MicroRNA Is a Big Topic in Bio
One of the tiniest entities in the human genome is becoming a very big deal in biology, with implications for the treatment of cancer, diabetes and brain disorders.
MicroRNA, or miRNA, was considered relatively unimportant less than a decade ago. In 2001, researchers published just four papers on the subject. In 2004, scientific journals featured miRNA discoveries in nearly 200 papers, according to the National Library of Medicine's online journal database.
The tiny bits of RNA play a part in gene regulation, which involves how and when genes turn on and off. When the human genome
MiRNA seems to stifle the production of proteins exclusively -- a function opposite that of its better-known relative, messenger RNA, or mRNA, which translates instructions from genes to create proteins.
"MiRNA has become quite a hot area of study right now because for many years we believed that we had basically solved a lot of the problems of gene regulation," said Frank Slack, assistant professor of molecular, cellular and developmental biology at Yale University. "But over the past five years, we found this huge, hidden family of microRNAs that we didn't know about that are now showing up in almost every area of biology."
Silencing proteins can be a good or a bad thing, depending on the circumstances. Slack's lab recently discovered an miRNA that can stop a gene from producing a protein that causes lung cancer. It published the discovery in the March issues of the journals Cell and Developmental Cell.
Researchers have already published several dozen studies this year involving miRNA in plants, humans and other animals: Researchers at the New York University School of Medicine discovered an miRNA that regulates brain development in zebra fish. Stanford University researchers linked an miRNA to blood-cell development, a discovery that could have implications for diseases like leukemia. And Japanese researchers associated an miRNA with HIV resistance in AIDS patients, just to mention a few examples of miRNA gene regulation.
Researchers estimate there could be anywhere from 200 to 1,000 miRNAs -- the range is wide because miRNAs are so small, making them difficult to detect. Gary Ruvkun, a Harvard University researcher and pioneer of miRNA research, has called the tiny entities "the biological equivalent of dark matter, all around us but almost escaping detection."
In a paper published in the Jan. 14 issue of Cell, David Bartel, a biology professor at the Whitehead Institute at the Massachusetts Institute of Technology
The accelerating number of discoveries in miRNA can be linked to another recently discovered RNA phenomenon, called
"The RNAi excitement led to several labs identifying and connecting those pathways together -- that really intensified research on miRNAs and led to discoveries," said Scott Hammond, an assistant professor in cell and developmental biology at the University of North Carolina at Chapel Hill.
Some researchers believe miRNA is even more exciting than RNAi, because it's a naturally occurring phenomenon in the human body, while RNAi is man-made and injected into cells (researchers suspect it also happens naturally in the body, but haven't yet defined the mechanism).
"MiRNA comes from our own genes, whereas RNAi come from transposons or viruses -- things we normally want to try to eliminate," Slack said. "The exciting thing is miRNA is made in cells all the time, so you would be usurping a natural process instead of trying to force an unnatural process onto a cell."
Because miRNAs are so small, scientists need new technologies to look at them, and several promising applications have emerged. U.S. Genomics, a biotechnology company located near Boston, believes it has the killer app. The company's chief executive, Stephen DeFalco, says its Trilogy 2020 Single Molecule Analyzer is powerful enough to allow scientists to see tiny miRNAs one molecule at a time, without having to amplify their numbers, which is necessary in older technologies such as polymerase chain reaction, or PCR.
"If you need to see a needle in a haystack, you make a billion needles," DeFalco said. "That's what PCR does. We're able to see a single needle."
The company has tested the technology at several research centers including the Mount Sinai School of Medicine in New York City, where researchers used Trilogy to study mRNA in diabetes, miRNA in the kidney and the phosphorylation of proteins.
Dr. Erwin Bottinger, vice chair of medical research at Mount Sinai, said he believes Trilogy is a key step toward personalized medicine. The ability to study single molecules, he said, will allow extremely accurate diagnoses.
RNA is a chemical relative of DNA found in the nucleus and cytoplasm of cells. In addition to the messenger- and micro- varieties, it has several other iterations including transfer RNA and ribosomal RNA. Messenger RNAs are typically about 40 times longer than miRNAs.
Hammond and his colleagues have come up with a microarray method for studying miRNA, which rather than studying single molecules allows researchers to study hundreds of miRNAs at once. Microarray is the gold standard for looking at DNA, but it hadn't been optimized for studying miRNA.
Hammond and his colleagues don't have immediate plans to market the technology, but he said many researchers have expressed interest in using it since he described the method in the October 2004 issue of Nature Methods.
"Several dozen labs have contacted us and asked us to collaborate and look at some of the specific systems they're interested in," Hammond said.
Hammond said his lab also expects to publish an miRNA finding related to a disease pathway shortly.