Would be less invasive than gene therapy // Would have fewer side effects // Would preempt a disease rather than mop it up once it starts.
Shoot the Messenger
It all started with petunias. In the mid-1980s, Richard Jorgensen and Carolyn Napoli were working as plant geneticists for an Oakland biotechnology startup that specialized in boosting agricultural yields—increasing frost tolerance with a sort of antifreeze bacteria called Frostban and quickening the ripening of fruits, among other advances. Yet if such improvements were apt to delight farmers, they didn’t always impress potential investors. So the researchers decided to try something more obviously spectacular: creating an extraordinary flower. They chose petunias (Petunia hybrida) because of the plant’s large, colorful blooms and because even then, early in the history of genetic research, scientists had developed sound methods for introducing genes into petunia cells.
In the laboratory, petunias can be grown from single cells, so Jorgensen and Napoli inserted into leaf cells a gene known to produce large amounts of the protein responsible for the flower’s purple pigment. They nurtured the cells into full-grown plants, then transplanted them into soil in a greenhouse. But when the blooms appeared, they were white, not vividly violet. Adding a purple pigment gene had somehow caused the plants to make less of the hue. After ruling out an experimental mishap, they realized an unknown process must be at work.
During the next several years, Jorgensen, Napoli and other plant researchers began to unravel the mysteries of a phenomenon they dubbed co-suppression, a form of gene silencing. But remarkable as it may now seem, the discovery had little impact outside the world of plant research until 1998, when a small team of scientists published a paper detailing a similar type of co-suppression they had discovered in a tiny worm. Interest in this type of gene silencing grew exponentially, and today, 20 years later, the same mechanism that drained the color from petunias is being tested in numerous human clinical trials. It appears capable of remarkable things.
Now known as RNA interference, or RNAi, the mechanism has already transformed the way geneticists figure out the function of genes, sparking “a revolution in our understanding of basic biology,” says Judy Lieberman, a biomedical researcher at Harvard Medical School. But the real excitement involves what RNAi could do outside the laboratory, potentially spawning a vast pharmacopoeia that could selectively eliminate harmful proteins produced by wayward genes in difficult-to-treat diseases.
Unlike gene therapy, which attempts—with limited results—to cure disease by replacing defective genes with properly functioning ones, RNAi allows researchers to tap a pathway that primitive organisms use to turn off invading viruses. Because the workings of the mechanism are natural to the cell, RNAi is theoretically much easier to implement than gene therapy, less invasive (because you’re not actually altering a person’s DNA) and has fewer potential side effects. What’s more, if there are problems, it can be washed from a person’s system.
If RNAi works as researchers hope, it might curb cancer genes; inflammatory genes associated with Crohn’s disease and inflammatory bowel disease, among others; and even genes that cause high cholesterol. Already, there are clinical trials of treatments for AIDS, acute renal failure, respiratory syncytial virus and the wet form of age-related macular degeneration.
Not that there aren’t some very real obstacles, such as simply being able to get a drug carrying an RNAi molecule to the right place in the body and avoiding a massive immune system attack against foreign genetic material. Yet while the hype is huge, the research so far is convincing.
Although known to researchers for decades, RNA had always been considered a mere servant to the more fundamental DNA. Though both kinds of nucleic acid are made of strings of nucleotides, the building blocks of the genetic code that determines every individual’s unique makeup, RNA generally has just one strand of code, while DNA has two. Encapsulated in the cell’s nucleus, DNA holds an organism’s entire archive of genes. To tap that archive, the organism creates RNA, a complementary string of nucleotides that is a copy of a section of DNA code. Exiting the nucleus, the RNA—in this capacity, called messenger RNA, or mRNA—enters the cytoplasm, where the code is translated into proteins.