In the nearly 40 years since Nobel Prize-winning scientist Sydney Brenner proposed using a tiny, transparent soil worm called Caenorhabditis elegans as a model organism for biomedical research, C. elegans has become one of the most-studied organisms on the planet. Researchers have determined that C. elegans has exactly 959 cells, 302 of which are neurons. They have sequenced and annotated its genome, developed an impressive array of tools to study its DNA, and characterized the development of many of its tissues.
But what researchers still don’t know is exactly how all of these parts work together to coordinate this little worm’s response to changes in nutrition, environment, health status, and even the aging process. To learn more, 2015 NIH Director’s Pioneer Award winner Coleen Murphy of Princeton University, Princeton, NJ, has set out to analyze which genes are active, or transcribed, in each of the major tissues of adult C. elegans, building the framework for what’s been dubbed the C. elegans “tissue-ome.”
Although C. elegans and humans diverged from a common ancestor more than 300 million years ago, they share about 40 percent of their protein-coding DNA in common. These genetic similarities, along with the ease of manipulating the C. elegans genome and its relatively short life span, has made it a great system for unraveling the molecular mechanisms that underlie development, behavior, and aging in a multi-cellular organism.
However, researchers have run into difficulties when they’ve attempted to conduct cell-specific analyses of gene transcription in various types of C. elegans tissue. That’s because the adult worm is enclosed in a tough outer cuticle that makes it difficult to isolate, sort, and analyze the individual cells that make up the different types of tissue. Murphy’s lab recently developed a technique to dissociate tissues from the cuticle more gently , clearing the way for the first comprehensive analyses of tissue- and cell-specific gene activity in C. elegans.
With funding from her Pioneer Award, Murphy and her colleagues have begun the initial profiling of genes that are active, or expressed, in each of the adult worm’s major organs and cell types. (Quick note: Worms don’t have a circulatory system. They have two simple nervous systems, but no brain.)
The profiling will lay the groundwork for the project’s more-complicated second phase: developing computational methods to figure out the signaling interactions between cells and the larger networks of communication between tissues. If successful, Murphy wants to track the molecular changes in communication as worms age. Interestingly, one place that she will look is the worm’s skin and intestine. Recent evidence suggests that certain cells in these tissues may coordinate signals from neurons to influence reproduction and lifespan.
One of Murphy’s mentors as a postdoctoral student was Cynthia Kenyon, who studied C. elegans at the University of California, San Francisco for many years and is now Vice President for Aging Research at the company Calico, South San Fancisco. More than 20 years ago, Kenyon discovered that worms with changes in a gene called daf-2 lived twice as long as others. Kenyon later showed that daf-2 encodes a cell-surface receptor that, like a molecular doorman, controls entry into an insulin-signaling pathway that regulates lifespan in C. elegans. This complex pathway, which plays an important role in metabolism, has been maintained through evolution, and subsequent research suggests that it also influences lifespan in mice and humans.
Murphy has now studied daf-2 mutants for several years and has found something fascinating. Although worms might seem limited in their cognitive abilities, they are actually quite capable of fairly complex navigational calculations and other learned behavior, such as how to find food. Murphy has discovered that the daf-2 worms have better long and short-term memories than other worms, and they hang onto these cognitive abilities longer as they age. Murphy wants to use data generated with her Pioneer Award to begin dissecting the molecular differences between the daf-2 and normal worms to see if she can uncover specific links between metabolism, lifespan, and learning.
Murphy says that she and her colleagues have already made good progress on the “tissue-ome.” Her hope is others in the worm field will join in to add to the data and help solve some of the computational problems that will undoubtedly arise. She also envisions that this first attempt to build a system-wide understanding of C. elegans will serve as a blueprint for efforts to do the same someday for more complex organisms, including humans.
 The C. elegans adult neuronal IIS/FOXO transcriptome reveals adult phenotype regulators. Kaletsky R, Lakhina V, Arey R, Williams A, Landis J, Ashraf J, Murphy CT. Nature. 2016 Jan 7;529(7584):92-96.
Coleen Murphy (Lewis-Sigler Institute, Princeton University, Princeton, NJ)
Video: Coleen Murphy researcher and role model (Princeton)
Murphy Project Information (NIH RePORTER)
NIH Support: Common Fund; National Institute of General Medical Sciences