In Gray Matter's Gray Zone: Mutations Show Brain's Growth

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In Gray Matter's Gray Zone: Mutations Show Brain's Growth

By SANDRA BLAKESLEE

Published: April 20, 2004

not long after scientists invented machines that could peer inside people's

heads, they began finding huge surprises.

The brain's gray matter, or cortex, is normally a crumpled-up sheet of

highly uniform cells, arranged in six layers. All human brains, it was

thought, followed this design.

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Yet in the last decade, detailed pictures of human cortices have revealed

anatomies reminiscent of a painting by Dalí. Some people walk around with

gray matter full of nodules or with cortical layers that are upside down.

Others have a double cortex, with two sheets of gray matter instead of one.

Still others have cortices that are shrunken or smooth or that poke holes in

the brain's casing, flowing like lava, outside the brain cavity.

Children born with malformed brains often suffer from mental retardation or

epileptic seizures. But a surprising number have normal intelligence and

grow up to lead successful lives.

In either case, scientists say, congenital malformations provide important

clues to how the human brain evolved. The mutated genes that cause misshapen

brains are likely to be the same ones that in their healthy form led to the

greatly enlarged, highly intelligent human cortex.

To track down these mutated genes, scientists are studying children and

adults whose brains are malformed.

The human cortex is about the size of a formal dinner napkin. To fit in the

skull, it is scrunched and folded to form numerous bumps and crevices. It

also has enormous frontal lobes ‹ the seat of advanced motor function,

social abilities, language and problem solving.

Of the 30,000 human genes, a third are expressed in the brain, said Dr.

A. Walsh, a neuroscientist at Harvard and a leader in the search

for the genes.

He and other researchers have in the last few years cloned or mapped the

location of more than 50 genes involved in building a healthy human cortex.

Many of the genes for brain development are involved in patterning and

building the cortex, a process that starts in the first trimester of fetal

life when brain cells, or neurons, are born in a region lining the cerebral

cavity. Precursor cells in this " proliferative zone " give birth to neurons

that migrate up and out into the cortex, forming its layers. Other cell

types arrive from different areas to complete the picture.

In this migration, everything that can go wrong does go wrong, Dr. Walsh

said. For example, he said, in one class of malformation, " cells never get

out of the driveway, " failing to migrate to the cortex.

Instead, these cells form blobs or nodules of neurons that line ventricles.

People with the malformation often have dozens of these nodules, each less

than an inch in diameter.

The effect of the neuronal clumps varies, Dr. Walsh said. Some people with

the malformation have normal intelligence, some have dyslexia, and some

never learn to walk. It is not known if the nodules are involved in

thinking. At least two genes have been implicated in their formation.

In another type of abnormality, cells begin migrating to the cortex but only

make it halfway to their proper location. The result is a double cortex, two

separate cortical sheets of gray matter, one atop the other.

" It's as if cells can migrate for the easy part of the journey, but when the

going gets tough, they have no snow tires, " Dr. Walsh said.

Twenty-five percent of the people with this kind of malformation have a

thick but normal cortex and a thin cortex that is abnormal, Dr. Walsh said.

Many have normal intelligence. In another quarter of patients, the thickness

is reversed: they have a thin normal cortex and thick abnormal cortex, and

they tend to have dozens of seizures a day.

The other 50 percent with the malformation have a mixture of normal and

abnormal cells, making it difficult to see distinct cortical layers. The

problem occurs when a gene that helps establish the internal structure of

cells, called double cortin, is mutated, researchers have found.

In still other conditions, newborn cells make it all the way to the cortex

but they are too small.

At the University of Leeds in England, Dr. Geoffrey Woods studies families

with microcephaly genes, whose children are born with tiny heads and tiny

brains and suffer from mental retardation. The whole brain looks normal, he

said, but it is about the size of a gorilla or chimpanzee's brain.

Dr. Woods has found two genes that can lead to microcephaly. One, ASPM, is

active in the proliferative zone where neurons are born. In comparisons

between humans and other animal species, Dr. Woods has found that one region

or domain of the gene is repeated more often as brains grow larger. Thus, a

simple worm has two copies of the region; a fruit fly, 24; a mouse, 61; and

a human has 74 copies of the domain spread throughout the gene.

Yet the idea that the ASPM gene is responsible for the very large human

cortex has not held up on closer scrutiny, said Dr. Vladimir Larionov, a

neuroscientist at the National Cancer Institute in Bethesda, Md. Dr.

Larionov has found that monkeys, chimps and gorillas, with their smaller

brains, have the same number of repeated domains in their ASPM genes as

humans. It remains to be seen, he said, if the domains are equally active in

humans and apes.

In one of the most startling examples of brain deformity, neurons explode

out of the proliferative zone like lava, flowing to form a thick mass

instead of an orderly, folded up cortex. The result is that the cortex is

either smooth, like that of a mouse, or it forms six layers but they are

upside down, with layer one, normally the top layer nearest the brain's

outer surface, at the bottom. Children with this malformation are retarded

and have seizures.

In other cases, the neurons successfully migrate out to the cortex but then

do not stop. They punch holes in the cortical membrane and, again like lava,

congeal in a cobblestone pattern. In some people, almost all of the brain is

outside where the cortex normally resides, Dr. Walsh said, adding that at

least three genes appear to be involved.

It is not only the cortex that can develop abnormally. In some instances,

the left and right hemispheres of the brain do not fully separate. Fused or

partly fused hemispheres are the most commonly recognized birth defect found

with prenatal ultrasound, Dr. Walsh said.

If the two sides are mostly joined, the infants do not survive. If a small

area is fused, the children tend to have trouble moving each side of their

bodies independently. Many never learn to walk, he said, as if they were

" limb tied. "

In research reported last month in Science, Dr. Walsh found eight mutations

in a gene that helps create the very large human frontal cortex. Children

born with these mutations, he said, have an overproduction of the folds in

the brain's frontal region, which is smaller and thinner than normal, and

they are slow to walk, inarticulate and clumsy. But the finding suggests

that random mutations during human evolution could be what caused particular

brain regions, like the frontal lobes, to enlarge.

Brain malformations are rare, making it hard for researchers like Dr. Walsh,

who are trying to pinpoint the genes responsible for them, to find enough

cases to study.

Dr. Walsh's success is partly a result of his research strategy: he has

focused on populations and regions, like the Middle East, where the

deformities are more easily found because families are large, marriage among

close relatives is common and the people stay in the same villages or cities

for generations.

In Riyadh, Saudi Arabia, for example, 58 percent of women marry blood

relatives, Dr. Walsh said, so researchers need to find only 10 affected

families to have enough cases to study instead of the thousands of families

that would otherwise be required.