Modern molecular biology holds the promise of allowing us to correct genetic diseases. Experiments with gene therapy indicate that it should be possible to provide a functional version of a gene to cells that have a defective copy.

The challenge here is that it requires inserting the DNA of the gene into a large number of cells in a living organism. Viruses are highly (and unfortunately) efficient at inserting their own genes into human cells, and many gene therapy tests have used modified viruses. But the human immune system can respond to these modified viruses, neutralizing the therapy. Now, researchers have created a gene therapy virus that nobody's immune system has ever seen—because it's been extinct for many years.

There are a lot of viruses that have been suggested as possible gene therapy tools, but all of them have some drawbacks. Some viruses only infect a few specific cell types; others insert DNA randomly in the genome, creating a risk of mutations.

Adeno-associated virus, hitchhikes along with infections of adenovirus, a common cause of respiratory infections. It can avoid some of these problems, as the virus doesn't integrate into the genomes of infected cells, and it infects a wide variety of cell types. And it's possible to replace almost the entire viral genome, simply leaving a few short DNA "tags" that allow the DNA to be packaged up inside a virus particle.

The downside of the adeno-associated virus is that the DNA it inserts is gradually lost from the infected cells. So you have to regularly refresh the therapy with a new round of infection. And after a round or two, the immune system will be primed and ready to attack the virus. In fact, many people can't even be enrolled in gene therapy trials because they have previously been infected by the virus.

One potential solution to this problem is to develop a library of different adeno-associated virus strains, each of which can be used after the immune system recognizes the previous one. Unfortunately, only a handful of virus strains exist, and it's difficult to engineer a new one. That's because the immune system recognizes the virus' protein coat, a complicated mesh of three proteins. Changing these proteins has the potential to disrupt the virus, eliminating its ability to infect anything.

So a bunch of Harvard biologists got a clever idea: what if they resurrected an earlier version of the adeno-associated virus that nobody alive had ever seen? The existing strains that infect primates evolved from common ancestors. If they could figure out what the common ancestor looked like, it would be guaranteed to infect and be new to the immune system.

Fortunately, researchers who study the evolution of proteins had already developed algorithms that can take a set of existing protein sequences and, by assuming they have a common ancestor, calculate the most probable sequence of that common ancestor. Using this algorithm, the authors walked back down the evolutionary tree, eventually reaching the base of the branch that led to primate adeno-associated viruses.

They then ordered up the DNA needed to bring this virus back into existence. They confirmed that the immune system had never seen it and that they could use it as a gene therapy vector—it successfully inserted genes into the livers of mice. Better yet, they were able to make the viruses present at the branch points in the evolutionary tree as well. Not all of these worked, but the authors were able to add nine new adeno-associated viruses to the collection of strains we have available to us.

This isn't the first time that ancestral versions of proteins have been re-created. But the work has mostly been done by people curious about evolution. As far as I'm aware, this is the first case where these evolutionary methods have been used to build a tool. And if gene therapy ever lives up to its promise, it could be a very useful tool.

Cell Reports, 2015. DOI: 10.1016/j.celrep.2015.07.019 (About DOIs).

Correction: the virus involved is adeno-associated. The story has been updated to reflect that.