An embryo starts out as just a single cell. It’s not long before it divides into two cells, then four, then eight, and so on — a process marked by rapid growth, in which these early, unspecialized cells proliferate wildly to start building all the tissues of the body. As development proceeds, these embryonic (and later fetal) stem cells become more specialized, differentiating into the precursors of various cell lineages, which in turn give rise to more mature cells: blood cells, nerve cells, muscle cells, intestinal cells. Major functional changes in these tissues continue to take place after birth, as the organism adapts to life outside the uterus, for the first time using its lungs to breathe air and its digestive system to process food.

A few cell populations retain some of that early plasticity as adult stem cells, helping both to maintain tissues on a day-to-day basis and to heal wounds. In recent years, moreover, it’s become clear that those aren’t the only cells that stay flexible: Sometimes, when the repair process calls for it, more specialized cells can take a few steps back, or “de-differentiate,” to re-enter a stemlike state, too.

But new results suggest that that plasticity may go even deeper than scientists have thought. Three research teams have observed that during tissue regeneration, the typical solutions offered by adult stem cells (and the de-differentiated cells resembling them) aren’t enough. Instead, the cells of the damaged tissue turn the clock back all the way to a more fetal state, tapping into the proliferative power that once characterized development — and a program thought to have long gone silent.

Atom Bombs and Self-Renewing Cells

In the early 1900s, scientists theorized that the specific blood cell types they’d learned to distinguish from one another under a microscope — red blood cells, white blood cells and platelets — came from a common, more primitive source: a stem cell. But it wouldn’t be until the 1950s and ’60s that researchers could offer definitive proof of their existence and begin to delineate their unique properties.

The discovery of the first stem cells came about indirectly from the atomic bombings of Hiroshima and Nagasaki in 1945. Medical workers observed that exposure to radiation caused a precipitous drop in the survivors’ white blood cell counts, and experiments in mice showed that bone marrow transplants could offset those losses. Work over the following decades gradually revealed why: A population of cells in the marrow could both self-renew and differentiate into various, more specialized blood cell lineages. These were the blood-making stem cells.

They departed from the behavior of more specialized cells in several key ways. When a differentiated cell divided, it produced two copies of itself — and depending on the cell type, the number of times it could do so was limited. That wasn’t the case with the stem cells isolated from the bone marrow. When they divided, they did so over extremely long periods of time, in a process known as proliferation. Moreover, those divisions were asymmetric: Each stem cell produced not only a copy of itself but also a daughter cell fated to become a specific type of blood cell. For those daughter cells that gained a differentiated identity, there was generally no going back.

As stem cell populations were later found in other organs as well, that “paradigm … serve[d] as a template to interpret experimental observations on any other mammalian tissue,” Hans Clevers, a molecular geneticist at the Hubrecht Institute in the Netherlands and one of the world’s top experts on stem cells, wrote in 2015. But that wasn’t necessarily a good thing. “Attempts to fit observations on solid tissues into the [blood stem cell] hierarchy mold,” Clevers continued, “have led to confusing theories, terminologies, experimental approaches and heated debates, many of which remain unresolved.”

The Plasticity of Everything

Still, by the time Clevers penned those words, the conception of what it meant to be a stem cell was already undergoing a massive overhaul. In the late 1990s, stem cells from human embryos were isolated and cultured for the first time, revealing that unlike adult stem cells, which could give rise only to cell types found in their tissue of origin (a blood stem cell in the bone marrow might generate a neutrophil, for instance, but wouldn’t differentiate into a nerve cell in the brain), embryonic stem cells harbored the potential to become any cell type in the body.

Meanwhile, adult stem cells found in tissues other than bone marrow didn’t always seem to act similarly to the blood stem cells. Ones discovered in the intestine and characterized throughout the 1990s and 2000s indicated that certain stem cell populations could replicate far more vigorously than those residing in the bone marrow, and could sometimes divide symmetrically. Several organs, including the pancreas and kidney, didn’t seem to have populations of cells that functioned exclusively as stem cells at all — implying that other cells in those tissues might have to assume stemlike duties in certain cases. In Clevers’ words: “The search for stem cells as a physical entity may need to be replaced by the search for stem cell function.”

The real turning point in demonstrating clear evidence of such plasticity came in 2006, when Shinya Yamanaka and Kazutoshi Takahashi at Kyoto University in Japan took connective tissue cells from adult mice and, by introducing just four genes to them, succeeded in essentially wiping the slate clean and transforming them into embryonic-like stem cells. (The work eventually won Yamanaka a Nobel Prize.)

Scientists rapidly followed up with investigations into whether this might be occurring naturally, too. It certainly seemed to happen in the formation of tumors — cancers have stem cells, as well as differentiated cells driven by mutations to a more stemlike state — but could such a process also represent something ordered, something healthy? The answer turned out to be yes. Throngs of cell types throughout the body — in the skin, in the lung, in the stomach — can de-differentiate when exposed to an injury that causes inflammation and damage to normal stem cells. While cells that have differentiated more recently are particularly prone to regaining their stem cell origin in these situations, research is also beginning to show that cells even further down the specialization path can go back.

Just yesterday, a group of researchers led by Riccardo Fodde, a geneticist at Erasmus University Medical Center in the Netherlands, reported that one such cell type — the paneth cells in the intestine, which secrete molecules that control the gut’s bacterial composition and digestive health — loses its normal gene expression patterns in favor of stemlike ones after injuries. These cells do not normally divide at all, but once they are coaxed into this stemlike state, they proliferate rapidly like stem cells, giving rise both to copies of themselves and to more differentiated cells.

Similar results have been demonstrated in other cell lineages as well. Some labs are even trying to capture cells in the act of de-differentiating. “Our cells are much more plastic, much more capable of responding to injury, than we ever thought,” Fodde said. So much so, added Simon Buczacki, a cancer researcher at the University of Cambridge, that “what everyone is saying at the moment is that everything is plastic, everything can become a stemlike cell if it’s pushed.”

Return to a Fetal State

But what did that transition look like at a more molecular level, exactly? Particularly given how complex the concept of a stem cell has turned out to be, what did the “stemlike” state of a de-differentiated cell really entail?

A few recent papers, one published in 2016 and two others within the last year, provide what many researchers consider to be compelling evidence that at least some differentiated cells can transiently express a developmental gene program that rewinds not just back to an adult stem cell state but all the way back to a state similar to that of a developing fetal organ.

In retrospect, the findings might not come as too much of a surprise: Researchers who study salamanders and other amphibians, the paradigms for tissue regeneration, see this happening on a far grander scale all the time. Those organisms can regrow entire limbs — bone, muscle, cartilage and all — by recapitulating a developmental program from a bud-like structure that forms on the injury site. But humans and most animals aren’t capable of this kind of tissue generation.

At most, scientists have hypothesized that the de-differentiation process implicated in both tissue regeneration and cancer involves the activation of some sort of embryonic or developmental pathway. But studies of embryonic gene activity in such cells that could support that conjecture have had mixed results. “It’s an attractive idea,” said Andrew McMahon, a stem cell researcher who studies the kidney at the University of Southern California. “But frankly, the evidence for that isn’t there.”

Part of what is significant about the newest findings, then, is that they suggest researchers studying regeneration in humans and other animals might have been looking for the wrong signs: Rather than embryonic genes, perhaps they should have been searching for the fetal markers that emerge a little later in development.

That’s not what Richard Locksley and Ophir Klein, researchers at the University of California, San Francisco, initially set out to do. Locksley, an immunologist seeking to gain a better understanding of allergies and the immune system, wanted to track the role stem cells played in the intestine’s response to damage from parasitic worms in mice.