Received: by alpheratz.cpm.aca.mmu.ac.uk id RAA25546 (8.6.9/5.3[ref pg@gmsl.co.uk] for cpm.aca.mmu.ac.uk from fmb-majordomo@mmu.ac.uk); Sat, 22 Apr 2000 17:23:55 +0100 Subject: Fwd: With A Song In Their Heads Date: Sat, 22 Apr 2000 12:20:25 -0400 x-sender: wsmith1@camail2.harvard.edu x-mailer: Claris Emailer 2.0v3, Claritas Est Veritas From: "Wade T.Smith" <wade_smith@harvard.edu> To: "Memetics Discussion List" <memetics@mmu.ac.uk> Content-Type: text/plain; charset="iso-8859-1" Content-transfer-encoding: quoted-printable Message-ID: <20000422162024.AAA16191@camailp.harvard.edu@[204.96.32.123]> Sender: fmb-majordomo@mmu.ac.uk Precedence: bulk Reply-To: memetics@mmu.ac.uk
I remain fascinated with reports like this- and by looking into them and
seeing where their branches may also grow.
- Wade
__________________
With A Song In Their Heads -- Birth of new brain cells induced in birds
http://www.hno.harvard.edu/gazette/2000/04.20/birdbrain.html
By William J. Cromie Gazette Staff
Brain cells that make it possible for zebra finches to sing were forced
to die then brought back to life by researchers at Harvard and
Rockefeller universities. In a major biological first, quiescent stem
cells naturally present in the birdsı brains were induced to replace the
lost cells and restore the finchesı ability to sing their distinctive
song.
Upon the death of mature song cells, immature cells were induced to
"awake" from a dormant state. They moved to the right place in the brain,
and made connections needed to repair the damage.
"Our results represent the restoration of a brain circuit involved in a
complex learned behavior," says Jeffrey Macklis, associate professor of
neurology in the Division of Neuroscience at Harvard Medical School. "It
is a step toward doing the same thing in mammals."
Mammals include humans, and Macklis sees the future possibility of using
such approaches to treat damage done by spinal cord injuries, strokes,
and degenerative conditions such as Huntingtonıs and Alzheimerıs
diseases. Even keeping normal brain cells healthy, and thus slowing
aging, is not out of the question.
The old ideas that humans lose brain cells as they age, and that these
cells cannot be replaced are simply not true. Evidence from experiments
with adult monkeys and mice points to the existence of so-called
multipotent precursors, immature or uncommitted cells that can develop
into different types of brain cells with the proper stimulation.
"From direct evidence in the hippocampus of the human brain, it is
assumed that human adults also can, to some extent, grow replacement
brain cells," Macklis notes.
During early development, millions of precursor cells are active, but by
adulthood most have been used up. However, a small number survive and
continue to reproduce. Such potential replacements have been found in at
least two places in mammal brains, a part of the hippocampus that deals
with learning and memory, and in the olfactory bulb where nerve cells
connect the nose to the brain.
"My intuition tells me that conditions do exist under which we can create
other types of brain cells," Macklis says. "The key is learning to
understand the molecular controls that govern why certain cell types can
or cannot be replaced."
At the same time, Macklis and his colleagues at Childrenıs Hospital in
Boston work on the feasibility of transplanting immature cells into adult
brains to replace cells lost to disease or injury. They have done this
successfully in mice.
With a Song in Their Heads
Songbirds are an excellent place to do research on brain restoration;
some of them do it naturally every year. Canaries, for example, fall
silent each fall when cells in a high-level vocal center of their brains
die off. In winter, the cells undergo a wave of rebirth, and canaries are
ready to sing again in the spring.
Mammal brains donıt have that kind of flexibility, so Macklis and his
colleagues, Constance Scharff and Fernando Nottebohm at Rockefeller
University in New York City, turned to zebra finches. These songbirds
sing a complicated 10- to 12-note song somewhat like that of a canary,
but the rate of birth of its song cells is more like that of mammals.
The finches lay down song circuits soon after hatching and donıt undergo
the dramatic changes that typify canaries. However, their brains do
produce a small but constant trickle of new brain cells.
Macklisı research team had previously shown that the induced deaths of
brain cells in mice can lead to development of the proper type of
replacement cells when the brain receives a transplant of multipotent
precursors. The scientists asked themselves if the same thing could be
done naturally in zebra finches by killing off song cells. In other
words, would the population of quiet precursors awake naturally and
restore their song without the help of transplants?
The research team used laser light to injure a specific group of song
cells in the finchesı brains. This activity set into action a natural
process called apoptosis, whereby abnormal cells commit suicide. The
suicide, Macklis theorized, would set off a chain of events that would
lead to the replacement of dead cells to death fostering life.
It worked.
There was a direct correlation between the number of old brain cells that
died and the number of new brain cells born. At the end of four months,
zebra finches who had lost their "voices" began to sing again.
"This is the first specific induction of new brain cells that became
successfully integrated into a circuit that controls a complex behavior,"
Macklis notes. It follows, by two years, his groupıs first successful use
of transplanted precursors to replace degenerated brain cells in mice.
Overcoming Limitations
The next step was to try to induce the birth of other types of song cells
in zebra finch brains. However, the Harvard and Rockefeller experimenters
found limitations in what type of replacements they could make. When they
attempted to recruit a second cell type, which connects with a different
part of the song system, only the first type of cell was formed.
"We think that once precursor cells enter the song system, itıs easiest
for them to respond to signals that make them one kind of brain cell
rather than other kinds," Macklis says. "To get other kinds of
replacement cells, weıre going to have to learn what molecules in the
brain control new cell birth and development. Such knowledge should lead
to the tailoring of specific types of cells needed to repair damage in
specific brain circuits in mammals, such as spinal cord injuries."
Macklis believes this can be done by solving the mystery of why new cells
can flood a canaryıs brain but are limited to a trickle in zebra finches
and mammals. Once such limitations become clear, Macklis believes they
can be overcome "by a complex series of control factors able to take
immature precursor cells down specific pathways that lead to different
types of mature brain cells." Such cells hold the potential for reversing
paralyzing spinal cord injuries or loss of memory in Alzheimerıs disease
and aging.
Some light on how these goals might be accomplished comes from the
transplantation of stem cells into the brains of adult mice, and
successfully coaxing them into replacing dying cells. Many of the
transplanted cells now look and seem to function just like those they
replaced.
One key step to success involves transplanting precursors at just the
right stage of development. Experiments already done show the most
immature cells are not as effective as those that have already made some
decisions about what they will become. "We lose some flexibility with
this approach, but we gain increased efficiency in getting the different
kinds of cells we want," Macklis explains.
What is learned from this work bears directly on strategies for
manipulating precursors already present in the brain. "These cells are
tougher to guide down the right paths, but ultimately they offer great
power for therapeutic applications," Macklis says.
"I think our work with birds sets a strong precedent for the idea of
manipulating precursors in mammals," he continues. Of course, the mammal
of choice would be humans.
"Some of the cells we targeted in the finch experiments bear a direct
relation to those that degenerate in Huntingtonıs and other nervous
system diseases," Macklis notes. "If we could have a fantasy of where
this field could be in another two or three decades, it would include the
ability to manipulate precursor cells without the need to transplant
them."
Macklis sees the application of this approach to spinal cord injuries in
the next decade. Further away will be attempts to treat diseases such as
amyotrophic lateral sclerosis (Lou Gehrigıs disease), Huntingtonıs, and
Alzheimerıs diseases.
"We have much work to do with mice in order to understand the molecular
controls and the genes involved," Macklis points out. "But once thatıs
done, we may also be able to find ways to keep existing brain cells
healthier for longer."
Thatıs tantamount to delaying aging.
Copyright 2000 President and Fellows of Harvard College
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