Photo by Todd McNaught
Researchers in the Basic Sciences Division have uncovered a genetic switch that controls an organism's ability to enter into a state of suspended animation, a reversible condition in which all metabolic activity ceases. This extreme form of quiescence, which is analogous to hibernation in mammals, enables animals to survive adverse situations.
In the Nov. 7 issue of Science, graduate students Todd Nystul and Jesse Goldmark, former postdoc Dr. Pam Padilla and Dr. Mark Roth report the identification of a gene that is required for embryos of the tiny soil worm Caenorhabditis elegans to survive a metabolic shutdown brought on by oxygen deprivation. The authors demonstrated that the gene, known as san-1, acts as a safety net that prevents cells from dividing when they encounter environmental stress.
Because genes similar to san-1 exist in virtually all organisms, the researchers suspect that metabolic quiescence in many animals, including mammals, may be regulated in a similar fashion. The study-the first to demonstrate that suspended animation is a coordinated process under genetic control-may also offer insight to cancer biologists, since a portion of cells found in many tumors are metabolically inactive, causing them to be unresponsive to many types of chemotherapy.
"Cells in our bodies sometimes have to cope with very low levels of oxygen," Nystul said. "Our study suggests that if these cells are not able to respond by shutting down when they should, they could make irreparable mistakes, like not segregating their DNA appropriately when they divide-an event that could lead to cancer."
The findings are the first evidence of an actual mechanism to control suspended animation brought on by oxygen deprivation. "This says that it's not just a passive consequence of metabolism slowing due to a lack of oxygen," said Goldmark, who, along with Nystul, is a student in the Molecular and Cellular Biology graduate program. "Such a mechanism makes sense in light of the enormous number of different processes in a dividing embryo that must be stopped and started in a coordinated fashion for the organism to survive."
In a study published in 2001, Roth's laboratory was the first to demonstrate that extreme oxygen deprivation can induce suspended animation in a vertebrate organism, the zebrafish. To identify genes that regulate this process, the researchers turned to a simpler organism-C. elegans. The worm is highly amenable to genetic analysis and has proven to be an excellent model system with many fundamental cell similarities to more complex animals, including humans.
By better understanding how suspended animation is controlled, scientists may someday be able to help humans survive the cellular damage that results from extreme oxygen deprivation, a situation that can occur during a heart attack.
To identify genes that are required for suspended animation, the researchers tested thousands of individual worm embryos-each of which was manipulated to contain a different defective gene-to identify those that were unable to survive exposure to near-complete oxygen deprivation for 24 hours. Worms that lacked san-1 demonstrated poor recovery from oxygen deprivation compared to control worms.
Further analysis of san-1 revealed that the gene produces a protein similar to a family of other proteins known as spindle checkpoint components, which survey cells for damage before allowing newly duplicated chromosomes to separate during cell division. Such checkpoints, upon sensing unfavorable conditions, cause cells to arrest at a specific point in the cell cycle until conditions improve.
That a cellular checkpoint would play a role in suspended animation makes good biological sense, Roth said.
"An organism would not want to undertake an irreparable event," he said. "You only get one chance to segregate your chromosomes correctly."
The researchers found that san-1 is specific for extreme oxygen deprivation and does not play a role in the worm's adaptation to mild oxygen deprivation. Roth's lab has previously shown that a separate protein, called HIF-1, which controls adaptation to mild oxygen deprivation, is part of a process distinct from suspended animation and is not required for survival of extreme oxygen deprivation.
Roth said that the commonality of spindle checkpoints among all nucleated organisms opens intriguing possibilities for their research.
"We don't yet know that suspended animation is a process that is conserved among all organisms," he said. "But this makes us wonder whether it might be."