Blue Dreams

by Lauren Slater

  More recently, psychology professors William Hirst, of the New School for Social Research, and Elizabeth Phelps, of New York University, conducted a study of flashbulb memories: intense recollections—including, for example, where you were when you learned something—associated with extreme events such as the assassination of John F. Kennedy or the explosion of the Challenger space shuttle. On September 11, 2001, almost every American citizen absorbed a flashbulb memory of two towers falling or of a low-flying plane against a brilliant blue sky, or of columns of smoke and ash. It was a tragedy that also provided an unprecedented opportunity to ascertain how immutable flashbulb memories really are.

  Phelps and Hirst surveyed several hundred people about their September 11 recollections over a period of ten years, observing the subjects’ memories deteriorate even as the subjects exhibited no clue that their deeply felt stories were morphing. All the participants whom Phelps and Hirst surveyed had formed a flashbulb memory of the 9/11 attacks. It turned out that most of the forgetting, which was manifested in errors of either omission or commission, occurred in the first year after the event. The deviations ranged from simple tweaks to wholesale revisions, and even in the case of extreme changes, the subjects were unaware that they were deconstructing and reconstructing what seemed, to them, a very stable story. Researchers believe that the act of repeating a narrative somehow contaminates it, meaning that nowhere in our brains do any permanent, unmarred memories reside, no matter how much it may feel that way. Their theory has since become a central concept in memory research. If you recall, let’s say, your bat mitzvah on a day when you’re feeling hungry, your memory will likely focus more on the sweet sandwiches served and less on your haftarah portion, and that shift in mental weight alters the network of neurons in which the memory was encoded. Each subsequent recollection does the same. It’s almost sad to learn this, to relinquish the idea that there are neural nooks where pieces of our past are stored, like a safe-deposit box to which we alone have the key. That’s just not the way it works. Our memories, instead, are fragile and friable.

  Brain Scrub

  And so we return to Sacktor in his lab and his years-long inquiries into the role of PKMzeta. When we recall an event, it is because a series of linked neurons are sparking, firing, speaking to one another: the auditory portion of the memory is stored in the neurons in the auditory portion of our brains; the olfactory portion of the memory is linked to neurons in the olfactory portion of our brains; and the movement portion of the memory is tied to the neurons of our motor cortex. All these neurons connect to form the whole memory gestalt. Sacktor began to realize that PKMzeta, this enzyme, seemed always to be present in the brain, especially whenever cells were speaking to one another in the act of making memories, reaching out to one another across gaps between neurons to form the bridges that allow memory to exist, with one association cemented to another and in the process a person’s past created.

  In isolating and purifying PKMzeta, and in seeing its constant presence and activation in neuronal networks of memory, Sacktor sensed he was onto something. But what, exactly, was it? Was PKMzeta the Holy Grail of memory, the key chemical that allows us to retain our recollections? It seemed so, especially when a recent study in Science reported that adding more PKMzeta to the brains of rats strengthened their memory. Jerry Yin, a neuroscientist at the University of Wisconsin, did a related experiment using fruit flies with similar results. The higher the amount of PKMzeta in their systems, the longer they remembered. And Maria Eugenia Velez, a physiology researcher at the University of Puerto Rico, has found that PKMzeta plays a critical role in creating and maintaining addictions, cementing the associations that lead to keen cravings and thereby embedding behaviors deep in the pliable paste of the brain.

  Sacktor compares PKMzeta to a sheepdog, because the molecules do one thing in a perseverative fashion: they “herd” AMPA receptors, which are membrane proteins crucial to receiving neural signals. Once the receptors are sandwiched between the nerve cells, it is the job of the memory molecule to make sure its AMPA receptors do not drift, thereby ensuring that memory remains cohesive during chemical cascades.

  Recently, though, there have been some serious challenges thrown at Sacktor and at his PKMzeta theory of memory maintenance. Richard Huganir, director of the neuroscience department at Johns Hopkins, did a study in which he deleted two genes in embryonic mice, one a gene for PKMzeta and one a gene for a related protein called PKCzeta. Another researcher, Robert Messing, who runs a pharmaceutical lab at the University of Texas, also created mice that were missing critical memory genes. The results? The mice that had been genetically altered to produce no PKMzeta had no memory attenuation or loss at all. And Messing’s mice, also missing critical memory genes, were able to recall objects and to form embedded memories for fears and for places with no trouble. The most telltale sign of a healthy memory is what scientists call “long-term potentiation,” which has to do with how strong the synapses between neurons grow. It’s this characteristic that is considered the bedrock of all learning and memory development. And by this measurement as well, Huganir’s mice demonstrated themselves to be at regular, standard levels.

  Sacktor is not shaken by these challenges to his hypothesis. A graduate of Harvard and the Albert Einstein School of Medicine, he is supremely confident, a self-belief that likely powered him through the years prior to 2006, when only a small group of people paid attention to his work. In response to these recent studies, which have stirred questions about the crowning role of PKMzeta’s relationship to memory, Sacktor argues that the results are “not too surprising.” There may be a different gene that can explain why the mice were able to remember all that they did. In other words, memory may have a backup system that shifts into gear when PKMzeta is compromised or lost. Specifically, Sacktor believes that the backup system is generated by a molecule closely related to PKMzeta that is formed when PKMzeta is absent. “It turns out that when PKMzeta is genetically eliminated in mice,” he writes, “another gene, called PKCiota/lambda, takes over PKMzeta’s function for long-term memory storage.”

  As confident as he is about his hypothesis, Sacktor is a man who continues to practice science with rigor. He says he hated school and was always the fat, shy, smart kid, the one who sought solace in books, in work. Therefore, while he believed, on the basis of his observations, that PKMzeta plays a critical role in memory formation and retention, he sought out a truly novel way to test his hypothesis. Sacktor used ZIP, zeta inhibitory peptide, which blocks PKMzeta, and then observed the results. He injected ZIP directly into the brains of one group of lab rats that had been trained to avoid the places in their cages where mild electrical shocks were delivered to their feet, and another group that had been trained to avoid foods they associated with nausea. The rats had quickly and thoroughly absorbed these lessons, carefully walking or trotting around their miniature minefields, the spatial memory clearly engraved in their brains.

  Once ZIP went to work blocking PKMzeta in the rats’ brains, however, Sacktor and his graduate students watched in awe as the memories came undone, amazed to see how the rats completely forgot about the charged places in their cages and the foods they had learned to dislike, chowing down on kibble they had learned to find disgusting and, perhaps more surprising, walking every which way and getting small shocks as a result, their memories having clearly been wiped out by ZIP, like some sort of ScrubaDub for the brain. Unlike propranolol, which had a diffuse and subtle effect and which, most significantly, left the traumatic memories intact even as it diluted the emotional tone associated with them, ZIP completely nuked the memory, and did so selectively. In other words, the lab rats, which had also been trained to do a variety of tricks and to respond to an assortment of rings and dings, did not forget everything. They forgot only about the wired places in their cages and the negative associations with certain foods, suggesting that ZIP was not only a fine-tuned memory eraser but also some sort of memory editor, cutting out only c
ertain spots in the rodents’ brains. Sacktor and colleagues then went on to prove that ZIP did not cause damage, because afterward the rats were able to relearn the lessons that ZIP had eradicated.

  A rodent is a far cry from a human being, or at least it appears that way. Rats are 1/165th our size, their brains no bigger than our pinkie pads. But while we look a lot different from white Wistar lab rats, our DNA is disturbingly similar. This means that there’s a reasonable chance that a variant of ZIP could work in humans in some of the same ways and that we, thanks to Sacktor, may have in our hands the first real pill designed for forgetting, to be used, to be used…how?

  Eventually the specific science works its way down to this vast amorphous philosophical question of how we might employ something as powerful as ZIP, as well as the ethical implications of having it at our disposal. Conceivably, the drug could be used for those with entrenched addictions, wiping out the associations of neurons that “remind” the addict of his debilitating craving. Or it could be used after a traumatic event, allowing the survivor to bypass what could become PTSD, a disorder of memory gone awry. It could be used, surprisingly, for chronic pain, which researchers have found is strongly linked to memory. ZIP could eradicate a person’s memory of her own pain, thereby allowing some long-suffering souls deep and much-needed relief. Sacktor himself proposes that ZIP could be used in place of a cingulotomy, a procedure in which a small region of the brain is destroyed and along with it, or so it is hoped, the all-encompassing depression or obsession that has utterly ruined the patient’s life. Instead of destroying that neural tissue, Sacktor says, “ZIP might be injected to try to ‘reset’ the synapses in that region.” This is something that could be attempted because ZIP spreads out only 1 to 2 millimeters from the point of injection.

  And then there are the more nefarious potential uses: ZIP in the hands of governments determined to control their citizens in sinister ways. But we need not even go that far to encounter the potential problems. PTSD is devastating and can rob a person of years of productive living. But still, knowing that, would we actually want to scrub away experiences from the human brain? What would happen, for instance, if we were to edit the memories of a guilt-ridden criminal? Wouldn’t he or she, finally freed from the troubling weight of a bad conscience, become more likely to repeat the crime? Might our bad memories be what tether us to good behavior? Do our painful memories hold within them clues and cues about how to navigate our current and future circumstances, illuminating for us mistakes we don’t wish to repeat? Furthermore, by completely removing even the most haunting occurrences, one is in a very real sense stripping a person of critical parts of his or her life story, and of the chance to make meaning of them, which is what humans strive for and part of what brings dignity to existence. It’s possible that ZIP, in wiping out barbed memories, may take too much, or more than we can afford to lose if we humans hope to be humane.

  Michael Mithoefer, the psychiatrist and researcher in South Carolina who ran trials in which MDMA was used to help trauma survivors overcome crippling PTSD, is uncomfortable with the potential of a drug like ZIP. Unlike ZIP, MDMA doesn’t stamp out the memory. Mithoefer’s subjects took MDMA and were infused with fond feelings and an expansive sense of well-being, and in this state talked about the trauma, thereby forging new neuronal connections around it. This seems a less problematic way of treating memory disorders: the person does not lose her experience but rather learns to rewrite its emotional overtones. With ZIP, overtones, undertones, and chiaroscuro all go the way of the wind as the memory plunges down some black hole where, having disintegrated entirely, it ceases to exist. There are many who share Mithoefer’s reservations. In the wake of an April 2009 New York Times article on Sacktor and PKMzeta, Nobel laureate and concentration camp survivor Elie Wiesel also expressed skepticism. “I am somewhat hesitant to trust the proposed therapeutic means to use forgetting as a tool for healing,” he wrote. “Once forgetting has begun, where and when should it stop?”

  That we in all probability now possess the means to do this puts us, as human beings, in a position we’ve never been in before, powerful in a way we are likely not ready to be. But beyond the theoretical or philosophical questions, there are also problematic practical implications in losing your past, even just a piece. According to Daniel Schacter, a memory researcher at Harvard who feels we need the past in order to shape our future, “A rapidly growing number of recent studies show that imagining the future depends on much of the same neural machinery that is needed for remembering the past.”

  With all the potential drawbacks, one would think that a drug like ZIP would spook the average citizen. But this does not appear to be the case, at least to judge by a lot of the online comments from readers of the New York Times in response to an interview with Sacktor that ran on April 13, 2009, about a week after the initial piece:

  I’m very interested in this. Is there a possibility it will be able to work in our lifetime? Or anytime soon? I am one of those who has gone through a tragic experience…I need to be able to erase my memories basically up to a year ago, or the rest of my life I will never be able to be social again…I want to know if this procedure could be possible anytime soon.—Zach

  I will like to erase my memories. I’ve got a lot of anxiety problems and I suffer of depression. I tried to suicide myself like three times, I think you can help me. If you want to try that drug on human beings, I’m willing to be the first one. Please answer me quickly and thank you.—Francisco Velez

  I would like to know if I can get my marriage erased. It’s screwing up my life. All I think about is him and it’s affecting my health. I want to forget about him.—Debra

  Are you accepting human trials for this procedure? I would be willing to enter into this trial as I’ve had such significant trauma in my life that 25 years of therapy still can’t erase. I suffer horribly from PTSD and my quality of life is practically nonexistent.—Connie Bergen

  Ever been so traumatized by something that you couldn’t leave your bed for weeks? couldn’t speak for months? couldn’t wake up in the morning without massive panic attacks, despite therapy and medication for years?…Makes it a bit difficult to function, never mind “learn” from…I’d allow this to be tested on me in a second. No regrets.—Ciarabug

  I would like to know how can I become a tester for such a thing. I truly need to erase my mem. IDC if it erases all of me so be it I just want to live anew without having traumatizing mems with me.—Lynette

  I am weighed down every single day by one bad memory, I’ve considered suicide many times, please, if you are going to do any human trials in the future I will be more than happy to take part, it can’t be worse than what I feel now.—T.

  I have a son who was molested from the age of 6 to 16. The perp was found not guilty. His life is a wreck from this even with all the work he has tried, including being committed for extensive treatment that he wanted to try and move on. He wants to try this drug, what can be done so he could try to get his life back?—S. Smith

  How far away are you from needing volunteers for a clinical study? I would be willing. I have a 2 year old memory I really need to erase.

  Just emotional, nothing criminal.—Bob T.

  Please experiment on me! I want to erase my memory.—Stella

  I want to volunteer for a human experiment of this memory erasing drug. I am 100% serious. I am willing to be a test subject for this product. Contact me via email.—Thomas

  I would also like to be a part of the testing program for this process, if it’s possible. I live in Los Angeles, but I will travel anywhere in the world for this opportunity and even pay for any expenses incurred during the process. Please contact me, thank you and God bless.—Richard

  I personally believe this would be a very good thing for the general population…I would volunteer for a study myself. I would love to be able to be rid of some of my childhood memories that still haunt me and cause me to lose sleep and distract me from daily chores.�
�David M.

  I am interested in your research. Please tell me if it is available and where in South Africa I can get this drug. I really need your help.—Tariro Vakisai

  Memory Steroids

  But now we come full circle, to where we started, with forgetfulness. So far there are still very few treatments for Alzheimer’s, a disease discovered more than a century ago when Alois Alzheimer, a doctor working in a mental asylum in Germany, opened the skull of a recently deceased patient whose disorder had always eluded him. Slicing into her brain, Alzheimer found odd tangles of protein fibers and a sticky plaque called amyloid, so much that the organ was basically stuffed with a deadly jam that had been muffling her memories. In the end, the patient had been so incapacitated that she could not even swallow.

  The good news is that if we may soon possess the ability to medicinally edit our histories, we also, simultaneously, may be able to do the opposite. While ZIP can nuke a memory, there’s a good chance that PKMzeta can enhance it, a possibility that is only becoming more necessary. Barring a cure for Alzheimer’s, by 2050 more than 16 million Americans will suffer from this disease or some other age-related type of dementia. Neuroscientists are brainstorming ways to prompt cells to make more PKMzeta, the theory being that if the molecule is available to the brain in larger amounts, neuronal memory circuits might not decay. “It’s just an idea, at this stage,” Sacktor admits, but one can hear the excitement in his voice—and in the field.

  The current drugs on the market for Alzheimer’s just treat its symptoms rather than blocking the actual mechanism for the disease. At best they can only slow the process of memory loss for six months to a year. It’s probably for this reason that the discovery of PKMzeta is so exciting. If scientists can figure out a way to make PKMzeta into a drug that causes the brain to produce more of the molecule, then we just might have, for the first time, a way of treating a devastating disease that haunts a huge population.