text: January 10, 2014 by Jeffrey Norris, University of California, San Francisco
  Extracellular RNAs, or ExRNAs, travel in body fluids including fluid surrounding the brain and spinal cord, urine and blood. Credit: NIH Common Fund
  There's still much to be learned about so-called extracellular RNA (exRNA), including what exactly it does and how much power it has to direct or disrupt physiological processes throughout the body. The potential, however, could be enormous: What if testing a person's exRNA sample, like a blood test, could diagnose his or her disease earlier and more accurately? What if exRNA could be programmed and sent throughout the body to instruct diseased cells to become healthy again?
  "We don't know much yet about this new family of exRNAs. But they appear to play both protective and pathogenic roles in health," NIH Director Francis Collins, MD, PhD, wrote shortly before the funding announcement.
  "Extracellular RNA is the most recent, and one of the most surprising and potentially far-reaching elements of the RNA world to be uncovered over the past three or so decades," said Keith Yamamoto, PhD, vice chancellor for research at UCSF.
  ExRNA's Role as Biomarker and Beyond
  Although exRNA is clearly in the human bloodstream and scientists are getting better at detecting it, UCSF microbiologist Michael McManus, PhD, is surprisingly agnostic about extracellular RNA's importance in communication between cells.
  "Whether extracellular RNA actually plays important roles in human physiology has not been convincingly demonstrated," said McManus, an associate professor in the Department of Microbiology and Immunology and a principal investigator on one of the NIH grants.
  An alternate explanation for the presence of exRNA: "It's possible that cells that are diseased and dying could be emptying their contents into the bloodstream, and the body might just be clearing them," he said.
  McManus' group has teamed up with labs led by two of the world's pioneering experts on exRNA: Craig Hunter, PhD, of Harvard University, whose studies of the nematode worm C. elegans led to the identification of proteins on the cell surface that allow entry of exRNA; and Olivier Voinnet, PhD, chair of RNA biology at the Swiss Federal Institute of Technology in Zurich, who was the first to discover that RNA could act as systemic signal in plants. Voinnet also leads research to identify any exRNA in milk that may have biological effects.
  The researchers will apply their expertise to a new mouse model being developed by McManus. "Our system will prove definitively whether exRNA is active in mice and will set the foundation for further exRNA exploration," he said.
  Even if exRNA does not prove to be a major player in shaping human physiology, "there is a good chance that exRNA could be a really powerful biomarker to identify and characterize disease," McManus said.
  That could be key to more accurately diagnosing and treating patients, according to Yamamoto, adding that "the exRNA program at UCSF will be an integral part of precision medicine."
  "Just as clinics now often take blood to assess proteins, the application of precision medicine may lead to valuable clinical tests for specific exRNA molecules in blood," McManus said.
  "We expect to discover novel paradigms for extracellular RNA function and common underlying themes across organs, in systems of organs working together, and in animal models," Blelloch said.
  Robert Blelloch, MD, PhD, and Michael McManus, PhD, stand in their lab at the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research. Credit: Susan Merrell
  Blelloch himself is focusing on the prostate. He has identified RNA in blood that can serve as a biomarker of prostate cancer severity, but now aims to see if this exRNA is biologically active in tissue. "We expect these studies to reveal new roles for exRNA in driving prostate cancer progression," he said.
  Liver: Andrei Goga, MD, PhD, an associate professor in UCSF School of Dentistry's Department of Cell & Tissue Biology, is testing whether activation of cancer-associated "oncogenes" in liver cells triggers secretion of exRNAs that play roles in early tumor growth, cancer spread and resistance to drug treatment. Goga has found preliminary evidence that the oncogenes Ras and Myc can trigger exRNA activation.
  Nervous System: Noelle L'Etoile, PhD, an associate professor in the UCSF School of Dentistry's Department of Cell & Tissue Biology, is working with biophysicist Bo Huang, PhD, to observe how environmental stimuli can evoke exRNA secretion in the nervous system of the C. elegans worm, triggering downstream physiological effects in distant organs. The researchers are focusing on odorant detection in the worm, which is the way it detects food availability, and how exRNA secreted in response to odorants might impact reproductive physiology in the gonad.
  "This concerted effort among the multiple investigators here at UCSF together with their international partners should bring clarity to an exciting, but currently messy burgeoning field," Blelloch said. "Being so new, it is high-risk science, but has the potential for having a great impact."