Phage work struggles for respect, funding

Still marred by a bad beginning

When a small biotech shop in Bothell, WA, announced last spring that it had expanded its work in TB research, there was scarcely a peep from mainstream scientific circles.

No wonder. In many places, confessing to an interest in phage therapy carries the same cachet as pulling out a membership card for the Flat Earth Society.

"Most scientists and academics think phage therapy is a lot of nonsense," says Carl Merril, MD, a senior staff member in biochemical genetics at the National Institutes for Health’s intramural research program, and one of a small band of American microbiologists who are plugging away in phage therapy. "But that’s a shame. There’s a lot of potential there."

The Washington biotech shop — Phage Therapeutics International — is working on a way to enable phages, which are basically viruses that invade and kill bacteria, to get at TB microbes that are already sequestered inside macrophages. That’s a harder target than, say, a staphylococcus circulating in the bloodstream, and is one of the biggest challenges in TB phage therapy research.

"Our technology for delivering phages to mycobacteria sequestered in the intracellular space isn’t what I’d call polished yet, but we’re developing a means for doing it," says Richard Honour, PhD, chief executive officer of Phage Therapeutics. "Not only are we getting the phage inside the macrophage, but also into the phagosome itself, where the bacilli reside."

The work so far has proceeded only in the lab, but collaborators abroad are due to start animal trials soon, Honour adds.

The real problem is how to get the phages deep inside the lungs, where most of the invaders are hiding out. "It's not as if the bugs are just sitting there on the surface of the lung, waiting to be attacked," says Clif Barry, PhD, a senior investigator in TB research at the National Institutes of Health in Bethesda, MD. "They’re deep within lung tissue; what are you going to do, inject them? That's what I call a real delivery problem."

Honour is nonplussed. "Maybe we’ll use some sort of inhalation therapy," he says. Besides, he adds, phage therapy could still help by attacking microbes that are circulating, thus lowering the overall bacterial burden. "Especially in developing countries, TB is such a complex disease, with so many phases," he says. "It's a problem that will take lots of different approaches to solve. I think we can have an impact."

Honour also has a request for the public-health community. To build phages lethal to multidrug-resistant strains of TB, his company is assembling a library of drug-sensitive and drug-resistant TB isolates, and also needs old phage-typing collections. "The isolates would be very useful in screening, and some of the old genetic material from the phages might turn out to be very valuable," he adds.

At first glance, it’s tough to see why more entrepreneurs like Honour, with his 10-person fledgling company, aren’t tinkering with phages. After all, phages are found everywhere there are bacteria; they are cheap and easy to work with; and once inside their target microbe, they multiply exponentially, swiftly wiping out entire bacterial populations — without the side effects of antibiotic therapy. Because each phage type is very specific in its choice of microbial host, phages aren’t prone to doing incidental damage to benevolent bacteria dwelling in the host animal, either.

According to Merril, the trouble is that phage research (which dates back to 1916, when phages were first discovered) has been haunted by poor judgment, plus some awful luck.

Seminal work in phage research has always been centered in, of all places, Tbilisi, the capital of the former Soviet republic of Georgia. (That’s where one of the two co-discoverers of phages decided to set up shop.) Even phage skeptics concede that Tbilisi researchers have produced some truly spectacular successes. The trouble is that because of the hit-and-miss quality of the work — the old Soviet Union never bought into the system of clinical trials — almost none of the successes have been replicable.

Here in the United States, meanwhile, phage therapy’s early boosters made preposterously inflated claims for the new therapy, managing in the process to convince several big drug companies to invest heavily in the new technology.

The claims never panned out. Then, in a near-fatal blow, a professional medical association pronounced phage therapy to be worthless humbuggery. "That really put the kibosh on things," sighs Merril.

Worst of all, though, was timing. Once penicillin and other early antibiotics were discovered, U.S. medical researchers began devising the system of clinical trials — the very discipline that might have rescued phage therapy and set it on a more rigorous course. But it was too late. American medical researchers had already turned their backs on phage therapy; now, they turned all their attention to antibiotics.

It’s not surprising, then, that most scientists simply shrug when the subject comes up. "Sure, phage therapy sounds great," says Barry. "But in truth, we’re nowhere near having an effective therapy."

Along with all the problems specific to TB phage-therapy, the field in general is hindered by the fact that the phages’ microbe-targets can mutate, an act that can render the bugs immune to phage attack. Of course, phages might well match that with mutations of their own. But that conjures up the untidy specter of a clutter of serial phage mutations, all of which would have to be painstakingly patented, Barry notes.

Merril denies that mutations are a problem. For one thing, seminal work published decades ago (and painstakingly replicated in two subsequent experiments) found that phage therapy actually provokes fewer mutations in target microbes than antibiotic therapy, he says.

The real challenge, he adds, is the way animal hosts tend to clear phages from circulation before they get the chance to attack target microbes. Merril has published work showing that by successively selecting phages that remain in a mouse after a period of time, a phage can be cultured that will stay in circulation for long periods of time.

More recently, Merril says he’s tackled the problem of how to give phages (which are very picky in their choice of target) a broader spectrum of killing activity. To do so, he’s equipped phage tails with extra enzymes, so the viruses can break through varying compositions of pathogen cell walls. That makes them effective against a broader range of strains of a pathogen — a finding that has potential applications for TB.

"In some situations, phages can be life-saving," concludes Merril. "We need to set aside these theoretical arguments about what phages can or can’t do, and start doing some real work."