Plug and play with RNA. RNA molecules are known primarily as messengers that transmit the genetic code necessary to produce proteins from DNA to cells. But recent studies have shown that they also play important regulatory, structural, and enzymatic roles in the cell. A team of biomedical engineers led by Jim Collins, an ENG biomedical engineering professor, a University professor, and codirector of the Center for BioDynamics (CBD), recently exploited the regulatory function of noncoding RNA to engineer tiny modular regulators that are able to control gene expression.
Farren Isaacs, an ENG postdoctoral research associate and lead author of the project, says that multiple “riboregulators” can be plugged into a cell and linked to multiple genes because of highly specific RNA-RNA interactions and the modular nature of his research team’s design. The research team tested and developed their riboregulator in Escherichia coli, a form of bacteria commonly used in genetic experiments. To turn off the action of a particular gene, they inserted a short sequence of DNA (known as a cis-repressive sequence) into the DNA adjacent to the site where molecules known as ribosomes would normally bind and initiate the synthesis of proteins. As RNA is produced (by a process known as transcription) the inserted sequence causes a loop to form at the end of the cis-repressed RNA (crRNA). This loop blocks the ribosomes from binding, effectively preventing the protein from being produced. To reactivate the gene, the researchers engineered a noncoding RNA (a trans-activating, or taRNA) that binds strongly with crRNA and opens the loop structure so that binding can occur and protein synthesis can begin.
According to the researchers, because the riboregulators operate after transcription, they are not limited to functioning with a specific promoter or gene. Also the effect is tunable — the amount of gene expression can be tightly controlled within the regulatory system. The researchers envision networks of these tiny gene circuits designed to carry out a variety of interesting processes — turning cells into environmental monitors that detect heavy metals in the environment, or into sensitive tools to help investigate how toxic genes and bacteria operate, perhaps leading to the development of more effective antibiotics. In addition, this work may give insight into mechanistic actions of RNA-based processes and help identify natural RNA regulators.
This work was reported in the July 2004 issue of the journal Nature Biotechnology. Along with Isaacs and Collins, authors are Daniel Dwyer, a graduate student in the CBD, Chunming Ding, a research assistant professor in the Bioinformatics Graduate Program, Dmitri Pervouchine, a CBD postdoc, and ENG Professor Charles Cantor, a codirector of the Bioinformatics Graduate Program.
Overburdened? The cost of prescription drugs has increased significantly for all Americans, but the burden has grown disproportionately in states with poorer, sicker, and older people, says a new study by Alan Sager, an SPH professor of health services, and Deborah Socolar, an SPH research analyst.
The cost burden — spending on prescription drugs divided by average income — has risen in the United States by 50 percent, from 1.2 percent of income in 1998 to 1.8 percent in 2002. But the differences among the states is striking. Tennesseeans, with the highest burden (3.1 percent), have nearly two and a half times the burden of Californians (1.3 percent). And according to the researchers, the gap across states continues to widen.
The researchers found that using more prescription drugs was the strongest predictor of a state’s burden level, followed by average personal income and the price of drugs. Use of prescription drugs was highest in states with more insured people, lower incomes, higher heart disease and diabetes rates, more physicians, and older populations.
“With today’s drug cost burdens, higher spending is not sustainable,” write Sager and Socolar. “Yet 70 million Americans lack drug coverage and millions more are underinsured. High U.S. prices keep coverage unaffordable and mean that many Americans go without needed drugs.” According to the researchers, the only practical recourse is to cut drug prices — a strategy that will make drugs available to more people, and by increasing use of needed medications, maintain drug makers’ revenues at levels high enough to support continued pharmaceutical research. Two states with high burdens, West Virginia and Maine, have already moved to control prescription drug prices.
The complete report is available from the SPH Health Reform Program Web site, http://www.healthreformprogram.org.
Briefs" is written by Joan Schwartz in the Office of the Provost. To read
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