Stanford research shows how living cells retain memories

Stanford University School of Medicine
Wednesday, 26 November 2003

Researchers at the Stanford University School of Medicine have shown for the first time how a living cell turns a fleeting chemical signal into a permanent memory. Among other things, the process ensures that once a cell matures into an egg it won't unexpectedly revert back. The findings serve as confirmation of a theory proposed 42 years ago by Nobel prize-winning molecular biologists Francois Jacob and Jacques Monod.

"These very smart molecular biologists came up with a grandiose hypothesis on how cells of all kinds can take a transient stimulus and convert it into a permanent memory, but they didn't have the tools to test it then," said James Ferrell Jr., PhD, professor of molecular pharmacology and principal investigator of a study that will appear in the Nov. 27 issue of Nature.

Decades later, with necessary tools in the form of modern biochemical techniques, Ferrell and Stanford postdoctoral scholar Wen Xiong, PhD, (now at UC-San Diego) put the theory to the test in the cell they were most familiar with: the frog egg.

The theory points to the existence of simple positive feedback loops that allow a cell to "remember" it had received a particular stimulus once upon a time. For example, once a chemical stimulus would activate protein "A," that protein would turn on protein "B," which would circle back and promote the activity of protein "A," thereby creating a positive feedback loop. This self-perpetuating loop would allow the cell to remember the initial stimulus that set it into motion.

To test the theory that feedback loops can serve as "memory modules," Ferrell and Xiong took several steps. First they showed that a positive feedback loop was involved in the development of oocytes into frog eggs. "That part wasn't too hard," said Ferrell. "We incubated oocytes with their maturation stimulus, progesterone, and showed that the proteins in the feedback loop stayed activated for days after the progesterone was washed away."

Next, they wanted to find out whether the loop could turn a transient stimulus into a permanent response. They wondered whether positive feedback was really required for this permanent response. Would the eggs "demature" if they blocked the loop?

The researchers came up with several ways to block the feedback from protein "B" (really a protein called MAP kinase) to protein "A" (Mos), without interfering with "A's" ability to activate "B." In these experiments, they found that when the feedback blockers were present, they could still activate "B," but now when they removed the maturation stimulus, "B" promptly switched off.

As a result, the interactions among the proteins in this particular circuit looked as if the cells had reverted to their immature state. The cells themselves, however, appeared to be dying.

"So, we have not found the fountain of youth," Ferrell said. "There seems to be more than this one positive feedback loop that maintains eggs in a mature state."

Ferrell said he plans to explore this mechanism's ability to direct a cell's development path one way or the other. He's investigating whether it might be the key to understanding how different parts of one cell can have distinct characteristics, for example, a "head" with chemical receptors on one side and a tail on the other.

"This has the potential to work as a pretty miraculous self-organizing scheme that would allow the cell to create discrete spatial patches within itself even though there are no physical boundaries between them," he said.

"I believe further studies will show that this is the major mechanism for creating a memory in cells," Xiong said. "However, it might not be the only one." Furthermore, she added, feedback loops likely control other biological processes in addition to memory.

"The correct balance between both positive and negative types of feedback could generate a variety of signaling patterns corresponding to the biological needs of cells," she said.

The research was funded by the National Institutes of Health.

For more information, or to contact Stanford University School of Medicine, see their website at: www.med.stanford.edu