of bacteria, and some only against specific strains of those species. They’re hard to work with. This is why Yale scientists are still ploughing through libraries of viruses to find a specific treatment for Halstead.
Scientists also worry there is little strong trial data backing up the treatments, largely because the 1920s “golden era” of phage therapy took place before the proliferation of modern randomised control trials. More recent research is in Russian and Georgian, which means “it might as well not exist”, Ireland says. “It takes a certain type of medical professional to say, ‘I’m going to get some Russian papers translated.’ "
And while the George Eliava Institute in Tbilisi is a world leader in the field, its scientists’ expertise does not always travel well. “The Georgians are still using 20th-century microbiology techniques to figure out what kills what,” Ireland says. “They have a recipe they’ve refined that works, but they don’t know what’s happening on a molecular or genetic level. In the West we want to know how it works at that level of detail.”
The Georgian approach may not be acceptable to Western science, but for Western patients with no other option, it is a huge draw. Between 2012 and 2019 clinics in Tbilisi treated 10,000 patients from 71 countries. Scientists estimate that less than a quarter of patients suffer a recurrence of their infection.
Other countries such as India are starting to embrace phage therapy, and big companies in the US and parts of Europe are seeing the commercial potential. But in the UK there are big hurdles. According to Phage-UK, a new non-profit group that aims to ease the way for the therapy, only 13 patients have been treated using phages in Britain since 2009, most of them under “compassionate use” rules for those who have no other medical options left.
One of those was Isabelle Carnell-Holdaway, a 17-year-old with cystic fibrosis who was given a 1 per cent survival chance after she became infected with a drug-resistant superbug called Mycobacterium abscessus. In 2018 doctors at Great Ormond Street Hospital in London treated her with three phages, whittled down from 15,000 potential matches over a period of months. Within days she stabilised, her infected sores closing up for the first time in months. She left hospital a few weeks later. The reprieve enabled her to study for her A-levels and learn to drive, but tragically she died in 2022 from complications associated with her multiple health challenges.
Ireland writes: “As one phage expert put it, regarding the process of gaining approval from drug regulators to use phage therapy for compassionate use, ‘They never say no, but often the yes comes too late.’ " The further an infection has progressed, the harder it is to treat.
Yet obtaining even approved drugs for those at the end of their lives is a challenge. Ben Temperton, associate professor of microbiology at the University of Exeter, says these have to be imported, because “if a phage is produced in the UK, it has to be made under GMP rules to avoid significant liability risk and challenges in gaining approval”.
GMP stands for “good manufacturing practice”, which sounds like a good thing. But these rules, which were set up for the pharmaceutical industry to ensure consistent dosage, toxicity and purity, are almost impossible to achieve for phages. “It works fine for chemicals that you can produce on a mass scale, but phages are biological entities that need to be replicated inside a bacterial host,” Temperton says. “I had a quote from a company that does this in Slovenia and to make phages under GMP was going to cost £1 million [about NZ$2m]. That’s for one specific patient, and it was going to take nine months. If we did it without GMP it would cost a few hundred pounds.”
He points out that phages are entirely safe. In the US some are already approved by the Food and Drug Administration as additives to keep food free of germs. Phages remain inert when they come into contact with human cells, springing into life only when they encounter bacteria.
Moves are afoot to create a GMP phage manufacturing facility in Britain, but experts believe it is at least five years away. In the meantime many patients seek phage therapy abroad.
Simon Jones, a 50-year-old IT engineer from Coventry, travelled to Tbilisi after suffering repeated urinary tract infections (UTIs). “I had been treated with multiple courses of antibiotics without much impact,” he says. An infection eventually spread to his prostate. “The treatment options for chronic bacterial prostatitis are quite limited. And living with it means pretty constant pelvic pain, going to the loo every hour, lots of tiredness, not being able to travel very well. It’s not pleasant.”
He took the plunge and travelled to Georgia in October 2018, leaving his wife and two teenage daughters at home. “Tbilisi is lovely but it was a bit strange waking up in an Airbnb in a foreign country without my wife and kids, and realising I was about to have medical treatment without really knowing what was going to happen.”
The initial two-week treatment cost £4500, and for nine months afterwards the Georgian clinic sent him phage vials at £500 per three-month pack. “The treatment comes in a little bottle and you drink a shot twice a day,” he says. “It is quite painless; it tastes like seawater.” (Phages can also be administered via suppository or IV drip.)
Nine months of treatment cleared Jones’s infection for three years. But it returned. Three months of phage treatment saw it off the first time it came back, and he recently saw off another bout. “That is the history of bacterial prostatitis, unfortunately,” Jones says. “It comes back. But without the phages I’m not sure where I’d be — I’d either not be here or be in a much worse place.”
The totality of what these viruses do and could do for us is immense.
For many, phage therapy is an unreachable dream. Leah Herridge, 36, has been treated for a chronic UTI for four years. The antibiotics keep it at bay but have not cleared the infection. “I just want my life back,” she says. “But I can’t afford to go and get phage treatment.”
Herridge, who works in NHS management, is largely confined to her south London home because of the pain. “I used to run a five-a-side football team, I went to spin, went to boxing, I ran, went to gym classes, I was out for dinner all the time. Life changed overnight when I got this condition. It has caused so much misery.”
Her suffering is exacerbated by the fact that her husband, Dennis, 36, is in California. “I’m desperate to move over, and we’ve been wanting to start a family,” she says. “We waited and waited for me to get better and I just haven’t.” Dennis, who is American, can’t leave the US because the terms of his training as a pharmacist mean he needs to work in a public hospital for 10 years. “He can’t move here until 2025,” Herridge says. She is stuck in limbo and phages offer a solution.
Part of the miracle of phages is that they can be used in conjunction with antibiotics that have stopped working. Scientists believe this is because bacteria are forced to focus their defences on repelling the phages, making them vulnerable to attack from antibiotics they had adapted to repel.
For now this remarkable treatment is out of Herridge’s reach. That may soon change. Innovators in Belgium are trying to create synthetic phages that can be made on demand to tackle any bacterial infection — a process they describe as being like an “espresso maker” for viruses. In the US scientists are using AI to design artificial phages that can treat a wide range of bacteria rather than just specific types. Others are using cutting-edge robotics to build giant banks of purified, pre-licensed treatments that they claim will soon be able to provide a pharmaceutical-grade phage within 24 hours of receiving a patient’s bacterial strain — essentially a huge vending machine for phages.
For Leah Herridge, such treatments could mean a future not defined by her illness. For Abigail Halstead, they could simply mean survival. As Tom Ireland puts it: “Phages are one of the most important and yet underappreciated life forms on this planet. The totality of what these viruses do and could do for us is immense.”
- The Good Virus: The Amazing Story and Forgotten Promise of the Phage, by Tom Ireland (Hodder & Stoughton), is out now
Written by: Ben Spencer
© The Times of London
