DETROIT- David Rueda, Ph.D., assistant professor of Chemistry in the College of Liberal Arts and Sciences at Wayne State University, was recently published in the Proceedings of the National Academy of Sciences, a prestigious scientific journal. The article discussed the development of a new paradigm for large RNA folding - research that could lead to new therapeutics for many of the world's most deadly diseases and provide new information on the origin of genetic diversity in humans.

David Rueda, Ph.D.

RNA is a nucleic acid similar in composition to DNA, and is sometimes referred to as DNA's "chemical cousin." Like DNA, RNA contains genetic information. Unlike DNA, RNA performs many vital cellular functions. The past two decades have seen several Nobel Prizes awarded for discoveries of RNA's many important roles in the maintenance, transfer and processing of genetic information, as well as the control of gene expression in living cells. As its significance has become more apparent, RNA has become an increasingly important target for understanding disease prevention and treatment.

"There are a lot of diseases associated with RNA machines not working properly," Rueda said. "RNA performs many fundamental functions within the cell, and if they don't happen correctly, serious diseases can result - Alzheimer's, cancer, and Huntington's disease, for example."

Rueda's research, in collaboration with Roland Sigel, Ph.D., at the University of Zurich in Switzerland, focuses on group II introns, some of the largest RNA enzymes, and their ability to function properly - a phenomenon that depends on their "folding" into specific three-dimensional forms. Using a method called single molecule spectroscopy, Rueda observed individual RNA molecules in motion as they organized into the structures that perform their biological functions.

"We can basically follow these molecules in real time, watching them work," Rueda said. "In doing this, we now understand how each molecule goes from the unfolded state to the folded state. We have identified important intermediate states that had never been observed before, and the time scales at which these steps happen, which had also not been measured before."

Rueda's new paradigm explains that with the addition of magnesium, large multidomain RNA molecules can become more dynamic, which allows them to become active. This finding is the opposite of what had previously been previously believed.

Since many types of RNA are still not well understood, Rueda's immediate goals are to match different RNA structures with their function and characterize the folding steps that take place to reach the active form.

Beyond this, a longer term goal is to visualize an unfolded RNA and predict its final structure and function. "We're still very far from the final goal, but this new evidence allows us to cover some ground in the big picture," Rueda said.

Once this long term objective is reached, a wide number of applications will become possible, including the development of new antibiotics that target RNA of dangerous bacteria. "Pharmaceutical companies are now starting to focus on RNA research to develop the drugs of the future," Rueda said.

A similar application could be used for cancer treatment, where information on the structure and function of transfer RNA could give scientists the ability to shut down the production of cancer-linked proteins.

In addition, progress in the treatment for Alzheimer's disease could become possible once researchers gain a better understanding of the spliceosome - an RNA gene editing mechanism that fails to work properly in people with Alzheimer's.
Along with breakthroughs in medicine, Rueda's work may provide answers to larger scientific questions on the origin of genetic diversity found in humans, since group II introns are capable of both cutting themselves out of and inserting themselves into DNA. It is now believed that about 40 percent of the genes found in humans were inserted at some point in evolutionary history by this type of RNA from outside sources.

For his work in multiple areas of RNA research, Rueda was the recipient of two federal grants in 2008. In April, he received the National Science Foundation's Career Award to develop a method of single molecule spectroscopy that uses lasers to move RNA from one stage of folding to the next. In July, he received more than $1.3 million from the National Institutes of Health to study the structure and dynamics of gene-editing spliceosomes.

James Rigby, Ph.D., chair of Chemistry at Wayne State, said Rueda's achievements to date are indicative of a promising career. "David is off to a great start here at WSU," he said. "His research is both cutting edge and sophisticated, and he has already received substantial financial support for his programs in what is a particularly difficult environment for federal funding. We are very proud of David's accomplishments to date and it is clear that this is only the beginning for him."
To view the full article, visit http://www.pnas.org/content/105/37/13853.full.

Group II introns undergo several folding stages before reaching a three dimensional structure capable of gene transferring editing.

Wayne State University is one of the nation's pre-eminent public research universities in an urban setting, ranking in the top 50 in R & D expenditures of all public universities by the National Science Foundation. Through its multidisciplinary approach to research and education, and its ongoing collaboration with government, industry and other institutions, the university seeks to enhance economic growth and improve the quality of life in the city of Detroit, state of Michigan and throughout the world.