It was the day before Christmas, and the normally busy MIT laboratory on Vassar Street in Cambridge was quiet. But creatures were definitely stirring, including a mouse that would soon be world famous.
Steve Ramirez, a 24-year-old doctoral student at the time, placed the mouse in a small metal box with a black plastic floor. Instead of curiously sniffing around, though, the animal instantly froze in terror, recalling the experience of receiving a foot shock in that same box. It was a textbook fear response, and if anything, the mouse’s posture was more rigid than Ramirez had expected. Its memory of the trauma must have been quite vivid.
Which was amazing, because the memory was bogus: The mouse had never received an electric shock in that box. Rather, it was reacting to a false memory that Ramirez and his MIT colleague Xu Liu had planted in its brain.
“Merry Freaking Christmas,” read the subject line of the email Ramirez shot off to Liu, who was spending the 2012 holiday in Yosemite National Park.
The observation culminated more than two years of a long-shot research effort and supported an extraordinary hypothesis: Not only was it possible to identify brain cells involved in the encoding of a single memory, but those specific cells could be manipulated to create a whole new “memory” of an event that never happened.
“It’s a fantastic feat,” says Howard Eichenbaum, a leading memory researcher and director of the Center for Neuroscience at Boston University, where Ramirez did his undergraduate work. “It’s a real breakthrough that shows the power of these techniques to address fundamental questions about how the brain works.”
The prospect of tinkering precisely with memory has tantalized scientists for years. “A lot of people had been thinking along these lines,” says Sheena Josselyn, a senior neuroscientist at the Hospital for Sick Children in Toronto, who studies the cellular underpinnings of memory, “but they never dreamed that these experiments would actually work. No one ever thought that you could actually, really do this.”
Except Ramirez and Liu. Their work has launched a new era in memory research and could someday lead to new treatments for medical and psychiatric afflictions such as depression, post-traumatic stress disorder and Alzheimer’s disease. “The sky is really the limit now,” says Josselyn.
Though the work so far has been done on lab mice, the duo’s discoveries open a deeper line of thought into human nature. If memories can be manipulated at will, what does it mean to have a past? If we can erase a bad memory, or create a good one, how do we develop a true sense of self? “Memory is identity,” the British author Julian Barnes writes in his memoir Nothing to Be Frightened Of. “You are what you have done; what you have done is in your memory; what you remember defines who you are.”
“I was always amazed by the level of control that science can have over the world,” says Ramirez, who collected rocks as a kid and remembers being astounded that there actually were ways to figure out how old rocks were. “The example is kind of banal by now,” he says, “but as a species we put somebody on the moon. And we figured out for the most part how to eradicate things like smallpox, things that you can’t see, whose existence you have to infer from indirect measurements, until your microscopes get good enough.”
What Ramirez, now 26, and Liu, 36, have been able to see and control are the flickering clusters of neurons, known as engrams, where individual memories are stored. Joining forces in late 2010, a few months after Ramirez began his graduate work at MIT, the two men devised an elaborate new method for exploring living brains in action, a system that combines classic molecular biology and the emerging field of optogenetics, in which lasers are deployed to stimulate cells genetically engineered to be sensitive to light.
Armed with state-of-the-art tools, and backed by MIT’s Susumu Tonegawa, a Nobel laureate for his work in immunology whose lab they were a part of, Ramirez and Liu embarked on a quest that resulted in two landmark studies published 16 months apart, back-to-back blasts of brilliance that advanced our understanding of memory at the cellular level. Ramirez describes the discoveries, as he does almost everything, with exuberance: “The first paper was like catching lightning in a bottle, and the second paper was like lightning striking the same place twice.”
In the first study, published in Nature in March 2012, Ramirez and Liu identified, labeled and then reactivated a small cluster of cells encoding a mouse’s fear memory, in this case a memory of an environment where the mouse had received a foot shock. The feat provides strong evidence for the long-held theory that memories are encoded in engrams. Most previous attempts involved tracking either the chemical or the electrical activity of brain cells during memory formation. Ramirez and Liu rejected those methods as too inexact. Instead, they assembled a customized set of techniques to render mouse brain cells in their target area (a part of the hippocampus called the dentate gyrus) sensitive to light.