Bacteria Phages Could Replace Antibiotics

[Guest guest]

I have mixed feelings about the news in the article below.

On the one hand, the technology presented points to a lessening or

even elimination of the huge global problem of antibiotics,

antibiotic resistant superbugs, and environmental poisoning with

antibiotics. On the other hand, there is the pssibility of

genetically modified phages -- and that is something I do not want to

see happen.

 

While I am cautious about any new technology applied to

medicine, this one as been around almost a century & in use in

Eastern Europe for a long while now. Provided the big Pharm

companies keep their dirty little minds away from gen-mod phages, I

think it could be very useful for our future.

 

Alobar

 

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How Ravenous Soviet Viruses Will Save the World

 

They're called phages. And they eat drug-resistant bacteria for

breakfast.

 

By Richard Martin

 

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 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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Contributing editor Richard Martin (rmartin) wrote about

AIDS vaccines in Wired 11.01.

 

 

http://www.wired.com/wired/archive/11.10/phages_pr.html