John Lisman’s Quest

For 30 years, a one-of-a-kind neuroscientist fought to understand the hidden dynamics of memory. Even after his death, his work continues.

John Lisman ’66
Alyssa Carvara
John Lisman ’66

A year ago last February, Brandeis neuroscientist John Lisman ’66 and his family went on a vacation at a resort near San Diego. They swam in the saltwater pool and hiked in the surrounding hilltops. They toured the desert and visited a relative working at a nearby organic-farming commune.

While he was in California, Lisman received an email from officials at the National Institutes of Health (NIH) saying they’d approved a major grant for his lab. For three decades, Lisman had been researching a single brain molecule he was convinced played a major role in the formation of long-term memories. But his theory had fallen out of favor over the past decade, and the NIH kept denying his requests for funding. His lab operated on a shoestring budget, with no graduate students or postdoctoral fellows. When he needed a certain type of microscope, he had to build it himself using secondhand parts.

Recently, though, he’d achieved a breakthrough in his research that generated the strong­est proof yet that he’d been right all along. Receiving this NIH grant now showed that interest in his work had been reinvigorated.

Lisman wanted to celebrate. The hotel set up a grill, and Lisman, his two children, three grandchildren and wife Natasha ’68 enjoyed a steak dinner. “His efforts were finally being recognized,” Natasha says. “It was the pinnacle of his career.”

Soon after Lisman came back to Massachusetts, he checked into a hospital for routine back surgery. A preoperative test turned up fluid in his left lung. More tests revealed he had cancer. “The prognosis is I can live either for a short time or a very short time,” he wrote to a Brandeis colleague. “There is no treatment.”

He died several months later, in October 2017, at age 73.

While some researchers remain skeptical about Lisman’s work, many others think he achieved a major advance in our understanding of memory. As one colleague puts it, Lisman was “one of the few great theoreticians of the brain.”

A ‘big ideas’ guy

This April, Natasha Lisman was in the midst of a move, leaving the Watertown apartment where she and John had lived for more than 20 years for a new place closer to her children, who live in Brooklyn.

The Watertown living room and dining area, flooded with sunlight and overlooking the Charles River, bore few signs of the couple’s life together. Most of their possessions had been boxed up and shipped. A real estate agent had stripped the walls of decoration and installed nondescript, generic furniture meant to have the widest appeal to potential buyers.

Natasha — an elegant, passionate woman who worked for 35 years as a civil litigator in a boutique Boston law firm and continues to do extensive pro bono legal work — sat on a couch, drinking tea. “This whole process of having your home transformed is very difficult,” she said. Even after six months, her husband’s death didn’t seem fully real. “He was just so vital, and full of energy and zest for life. It’s hard to believe this has happened. I miss him so much.”

Her husband was a “big ideas” guy, Natasha says. “He could make these giant intellectual leaps.” Sometimes they took him far out there. Until the day he died, he believed a landscape the couple bought for $35 at an estate sale was an original by the French painter Maurice de Vlaminck (it was clearly a knockoff). He thought the CIA assassinated President John Kennedy.

But when it came to science, Lisman’s intuition was usually spot on. And when these hunches were correct, they resulted in major advances.

While he was getting his PhD at MIT, a mentor told him, “Don’t let a fact stand in the way of a good theory. Facts are a dime a dozen. Good theories are not.” Lisman believed this throughout his career, less interested in scoring incremental advances in knowledge than in finding big breakthroughs.

At some point early on, Lisman formulated what became known among his colleagues as Lisman’s Law. When a fellow scientist told him, “In order to believe it, you need to see it,” he replied, “In order to see it, you have to believe it.” Although definitely not what you learn in grade school about the scientific method, Lisman’s Law guided his research. You need a theory first so you know where to look for evidence, he believed.

Lisman the scientist was also fascinated by the arts. His father, a refugee from Nazi Germany, made his living taking family portraits, and Lisman would work with him during the busy Christmas seasons. In the 1980s, he began amassing his own body of work, taking black-and-white portraits of famous neuroscientists when he traveled to scientific conferences or visited colleagues’ labs, using the Graflex camera his father had brought with him from Europe. Lisman loved the theater, too, often corralling a group of people to go with him to a play, then inviting everyone back to his apartment for a literary salon with the director.

Natasha says her husband’s scientific theories arose from an aesthetic. “Something made sense to him,” she explains, “if it was the simplest and most beautiful.”

In the mid-1990s, Lisman temporarily shifted his focus from long-term to short-term memory. He proposed a grand theory based on what seemed to everyone else a chance numerical correspondence. Research had shown that the maximum number of things a human can remember at a time is about seven. Meanwhile, the numerical relationship between certain frequencies of brain waves is also about seven. Lisman thought this relationship played a key role in both enabling and limiting short-term memory storage.

Although his colleagues weren’t sure at the time, more and more research suggests he was right. His former graduate student, Ole Jensen, PhD’98, is currently setting up a Centre for Human Brain Health at the University of Birmingham, in England; much of its focus will be on the connection between brain oscillations and memory.

Lisman “taught me the importance of a certain recklessness,” Jensen says. “It’s important to have the courage to leave your comfort zone.”

Lisman (right) and Art Wingfield, now the Nancy Lurie Marks Professor Emeritus of Neuroscience, in 1994.
University Archives and Special Collections Department, Brandeis
Lisman (right) and Art Wingfield, now the Nancy Lurie Marks Professor Emeritus of Neuroscience, in 1994.

Zeroing in on CaMKII

During the 1980s, neuroscientists were intensely focused on the problem of long-term potentiation, the process whereby memories become permanent. Although a memory may feel abstract or nonphysical, it’s the product of biological processes in the brain. A sensory experience — seeing a dog or smelling a flower — triggers the firing of a set of neurons. The same neurons fire again the next time you see a dog or smell a flower.

But what causes a memory to persist? Why do certain recollections of an experience last a lifetime? As Lisman saw it, the answer to such questions was the holy grail of neuroscience.

In a 1985 paper in Proceedings of the National Academy of Sciences, 11 years after arriving at Brandeis as an assistant professor, Lisman proposed a possible answer: a single molecule, responsible for both strengthening and making permanent the connections between neurons in a memory.

Lisman thought the memory molecule would be an enzyme, a type of protein that activates biochemical reactions. It takes a cascade of these reactions to facilitate the passage of a signal from one neuron to another. The right enzyme could keep this process going. It would cause a long-lasting increase in the efficacy of the connections between brain cells so that eventually the connections stuck. Over time, what had started as a temporary hookup between neurons would become hard-wired in the brain, and the memory would remain.

However, enzymes in the brain don’t last very long. Once they perform their function, they degrade quickly, often within a day. If Lisman was right, there would have to be an enzyme that could last for decades. There didn’t seem to be any enzyme that could perform the function he described.

Three years later, Lisman went ahead and suggested a candidate anyway — calcium/calmodulin-dependent protein kinase, or CaMKII for short. But at this point he could only speculate how CaMKII could persist and remain activated, an explanation “completely out of his imagination,” says his longtime collaborator, research scientist Nikolai Otmakhov.

Otmakhov began working with Lisman in 1994, two years after coming to the U.S. from Russia. The two scientists spent more than 20 years trying to prove CaMKII is the memory molecule. They kept failing. Lisman published the negative results anyway. “He published results that undermined his own theory,” Natasha says. “That’s honest. It showed his integrity.”

Lisman handled the setbacks by finding weaknesses in the study’s design and proposing an alternative approach. “The problem was never his theory,” says Otmakhov. “He said there was something wrong with the experiment.”

In 2009, The New York Times reported on its front page that the memory molecule had been discovered. The work was done by scientists at SUNY Downstate Medical Center, in Brooklyn. The molecule, according to their work, was the enzyme PKMzeta.

Lisman found multiple problems with the SUNY team’s experiment. He couldn’t believe so much attention was being lavished on their findings when the results were far from conclusive. But the scientific community had moved on. As Lisman put it in an interview, the mystery of the memory molecule was considered “a solved problem.”

Down but unbowed

By now the Zalman Abraham Kekst Chair in Neuroscience at Brandeis, Lisman suddenly found it hard to get funding. The NIH, previously a reliable backer, turned down his grant proposals to do more research on CaMKII. He scraped together funds from private foundations and piggybacked onto other researchers’ grants, but by the early 2010s his lab was out of money.

Lisman jettisoned his graduate students and postdoctoral fellows, and brought in undergraduates to do PhD-level work. At several points, he told Otmakhov he had only enough cash on hand to pay him for a few more months. “I was really worried,” Otmakhov says. “If I’d lost my job, I would have had to sell my house. I couldn’t have afforded my mortgage.”

Every year when it came time to apply to the NIH, Otmakhov asked Lisman to reconsider his approach — to scale back his claims for CaMKII or acknowledge PKMzeta was also involved — so they’d have a better chance of success. The two men never clashed. It wasn’t Lisman’s style to lose his temper or raise his voice. He simply refused to budge. And Otmakhov never quit the lab, he says, because “I agreed with his arguments that his theory could be correct.”

Lisman’s belief in CaMKII was “partially faith-based,” says Leslie Griffith, the Nancy Lurie Marks Professor of Neuroscience, another longtime collaborator. She says she warns her graduate students not to get too attached to a theory. “It’s dangerous,” she says. “There are people who fall in love with their ideas and never change them.” Lisman knew this but was willing to chance it. He wanted to do big, bold, daring research. His charm and charisma convinced you he could pull it off.

For all his certainty and ambition, Lisman never became arrogant or fell prey to self-delusion, many colleagues say. He had an exacting, rigorous mind and held himself to the highest standards, which prevented him from making sloppy errors or cutting corners. He wouldn’t accept his own theory until he had complete proof.

At weekly meetings, his graduate students reported on the latest scientific papers on CaMKII. He invited arguments that showed he was wrong. Though not willing to abandon his theory, he frequently modified it and acknowledged errors in his thinking. “He wanted intense discussion,” says Griffith. “Win or lose, he wanted all the issues out. He didn’t want to just be told he was right.”

When Lisman lost his graduate students, he expected his undergraduates to challenge him vociferously as well. Ole Jensen, who worked in the lab in the late 1990s, says Lisman “didn’t care whether you were an undergraduate or a Nobel Prize winner. He wanted to hear your criticism.”

Lisman (left) with colleagues in 1995.
University Archives and Special Collections Department, Brandeis
Lisman (left) with colleagues in 1995.

Striking gold

Everything changed for Lisman in 2013. In papers published in the same issue of the journal Nature, two separate groups of researchers said they’d found significant problems with the evidence supporting PKMzeta as the long-sought-after memory molecule. Now the tide turned against the SUNY research. “Within a week of those papers coming out, pretty much all across the Western world, work stopped on PKMzeta,” Todd Sacktor, one of the SUNY scientists, later told a reporter from the online site STAT.

Around the same time, a group of researchers at the University of California, Berkeley, reported that CaMKII could, in theory, endure in the brain using the molecular mechanism Lisman had postulated back in 1988.

CaMKII is what’s known as a holoenzyme, meaning each molecule consists of 12 identical sub-units. Should one of these subunits degrade, the functioning of the entire molecule would be impaired. But this could be prevented if a new sub-unit took the degraded one’s place. The Berkeley group showed this was possible, enabling the long-term survival of CaMKII.

Lisman always said he would consider his theory proven only if he could show CaMKII functioned as a memory molecule in a living animal. In September 2017, with less than a month to live, he published a paper in Neuron showing he’d done just that.

He had devised an experiment in which a rat was placed on a rotating platform. Each time the animal passed a designated location, it got a small shock. Eventually, the animal learned to avoid the shock zone by running in the opposite direction.

Lisman and his team then temporarily turned off the CaMKII molecules inside the rodent’s brain. The rat ceased getting off the platform to avoid the shock; its memory of the shock zone’s location had been erased. It had to relearn how to avoid the shock — showing that the original recollection had truly been deleted. If CaMKII didn’t function properly, the animal could not hold on to memories.

Tom Rossetti ’17, one of the undergraduates Lisman brought on when he could no longer afford graduate students, was the lead author on the Neuron paper that explained the CaMKII findings, an almost unprecedented achievement by an undergrad. Lisman “taught me techniques you’re not supposed to learn until graduate school,” says Rossetti, who is earning his PhD at Weill Cornell Medicine, in New York. “I am the scientist I am now because of the work I did in that lab.”

Rossetti recalls Lisman’s reaction when he first learned of the results from the experiments with the rats: “He was ecstatic.”

A legacy still in the making

Soon after he discovered he was dying, Lisman gathered his family at his Watertown apartment. He was “not into grieving,” he told them, and wanted “to live out the rest of my life as beautifully as possible.” This meant spending time with his family in Woods Hole and taking a vacation with Natasha in Vermont.

It also meant doing as much research as his health permitted. “He worked like a machine” in his final months, says Otmakhov, probably the hardest he had in his entire career.

In 2017, he co-authored 10 papers, including one on the philosopher John Locke’s theory of consciousness and another, published several months after his death, that provided the strongest proof yet for his theory of brain-wave frequencies and short-term memory. He delivered presentations at several conferences around the world and organized a weeklong Woods Hole retreat at which top neuroscientists discussed their research. “Interesting work, interesting conversations, interesting conferences,” Natasha says. “He wanted to squeeze as much of them as possible into his remaining months.”

He worked doggedly to ensure his lab would continue without him. He arranged for Griffith, Otmakhov and several other collaborators to take over his NIH grants. They will be looking at CaMKII, hoping to provide more-detailed evidence on the molecule’s behavior and functioning. There are still some who doubt Lisman’s findings, including his competitors at SUNY. Griffith says it may turn out both CaMKII and PKMzeta play a role in long-term memory.

Lisman also had a theory for a new way to treat Alzheimer’s. Susan Birren, a professor of neurobiology at Brandeis, is now working with his lab on that research; animal trials are ongoing in Finland. Plus, he’d done research on schizophrenia. It, too, is being continued. Overall, Griffith says, Lisman’s lab has enough momentum and funding to continue for another four to five years.

In the very long term, Lisman’s work on the memory molecule may open up new ways of treating mental illness and neurodegenerative diseases. He showed he could delete a memory in a rat. One day, we may be able to erase memories that underlie trauma or drug addiction. Although it would raise serious ethical issues, such an intervention might allow us to change our pasts by wiping out our recollections of unhappy experiences.

Lisman gave his last scientific lecture from a hospital bed in the intensive care unit at New York’s Memorial Sloan Kettering Cancer Center. He spoke to colleagues gathered at Brandeis for the Volen National Center for Complex Systems’ annual retreat. He was in a hospital gown and, understandably, didn’t want to be seen, so the audience listened as he led them through a Power­Point presentation on CaMKII. “It’s a quest of over 30 years,” Lisman said about his findings. “I don’t think it’s very common these days to have such a long quest.” His voice was clear and strong. Several Brandeis professors in the auditorium thought it was the best talk he’d ever given.

“Once he’d finished, he felt he could let go,” says Natasha, who was at his bedside. His lungs soon filled with fluid. The doctor told the family there was nothing more that could be done.

“He would have loved to live,” says Natasha, “but he felt he’d basically achieved his major objectives in life. His work finally got recognition. He’d had a wonderful marriage, beautiful children and grandchildren, and lived in beautiful places. He had a good life.”

John Lisman’s family has established a neuroscience scholarship for undergraduates in his name. To donate, go to bit.ly/2NaBhGq.

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