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The End of Alzheimer's?

Source:2017-11-27 Bostonmagazine/Jamie Ducharme

MIT neuroscientist Li-Huei Tsai is hoping to vanquish the disease with simple LEDs. —By Jamie Ducharme

(Li-Huei Tsai is NCHU distinguished alumni, she obtained a Bachelor’s degree of Veterinary Medicine at NCHU in 1983.)

On an afternoon last year, in a lab nestled in the heart of MIT’s campus, Li-Huei Tsai finally saw the light.

For years, the 57-year-old neuroscientist had been hunting for something—anything—that could combat Alzheimer’s disease, a neurodegenerative condition that robs roughly 44 million victims worldwide of their memory, cognitive function, and dignity. She’d found early success with a technique that used light to alter brain activity, but there was a problem: The method required scientists to genetically modify specific neurons. If she was going to find a cure to help the masses, Tsai needed a simpler, less invasive solution.

So she and her colleagues went back to the drawing board, poring over medical journals and studies in search of a fix. They found the inspiration they needed in a decades-old issue of Nature. Back in 1989, Tsai learned, a team of German scientists had found a way to manipulate brain waves in cats using only visual stimulation. “The concept was so straightforward,” she says. “The approach is so noninvasive.” It didn’t take long for Tsai’s team to start wondering: If it worked in felines, why not mice—and, someday, people?

Within months, they began testing the effect of LED light on the Alzheimer’s brain, effectively fusing Tsai’s early findings and the German researchers’ nearly forgotten breakthrough. Slowly, it appeared that repeated exposure to pulsating lights could vanquish amyloid plaques and tau tangles, two protein deposits that lead to cognitive decline in Alzheimer’s patients. In 2015, Tsai finally achieved the result she was hoping for: concrete evidence that LEDs—rather than drugs, surgery, or even expensive equipment—might really work. “The very initial response was, ‘Oh my God, this cannot be true,’” she remembers. “I think I even jumped up and down, just by myself. I didn’t want other people to see it.”

When Tsai and her colleague, Ed Boyden, of MIT’s McGovern Institute for Brain Research, published the results of their LED work in Nature last December, the paper made a splash, even in the typically guarded medical research world. Then, nine months later, Tsai made headlines yet again, this time for a second potential Alzheimer’s therapy. Writing in Cell Reports, her team described a method of blocking HDAC2, an enzyme that leads to cognitive decay in Alzheimer’s patients. Developing a pharmaceutical with the same effect, Tsai says, could one day turn back the clock on Alzheimer’s-related memory loss. “The idea that you actually could have an approach for something that might help return some of the memory loss is really intriguing,” says James Wessler, president and CEO of the Alzheimer’s Association’s Massachusetts and New Hampshire chapter. That glimmer of hope would have been exciting on its own, but coming on the heels of her first revelation, Tsai’s discovery established her as a bona fide rock star in the neuroscience world.

Of course, the bittersweet reality of researching a disease with no known cure is that you’re in good company. With an estimated $1.4 billion poured into Alzheimer’s research this year alone, scientists in Boston and beyond are working furiously to unlock the secrets hidden in the brains of millions worldwide. Auspicious work in the field abounds, and a number of clinical and pharmaceutical trials are under way, but nothing has delivered on its early promises—at least not yet. As it stands, Tsai is arguably the person to beat in one of the most hotly contested races in science: to be the first to prevent, or even reverse, Alzheimer's disease.

One of Tsai's earliest memories is of the first time her grandmother forgot. Tsai was three, maybe three and a half. They had gone to the market for vegetables, as they did every day. But as the pair strolled back toward the tiny government-owned apartment they shared in Taiwan, the sky darkened and opened up. Lacking an umbrella, Tsai and her grandmother ducked under a bus stop to wait out the downpour. “The rain stopped, and she just kind of stood there,” Tsai remembers. “And I said, ‘Grandma, let’s go home.’ And she turned to me, and I felt I was looking at a stranger because her expression was so foreign to me. And she said, ‘Home?….Where is home?’”

Tsai is subdued as she tells this story, staring out of her office’s enormous window overlooking Vassar Street. “Today,” she says quietly, “I still can see it.” On some level, that was the moment her Alzheimer’s work began—but it would take her decades to realize it.

Though Tsai was fascinated with the natural world from an early age, Taiwan during the 1960s and 1970s was hardly a discovery hub; becoming a scientific researcher didn’t even register as a career option. While most of Tsai’s science-minded classmates flocked to traditional medical school, she didn’t see herself treating people. Veterinary science seemed a better fit, so she gave it a try. But as graduation neared and her classmates began to declare specialties—“farm animals or dogs and cats or what have you,” she says—Tsai began to realize she did not, in fact, want to become a practicing vet. When several of her schoolmates set out to the United States for graduate school, she decided to do the same.

Tsai arrived at the University of Wisconsin in 1984 and enrolled in a veterinary science program. The culture shock was instant: The language, the people, and even the climate were different, but so was the science. “For the first time in my life,” Tsai remembers, “I was exposed to laboratory research.”

Tsai also took classes there with Howard Temin, the late Nobel Prize–winning cancer researcher. Under Temin’s influence, Tsai made a decision that would change her life: quitting veterinary medicine for pure medical research. After earning her PhD in Texas, Tsai found herself in Boston, working with a neurologist on a gene-cloning project at Mass General. It was there that she made her first big discovery: uncovering how the gene p35, combined with a specific enzyme, helps the nervous system develop properly. Finally, after more than a decade of dipping her toes into the scientific waters, Tsai felt something click. Neuroscience felt right. She joined the pathology faculty at Harvard Medical School in 1994. “It was amazing that people actually believed me, that I could become a neuroscientist,” Tsai says now. “That’s why I love this country. If you have a dream, if you have a passion, you tell people what you want to do, and you get an opportunity.”

These days, Tsai is pouring much of that passion into her LED light therapy. According to early research, these flickering lights work by kick-starting gamma oscillations: brain waves that are normally involved in memory, perception, and attention, but are woefully scarce in the brains of Alzheimer’s patients. Reestablishing gamma oscillations, her research suggests, may all but rewire their gray matter, perhaps breaking up amyloid plaques and tau tangles enough to restore the brain to a near-pre-disease state. To hear MIT’s top brass tell it, it’s a breakthrough that could change the future of medicine as we know it. “She’s one of those brilliant people who one day may get a Nobel Prize,” the school’s president, Rafael Reif, gushes.

Now that the initial buzz of discovery has worn off, though, Tsai is ready for the next step: expanding testing from rodent to human subjects. “Whether it will have an impact or not on people,” she says, “we’ll find out sooner rather than later.”

But in the race to cure Alzheimer’s, the competition is fierce—and she can hear the clock ticking.

For the past several years, Tsai has lived life on the go, balancing a 24/7 job with raising a daughter. She even told Asian Scientist in 2011 that she wasn’t a “tiger mother” because she didn’t “have the time and energy for that.” Yet for 30 to 60 minutes daily, Tsai makes the time to become a human trial of one.

She keeps a small black box, as nondescript as a piece of computer equipment, in her office at MIT. Each day, she places it on her table and sits before it as it emits light at precisely the frequency pinpointed in her research, hoping the experiment works—for the sake of both her science and her brain.

Soon, Tsai won’t be the only guinea pig. A Boston-based startup called Cognito Therapeutics, cofounded by Tsai and Boyden, is dedicated to translating their findings into a device approved for patients. The company’s general manager, Zach Malchano, says Cognito plans to begin enrollment for human trials by the end of 2017, with the hopes of advancing the research as soon as possible. “It’s an extremely compelling approach,” he says. “There’s more to the story than one might appreciate from an initial read-through of [their paper].”

The story won’t end happily, though, until Cognito has cold, hard results. And that’s a fact not lost on Tsai’s competitors, as scientists across the globe race to find an Alzheimer’s cure—and the recognition and riches that will undoubtedly come with it. The National Institutes of Health is currently running dozens of drug trials, exploring how everything from cutting-edge pharmaceuticals to coconut oil could treat the disease. Francisco Lopera, of Colombia’s University of Antioquia, is trying to better understand the illness by studying the genes of an extended family that has succumbed to early-onset Alzheimer’s for generations. And Ben Trumble, a researcher who studies the Tsimane people of Bolivia, is hoping to determine whether a parasitic infection may account for remarkably low rates of Alzheimer’s-related dementia in that population, another path that could someday lead to new treatments.

Then there’s Rudy Tanzi, the director of the Genetics and Aging Research Unit at Mass General and one of the most prolific Alzheimer’s researchers in the world. Among other projects, Tanzi has also been experimenting with LED light therapy, albeit through a different lens than Tsai. While Tsai’s work involves stimulating the visual cortex with lights flashing at a relatively high frequency, Tanzi’s uses lower-frequency light transmitted through LED goggles. His lab has also experimented with direct transcranial stimulation, which uses an electrical current instead of lights to arouse the brain. This technique, he says, could actually offer better results than LED therapy, which he posits might not spread far beyond the eyes. Light “hits the visual cortex, and it gets those nerve cells firing at that certain rate, and then you have to hope that the rest of the brain will follow suit,” Tanzi explains.

Still, he agrees that reducing amyloid plaques—the central tenet of Tsai’s LED work—is the best way forward, even as a growing number of scientists look for new Alzheimer’s strategies after decades of unsuccessful trials and therapies. “Because so many trials that have targeted amyloids have failed, many people are arguing that’s the wrong way to go,” Tanzi says. “I think that’s throwing out the baby with the bath water. All of the genetics have taught us that amyloid triggers this disease, and we need to hit those early on and know who’s got the highest amount of plaque and start treating them.”

While Tanzi says that any “shot on goal” against Alzheimer’s is great, he maintains that Tsai still needs to replicate both her LED light and HDAC2 results—and prove that they apply to humans, not just mice—before he’s convinced of anything. “If we wanted to cure Alzheimer’s in mice,” he says, “we’ve already done that several times.”

Tsai’s desk at MIT sits beneath a shelf heavy with empty Veuve Clicquot champagne bottles, neatly arranged in two long rows that commemorate each incremental breakthrough in her research. Truth is, she’s run out of places to put them. “When I was young, I would think, ‘I will make even more important findings,’” she tells me, the army of orange-labeled cruets looming behind her. “But now I realize, ‘You know, I’m getting old. We should just live in the moment. We should just celebrate.’”

Still, Tsai is careful not to talk in hyperbole when it comes to her research; the most ebullient she gets is saying she’s “very excited” about her LED light project. She also demurs when talk turns to the future. “You want to be fast, but you also want to make sure to use the most rigorous, the highest-standard work,” she insists. But in the next breath, she admits that scientific responsibility is sometimes at odds with the part of her personality that lives for the eureka moment “when you are the only one in the world who knows how something works.” And her motivation to get there isn’t strictly professional.

Tsai is fortunate: Neither her father, 94, nor her mother, 85, has Alzheimer’s. Her dad has gotten a little foggy, she says, but her mom’s mind is still razor sharp. “I’m very lucky,” she says. “Knock on wood.” Even so, her grandmother’s diagnosis is clearly never far from her mind. That searing memory—her blank face at the bus stop—still haunts Tsai, motivating both her work and her lifestyle 50 years later. “Of course,” she says immediately when I ask if her family history ever informs her research. “Almost everybody will have the risk of Alzheimer’s disease. Of course, if you have a family history, that makes it even worse.”

She leaves it at that, and we move on to talking about upcoming projects (understanding the brain as a whole system), her daughter (she’s a student at Johns Hopkins), and her hobbies (gardening and hiking). But I can’t help but think back to an earlier moment in our conversation, the first time I got an inkling of a deeper motivation that will likely never make it into a Nobel Prize speech or any big-name scientific journals: anxiety. “If you have cancer, you tell people you have cancer. If you know you have early-stage Alzheimer’s disease, you don’t dare to tell people, because you feel that you are diminished,” Tsai told me. “This is really a problem. And this problem is not going to go away.”

It might, though, if Tsai keeps pushing forward—if that human trial of one becomes a human trial of many, and if she gets the replication results she and so many in the field are hoping for. If that day comes, it will represent perhaps the most promising major breakthrough in the fight against Alzheimer’s disease the scientific community has ever seen. And no matter how hard Tsai tries, it’s difficult to downplay the magnitude of that possibility. In other words, she just might need to make room for a few more champagne bottles on her shelf.
Photograph by Jeff Brown

Photograph by Jeff Brown