January 4, 2000 New York Times
By SANDRA BLAKESLEE
As scientists look back at all the discoveries made in the 1990's, the so-called Decade of the Brain, one finding stands out as the most startling and, for many scientists, the most difficult to accept: people are not necessarily born with all the brain cells they will ever have.
In fact, from birth through late adolescence, the brain appears to add billions of new cells, literally constructing its circuits out of freshly made neurons as children and teenagers interact with their environments. In adulthood, the process of adding new cells slows down but does not stop. Mature circuits appear to be maintained by new cell growth well into old age.
Although the Congressionally mandated "Decade" produced many other discoveries, from ways to obtain images of fleeting thoughts inside a person's head to new drugs for a wide variety of mental disorders, the finding that the brain develops and maintains itself by adding new cells is the most revolutionary.
If these findings hold up to further scrutiny, the next decade of brain research promises to generate a total revision of how scientists think human minds are organized and constructed.
Findings have already shed new light on mechanisms of learning, memory
and aging in normal brains and suggest daring new ways to treat strokes
and other brain disorders. Moreover, they may provide solutions to some
abiding mysteries -- including the way young children who have half their
brains surgically removed to treat severe epilepsy go on to develop normally,
they had whole brains in half the usual amount of space.
Some researchers have begun isolating special cells that continue to divide and produce new brain tissue, with the hope of implanting such cells into areas of the brain that are damaged by disease or accidents.
For decades, it was axiomatic that people were born with all the brain cells they would ever have. Unlike the bones, the skin, the blood vessels and other body parts, where cells divide throughout life to give rise to new cells, it was believed that the brain did not renew itself.
Though the brain did add vast amounts of new connections early in life and could compensate somewhat for many injuries, it was thought that no one could be expected to grow more brain cells with age. Quite the opposite. People were told that the only thing they could look forward to was gradual mental deterioration as cells died off and were never replenished.
These ideas were so firmly established that many scientists have a hard time believing the findings, reported in the last couple of years by a number of investigators, that the human brain makes new cells after birth, said Dr. Fred H. Gage, a neuroscientist at the Salk Institute in La Jolla, Calif. Even when they accept the idea that such cells may exist, they argue there is no proof that they do anything important, he said. And those skeptical of the new developments, like Dr. Pasko Rakic, a neuroscientist at Yale, say that if scientists expect others to change longstanding thinking about brain development, the standard of proof must be set very high.
Dr. Per Andersen, a neurobiologist at the University of Oslo in Norway, said neuroscientists had responded to several of the new findings with "resounding silence." This is probably not because of "active neglect," he said, but "it takes some time to let unexpected results sink down in the mutual consciousness of neurobiologists." In short, the new findings are simply too startling and revolutionary to digest all at once.
Dr. Morten Raastad, also from Oslo, compared resistance to the idea of brains' growing new cells to the way scientists once resisted the idea of plate tectonics and continental drift.
The theory was first proposed in 1915, but it was not until scientists completed sea-floor magnetism studies in the 1960's that it was accepted, he said.
The traditional view of human brain development is based on experiments done in the mid-1960's on macaque monkeys by Dr. Rakic.
He said then that based on available techniques for detecting dividing cells in brain tissue there was no evidence that new cells were being born in the monkey brain.
He and others inferred this must be true of all primates, including humans.
According this theory, brains grow as new connecting fibers, called synapses and dendrites, proliferate around a fixed number of brain cells after birth.
Cells not connected into circuits through these growing fibers would die off.
Thus brains develop by pruning and sculpturing, not by building networks with billions of new cells, Dr. Rakic and others theorized.
The fact that many people do not recover the ability to speak or walk after having strokes or other traumatic brain injury cemented the view that adult brains did not add new cells.
If they did, people thought, recovery would be more common.
The first crack in this belief occurred in 1965, when scientists reported that new nerve cells were generated in a region of the adult rat brain called the hippocampus. This is where memories for places and things are first formed.
A year later, they discovered that new cells were migrating to the olfactory bulb, where smells are decoded.
These researchers identified a zone within two hollow cavities of the rat brain, called ventricles, where new cells are born and then migrate to the brain's interior.
The zone contains so-called stem cells that give rise to many other cell types, including neurons and glial cells that nourish neurons.
The new cells seen in the rat brains appear at a higher rate after challenges like intense training, injury or an infection, Dr. Raastad said. Within a few years, researchers found the cells in adult mice, guinea pigs, rabbits and monkeys. In the mid-1980's, other researchers found irrefutable evidence that new cells were born in the brains of adult canaries learning new songs and chickadees that were remembering where they had stashed their winter seeds. But researchers still did not believe that new cells were created in human brains, Dr. Raastad said.
In 1997, Dr. Elizabeth Gould, an assistant professor of neuroscience at Princeton and colleagues showed that neurogenesis, or the birth of new cells, occurred in the hippocampuses of tree shrews and marmoset monkeys. But Dr. Rakic and others said this was not possible in humans.
In 1998, Dr. Gage demonstrated that the number of brain cells in the hippocampuses of mice raised in stimulating environments increased by 15 percent -- and that the cells were born in the ventricle zone.
"This made us go look for the same in humans," Dr. Gage said. Swedish colleagues were using a special substance that integrates into the DNA of dividing cells to track tumor cells in cancer patients, he said.
Last year, this substance was found in the hippocampuses of five cancer patients whose brains were dissected immediately after they died.
This was a "thrilling" discovery, Dr. Gage said. It means that the human brain makes new cells in an area already known to be involved in short-term memory.
Some sort of neurogenesis may be widespread in the brain and spinal cord for maintenance, he said. Like skin, the brain may be repairing itself all the time. But like a big gash to the skin, a large brain injury like a stroke can overwhelm the repair system.
As for the rest of the brain, including the cortex, where complex functions like language and long-term memories reside, Dr. Gould injected the same dye used in the human experiments into macaque monkey brains. By tracing the chemical, she found that neurons had been born in the ventricles and had migrated into the higher cortex, where they made new axons.
They appeared to connect up to local circuitry and perhaps extend into wider circuits, she said, adding that the same might be true for human brains.
But the most surprising finding about new cell growth in the human brain has been virtually ignored by most neuroscientists.
This part of the story began more than two decades ago when a young doctor in training, , William Rodman Shankle, salvaged a stack of cardboard boxes containing the largest database ever collected on the developing human cerebral cortex.
The data had been collected from 1939 to 1967 by Dr. Jesse L. Conel of Boston Children's Hospital, who examined the brains of infants and children up to age 6 who had died from accidents or diseases not affecting brain cells. Before his death, he made more than four million measurements, including the width, thickness and packing density of brain cells at birth and at 1, 3, 6, 15, 24, 48 and 72 months of age.
Dr. Conel published eight volumes of research. Several boxes of his raw data were about to be thrown out -- tissue samples and slides already having been discarded -- when Dr. Shankle, now a neurologist at the University of California at Irvine, noticed them stacked in a hallway at Boston University and rescued them.
Dr. Conel did not have computer tools to measure exact numbers of cells, Dr. Shankle said, but he did describe, at each age and within 35 brain areas, the appearance of vertical columns of neurons.
It is now known that higher brain functions stem from arrays of these columns.
Dr. Shankle and his colleagues re-examined Dr. Conel's data using modern mathematical and computer techniques to allow for cell shrinkage and to distinguish neurons from other kinds of brain cells.
They found an astonishingly dynamic pattern in all 35 areas.
In each square millimeter of tissue, Dr. Shankle said, the number of neurons rises by a third from birth to 3 months as new cells are added.
Then the number plummets back to birth level between 3 and 15 months.
After this point, the number increases rapidly, doubling by the age of 6 years. It probably continues increasing, although at a slower rate, up to age 18 or 21, Dr. Shankle said.
The brain enlarges by making new columns, not by making existing ones larger, Dr. Shankle said.
"I suspect that a single set of rules constructs all brains," he said. "Children progress through the same stage of development at same rates independent of their culture."
This rapid growth and construction of brain tissue may help explain why children whose left or right brain hemispheres are removed entirely seem to develop more or less normally, Dr. Shankle said. The rate of growth, or plasticity, is so large early on, they can learn to do most things with their remaining brain tissue.
Dr. Anderson said that Dr. Shankle's findings were "well described and adequately analyzed," and concluded, "I see no major flaws in his handling of the material."
But Dr. William T. Greenough, a University of Illinois neuroscientist, said he was not yet convinced that Dr. Shankle had proved that the growth was from new nerve cells and not from supporting cells called glia. "He may be right," he said, "but the work needs to be replicated."
Meanwhile, Dr. Steven A. Goldman of Cornell Medical Center in New York City is studying human brain tissue removed from epilepsy patients and has found progenitor cells in the ventricles.
About 10 percent of cells in this zone are progenitors that give rise to other cell types, he said. This is a trivial number compared with the brain's 100 billion cells, but it may be enough to carry out maintenance and repair of the higher cortex, he said.
The challenge is to make such cells useful, Dr. Goldman said. "We still
don't know where they go," he said, "but we do know they're dividing. Some
are becoming neurons." If ways could be found to induce their expansion
in the human brain, he said, new treatments for a wide variety of brain
disorders would be on the near horizon.