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cerebral palsy

Introduction to Stem Cell Therapy

Stem cell therapy presents the potential promise for re-wiring the defective nervous system. The technology is provocative and promising, but the future is far from certain. Nevertheless, the science that is unfolding about neural development is exciting in its potential implications.

Stem Cell research has shown how environmental cues can control the pace as well as the pathway of development. Mammalian neurological development is highly regulated. The fate of each cell is governed by interactions with its neighbors. For instance, the cells in a half-embryo, or in a chimeric double embryo, must adjust their behavior so as to generate an animal that is normal in both pattern and size. When the circumstances of development are more grossly abnormal, however, the embryonic cells can go wildly out of control. Some important lessons can be learned from these phenomena.

If a normal early mouse embryo is grafted into the kidney or testis of an adult, it rapidly becomes disorganized, and the normal controls on cell proliferation break down. The result is a bizarre growth known as a teratoma, which consists of a disorganized mass of cells containing many varieties of differentiated tissue - skin, bone, glandular epithelium, and so on - mixed with undifferentiated stem cells that continue to divide and generate yet more of these differentiated tissues.1 Teratomas with similar properties can also arise spontaneously from germ cells in the gonads as the result of various developmental accidents.

We now know that it is possible to derive transplantable cancers from teratomas. Such teratocarcinomas will grow without limit until they kill their host. They can be maintained indefinitely by grafting samples of the tumor cells serially from one host to another, and they always include some undifferentiated stem cells, together with a variety of differentiated cell types to which the stem cells give rise. The teratocarcinoma stem cells can also be maintained in culture as permanent cell lines.

One might think that teratocarcinoma stem cells originate, as in other cancers, through mutations in genes responsible for the normal controls of cell behavior. A number of observations, howerver, suggest otherwise. Stem cells with very similar properties can be derived by placing a normal inner cell mass in culture and dispersing the cells as soon as they proliferate. Once dispersed, some of the cells, if kept in suitable culture conditions, will continue dividing indefinitely without altering their character.

The resulting embryonic stem (ES) cell lines are similar to teratocarcinoma-derived cell lines, but they can be generated at such high frequency from normal embryos that it is unlikely that they arise by mutation. Instead, it appears that separating the cells from their normal neighbors and placing them in the appropriate culture medium arrests the normal program of change of cell character with time, and thus enables the cells to continue dividing indefinitely without differentiating.

The presence in the medium of a protein growth factor known as leukemia inhibitory factor (LIF) seems to be critical for this suspension of developmental progress. With a slightly more complex cocktail of growth factors, embryonic germ cells can be induced to behave in the same way in culture.2

The state in which the ES, teratocarcinoma, or germ-cell-derived stem cells are arrested seems to be equivalent to that of normal inner-cell-mass cells. This can be shown by taking the cells from their culture dish and injecting them into the blastocoel cavity of a normal blastocyst. The injected cells become incorporated in the inner cell mass of the blastocyst and can contribute to the formation of an apparently normal chimeric mouse. 3 Descendants of the injected stem cells can be found in practically any of the tissues of this mouse. They differentiate in a well-behaved manner appropriate to their location and can even form viable germ cells.4

This capability of ES cells forms the basis for a widely used technique that allows mice to be generated with a genetically engineered mutation in any chosen gene whose DNA has been cloned. To produce such "gene-knockout" mice, mutant ES cells are made by selecting for a DNA insertion that replaces the chosen gene by an artificially altered version; the mutant ES cells are then used to produce chimeric mice that carry the mutation in their germ cells.5, 6, 7, 8

These extraordinarily adaptable behaviors of ES cells shows that environmental cues not only guide choices between different pathways of differentiation, but in certain cases, they can also stop or start the developmental clock - the processes that drive a cell to progress from an embryonic to an adult state.9

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Brains Can Grow New Cells

In October, 1998, Fred Gage of the Salk Institute reported that the adult brain was able to grow new cells in the hippocampus area. Mice research indicates that neuronal stem cells do indeed migrate to various parts of the mouse brain in order to grrow new neurons. The question for humans is how to make the neuronal stem cells in the hippocampus area mature in a healthy manner and migrate to other parts of the brain.

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Brain Plasticity

Researchers at the Massachusetts Institute of Technology have reconfigured newborn ferret brains so that the animals' eyes are hooked up to brain regions where hearing normally develops.10 The surprising result is that the ferrets develop fully functioning visual pathways in the auditory portions of their brains. In other words, they see the world with brain tissue that was only thought capable of hearing sounds!

These findings run counter to previous theories of how brains develop specialized regions for seeing, hearing, sensing touch and - in humans - generating language and emotional states. Prior theorists argued that genes operating before birth created these specialized regions or modules. This meant that the visual cortex was destined to process vision and little else. The ferret experiments showed that brain regions are not set in stone at birth. Rather, they develop specialized functions based on the kind of information flowing into them after birth.

"Some scientists are going to have a hard time believing these experiments," said Dr. Jon Kaas, a professor of psychology at Vanderbilt University in Nashville. They demonstrate Ó that the cortex can develop in all sorts of directions. It's just waiting for signals from the environment, and will wire itself according to the input it getsÓ"

As in humans, the ferret's optic and auditory nerves travel through the thalamus before reaching areas in the cerebral cortex where vision and hearing are perceived. In humans, this very basic wiring is present at birth, but in ferrets, these important nerves grow into the thalamus after the animal is born. Dr. Sur found that if he stopped the auditory nerve from entering the thalamus, the optic nerve would arrive a few days later and make a double connection. It would go on through the thalamus and connect itself up to both seeing and hearing regions of the cortex.

The researchers then waited to see what would happen to the hearing region of the brain once it was getting all its signals from the retina.

After a ferret or a human is born, cells in the brain's primary visual area become highly specialized for analyzing the orientation of lines found in images or shapes. Some cells fire only in response to vertical lines (if presented with a horizontal or slanted line, they don't do anything).

Other cells fire exclusively when a horizontal line falls on them and yet others fire in response to lines slanted at various angles. These specialized cells are draped across the primary visual area in a somewhat splotchy fashion that resembles a bunch of pinwheels.

The hearing region of the brain is organized very differently. Each cell is connected to the next in a kind of single line. There are no pinwheel shapes.

After the re-wired ferrets matured, cells in the auditory cortex were organized pinwheel fashion. Researchers found horizontal connections between cells responding to similar orientations.

The re-wired map was less orderly than the maps found in normal visual cortex, Dr. Sur said, but looked as if it might be functional.

The researchers then asked, what does the re-wired ferret experience? Does it see or does it hear with its auditory cortex? Re-wired ferrets were trained to turn their heads one way if they heard a sound and in the other direction if they saw a flash of light. In these experiments, one hemisphere was re-wired and the other was left normal as a control. Thus the animals could always hear with the intact side of their brains and were deaf in the re-wired side.

Not surprisingly, when the light was presented to the re-wired side, the animals responded correctly. But when connections to visual areas were severed on the re-wired side, the animals still responded to the light. That meant that they were seeing lights with their re-wired auditory cortex, Dr. Sur said.

The research reopens the question of what are the relative contributions of genes and experience in building brain structure, according to Dr. Kaas. Genes, Dr. Kaas suggests, create a basic scaffold, but not much structure. Thus, in a normal human brain, the optic nerve is an inborn scaffold connected to the primary visual area. But it is only after images pour into this area from the outside world that it becomes the seeing part of the brain. All the newborn cortex knows about the outside world comes from the electrical activity of these inputs, or images that fall on the retina, sounds that reach the inner ear or touch sensations that press on the skin, Dr. Kaas said.

As the inputs arrive, the cells organize themselves into circuits and functional regions. As these circuits grow larger and more complex, they become less malleable and - probably with the help of changes in neurochemistry - become stabilized. This is why a mature brain is less able to recover from injury than a very young brain.

Young brains are astonishingly plastic, Dr. Kaas said. For example, children who suffer from a severe form of epilepsy that is treatable only by removing one-half of their brains can learn to walk, talk, throw balls and otherwise develop normally with only half a brain, if operated on early in life.

But in recent years, scientists are also discovering that adult brains, as well, can undergo surprising changes in response to experience. Imaging experiments carried out on blind people show that when they learn to read Braille, "visual" areas of their brains light up.

Touch seems also to reside in visual areas. Similar experiments show that deaf people use the auditory cortex to read sign language, whereas people who can hear use the visual areas of the brain for this purpose.

Dr. Sur said his laboratory was now searching for molecules that help produce these kinds of changes in mature and developing brains. If the chemistry of regrowth and reorganization can be understood, he said, it would offer new avenues for helping people recover from damage caused by strokes, accidents and various brain diseases.

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Intravenous Injection of Stem Cells

Still unavailable in the United States except in the arena of strictly controlled research, intravenous injections of stem cells are being given in several clinics elsewhere. Regarding Cerebral Palsy, some of the results have been favorable - however, to date, only anecdotal and testimonial data are available. As more scientific reports become available, we will post them here.

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Childrens Neurobiological Soultions

Children's Neurobiological Solutions, Inc. (CNS) is a national, non-profit, 501(c)(3) organization, whose mission is to orchestrate cutting-edge, collaborative research with the goal of expediting the creation of effective treatments and therapies for children with neurodevelopmental abnormalities, birth injuries to the nervous system, and related neurological problems.

In addition, CNS strives to provide families and health care providers with user-friendly access to state-of-the-art information and education supporting their decision-making processes.

Approximately 15 million children in the United States, between the ages of 0-19 years, are afflicted with neurological conditions that severely limit their quality of life and lifespan.

Special education alone for these children costs society approximately 36 billion dollars annually. These costs include more personnel for learning disabled classes, transportation to out of district placements, out of district schools for more involved children, equipment, aids, etc.

There are no known cures and limited biomedical therapeutics. The majority of present and past research and fundraising dollars focus on saving lives and supportive services such as physical therapy, special education and care giving.

Recent advances in biomedicine, particularly in the fields of developmental neurobiology, stem cell research and genetics, has opened the gateway towards the discovery of brain repair therapies which can enhance mobility and cognition, giving quality of life and health to these children.

Taking advantage of these exciting new fields, Children's Neurobiological Solutions has developed a world-renowned, cross-institutional Scientific Advisory Board of neuroscientists and clinicians, collaborating to achieve aggressive research goals. CNS's research goals are focused on the discovery and development of therapeutics that will improve the functional abilities and health of these children, enhancing their quality of life and reducing the burdens of their caretakers and society.

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Articles & Research on Stem Cells & Stem Cell Therapy

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Due to the increasing importance of the rapidly developing field of stem cell research and advances in its potential and practical application, this subsection will be updated regularly to bring you the benefit of this curent knowledge, not only for Cerebral Palsy, but for many other diseases and bio-neurological conditions for which there has previously been no cure and minimal hope of prevention.

Stem cell therapy is still a very controversial, yet amazingly promising area of hope for the amelioration of many tragic diseases and what we now consider as "developmental disorders". We urge you to keep abreast of the advances in this arena, because it is more than likely that it will benefit so many.

Some of the resources and sources of articles listed below may require you to "register" in order to be available to download these very important documents. Please know that such "registration" is absolutely free of charge and usually only requires your entering your email address and perhaps answering a few questions. We strongly urge you to not let this slight inconvenience deter you from accessing these resources. These are very reputable sites - such as Scientific American, Harvard Medical School, The New York Times, Boston Childrens Hospital and the New Scientist Journal, that respect your Internet privacy rights and are used by medical researchers aroubd the world.

Please report any broken or outdated links to our Webmaster.

Also, see our List of Articles & Information on Live Cell and Stem Cell Therapy in the Autism Section of our website.

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Specific Articles & Research on Stem Cells & Stem Cell Therapy:

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  1. Gurdon JB. The generation of diversity and pattern in animal development. Cell 1992; 68: 185-199.

  2. DiBerardino MA, Orr NH, McKinnell RG. Feeding tadpoles cloned from Rana erythrocyte nuclei. PNAS (USA). 1986; 83: 8231-8234.

  3. Gurdon JB. Transplanted nuclei and cell differentiation. Sci Am 1968; 219(6): 24-35.

  4. McKinnell RG. Cloning-nuclear transplantation in amphibia. Minneapolis: University of Minnesota Press, 1978.

  5. Capecchi MR. The new mouse genetics: altering the genome by gene targeting. Trends Genet. 1989; 5: 70-76.

  6. Illmensee, K. Stevens L.C.Teratomas and chimeras. Sci. Am. 1979; 240(4):120-132.

  7. Papaioannou VE, Gardner RL, McBurney MW, Babinet C, Evans MJ. Participation of cultured teratocarcinoma cells in mouse embryogenesis. J.Embryol. Exp. Morphol. 44:93-104, 1978.

  8. Robertson EJ. Pluripotential stem cell lines as a route into the mouse germ line. Trends Genet. 2:9-13, 1986.

  9. Williams RL. Myeloid leukemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature 1988; 336:685-687.

  10. Blakeslee S. 'Rewired' Ferrets Overturn Theories of Brain Growth. April 25, 2000 New York Times. See also Sur M., et al. In Nature, April 20, 2000 issue.

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Written and overseen by Lewis Mehl-Madrona, M.D., Ph.D.

Program Director, Continuum Center for Health and Healing,
Beth Israel Hospital / Albert Einstein School of Medicine

Hosted and maintained by The Healing Center On-Line © 2001