In 1953, James Watson and Francis Crick published a short, seminal paper in Nature proposing a structure for DNA. Since then, in the minds of the public and many scientists, DNA has reigned supreme. Its stately double helix, holding the blueprint to our genes, winds elegantly upward like a spiral staircase carrying the code of life.
For many years, the “central dogma of molecular biology” went like this: double-stranded DNA is the keeper of the genetic code. When the body needs to read a piece of the code in order to make a protein, DNA is copied into a molecule of RNA, which carries the information to the cell’s protein factories. In this version, DNA was the library, RNA merely the messenger. This simple view no longer holds. Now, biologists see RNA’s role as far more complex and critical. No longer just a messenger, RNA is stepping into the limelight.
One scientist riding RNA’s rising fortune is Inna Afasizheva, an assistant professor in the molecular and cell biology department at Boston University’s Henry M. Goldman School of Dental Medicine (SDM). Afasizheva, who began working with RNA two decades ago as a graduate student, received a five-year, $2 million grant in March 2015 from the National Institutes of Health (NIH) to study an unusual RNA conversion process in a parasite called Trypanosoma brucei. This single-cell pathogen, transmitted by the bite of the tsetse fly, causes African sleeping sickness, an aggressive disease that leads to rapid weight loss, coma, and death. Afasizheva hopes to uncover fundamental molecular mechanisms of a process called “RNA editing,” unique to this parasite, which may lead to a cure for this deadly disease.
“Because this process is found only in Trypanosoma, it’s very attractive for drug design because it will not target any proteins in human cells,” says Afasizheva. “We may eventually find a drug which will be useful for treating African sleeping sickness, because there are no good treatments right now.”
In the mid-1980s, scientists discovered something curious about RNA in Trypanosoma: it didn’t seem to follow the central dogma. The RNA was copied from the DNA as usual, but the message was unreadable to the cell’s protein factories, called the ribosomes. However, when the RNA message was somehow edited, either by adding or deleting a specific part called a uridine, the ribosomes could read it. The question was: how? That’s where Afasizheva came in.
Afasizheva began studying RNA editing in 1999 and has contributed to significant discoveries about the process. This is no small feat, given that RNA is an exceptionally fragile molecule that interacts with myriad proteins in the cell. “RNA is not easy to work with because it is degraded very fast,” says Afasizheva. “Not many people can work with it, but I feel like I can. Sometimes I think I do have a magic touch.”
That magic touch—along with years of meticulous, patient work—has paid off. Afasizheva discovered an editor enzyme that adds uridines to one end of RNA, and two more enzymes that work together to edit inside the sequence. She also found something called the guide RNA-binding complex, an assembly of proteins that holds the RNA in place for editing. Most recently, she discovered proteins called PPRs in the parasite’s mitochondria, where sugar is converted to energy. “I never thought that RNA was less important than DNA,” says Afasizheva. “Without RNA, proteins will not be synthesized. It’s at least equally important.”
The NIH grant will allow Afasizheva to continue her study of PPRs, which seem to regulate RNA editing and some types of RNA alterations.
“I’m a basic scientist, meaning that I always work on fundamental science. And this particular line of research on trypanosomes actually helped us understand processes that were not really clear in more conventional model organisms such as yeast, fruit flies, or mice,” says Afasizheva. “But my long-term hope is definitely drug design. Because PPRs are very important in the processing pathway for RNA, they may be targeted by drugs which will not affect any other pathways in the human body.”