Thursday, April 9, 2009

Fight Infection with Infection

There was a recent article in Popular Science magazine on bacteriophage therapy. Scientists, including d'Herelle the discoverer of phages, have long recognized the value of phage therapy. In fact, the protagonist of Sinclair Lewis's novel Arrowsmith (publ. in 1925) cured the residents of a fictitious Caribbean island of plague using phage.

Despite its early popularity, phage therapy never quite caught on in the West. Most speculate that the arrival of antibiotics precluded their widespread acceptance, except in the former Soviet Union (e.g. Georgia).

The article discusses some of the advantages of phage therapy.

They prey only on bacteria, never human cells, they rarely spread from person to person, and, perhaps most important, bacteria have trouble becoming immune to them. As living organisms, phages are constantly changing and adapting in tandem with their host bacteria to kill them more effectively. Phage therapy could therefore eliminate the vicious cycle in which bacteria evolve resistance to antibiotics, necessitating the development of new, even more powerful drugs, at which point the process begins all over again.
I'm skeptical that phages rarely spread from person to person (but the research on this is minimal if not nonexistent), and bacteria DO become immune. In fact, bacteria frequently win arms races with phage in coevolution experiments.( A good example is the trap cells I used in my virus trap experiments. Several attempts to generate phage able to infect these trap cells have failed). Nonetheless, the article is correct in that, unlike antibiotics, phage evolve. This is a powerful tool to generate new phage variants.

Unfortunately, as the article points out, this precise point makes it difficult for phage treatments to past muster at the FDA.
Although there have been no reports of adverse effects resulting from mutations, phages that don't normally nest inside the human body could potentially swap genes with other phages that do and produce foreign proteins that trigger an immune reaction. And it's impossible to say exactly how a virus might mutate when exposed to different bacteria, says Paul Sullam, a microbiologist at the University of California at San Francisco.
FDA regulation, which some would say is excessive, has slowed phage therapy research in the US.
"People in this country have a right to be incensed that we have a very different situation here than in Europe with regards to phage," says Betty Kutter, a phage researcher at Evergreen State College. "Our whole regulatory environment has been one major thing that has slowed people down."

So where does one go when they have an uncurable infection? The Eliava Institute of of Bacteriophage, Microbiology and Virology.
Randy Wolcott calls Eliava the "mother ship of phage research," a worldwide Mecca for people suffering from antibiotic-resistant infections. Only it doesn't look like the sort of place you'd want to go with a health problem. When Wolcott visited to hunt down alternatives for his patients, the four-story facility bore a closer resemblance to a neglected sanatorium. The walls were unpainted, the rooms were dark, and the equipment looked like museum pieces. "The conditions were abysmal," he says. "Yet the science is amazing."
Perhaps, as Rockefeller's Vincent Fishetti says , the way to go is phage-based therapy.
This distinction might seem arcane to nonbiologists, but in Fischetti's mind, it's a crucial one. While Wolcott sees phages as a major therapeutic coup, Fischetti sees them as merely an intermediate step toward a new generation of even better bacteria-fighters. He contends that the uphill regulatory battle phages face, as well as the risk of mutations, make them too big a gamble for American drug companies. "Phages are going to be a boutique treatment, nothing more," he says. So he is taking an alternative approach, purifying the phage to extract the lysin, the enzyme it uses to dissolve the bacterial cell wall and kill the bacterium. Having observed that lysins were the phages' "active ingredients," Fischetti aims to harvest the lysins from them and turn them into stable antibacterial drugs. If successful, he could accomplish a double feat previously thought impossible: getting the bacteria-fighting benefits of phages to patients, while doing an end run around the regulatory Rube Goldberg machine that researchers like Wolcott face.
Incidentally, I am currently hosting a doctoral student from the Eliava Institute, Sophie Rigvava, who is characterizing the phages of Enterococcus faecalis in my laboratory.

I've posted a few times on phage therapy here, here, here and here.

Photo: Phages [in orange] prey on a lone bacterium, using prong-like proteins to anchor themselves to the cell before they inject their genes into it Lee D. Simon/Photo Researchers



    I have no idea whats going to happen to me when I take a new antibiotic (usually its violent vomiting within 30 minutes, but its been worse). But the FDA is worried about magic viruses, so they arent encouraging phage therapy research.

    I dont want pure lysins either. That defeats one of the 'purposes' of phage therapy: host cell specificity. Im sure part of my 'problem' with antibiotics involves my own flora getting killed off.

    I want phages. :(

  2. Yeah you are right. Phages can deliver lysins right to the target. Besides they look much cooler.

  3. I should read the article, but another substantial problem is that phages can and do pick up genes from host bacteria and transmit them to other hosts - this is a major driver of Staph and Strep toxin evolution, in all likelihood. While using lytic phages (like the T-even) would presumably reduce the risk of this, it does seem sensible to be concerned about how this might impact the evolution of virulence. I think the objection you raised (about bacteria becoming resistant to the phage) is also a big one, but maybe as an adjunct therapy along with a conventional antibiotic, the phage could help a lot. I tend to agree with Fischetti, though, that the holins and lysins are probably the low hanging fruit from a drug discovery perspective.
    I'm rambling a bit, but one other thing to note is that the phage/host interaction is even more complex in many environmental bugs, and the bacteria have developed CRISPRs as a defense mechanism, along with some other recombination based mechanisms for rapidly becoming resistant to a phage. It might be that this is another case of colicentricity, where what works w/ T-even phages is interpreted too broadly...

  4. What if you let the phage do the coevolving outside the patient? That is, take a culture of a patient's bacterial infection, coevolve it with phage, and when the phage is able to kill the original bacterial strain, extract the lysins from the newly-evolved phage and use them to treat the patient. You'd basically be evolving a new drug for every patient.

    I write, it should be said, as one of those people who thinks of phage as basically magic. ;)

  5. I think the article, nor the discussion has brought out that FDA, EPA and USDA have all approved phage applications. It is my opinion that the problem with phage therapy is that people think that they should compete and/or replace antibiotics. It is my opinion that they should be reserved for human use when antibiotics fail. This would mean that governments would set-up phage therapy institutes as per the model in Poland (BTW - both Poland and Georgia have clinics that will treat patients from other countries). Please note that if all the "if's" that people raise as red herrings are true, then we would probably have seen them in Russia, Poland and Georgia. I give a presentation on "phage therapy - getting beyond bullshit". You can find a summary on my blog - and I have also posted an number of pieces on phage therapy.

  6. Holins and lysins are attractive targets by themselves, but bear in mind that they usually specialized for lysis from within. Although some gram+ (e.g. Staph aureus) are susceptible to lysis from without, gram- are more problematic and frequently have external protective layers (e.g. LPS or capsule) that make lysis from without more difficult.

    Spokesthingy is correct that some phage treatments are available in the US, with being the prime example.

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