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BBS Special Issue CONTROVERSIES IN NEUROSCIENCE II: Neural Transplantation
Below are the abstracts of 3 forthcoming target articles for a special
issue on Neural Transplantation that will appear in Behavioral and Brain
Sciences (BBS), an international, interdisciplinary journal that
provides Open Peer Commentary on important and controversial current
research in the biobehavioral and cognitive sciences. This will be the
second in a new series called "Controversies in Neuroscience,"
undertaken in collaboration with Paul Cordo and the RS Dow Neurological
Science Institute.
Commentators must be current BBS Associates or nominated by a current
BBS Associate. To be considered as a commentator on any of these
articles, to suggest other appropriate commentators, or for information
about how to become a BBS Associate, please send email to:
harnad@clarity.princeton.edu or harnad@pucc.bitnet or write to:
BBS, 20 Nassau Street, #240, Princeton NJ 08542 [tel: 609-921-7771]
Please specify which article or articles you would like to comment on.
(Commentators are allotted 1000 words to comment on one article, 1750
words to comment on two, and a maximum of 2250 words to comment on all
three target articles.) To help us put together a balanced list of
commentators, please give some indication of the aspects of the topic
on which you would bring your areas of expertise to bear if you were
selected as a commentator.
Within the next week or so, electronic drafts of the full text of each
article will be available for inspection by anonymous ftp, archie,
gopher or versonica on host princeton.edu directory pub/harnad/BBS
according to the instructions that follow after the abstracts. These
drafts are for inspection only; please do not prepare a commentary
until you are formally invited to do so.
1. NEURAL TRANSPLANTATION AND RECOVERY OF COGNITIVE FUNCTION
John D. Sinden, Helen Hodges & Jeffrey A. Gray
Filename: bbs.sinden
2. FETAL BRAIN TISSUE GRAFTS AS THERAPY FOR BRAIN DYSFUNCTIONS
Donald G. Stein & Marylou M. Glasier
Filename: bbs.stein
3. GENE REPLACEMENT THERAPY IN THE CENTRAL NERVOUS SYSTEM
Edward A.Neuwelt, Michael A. Pagel, Leslie L. Muldoon & Alfred Geller
Filename: bbs.neuwelt
---------------------------------------------------------------------
1.
NEURAL TRANSPLANTATION AND RECOVERY OF COGNITIVE FUNCTION
John D. Sinden, Helen Hodges & Jeffrey A. Gray
Department of Psychology
Institute of Psychiatry
De Crespigny Park Denmark Hill
London SE5 8AF England
spjtjds@ucl.ac.uk
jgray@ux.psych.lon.ac.uk
KEYWORDS: Cholinergic system, cerebral ischaemia, cognitive function,
diffuse versus point-to-point neuronal systems, neural grafts.
ABSTRACT: Cognitive deficits were produced in rats using different
methods of damaging the brain: chronic ingestion of alcohol, causing
widespread damage to diffuse cholinergic and aminergic projection
systems; lesions (by local injection of the excitotoxins, ibotenate,
quisqualate and AMPA) to the nuclei of origin of the forebrain
cholinergic projection system (FCPS), which innervates the neocortex
and hippocampal formation; transient cerebral ischaemia, producing
focal damage, especially in the CA1 pyramidal cells of the dorsal
hippocampus; and lesions (by local injection of the neurotoxin,
colchicine) to the granule cells of the dentrate gyrus. Following
chronic alcohol or lesions of the FCPS, transplants of cholinergically
rich fetal brain tissue into the terminal areas (neocortex or
hippocampus) restored performance almost to control levels, with a
time-course consistent with growth of the transplants and integration
with host tissue; transplants of cholinergically poor fetal tissue
(hippocampus) were without effect, as were transplants of
cholinergically rich tissue into the region containing the nuclei of
origin of the FCPS. Grafts of primary cells enriched in glia and
cultured neuroblastoma cells into the terminal areas of the FCPS were
equally effective, suggesting that there are multiple mechanisms by
which neural transplants can restore cognitive function following
diffuse cholinergic damage. In contrast, after ischaemia- or
neurotoxin-induced damage to CA1 or dentate granule cells respectively,
cholinergically rich fetal transplants into the damaged hippocampal
formation were ineffective in restoring performance. However, after
ischaemic damage, performance was restored by suspension grafts of CA1
cells but not by transplants containing CA3 pyramidal cells or granule
cells; and after colchicine damage, performance was restored by solid
grafts containing granule but not CA1 pyramidal cells. Furthermore,
electrophysiological evidence has demonstrated functional, graft
type-specific host-graft fuctional neuronal connectivity. Thus,
restoration of cognitive function by neural transplants is possible
after damage to either diffuse (cholinergic) or point-to-point
(intrahippocampal) forebrain systems, but the transplant must be
appropriate to the damage to be repaired. Since the different types of
brain damage studies provide partial analogues of human alcoholic
dementia, Alzheimer's disease and heart attack, these results are
encouraging with regard to the eventual application of neural
transplant surgery to the treatment of cognitive deficits in humans.
-----------------------------------------------------------------------
2.
FETAL BRAIN TISSUE GRAFTS AS THERAPY FOR BRAIN DYSFUNCTIONS:
SOME PRACTICAL AND THEORETICAL ISSUES
Donald G. Stein & Marylou M. Glasier
Laboratory of Brain Research and CNS Plasticity
Institute of Animal Behavior
Rutgers University
Newark, NJ 07102
stein@draco.rutgers.edu
KEYWORDS: Brain damage; functional recovery; grafts; neural grafts;
neural transplants
ABSTRACT: Grafting embryonic neural tissue into the brains of adult
patients is currently being used to treat Parkinson's disease and is
being given serious consideration as therapy for a variety of other
degenerative and traumatic disorders. This target article evaluates the
use of transplants to promote recovery from brain injury and highlights
the kinds of questions and problems that must be addressed before this
form of therapy is routinely applied. It has been argued that neural
transplantation can promote functional recovery through the replacement
of damaged nerve cells, the reestablishment of specific nerve pathways
lost as a result of injury, the release of specific neurotransmitters,
or the production of factors that promote neuronal growth. The latter
two mechanisms, which need not rely on anatomical connections to the
host brain, are open to examination through nonsurgical, less intrusive
therapy. Subjective judgments in selecting which patients will receive
grafts and in assessing the outcome of graft therapy make evaluation of
the procedure methodologically difficult. In addition, little long-term
assessment of transplant efficacy and effect has been done in nonhuman
primates. Carefully controlled human studies, with multiple testing
paradigms, are also needed to establish the efficacy of transplant
therapy.
-----------------------------------------------------------------------
3.
GENE REPLACEMENT THERAPY IN THE CENTRAL NERVOUS SYSTEM:
VIRAL VECTOR MEDIATED THERAPY OF GLOBAL NEURODEGENERATIVE DISEASE
Edward A.Neuwelt, Michael A. Pagel, Leslie L. Muldoon
Oregon Health Sciences University,
Portland OR 97201
Alred Geller
Children's Hospital
Boston, MA 02115
KEYWORDS: adenovirus; blood-brain barrier; gene therapy; herpes
virus; pHexosaminidase
ABSTRACT: This target article describes the current state of global
gene replacement in the brain through the use of viral vectors and it
assesses possible solutions to some of the many problems inherent in
gene therapy for the central nervous system (CNS). Gene replacement
therapy is a way to generate normal human proteins in deficient cells,
making cures possible for certain genetically inherited enzyme
deficiences, metabolic diseases, and cancers. The two major issues to
be addressed are the delivery of genetic material to the brain and the
expression of recombinant genetic material in CNS target cells. Focal
inoculation of recombinant virions or other genetic vectors has
limitations when there is global brain disease. A new
blood-brain-barrier (BBB) disruption technique, in which hypertonic
mannitol transiently shrinks the BBB endothelium, allows the passage of
high molecular weight compounds and even viruses. CNS gene therapy will
require a viral vector system that allows long-term, nontoxic gene
expression in neurons or glial cells. Retroviral vectors have
limitations in CNS gene replacement, although they are suitable for
expressing recombinant genes in intracerebral grafts, or toxic genes in
brain tumors. Mutant neurotropic viruses with reduced neurotoxicity
(e.g., defective herpes simplex virus type 1 [HSV-1], the HSV-1
amplicon vector system we have developed, or adenovirus mutants) have
potential for direct treatment of neurons. Injecting these vectors into
rodent brains can lead to the stable expression of foreign genetic
material in postmitotic neuronal cells. We discuss our BBB disruption
delivery technique, our defective HSV-1 aplicon vector system, and our
feline model for the neuronal lysosomal storage disorder
Gm2-gangliosidosis (Sandhoff disease), which may prove to be a useful
model system for CNS gene therapy.
----------------------------------------------------------------------
To help you decide whether you would be an appropriate commentator for
this article, electronic drafts are retrievable by anonymous ftp from
princeton.edu according to the instructions below (the filenames are
bbs.sinden bbs.stein and bbs.neuwelt). Please do not prepare a
commentary on these drafts. Just let us know, after having inspected them,
what relevant expertise you feel you would bring to bear on what aspect
of each article.
-------------------------------------------------------------
To retrieve a file by ftp from a Unix/Internet site, type either:
ftp princeton.edu
or
ftp 128.112.128.1
When you are asked for your login, type:
anonymous
Enter password as per instructions (make sure to include the specified @),
and then change directories with:
cd /pub/harnad/BBS
To show the available files, type:
ls
Next, retrieve the file you want with (for example):
get bbs.sinden
When you have the file(s) you want, type:
quit
In case of doubt or difficulty, consult your system manager.
A more elaborate version of these instructions for the U.K. is
available on request (thanks to Brian Josephson).
The files are also retrievable through archie, gopher, veronica, etc.
----------
Where the above procedures are not available (e.g. from Bitnet or other
networks), there are two fileservers:
ftpmail@decwrl.dec.com
and
bitftp@pucc.bitnet
that will do the transfer for you. To one or the
other of them, send the following one line message:
help
for instructions (which will be similar to the above, but will be in
the form of a series of lines in an email message that ftpmail or
bitftp will then execute for you).
-------------------------------------------------------------
Below are the abstracts of 3 forthcoming target articles for a special
issue on Neural Transplantation that will appear in Behavioral and Brain
Sciences (BBS), an international, interdisciplinary journal that
provides Open Peer Commentary on important and controversial current
research in the biobehavioral and cognitive sciences. This will be the
second in a new series called "Controversies in Neuroscience,"
undertaken in collaboration with Paul Cordo and the RS Dow Neurological
Science Institute.
Commentators must be current BBS Associates or nominated by a current
BBS Associate. To be considered as a commentator on any of these
articles, to suggest other appropriate commentators, or for information
about how to become a BBS Associate, please send email to:
harnad@clarity.princeton.edu or harnad@pucc.bitnet or write to:
BBS, 20 Nassau Street, #240, Princeton NJ 08542 [tel: 609-921-7771]
Please specify which article or articles you would like to comment on.
(Commentators are allotted 1000 words to comment on one article, 1750
words to comment on two, and a maximum of 2250 words to comment on all
three target articles.) To help us put together a balanced list of
commentators, please give some indication of the aspects of the topic
on which you would bring your areas of expertise to bear if you were
selected as a commentator.
Within the next week or so, electronic drafts of the full text of each
article will be available for inspection by anonymous ftp, archie,
gopher or versonica on host princeton.edu directory pub/harnad/BBS
according to the instructions that follow after the abstracts. These
drafts are for inspection only; please do not prepare a commentary
until you are formally invited to do so.
1. NEURAL TRANSPLANTATION AND RECOVERY OF COGNITIVE FUNCTION
John D. Sinden, Helen Hodges & Jeffrey A. Gray
Filename: bbs.sinden
2. FETAL BRAIN TISSUE GRAFTS AS THERAPY FOR BRAIN DYSFUNCTIONS
Donald G. Stein & Marylou M. Glasier
Filename: bbs.stein
3. GENE REPLACEMENT THERAPY IN THE CENTRAL NERVOUS SYSTEM
Edward A.Neuwelt, Michael A. Pagel, Leslie L. Muldoon & Alfred Geller
Filename: bbs.neuwelt
---------------------------------------------------------------------
1.
NEURAL TRANSPLANTATION AND RECOVERY OF COGNITIVE FUNCTION
John D. Sinden, Helen Hodges & Jeffrey A. Gray
Department of Psychology
Institute of Psychiatry
De Crespigny Park Denmark Hill
London SE5 8AF England
spjtjds@ucl.ac.uk
jgray@ux.psych.lon.ac.uk
KEYWORDS: Cholinergic system, cerebral ischaemia, cognitive function,
diffuse versus point-to-point neuronal systems, neural grafts.
ABSTRACT: Cognitive deficits were produced in rats using different
methods of damaging the brain: chronic ingestion of alcohol, causing
widespread damage to diffuse cholinergic and aminergic projection
systems; lesions (by local injection of the excitotoxins, ibotenate,
quisqualate and AMPA) to the nuclei of origin of the forebrain
cholinergic projection system (FCPS), which innervates the neocortex
and hippocampal formation; transient cerebral ischaemia, producing
focal damage, especially in the CA1 pyramidal cells of the dorsal
hippocampus; and lesions (by local injection of the neurotoxin,
colchicine) to the granule cells of the dentrate gyrus. Following
chronic alcohol or lesions of the FCPS, transplants of cholinergically
rich fetal brain tissue into the terminal areas (neocortex or
hippocampus) restored performance almost to control levels, with a
time-course consistent with growth of the transplants and integration
with host tissue; transplants of cholinergically poor fetal tissue
(hippocampus) were without effect, as were transplants of
cholinergically rich tissue into the region containing the nuclei of
origin of the FCPS. Grafts of primary cells enriched in glia and
cultured neuroblastoma cells into the terminal areas of the FCPS were
equally effective, suggesting that there are multiple mechanisms by
which neural transplants can restore cognitive function following
diffuse cholinergic damage. In contrast, after ischaemia- or
neurotoxin-induced damage to CA1 or dentate granule cells respectively,
cholinergically rich fetal transplants into the damaged hippocampal
formation were ineffective in restoring performance. However, after
ischaemic damage, performance was restored by suspension grafts of CA1
cells but not by transplants containing CA3 pyramidal cells or granule
cells; and after colchicine damage, performance was restored by solid
grafts containing granule but not CA1 pyramidal cells. Furthermore,
electrophysiological evidence has demonstrated functional, graft
type-specific host-graft fuctional neuronal connectivity. Thus,
restoration of cognitive function by neural transplants is possible
after damage to either diffuse (cholinergic) or point-to-point
(intrahippocampal) forebrain systems, but the transplant must be
appropriate to the damage to be repaired. Since the different types of
brain damage studies provide partial analogues of human alcoholic
dementia, Alzheimer's disease and heart attack, these results are
encouraging with regard to the eventual application of neural
transplant surgery to the treatment of cognitive deficits in humans.
-----------------------------------------------------------------------
2.
FETAL BRAIN TISSUE GRAFTS AS THERAPY FOR BRAIN DYSFUNCTIONS:
SOME PRACTICAL AND THEORETICAL ISSUES
Donald G. Stein & Marylou M. Glasier
Laboratory of Brain Research and CNS Plasticity
Institute of Animal Behavior
Rutgers University
Newark, NJ 07102
stein@draco.rutgers.edu
KEYWORDS: Brain damage; functional recovery; grafts; neural grafts;
neural transplants
ABSTRACT: Grafting embryonic neural tissue into the brains of adult
patients is currently being used to treat Parkinson's disease and is
being given serious consideration as therapy for a variety of other
degenerative and traumatic disorders. This target article evaluates the
use of transplants to promote recovery from brain injury and highlights
the kinds of questions and problems that must be addressed before this
form of therapy is routinely applied. It has been argued that neural
transplantation can promote functional recovery through the replacement
of damaged nerve cells, the reestablishment of specific nerve pathways
lost as a result of injury, the release of specific neurotransmitters,
or the production of factors that promote neuronal growth. The latter
two mechanisms, which need not rely on anatomical connections to the
host brain, are open to examination through nonsurgical, less intrusive
therapy. Subjective judgments in selecting which patients will receive
grafts and in assessing the outcome of graft therapy make evaluation of
the procedure methodologically difficult. In addition, little long-term
assessment of transplant efficacy and effect has been done in nonhuman
primates. Carefully controlled human studies, with multiple testing
paradigms, are also needed to establish the efficacy of transplant
therapy.
-----------------------------------------------------------------------
3.
GENE REPLACEMENT THERAPY IN THE CENTRAL NERVOUS SYSTEM:
VIRAL VECTOR MEDIATED THERAPY OF GLOBAL NEURODEGENERATIVE DISEASE
Edward A.Neuwelt, Michael A. Pagel, Leslie L. Muldoon
Oregon Health Sciences University,
Portland OR 97201
Alred Geller
Children's Hospital
Boston, MA 02115
KEYWORDS: adenovirus; blood-brain barrier; gene therapy; herpes
virus; pHexosaminidase
ABSTRACT: This target article describes the current state of global
gene replacement in the brain through the use of viral vectors and it
assesses possible solutions to some of the many problems inherent in
gene therapy for the central nervous system (CNS). Gene replacement
therapy is a way to generate normal human proteins in deficient cells,
making cures possible for certain genetically inherited enzyme
deficiences, metabolic diseases, and cancers. The two major issues to
be addressed are the delivery of genetic material to the brain and the
expression of recombinant genetic material in CNS target cells. Focal
inoculation of recombinant virions or other genetic vectors has
limitations when there is global brain disease. A new
blood-brain-barrier (BBB) disruption technique, in which hypertonic
mannitol transiently shrinks the BBB endothelium, allows the passage of
high molecular weight compounds and even viruses. CNS gene therapy will
require a viral vector system that allows long-term, nontoxic gene
expression in neurons or glial cells. Retroviral vectors have
limitations in CNS gene replacement, although they are suitable for
expressing recombinant genes in intracerebral grafts, or toxic genes in
brain tumors. Mutant neurotropic viruses with reduced neurotoxicity
(e.g., defective herpes simplex virus type 1 [HSV-1], the HSV-1
amplicon vector system we have developed, or adenovirus mutants) have
potential for direct treatment of neurons. Injecting these vectors into
rodent brains can lead to the stable expression of foreign genetic
material in postmitotic neuronal cells. We discuss our BBB disruption
delivery technique, our defective HSV-1 aplicon vector system, and our
feline model for the neuronal lysosomal storage disorder
Gm2-gangliosidosis (Sandhoff disease), which may prove to be a useful
model system for CNS gene therapy.
----------------------------------------------------------------------
To help you decide whether you would be an appropriate commentator for
this article, electronic drafts are retrievable by anonymous ftp from
princeton.edu according to the instructions below (the filenames are
bbs.sinden bbs.stein and bbs.neuwelt). Please do not prepare a
commentary on these drafts. Just let us know, after having inspected them,
what relevant expertise you feel you would bring to bear on what aspect
of each article.
-------------------------------------------------------------
To retrieve a file by ftp from a Unix/Internet site, type either:
ftp princeton.edu
or
ftp 128.112.128.1
When you are asked for your login, type:
anonymous
Enter password as per instructions (make sure to include the specified @),
and then change directories with:
cd /pub/harnad/BBS
To show the available files, type:
ls
Next, retrieve the file you want with (for example):
get bbs.sinden
When you have the file(s) you want, type:
quit
In case of doubt or difficulty, consult your system manager.
A more elaborate version of these instructions for the U.K. is
available on request (thanks to Brian Josephson).
The files are also retrievable through archie, gopher, veronica, etc.
----------
Where the above procedures are not available (e.g. from Bitnet or other
networks), there are two fileservers:
ftpmail@decwrl.dec.com
and
bitftp@pucc.bitnet
that will do the transfer for you. To one or the
other of them, send the following one line message:
help
for instructions (which will be similar to the above, but will be in
the form of a series of lines in an email message that ftpmail or
bitftp will then execute for you).
-------------------------------------------------------------