At first it sounds like a terrible plan, the kind that results in zombies ruling the Earth. Imagine a killer virus, a bug that mutates so often that it inevitably finds a way to resist every drug. Now, rather than fight its ability to evolve, you enhance it. You speed up the mutation rate, forcing such dramatic genetic change that the virus crashes completely. In the movies, this technique, known as lethal mutagenesis, would create a supergerm, but in real life it’s spawning a powerful new class of antiviral drugs. “It’s a fundamentally different strategy,” says University of Washington biologist Robert Smith. “Death by mutation.”
The trick is disguising the drug’s molecules as the building blocks of HIV. When the virus replicates, it inserts the KP-1461 imposters throughout its genetic code, creating so many mistakes that it no longer has enough viable DNA to sustain its basic functions, let alone take over a host cell. As a result, the virus dies.
But nailing that cutoff remains a sticking point. Mansky is lab-testing a drug cocktail that kills nearly the entire population of HIV cells after just one round of replication, but human tests are a few years away. Koronis’s clinical trials of KP-1461 last summer weren’t as effective as lab tests. Jeff Parkins, the vice president of clinical development, says researchers are honing the dosing strategy for trials planned for later this year.
Harnessing lethal mutagenesis may soon become easier, following a new mathematical formula by bioengineer Michael Deem of Rice University that could help researchers fine-tune compounds earlier in the process. Given a few key variables, such as how often viral genes shuffle inside cells, his equations can provide the minimum mutation rate to safely kill a virus. At this pace the virus won’t have time to correct errors or absorb drug-evading changes, and it will crash. “It’s not going to come back and cause problems,” Deem assures.
Coupled with work like Deem’s, lethal mutagenesis could lead to a penicillin-like drug that knocks out numerous viruses—influenza, SARS and more. Parkins maintains hope that his company’s drug could eradicate HIV, or at least offer an alternative to current treatements. And that, researchers say, is what makes the mutation tactic attractive. “Even if it just leads to a different antiviral,” says virologist Satish Pillai of the University of California at San Francisco, “it would still be great for patients who have very few options left.”
Five amazing, clean technologies that will set us free, in this month's energy-focused issue. Also: how to build a better bomb detector, the robotic toys that are raising your children, a human catapult, the world's smallest arcade, and much more.