A Nobel Prize for The Shadow Network

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This morning it was announced that two American scientists won the Nobel Prize in Physiology and or Medicine, for their 1998 discovery of a hidden network of genes. It may seem odd that a network of genes could lurk undiscovered for so long. But the cell is very much a mysterious place. In the 1950s, scientists established the basic model for how genes work. A gene is made of DNA, the cell makes a single-stranded copy of a gene in a molecule called RNA, and it then uses the RNA as a template for building a protein. This so-called Central Dogma proved to be correct for many thousands of genes, but not all of them. In many cases, a gene’s RNA is not a mere messenger. It grabs onto other RNA molecules or proteins, and carries out some important chemistry of its own.

Different RNA molecules carry out different kinds of chemistry. Scientists are a long way from figuring out everything they do, but they now understand a few sorts pretty well. This year’s Nobel–awarded to Craig C. Mello, a Howard Hughes Medical Institute investigator at the University of Massachusetts Medical School, and Andrew Z. Fire at Stanford University School of Medicine–recognizes one part of the RNA network, called RNA interference. A class of small RNA molecules can grab onto ordinary RNA molecules and destroy them.

This may seem like a harmful thing for a molecule to do, but it is actually essential to the proper workings of the cell. A cell needs to keep its proteins in balance, and that balance changes with changing conditions. Using RNA interference, a cell can quickly reduce or increase the amount of a specific protein to the proper level.

Like all great discoveries, Mello and Fire’s discovery of RNA interference has sent other scientists in all sorts of unexpected directions of research. Some have turned RNA interference into a powerful tool for probing the function of genes. They engineer silencing RNA to shut down a particular gene. They then observe what happens to an animal or a cell when it can no longer make the gene’s protein. RNA interference may also become a new path for medicine, allowing doctors to target troublesome genes.

Scientists have also been wondering about the history of RNA interference. Mello and Fire first discovered it in worms, but that does not mean it’s a quirk of those particular animals. In fact, RNA interference is widespread in animals, as well as in plants, fungi, and many other groups of species. Having compared their RNA interference genes, scientists have concluded that those genes are an ancient but still-evolving system for fighting off parasites.

In some cases, these parasites are invading viruses. Some viruses (such as the tobacco mosaic virus shown here) carry genes made of RNA instead of DNA. Their hosts can defend themselves against the viral genes with RNA interference, grabbing incoming virus RNA and cutting it apart. We and many other species carry a lot of virus-like pieces of DNA in our own genomes, too. These mobile elements, as they’re sometimes called, make RNA copies of themselves which then get converted back into DNA and inserted into other places in our genome. Almost half of our DNA is made up of these mobile elements. To slow the spread of these genomic parasites, many species use RNA interference to destroy their RNA copies.

All well and good–except that parasites evolve as well. A cell can only use RNA interference to defend itself against a virus if it can recognize the virus’s genes. If a virus mutates so that its RNA becomes hard to recognize (but still carries out its original function), it will evade the cell’s defenses. Viruses are also able to block RNA interference. They produce molecules that interfere with the enzymes that help prepare silencing RNA that will attack the viruses.

Hosts that can overcome these counterstrategies will be favored in turn by natural selection. And so virus and host get trapped in a coevolutionary arms race. In March, scientists at the University of Edinburgh estimated the speed of this evolution by comparing genes involved in RNA interfence from different species of Drosophila fruit flies. They found that new variants of these genes have emerged in the different species–even in populations of the same species. These variants reveal that RNA interference genes are rapidly evolving in fruit flies. In fact, they are among the fastest evolving genes in the fruit fly genome.

Fruit flies and humans use many similar genes to assemble interfering RNA molecules. So do plants and yeast. Scientists can trace the ancestry of some of these genes to a common ancestor of all living eukaryotes–one of the three main branches of the tree of life. That single-celled ancestor may have lived a couple billion years ago. It had a simple RNA-based defense system, which later became more elaborate in different lineages. The genes not only changed their targets, but also increased their targets, as accidental mutations created extra copies of the RNA interference genes. Along the way, RNA interference also took on new functions–not just fighting viruses, but keeping tight control over the cell’s own functions.

Bacteria are victims of viruses as well, and they appear to use their own RNA-interference system to fight them. But this system doesn’t appear to share a common ancestry with the one we and other eukaryotes use. Instead, they evolved their own set of genes. It’s a case of convergent evolution–the bat and bird wings of the RNA world. RNA interference may have been especially important four billion years ago, in the earliest stages of life on Earth. Many scientists have argued that DNA did not yet exist. Only RNA-based life covered the planet–both as self-sustaining organisms and their RNA viruses. Without any elaborate immune system made up of specialized cells, the RNA hosts would have clearly benefited from RNA interference. And viruses may have evolved some extraordinary counterdefenses–perhaps even the first copies of DNA.

(See also Pure Pedantry and other Scienceblog posts for other takes on the announcement.)