Carlos Lois, whose grandfather was a neurologist, learned early about the terrible effects of nervous system diseases and injuries.
“On weekends, patients would come to his house,” says Lois, who grew up in Spain. “When you’re five, and you see someone your age who can’t move anything but his head because of a spinal cord injury, it really has an impact on you.”
Such experiences would point Lois toward a career helping victims of injury and disease. Initially, he trained in medicine, but about a decade ago Lois concluded he could have more impact as a scientist. He also decided to target what has been a major barrier to progress against brain disease: the fact that, with limited exceptions, the brain cells we have in adolescence are all we’ll ever have.
That regeneration is impossible for most types of brain cells — as opposed, say, to liver cells — makes sense. If memory-bearing cells routinely died off and were replaced with new ones, the memories would perish with them. In the case of cells lost to disease or injury, though, such replacements could be invaluable.
“One of the key questions we’re pursuing is, Can we grow or harness new cells to replace those lost in Alzheimer’s, in Parkinson’s, or because of a stroke or an injury?” says Lois.
When Lois started graduate work at Rockefeller University, discoveries were beginning to offer real grounds for hope that the answer would be yes. Research in adult mice had shown that some brain cells can regenerate — notably those in a brain region devoted to smell and another involved in forming memories. And thanks to a group of Swedish patients with terminal cancer who volunteered to be study subjects, it soon became clear that adult humans, too, can grow new brain cells — but again, only in those two regions.
Yet most brain diseases attack other areas. Alzheimer’s affects the cerebral cortex, the most prominent of our brain structures. Parkinson’s, the movement-inhibiting disease that afflicts actor Michael J. Fox, among others, damages a brain center called the basal ganglia.
Lois has been probing two issues related to replacing brain cells destroyed by such conditions. One is how new brain cells function. The other is how some brain cells move within the organ.
His study subjects for probing how cells move are lab mice, and his goal with them is to manipulate a process known formally as cell migration. Lois was the first scientist to show that this phenomenon, familiar in embryos, can also occur in adult mammals. And while the journeys are measured in fractions of an inch, they’re critical to the cells’ becoming appropriately located and fully connected participants in the brain’s operations.
Right now, it’s assumed that in adult humans new cells migrate only to those two previously identified regions. But suppose you could cause either implanted or internally generated cells to move to an area ravaged by Alzheimer’s or Parkinson’s? “If we can understand more about how cells migrate,” notes Lois, “we could look at using new cells to replace those that have been destroyed.”
Today, as Lois continues to explore braincell migration, he’s also probing how new cells function in the brain — and his study subjects in this case are male songbirds.
The brains in these birds, he says, are champion brain-cell regenerators. “Canaries sing during the mating season,” he notes by way of example, “and each year, the same bird sings a different song.” The changes are subtle, like speaking a language with a new accent. But the brain alterations that seem to underlie those variations are massive. “You may be talking about a song center with 150,000 cells,” says Lois, “and 110,000 are replaced every year.”
While understanding more about this amazing transformation offers obvious potential for medical applications, Lois cautions that right now it’s largely unexplored terrain.
His first goal in probing the cells that form in the brains of adult songbirds is to create a technology for introducing new genes into bird DNA. As a postdoctoral fellow in the lab of David Baltimore — formerly a Nobel Prizewinning biologist at MIT and now Caltech’s president — Lois devised a heralded method for doing that in mammals. Now, he’s seeking to create the first genetic engineering technique specifically for birds.
The approach, says Lois, would let researchers “manipulate very precisely both the formation and function of the new cells.” His own goal would be to use the technique to explore the cells’ role in shaping the birds’ memorization capabilities. “That kind of work is crucial if we want to harness new cells to function effectively in different parts of the brain,” he says.
Any early medical benefits from this work are likely to flow from the genetic engineering advances, not the studies per se. Right now, Lois notes, it’s complicated and expensive to develop agents like pure insulin. If efforts like his succeed, “You can imagine a chicken that would produce thousands of dollars worth of pure insulin in the white of its eggs.”
Still, new inroads against brain disease aren’t necessarily a distant hope. Parkinson’s disease is a function of a single missing natural agent called dopamine, notes Lois. If scientists make headway on getting new dopamine-producing cells to implant fully in the right parts of the brain — migrating there, if necessary — medical progress may not be far off.
“I can imagine that happening within the next five years,” says the scientist. “That seems quite possible.”