Strange medicine

SET a thief to catch a thief is an old proverb. In the 1920s, shortly after the discovery of viruses, it was put to good use by doctors. They found they could treat certain infections with bacteriophages—viruses that attack bacterial cells but not mammalian ones.

Phage therapy, as this practice is known, fell out of favour in the West after the development of antibiotics, although it continued in parts of the old Soviet sphere of influence. (These days, research is still carried out in Georgia and Poland). But antibiotics are faltering as resistant strains of germ evolve. Some Western researchers are therefore looking afresh at phages, hoping, with modern methods, to turn them into tailored treatments for infection.

One such group of scientists works at Synthetic Genomics in La Jolla, California. This firm, the creation of Craig Venter, an entrepreneurial geneticist who once took on the American and British research establishments in a race to sequence the human genome, plans to re-engineer several sorts of organism—phages included—into what it hopes will be useful products.

The phage work is run by Sammy Farah, head of the firm’s vaccines and therapeutics unit. His team is developing phages for use against antibiotic-resistant strains of Pseudomonas, a bug that causes skin infections, sepsis and—particularly in those with cystic fibrosis—potentially fatal pneumonia. Phage therapies in Georgia and Poland mix dozens of strains of wild phage together into a cocktail, in the hope that one will do the trick against the bug that a patient is infected with. Dr Farah and his colleagues, by contrast, are able to synthesise viruses from scratch, using off-the-shelf chemicals. They can thus design them precisely, down to the last atom.

The plan is to come up with one or two super-phages that will hit multiple strains of Pseudomonas. In effect, these phages will be giant self-replicating drug molecules that automatically calibrate the size of their dose—for, when all of the target bacteria have been killed, they can no longer breed. The benefit, from the patient’s point of view, is help for an infection that is currently untreatable except, perhaps, by getting on a plane to Warsaw or Tbilisi. From the firm’s point of view, an equally important benefit is that synthetic viruses can be patented. Wild ones cannot.

Dr Farah’s team began work with 300 variegated samples of their target, and 25 strains of an appropriate phage. They sequenced the genomes of all the bugs and all the phages and tested how well each phage did against each bug.

They then searched for correlations between the efficacy of an attack and the genetic sequences of the bacterium and virus involved. These data let them design a new generation of phages and try again—producing ever more efficacious viruses.

Being an effective bacterium-killer is not enough. Now, the team is adding other properties. One is an ability to disrupt biofilms. These are sheet-like colonies formed by Pseudomonas (and other bacterial species) over the surface of the tissue they are infecting. Biofilms are defensive structures. By banding together to form them, bacteria make it harder for viruses to attack and harder for drugs to penetrate.

Dr Farah also hopes to add what might be called resistance to resistance, for—just as has happened with antibiotics—natural selection will inevitably shape how the target bacteria respond to viral attack. Bacteria have their own immune systems that recognise and destroy viral genes. This leads to an arms race as the viral genes evolve to evade detection. Dr Farah thinks he can give his viruses a head start, slowing down the evolution of resistance.

He hopes, too, to make his phages invisible to the human immune system. Even though phages are harmless to people, the immune system still recognises them as alien and attacks them. Dr Farah plans to slow this attack, giving them a better chance to work.

So far, all this has proved effective in the modern equivalents of Petri dishes. The team has now started tests in animals. If all goes well, they hope to begin human trials in two years’ time. If those work, antibiotics may, at last, have a serious rival.