TODD SACKTOR: THE SEARCH FOR THE MEMORY ENZYME

By Michael Humphrey

TODD SACKTOR USED TO TELL a story about the day he chose science as
his field. The year would have been 1966. The memory is a snapshot: He is sitting
on the floor of his grandmother’s Bronx high-rise apartment overlooking the
Hudson River. He is reading a newly purchased book called Understanding the
Brain by the Nobel laureate John Eccles. It’s a happy day for the nine-year-old in
what was sometimes a tumultuous childhood – the family drove from Baltimore to
see his beloved “granny,” for Thanksgiving, perhaps, though he can’t be sure of
that detail. Sacktor devours Eccles’ illustrations, clear descriptions and grand tone
– the book claims the human brain is “the most complexly organized matter in the
universe.” He closes its pages with missionary zeal to take Eccles’ title seriously –
he will understand the brain.
In 1990, his first year at SUNY Downstate Medical Center in the
gritty East Flatbush district of Brooklyn, Sacktor made what many
believe was a major discovery to do just that. He discovered an
enzyme in the brain called PKMzeta, which he suspected – and has
since demonstrated – keeps a long-term memory persisting in the
brain, even when the mind is not consciously engaging it. What that
9-year-old child could not have known, what even Sacktor the adult did not realize
at first, was a basic truth about science – claiming a novel discovery places you
squarely in the professional desert. For the next 16 years, his peers largely
ignored his work while he published in lesser journals and gave unheralded talks.
Still, Sacktor single-mindedly pursued the purpose of the enzyme’s existence,
certain he was onto a big discovery.
Then five years ago a team of neuroscientists, led by Sacktor, ran a series of
tests on rats’ memories that revolved around the enzyme. Their finding, named a
“Top Ten Breakthrough of 2006” by Science, was simple, fascinating and
disturbing – keep PKMzeta from doing its job for just a few hours and memories
that could have lasted a lifetime are forgotten forever without any damage to the
brain. Two months ago, a Science report written by a team at the Weizmann
Institute showed that an “overexpression” of PKMzeta enhanced memory retention
of rats.
Deep in the recesses of the Society for Neuroscience website is a snapshot
of Sacktor from 2008. The society has just awarded him the Research Award for
Innovation in Neuroscience, which comes with a $25,000 prize. In his black suit
and black tie, Sacktor, a 52-year-old, smallish, wispy-haired man with sharp
features, peers down at the camera from the podium, his mouth smiling but
closed, his round face nearly expressionless. His eyes tell the story. They are not
wide, thankful eyes of other neuroscientists pictured on the website from previous
award ceremonies, but the dark and cool, half-closed eyes of someone who just
proved his point.
On a bright Thursday afternoon shedding harsh light on Sacktor’s dingy
Downstate laboratory, Research Assistant Professor Panayiotis Tsokas walks in
with a cage holding two large black and white rats, brought in pairs to relieve their
stress of being moved. One rat will live to see another day. Tsokas picks up the
other. He places the rat in the bottom portion of a Culligan bottle cut in half,
originally intended for a water cooler but now filled with an anesthetic gas. He
places a tin lid on top and weights the lid with the cover of an old steel oxygen
bottle. The rat pushes its nose against the plastic, looking out to the lab filled with
chemical bottles, arcane machinery and posters of Albert Einstein. It takes three
steps and falls to his side, relaxes gently until its breathing becomes barely
perceptible. Tsokas prepares a tiny guillotine by the lab sink.
Meanwhile, sitting in his office, Sacktor stirs a test tube-shaped stainless
steel tea infuser in a mug of hot water. His Society for Neuroscience plaque hangs
near the door, neither hidden nor highlighted. As the leader of his lab, Sacktor
never touches the experiments. His job is to think – to ask new questions and
examine results. He says what Tsokas is about to do requires such precision and
speed that it takes about nine months to master. The goal is to harvest the rat’s
hippocampus, a section of the brain essential to most kinds of memories. Sacktor
is not finished making his point about PKMzeta, the memory molecule. Knowing
what retains memory might give scientists the clues needed to track specific
memories forming in the brain – that’s what Sacktor is after these days. It also will
further prove his theory, sink his discovery deeper into the realm of accepted
wisdom about memory.
Tsokas, an associate professor at Downstate, pulls out the unconscious rat,
slides its head beneath the hovering blade and with one firm press of the
guillotine gate beheads the animal. Now it’s a race. He grabs scissors to split the
scalp and skull, then a scalpel to carefully but quickly extract the brain, which
begins to decay almost immediately after death. Tsokas has minutes to extract
the hippocampus before that happens. He runs down the lab hall, brain in a small
container, to a walk-in freezer where he expertly extracts the gelatinous
membrane, smaller than a baby pea. While dissecting, Tsokas talks about Sacktor.
“He’s very open to ideas, he’s ready to try whatever you think might work.” He
divides the hippocampus into thin sections with a miniature round-blade slicer,
then races back to the lab, where he sets the hippocampus slices into a solution
that mimics spinal fluid. Because he acted fast enough, the hippocampus will
perform as if it were functioning in the brain for about a day. The slices will be
studied with a process called Long Term Potentiation, which delivers shocks to the
hippocampus to study how the brain’s neural pathways respond. These shocks,
many scientists believe, are roughly analogous to experiences that become
memories. When shocked, PKMzeta proliferates and takes on a life of its own.
“I wish we didn’t have to kill animals,” Tsokas says over the morbid scene in
the sink, “but it’s going to help someone someday.”
+
Basic neuroscience does not necessarily search for cures to a disease, but
rather for answers about the fundamental nature of the brain. This is Sacktor's
job. Basic neuroscientists believe their work in the murky depths of neural
networks will someday surface as important to everyday life, but oftentimes they
don’t know exactly how.
April 6, 2009 was one of those rare days when Sacktor watched his work
emerge in the real world. He sat in the kitchen of his Yonkers turn-of-the-century
shingle house reading the Monday New York Times with more than a passing
interest – his name was on the front page above the fold, under the article, “So
You Just Want to Forget? Science is Working on an Eraser.” The article reported
how Sacktor’s team was able to erase a living rat’s memory without damaging the
brain. “The discovery of such an apparently critical memory
molecule,” Times writer Benedict Carey wrote of Sacktor’s work, “and its many
potential uses, are part of the buzz surrounding a field that, in just the past few
years, has made the seemingly impossible suddenly probable: neuroscience, the
study of the brain.”
 “Oh great,” Bette Sacktor, Todd’s wife of 21 years, joked when she learned
of the front-page treatment, “now you’re going to be even more intolerable to live
with.”
Living with Sacktor means living with his quest and with his near-obsession
for a microscopic protein. It means living with his monumental confidence about
being right, even when close colleagues had their doubts.
“It always seemed a silly thing, intellectually, to imagine there would be one
molecule that would be crucial for memory,” says André Fenton, a former SUNY
Downstate colleague now at NYU.
+
Sacktor’s search may have appeared quixotic, but he is no Don Quixote. He
is too self-aware – he admits to being arrogant, stubborn and lazy, which are
deficits, he says, overcome by being smarter than most people. He is also too
informal for Spanish knight analogies – his regular uniform consists of oxford shirt,
chinos and Ecco shoes. Years in Yonkers have bent his accent towards New York
over his native Baltimore – the rising octave of his voice as he finishes a thought
invokes comedian over neurosurgeon, as if he’s saying, “but seriously folks”
instead of “when you electrically stimulate the synapses.” He seems too relaxed
to appear a crusader – he gets in the office late most days, plays squash at the
gym as part of his workday, and avoids doing too many experiments at once.
Most importantly, he is not delusional like Quixote. Interviews with leading
neuroscientists revealed a general consensus that discovering PKMzeta has
placed Sacktor among the most important brain researchers of his generation.
“Yeah, I think I am,” Sacktor agrees.
His research may eventually mean editing our memory bank, erasing
traumatic memories and enhancing important ones, although that is many years
away. It could also mean finding a cure for addictions and persistent pain, which
turn out to work very much like memory. It could have serious implications for the
study of dementia, such as Alzheimer’s. But at this stage, his research still stirs up
controversy. Sacktor not only claims the enzyme he discovered is necessary for
memory storage, he claims it is sufficient, meaning all of the other 100-plus
molecules nearby are just pawns in PKMzeta’s game.
“It’s still a new finding in scientific terms,” says University of California –
Irvine professor James McGaugh, a pioneering neuroscientist who has studied
memory since the 1950s who’s dubious about the sufficiency claim. “What needs
to happen next is that young scientists take up the findings and test them, build
on them, make new discoveries based on his work. Once his name is not on every
paper about PKMzeta, then you will know it has become established.”
 Some scientists are not ready to concede Sacktor’s discovery is primed for
canonization.
“One of the real pitfalls of doing science is that your tools may not be as
good as you think they are,” says John Lisman, a neuroscientist at Brandeis
University. Lisman believes he has found a different molecule that maintains long-
term memory. “One kind of tool people have is drugs, another tool is genetic
modification. So far, all of his work has relied on the pharmacological approach.
That is a major hole in his research.”
Sacktor says a genetic test is underway. A mouse has been genetically
mutated so it won’t produce the memory molecule, which means it should not be
able to retain long-term memories.
Even before those tests are complete, McGaugh, who called himself an
objective observer, says, “it appears he has answered a question that long
perplexed scientists. How do humans remember something long-term without
actively keeping the memory in mind? He may have filled in a blank.”
Filling in a blank is the best any one scientist could hope to do. That’s what
wins Nobel Prizes and changes textbooks. Sacktor says none of that matters to
him anymore.
+
“What matters is that PKMzeta is remembered,” he says at his kitchen table
in his modest home in southern Westchester County. He says a major literary
agent has approached him, but “I’m too lazy to write a book.” He could entice
pharmaceutical companies to use his discoveries, but he says any riches gained
from his intellectual property are not necessary.
“I'm in my fifties and there are fewer and fewer things I want to buy,” he
says. “I drive a Toyota Highlander, it’s a good car. Why would I want to be in a
BMW?”
Driving that Highlander through Yonkers one Sunday evening, Sacktor talks
about his hero Albert Einstein, specifically about the physicist’s ability to focus on
the essential questions of a problem. Sacktor has taken that lesson to the
microscopic level.
“I love PKMzeta,” says Sacktor and he’s not using “love” loosely. After all, he
guards PKMzeta’s Wikipedia page, making sure no one misrepresents it. When he
hears the memory molecule called “strange,” he says he prefers the term
“atypical.” He freely gives out the antibody that makes it possible to see the
enzyme and provides other scientists with generous intellectual input to assist
their research, which is why his name appears on almost every paper about
PKMzeta.
 “He’s incredibly generous with his time,” says Maria Eugenia Velez, a PhD
candidate in physiology at the University of Puerto Rico, who in her research has
found that the memory molecule plays a similar role in creating addictions as it
does in creating memories. Sacktor has agreed to sit on Velez’s dissertation
review panel, “which is a real honor for me. I know he does it because he cares
about PKMzeta.”
Sacktor can make an argument that the enzyme he discovered is
fundamental to the human experience. During a visit to his office, Sacktor takes
me through a mental test regarding the issue of consciousness, how any person
has an individual identity. He sits relaxed in his ergonomic desk chair while I sit on
a couch that looks out towards two unwashed windows. On the window sill to my
right stands a small golem, a Jewish religious symbol that a friend brought back
from Prague. Next to it is a Krishna statue, which another friend brought back
from India. They are nothing but art to Sacktor who says, “Whenever I find myself
in a state of magical thinking, I ask, ‘What’s the mechanism for that.’ So if I want
the Yankees to win the World Series, does that desire have any effect on the
outcome? Of course not, there’s no mechanism.’ At first he’s reluctant to allow the
discussion about consciousness to go on the record because, “this is so goofy. But
you might find it interesting.”
Sacktor begins a Socratic dialectic that mirrors the plot of the movie Freaky
Friday, starting with the premise that he and I switched brains, keeping all other
body parts. “So would you be where I am sitting and would I be where you are
sitting?” he asks.
I answered yes, though I am now in his body I remain myself. Then, he
continued – imagine we switched only the cerebral cortex and hippocampus, the
knowledge centers of the brain. Would I still be me but in Sacktor’s body? Again, I
answered yes.
“I would agree with that,” Sacktor says. “We might get more emotional
about some things, some aspects of our character might change. But we’d say,
‘That's weird, I'm not myself.’ So now, neurosurgery has gotten thousands of
years advanced and we could simply switch the PKMzeta locations. We place
PKMzeta in your brain in the exact same places as they are in my brain and vice
versa, so now what? In fact, we could do this experiment today: Erase the
PKMzeta from your mind…” and I cease to be me.
“You're a zombie,” Sacktor says.
I ask, when I get back out in the world, with a blank slate, would I make
similar decisions as before, would my tendencies be the same?
 “I would guess that, yeah,” Sacktor replies, “your tendencies would be the
same, but maybe not a whole lot more than identical twins’ tendencies are the
same.”
Therefore, PKMzeta is necessary for consciousness, for the details needed
for me to be me. “But it’s not sufficient for consciousness. You also need ongoing
experiences for that.”
Sacktor was reluctant to have that exercise printed because it extends the
discussion beyond what science knows about the brain.
Neuroscience is a humbling subject, memory especially. For instance,
Sacktor discovered a few years ago that his childhood memory about reading
Eccles book in his grandmother’s apartment could not possibly be accurate.
Sacktor found his copy of Eccles’ book at his childhood home in Baltimore.
Understanding the Brain was published in 1973, at least three years after his
grandmother left the Bronx to be closer to his mother. How could Sacktor’s
memory be that vivid, that important, and still be wrong? How well can we trust
our memories? “No one knows,” he says. “Memories are not perfect, obviously,
but it is the best we’ve got.”
+
His father Bertram and mother June both grew up in the Bronx, but they
moved to Baltimore where Bertram, a biochemist, worked at the Edgewood
Arsenal. He eventually moved to the National Institute of Aging, where he was
chief of the biological chemistry lab. Sacktor was born in Baltimore, the second
child. His first memory is of his older sister April when he was less than three
years old. They were in the downstairs den at their home.
“And I asked her, could you read me this book?” he remembers. “And she
said, ‘No, go ask mother.’ So I feel bad I can’t read, I feel bad that she yelled at
me and I remember walking glumly up the stairs to find my mom.”
It is his only memory of her. Before Sacktor turned three, April died of
leukemia. The death was devastating, Sacktor says – Bertram stayed away from
home more often and June fell into a depression that almost led her to suicide.
“She couldn’t live with the loss,” Sacktor says, “but what kept her going was
me.”
The birth of Ned, about three years later, made life better for the family, but
it was never an easy childhood for Todd.
“I hated school,” Sacktor says of his time at Gillman, an all-boys school in
Baltimore that prepared students for prestigious colleges. “I was a fat, smart and
shy kid. No redeeming social value for a boy.” There were problems at home too.
Sacktor was close to his mother, who died in 2008 from Parkinson’s disease, but
he says his relationship with his father was contentious.
“Contentious seems like too strong of a word,” says Ned, a professor of
neurology at Johns Hopkins University who admits his relationship with Bertram
was easier. “I think they had their arguments, but like all fathers and sons do.”
Sacktor disagrees. “It was more than that,” he says. “It was very serious.”
The disagreements began with typical topics – cleaning the room, talking back –
but they ended, Sacktor says, in screaming matches and two fistfights. Digging
into the specifics of those fights yields little. “I can’t remember a specific time,”
Sacktor says, uncharacteristically tightening his jaw. “It happened a lot.”
Sitting in his home one afternoon, I wonder out loud if Bertram’s demands
on Todd made it possible for him to withstand the rigors of science, especially
breakthrough science. He shakes his head. Did that tension propel him to go
beyond his father in science?
“Probably,” Sacktor says, as if divested from the subject.
+
Sacktor studied biology at Harvard, taking courses to prepare himself for
medical school. He wanted to pursue the neurology of memory because,
“psychiatry wasn’t hard enough.” It took him time to find his place, says Harvard
roommate Steve Greenberg, now director of clinical research at the
pharmaceutical company Merck.
“We didn’t fit in the pre-med mold,” says Greenberg. “We had a lot of
interests outside of medicine and biology, both of us were very curious and
wanted to explore and discuss a number of fields. In fact, the house we finally
lived in had a reputation for people who were artsy, not scientists.”
Sacktor calls himself a mediocre student at Harvard, something Greenberg
says is “a little self-effacing.” Sacktor’s GPA was 3.3, “and that’s mediocre,” he
says, “but remember, I’m lazy and I was lazy at Harvard.” After graduation he was
accepted at Albert Einstein Medical School, in the Bronx, which didn’t thrill him.
“It started a series of events where I thought the worst thing in the world
was happening to me and it turned out to be the best,” Sacktor says. After
earning his MD, he interned at Montefiore Medical Center, followed by a residency
at the Neurological Institute at Columbia University Medical Center, “my sixth
choice for a residency. When I complained to my advisor at Einstein about not
getting into my first five choices, she said, ‘You are such an idiot.’” Some of the
best research on memory in the country happened at Columbia. Molecular
biologist Jimmy Schwartz was there studying memory of the Aplysia, a sea snail
with a conveniently simple and large neural network, his advisor told Sacktor,
“‘and he’s smarter than you.’ That piqued my interest, because I like being around
people smarter than me, that means you’re going to learn.”
Sacktor primarily did hospital rounds at the Neurological Institute the first
two years, but his third year was spent in Schwartz’s lab, away from patients and
alone with molecules.
Schwartz believed memory maintenance could be boiled down to a simple
molecular mechanism, but it was no easy matter to find the important one. A
Harvard study pinpoints 117 molecules involved in the memory formation
process. Given the years it takes to thoroughly study one molecule, trying to find
the key enzyme was treacherous for a career – there might be one, maybe two
chances at finding it. So most neuroscientists left the research behind. But there
was one clue, another Schwartz idea – the molecule would have to be self-
sustaining some way, an organic Energizer bunny.
Fortunately for Sacktor, the relationship with his father Bertram greatly
improved after he left home for college. Not only was the reconciliation
emotionally gratifying, it proved to be professionally important.
“They didn’t have the tension of living together every day,” says Bette, a
practicing psychologist. “And they also had so many interests in common, they
could always talk about science.”
One day in 1985 they were discussing Sacktor’s work when Bertram
suggested to Todd that he look at a group of molecules called PKC, which
happened to include PKMzeta, though no one knew that at the time.
“He thought they looked interesting,” Sacktor says. “There was a lot of fog
around the field right then and everyone was looking for anything to clear the
fog.”
Sacktor set to work on investigating the enzymes, looking for clues that one
might be self-sustaining and populous during memory maintenance. Bertram
never got to see the results. On July 8, 1988, Sacktor received a phone call from a
doctor in Maine, near Acadia National Park. The doctor told him his father had a
heart attack while running.
“I remember asking him if he was okay,” Sacktor says. “And he said, ‘No, he
died.’”
Bertram was 66. At the time, Sacktor was seeing a psychiatrist, who asked
the usual introductory question the next week, “How was your week?” Sacktor
added to a short list that his father died. “He was shocked, because obviously my
father was a major piece of my therapy,” Sacktor says, trying to illustrate the
continued ambivalence of his relationship with his father.
 But Bette says, “I think Todd is very glad he and his dad had a good
relationship when Bert died.”
Sacktor left Columbia in 1990 with Bob Wong, a Columbia researcher who
accepted the chairmanship of the pharmacology department at Downstate.
“I felt like it might not be a good move,” Sacktor says, “but I liked Bob, and
again, it turns out it was the best thing that could have happened to me. My
father told me there were two important things for a young researcher – hard
money, meaning I didn’t have to raise funds for my salary, and a chairman who
likes you.”
Sacktor didn’t unlock the mystery of the PKC molecules until he got to
Downstate, where he had his own lab for the first time. He switched from studying
sea snails to the hippocampus of rats. He studied eight PKC strains – alpha
through theta – looking for any one that increased rapidly when the hippocampus
slice was shocked. That’s where PKMzeta made itself known.
“We ran four tests before we were sure,” says Sacktor, who kept seeing the
memory molecule proliferate after the hippocampus slice was shocked. “But once
I saw the same results all four times, I knew we had something.”
+
PKM stands for Protein Kinase M. Kinase is an enzyme that transfers
negatively charged phosphate groups from a high-powered donor molecule to
other molecules such as carbohydrates, amino acids and nucleotides – causing
the molecule to change its function. In PKM, protein is the target of the kinase,
which explains the first word of its name. “M” stands for magnesium ATP, the
molecular source of the energy. Most protein kinases have a natural modifier –
usually another molecule that tells it to work or stop. PKMzeta heeds no master,
Sacktor says, “they’re like a husband, they just do what they want to do.” That bit
of information matched Schwartz’s theory that the molecule would have to be
self-sufficient.
In his research, Sacktor developed a metaphor for the enzyme’s role near
the synapse, where long-term memories are stored, comparing it to a sheep dog.
The memory molecule likes to work in packs and as a group they do one thing
obsessively – they herd AMPA receptors, membrane proteins that are key to
receiving neural signals. After herding the receptors to the site of connection
between nerve cells, the memory molecules stand guard to keep AMPA receptors
in place. This herding and guarding sustains the memory through continual
chemical reaction. How the molecules stay at the right synapse to perpetuate a
particular memory is still a mystery, but it seems it has something to do with the
"dogs'" obsession with the AMPA receptors.
 The best way to prove Sacktor’s case was to erase the memory in a living
animal by stopping the PKMzeta from doing its work. That’s when he asked
Fenton, the behaviorist who thought Sacktor was being “silly,” to help. Yadin
Dudai and Reut Shema at Weizmann Institute in Rehovot, Israel also got involved.
Fenton taught rats to avoid a shock, Dudai taught rats to avoid food that they
associated with nausea and Sacktor taught rats to find a reward. Then the rats
were injected with a drug called ZIP, which temporarily blocks the memory
molecule’s obsession with AMPA receptors. After two hours with this drug in their
system, the rats completely forgot what they learned. What proved their brains
were not simply damaged was the fact that the rats could be retrained to
remember what they had forgotten. And they never forgot the rules of the game –
they knew to stay away from shocks and nauseating food associations or to go
find the reward. They just forgot what exactly they should avoid and what to seek.
“What we've learned is that PKMzeta stores the kinds of information that
allow animals to have precise memories of their experiences,” Fenton says,
“precise association, the specifics of the information, not the general concepts.”
Fenton is now a believer. “I thought it was silly, but I was wrong.”
“There is more coming,” Dudai says, referring primarily to the study
published in Science that showed adding more PKMzeta in the mammalian brain
strengthens memories. “More evidence that the theory is right and more
implications about what it might mean.”
For Sacktor, one goal of tracking the memory molecules is to figure out how
the packs are able to retain memories over long periods of time – one individual
molecule lives about two weeks. Another long-term result of Sacktor’s current
research may be the ability to find specific memories in the brain.
“We’re not sure how a memory works across the neural network,” cautions
the UC Irvine neuroscientist McGaugh. “It appears that different aspects of a
memory are stored in different parts of the brain.” So the emotional aspects of
memory might be stored in one place, while the spatial information of the place it
happened is placed in another. By some unknown mechanism, the different areas
are brought together in recollection. Sacktor doesn’t expect to answer how that
happens in his lifetime.
“That’s for the next generation of scientists to look at,” Sacktor says, “but
they won’t have to work to find the mechanism for memory storage. They already
know it’s PKMzeta.”
+
Science is more than a profession – it is a subculture. An uneasy balance of
competition and collaboration is the natural state. Scientists are already
professional skeptics and getting their grants funded and their work recognized
drives them to not only pursue their own hypotheses, but also cast harsh light
onto competing theories. Sacktor’s desert experience is not that special, says his
Harvard roommate Greenberg, “it’s the rule rather than the exception.”
“The reality is there are two ways for a theory to get traction,” says Jerry
Yin, a neuroscientist at the University of Wisconsin – Madison. “Either your
experiments and data are so compelling that people can’t ignore them or you
speak very loudly. Todd’s success comes from the first one.”
During the 1990s, John Lisman held the spotlight Sacktor now enjoys.
Lisman still is not convinced PKMzeta is necessary for memory storage. The
molecule Lisman discovered, CAM Kinase II is also self-sufficient. It is plentiful too,
accounting for between 2 and 4 percent of the brain’s molecular make-up.
PKMzeta makes up just .02 percent of the brain’s chemistry. CAM Kinase II has
also been proven to be essential during the initial processing of memory, called
induction. All this made Lisman’s theory appear more compelling than Sacktor’s.
But Lisman admits there have been no physiological tests – analogous to
Sacktor’s rat experiments – that show CAM Kinase II is essential to long-term
memory in live animals.
Yin, who studies memory in fruit flies, first heard Sacktor at a conference in
1998. Impressed with the findings, Yin decided to try the first behavioral tests of
PKMzeta on fruit flies. After several modifications, Yin showed that not only do
fruit flies forget what they learned without PKMzeta, they also remember longer
with higher amounts of the enzyme in their system. Yin’s results began to turn the
tide toward Sacktor. The subsequent rat experiments created a tidal wave for the
Downstate team.
Talking to Lisman today gives a sense of what Sacktor must have felt like 10
years ago. Lisman says he is having trouble getting grants for his research now,
because so much of the scientific community has grown enamored with Sacktor’s
answer.
“I wish it was more of a debate, we’ve never debated,” says Lisman. “What I
like about Todd’s work is he has been really involved in convincing people that his
theory is right.”
“I would love a debate, anytime,” Sacktor says, a gamesome smile on his
face. “Because I have the data.”
Yin says that Sacktor’s data is increasingly indisputable, although he does
not agree with all of the conclusions.
“I think it is very hard to dispute that PKMzeta is necessary for maintaining
long-term memories,” says Yin. “I don’t think it’s going to prove sufficient. I think
other molecules will also prove important and even vital.”
 Sacktor agrees, “it’s possible” that Yin’s critique is accurate, but sufficient is
an ambiguous word in biology. What they know now is that all other molecules
appear to be supportive parts in a system. PKMzeta is the leader that drives the
system and no other molecule known today is needed or sufficient for that. He
noted Yin’s own research, where adding only PKMzeta improved memory, as a
good argument for sufficiency.
Sacktor’s department chairman Bob Wong is well aware of Sacktor’s
competitive streak. They play squash nearly every working day and Sacktor wins
the majority of matches. Wong watched his colleague struggle through years of
being ignored and Sacktor admits he grew depressed over the indifference from
colleagues. But Wong says Sacktor did the only thing he could – keep doing
experiments and persevere.
“There’s an old saying in science about breakthrough discoveries,” Wong
says. “First they ignore it, then they get mad about it. Then they act like they
knew it all along. Right now, we’re between phase two and three.”
Will Sacktor’s perseverance prove valuable for humanity? Not everyone
thinks so. Elie Wiesel, the Nobel laureate and survivor of the Nazi death camp in
Auschwitz, wrote an editorial in the New York Daily News questioning the ethical
ramifications of Sacktor’s research.
“I am somewhat hesitant,” Wiesel wrote, “to trust the proposed therapeutic
means to use forgetting as a tool for healing. Once forgetting has begun, where
and when should it stop?”
Sacktor, also Jewish, replied to the Daily News, which never published his
letter. Sacktor regrets that decision, he says, because he’s afraid people will
misunderstand the point of all those hippocampus slices, all those amnesiac rats
relearning lessons they once knew. It is in the letter that Sacktor reveals
something deeper than a love for an enzyme, or even for winning the game. The
point was not to erase memories, he wrote, but instead “the search for knowledge
and the faith that that knowledge will bring benefit to mankind.”