A Stalinist Antibiotic Alternative
nytimes.com
A hoary Soviet method for fighting infections may prove invaluable in an
age of antibiotic resistance. Maybe that's why pharmaceutical companies
are flocking to a remote laboratory in Tbilisi. By LAWRENCE OSBORNE
In a barely heated
ward for newborns
on the top floor of
the Georgian Republic
Children's Hospital,
Tamila Gogitidze
carefully opens a glass
ampul filled with amber
liquid. The hospital, in
the Degomi suburb of
Georgia's decaying
capital city, Tbilisi, is a
spartan affair: its
radiators are
ramshackle, the
electricity intermittent
and the raw concrete
heavy on the eyes. A
few American posters of babies cavorting in cabbages seem direly out of place.
The liquid trapped inside the ampul, meanwhile, can be identified from a box on the
floor. Its label is Latin: Bacteriophagum Intestinalis Fluidum. Gogitidze, a nurse on
the intensive care unit for newborns, cracks open the ampul, pours the liquid onto
a teaspoon and prepares to administer it to one of her babies, a 3-month-old boy
abandoned at the hospital a few days before by his impoverished family. He is
screaming lustily.
"Look," Gogitidze says, holding up a tiny wrist. "The parents made a kind of crude
tattoo so that they can identify him later on. But for now, we must focus on his
intestinal infection."
The fluidum is tipped like any cough syrup into the boy's blubbering mouth. His
face contorts into a horrible wince; I look apprehensive. But Dr. Tamar Gotua, head
of the intensive care unit, takes my arm and says: "We use them with almost all our
children. Don't look so worried!"
It's hard not to feel worried in Georgia. After years of bloody civil war following
the collapse of the Soviet Union, the republic is in free fall. Electricity runs for only
part of the day; blackouts are a daily, if not hourly, occurrence. Nevertheless, in
this dilapidated neonatal ward a possibly revolutionary medicine, one essentially
unknown in the West, is being casually administered on a simple teaspoon:
bacteriophages, or microscopic viruses that actually "eat" bacteria.
Downstairs in the same hospital, I talk with Dr.
Irakli Pavlenishvili, head of pediatrics, in an
office so cold that our breath mists. The doctor
offers me some Greek brandy and warms his
hands by a portable electric heater. We
chain-smoke furiously. "We've been using
phages for years," he says briskly, looking up
nervously at the flickering lights. "There are no major side effects. They're a living,
natural force, not a toxic chemical. I wish our electricity were as reliable!"
Today, the West is paying renewed attention to this unheralded therapy created
behind the Iron Curtain. The reason: antibiotic resistance. Although drugs like
penicillin have held killer bacteria at bay for half a century, the bugs keep
genetically adapting to them, evolving into tougher, smarter variants of ancient
adversaries. The systematic overuse of antibiotics by doctors, especially in the
United States, has helped breed "superbugs" -- bacteria resistant to even the most
potent antibiotics, like vancomycin.
Last year, The New England Journal of Medicine published an alarming editorial
about superbugs. "The outlook is rather grim," it wrote. "The adaptive potential of
the microbial world is such that for each new antibiotic that is introduced, several
escape mechanisms are soon devised."
Alexander Tomasz, a leading microbiologist at Rockefeller University, agrees: "The
miracle days of antibiotics are over. We simply didn't think enough about the
evolutionary consequences of drug use." With leading medical researchers in the
West looking anxiously for antibiotic alternatives, bacteriophage therapy is
suddenly looking "very promising," as Tomasz puts it.
"I'm convinced that bacteriophages will work," says Carl Merril, chief of the
biochemical genetics laboratory at the National Institutes of Health. "But there's
the psychological obstacle of a new treatment coming from the former Soviet
Union. It's unusual, to say the least."
hey may sound exotic, but bacteriophages are in fact among the most
common organisms on earth. (The word derives from the Greek phagin, "to
eat.") Viral predators only one-fortieth the size of the average bacteria cell,
they swarm unseen around us, busily searching and destroying their favorite food:
germs. In electron microscope images, phages show up as ghostly, spiderlike
creatures with transparent box-shaped heads, rigid tails and a tangle of legs for
gripping their prey. They are so tiny that a single drop of tap water may contain a
billion of them.
How do phages kill bacteria? The answer is, with chilling efficiency. Latching onto
the walls of a bacteria cell, the phage injects it with the genetic material stored in
its very own head. Like a living syringe, it gradually empties itself into the victim
and takes over its genetic machinery. Inside the helpless bacteria, bits and pieces
of "daughter" phages begin to appear with sinister rapidity: rows of little heads,
lines of tails, then legs. These different body parts assemble into miniphages,
using the host cell as a kind of factory. As the phages multiply exponentially
inside it, the bacterium's walls weaken -- then explode like a soap bubble. Scientists
call this rather nightmarish process "lysis." It is the flash point of a gigantic
microbial war between phages and bacteria, in which humans are a mere side issue.
These deadly microscopic hit men were discovered
independently during World War I by the English
microbiologist Frederick Twort and the flamboyant
Canadian biologist Felix d'Herelle, then working in a
laboratory at the Institut Pasteur in Paris. It was
d'Herelle who gave them their name in a 1917 paper
that predicted a revolution in the treatment of
infectious diseases.
D'Herelle first discovered bacteriophages while
working in the Mexican state of Yucatan in 1910. He
noticed them in the most unlikely of places: the
diarrhea of locusts. During an invasion of these
insects, d'Herelle collected sick specimens and
observed their abundant stools. He concluded that
the locusts were suffering from septicemia caused
by coccobacilli bacteria. D'Herelle smeared some of
the diarrhea onto plates of agar to grow cultures, but then noticed something odd.
After a while, clear circular spots a few millimeters across had appeared in the agar,
suggesting that something was munching away at the coccobacilli. What were
these tiny bacteria-eaters?
Back at the Institut Pasteur, d'Herelle repeated the experiment in 1915 with stools
taken from a Paris-based squadron addled with dysentery. In the excrement of the
officers, d'Herelle again detected agents that consumed the bacteria
spontaneously. Nature, d'Herelle boldly announced to the world, had provided
humankind with a living, natural weapon against germs.
Phages were popularized by Sinclair Lewis in his 1925 novel "Arrowsmith," about
a young doctor who goes to the West Indies to use them against an epidemic of
bubonic plague. "You may," says one of the novel's characters to Martin
Arrowsmith, who was inspired by the real-life d'Herelle, "have hit on the supreme
way to kill pathogenic bacteria!"
But it was not to be. Phages proved to be a hit-or-miss affair as a therapy. One
problem was that there are hundreds of types of phages, and each type kills only
one variety of bacteria. Predator and prey must be perfectly matched, a daunting
process. What's more, there were early problems with purification. When phages
burst out of the victim's cell, they leave behind debris that can contaminate the
solution. This debris can prove fatal to humans, a problem that the purification
technologies of the early days were unable to solve.
As a result of these difficulties,
phages were quickly outpaced by a
rival drug: penicillin. Although Eli
Lilly actually manufactured
therapeutic phages for the United
States market in the 1930's, after
World War II they were largely
consigned to the margins of
Western medicine -- even as they
took center stage in DNA research,
where their simple molecular
structure made them an ideal tool
for peering into the inner workings
of genes. Sir Francis Crick and Max
Delbruck, two architects of DNA
theory, were phage researchers.
Phage research helped unlock
molecular biology at the very moment that they disappeared from the medical
scene.
Yet there is a twist to this story. The aristocratic d'Herelle was a passionate
Communist and admirer of Stalin. In 1934, he accepted an invitation from the Soviet
government to join the Institute of Bacteriology in Tbilisi, recently set up by a
young Georgian microbiologist named George Eliava. The Eliava Institute, as it
became known, became the world's leading center of therapeutic phage research.
One of its first successes was a powerful dysentery phage for the Red Army
during the World War II. Over the ensuing decades, the institute began supplying
precisely targeted phages to hospitals all over the Soviet bloc. The Eliava Institute
became the largest phage library in the world, with a permanent "museum" of more
than 300 phage clones.
"We've been perfecting bacteriophages as a medicine for over 70 years, just as
d'Herelle said we could," explains Nina Chanishvili, a senior researcher at the
Eliava Institute today. "But has anyone been listening?"
n an icy December day, Chanishvili and I walk through the hilly Tbilisi
district of Saburtalo on our way down to the Eliava Institute. The path
winds vertiginously through plots of spindly pomegranate trees touched
with snow. Clumped along the hillside are rotting Soviet-era apartment blocks. On
the streets, the shops are lighted only with candles.
Nina's uncle, Teimuraz Chanishvili, has helped direct the Eliava Institute for a
quarter of a century, and she, too, has devoted most of her life to phage research.
But the last 10 years have been cruel. In recent years, she says, the institute's
phage output has dwindled alarmingly. Virtually unpaid, the institute's workers
now cling to a fading infrastructure. When high-tech equipment breaks down, they
must work with improvised materials. Also, adds Chanishvili, "because of the
power cuts, we've lost about half of our phage library." (Phage cultures must be
refrigerated.) Georgia's economic collapse has dwindled the demand for phages as
well. Once the institute manufactured phage sprays, salves, ointments, tablets --
you name it. But now, even at $3 to $5 for a box of 10 ampuls, many of Tbilisi's sick
simply cannot afford them.
The institute, however, still sits in its graceful park of cypresses overlooking the
Mtkvari River, and over the wall I see the handsome cottage that Stalin had
specially built for d'Herelle. It is still called "d'Herelle's cottage," though it was later
occupied by the Georgian K.G.B. Inside, the institute is a cavelike labyrinth of
damp cement corridors, stairwells dripping wires and mournfully antiquated labs.
The old fermentation vats that used to churn out phage preparations for the Soviet
Ministry of Health stand abandoned in a room with no glass in the windows.
Upstairs, Chanishvili shares a cramped and unheated lab with a fellow researcher,
Marina Tediashvili, and half a dozen young medical students. They are all women.
They are all shivering. "Of course," says Tediashvili, "the men naturally move on
to better things." Equipment is largely rudimentary. Among the centrifuges, water
baths and piles of petri dishes stand dozens of beer and vodka bottles that the
women use as containers for their solid agar. To melt the agar, they pop one of the
vodka bottles inside an old Nescafe tin sitting on a hot plate. "We like vodka
bottles," Chanishvili feels obliged to explain, "because they're so transparent."
The interns spend most of their time on the tedious chore of planting phage
cultures in the specimens of bacteria, turning each petri dish into a kind of phage
farm. I watch as one of the women sterilizes the tip of an applicator in a Bunsen
burner, drips a blob of phage solution onto a plate of E. coli and carefully closes
the plastic lid. "E. coli causes epidemics worldwide," explains Tediashvili. "But
these phages find E. coli tasty. They go through it like Oreos."
Holding up an E. coli dish that has been incubated for two days, she points to a
smattering of irregular, clear circles carved out of the agar. They look like the
perforations of a shotgun blast. "Isn't that beautiful?" she whispers. A dish of
salmonella is peppered with smaller, more regular bullet holes.
Chanishvili explains that she and her colleagues initially catch phages in gunky
places where the creatures are known to thrive: sewage water, for example. They
are then stored in a liquid broth kept in a refrigerator at 4 degrees Celsius. Oddly
enough, they don't need to be fed with tasty germs to stay alive. "Phages can live
for months without food," Chanishvili says. "Without additional germs to feed on,
they cannot multiply out of control." If their numbers begin to decrease, however,
a few bugs are thrown to them and they multiply again.
In the same wing, I am taken to see Amiran Meipariani, head of phage research.
Meipariani has been here since 1946, at the height of the Stalin era, and his
sardonic blue eyes seem to have seen it all. Like most Georgian doctors, he
chain-smokes and shrugs frequently. His office is filled with disconnected Soviet
telephones; on the wall hangs a faded portrait of Felix d'Herelle.
"As you can see, we've fallen on
hard times," he says, shrugging.
"But it is now realized worldwide
that an alternative to antibiotics
should be sought and that the best
one is bacteriophages. Perhaps it's
a boon for us. Did you know that
NATO is now interested in one of
our inventions?" His eyes light up
puckishly. He is referring to a
topical phage application invented
by the Eliava Institute and known
as a "PhageBioDerm," a kind of
bandage saturated with a cocktail
of five to nine different phages that
can treat infected burn wounds. It is the perfect military Band-Aid. Russian
soldiers have used them in Chechnya. "Of course, women and kids can use them
in the kitchen, too," he adds with a sales-pitch smile.
The Eliava has a local patent on the phagoderm, which it manufactures itself along
with the "intestiphage," the 17-phage cocktail I saw being administered to the
abandoned baby. All in all, the Eliava produces about 10 different phage
applications that target about 15 different bacteria genera. By creating drugs that
combine many phages at once, their administration can be simplified to a single
dose.
Considering the difficulties involved in doing science in Georgia, the
advancements made by the Eliava are remarkable. Chief among these has been the
creation of an intravenous remedy to the deadly staph aureus bacteria, a strain
that threatens to one day outpace vancomycin. According to the Eliava, it's been
used successfully on dozens of patients.
In the past few years, the Eliava's skill has attracted the attention of Western
entrepreneurs eager to harness the knowledge bottled up in Tbilisi's laboratories.
But the Georgian scientists worry about this development as much as they
celebrate it. Who will ultimately benefit from the commercial exploitation of their
work? Will the Americans and Europeans simply steal their expertise and
innovations? "The local market has collapsed," says Meiparinai with a final shrug.
"But who will patent phages in the West? Who's going to make the millions?"
Then he corrects himself. "The billions, I mean." Indeed, the worldwide
antibacterials market is estimated to be worth $25 billion a year.
So far, the Eliava's experience of cooperation with American companies interested
in phages has not exactly been propitious. In 1996, a Canadian venture capitalist
named Caisey Harlingten came to Tbilisi, eager to talk to the Chanishvilis about
their work. What happened next was, as Chanishvili puts it tersely, a "culture
clash." Although a start-up company that came to be named Phage Therapeutics
was quickly set up in Seattle, the planned Tbilisi affiliate was closed almost as
soon as it opened. "Harlingten told me," says Chanishvili bitterly, "that the
American consumer would never accept a medical product from the Soviet Union."
Meanwhile, Phage Therapeutics is busy readying Eliava-inspired medicines for the
U.S. market.
"We gave the Americans access to all this background research," she goes on,
"and they simply walked away with it. They told us we were stupid at business.
Well, that at least was true."
That evening, I meet with Teimuraz Chanishvili at his home on Kazbegi Street, a
lampless street of elegant 19th-century Russian houses. A Nabokovian charmer
now in his 70's, he greets me at the top of the stairs in his dressing gown. "Come
and look at the TV," he says excitedly. "The Americans have stolen my phage
photographs!" By one of those coincidences that even a journalist couldn't
invent, there indeed is an American documentary about phages playing on the TV.
Teimuraz's uncopyrighted images of phages float like extraterrestrial prawns across
the screen. "I didn't get a cent!" he cries, shaking his finger at the screen.
Later, we have a calmer chat over chestnut soda, and he tells me the sad story of
George Eliava. The man who established the bacteriophage's central place in
Soviet medicine was not exactly rewarded for his efforts. When not doing brilliant
science, Eliava was a handsome playboy who had the misfortune to fall in love
with a woman also admired by Lavrenti Beria, Stalin's secret police chief. Despite
Stalin's high regard for bacteriophages, it was Eliava's death warrant.
"Beria had Eliava shot in 1937 on a pretext," Teimuraz says matter-of-factly.
"That's the way it was back then." He adds with a chuckle, "Thankless work,
bacteriophages!"
As if on cue, the lights go out.
n the well-lighted laboratories in Europe and the United States, however, the
prospects for phages are glittering. In this country alone, at least three start-up
companies are vying to be the first to push a phage therapy through Food and
Drug Administration approval. In addition to Harlingten's Phage Therapeutics in
Seattle, there are Intralytix in Baltimore -- a company with numerous Georgian
expats on the payroll -- and Exponential Biotherapies on Long Island, a small
biotech company run by Dr. Richard Carlton that expects to petition the F.D.A. to
begin clinical trials on a phage drug this spring.
Big challenges face these companies. One pitfall of early phage therapy was that
wild phages are expelled very quickly by the body's filtering system, often
reducing their effectiveness. The immune system, in other words, treats them as
foreign bodies. Can new technologies, however, pinpoint "domesticated" phages
that can linger longer in the body? While the Eliava has had some success on this
front, American scientists hope to do even better.
The work of Carl Merril has led the way. In the April 1996 edition of Proceedings of
the National Academy of Sciences, the N.I.H. researcher published the result of
some intriguing experiments with phages and mice. Essentially, he was able to
selectively breed "mutant" phages that remained in the mice far longer than the
wild variety. "We altered the code proteins in the phages," Merril explains, "to
make them more durable." In the same issue, the Nobel laureate Joshua Lederberg
of Rockefeller University wrote, "This is an ingenious surmounting of one of the
hurdles to the use of phage in therapy."
continues..... |
