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New Class of Genetic-Editing Molecules Found : Biology: A team of scientists report that their discovery may curb widespread tropical diseases and shed new light on how life is formed.


NEW ORLEANS — UCLA molecular biologist Larry Simpson will report today at a meeting of the American Assn. for the Advancement of Science here that he and his colleagues have discovered a new class of molecules that contain genetic information.

The new molecules were isolated from a family of parasites, called kinetoplastids, that cause widespread tropical diseases, such as Chagas' disease and sleeping sickness. Genetic information from the new molecules combines with that from conventional genetic repositories within the parasites to produce proteins that are crucial to the life cycles of the microorganisms.

The discovery provides fundamental new insights into the process by which genetic information is converted into living organisms and may shed new light on the origins of life. Perhaps more important, it may provide new ways to attack the parasites, which affect tens of millions of people in equatorial regions who lack any good therapy.

The new discovery solves a mystifying biological riddle posed 18 months ago when Simpson and his colleagues first reported an unprecedented and unsuspected deviation from one of the fundamental dogmas of molecular biology: that all genetic information is contained in deoxyribonucleic acid (DNA) and that this information is faithfully copied in the production of proteins and other cellular components.

The discovery is particularly attractive, Simpson said in an interview, because "it is a novel solution (to the riddle) that still holds to the tenets of molecular genetics."

The flow of information in cells has always been thought to be unidirectional. DNA is the master blueprint of the cell; it contains all the information necessary to produce a cell and keep it operating.

For the information in a given gene to be used, it must first be copied from DNA into what is known as messenger ribonucleic acid (mRNA), which serves as the cell's working blueprints. The sequence of individual chemicals called bases in mRNA tell the cell's protein-making machinery what amino acids to put in a protein and in what order. Other sequences of bases tell the protein-making machinery when to start or stop.

Simpson and Kenneth Stuart of the University of Washington in Seattle reported in mid-1988 that the DNA blueprint for at least five proteins important in cellular activity in a family of kinetoplastids called trypanosomes is garbled and unusable.

But they found that some then-unknown mechanism in the trypanosome cell substantially alters or "edits" copies of this genetic information, by as much as 60% in two cases, and produces functional proteins.

The process might be considered analogous to photocopying a page out of the book and discovering that the copy contains information not found in the original.

The major questions then were how this RNA editing occurs and, more important, where the extra genetic information comes from.

Simpson believes he has found the extra genetic information in the mitochondria--energy-producing bodies--of the trypanosomes and he has pieced together a pathway by which the extra information could be added to mRNA.

The information-containing molecules in the mitochondria are pieces of RNA that Simpson calls "guide RNA" (gRNA). The existence of the gRNA was previously known, but not its function. Simpson thus has, in a sense, solved two mysteries for the price of one.

The gRNA Simpson has discovered in the mitochondria contains precisely the segments of RNA that are missing or garbled in mRNA destined for production of the five proteins previously studied. Simpson and his colleagues have already identified some of the series of enzymes that would be needed to replace the garbled information in mRNA with the correct information from gRNA.

The RNA editing process could also have evolutionary implications, Simpson said. Current thinking about the origin of life now holds that the first life was composed entirely of RNA, which carried genetic information, provided structure, and served as enzymes. The mechanism he is proposing, Simpson said, would have been very useful in this "RNA world" as a "simple way to transfer information from one RNA to another and as a way to repair RNA or maintain sequence integrity."

The overall significance of Simpson and Stuart's discovery remains to be shown. Several other forms of RNA editing have been identified both before and since their original discovery, but none is as complex as that which occurs in the kinetoplastids.

But Stuart noted that most living organisms, including humans, have in their genetic complement what are known as "pseudogenes"--long strings of DNA that superficially resemble genes, but that are missing certain key segments that are necessary for a gene to function.

The pseudogenes, he said, are very similar to the kinetoplastid genes he and Simpson have studied, and it is possible that genetic information in all species could sometimes be processed in this unusual manner.

But even if the RNA editing process should prove to be restricted to kinetoplastids, it could be valuable, Simpson said. One illness caused by trypanosomes, the chronic wasting disorder called Chagas' disease, affects more than 30 million people and there are now no drugs to treat it.

Simpson has already found that the anti-coagulant drug heparin can, by coincidence, impair the RNA editing process and thus interfere with the growth and replication of trypanosomes. Although heparin itself is too dangerous to use as an anti-parasite therapy because of the greatly increased risk of bleeding, the discovery suggests that it should be possible to develop other drugs, perhaps closely related to heparin, that would interfere with trypanosome metabolism without affecting human cells.

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