Steffanie Strathdee hunched over her laptop,
fretting. She barely noticed the kittens asleep next to her or
the serene Buddha figure across the living room, anchored next
to the glass doors that looked toward the gleaming Pacific. Her
mind was 20 miles away in the intensive care unit of the
University of California-San Diego’s medical center, where her
husband, Tom Patterson, lay in a coma.
Patterson was 68; Strathdee was 49. They had been married 11
years, after meeting in a grant review group convened by the
National Institutes of Health. He was a psychologist and she was
an infectious-disease epidemiologist; when they fell in love,
they also formed a powerhouse research team, studying the effect
of the AIDS virus on vulnerable people in Tijuana, Mexico.
But it was a bacterium, not a virus, that was bedeviling them
now. Three months earlier, on the last night of a Thanksgiving
vacation in Egypt, Patterson had suddenly fallen ill, so
severely that he had to be medevaced to Germany and then to
UCSD. There were several things wrong—a gallstone, an abscess in
his pancreas—but the core of the problem was an infection with a
superbug, a bacterium named Acinetobacter baumannii that was
resistant to every antibiotic his medical team tried to treat it
with. Patterson had been a burly man, 6-foot-5 and more than 300
pounds, but now he was wasted, his cheekbones jutting through
his skin. Intravenous lines snaked into his arms and neck, and
tubes to carry away seepage pierced his abdomen. He was
delirious and his blood pressure was falling, and the medical
staff had sedated him and intubated him to make sure he got the
oxygen he needed. He was dying.
Strathdee’s friends knew she was desperately searching for
solutions, and one told her about an acquaintance with an
intractable infection who had traveled to Eastern Europe to seek
out a century-old cure. Strathdee spent days reading whatever
she could find about it, and now she was composing a last-ditch
email to the hospital’s head of infectious diseases, the person
who would rule on whether they could use it to help her spouse.
“We are running out of options
to save Tom,” she wrote. “What do you think about phage
therapy?”
Strathdee didn’t realize it at the time, but her attempt to save
her husband’s life would test the bounds of the American medical
system—and throw its limitations into stark relief.
The treatment Strathdee had fixed on as a last-ditch hope is
almost never used in the United States. The Food and Drug
Administration has not licensed phage therapy, keeping it out of
pharmacies and hospitals. Few physicians have used it even
experimentally, and most civilians have never heard of it. But
phages are a natural phenomenon, frequently deployed in the
former Soviet Union. When used properly, they can save lives.
To understand how phage therapy works, it helps to know a little
biology, starting with the distinction between bacteria and
viruses. Most of the drug-resistant superbugs that cause medical
havoc are bacteria, microscopic single-celled organisms that do
most of the things that other living things do: seek nutrition,
metabolize it into energy, produce offspring. Viruses, which are
much smaller than bacteria, exist only to reproduce: They attach
to a cell, hijack its reproductive machinery to make fresh
viruses, and then, in most cases, explode the cell to let viral
copies float free.
Phages are viruses. In the wild, they are the cleanup crew that
keeps bacteria from taking over the world. Bacteria reproduce
relentlessly, a new generation every 20 minutes or so, and
phages kill them just as rapidly, preventing the burgeoning
bacterial biomass from swamping the planet like a B-movie slime
monster. But phages do not kill indiscriminately: Though there
are trillions in the world, each is tuned evolutionarily to
destroy only particular bacteria. In 1917, a self-taught
microbiologist named Félix d’Herelle recognized phages’ talent
for targeted killing. He imagined that if he could find the
correct phages, he could use them to cure deadly bacterial
infections.
That was a gleaming hope, because at the time, nothing else
could. (Sir Alexander Fleming wouldn’t find the mold that makes
penicillin, the first antibiotic, until 1928.) Treatments were
primitive: aspirin and ice baths to knock down fever, injections
of crude immunotherapy extracted from the blood of horses and
sheep, and amputation when a scratch or cut let infection
burgeon in a limb and threaten the rest of the body with sepsis.
Phages—whose full name, bacteriophages (or “bacteria eaters”),
was given by d’Herelle in 1916—did something that medicine had
never before been able to accomplish: They vanquished the
infections for which they were administered without otherwise
harming patients. A medical sensation and a cultural phenomenon,
they provided the key plot device in the novel Arrowsmith, about
an idealistic doctor, that won the Pulitzer Prize in 1926, and
they saved the life of the Hollywood cowboy actor Tom Mix, a
1930s superstar.
At least 23,000 people in the
U.S. die each year from resistant infections, and 2 million are
made sick enough to go to a doctor’s office or hospital.
D’Herelle was a restless researcher who seems to have felt
undervalued despite being awarded jobs in Paris and Vietnam and
at Yale. That insecurity made him vulnerable to an offer he
received in 1933 to relocate to Tbilisi in Georgia, home
territory of Soviet dictator Joseph Stalin. With a protégé,
Georgi Eliava, d’Herelle co-founded the Eliava Institute of
Bacteriophages, Microbiology and Virology. Stalin showered the
institute with attention and money because it offered something
he badly wanted: a scientific achievement that he could portray
as a pure product of communism. Antibiotics became the basis of
infectious-disease medicine in the West, but behind the Iron
Curtain, phages took their place.
Eliava was murdered in a political purge in 1937, and d’Herelle
died in 1949. Their institute dwindled, but it survived the
collapse of the Soviet Union in 1991 and the Georgian civil war
the following year. When the former USSR opened up to the West,
physicians in the United States and Europe learned the Eliava
Institute was one of the few places in the world where
researchers were still studying and administering phages. That
was fortunate timing, because antibiotics in the West were
losing their power under the onslaught of antibiotic resistance.
Antibiotics began as natural compounds, the chemical weapons
that bacteria aim against each other to compete for living space
and food. For millennia before humans arrived, bacteria
countered those attacks with mutations—and when humans turned
those natural weapons into medicine, by taking them into
laboratories to synthesize and perfect them, bacteria kept on
adapting. The mutations they produced in response to antibiotics
are what we call antibiotic resistance.
Penicillin-resistant staph infections swept the world not long
after penicillin came into use during World War II.
Methicillin-resistant staph (MRSA) immediately followed the 1960
debut of methicillin, designed to replace some of penicillin’s
lost firepower. Over the decades, as each new antibiotic
arrived, resistant infections have arisen to undermine them. In
the United States, the Centers for Disease Control and
Prevention estimated in 2013 that at least 23,000 people die
each year from resistant infections, and that 2 million are made
sick enough to go to a doctor’s office or hospital. Worldwide,
the death toll is estimated at 700,000 people a year. And
because resistance is accelerating ahead of production of new
drugs to counter it, the death toll is expected to rise to 10
million per year and cost the world as much as $100 trillion in
lost economic activity by 2050.
Superbugs pervade health care, causing grave infections after
surgeries and in intensive care units, and because antibiotics
are routinely added to livestock feed, they permeate the food
supply. In 2015, for instance, an FDA project discovered that 47
percent of salmonella bacteria samples found in retail chicken
were resistant to tetracycline, as were 76 percent of the E.
coli found in ground turkey.
Phages’ vast biological diversity helps them against the
mutations that make up disease organisms’ resistance defenses.
Plus, because phages kill only specific strains of bacteria,
they can quell infections without inducing a terrible diarrheal
disease from Clostridium difficile (usually known as C. diff)
that occurs when the balance of bacteria in the gut is disrupted
by antibiotics wiping out good bugs along with the bad. The CDC
estimates that in 2011 there were more than 450,000 cases of C.
diff infections in the United States, leading to more than
15,000 deaths. It’s possible that using phage therapy instead of
antibiotics could prevent some of them.
But for phage therapy to be deployed routinely in the United
States, phages would have to be approved as drugs by the FDA. To
treat an American patient with them now requires emergency
compassionate-use authorization—effectively an acknowledgment
that nothing with an FDA license can save the patient’s life.
And Strathdee was about to learn that because phages have no
such approval, awareness of them is scarce and unevenly
distributed, and finding the right researchers and physicians
requires extraordinary luck.
Strathdee directs UCSD’s Global Health Institute and like her
husband is a professor in the medical school. Decades earlier,
she had tinkered with phages in lab science classes, using them
as a tool to differentiate bacteria. Before her husband got
sick, she had never heard they could be used as treatments.
The physician whom she’d emailed—Dr. Robert “Chip” Schooley, at
the time UCSD’s chief of infectious diseases, and an old
friend—knew a little more. Anyone who works in infectious
diseases is aware of the peril of drug resistance, and the wish
for reliable alternatives to antibiotics is a constant companion
to that work. But phages had no direct relevance for him because
his personal expertise is disease-causing viruses—HIV and
hepatitis—that phages would not affect.
He knew the next step to take, though. The FDA maintains a
hotline that lets physicians ask permission to use an unapproved
treatment on a single patient if every other hope has been
exhausted. The FDA’s reviewer agreed to let the pair attempt
phages.
Time was short, and the odds were against Strathdee. She needed
to find someone who was conducting phage research, who had
already isolated phages that worked against Acinetobacter, and
who would be willing to test those phages on Patterson’s
infection to see if there was a match.
“She has persuasive power,”
Young recalled. “And she has made herself probably the most
knowledgeable civilian in the world on the use of phage therapy.
She got us mobilized.”
She cast a wide net, sending about 10 emails to labs around the
world, including the Eliava Institute. Two and a half hours
later, she got a message from one of the few phage research
groups in the United States, the Center for Phage Technology at
Texas A&M University, run by a biologist named Ryland Young.
Strathdee called Young and talked at him for more than an hour.
What happened next illustrates how time-consuming it can be to
try to use an unapproved treatment. Young’s lab has been
isolating and testing phages since 2010 and has several hundred
individual viruses in its collection, but when Strathdee called
fewer than 10 of them were known to work against Acinetobacter.
Young put out a call to the small worldwide network of phage
researchers, asking for contributions, and was sent some 35 new
viruses. He and his lab tested all of them on a sample from
Patterson’s infection, sent by Schooley. None of Young’s phages
made a dent. One virus, sent by a company called AmpliPhi, did
kill cells from the infection. They would need more to make a
difference, so Young and his team embarked on what he drawlingly
calls “a good old-fashioned phage hunt.” To find a phage that
worked against Acinetobacter, Young reasoned, he would have to
go look for Acinetobacter in the wild. So he sent his students
hunting for environmental samples, dipping into effluent from
sewage-treatment plants, pulling water from ponds, and taking
swabs of pigs on ranches near the university. Among the 126
samples obtained during the expedition, the Texas lab identified
three phages that worked against Patterson’s strain of
Acinetobacter.
Now they had individual viruses that might do the trick—but they
needed to grow enough of them to make up a treatment. They let
the bacteria from Patterson’s infection reproduce under lab
conditions and then unleashed the phages on them. The viruses
worked the way they had evolved to: They attached to the
bacteria, inserted their DNA, copied themselves, and exploded
the pathogens. The team fed the phages more and more
Acinetobacter. In 10 days, they had trillions of copies. Young
shipped them in a refrigerated box to Schooley, who meanwhile
had been explaining to the university’s biohazard-safety
committee why letting a minimally tested living virus into an
ICU full of very sick people would not be a risk. (If the phage
escaped, it would affect only patients who happened to have the
exact same infection as Patterson, and no one else there did.)
Schooley had also found another source of phages, in a lab
maintained by the US Navy. In tests, four of the Navy phages
killed the bacterium from Patterson’s infection as well.
The Texas phages arrived in San Diego first, all four of them
combined into a cocktail to increase the odds of success. They
had to be scrubbed of cellular toxins and debris from the
bacteria they had been grown on, because those contaminants
could have sent Patterson into shock. Schooley and his team
infused the clean solution into the drains that pierced
Patterson’s abdomen, hoping to sterilize the cavities where the
infection was lurking. That was on a Tuesday. Patterson didn’t
get better, but he also didn’t get worse—encouraging, given how
rapidly he had been slipping away. Two days later, the Navy
phages arrived, and the UCSD team took a gamble and gave them to
him intravenously, to chase the bacteria that had found homes in
his lungs and bladder and blood. That was on a Thursday. On
Saturday night, Patterson awoke from his coma and recognized his
daughter. The phages had done their work.
He was not yet cured, not by a long shot. His infection surged
and he crashed back into septic shock the next week, only to be
brought out of it with more phages. The same thing happened
again a month later, and this time the Navy lab analyzed his
infection and tinkered with the phage cocktail.
The whole treatment process
was a scramble. “We had two people working literally 24/7 for
six weeks to find and supply phages to the clinical team at
UCSD,” Young said. “That is not sustainable.”
The effort was such an emergency, Young added, that his group
did not have time to fully analyze the phages they sent. Later
they discovered that almost all the viruses used in the first
round of Patterson’s treatment, both from Texas A&M and from the
Navy, targeted the same single attachment point on the outside
of the bacterium. It was as if they were all the same drug,
instead of eight different ones. That meant the bacterium had to
make just one small mutational change to defend itself against
them, producing phage resistance—a problem that appears in only
a small number of scientific papers about phages and that
medicine has not yet had to develop strategies against, because
phages have not been a treatment in most of the world.
“If we had been able to do
genetic and molecular analysis of the phages, we could have
avoided that,” Young said. “The ideal thing would be to have a
walk-in cooler of thousands of phages, each of which you know
everything about.”
Actually, two decades ago, someone attempted to do just that.
Alexander Sulakvelidze, who holds a doctorate in microbiology,
is a native of Tbilisi, the home of the Eliava Institute.
Sulakvelidze grew up experiencing phage treatments as a routine
part of medical care, off-the-shelf products that doctors would
prescribe like Western physicians prescribe antibiotics. Then he
came to the United States to serve a postdoctoral fellowship at
the University of Maryland School of Medicine. One day during
his fellowship, his supervisor, Dr. J. Glenn Morris, announced
that a patient was gravely ill with a resistant bug called VRE
and would likely die.
“I asked him, ‘Why can’t
bacteriophages get rid of the VRE?'” Sulakvelidze recalls. “I
thought it was a naive question.” But later, after the patient
died, Sulakvelidze says he realized, “Something very strange is
going on. Somebody just died in the most developed country in
the world, from something that could probably be very easily
cured in a country like Georgia.”
Out of that realization, Sulakvelidze and Morris and a handful
of other researchers formed a company, Intralytix, in 1998. They
set out to license phage treatments for VRE, considered at the
time the most dangerous of the superbugs. It did not go as
planned.
“The investors had no idea
what the risks are, the patentability, the return on
investment,” he said. “The regulatory agencies had no idea how
to regulate this. It was a huge uncertainty.”
This was only a few years after the opening of the USSR. Most of
the research written about phages had never been published in
English and never evaluated by Western scientists. To make a
case for phages in American medicine, clinical trials such as
the ones that prove antibiotics’ efficacy would have to be
conducted.
But here was the problem. To be approved, an antibiotic must at
least reliably kill the common strains and subtypes of the
bacteria that cause a particular infection; the
broadest-spectrum antibiotics, which doctors usually reach for
first, kill multiple species in several groups. But phages do
not work against entire groups or even against species. They are
weirdly specific and attack bacteria (or not) based on minute
genetic differences.
Clinical trials of antibiotics—which progress through three
phases before approval and in the third phase can include
thousands of patients—are constructed to prove a compound is
safe and effective and causes a cure, no matter what minor
genetic differences exist from one infection to another. Phages
cannot pass that test, because any one phage will only work on a
subset of patients.
After hitting a roadblock with the FDA, Sulakvelidze and
Intralytix canceled the plan to try to get phages approved as
drugs. But they had discovered another opportunity: Food safety
is regulated by a different FDA division than drugs are. The
company pivoted to isolating phages that would kill the most
important foodborne-illness organisms—listeria, salmonella,
Shigella, and E. coli. Between 2012 and 2016, the FDA’s food
safety arm granted “generally recognized as safe” status—a much
lower bar than a new drug approval—to phage cocktails targeting
three of the food safety bugs. Sulakvelidze thinks the FDA’s
comfort with phages for food is an opening. He is on track to
begin trials of a new human product this year.
It’s impossible to know whether Sulakvelidze will be successful,
because the FDA says federal law prohibits it from talking about
the process of possibly licensing phages for medical purposes.
The agency seems to take the position that since it might
someday be required to rule on drug licensing for phages, it
can’t give any information now about why there have been so few
licensing attempts. It won’t even comment on how many licensing
attempts there have been, though the ClinicalTrials.gov database
maintained by the National Institutes of Health shows that in
the United States over the past two decades, 15 studies have
used phages: Just two applied phages as a treatment and got
through phase one—which uses a small group of people to test
safety but doesn’t test efficacy—and those studies did not
proceed. The FDA declined to make any of its scientists
available for an interview. A spokeswoman, Megan McSeveney, said
in a statement that the agency “stands willing to work with
bacteriophage developers to provide scientific guidance and
clarify regulatory and data requirements necessary to move these
products forward in development as quickly as possible.”
“You have spectacular
life-and-death stories … yet you have the real dilemma of
demonstrating that these are in fact reliable.”
The NIH, which focuses purely on research and isn’t responsible
for drug licensure, was a little more forthcoming. “Given the
problems that we have with antibiotic resistance in this country
and throughout the world, it certainly behooves us to explore
alternative means of controlling and fighting and countering
bacterial infections,” Dr. Anthony Fauci, director of the NIH’s
National Institute of Allergy and Infectious Diseases, told me.
“Certainly phage therapy is one of those.” In 2016, Fauci said,
the NIH wrote about $5 million in grants to medical research
centers to gather data on antibiotic alternatives, including
phage therapy’s potential against “a variety of recalcitrant
infections.” (The US medical establishment isn’t alone in
struggling with phage research; the first major EU-backed
clinical trial, called Phagoburn, did not proceed beyond phase
two.)
Elsewhere in the NIH, Randall Kincaid, a pharmacologist and the
senior scientific officer in what’s called the concept
acceleration program, explained that launching new categories of
treatments isn’t as simple as working out the right structure
for a clinical trial. The research has to be worth the end
result, he said—which means knowing that physicians will use the
treatments when the compounds enter the market, and also that
pharmacy managers will buy them.
“You have spectacular life-and-death stories, and everyone
wishes to see this pushed forward as concerns about
antimicrobial resistance increase, yet you have the real dilemma
of demonstrating that these are in fact reliable,” he said. And
commercially viable: Since phages are hyperspecific and can’t be
pulled off a pharmacy shelf as an antibiotic can, physicians may
be deterred from seeking them out, he added—and that would make
the trouble and expense of clinical trials pointless.
A set of treatments that the FDA recently accepted might show a
path forward for testing and approving phages. Personalized
cancer treatments known as CAR-T (for “chimeric antigen receptor
T-cell therapy”) involve extracting immune system cells from a
patient’s blood so they can be genetically modified in a lab and
then reinfused into the patient. In 2017, the FDA gave licenses
to two CAR-T treatments, Kymriah for advanced leukemia and
Yescarta for a type of lymphoma.
Like phages, CAR-T treatments are tuned to an individual
patient. But here’s a key difference that made drug developers
think CAR-T was worth pursuing for two decades: If it goes into
widespread use, it will make manufacturers tons of money. The
cost of a single dose of Kymriah is projected to be a
breathtaking $475,000. But antibiotics have never been priced
anywhere near as high as cancer drugs, and it seems unlikely
that prices would rise for the phages that might supplant them.
Those low prices have historically been one reason it has been
hard to get drug companies to develop new antibiotics. Consider:
In contrast to Kymriah, the antibiotic Avycaz, hailed as a major
advance when it was approved in 2015 for hospitalized cases of
grave drug-resistant pneumonia, costs as little as $3,500 on
price lists and rarely rises above $15,000—and that’s for 10
doses.
“I always thought viruses were
the bad guys, evil. Now I can see that viruses may actually be
used for good, too.”
For phages to justify investment, developers will have to make a
case for using them not just to save the 23,000 people who die
of resistant infections in the United States each year, but also
to treat some of the 2 million who seek a doctor’s help or
hospital care. There are applications: Phages could coat
artificial joints and heart valves to prevent pathogenic
bacteria from developing sticky drug-resistant mats called
biofilms. Phage solutions could be infused into the raw surfaces
of diabetic foot ulcers, which are hard to treat because they
have a thick, fibrous backing that prevents intravenous drugs
from penetrating; that is partly why diabetic patients were
among the first victims of VRSA, a staph resistant to even the
last-resort antibiotic vancomycin. Intralytix has proposed using
phages to kill disease bacteria that are picked up from food and
water and live quiescently in the gut for unpredictable periods
of time—the superbugs NDM and MCR, which originated in India and
China, spread around the world that way. The process of clearing
out bad bacteria that aren’t currently causing an infection is
called decolonization, and it’s difficult to accomplish with
antibiotics, which kill good cells along with bad ones. Phages
could be more targeted.
A handful of companies still believe in the possibility of
phages, enough to invest in research while the FDA works out its
issues. One is AmpliPhi Biosciences, which conducted one of
those phase-one treatment trials in the NIH database. AmpliPhi
sits north of the UCSD medical center where Patterson was
treated, and its phages were among those that became part of his
treatment after Young at Texas A&M launched his worldwide plea
for phages that might help.
Paul Grint, AmpliPhi’s CEO, is a physician who was a successful
antibiotic developer earlier in his career and understands from
the inside the Catch-22 of the federal research bureaucracy. The
company’s phase-one trial investigated the safety (but not the
effectiveness) of a cocktail of three phages that work against
drug-resistant staph bacteria by applying the solution to the
forearm skin of healthy volunteers. With that box checked,
AmpliPhi has been strategizing how to move to the next step,
which requires using the cocktail in patients who are
experiencing staph infections.
Grint’s solution is to patiently assemble an array of single
cases, by contributing his company’s phages to cases such as
Patterson’s. “We’ve set a goal of, say, 10 by the end of this
year, and 10 to 15 in the early part of next year,” he told me
in 2017. “We will then have a data set that allows us to better
design a phase-two study and answer some of the questions that
regulators have.”The FDA’s emergency exemptions only allow for
treating one patient at a time. But in research, one case is an
anecdote. To demonstrate to the FDA that a phase-two trial would
be safe, the developers need more data than a single case can
give them.
But while companies and the FDA negotiate, patients need saving
now. In October last year, a 25-year-old woman in Pittsburgh
named Mallory Smith, who had cystic fibrosis and had received a
lung transplant, developed an infection in her new lungs with a
stubborn bacterium named Burkholderia cepacia, to which CF
patients are more susceptible. The infection was resistant to
every antibiotic her physicians treated it with. Her father, who
had heard of Patterson’s ordeal, turned to Strathdee for help.
On November 7, Strathdee posted a plea on Twitter, asking
scientists for any phages that might have a hope of matching:
“#Phage researchers! I am working with a team to get
Burkholderia cepacia phages to treat a 25 y old woman with CF
whose infection has failed all #antibiotics. We need…phage
URGENTLY to find suitable phage matches.” Of the several hundred
phages from around the world that Strathdee was offered, Smith’s
father recalls that at the last minute two looked like a match.
They were rushed to Smith’s hospital and administered, but it
was too late. Mallory Smith died November 15.
Patterson, however, made it. He left the hospital in mid-August
2016—gaunt and weak, having lost most of his muscle mass but
having beaten the superbug using phages. He was the first person
in the United States to have been successfully treated
intravenously.
He is still frail; the last-resort antibiotics he was given
before the phage treatment temporarily harmed his kidneys. On
the day I met him in their home in Carlsbad, California, he had
just taken a nap, and he talked to me from a recliner, with a
blanket and a cat stretched across his lap.
“I’ve studied AIDS for many,
many years, since the beginning of the epidemic, and I always
thought viruses were the bad guys, evil,” he said. “Now that
I’ve gone through what I have, I can see that viruses may
actually be used for good, too.”
Strathdee, who is working on a book with Patterson about their
experience, says she hopes to see phages become a routine option
for serious infections, available to substitute for antibiotics
or to be administered alongside them, given early in treatment
and not as a desperate last resort when nothing else may work
well.
“It certainly seems to me a
lot less risky than antibiotics,” she said. “They’re
self-limiting: When the bacteria they attack are gone, they’re
gone. That’s a pretty good designer drug, and nature gave it to
us.” |
