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By Valerie Gregg
They were overlooked for decades, dismissed out of hand as the flotsam and jetsam of cellular degradation. But over the past few years, molecular biologists have discovered that the tiny segments of RNA once thought to be random pieces of genetic material actually do something—several things, in fact.
     Now, Emory genetic researcher Peng Jin hopes to expand on recent discoveries about the small RNA known as microRNA (miRNA for short) to develop new diagnostic tests and possible genetic therapies for brain tumors and neurodegenerative diseases like Alzheimer’s.
     “We are exploring a new frontier here,” says Jin. “There is a lot still to learn, but there is enormous potential for helping patients once we better understand miRNA. This area is so new that the basic work needed to receive grants from the National Institutes of Health simply hasn’t been done yet. We are taking a hypothesis-generating approach. We need to get preliminary data so that we can get NIH funding
later on.”
     MiRNAs were first described more than a decade ago by scientists working with Caenorhabditis elegans, a species of nematode worm favored by researchers because of the simplicity of its genome. During their normal life cycle, these worms go through four stages of development. But a particular group of worms were observed getting stuck in the first stage. The larvae kept growing larger but not maturing into adults. A team of researchers at Harvard University isolated the gene that caused this malfunction but found that instead of coding for a protein as most genes do, it coded for a particular molecule of RNA.
     In typical cell development, double-stranded DNA is “read” by single-stranded messenger RNA, which translates (“codes”) the genetic information into proteins that drive cell development. The nematode discovery showed that some genes instruct the RNA not to code for proteins, but for other nontranslating RNA. Small bits of noncoding RNA had been observed inside cells for years, but scientists thought they were just evidence of cell aging or environmental damage.
     Gradually, different groups of researchers realized these micro-RNAs play a vital role in cell development. These short segments interact with the longer strands of messenger RNA and alter the coding and translation process to influence the degree to which certain proteins are expressed.
     Scientists now believe miRNAs are a key force controlling gene expression. They are thought to play a role in determining the differentiation of stem cells into different, mature cell types, and some researchers belive they influence tissue development as well.
     Exactly how they do this, however, is not well understood.
     Although more than 1,650 separate miRNAs have been identified in animal and plant genomes, scientists have nicknamed them “biological dark matter” because the way they affect gene expression remains unclear.
     A recent Young Investigator award from California’s Arnold and Mabel Beckman Foundation will help Jin solve some of these mysteries. The $264,000 awards support the research of promising young faculty members early in their academic careers in the chemical and life sciences. Jin was one of only 24 scientists in the country chosen as a recipient, largely because his work will take miRNA research in a new direction.
     “This is one of the hottest areas of biology,” says geneticist Steve Warren, chair of the Department of Human Genetics at the School of Medicine. “Only a handful of labs are currently working on microRNAs, although the number is growing.”
     Jin is the only researcher working on the relationship between miRNAs and stem cells, and his work should open up new avenues for further study, Warren says.
     “MicroRNAs were only discovered a few years ago, and it was quite a shock for many scientists that humans had hundreds of genes, highly conserved throughout evolution, that do not code for any proteins,” says Warren. “We still understand very little about their function, particularly in mammals. Certainly, there are diseases due to or influenced by defects in the microRNA pathway. It is likely that we’ll find that microRNAs play a widespread role in disease development, particularly cancer, and in determining a person’s predisposition to disease.”
     Most work in this area is still conducted on C. elegans and Musca domestica, the common house fly. But Jin will use his Beckman award to work on a bigger target—people.
He plans to expand his work examining the functions of miRNA in neural stem cells, studying how miRNA influence the generation of distinct cell types.
     “By doing this,” says Jin, “we hope to establish basic scientific knowledge that could one day lead to new treatments for neurodegenerative diseases like Alzheimer’s and Parkinson’s disease.”
     Jin hopes to identify more of the unknown types of miRNA in neural stem cells to broaden the picture of how they function. Emory researchers are interested in more than just chronicling the molecules’ function, however. Genetics faculty are working with scientists at the Winship Cancer Institute to study brain tumors and leukemia. They plan to develop new genetic tools for cancer diagnosis by finding genetic biomarkers linked to development of these diseases.
     “Published genetic data from different types of breast tumors, for example, show that a certain microRNA is either overexpressed or underexpressed in particular developmental paths of tumors,” Jin says. “We hope to take that a step further. Using our technology, we can compare different types of brain tumors and identify whether a particular microRNA is either overexpressed or underexpressed. This ability could lead to finding biomarkers for diagnosis.”
     One day, scientists may also be able to manipulate miRNA to treat such diseases and genetic conditions and not just diagnose them earlier, Jin says.
     For example, scientists could try to suppress the growth of tumors either by knocking down or overexpressing certain miRNA. “That’s way down the road, but that’s where this work with microRNA may lead,” says Jin. “In the long run, it could have a huge impact on therapies for a variety of cancers and neurodegenerative diseases.”
     It is this potential that has kept Jin at Emory and pursuing this difficult area of study. Opportunities to collaborate with clinicians and one day see his research save lives are his primary motivators, he says. “There are opportunities here for geneticists to have a clinical impact that simply do not exist elsewhere.
     “Here we have the research tools to connect basic science with real people,” Jin says. “I want my work to help real people, and I hope to see the result of my work during my lifetime—not just for the sake of discovery. I want to make a difference.”

Valerie Gregg is a freelance writer based in Atlanta.


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