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EVER since his heart attack, George’s memory has been shot. Has he spoken to
the grandchildren lately? He can’t remember. Has someone just phoned? He can’t
recall. The heart attack cut off the supply of oxygen to his brain and certain
cells were damaged. Permanently, irreparably damaged.

Irreparably? So he was told. Now, however, a few hundred middle-aged rats
suggest that one day it may be otherwise. They also suffered heart attacks and
failed memories as a result, but when a team of scientists at the Institute of
Psychiatry in London injected them with genetically engineered brain cells from
very young mouse embryos, the rats got their memories back. The injected cells
migrated to the region of damage, took on the form the brain cells had before
they were injured, and started doing their work.

“Our cells prefer areas of damage. They avoid the undamaged parts,” says
Jeffrey Gray, a senior member of the research group. “Why that is so, I’m not
sure,” he told corporate and university scientists at a small private seminar in
Oxford in January, “but it does look promising.”

Brain patches

Promising indeed. If the mouse cells really can detect where a brain needs
mending and where it does not, this new technique may open the door to the
prospect not only of neuro-repair for humans but of routine neuro-maintenance as
well. Why wait until the Alzheimer’s is full-blown before injecting some
replacement cells? Why wait till memory is completely ravaged by old age before
seeking treatment? If what the team reports is true, engineered embryo cells
should be able to seek out and patch up any old brain damage—whether you
know you have it or not.

The idea of replacing old, damaged brain cells with spanking new ones is not
original. Indeed, the first adult-to-adult transplant in animals was attempted
back in 1890. But the operation didn’t become truly viable for humans until
1990, when a group led by Anders Björklund at Lund University in Sweden,
showed that they could alleviate the worst symptoms of Parkinson’s disease by
transplanting brain tissue from aborted human fetuses. Since then, hundreds of
patients with Parkinson’s have received fetal tissue transplants, sometimes with
impressive results.

That technique has a few limitations, though. Six or seven freshly aborted
fetuses are needed for each operation. The fetal cells must be taken at a very
specific time during development—just at the point when they are
differentiating into the type of cells they will replace. Too early, and they
won’t be the right kind of cells; too late, and you risk damaging the developing
axons as you transplant them.

This is all fine and well for Parkinson’s, since the cells needed for the
transplant begin to differentiate at around the sixth or seventh week, falling
within the normal range for human abortion. But the hippo-campal cells that
George needs to restore his memory do not start to specialise until the end of
the first trimester, at which point abortion is less common. What’s more, when
it comes to fetal tissue transplants, the cells must be taken from the very
region of the fetal brain that the surgeons aim to repair in the
patient—no easy task.

Like a handful of similar techniques being developed around the world, the
one being pioneered by Gray and his colleagues John Sinden and Helen Hodges has
the potential to get around these problems because it uses cells grown in a
flask rather than brain tissue from an aborted fetus. And what puts the
Institute of Psychiatry team at the head of the pack, is that they have shown
with behavioural tests in rats that those laboratory-grown cells actually
restore lost brain function.

The team started with a very special rodent, the “immortomouse”, developed by
a collaborating lab at the Ludwig Institute for Cancer Research in London.
Immortomice are genetically engineered so that every cell in their bodies
contains a gene that instructs cells to divide, and which is sensitive to
temperature and gamma-interferon, a protein that regulates tissue growth.

At body temperature, this gene is inert. But when immortomouse cells are
grown in a culture flask at 33 °C and gamma-interferon is added, the
gene is activated, and instructs the cells to keep dividing far longer than
normal, ignoring the signals that would usually tell them to die after a few
rounds of cell division.

Immortomouse cells grown in a flask stop dividing if you raise the
temperature back to 37 °C. Gray, Sinden and Hodges knew from their own
unpublished experiments that cells taken from the hippo-campus of very early
immortomouse embryos do something even more extraordinary as they lose their
ability to divide.

As long as they are given the necessary growth factors—proteins that
direct cell growth—they become specialised, producing everything from
nerve cells to glia, the brain’s supporting tissue. Unlike the pluripotent stem
cells, nerve cells in adult animals are incapable of dividing and spawning new
types of cells even in the presence of growth factors.

The researchers wanted to find out whether the stem cells’ ability to create
different types of tissue might help to repair the kind of brain damage and
memory loss that is suffered by about 10 per cent of people who have heart
attacks. They used a technique known as a “4-vessel occlusion” to trigger a
15-minute heart attack in normal lab rats. The animals survived, but their
memories were impaired and they performed exceptionally badly on standard tests,
such as remembering the location of a platform submerged in milky water.
Postmortem examinations of these heart attack rats showed that cells from the
CA1 region of the hippocampus were obliterated—the very cells that are
damaged by human heart attacks.

Two weeks after the heart attacks, Gray, Sinden and Hodges injected
immortomouse stem cells into the rats’ brains. When they were tested just six
weeks later, the rats did almost as well on the water test as healthy control
rats. Subsequent work on marmoset monkeys shows that even four months after
damage to the CA1 region, an injection of the engineered mouse stem cells undoes
the damage. A transplant from one species to another is possible because the
stem cells do not appear to trigger an immune response in a recipient. No one
knows for sure why, but it is probably due to the combined effect of the immune
system not being very active in the brain, and the stem cells lacking some of
the surface proteins that act as a red flag to immune cells.

Restoration work

More remarkable, however, and what holds great promise for medical science,
was what an examination of the animals’ brains revealed about how the injected
cells went about their restoration work. First, even in adult animals that had
long since lost the capacity to grow new brain cells, the injected stem cells
developed into very specialised CA1 cells. Secondly, the cells seemed to
know exactly where to go. The researchers had injected the cells close to the
site of damage, but not too close in case the injection itself caused even more
damage.

As it turned out, not aiming directly for the bull’s eye didn’t matter at all
because the cells compensated, migrating up to 3 millimetres in rats and 8
millimetres in marmosets in pursuit of damage—some of which, Gray hinted
at the Oxford seminar, was not the original target of the transplant. Says Gray:
“They’ve gone to the site of damage and taken up their home there.” In earlier
experiments, where the researchers had transplanted already specialised CA1
cells straight from fetuses into rats with damage to their CA1 region, the cells
simply set up shop where they landed, forming a distinct mass that sat on top of
the damaged area.

The cell’s migration to the area of damage was a “big surprise”, but not
inexplicable, according to Helen Pilcher, another member of the institute’s
team. “Stem cells are inherently migratory,” she says. After all, the tremendous
increase in brain size and complexity during development is largely a function
of stem cells dividing and migrating to new positions before they finally become
specialised for their permanent tasks.

All the available evidence suggests that the developing brain provides a
carefully choreographed sequence of chemical markers to show stem cells the way.
But how do cells know where to go in the already developed adult brain? “Part of
it may be the damaged brain sending out messages saying, `Come over here’,” says
Pilcher. For instance, damaged brain cells release various growth factors which
could act as a beacon.

Once the cells find their target, the local environment,
including—presumably—local growth factors, appears to be all it
takes to ensure they become the right sort of specialised brain cells. At least
one lab, Evan Snyder’s at the Harvard Medical School in Boston, had already
shown that brain stem cells from mice embryos will become specialised and
produce both neurons and glial cells when injected into brains of newborn
mice.

But in newborn mice, the brain is still developing. The Institute of
Psychiatry team showed that the stem cells behave the same way in the fully
developed brain of middle-aged or elderly animals. “Perhaps damage [itself] is
in some way a condition that resembles the developing brain,” says Sinden. “It
remains an interesting finding. It’s not something the literature suggested
would happen.”

The Institute of Psychiatry team also checked carefully, but found no signs
of cancer in the rats and marmosets. “We’ve never seen tumour formation in our
animals,” says Gray. Other tests indicated that the immortomouse gene had
switched off once the stem cells reached the animals’ brains. Those results are
important because the new technique does carry at least the theoretical risk
that the genetically-engineered cells would fail to stop proliferating despite
the higher temperature of a patient’s brain.

Giant leap

“From what I’ve seen, [their work] is extremely impressive—especially
the behavioural data,” says Samuel Weiss, a neurobiologist at the University of
Calgary, who is following the London team’s progress. But, he cautions, “the key
question is whether the same technology can be adapted to humans . . . It’s a
giant leap from mouse to man.”

But that race is now on. In July last year, backed by £250 000 from
Chris Evans, the Welsh biotech daredevil, Gray, Sinden and Hodges formed a
company, ReNeuron, to pursue the idea. This January, Evans’s investment company,
the Merlin Fund, handed over an additional £5 million. The team has filed
for a patent for their “pluri-potent neuro-epithelial cells”—and, more
importantly, the use of a human variant of such cells to treat brain damage
caused by all manner of ills that humans are prey to such as “traumatic brain
injury, stroke, perinatal ischaemia including cerebral palsy, Alzheimer’s
disease . . . and Creutzfeldt-Jakob disease . . .”

Now, the team is identifying a range of human brain cells in 7 to 12-week-old
embryos that will grow in culture flasks and have the ability to spawn
different cell types. Once they have done that, they plan to insert into
the stem cells a temperature-sensitive gene. (The additional sensitivity to
gamma-interferon that the immortomouse gene has is probably not necessary,
says Sinden.) Finally, they will test the engineered human stem cells on rats
and monkeys before trying them in humans.

If it proves impossible to grow, engineer, or do effective transplants with
human stem cells, the team is even considering a fallback plan. Given that the
mouse cells worked in the marmosets, they may work in humans too, says Sinden.
Whatever the source of the stem cells for human transplants, if Gray, Sinden and
Hodges can make the technique work, no more human fetuses will need to be used
for such grafts.

Meanwhile, a few other groups also have their eyes on the prize of human
stem-cell transplants. “We believe we have [identified] some human stem cells,”
says Snyder, who is interested in the potential of the cells for repairing
spinal cord injuries, and heritable brain disorders such as Tay-Sachs disease.
His team, and two others working on human brain stem cells, one led by Angelo
Vescovi at the University of Calgary in Alberta, the other by Ron McKay at the
National Institutes of Health near Washington DC, are expected to publish their
results in the next few months.

And almost everyone in the know agrees that trials using stem cells to repair
the human brain are likely to begin within five years. “We are on the verge of
seeing this happen,” says Weiss. The institute team says that its first target
will be acute damage, such as that caused by carbon monoxide poisoning or heart
attack, as well as degenerative diseases such as Huntington’s disease.

But if the cells really are being beckoned by areas of damage, couldn’t they
sort out the widespread brain injury caused by, say, stroke? Oxygen deprivation
at birth? Or even the mental decline that goes with normal ageing?

“At this stage,” says Gray, “there’s nothing we can exclude.” Sinden agrees,
but cautions that the most severe brain injuries and diseases will get priority
and approval first. Already, hundreds of people have asked them for help. “We
have a very, very full postbag,” he says.