By Sigal Samuel May 14, 2019
Isabelle Holdaway, age 15, was out of options. After undergoing a lung
transplant necessitated by her cystic fibrosis, she’d gotten an infection
that wasn’t responding to antibiotics. Her liver was failing. Her skin was
covered in lesions. Her chance of survival was less than 1 percent.
But today, just a few months later, she’s doing much better — thanks,
apparently, to a virus scraped from the bottom of a rotten eggplant in
soil teeming with worms.
Holdaway, who lives in London, was treated with an experimental “phage
therapy,” devised by her local doctors and researchers at the University
of Pittsburgh. Phages — viruses that infect and kill specific bacteria —
are often found in really dirty places. Ditches. Ponds. Sewage.
The idea of purposely dosing your body with a virus found in such
conditions might provoke a shudder of disgust. But as more infections
become resistant to traditional drugs due to our chronic overuse of
antibiotics, more patients are turning to phage therapy as a last resort.
And some scientists are racing to meet the demand. They travel the world
to hunt for new viruses and then store them in freezers, assembling vast
phage libraries. Pittsburgh’s has more than 10,000 different viruses,
which can be used to target different strains of bacteria.
Holdaway was treated with a cocktail of three phages. One came from the
above-mentioned eggplant, which was found in South Africa in 2010. The two
others, found in the US, were genetically modified to become more
efficient killers of Holdaway’s bacteria. Her case marked the first time a
patient was treated with genetically engineered phages.
She’s still undergoing that twice-daily therapy, but her health has
already improved dramatically. The infection has been reined in. Her liver
has recovered. The lesions have mostly disappeared.
It’s a pretty incredible story, but it’s important to note that this was
not a full clinical trial, so scientists can’t say for sure that the phage
treatment is what saved Holdaway’s life. However, Benjamin Chan, an
associate research scientist at Yale University who was not involved in
the study of her case, told me there’s “a very, very good chance” that the
phages were responsible. “You saw improvement correlating with
administration of the phage,” he said.
And Holdaway is one of a number of other patients who’ve seen positive
results after undergoing phage therapy. This treatment provides a bit of
much-needed hope at a time when standard antibiotics are starting to fail
miserably. Already, 700,000 people around the world die of drug-resistant
diseases each year, including 230,000 deaths from multidrug-resistant
tuberculosis. And the problem is only getting worse.
How phage therapy was found, lost, and found again
This therapy might sound outlandish, but it’s not actually new — it dates
back to a century ago. Phages were often used to treat infections in the
first few decades of the 20th century, and in some places in Eastern
Europe and Russia, that’s still the case.
But in the West, phages were mostly abandoned when antibiotics came along.
The new class of drugs was easier to use, and more versatile: An
antibiotic can be used to treat many different infections, whereas a phage
is much more specific — it might only successfully infect a particular
strand of a particular species of bacteria.
Another advantage of antibiotics was that instead of hunting for them amid
pond scum and sewage, you could make them in the lab. It was a clean and
convenient solution, and it saved millions of lives.
The problem is that, practically as soon as a new antibiotic is
introduced, the bacteria it targets begin to evolve in response,
developing a resistance to the drug. And for decades, doctors, farmers,
and others have been driving the resistance by doling out an overabundance
of antibiotics.
The result? Not only infections like tuberculosis, but also common
problems like STDs and urinary tract infections are becoming resistant to
treatment. According to a major new UN report, if we don’t make a radical
change now, drug-resistant diseases could kill 10 million people a year by
2050. That’s more people than currently die of cancer.
This is a looming emergency that has so far gone mostly unnoticed by the
US public. The big pharmaceutical companies, having determined that
there’s not much money to be made in researching and developing new
antibiotics, also tend to ignore it. But for patients already suffering
from drug-resistant diseases, the emergency is here and now. They’re
desperate for a treatment, even if it’s an untested one.
Enter phage therapy.
How the therapy works
A typical phage looks like a lunar lander. When it comes into contact with
bacteria, it uses its “feet” to grab onto it. It injects its own DNA into
the host and then starts to reproduce, making so many copies of itself
that it eventually bursts open the bacteria.
There are several advantages to the way phages work. Because a phage is so
host-specific, scientists can deploy phages that will only grab onto the
bacteria they want to eradicate — unlike broad-spectrum antibiotics, which
often kill the good bacteria in your gut along with the bad. Even better,
deploying phages can cause the bacteria to evolve in response, and that
evolution sometimes involves switching from being antibiotic-resistant to
being sensitive to antibiotics.
That’s a great result because it means patients have more treatment
options: After undergoing a round of phage therapy, they can complement it
with a course of antibiotics, which may now actually work for them — as
appears to be the case for one of Chan’s patients with cystic fibrosis.
Phages are believed to be the most abundant lifeform on Earth. At any
given time, there are an estimated ten million trillion trillion of them
drifting around. So how do scientists find the right ones?
“It’s informed guesswork,” said Chan, who has hunted for phages all over
North America, South America, Sub-Saharan Africa, and Asia.
Because phages are highly dependent on their hosts, which are certain
strains of bacteria, you have to go to places where you can find the
bacteria you’d like to be able to kill. For example, if you want to find
phages that’ll kill cholera-causing bacteria, you’d have to go to a
country that still has cholera outbreaks, perhaps a country that doesn’t
have a good water treatment system. You’d take a water sample, bring it
back to your lab, and genetically sequence the phages found in it. You’d
identify if and how a phage is attaching to cholera-causing bacteria. Then
you’d store it in vials in your freezer so it’ll be there, waiting, for
the day a sick patient calls and asks for help.
Chan’s globe-trotting work is not glamorous. “We often go to sewage
treatment plants and just scoop out sewage,” he said. “A lot of the phages
are in sewage because that’s where you find a lot of human-associated
bacteria.”
But he’s encouraged to see the dirty work paying off. Over the past three
years, he said, he’s noticed increasing excitement about phage therapy. At
Yale New Haven Hospital, he and his colleagues have treated 16 patients
with phage therapy as of last week. “That number is growing crazy
quickly,” he told me, adding that he receives new requests for treatment
daily. As his list of prospective patients grows longer, he’s hoping to
start a clinical trial by the end of this year.
Not every patient who requests phage therapy ends up getting it. Because
it’s untested, it can only be legally dispensed on a compassionate basis —
that is, only when all the standard treatments have failed. For each case,
scientists have to demonstrate to the FDA that other treatments haven’t
improved the patient’s health and explain how phages will get the job
done. In an emergency situation, FDA approval can be obtained within
hours.
Chan believes that once clinical trials have been completed, phage therapy
will quickly grow more popular. He acknowledged the yuck factor of getting
injected with a virus culled from sewage, but said that when someone has a
truly terrible infection, they get over that psychological hurdle pretty
fast. “In the cases we’re treating, people have these infections for years
and things are getting much worse,” he said. “These people are like,
‘Dude, just fix it.’”
But phages won’t fix every patient’s problem. Since they’re so
host-specific, the therapy is limited in a way broad-spectrum antibiotics
are not, some researchers have noted. It can take a long time — sometimes
too long — to find a phage that’ll work on a specific strain of specific
bacteria. The same London doctors who treated Holdaway also tried to treat
another girl with cystic fibrosis who suffered from a different strain,
but by the time the right phage was found for her, she had died.
Another hurdle will be getting pharmaceutical companies to invest in
research and development. But Chan said he’s already getting inquiries
from Big Pharma companies, some of which are “actively and aggressively
working in the phage space now.” These include heavy-hitters like Johnson
& Johnson and Merck.
Depending on how phage therapy gets regulated, that could increase or
decrease the financial incentives for companies to invest in phage
therapy. For now, there’s no across-the-board regulation, just ad hoc FDA
approvals or rejections for individual patients. This therapy is so new to
the West that it’s hard to say how big a role it will come to play. But as
the antibiotic resistance crisis worsens, it’s clear there’s appetite for
alternative treatments like this one.
