by Bill Case

Daniel Alkon, M.D., is a scientist. He specializes in the long series of complex chemical and biological processes that take place when a thought passes through the human mind.

But when he talks—to a group of WVU students, to other scientists, to leaders of pharmaceutical companies, and government—he's a storyteller. He weaves science, philosophy, emotion, values, and memory into a story that includes a bit of his personal history, a discussion of a chemical process that is shared by a single-celled paramecium and the human brain, and the strategy the National Institutes of Health has followed to study memory over the past three decades.

Dr. Alkon—the scientific director of WVU's new Blanchette Rockefeller Neurosciences Institute—led an NIH research lab for most of his career. Science, he says, is a very human endeavor.

What It's All About
"Research is about people," he says. "Even in non-clinical areas, what we call physical descriptions are reflections of the workings of the human mind. In physics, scientists have to be on the watch for how the observer—and the act of observing—affects the phenomena being studied. That's true in biology, too."

Especially so, he says, when the phenomenon under study is human thought itself. "There's emotional involvement in research. Research is like hunting. You're after game, and the excitement builds when you choose a target and set up the hunt."

His hands start to move—sometimes in parallel, sometimes toward the audience or toward each other—as he describes the process of organizing a scientific foray into the world of the human brain.

"You never remember an isolated bit of information," he begins. "Memory is always an interconnected set of relationships in time and space—constellations of information. A face is a set of features. The sound of a name is a set of sounds in a particular sequence. And for each word or face you remember, there is a set of associated emotions attached."

The question he faces as a scientist is to ascertain how the brain stores information in a way that makes it possible, in a fraction of a second, to form all these associations and to store them in a way that is accessible later.

Ask a Snail
The brain doesn't give up its secrets easily. Alkon's research—and that of his NIH colleagues—started with snails.

"When you work with simple animals, you can study a system with fewer possible associations. You examine the physical, chemical, and structural changes that take place when the animal learns a Pavlovian response."

What they discovered with the snails was a chain-reaction series of chemical changes at the cellular level. (For the biologically inclined, one such change involves what are described as "positively charged, calcium-dependent potassium channels.") The same chemicals, and the same reactions, exist in human brain cells—and in the snails. Up and down the biological scale, from the denizens of the intertidal estuaries to the members of the National Academy of Sciences, the learning process appears to be associated with a very similar set of chemical pathways.

They called the process the "molecular cascades" of memory. And, over decades of work, they painstakingly described the parts of the process that they could observe.

"We come into life with a few programmed values—we'll recoil from a hot stove—and lots of degrees of freedom, lots of unprogrammed responses in our nervous system. As we learn, we transfer values to them," Alkon says.

"None of the most sophisticated computers are even close to the brain in complexity," he added. Each integrating cell in the brain—too small to see with the human eye—has 100,000 to 200,000 sites of contact, each of which can be associated with a particular chemical process. There are millions of such cells in each part of the brain.

Where Does This Lead Us?
Curiosity about the brain is one thing. But as lifespans have increased, more and more people have begun to fear that their bodies will outlive their brains. Alzheimer's disease is perhaps the most common, and least well understood, degenerative disease of the human mind.

"Alzheimer's disease, in its early course, is almost entirely focused on memory loss," Alkon says. Although most people think of Alzheimer's as a brain disease, Alkon and his colleagues for years have investigated the possibility that the disease is systemic. "There is a possibility that the changes that cause Alzheimer's are taking place throughout the body, at the cell level—but the clinical problems they cause, in the early stages, are only in the brain."

There is evidence to indicate that in the earliest stages of Alzheimer's, the potassium channels in the cells—the same channels that appear to be involved in memory in snails and in people—start to change. "Early in Alzheimer's, cells get a certain beta-amyloid that kills a specific potassium channel," Alkon says. "That means that we may have a diagnostic test for Alzheimer's—if we can detect a lower level of activity in the cascades of memory in the cells."

It won't be easy, he warns. "This is a system of incredible complexity. There are no simple cascades of memory—there are cascades within cascades. But the bottom line is, if we are successful, we can prevent memory loss, or enhance human memory, with chemicals."

Why WVU?
Alkon, as lead scientist at WVU's Blanchette Rockefeller Neurosciences Institute, is animated when he talks about the atmosphere for science at WVU.

"I have a sense of mission about research," he says. "And research into afflictions of the mind is a mission I identified with as a physician-in-training, in my 20s. I've never stopped."

At WVU, he says, he's found an element crucial to research success. "Research is about people. It's for people. And it's by people. And it needs advocates. WVU has very powerful advocates for research, at the very top of the institution. And having people in leadership positions who advocate and value research means that this institution is looking to the future."

The Rockefeller Institute, he says, will be a place where scientists can pursue any aspect of memory and thinking. "The Alzheimer's work will be just one element of a very diverse institute," he promises. "Each scientist, as an individual, can independently approach neuroscience. But each will also be a member of a team—doing basic neuroscience for its own sake, and research into the implications of this knowledge for people."

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