May 1, 1999

Scientists Try To Grow Brain Parts

By DANIEL Q. HANEY AP Medical Editor

BOSTON (AP) - Scientists want to fix the things that go wrong inside
your head. Their plan: Grow replacement parts for broken brains.

They make it sound easy. Just brew a batch of gray matter. Drill a hole
in the skull. Put in the new stuff. Wire it up like the original.

Voila! New brains.

Despite its whiff of mad scientist run amok, this scenario is
surprisingly close to reality. Researchers can already do amazing things
with mouse brains. And as they so fondly and frequently point out, mice
really are an awful lot like us.

Some human experiments already hint at what's possible. Since the 1980s,
doctors have cautiously tested
transferring brain cells from aborted fetuses to victims of Parkinson's
disease. For some, it seems to work remarkably well, restoring lost
control of movement.

But to those on the cusp of this new technology, Parkinson's is almost
too easy. It involves the death of just one small bit of material, the
brain cells that make the message-carrying neurotransmitter dopamine.

No, they have their sights on much more complicated targets. In the
years to come, they see the possibility of rewiring broken spines,
patching up strokes, correcting multiple sclerosis, undoing inherited
metabolic disorders, maybe even rebuilding the wrecked brains of
Alzheimer's disease victims.

``I mean not just putting in cells to produce a neurotransmitter or make
a little local connection,'' explains Dr. Jeffrey Macklis of Children's
Hospital and Harvard Medical School in Boston. ``I mean really rewiring
complex circuitry in the brain. Ten years ago, this would have been
considered totally crazy. Five years ago, it would have been a little
bonkers.''

Macklis goes on to talk about his mice, the critters of choice for those
who study such things. When immature cells are transplanted under
precisely the right conditions, they migrate across the animals' tiny
damaged brains. They take root in just the spots where they are needed.
They morph into the exact brands of cells that are missing. They connect
up with other parts of the brain. In short, they seem to work.

``Mice brains are fundamentally not that different from humans','' says
Macklis. ``The idea of using immature cells and guiding their
differentiation to rebuild complex circuitry is no longer crazy.''

Until recently, human fetuses were the only source of brain material for
such jobs, but they were never ideal. Doctors' qualms go beyond the
ethical thickets of recycling aborted material. Fetuses will always be
in short supply; it takes several to treat just one patient. And quality
is hard to control, especially considering that many were aborted for a
reason, such as genetic abnormalities.

But now scientists seem certain that transplanting brain material - what
they call cell therapy - is about to become practical. The reason is the
discovery of entirely new reservoirs of brain material. At dozens of
universities and biotech firms, they are developing three main varieties
- animal brains, cancerous growths and the tissue wellspring called stem
cells.

One of these sources can be found at a gleaming biomedical lab off a
country road about 60 miles west of Boston. The first thing that makes
the place seem a little odd is the technicians' get-ups: green surgical
scrubs with knee-high black rubber boots. Then there's the smell.

Despite fans that turn over the air 19 times an hour and filter it
cleaner than an operating room's, the lab carries a certain barnyard
redolence, an unmistakable eau de pig. This lab is also a barn, home to
65 or so grunting, rooting animals. But the end product is brain parts,
not pork chops.

``This is literally the cleanest pig facility on the face of the
earth,'' says David Boucher, the veterinary technician who makes sure
the walls sparkle, the germs stay far away and the animals themselves
enjoy unpiglike spotlessness.

It may be the world's most expensive pig facility, too. The 275-pound
Yorkshire sows - ``the girls,'' Boucher affectionately calls them - cost
between $20,000 and $30,000 apiece to raise this way. However, the price
will fall dramatically if pig cells are approved for routine human
medical use, and production scales up.

When it's time for a still-experimental transplant, the technicians kill
three artificially inseminated pigs that have been pregnant exactly 27
days. Then they surgically remove their fetuses. (Killing the sows, they
say, is the only way to get the unborn pigs out antiseptically.) It
takes the brains of 26 pig fetuses to gather 48 million
dopamine-producing cells, enough for one person with Parkinson's. The
cells are shipped to a hospital, and less than 72 hours later, they are
inside someone's brain.

So far, these pig cells have been tested on 20 people with Parkinson's,
six with epilepsy and six with Huntington's disease. Of the first 11
Parkinson's patients treated, three improved significantly.

``I have no doubt this can work and produce tremendous benefit,'' says
Dr. Greg Stewart of Genzyme, which is developing the treatment with
Diacrin, another biotech firm.

While the supply of fetal pig cells is not a problem, there are other
drawbacks. Patients may need to take immune-suppressing drugs to keep
their bodies from rejecting the tissue, and there is a remote chance
that dangerous animal viruses might be passed along.

``I don't think it's an elegant way to solve the problem,'' says Dr.
Michael Levesque of Cedars-Sinai Medical Center in Los Angeles.

A bit more elegant, perhaps, is a method being tested at the University
of Pittsburgh. Doctors there are
experimentally transplanting human cells into the brains of stroke
victims.

The cells are similar to stem cells, the factories that manufacture
various kinds of tissue inside the body. But there's a catch: These
cells began as cancer, grown in test tubes from a 22-year-old's
testicular tumor.

The transplants are being tested on 12 stroke victims. All suffer
paralysis or other serious disability, even though the strokes destroyed
only a small bit of their brain tissue.

Three seem to have improved. One walks better, another is less stiff,
while a third has better control of arm and leg movements. Are the extra
cells responsible? Or is this the natural course of recovery?

Dr. Douglas Kondziolka, the surgeon in charge, does not know. Still, he
says, ``We were hoping for a glimmer of efficacy so we could continue
on. We've seen even a little more than a glimmer.''

Fixing a stroke, however, is far more challenging than relieving
Parkinson's. A stroke leaves a dead zone inside the brain. Missing are
many kinds of cells that were hooked up in complex patterns.

In their attempt at repair, surgeons add their cancer-derived cells to
the ring of damaged tissue that surrounds the dead area. Just why this
might do some good isn't completely clear. But the doctors speculate
that the new cells help the hurt ones by restoring connections,
releasing neurotransmitters and pumping in amino acids.

As best they can tell, the transplanted cells have been transformed from
cancerous gonadal cells to stable nerve cells through a series of
manipulations. But the idea of using cancer cells makes some doctors
uneasy. Others worry that the challenges of repairing strokes are just
too vast to even attempt yet.

``I do believe that we will be able to treat strokes and the more
complicated disorders. I just don't think we're ready to do that yet,''
cautions Dr. John Kessler of Albert Einstein College of Medicine in New
York City.

Many agree that the most elegant solution of all to the supply problem
is stem cells. These are the body's mother cells. They divide over and
over to form new tissue, such as blood cells and skin.

For generations, scientific dogma held that the adult brain cannot
repair itself, because it lacks stem cells. Wrong. Recently, scientists
found that adult brains do indeed harbor stem cells, although their
exact function is still a mystery. But when coaxed properly in a test
tube, they will divide over and over again, making brand-new neurons.

Suddenly, it seems, cancer cells and animal cells may be unnecessary.
The real thing, human brain cells, will be available. But what kind of
stem cell is the proper seed?

Since stem cells divide endlessly, a single sample started from a human
fetus could provide all that's needed. But the recipient's immune system
might attack these as foreign. Perhaps the patient's own body is a
better source of stem cells.

At Cedars-Sinai, scientists isolate stem cells from tissue saved during
brain operations on Parkinson's patients. In the lab, these stem cells
produce new brain cells. These in turn mature into dopamine makers, the
specific kind of brain cells that people with Parkinson's lack. Finally,
they are put back into the patients' brains.

Even if this works, however, the approach has an obvious shortcoming.
The only source of these brain stem cells is the patient's own brain,
not a particularly accessible reservoir.

However, brain stem cells may not be a necessary ingredient for
custom-making new brain tissue. Scientists believe it may be possible to
reprogram more readily available kinds of stem cells, such as the ones
that produce skin, so that they will churn out brain cells, instead.

But are transplants necessary at all? Maybe not. Repairs might actually
be engineered by remote control without ever putting anything into the
head.

Some scientists talk of stimulating the stem cells still inside the
brain so they divide and send off new nerve cells. Farfetched as this
sounds, they say it may be possible to direct the cells to travel to
distant parts of the brain and then take on the specialized duties of
cells that are missing or damaged.

Still, to cure a stroke or head injury, a reliable supply of brain cells
is just the start. Somehow they must be wired up so each communicates
with its neighbor in a sensible way.

``The biggest hurdle is not getting cells into the nervous system,''
says Kessler. ``It's not getting them to differentiate and to live. The
biggest hurdle is getting them to reconnect in the proper way. That is
an extraordinarily daunting process, when you think of the billions of
connections that have to be formed.''

Yet scientists such as Macklis and Dr. Evan Snyder, a Children's
Hospital colleague, think this is entirely possible. For one thing,
their experiments suggest that damaged parts of the brain send out help
signals that can recruit transplanted cells and show them what to do.

In mice, at least, immature neurons injected into the head will travel
across the brain to where cells are dying. There they assume the form of
the missing cells, stitching themselves seamlessly into the brain's
circuitry.

Cells injected into the brain's fluid-filled ventricles eventually
migrate all through the head. The researchers say such an approach might
eventually conquer diseases that involve many parts of the brain.

The whole idea of bringing in replacement cells from someplace else grew
out the belief that the brain cannot repair itself. But with the
discovery of brain stem cells, that dogma is crumbling.

``Cell therapy might be even more interesting, not less,'' says Snyder.
``Not only might it mean we put back cells that the brain does not grow
on its own, but maybe we will do it by augmenting a natural response.''

In short, these scientists envision a day when repairing a broken brain
will involve no transplants, no operations. Instead, it will mean
triggering the brain to awaken its supply of stem cells, to grow its own
spare parts, to literally fix itself.

Copyright © 1999 The Associated Press.
--
Judith Richards, London, Ontario, Canada
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