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Wired Magazine
How Ravenous Soviet Viruses
Will Save the World
They're called phages. And they eat drug-resistant
bacteria for breakfast.
By Richard Martin - October, 2003
As a child in the early '70s, Alexander Sulakvelidze dreamed
of rising to the top of the Soviet scientific establishment.
Fascinated by life at the smallest scales, he earned his PhD in
microbiology from Tbilisi State Medical University in his
hometown, the capital of Soviet Georgia. By the time he was 27,
he was deputy director of the Georgian equivalent of the Centers
for Disease Control and was collaborating with the Eliava
Institute, a local hotbed of research in infectious diseases. He
stood at the threshold of a brilliant career.
But when the Berlin Wall fell in 1989, the Soviet Union's
formidable scientific infrastructure toppled along with it. By
the early '90s, Sulakvelidze found himself laboring in a
backwater. Like a Georgian Ginsberg, he watched the best minds
of his generation go to waste.
"There was nothing left to do," he recalls. "Good scientists
would come to work and spend all day playing cards and chess."
Determined to avoid that fate, he turned to the US. He
applied for a National Academy of Sciences research fellowship
at the University of Maryland Medical Center under Glenn Morris,
one of the world's foremost epidemiologists. He got the nod, and
in 1993 Sulakvelidze left Tbilisi for Baltimore.
He arrived to find the hospital in the midst of its own
crisis. Enterococcus, a common bacteria that infests the human
stomach and intestinal tract, was showing signs of resistance to
vancomycin, the antibiotic of last resort. Between mid-'92 and
mid-'94, vancomycin-resistant Enterococcus, or VRE, infected 75
patients, killing 6. A random sampling in fall '93 found that 20
percent of patients had VRE in their bloodstream. People were
dying, and there was nothing anyone could do about it.
The Georgian microbiologist was nonplussed. Where he came
from, infections were treated not only with antibiotics, but
with viruses that attack and destroy bacteria. One day, as
Morris lamented his inability to fight the outbreak,
Sulakvelidze interrupted to ask: "Why don't you try
bacteriophages?"
With that question, Sulakvelidze initiated a new phase in the
age-old struggle between humans and microbes - one in which
scientists are enlisting the power of evolution rather than
fighting it.
The cause of the Maryland med center's sudden epidemic was no
mystery. Wanton use of antibiotics, both in human patients and
animals raised for food, reduces the danger of bacterial
infection, but also forces bacteria to adapt at a prodigious
rate. The germs that survive breed new generations of superbugs,
impervious to even the most powerful medicines.
In an escalating arms race, scientists have scrambled to
develop ever more potent drugs - but the bugs are winning. In
January 2002, seven people died at a Tokyo hospital when they
were infected with a drug-resistant strain of Serratia
enterobacteria. The following March, all heart surgery at
Scotland's Edinburgh Royal Infirmary was suspended after 13
patients came down with a methicillin-resistant strain of
Staphylococcus aureus, the number-one cause of hospital
infections. A month later, a 40-year-old diabetic woman in
Detroit was found to be suffering from the first known
vancomycin-resistant strain of S. aureus. Drug-resistant
infections kill 40,000 people each year and account for up to $4
billion in additional treatment costs, according to the National
Foundation for Infectious Diseases.
Where this leads is frightening to contemplate. A growing
chorus of experts foresee a world in which formerly vanquished
illnesses like tuberculosis and pneumonia rage out of control,
and immune-compromised patients succumb to once-harmless
infections.
"The war against bacteria is not something that can be won by
humans," Sulakvelidze says. "If you try to wipe them out, they
will always return. Only they will be stronger."
If the problem is classic Darwinian adaptation, the solution
might lie in the very same process. Thus, Sulakvelidze, Morris,
and others have turned their attention to bacteriophages, which
have evolved over eons to destroy bacteria. This approach to
fighting infection lets nature do the lab work usually carried
out at tremendous expense, and with high failure rates, by the
pharmaceutical industry. In contrast to engineered drugs, phages
are as numerous and varied as the bacteria they attack. What's
more, they evolve along with their prey, matching bacterial
adaptation step by step.
The hard part, as Sulakvelidze and Morris have found, isn't
harnessing them for medical benefit. Rather, it's bringing a
dusty Soviet remedy into the 21st century.
The discovery of phages is lost in murky rivalries and
scientific disputes. What's certain is that in 1917 an eccentric
French-Canadian scientist named Félix d'Hérelle isolated them
and named them bacteriophages - eaters of bacteria. Working
independently, George Eliava discovered the minute creatures
after collecting specimens from the Mtkvari River, which flows
through the Georgian capital of Tbilisi. Eliava, head of the
city's Central Bacteriology Laboratory, left a slide of river
water containing cholera bacteria under a microscope for three
days. When he returned, the germs were gone. Eliava surmised
that something had destroyed them, and, like d'Hérelle, he set
about isolating the tiny bacteria killers. Eventually, the
Georgian struck up a fruitful collaboration with his French
colleague. They worked together at the Pasteur Institute in
Paris and later at the Institute of Microbiology, founded in
Tbilisi in 1923 and later renamed in Eliava's honor.
It was there that a small band of scientists pioneered a new
therapy, scrupulously assembling the world's only library of
phages and developing cocktails of a dozen or more to treat a
variety of bacterial disorders from stomach aches to pneumonia.
Phages became part of the standard pharmacopoeia in the USSR,
and they even enjoyed a brief heyday in the US, where Eli Lilly
had an active phage-production program in the '30s. Soviet
medics used the viruses on World War II battlefields, and
soldiers with the German general Erwin Rommel carried phage
treatments in disease-ridden North Africa.
The embrace of phages in the West didn't last long, though.
American reviews of the Soviet research cast doubt on the
therapy's efficacy, and when penicillin - widely regarded as a
miracle drug - reached hospitals in 1941, Western doctors
essentially forgot about phages. They continued to be sold in
pharmacies throughout the Soviet Union, but the decline of
medical research in the post-Soviet era nearly wiped out their
use. By the 1970s, the Eliava Institute had fallen into a
desuetude that threatened to bury five decades of research. Like
Dark Age monks, the institute's scientists struggled to keep
their phage library alive.
"One day at the Eliava, the electricity failed," write
Michael Shnayerson and Mark J. Plotkin in their book The Killers
Within: The Deadly Rise of Drug-Resistant Bacteria. "Over the
next months, it went off more and more often, until in 1993 it
stopped coming on at all. The researchers packed their home
refrigerators with phages; those had power, at least, a few
hours a day."
While many of his colleagues languished, Sulakvelidze brought
the secrets of Soviet phage research to the US.
Scoop up a handful of water from the nearest creeK. Each
milliliter holds about 200 million phages. Something like 1031
phages teem in the world's rivers, lakes, and oceans. That makes
them, by some reckonings, the most abundant life-form in
existence. As single-minded as they are ubiquitous, they exist
only to replicate. The destruction of bacteria is simply
collateral damage.
Unlike antibiotics, which attack bacteria indirectly by
inhibiting cell wall synthesis, phages are cruise missiles that
breach the wall and hijack the cell's reproductive machinery.
So-called lytic phages reproduce like mad until the cell bursts,
releasing hundreds of tiny clones. This reproductive capacity
makes lytic phages ideal for human therapy. They're the only
drug that, once in the bloodstream, replenishes itself until the
infection is gone.
Phages have another important distinction: They come in
innumerable variations, each targeting a specific kind of
bacteria. A phage that attacks Salmonella ignores Staph aureus,
and vice versa. That's both the beauty and the disadvantage of
phages as therapeutic agents; unlike broad-spectrum
antibiotics,which kill every bug in their path, viruses can wipe
out pathogenic germs and "leave the good microflora alone," as
Sulakvelidze puts it. On the other hand, phage-based drugs must
be properly formulated to target the right bacteria.
The old Soviet phage preparations were both polyvalent
(containing multiple phages to target several varieties of
bacteria) and poorly characterized - even Eliava's scientists
didn't know precisely what was in them. Sulakvelidze's challenge
has been to develop an arsenal of viruses that can be combined
in known quantities to eradicate specific bacteria. He and his
Maryland team have assembled a library of monophages -
preparations containing only a single phage strain - and
sequenced their genomes, describing and classifying them to a
level undreamed of by Eliava and his successors.
"It was not uncommon for a single preparation to have up to
17 targets," Sulakvelidze says of Soviet-era therapies. "How
many phages in the preparation actually worked is anybody's
guess. Now we know exactly what goes into our cocktails. When we
need to reproduce one, we can make it exactly the same way."
To gather new strains, Sulakvelidze need only drop a bucket
into Baltimore's Inner Harbor. The waters of the Chesapeake Bay,
of which the harbor is an inlet, have enough exchange with the
Atlantic that he can find a phage for almost any species of
bacteria, he says. If one doesn't work, he simply refills his
bucket and looks for another that does.
"This upgradability is one of the unique qualities of
phages," Sulakvelidze adds. "Developing a new antibiotic takes
10 years and God knows how many millions of dollars."
As he puts it, "Mother Nature runs the best genetic
engineering lab out there. No institution or company can match
it."
Morris had heard of bacteriophages before his Georgian
colleague mentioned them. The viruses had been used since the
1960s to transfer genes among bacteria, and they played a
central role in the development of genetic engineering. But like
most Western scientists educated in the era of antibiotics, he
had never known them as a treatment for infection. As he and
Sulakvelidze dug up the relevant literature - which, by Western
standards, was scanty and slipshod - Morris became excited.
Here, he realized, was an entirely different kind of weapon in
the war against drug-resistant bacteria.
Sulakvelidze and Morris began to gather phages from the
nearest source: Baltimore's harbor and the Chesapeake Bay. To
pursue more rigorous studies, though, they needed money. In 1996
a tech investor named Caisey Harlingten, who had previously
financed technical advances in opthalmology, formed a company to
sponsor a collaboration between their lab and the moribund
Eliava Institute. The Americans hoped to take advantage of
Eliava's virus collection, phage-based medicines and decades of
experience using phages in bug-infested military and hospital
environments. As for the Tbilisi researchers, they were promised
royalties and new hope for saving their precious phages.
But the deal soured when Harlingten appointed a new CEO,
Richard Honour, to run the venture. Honour quickly decided to
cut ties with the Eliava Institute and develop genetically
modified phages in the US. Honour knew that the chances of
gaining FDA approval for phage-based medicines developed and
manufactured in Georgia were slight. Phages were available
everywhere. Why tie the company to an aging Soviet-era research
facility?
The rupture posed a dilemma for Sulakvelidze and Morris. To
continue with Phage Therapeutics, as Harlingten's company was
called, they would have to forsake the people who had carried
the torch of phage research through the dark post-Soviet period,
and who were Sulakvelidze's friends and countrymen. Moreover,
the Georgian was adamantly opposed to genetically engineering
phages: Why try to improve a weapon nature had honed over
countless millennia?
"As much as I hate to say it, from a financial standpoint it
makes little sense to establish a production facility in Tbilisi
today," Sulakvelidze admits. "But we thought it was
inappropriate to continue working with Harlingten. So we
terminated our contract."
At that point, Sulakvelidze and Morris had an ongoing
research program, a relationship with the Eliava Institute, a
growing library of phages - and competition. In addition to
Harlingten's Phage Therapeutics, a startup based on the work of
NIH researcher Carl Merrill had emerged. An expert in gene
transfer, Merrill first became fascinated by phages in the
1960s. In 1993, he began developing phage-based medicines for
the newly formed Exponential Biotherapies.
With no company and little business experience, Sulakvelidze
and Morris recruited four tech-savvy Baltimore entrepreneurs,
who rounded up money to start a new firm, Intralytix, in 1998.
Veteran tech exec John Vazzana, lured out of retirement to take
over Intralytix as CEO, was charged with leading Intralytix through the
desert of clinical trials, which would take years, to the
promised land of earnings.
By 2002, it had become clear that the company needed a
strategy that would buy time to bring Georgian medicines up to
Western standards. Already the competition was faltering: In a
delicious bit of irony, Phage Therapeutics had suspended
operations. It would take some fancy footwork for Intralytix to
avoid the same fate.
Vazzana's solution was as surprising as it was shrewd: He
proposed that Intralytix focus not on humans, but on animals.
The livestock population in the US numbers around 8 billion,
including 7.5 billion chickens, 300 million turkeys, and 100
million cattle. During their brief, inglorious lives, these
creatures receive as many as 10 different antibiotics, several
of which are also used in human medicines. Some of these are
therapeutic; when a few chickens become infected, growers treat
the entire flock. The rest are used as growth promoters; animals
on antibiotics stay healthier and grow faster. Unfortunately,
the bugs infesting those antibiotic-saturated animals get
smarter, making infections increasingly difficult to eradicate.
Government and industry have been slow to react, but they're
starting to take action. The European Union recently banned the
nonmedical use of antibiotics in animals, effective in 2006, and
similar legislation is being considered in Washington. In
February 2002, US poultry giants Tyson Foods, Perdue Farms, and
Foster Farms began phasing out growth-promoting antibiotics.
Sulakvelidze is developing phage-based products that will
help the industry moderate its use of antibiotics to treat
disease as well. The first, designed to combat Listeria
monocytogenes in poultry, was granted an experimental use permit
by the Environmental Protection Agency in June 2002.
Of course, food-safety products are only a stepping stone to
the real goal: a range of phage cocktails that would save the
lives of people with currently untreatable infections. And,
Sulakvelidze predicts, they'll likely be cheaper than
antibiotics.
Which is not to say they're completely unavailable at
present. Phage-based drugs are sold over the counter in Eastern
Europe, and word of their efficacy has spread among Western
victims of resistant infections. Given the FDA's glacial
approval process for new drugs, that's a recipe for a
black-market trade. Sure enough, North American patients are
showing up in Tbilisi, hoping for a miracle. It's only a matter
of time before phages are available in places like Bangkok and
Tijuana.
"It's frustrating," Morris says. "As a clinician, I'd like to
have phage products available in this country for my patients.
Every time an article appears on phages, I get 50 emails saying
'Where can I get this stuff?' What am I supposed to tell these
people?"
He might tell them that phages for human use are likely to be
available in the US within five years, and that the
bacteria-destroying viruses are already starting to be used on
poultry farms and in processing plants. As Western science
rediscovers a cure once thought obsolete, the day will come when
viral remedies are found on stateside pharmacy shelves next to
antibacterial soaps, and the golden age of antibiotics will give
way to a renaissance of bacteriophages. And this time, the bugs
could meet their match.
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