A new database of information on noncoding regions of the human genome indicates that most of it has biological functions. Also this week: gene therapy for smell-blindness.
Getting Beyond the Genes
Scientists have known that about 1% of the human genome encodes proteins that carry out functions necessary for life. Now, researchers have released an annotated database – effectively, a map – of other bits and regions of DNA once dismissed as "junk" but that now that appear to play some role in making us human.
On Wednesday, 442 scientists released 30 open-access papers containing data from the Encyclopedia of DNA Elements (ENCODE) project, a follow-on to the Human Genome Project, which, a decade ago, revealed the three billion base-pairs that serve as a blueprint for a human being.
Ewan Birney, of the European Bioinformatics Institute in Hinxton, England, and data coordinator for ENCODE, said in a Nature video that the project entails hundreds of terabytes of raw data that are "staggering not only in size but in detail."
"ENCODE is all about the data being used widely," Birney wrote in his blog. Ideally, it will aid in the interpretation of genome-wide association studies, the researchers said.
Although only that small proportion of the genome encodes protein, ENCODE found that about 80% of it has some biochemical activity. Birney noted in his blog, however, that the functions vary widely, with little clarity as to the importance of these bits and regions.
Indeed, ENCODE is in its early stages, even though it started out as a pilot project in 2003 and was promoted to a major program in 2007. Birney told Nature that mapping efforts are only halfway done, and "deeper characterization" of all genomic activity is just 10% finished.
Birney also hopes to characterize far more cell types beyond the 147 reported in the latest series across several journals including Nature, Science, Cell, Genome Research, Genome Biology, JBC, and others. Researchers can access the data online at nature.com/encode and via an app.
-- Kristina Fiore
Smelling the Roses
Gene therapy has restored the ability to smell in mice born without it and could lead to new therapies for people with congenital anosmia, according to researchers led by Jeffrey Martens, PhD, of the University of Michigan in Ann Arbor, Mich.
The work may also have wider implications – congenital anosmia is one of a class of disorders, some of them fatal, called ciliopathies, in which some cells lack hair-like organelles called cilia, the researchers noted online in Nature Medicine.
In the mice, a mutation in the IFT88 gene leads to a sharp reduction in cilia function in several different organ systems, including the olfactory system. Infant animals have difficulty growing because feeding is guided by odor and are typically a quarter the size of their normal littermates at the age of 3 weeks.
The researchers used an adenovirus to introduce a healthy copy of the IFT88 gene into the olfactory sensory neurons of newborn mice. The treated mice – more able after the procedure to smell their way to food -- gained 60% more weight than untreated animals.
As well, analysis showed that cilia structures were restored in the animals' olfactory sensory neurons.
-- Michael Smith
Sleep Signals of Alzheimer's
Sleep disruptions relating to deposition of amyloid-beta in the brain may be one of the first signs of Alzheimer's disease, new research suggests.
Levels of amyloid-beta fluctuate in the interstitial space of the brain in mice according to their sleep-wake cycle, rising while they are awake and falling during sleep. Similar findings have been seen in the cerebrospinal fluid of humans. But in both mice and humans, once the hallmark plaques of Alzheimer's disease become evident, the natural fluctuations in amyloid-beta are lost.
In a series of experiments with a mouse model of Alzheimer's disease, plaque formation resulted in a 50% increase in their time spent awake during the light phase of the day. This increase in wakefulness may lead to significant damage in the brain, particularly for learning, memory, and plasticity, according to David M. Holtzman, PhD, and a team of researchers from Washington University in St. Louis.
To confirm the significance of their findings, the researchers immunized a group of the mice against amyloid-beta. No changes in their sleep-wake cycles, Holtzman and colleagues reported in Science Translational Medicine.
Disturbed sleep has also been noted in humans with heavy amyloid plaque burdens.
-- Nancy Walsh
The Foreman of Gut Tissue Repair
Researchers have found a protein -- Wnt5a -- responsible for managing the repair of damaged tissues in intestinal inner lining.
The gut is repaired through glands -- called crypts of Lieberkühn -- containing stems cells that pump out new cells to repair damaged tissue. However, the crypts can be damaged, such as through inflammatory bowel disease, according to Thaddeus Stappenbeck, PhD, of Washington University in St. Louis, Mo., and colleagues, writing online in Science.
The researchers found that nearby surviving crypts expand to damaged areas and create channels that contain rapidly dividing stem cells that form new crypts.
Key to this process is a trigger in the gut's inner lining, in the form of Wnt5a. The protein causes the cells to stop dividing. Turning off the protein in mice with injured intestinal lining caused the stem cells to proliferate, Stappenbeck and colleagues found.
In a second experiment with stem cells grown in vitro, application of Wnt5a inhibited cell division.
-- Cole Petrochko
Preventing Radiation-Induced Mucositis
Patients undergoing radiation therapy for cancer often develop mucositis, a painful mouth condition possibly caused by a radiation-induced depletion of the epithelial stem cells needed to repair damaged tissue.
Now, researchers led by J. Silvio Gutkind, PhD, of the National Institute of Dental and Craniofacial Research, have shown – in cell culture and in live mice – that mammalian target of rapamycin (mTOR) inhibitors may help prevent the condition.
As reported in Cell Stem Cell, the mTOR inhibitor sirolimus (Rapamune) prevented radiation damage to epithelial stem cells taken from the mouths of healthy individuals by blocking the accumulation of reactive oxygen species and the development of oxidative stress. It did not, however, spare cancer cells.
In mice, the drug prevented development of mucositis during radiation therapy.
"Mucositis prevention would have a remarkable impact on the quality of life and recovery of cancer patients and at the same time would reduce the cost of treatment," Gutkind said in a statement. "Our study provides the basis for further testing in humans, and we hope that these findings can be translated rapidly into the clinic."
-- Todd Neale
Brain Stem Cells Lighten Mood
An injection of neural stem cells could reverse depression and memory problems that go along with brain injury, researchers found in a mouse study.
In mice with an injured hippocampus, an injection of donor stem cells there from elsewhere in the brain normalized scores on standard tests of memory such as a water maze, the group reported in Stem Cells Translational Medicine.
Depression -- another symptom of hippocampal injury -- appeared lessened as well, with mice less likely to give up and just float during a forced swim compared with similarly injured mice that didn't get the treatment.
Notably, the grafted stem cells turned into neurons and other types of cells, including the GABAergic cells that appear to play a role in major depressive disorders and memory problems in schizophrenia and old age.
This kind of treatment may help with neurodegenerative diseases as well, the researchers suggested. The hippocampus is one of the first regions of the brain to suffer the ravages of Alzheimer's disease and can also be injured by stroke, trauma, and some types of epilepsy.
-- Crystal Phend