Scientists are solving the ultimate medical supply problem: new brains
Associated Press
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.
Publication Date: May 01, 1999
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