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Viruses Called Bacteriophages
Resurface As Viable Option To Fight Infections
The idea of using one microbe to kill another is attributed
to the scientist Felix d’Herelle. In 1910, he observed that
bacteria in the stool of sick locusts, which he had collected
for analysis, seemed to disappear as if by magic. The same thing
happened seven years later, when he was working with stool
specimens from patients with bacterial dysentery. In each case,
the disappearance appeared to be connected with clear, round
spots on a lawn of bacteria on a laboratory dish. He figured
that something in that dish was causing the bacteria to
disappear.
After d’Herelle discovered that he had found beneficial
viruses that could overcome bacterial illnesses, he and many
others around the world used them freely. Although no harm was
reported from their use, they were not endorsed in the United
States because no scientific controls had been conducted.
Despite that, bacteriophages, as d’Herelle called them, after
the Greek word phagein, "to eat," were viewed as a viable
concept in the 1930s, when they were listed by Eli Lilly & Co.
as one of its biological therapies.
In the 1940s, bacteriophage therapy dwindled in popularity,
because its results were not consistent. Moreover, the arrival
of antibiotics seemed to make bacteriophage therapy unnecessary,
although it continued to be used in other parts of the world.
Fast-forward to more recent times: Carl Merril, MD, Chief of
a Biochemical Genetics Laboratory at the National Institutes of
Health (NIH), Bethesda, Md., told Pharmacy Practice News that
one reason bacteriophage therapy did not always work was because
the viruses were removed too quickly by the filtering organs of
the reticuloendothelial system–the liver and spleen. Publishing
this theory and supporting observations (Nature
1973;246:221-222), Dr. Merril suggested that flooding the system
with colloidal particles might be the answer. The piece was put
aside and the idea forgotten until about five years ago, when he
became fully aware of the threat from antibiotic-resistant
bacteria. "Then I realized, thinking back to the article, that
we could make or find mutant viruses that would stay in the
bloodstream long enough to kill off the bacteria," he said. He
and Richard Carlton, MD, established a cooperative effort to
make such long-circulating viruses and to test their capacity to
rescue animals infected with bacteria.
Dr. Carlton was astonished at first to learn that
bacteriophages, or "phages" for short, were used as a form of
antibacterial therapy. Now, as President and CEO of Exponential
Biotherapies, Port Washington, New York, he ticks off their
talents. "All the phages want to do is kill bacteria," he said.
"When a phage finds the receptor on a bacterium, it pierces it
and injects DNA. That triggers a multiplication chain: As many
as 40,000 clones–called daughters–of the attacking virus can be
produced in one hour." This is the tremendous potential of phage
therapy that excited the imagination of the public in the 1920s
and 1930s, Dr. Carlton said. "You can create so many phages at
the expense of the bacteria."
To solve the rapid-clearance problem, Dr. Merril and Dr.
Carlton have developed a "serial passage" technology, which
produces long-circulating phages that are greatly superior to
the wild-types in terms of rescuing animals from otherwise fatal
infections. The results are published in the Proceedings of the
National Academy of Sciences-US (1996;93:3188-3192). Exponential
Biotherapies expects to have its first phage product in clinical
trials in the summer of 2000, Dr. Carlton noted.
As scientists wonder how to control infectious diseases in
the face of antibiotic resistance, they look for more versatile
armaments that can target the most dangerous bacteria, Alexander
Tomasz, PhD, told Pharmacy Practice News. "Phages are a very
good choice because they can be selected or even genetically
engineered so that their spectrum of activity will narrowly
target a particular bacterial pathogen, without damaging the
rest of the microbial flora," explained Dr. Tomasz, who holds an
Endowed Chair of Bacteriology at Rockefeller University in New
York City, and is a member of the scientific advisory board at
Exponential Biotherapies. For instance, people undergoing
peritoneal dialysis for kidney problems often develop
staphylococcal infections by bacteria that colonize the nares of
the patients, Dr. Tomasz said. "I could see a nasal spray of the
appropriate staphylococcal phage providing relief in this
situation," he said.
In Tbilisi, in the former Soviet Union, Georgian scientists
continued to use phage therapy after the West abandoned it for
antibiotics. Now, Alexander Sulakvelidze, PhD, Assistant
Professor of Medicine at the University of Maryland in
Baltimore, is using his former experience as Chief of the
Biology Lab at the Georgian Center for Disease Control to
develop a library of monophages. "These are single clones of
phages from which we can selectively choose the ones that we
want and combine them into a complex phage cocktail," Dr.
Sulakvelidze told Pharmacy Practice News.
In order to take part in an NIH funding program designed to
foster collaboration between companies and university
researchers, Dr. Sulakvelidze and Glenn Morris, MD, who is
Chairman of the Department of Epidemiology and Preventive
Medicine at the University of Maryland School of Medicine,
Baltimore, formed Intralytix Corp. in Baltimore. Now, a new
product, Phage Bioderm–a biodegradable polymer impregnated with
various phages–is being developed as a joint project with
Georgian co-developers Zemphira Alavidze, PhD, who heads the
work in the United States at the University of Maryland, under
the auspices of Intralytix, and Ramaz Katsarava, PhD, who heads
the biopolymer center at the Ministry of Health in Tbilisi.
Intended to protect wound infections against the ravages of
Pseudomonas aeruginosa, Staphylococcus aureus or Streptococcus,
research in this country is being done at the University of
Maryland under the supervision of Dr. Alavidze, who led the
active phage therapy group in Tbilisi for many years. "In my
country, I have used Phage Bioderm with very good results," Dr.
Alavidze told Pharmacy Practice News.
The idea of using bacteriophages as a means of dealing with
environmental contamination is endorsed by Torrey C. Brown, MD,
President of Intralytix. "All the problems that come from
organisms in the environment or from food might be addressed
before they get to humans," Dr. Brown told Pharmacy Practice
News. "Bacteriophages could have a role in agriculture or food
processing."
For 37 years, Elizabeth Kutter, PhD, a faculty member at the
Evergreen State College, Olympia, Wash., has studied the role of
T4, a bacteriophage that infects certain Escherichia coli
strains. "A main focus of mine has been studying the process of
going from bacterial expression to viral expression after a
phage infects a bacterial cell–in other words, trying to
understand how viruses work," Dr. Kutter told Pharmacy Practice
News. "Ever since my first visit to Tbilisi in 1990, when I saw
how phages were being used therapeutically, I’ve had a very
strong sense that eventually this was going to be the wave of
the future and the process that would help to save my
grandchildren."
–Rayma Prince, www.McMahonmed.com
Developed from interviews with Carl Merril, MD, Richard
Carlton, MD, Alexander Tomasz, PhD, Alexander Sulakvelidze, PhD,
Zemphira Alavidze, PhD, Torrey C. Brown, MD, and Elizabeth
Kutter, PhD.
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