Draco among the viruses

Latest Wall Street Journal  column is on how anti-virals outwit natural selection:

Draco, who wrote Athens's first constitution in about 620 B.C., decreed that just about every crime should be punishable by death, because that was what petty criminals deserved and he could think of no harsher penalty for serious criminals. "Draconian" means indiscriminate as well as harsh.

So it is appropriate that the word "Draco" has been appropriated by the inventor of the first antiviral treatment that promises to work against all viruses. Until now, if antivirals worked at all, they were specific to particular viruses or even strains of virus: protease inhibitors for HIV, Tamiflu for some forms of flu and, of course, particular vaccines to prevent particular viral infections.

In this context, Draco stands for Double-stranded RNA Activated Caspase Oligomeriser. The "Dra" bit refers to a telltale sign of viral infection-double-stranded RNA molecules-while the "co" bit concerns the mechanism by which a cell commits suicide if so infected. In the lab,writes its inventor, Todd Rider of MIT's Lincoln Laboratory, "we have demonstrated that Dracos are effective against viruses with DNA, dsRNA, positive-sense ssRNA, and negative-sense ssRNA genomes; enveloped and nonenveloped viruses; viruses that replicate in the cytoplasm and viruses that replicate in the nucleus; human, bat and rodent viruses; and viruses that use a variety of cellular receptors."

In other words, at the lab bench, just about any virus will get the death sentence from Draco-from the petty rhinovirus that causes the common cold to the homicidal dengue fever. That's draconian. Moreover, it does not just seem to work in cells in a petri dish: In live mice infected with H1N1 influenza, Draco cured the animals. It sounds very promising, though there is much safety and efficacy testing to go before it can be given to patients.

Given that Dr. Rider's Draco combines some of our existing molecular tricks in a new configuration, it raises a question that often nags at me when miracle cures are discovered within the body itself: If it works so well, why didn't evolution equip our cells with it as a defense against disease? Interferon, for instance, was hailed as a cancer cure two decades ago, though in due course it proved disappointing.

Those cures that do not disappoint, like antibiotics, are foreign to our cells' metabolism. Penicillin was the special bacterium-killing invention of a fungus, so we had to wait until Alexander Fleming left the laboratory window open in 1928 before we could borrow it as a medicine.

What is new in Dr. Rider's approach is to link the "Dra" to the "co." Why did natural selection not think of that itself in some ancestral mammal?

John S. Dykes

I don't know the answer. Most of the viruses that cause serious disease disable our native defense mechanisms. They may target the double-strand recognition system or the cell-suicide pathway (or both). A virus usually keeps a cell from killing itself by interfering with the start of the chain of cause and effect that leads to suicide, whereas Dr. Rider has used a later link to keep that mechanism on-a link that viruses mostly do not attack.

Most likely, the evolutionary explanation for Dr. Rider's ability to do better than Mother Nature is that there is no way to get there from here. Inside the normal cell, the "Dra" bit is just so separate and different from the "co" bit that no accidental mutation has ever put them together.