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Finding a role for extracellular RNA

S. Ashraf Ahmed
AS a student of Dhaka University during 1968-74, we learned of only three functions of ribonucleic acids, abbreviated as RNA. They were messenger m and transfer! of information from DNA, and structural for ribosome r. RNA is a polymer of nucleic acids, called nucleotides.
Then soon after joining as a post-doc in 1983 at the National Institute of Health (NIH) in Bethesda, Maryland, I was intrigued by the title of a seminar for an enzymatic, fourth function of RNA. Until then enzymatic function was reserved for proteins only, and nothing else. So I attended the seminar. The speaker was Sydney Altman from Yale University who later won a Nobel Prize for this discovery. At that time he called the RNA enzyme as RNAse P. Being glued to the talk, I asked him a question on his use of a reagent called spermine. Soon upon return to lab, I made the reagent's pretty unconventional use in making protein crystals. The result was spectacular that partly shaped the rest of my research career! This coincidental connection permanently engraved RNAse P in my memory although it was nowhere near my immediate research interest.
Over the years RNA was found scattered all over, cytoplasm, nucleus and mitochondria, very large to very small. With confirmation of RNAse P as an enzyme, scientists were curious in finding specific roles for many types of the ubiquitous RNA in addition to those which were known by then.
Thus, we now have pre-mRNA from which a mature RNA is produced. As the name implies, small nuclear RNA or snRNA occurs in the nucleus, and functions both as an enzyme and in maintaining the structure of something called 'spliceosome'. Signal recognition particle RNA or SRP RNA recognizes signal peptide sequences for guiding the protein into specific cellular locations. Small nucleolar RNA or smoRNA helps processing of pre-rRNA for the assembly of ribosome subunits in the nucleolus. Small interfering RNA or siRNA and micro RNA or miRNA regulates gene expression.
Traditionally, RNA was thought to reside only inside cells. That notion started to change about fifteen years ago when scientists demonstrated that plant cells release RNA that travel throughout the body until it reaches a target cell. So these are extracellular RNA or exRNA.
In human and other mammals, exRNA has been detected in saliva, tear, blood and other body fluids encased in small bubble-like sacs called exosomes or in association with proteins and lipids. Like miRNA, exRNAs are small, ~22 nucleotides long.
Reports are there that (1) mammalian tumor-derived exRNAs can promote tumor growth, (2) endothelial cell-derived exRNAs regulate gene expression in smooth muscle cells, (3) rice exRNAs found in human circulation modulates LDL levels, (4) microbes secrete RNAs via extracellular vesicles; this may be a mechanism by which the microbiome may influence host cell function at a distance.
To find a definite answer on the role of exRNA in humans, last month the NIH announced a 17 million dollar 5-year exRNA Communication Initiative. Fund recipients will try to probe if exRNA plays a role of communication between different cell types, disease conditions, or any other biological role. One group of dentists will try to find a common exRNA in the saliva for diagnosis of diabetes and many types of cancer. One group will screen the blood of 3000 patients for diagnosis of any cardiovascular conditions. Other groups will investigate if exRNA can be utilized to fight certain diseases like multiple sclerosis, Huntington Disease, and cancer. A group will manipulate cells to produce a liver-specific endosome with ability to deliver miRNA into cancer tissues. One bioinformatics group will construct an "exRNA atlas” a public website resource for all researchers in the field.
Bangladesh scientists may start thinking if the emergence of any of the country's many prevalent diseases can be predicted beforehand by analyzing exRNA.
The writer, a former Dhaka University teacher, is a biomedical scientist working in the USA