COVER STORY

Your Beautiful Brain

Dispatches from the frontiers of neuroscience.

by Bill Retherford '14JRN Published Winter 2016
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Breakthroughs could happen sooner, however. Some of the Alzheimer’s medications available now “probably work,” says Kandel, except for one obstacle: “By the time patients see a physician, they’ve had the disease for ten years. They’ve lost so many nerve cells, there’s nothing you can do for them.” Possibly, with earlier detection, “those same drugs might be effective.” That’s not a certainty, insists Kandel, only a “hunch.”

Years ago, Kandel had another hunch — that age-related memory loss was not just early-stage Alzheimer’s, as many neuroscientists believed, but an altogether separate disease. After all, not everyone gets Alzheimer’s, but “practically everyone,” says Kandel, loses some aspects of memory as they get older. And MRI images of patients with age-related memory loss, as demonstrated by CUMC neurology professor Scott Small ’92PS, have revealed defects in a brain region different from those of the early-stage Alzheimer’s patients.

Kandel also knew mice didn’t get Alzheimer’s. He wondered if they got age-related memory loss. If they did, that would be another sign the disorders were different. His lab soon demonstrated that mice, which typically have a two-year lifespan, do exhibit a significant decrease in memory at twelve months. With that revelation, Kandel and others deduced Alzheimer’s and age-related memory loss are distinct, unconnected diseases.

"I think we have at least fifty years before we can explain every aspect of human behavior."

Then Kandel’s lab (again, with assistance from Small) discovered that RbAp48 — a protein abundant in mice and men — was a central chemical cog in regulating memory loss. A deficit of RbAp48 apparently accelerates the decline. Knocking out RbAp48, even in a young mouse brain, produces age-related memory loss. But restoring RbAp48 to an old mouse brain reverses it.

Now what may be the eureka moment — this from Gerard Karsenty, chairman of CUMC’s department of genetics and development: bones release a hormone called osteocalcin. And Kandel later found that osteocalcin, upon release, increases the level of RbAp48.

“So give osteocalcin to an old mouse, and boom! Age-related memory loss goes away.”

The same may prove true in humans. A pill or injectable could work, says Kandel: “Osteocalcin in a form people can take is something very doable and not very far away.” In less than a decade, age-related memory loss might be treatable. “This,” he says, “is the hope.”


As the ambitions of neuroscientists accelerate,
the field has moved its goalposts to a faraway place. “We’re trying to understand behavior,” says Bruno. “Behavior is not straightforward. It’s an incredibly ill-defined problem.”

Behavior encompasses everything. Perception, emotion, memory, cognition, invention, obsession, infatuation, creativity, happiness, despair. To completely understand how the brain governs behavior, to neurologically plumb the wisps of human thought, one must unshroud innumerable obscurities at the subcellular level. “How do you define happiness or beauty? Somehow it’s based on connections in the brain,” says Jessell. Always, it gets back to the ever-pinging networks: “Without knowing the links between these eighty-six billion neurons that exist within the human brain, we don’t have a hope of understanding any aspect of human behavior.”

Decipher those links, and we will have figured out how we figure things out. How brain connections, for instance, ignite love connections. We could, conceivably, fathom ourselves practically down to the last neuron. Says Axel: “Do we understand perception, emotion, memory, cognition? No. But we’re developing technology which might allow us entry into these arenas for the first time. Perhaps we will get there. Perhaps.”

“We are tackling infinity,” says Bruno. “Behavior is this infinite space of ideas. Oh, probably not truly infinite. We’re finite beings. Only so many neurons are in our heads. But think about all you can do, and the vast realm of possibilities you can react to. Think about how large a set that is. I mean, you can’t count all of those things. The range of human possibility is staggering.”

Acknowledge this, and one could easily argue we’ve barely begun to know the brain. “We really are at the very beginning,” says Bruno. “How far along? I’d say 5 percent. We’re trying to tackle a collection of problems and questions that put us on the 5 percent end.”

Learn the rest — the remaining 95 percent — and we will quite literally understand ourselves. But this will take time. “We have a very fragile understanding of the principles by which these things work,” says Jessell. “I think we have at least fifty years before we can explain every aspect of human behavior.” Or possibly longer. Says Kandel: “On this — to have a satisfying understanding of the brain — I think we’re a century away.”

So little is known. Almost everything we learn is something new. What now? Tackling infinity, of course. “What could be more important,” says Axel, “than to understand the most elusive, the most complex, the most mysterious structure that we know of in our universe? That’s pretty damn important.” The answers, always within, now lie ahead.



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