A gene by any other name is not quite the same, and scientists could exploit that fact to develop new vaccines for viral diseases, research suggests.
By “misspelling” the genetic code of the virus that causes polio so that the virus still reproduced but did so a thousand times slower than normal, researchers created a weakened version of the virus that trained mice’s immune systems to fight off the real one.
The technique presents a controlled, systematic way of making impaired viruses for use in vaccines, Eckard Wimmer and his colleagues at Stony Brook University in New York report in the June 27 Science.
Many vaccines contain weakened versions of viruses. Currently, scientists make these crippled viruses by letting the normal viruses reproduce in cells in the lab until they randomly develop mutations that make them less virulent. But the approach is time-consuming and imprecise.
Another disadvantage of this method is that it only creates a few deleterious mutations, so it’s relatively easy for the viruses to mutate back to their deadly form. This only occasionally happens, which is why children will rarely get polio from the vaccine.
The new method uses a “death by a thousand cuts” approach, as the researchers put it. By introducing hundreds of small differences in the viruses’ genetic code, the new approach makes it very difficult for the viruses to revert to its dangerous form.
“The virus has a near impossible chance of reverting this,” says study coauthor Steffen Mueller, also of Stony Brook. “This de-optimizing of the genome should work on every virus,” he adds.
Wimmer’s team caused a stir in 2002 when they assembled the poliovirus genome from scratch by stringing together the four chemical “letters” of the genetic code — A, T, C and G — in the correct sequence. The achievement raised fears that the technology could be used to make deadly viruses for bioterrorism.
“The most important aspect of [the research] is that it directly demonstrates how DNA synthesis, a technology that has recently been much maligned and feared for its possible use in bioterrorism, can instead be applied to rapidly produce preventive medicines,” comments Drew Endy, an assistant professor of biological engineering at the Massachusetts Institute of Technology.
When a gene is translated into a protein, each grouping of three adjacent letters of the genetic code spells a “word” that specifies a single subunit in the protein’s sequence. Some subunits can be specified by more than one three-letter word, making it possible to “spell out” the code for a protein in more than one way.
In human cells, some of these synonymous triplets get translated into proteins faster than others. By rewriting the code for poliovirus with triplets that are translated more slowly and then synthesizing viruses with this revised genetic code, Wimmer’s team made viruses that produce all the same proteins as real poliovirus — and thus evoke the same immune response — but should be too wimpy to cause the disease.
The research is a preliminary proof of concept, Wimmer and his colleagues note, and further research is needed to address safety issues. In the experiments, about one mouse in eight died after being injected with the weakened virus, suggesting that the virus may need to be crippled even further. The rest of the mice showed signs of immunity to polio and later survived a dose of poliovirus that killed nonimmunized mice.