Scientists Puzzled by Changes in Gene-Transmitted Chemical Messages

Researchers have made the startling discovery that some chemical messages sent by genes are changed before they arrive at their destinations, a finding that challenges a central tenet of genetics.

“It’s an absolutely astounding concept,” said Olke Uhlenbeck of the University of Colorado in Boulder, a biochemist familiar with the research. “Nobody has the foggiest idea how it works.”

The phenomenon is called RNA editing. One of its discoverers, Larry Simpson of UCLA, said the discovery could lead to new treatments for African sleeping sickness, a similar South American ailment called Chagas’ disease and leishmaniasis, a disfiguring skin disease.

Those diseases are all caused by the group of parasites called trypanosomes. The first evidence for RNA editing was found in trypanosomes by Rob Benne of the University of Amsterdam, who reported the discovery in 1986.

RNA editing has since been found in a slightly different form in a slime mold called physarum, in measles virus and in the human gene for the protein called apolipoprotein B, associated with heart disease.

Most recently, independent teams in France and Canada reported in Nature magazine in October that they had discovered RNA editing in wheat plants.

Researchers do not yet know how widespread RNA editing is or why it evolved, but it appears to be a normal part of the functioning of some genes. In trypanosomes, for example, researchers found that certain genes were missing crucial elements. Yet the elements were present in the genetic messenger chemicals associated with those genes.

RNA editing is the name that researchers gave to the process by which the missing elements were restored.

Although the initial discovery was made in 1986, the existence of the phenomenon has not been widely accepted until now, said another discoverer, Kenneth Stuart of the Seattle Institute for Biomedical Research.

“It was initially met with extreme skepticism,” said Stuart, who has occasionally collaborated with Simpson. When Stuart presented some findings to biologists last year, they were “met with disbelief,” he said.

Now, he said, other research groups have confirmed the findings and more clear-cut examples of RNA editing have been found. “We now have three examples in which more than 50% of the gene has been edited,” Stuart said.

“It’s been found by too many people in too many places now,” said Uhlenbeck, who studies interactions between RNA and proteins. “The reason I like it is that RNA has consistently been putting out surprises for the last couple of years, and this seems to be the next one.”

Earlier work on RNA splicing, a different process in which RNA is altered in accord with genetic instructions, earned a Nobel Prize last year for Thomas Cech of the University of Colorado in Boulder and Sidney Altman of Yale University in New Haven, Conn.

RNA editing differs in an important way from RNA splicing and other forms of RNA processing that were known previously, Stuart said. RNA editing is the only process that appears to require the addition of information not provided by the genes.

“It means that the genetic system has more capability than we had previously recognized,” he said. “People who think about things like this would not have predicted that such a complex mechanism for changing information even existed.”

The reason for the initial skepticism was that RNA editing seemed to violate what biologists call the central dogma of genetics, which holds that genetic information contained in the genes passes from the genes, by way of a messenger chemical, to proteins.

The genes, made of DNA, or deoxyribonucleic acid, direct the manufacture of messenger RNA, made of ribonucleic acid. The messenger RNA travels from the cell nucleus to protein factories called ribosomes, where the RNA directs the manufacture of the myriad proteins the cell needs to survive and reproduce.

In RNA editing, changes are made in the RNA after it is produced by the genes but before it arrives at the ribosomes.

“Imagine a book that has less than half its pages,” Stuart said, “and somehow, upon reading it, all the missing pages get magically put back in. Or you type it into your computer and all the vowels are missing, and when you send it to the printer all the vowels somehow get put back in.”

The discovery of RNA editing poses a difficult question. Where are the missing pages--or the missing vowels--coming from? Where does the cell get the information to restore or delete parts of the messenger RNA?

If the information is not coming from the genes, the central dogma of genetics has been violated.

“What I hypothesize is that the genetic information actually resides in the genes in encrypted form--in an abbreviated or compact form,” Stuart said. If that is the case, then the central dogma would not be violated; the editing information would be coming from the genes.

Simpson, who calls the edited genes “cryptogenes,” also believes that the information added by the editing is somehow hidden in the genetic code.

The discovery of RNA editing in trypanosomes could lead to the development of a drug that would kill them without harming human cells, Simpson said.

“These are very important human and animal parasites,” he said. If RNA editing is found to be widespread in human cells, it is likely to occur in a different form; drugs that attack trypanosomes by interfering with RNA editing might, therefore, have no ill effects in humans.

“We could kill the parasite and not harm the host,” he said. “Any time you find something that’s unique to a parasite, it’s incredibly significant.”