SEPTEMBER 17, 2012
Time moves forward and fixes your body into place. An embryo divides; one cell becomes many. These cells divide again; a brain, arms, and fingernails are formed. You’re born; you grow; you look and behave in ways that scream you. How does this happen? Your genes tell your body what to do, using proteins as instructions. But what tells your genes what to do? Among other things, your epigenes do. These are biochemical tags that switch your DNA’s protein-making ability on and off without changing the DNA itself. When a cell becomes part of a nostril hair rather than part of a memory-processing brain synapse, that’s because it took orders from your epigenes. Your epigenome (the totality of your epigenes) tells your genome (the totality of your genes) what your final profile should be—short or tall, hairy or smooth-skinned, handy or klutzy, schizophrenic or neuro-cognitively non-challenged.
So far, so good. But there’s an irony lurking here that any good playwright would recognize as tragic. Your epigenome responds with acute sensitivity to environmental stimuli—to what your mother happened to drink when she was pregnant; to the cigarettes your father smoked even before you were born; to the neglect you may have suffered as a baby; to the black carbon pollution in the air when you were growing up. And yet, no matter how much the vicissitudes of time and chance may have altered the course of your development, once you have developed, you’re never allowed to go back.
Or are you? What if biological time could flow backward? Could you go back to some primordial, pre-traumatic state? In a study published Sunday in the journal Nature Neuroscience, an epigeneticist and a bee expert describe how they managed to turn back the developmental clock on some honeybees.
Bees, you have to understand, are not easy to change. Unlike us, they are unusually fixed in their social roles. Once they get slotted into one of the tasks required to maintain their hive--queen, nurse, forager—they don’t get to reshuffle that division of labor. Queens are queens from birth. The remaining bees become workers. At first, all workers are nurses. They care for the larvae laid by the queen. Then some nurses become foragers.
In the Nature Neuroscience experiment, the scientists not only made the foragers go back to acting as nurses (which is rare, but not unheard of), but they also proved what had only been theorized before: that when the bees’ behavior reverted back to an earlier state, the epigenetic profile of their brain also reverted to its earlier state.
The experiment—a collaboration between Andy Feinberg, director of the Center for Epigenetics at Johns Hopkins University, and Gro V. Amdam a bee biologist at Arizona State University as well as the Norwegian University of Life Sciences—went like this. First, they removed all the nurses in a hive while the foragers were away. Then, “through a mysterious mechanism I can’t begin to fathom,” Feinberg told me, the foragers came back and re-assumed the role of nurses, feeding and raising the abandoned larvae. At that point, the researchers extracted the forager-turned-nurse bees’ brains. They had already noticed that forager brains had one pattern of markings on their DNA, and that nurse brains had another. A common epigenetic process is called “methylation,” which shuts a gene off the way a spigot shuts off the water. The scientists found nurse-like levels of methylation in as many as 155 genes in the ex-foragers’ brains. (To screen for any distortions that could have been caused by comparing bees at different stages of development, the researchers had made sure that all the bees were same age.)
So what’s a bee to you? Well, if bees can change permanently back into something they were before time forced them toward their fate, then so can you. In the past decade or so, achieving developmental reversibility has become one of the most urgent ambitions in biology. When political controversies over the use of embryos in research reduced the number of available embryonic stem cells—that is, cells that still have the capacity to turn into anything—biologists began experimenting with ways to take developed cells and turn them back into non-developed ones. They’ve been able to do this for some time. As Mandy Fisher, director of the MRC Clinical Sciences Centre at the Imperial College of London, explained in a BBC podcast this week, “You can take cells from the skin and you can reset their developmental clocks, turning them right back to completely unspecialized cells, similar to those that you find shortly after the egg meets the sperm.” The medical applications of this are obvious. “It at least in principle suggests that you may be able to take skin derived from a patient and make bespoke stem cells to regenerate certain tissues,” said Fisher. Indeed, the New York Times reported last week that researchers have been able to make simple organs such as windpipes and bladders using similar methods.
But with the bees, the scientists weren’t returning individual cells to previous states; they were causing entire organisms to return to behaviors and epigenetic patterns they had moved beyond. And they were doing so in organisms known for their social rigidity. A leading expert on bee genetics, Gene Robinson of the University of Illinois, told me that one strength of this study is that the “behavioral states” of honeybees are so “exaggerated,” and yet, “here you have methylation correlated with stable behavioral states and even those are reversible.” Learning that both brain and social behaviors can be plastic to that degree allows us to imagine manipulating epigenetics to reverse all kinds of conditions: engrained reflexes such as neurotic anxiety, for instance, or loss of memory. We don't know whether this can be done in human, as opposed to bees, whose brains may contain less ambiguous epigenetic roadmaps to their behavior, but still, we can dream. Indeed, one of the leading epigeneticists working on learning and memory, neurobiologist David Sweatt of the Unviersity of Alabama in Birmingham, wrote me, “This is one of those papers that makes me envious--an elegant study generating a fundamental finding.” He imagines the paper becoming “a foundational paper in the nascent field of behavioral epigenetics.”
That epigenetic marks can be induced by behavior and can in turn induce behavior is not itself a new finding. The link was established most famously in 2003, when a Canadian psychiatrist and neurologist named Michael Meaney and his team showed that the pups of rat mothers who failed to lick and groom them not only grew up to become unusually fearful rats and bad mothers; they had brains that were methylated differently from those of well-licked pups, and their bodies never manufactured the hormonal and neurological mechanisms that would have helped them manage the stress of social encounters. In 2006, the same Canadian laboratory showed that drugs could alleviate the rat pups’ condition. A certain chemical could make the badly raised pups less nervous at the same time as it changed their brain’s methylation profile. An amino acid could make the well-raised pups less confident in the same way.
What’s new about Feinberg and Amdam’s paper is that it proves that if the behavior itself can be reversed—without drugs—so can the epigenetic patterns. And that raises the question: Could we use this information to unlearn bad habits or mental tics that have left seemingly non-erasable traces on our brains? Eric Nestler, a psychiatrist at Mt. Sinai Medical Center knowledgeable about the neuroscience of addiction, thinks that, eventually, we could. The study does “suggest that similar mechanisms engaged in addiction, depression, etc., might also be reversible,” he wrote me. “Such reversibility would have to be demonstrated, but it is not a stretch at all.”
The study may have evolutionary implications as well. Feinberg and Amdam believe that at least some of the genes that were turned on and off when nurses became foragers and vice versa were genes that regulate other genes. These surprisingly fungible uber-genes are “the supercontrollers,” Amdam explained; they govern the activity of the genes that actually control foraging or nursing. This implies that even after an organism has gone down a seemingly irreversible developmental pathway, should the organism finds itself living under new conditions, it can still muster its most high-powered genetic resources to head back up it. The organism has “range,” as Feinberg put it, by which he means: adaptability.
Is so wide a range always desirable, from a social perspective? Mightn’t adaptability to such a large degree make our responses a little too plastic, our psychology a little too easily flexible, as if we were all characters in Clockwork Orange? I can see all kinds of moral difficulties arising from social hyper-adaptability, but from the point of view of evolution, its utility is obvious: It promotes survival. “I suppose that if you lived in a fixed world, flexibility would be a disadvantage,” Feinberg told me. “But I know of no such world, not the one we live in, nor any of the others.”
Photo by Bente Smedal