memory sculpture
© Wikimedia Commons
Memory (sculpture, marble), by Daniel Chester French, 1886–1887, Metropolitan Museum of Art
Without memory, our lives would be exceedingly troublesome, and dangerous if not impossible. What if you had to look up what "green light" means every time you saw one? Many of us have had to witness loved ones suffering from dementia, including its common symptom of short-term memory loss. Human memory is somehow facilitated by the organ of the brain, where Alzheimer's disease and other forms of dementia take their toll. Cells have no brains. Yet biochemists are increasingly finding that cells do have memory.

Stem Cell Memory

The old picture of stem cells was that they remain pure and static, until signals trigger cell division and differentiation. Ongoing research reveals a new, more dynamic picture of stem cells: cells that can remember things and respond to their surroundings. According to Monique Brouilette in Quanta Magazine:
Stem cells, famous for replenishing the body's stockpile of other cell types throughout life, may have an additional, unforeseen ability to cache memories of past wounds and inflammation. New studies in the skin, gut and airways suggest that stem cells, often in partnership with the immune system, can use these memories to improve the responses of tissues to later injuries and pathogenic assaults.

"What we are starting to realize is that these cells aren't just there to make tissue. They actually have other behavioral roles," said Shruti Naik, an immunologist at New York University who has studied this memory effect in skin and other tissues. Stem cells, she said, "have an exquisite ability to sense their environment and respond." [Emphasis added.]
Most tissues have small reservoirs of stem cells that can replenish cells as they age or die. They can differentiate into any one of the cell types of the tissue. That's been their primary function, Brouilette writes, to serve as "miniature factories" for tissue regeneration. It was thought they had to remain "blank slates" that were unchanged from their histories. "But now a new picture is starting to emerge."

Studies of people with chronic inflammatory diseases led to the discovery of stem cell memory. Stem cells extracted from the nasal cavities of people unable to recover from chronic sinusitis showed activity in the genes for allergic inflammation long after the pathogen was gone. Did these stem cells remember a previous threat?
The fact that the targeted genes were active in stem cells meant that the stem cells were apparently in direct communication with the immune system. A hunch that this communication might have an effect on the chronic nature of the disease led the researchers to a further set of experiments.

They removed cells from the airways of allergy patients, grew them in culture for about five weeks, and then profiled their gene activity. They found that the genes involved in allergic inflammation were still active, even though the allergic threat of dust and pollen was long gone. In addition, the researchers described many of the cells as "stuck" in a less-than-fully-mature state.
Apparently these stem cells transfer their memories to future generations of cells. This can be a good design feature; it allows the cells to "retain a record of past assaults to sharpen their responses next time." In the sinusitis patients, however, the stem cells were apparently stuck in a feedback loop, "perpetually signaling to the immune system that an attacker is there," the scientists deduced. The only way they would do that would be if they had remembered a prior threat and had modified their genomes to deal with it.

"This opens a new paradigm," an outside immunologist commented, "where we don't only focus on the self-renewal potential of these cells but on their potential interaction with their surroundings." Another said, "we are realizing that cells can be tuned" to adapt to their environment more rapidly and effectively. For instance, inflamed skin on mice that was allowed to heal was found to heal 2.5 times faster the next time at that same spot. The "memory" lasted as long as six months. Moreover, the stem cells also appear to communicate with the immune system to work as a team.

How memory is stored in a cell is not known. It probably involves epigenetic factors, such as the packing of the genes for access, or changes to gene regulators. The picture that is emerging is one of stem cells in a wide range of tissues engaging in "chemical dialogues" with each other, "pooling their information to cope most effectively with changing conditions."
Whatever the details of those conversations might be, all the evidence points to stem cells playing a central role in helping to make tissues more adaptable by preserving some record of their history.

"It makes more sense that a tissue would just learn from its experience," Naik said. "That way it doesn't have to reinvent the wheel every single time."
Egg Memory

Another discovery about cell memory comes from the University of California, Davis. What researchers there found was an aspect of "oocyte quality control" that involves remembering when daughter cells, on the way to becoming eggs, experienced less-than-optimal repair after DNA damage. Such cells might lead to defective offspring, so as part of the "oocyte selection process," they are culled early. A gene named Rnf212 signals them to undergo apoptosis (programmed cell death).
In mice, as in humans, developing females initially form very large number of oocytes. Around six million oocytes enter meiosis in humans, but a stunning 5 million are culled by birth. By puberty, the ovaries contain only around 250,000 oocytes, which are steadily depleted until menopause.

This drastic reduction reflects selection for only the highest quality oocytes. Oocytes that experienced defects in meiosis, including damage to their DNA, are culled. Only those that pass through quality control checkpoints can continue and become established in the ovarian reserve.
The selection process includes a "cellular memory" of DNA damage, the press release explains. Slow DNA repair triggers RNF212 to tag these cells so that they become sensitive to apoptosis. The memory has to be able to count to ten:
The researchers found that RNF212 prevents the repair of lingering breaks to create a "cellular memory" of defects that occured in earlier stages of development. This allows the cell to assess how bad the defects were. If the number of unrepaired breaks passes a critical threshold of around ten, the cell is deemed to be of poor quality and undergoes apoptosis. If there are only a few lingering breaks, repair is reactivated and the oocyte is allowed to progress and become part of the ovarian reserve.

"It seems counterintuitive that a cell would actively impede DNA repair, but this is how oocytes gauge the success of earlier events. High levels of lingering breaks means there was a problem and the oocyte is likely to form a low quality egg," Hunter said.
Having more eggs in the reserve is not helpful if they are of low quality. "Thus, the reproductive system must balance quality and quantity of oocytes for optimal fertility." Mice without RNF212 tended to have more eggs, because more snuck through the quality-control process. But they were also more at risk of miscarriage and congenital defects in the offspring.

A Programmed Design Feature

The culling process appears to represent a programmed design feature to minimize the effects of mutations. Geneticist John Sanford, who organized the 2014 conference Biological Information: New Perspectives at Cornell (see Synopsis), where Douglas Axe, William Dembski, and Robert Marks spoke, gave a lecture last month to the National Institutes of Health (NIH) about mutational load and genetic entropy (see it on YouTube). Mutations are not increasing fitness, Sanford concludes: they are driving humans extinct. This fits the theme of Michael Behe's upcoming new book Darwin Devolves (preorder it here to get the associated free perks).

Without cells having rigorous, multi-part, irreducibly complex systems to repair damage, minimize mutational degradation, and maintain genetic integrity, we likely would not still be here to experience the awe of cellular memory.