Total Recall – I Swear I Wasn’t There (Even Though I Was)

Single Dose Memory Drug Resolves a Fundamental Question of Neuroscience

total-recallThe movie Memento has two mind-bending story lines: one moves forward in time, while the other moves backwards. Leonard is determined to avenge his wife's murder. However, unable to remember anything that happens day-to-day due to short term memory loss, he copes by tattooing notes on himself and taking pictures of things with a Polaroid camera.

A new class of “smart” memory editing drugs could conceivably eliminate the need to study at all.

Most of us have trouble remembering little things, like where we left the cell phone or the keys. But there are many individuals like Leonard who cannot remember events that occurred even minutes ago. By 2050 –- given today’s biotechnology and demographic trends –- it’s estimated that more than 100 million people worldwide will have Alzheimer’s disease or other dementias.

The New York Times recently reported on an announcement by Dr. Todd C. Sacktor and André A. Fenton at SUNY Downstate Medical Center, in which the doctors stated that a substance called PKMzeta is responsible for memory-related tasks in the brain. The Times characterized this as an “open door to editing memory.” Studies with rats and mice show that a drug called ZIP interferes with PKMzeta, erasing learned behaviors. Editing memory may also mean enhancing the ability to remember things.

Sacktor found that the PKMzeta molecule was present and activated in cells precisely when connected to a neighboring neuron, “The PKMzeta molecules appeared to herd themselves, like Army Rangers occupying a small peninsula, into precisely the fingerlike connections among brain cells that were strengthened.” The molecules stayed there indefinitely, “like biological sentries,” the stuff of memory associations.

Fenton, who specializes in spatial memory in mice and rats, devised a way to imprint animals with memories for where things are located. He taught them to move around a small chamber to avoid a mild electric shock to their feet. Once rats learn, they do not forget. Placed back in the chamber, they remembered how to avoid the shock.

But when injected with ZIP (a Zeta inhibitory peptide) directly into their brains, they had to start over again and learn how to avoid the electric shock. “When we first saw this happen, I had grad students throwing their hands up in the air, yelling,” Dr. Fenton said. “Well, we needed a lot more than that one study.”

Twelve other researchers have now independently confirmed Sacktor and Fenton's findings –- essentially resolving a fundamental question of neuroscience about how memories are stored. A jointly published paper describes how long-term memories are stored as physical traces in the brain using a molecular mechanism of long-term memory storage.

The researchers showed that “unpleasant memories are stored by the persistent action of the enzyme PKMzeta, a form of protein kinase C,” and that “these memories can be rapidly erased by injecting a PKMzeta inhibitor into the brain.” They confirmed that by using ZIP, “unpleasant long-term memories in the hippocampus, a region of the brain critical for storing spatial information, are rapidly erased.”

This raises many questions. If human memory can be erased like a computer's hard drive, what happens to the “overwritten” memories? Is there a biochemical equivalent to disk restoration software? Can the erased memories ever be recovered? How does this affect learned behavior?

If memories can be edited –- erased, enhanced, or supplanted –- what replaces them? Several novels and short stories by SciFi master Philip K. Dick explore this idea. His novelette, We Can Remember It for You Wholesale, loosely adapted as the movie Total Recall, describes a man who has “extra-factual memory” implanted so that he remembers things he supposedly never did, like visit Mars. He ends up deciding to have his implanted Mars memories suppressed and is offered a set of wish-fulfillment false memories in exchange. When he undergoes the memory-implanting procedure a second time, the implant company uncovers a different and older set of suppressed memories revealing that the unbelievable memories they are about to insert are already there and are true.

With the discovery of PKMzeta’s role in storing memories, it’s now easy to imagine a new class of performance-enhancing drugs that remove or replace unpleasant memories or restore hidden memories like the character in Dick’s novelette. For Alzheimer's patients or someone like Leonard in Memento, this might mean the difference between vegetative regress and remembering who, what, or where you are/were.

Smart drugs such as Modafinil – the latest in a growing number of pharmaceuticals that include Ritalin and Adderall to enhance cognition and mental performance –- let students study for hours without the jitters that often go hand-in-hand with pots of coffee, Red Bull, or amphetamines. A new class of “smart” memory editing drugs could conceivably eliminate the need to study at all.

Is editing a memory in some sense editing the self? Could I project an alternate identity –- perhaps even multiple identities –- and selectively edit memories to realize that identity or identities as me? This is a concept familiar with socially networked Internet users of services such as Facebook and MySpace, as well as virtual worlds such as World of Warcraft or Second Life. Alts –- alternate identities –- give users the ability to experiment with alternate versions of themselves. Initial studies of patients with Asperger’s syndrome –- people with extreme difficulty in social settings –- show great promise for the use of alts as a way of learning social skills.

The upside of PKMzeta is that it could open the door to new treatments for Asperger’s syndrome, age-related memory decline, trauma such as childhood abuse or war, and the emotional scaring of bad memories in general.

The downside of using ZIP-like drugs to erase memory is spelled out by Nobel Peace Prize winner and Holocaust survivor Elie Wiesel, “The authors and followers of the heinous ‘Final Solution’ were guilty not only of their unutterable crimes, but also of the will to erase their traces from the memory of others… Indeed they killed their victims two times: first with guns or in the gas chambers, and then by obliterating their memory.”

How easily we forget – or deny. Iran’s Mahmoud Ahmadinejad may have dropped language describing the Holocaust as “ambiguous and dubious” from his recent U.N. speech attacking Israel, but he’s previously called for it to be wiped off the face of the Earth and described the Holocaust as a “myth.” Wiesel comments, “This is why I am somewhat hesitant to trust the proposed therapeutic means to use forgetting as a tool for healing. Once forgetting has begun, where and when should it stop?”