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Disease Fight : Brain Graft Work Offers Fresh Hope

Times Science Writer

The 62-year-old retired clergyman was almost crippled by Parkinson’s disease in 1982 when he was wheeled into the operating theater of Stockholm’s Karolinska Institutet, where surgeons removed part of an adrenal gland from its site over one of his kidneys.

Then neurobiologists Lars Olson and Ake Seiger of the institute minced the walnut-sized organ into small clumps of cells that could pass through the needle of a hypodermic-like device.

Finally, neurosurgeon Erik-Olof Backlund of the University of Bergen, Norway, inserted the patient’s head into a metal frame that held it in a precise position, drilled a small hole in his skull, positioned the needle point at the correct location in the brain and injected the cells.

Before that operation, the patient could barely get around and his condition was rapidly deteriorating despite large quantities of drugs to control his disease.

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Condition Stabilized

But within days of the surgery, the patient regained some mobility in his arms and fingers and his body became less rigid. Even though those improvements disappeared two months later, the patient’s condition did stabilize and has not deteriorated further, Backlund recalled recently.

He and his colleagues have since performed three more such operations, with even more marked improvement in the patients’ conditions, although the responses still proved transient. The neurosurgeons nevertheless are optimistic about the procedure and are planning eight more operations in the near future, Backlund said.

The advent of human brain grafts marks what San Diego endocrinologist Floyd E. Bloom of Scripps Clinic calls “an extraordinarily exciting time in the study of the brain.” And such grafts raise the possibility of providing at least a partial cure for disorders such as Parkinson’s disease or Alzheimer’s disease, which are characterized by the death of brain cells.

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Careful Terminology

Scientists are generally careful to avoid the term “brain transplant,” lest it conjure up visions of Frankenstein and second-rate horror movies. And what Backlund and dozens of other scientists actually are doing is grafting relatively small numbers of brain or adrenal cells into the brain to replace cells that have died naturally or that have been killed by disease.

Those cells typically do not participate in thought processes of the brain. Instead, they secrete chemicals that are crucial to brain and body functions such as reproduction and water retention.

In the process of performing brain grafts, these scientists also are revolutionizing the study of the brain and the brain hormones that carry messages between cells. They are also, according to Scripps Clinic’s Bloom, “providing new answers to the eternal question: ‘Is it better to cure a disease with a surgical or a medical approach?’ ”

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Most scientists in the United States think that more work should be done with primates to establish the procedure’s efficacy before such operations are conducted on humans here, but many predict that brain grafts will be attempted within five years.

Attempts to transplant cells into the brain were made as long ago as 1890. “Establishment” scientists, however, insisted adamantly that the technique was at best unworkable and at worst immoral, and virtually all work was halted. Most physicians at that time considered the brain sacrosanct and “different” from other parts of the body.

Virtually no subsequent attempts were made to graft brain cells until the early 1970s, when Olson and neurobiologist Anders Bjorklund of the University of Lund, Sweden, braved the scorn of their colleagues and began grafting brain cells into rodents.

Their early successes at reversing some of the symptoms of Parkinson’s in rodents stimulated a broad surge of interest in the subject and it was the technique they developed that was used by Backlund.

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A typical approach to the problem of brain grafts was described at a recent Los Angeles symposium by neurobiologist Don Marshall Gash of the University of Rochester (N.Y.) School of Medicine. Gash has worked with the Brattleboro rat, a species that is born without brain cells that produce a hormone known as vasopressin, one of whose functions is to control water consumption and retention.

Deficiency’s Effect

As a result of this deficiency, Brattleboro rats consume more than their body weight in water each day and thus produce large amounts of urine.

Gash and his colleagues grafted vasopressin-producing cells from the brains of rat fetuses into the Brattleboro rats. In about 20% of the transplanted rats, Gash reported, water consumption dropped dramatically--although not to normal levels--and they produced much less urine.

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When Gash sacrificed the rats and examined the grafts, he found that the control of water consumption had occurred only when the fetal cells had been grafted at the site where vasopressin-producing cells occur in healthy rats, and thus where there are receptors for the hormone they produce. These studies showed that precise placement of the graft within the recipient’s brain is crucial to success.

Neurobiologists Earl A. Zimmerman of the Oregon Health Sciences University and Ann-Judith Silverman of Columbia University have performed similar work with rats whose brains do not produce a hormone called GnRH and whose reproductive organs therefore do not develop.

Produced Sperm

After Zimmerman’s group transplanted GnRH-producing fetal brain cells from healthy rodents into males, Zimmerman said, the rats’ testicles grew and they began producing sperm.

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Ten GnRH-deficient female rats received similar transplants, Silverman said, and their ovaries and uteruses grew to normal size. “All 10 mated, and six gave birth to healthy litters.”

A key point, Zimmerman noted, was that the scientists obtained “a total response in the females with only 20 to 25 cells.” A normal rat brain has more than 200 GnRH-producing cells.

The fact that so few transplanted cells can produce an effective response suggests that a small number of healthy cells also can make a major improvement in diseases such as Parkinson’s.

The majority of scientists studying brain grafts are working with animal models of human diseases that are more widespread, particularly Parkinson’s disease and Alzheimer’s disease. If the symptoms of these diseases can be cured by grafts in animals, then the prospects are good that the grafts may work similarly in humans.

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Affects 1 Million

Parkinson’s disease, which affects more than 1 million Americans, mostly over age 50, is characterized by difficulties in movement, body rigidity and tremors. As many as 30% of the victims also develop dementia--a severe loss of mental powers.

The disease is caused by the death of brain cells that produce the hormone dopamine. It can be controlled, at least in the early stages, by use of the drug L-dopa, which increases the brain’s dopamine supply. As the disease becomes more severe, however, patients receive less benefit from the drug.

Parkinson-like symptoms can be induced in rats by injecting dopamine-producing cells with the toxic chemical 6-hydroxydopamine. If the chemical is injected into cells on the left side of the brain, it will kill cells controlling the right side of the body and the rats will walk in clockwise circles. If it is injected into the right side of the brain, the rats circle in a counterclockwise direction.

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Neurobiologist William J. Freed and his colleagues at the National Institutes of Mental Health, working with Olson and Bjorklund, have shown that it is possible to correct this circling behavior by grafting dopamine-producing fetal brain cells into the brains of the damaged rats.

‘Blood-Brain Barrier’

Similar results were also obtained, according to Freed, when they transplanted cells from the rats’ own adrenal glands into the damaged brains. Although the glands normally produce dopamine, the chemical cannot reach the brain because of the “blood-brain barrier,” which prevents most chemicals in the blood from reaching the brain.

Alzheimer’s is a more complex disease whose cause is not yet known, but whose primary symptom is dementia. It affects as many as 2.5 million Americans, mostly over age 65.

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The disease is characterized by below-normal concentrations of several brain hormones, including dopamine, norepinephrine, and acetylcholine. Some of the symptoms of Alzheimer’s, such as failing memory and loss of agility, occur naturally during aging or can be produced artificially in animals, and there is evidence that these symptoms can be improved by transplants.

Neurobiologist John R. Sladek Jr. of the University of Rochester, working with Gash, has identified a group of rats that exhibit an age-related decline in norepinephrine production that is accompanied by certain behavioral changes. In particular, the rats have difficulty learning to avoid an electrical shock and they will not eat new foods.

Sladek said that grafting norepinephrine-releasing brain cells from fetuses into the old rats produced a “marked improvement” in their ability to learn to avoid shocks and also increased their acceptance of new foods. In contrast, grafting of brain cells that did not release norepinephrine produced no effect.

Recover Agility

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Bjorklund and Olson have similarly found that transplanted fetal cells can restore acrobatic activity in old rats. As tests of agility, the rats were required, for example, to walk along narrow rods.

Old rats, the Swedish group found, either cling tightly to the rod without attempting to walk or fall off frequently when they do try. When the rats were given transplants of embryonic cells that produce dopamine and acetylcholine, they regained the ability to walk along the rod. The old rats also exhibited the gait and posture of younger animals.

There is even some evidence that transplanted cells can actually become a part of the rodent brain’s neural circuitry, although scientists tend to view such experiments more skeptically.

Neurobiologist Donald Stein and his colleagues at Clark University in Worcester, Mass., and the University of Massachusetts Medical Center have shown that grafts of brain cells can improve the performance of rats on tests involving spatial learning--for instance, the ability to learn the pathway through a maze.

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Stein’s group removed part of the frontal cortex of the brain of 21 adult rats. Seven days later, they implanted frontal cortex tissue from fetal rats into eight of the damaged rats and cells from fetal cerebellums into six others.

Ability Improves

Stein then retested the rats’ maze-learning ability. As expected, rats whose brains had not been damaged performed much better on the tests than did those brain-damaged rats that did not receive a graft.

Surprisingly, the rats that received frontal cortex tissue also performed significantly better than those that did not receive a graft--suggesting that the added frontal cortex cells somehow managed to become at least partially integrated with the damaged brains so that they participated in thought processes. Rats that received cerebellar tissue, however, did not perform any better than those that received no graft.

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Promising results in the grafting of hormone-secreting brain cells have also been obtained in primates, which are much closer to humans and thus serve as a better model for human diseases.

The recent accidental discovery that the chemical MPTP--a trace contaminant in certain “designer drugs” synthesized as heroin substitutes--can produce a Parkinson-like condition in humans prompted scientists to administer the drug to primates. The animals then developed the same symptoms as people with Parkinson’s.

‘Continuous Improvement’

Sladek and his colleagues have transplanted fetal dopamine-releasing brain cells into three African monkeys that had been treated with MPTP. “During the 70 days between the transplant operations and sacrifice of the animals,” he said, “these monkeys showed continuous improvement in their brain and motor function.”

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Similar results with rhesus monkeys have been obtained by neurobiologist Roy A. E. Bakay of the Yerkes Regional Primate Research Center in Atlanta.

“The use of fetal tissue (in humans) does, however, raise some ethical issues,” and therefore the practice is unlikely to gain acceptance, according to neurosurgeon Charles A. Carton of the UCLA School of Medicine.

One way to work around the problem is the approach taken in Sweden--using the patient’s own adrenal glands. That solution is only partially satisfactory, however, because there are no equivalent tissues in the human body that produce many of the other brain hormones, such as norepinephrine and acetylcholine.

Gash has devised an alternate solution, the use of cells from a tumor of the human nervous system called a neuroblastoma. The tumor cells can be cultured in the laboratory to produce as many cells as desired, then treated with chemicals to stop their proliferation. After this treatment, the cells mature into neurons that produce acetylcholine.

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Used in Monkeys

Gash said he has transplanted the treated tumor cells into the brains of five adult African Green monkeys. A significant percentage of the grafted cells survived for 270 days--the longest period during which Gash monitored the cells--and produced acetylcholine.

These results, Gash said, suggest that the tumors “may serve as a practical source of donor tissue for neural implants.”

That use is still several years away, however. For now, the only practical approach is the use of adrenal glands. And even that approach has been criticized by some scientists as being premature.

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But Olson argued that patients selected for brain grafts are those who “cannot be helped by anything else. . . . Drugs no longer help. We believe it has become almost unethical not to do something to try to help.”


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