Short Take
An Oocyte (Almost) Never Forgets
Scientists reveal how a living cell holds on to its memories
By Rosanne Spector
Illustrations by Jeffrey Fisher
Our cells have memories — and good thing that they do. Without
their ability to turn a fleeting chemical signal into a permanent memory,
we’d never have made it past conception. A cell’s memory
assures, among other things, that once it matures into an egg it won’t
unexpectedly revert back.
So how does a cell manage to hold fast to a chemical message, long after
the messenger has gone?
Last fall, two Stanford researchers showed for the first time how a
living cell retains a memory. Along the way, they confirmed a theory
proposed 42 years ago in France by Nobel prize-winning molecular biologists
François Jacob and Jacques Monod.
“These very smart molecular biologists came up with a grand 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,” says James Ferrell Jr., MD, PhD, professor of molecular
pharmacology, one of the two researchers.
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. They published their experiments in
the Nov. 27, 2003, issue of Nature.
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,
even after that stimulus had ceased.
In effect, the chemical stimulus flicks on a switch; the positive feedback
loop prevents that switch from toggling back to the “off” position.
Message to cell: forget about it
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, at least in theory,” says 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.”
Figuring out how to wash the oocytes free of progesterone, however,
was easier said than done. “That proved to be mindbogglingly aggravating,
tedious, mundane work,” says Ferrell. “But it was what Wen
had to do to get an interesting answer to an interesting question.”
Next, they wondered whether positive feedback was really required for
this permanent response. Would the eggs
“Demature” if the loop was blocked?
The researchers came up with several ways to block the feedback from
protein “B” (really a protein called MAP kinase) to protein “A” (actually,
it’s called Mos), without interfering with “A’s” ability
to activate “B.” In these experiments, when they added a
feedback blocker and took away the maturation stimulus, they found the
cell lost its memory: “B” promptly switched off.
As a result, the interactions among the proteins in this particular
circuit changed, indicating that the cells had reverted to their immature
state. The cells themselves, however, appeared to be dying. Normal frog
oocytes look like tiny billiard balls, with one hemisphere grey, the
other brown, and a white stripe running between. Mature eggs gain a white
dot on top.
But these cells turned into grey puffballs, a sign they were on their
way out.
"So, we have not found the fountain of youth,” Ferrell says. “There
seems to be more than this one positive feedback loop that maintains
eggs in a mature state.”
Ferrell and Xiong are not the only contemporary scientists to explore
Jacob and Monod’s theory but they’re the first to show that
it occurs in nature.
Brandeis University professor John Lisman, PhD, proposed a similar idea
involving a different set of proteins, describing it in a theoretical
paper in the Proceedings of the National Academy of Sciences in 1985.
But experiments have not borne out that particular notion.
And then in 2000 Boston University professor James Collins, PhD, described
in Nature how he genetically engineered a “toggle” type memory
circuit into the bacterium E. coli. “So that was certainly proof-of-principle
for Monod and Jacob’s ideas anyway,” says Ferrell.
Xiong says she believes further studies will show that this is the major
mechanism for creating a memory in cells. “However, it might not
be the only one,” she adds.
What would the two Frenchmen say about Xiong and Ferrell’s experiment? “I
don’t know,” says Ferrell. “But probably that it was
magnifique!”
Their intellectual offspring, including Lisman and Collins, seem to
think so at least — as Ferrell and Xiong have discovered by way
of beaucoup congratulatory e-mails.
The research was funded by the National Institutes of Health.
Comments? Contact Stanford Medicine at
Back
To Contents
