Sunday, February 29, 2004

Neurogenesis and Stem Cells in the News
Making the World Safe for Rodents

After all the posting about the politically-motivated changes in the president's bioethics council , I thought I would put up some information to show why the subject is so important.  The first article, from the BBC, illustrates the therapeutic potential of a technique involving gene therapy.  The scientists inject genetic material into living tissue in an effort to alter the function of the tissue.  In the second article, several methods of using stems cells are discussed.  I edited out a lot of the second article, because it is long and packed with highly technical stuff.  I put some of the keys phrases in bold face, to make it easy to skim through and pick up the high points.  My intent here is to show that there is tremendous potential and that real progress is being made.  Citizens should be informated about this and the implications of this kind of research.  Politicians also need to have an awareness of the need for careful but honest consideration of the ehtical issues.

Scientists 're-grow optic nerves'
Scientists believe they have taken a big step forward in their effort to be able to repair damaged nerves.Optic nerves link the eye to the brain and enable people to see

Researchers at Harvard Medical School say they have had some success trying to regenerate optic nerves in rats.  Writing in the Journal of Neuroscience they said while they were unable to restore sight they achieved three times more regeneration compared to others.  Finding a way to re-grow nerves could lead to cures for a wide range of conditions from blindness to paralysis.

Permanent damage

Any injuries that cause damage to nerves tend to be permanent. This is because nerve cells cannot regenerate or repair themselves.  Scientists around the world are working on projects aimed at finding a way to get nerves to re-grow.  One of the reasons nerves are unable to regenerate is that proteins in the outer layer of nerve fibres are programmed to stop re-growth.
Scientists have developed ways to turn these proteins off. However, this has not proved enough to make nerves regenerate.  Dr Larry Benowitz and colleagues tried a two-pronged approach to try to stimulate re-growth.  First, they damaged the lens in the eyes of a group of rats with optic nerve damage. This nerve links the retina to the part of the brain that enables them to see.  Damaging the lens stimulates an immune response - cells travel to the eye and release growth factors to try to repair the damage. This causes nerve fibres to grow into the optic nerve.  Dr Benowitz then used a gene therapy technique to try to boost this growth by injecting a gene designed to turn the proteins that are programmed to stop re-growth off.  "When we combined these two therapies - activating the growth programme in nerve cells and overcoming the inhibitory signaling - we got very dramatic regeneration," said Dr Benowitz.  However, the scientists were unable to get the nerve fibres from the retina and those from the brain to hook up properly.  "It's a mapping problem," said Dr Benowitz. "We have to retain the proper organisation of fibre projections to the brain."

Further research

The scientists are now planning further studies to try to overcome this problem.  Kevin Shakesheff, professor of tissue engineering at the University of Nottingham, said scientists were still years away from being able to use these techniques in humans.  "There has been a lot of progress in this area," he told  "We have taken enough steps forward to indicate we can solve the problem. The science is really exciting.  "However, translating that excitement into clinical applications will take time."

Story from BBC NEWS:

Published: 2004/02/29 01:46:14 GMT


Conference Report - Stem Cells and Neurologic Repair
Highlights From the Annual Meeting of the American Society of Neuroscience; November 8-12, 2003; New Orleans, Louisiana
Posted 01/13/2004
Sara M. Mariani, MD, PhD


Stem cells, neurogenesis, and repair -- this powerful combination of words announces how far neuroscience has come in the past few years in the search for new venues of treatment,[1-4] forecasting tissue repair in brains damaged by stroke or in spinal cords injured by trauma.[5] Replacement of selected cell populations is also being proposed and investigated for Parkinson's disease or Alzheimer's disease,[6-8] neurodegenerative diseases affecting mostly adults in the later decades of their lives. But what are we doing for infants and children with cerebral palsy or developmental disability, congenital defects of their central nervous system (CNS) that severely impair execution of many functions?

Notwithstanding all the efforts of their caregivers, quality of life for these young subjects can be, at times, substantially compromised; even more so when they age and develop secondary complications. Many advances have been made in their management and rehabilitation. Yet, often these children's life expectancies are lower than those of their peers.[9]

Cerebral palsy and developmental disabilities are conditions that affect children from all countries and all ethnic backgrounds. It is estimated that there are at least 14 million children living with these diseases in the United States alone. Is there a way to give them a second chance?

These issues were addressed at a symposium held during the 33rd Annual Meeting of the Society for Neuroscience, in New Orleans, Louisiana, entitled: "Stem Cells and Pediatric Disorders: Forging New Paths to Progress" under the auspices of the Children's Neurobiological Solutions foundation. Neuroscience is, nowadays, certainly one of the "hottest" research fields in biomedicine. Will the hopes raised indeed meet their promise?

Three leading researchers who are experts in cutting-edge research on brain repair using stem cells, Dr. Evan Snyder, Dr. Nick Gaiano, and Dr. Martha Windrem, gave an overview of the state of the art in this field, outlining successes and limitations of the strategies that are currently being evaluated in experimental animal systems.

Delivery of Cells

In the past few years, Fishell and colleagues[14] have shown that dissociated cells can integrate into host tissues following intra-CNS delivery, and that they can differentiate in response to local cues in the striatum and the neocortex. The surrounding microenvironment, however, has to be ready to accept and "accommodate" the transplanted cells. Very similar results have been obtained with intraventricular injections.

Other studies using intraparenchymal cell transplantation under ultrasound image guidance[15,16] showed substantial expression by grafted cells of an alkaline phosphatase reporter gene. Cells were widely dispersed in the CNS (eg, in the cortex and in the hippocampus), as they had been selected to display this intrinsic property. Cell source and final localization are critical factors in all these approaches if specific targeting is being sought.

Engraftment of Oligodendrocyte Precursors

[...]Following intraparenchymal injection, selected fetal A2B5+/PSA-NCAM- cells were found to migrate extensively, with migration and proliferation occurring predominantly in the white matter (corpus callosum). A few cells were found to migrate also into the gray matter (eg, striatum and neocortex). The proportion of viable, myelinating cells substantially increased over time.[23] In quantitative terms, 50,000 OPCs were injected on each side of the brain in a very small volume of liquid, for a total of 100,000 cells per treated mouse.

Can these fetal OPCs indeed remyelinate extensive regions of the brain in Shiverer mice? By immunofluorescence microscopy, fetal OPCs appeared differentiated in myelin-producing cells in the cerebral cortex, but they remained in the precursor stage when infiltrating the striatum.[24] Following differentiation, the OPCs gave rise to oligodendrocytes able to ensheath "naked" axons in the host, with production of MBP. Electron microscopy revealed that the newly formed myelin was compact in nature, with major dense lines.

[...]The myelin newly produced by the grafted human cells interacted with the native axons to form Caspr+ paranodes and physiologically functional nodes of Ranvier. Of note, while untreated Shiverer mice are severely compromised at 4 months of age, mutant mice xenografted with human OPCs showed a significantly prolonged survival, comparable to that of wild-type mice, suggesting a functional and long-term correction of their myelination defect.[21,24] [...]

Neurogenesis and Brain Repair

[...] Snyder's group[26] showed that stem cells recovered from the brain were able to differentiate into progenitor cells able to generate neuroblasts as well as glioblasts, using lacZ as a tracking gene. These finding raised considerable interest and paved the way for further studies on the regeneration potential of the brain, and how to harness it using transplantation and/or manipulation of stem cells.  [...]

Enzyme Replacement

Examples of diseases amenable to this therapeutic approach are the lysosomal storage diseases (eg, Tay Sachs disease), in which congenital deficiency of key metabolic enzymes leads to abnormal intracellular accumulation of unprocessed substrates, and ensuing cellular toxicity and death. If affected cells can be engineered to produce the missing enzyme or the end product, this would lead to normal or reduced production of the toxic substrate.

Pilot studies in suitable animal models showed that intraventricular injection into newborn mice was associated with expression of the therapeutic enzyme all over the brain, and elimination of the storage disease. For example, expression of hexoaminidase-beta alpha chain (with green fluorescent protein tracking) in the brains of Sandhoff mice (an experimental model of Tay Sachs disease with abnormal accumulation of neutral glycosphingolipids) successfully shifted the survival curve in treated mice vs controls, indicating a beneficial effect on overall survival.[27]

Neuronal Replacement in the Brain

If cells could be grafted into sick tissues to correct a genetic defect, then, researchers argued, stem cells or progenitor cells could potentially be used, after appropriate selection and in vivo differentiation, to restore myelination in brains that had an intrinsic deficit in this critical developmental process.
And, indeed, similarly to the results of the studies presented by Dr. Windrem, transplantation of progenitor cells in Shiverer mice, which suffer from a congenital defect in myelination, led to significant reduction in shivering following in vivo remyelination by grafted cells.[28]

Neuronal Replacement in the Spinal Cord

Can NSCs, be of help in repairing defects of the spinal cord by cell replacement? Studies in rats with extensive spinal resections have shown a certain  degree of functional recovery following cell replacement in vivo.[31] But the surprising finding was that, apparently, the cells responsible for this improvement were derived from the host, not from the donor.

Thus, it seems that grafted cells may actually affect neurologic repair in more than one way, not only by differentiation and proliferation in vivo, but also by inducing some level of neuroprotection in vivo, possibly by mitigating the loss of connectivity associated with damage or resection, and by reducing formation of scar tissue.[...]


Preliminary studies are ongoing to evaluate feasibility and potential benefits deriving from intrauterine delivery of NSCs in the subventricular zone of fetal monkeys, but far more experiments and refinements are needed before this strategy may offer a reasonable therapeutic option in humans.[...]

So we see that progress is being made with gene therapy techniques, and with stem cells.  Clearly, these are techniques that have ethical implications, and there is a role for a Bioethics Council.  So far, under the political restrictions in the USA, humans are no better off; but we stand to have the healthiest population of lab rats and mice in the entire world.   This should put our minds at ease, in this age of Weapons of Mass Destruction.  If there is ever an all-out release of nuclear weapons, or if a devastating biological weapon ravages the planet, at least the surviving mice and rats of the USA will be here to fend off all those foreign rodents.