Full Text HL-94-010

SPECIALIZED CENTERS OF RESEARCH IN HEMATOPOIETIC STEM CELL BIOLOGY

NIH GUIDE, Volume 23, Number 14, April 8, 1994

RFA:  HL-94-010

P.T.


Keywords: 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  May 31, 1994
Application Receipt Date:  September 15, 1994

PURPOSE

The objectives of this program are to advance our knowledge of basic
stem cell biology in areas of stem cell isolation, quantitation by in
vivo assay, in vitro and in vivo growth and replication, gene
insertion, and engraftment.  This basic knowledge will be applied
clinically to enhance our ability to achieve successful hematopoietic
stem cell therapy to cure both genetic and acquired diseases and to
perform successful gene therapy using the hematopoietic stem cell as
the target for gene transfection and for life-long expression of
normal genes.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Specialized Centers of Research (SCOR) in
Hematopoietic Stem Cell Biology, is related to the priority areas of
maternal and infant health, and cancer.  Potential applicants may
obtain a copy of "Healthy People 2000," (Full Report:  Stock No.
017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-01)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit and non-profit domestic
institutions, public and private, such as universities, colleges,
hospitals, and laboratories.

This RFA is intended to support SCOR grants for basic and clinical
investigations.  Therefore, applications that include only basic or
only clinical research will not be responsive to this announcement.
In addition, clinical research projects focused on large
epidemiologic studies or large clinical trials will be considered
unresponsive to this RFA.  Awards will not be made to foreign
institutions.  However, under exceptional circumstances, a foreign
component critical to a project may be included as a part of that
project.  Women and minority investigators are encouraged to apply.

The Principal Investigator should be an established research
scientist with the ability to ensure quality control and the
experience to administer effectively and integrate all components of
the program.  A minimum time commitment of 25 percent is expected for
this individual.  The Principal Investigator must also be the project
leader of one of the component research projects.  If, through peer
review, this project is not recommended for further consideration,
the overall SCOR application will not be considered further.  If this
project is judged by peer review to be of low scientific merit, it
will markedly reduce the overall scientific merit ranking assigned to
the entire application by the review committee.  Project leaders must
agree to commit at least 20 percent effort to each project for which
they are responsible.

MECHANISM OF SUPPORT

This RFA will use the National Heart, Lung, and Blood Institute
(NHLBI) SCOR (P50) grant to support this research program.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  All current
policies and requirements that govern the research grant programs of
the NIH will apply to grants awarded under this RFA.

Basic and Clinical Research

The overall concept of a SCOR program focuses on scientific issues
related to the mission of the NHLBI.  It is essential, therefore,
that all applications include both basic and clinical research.
Interactions between basic and clinical scientists are expected to
strengthen the research, enhance transfer of fundamental research
findings to the clinical setting, and identify new research
directions.  Plans for transfer of findings from basic to clinical
studies should be described.

Each SCOR grant application and award must include research involving
human patients/subjects.  Support may be provided for human
biomedical and behavioral studies of etiology, pathogenesis,
prevention and prevention strategies, diagnostic approaches, and
treatment of diseases, disorders, or conditions.  Small
population-based studies, where the research can be completed within
five years, may also be proposed.  In addition, basic research
projects must be included that relate to the clinical focus.  A SCOR
may also contain one or more core units that support the research
projects.

Applications from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH, National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from the GCRC
program director/principal investigator could be included with the
application.

Duration of SCOR Programs

Each NHLBI SCOR program is limited to 10 years of support.
Exceptions to this policy will be made only if a thorough evaluation
of needs and opportunities, conducted by a committee composed of
non-federal experts, determines that there are extraordinarily
important reasons to continue a specific SCOR program.

Thus, under this policy, a given SCOR grant is awarded for a
five-year project period following an open competition.  Only one
five-year competing renewal is permitted, for a total of 10 years of
support, unless the SCOR program is recommended for extension.

The NHLBI comprehensive evaluation of the HEMATOPOIETIC STEM CELL
BIOLOGY SCOR program will be conducted during the second project
period according to the following timetable:

Program Announced                   FY 1994

Project Period (First Competition)  FY 1996 to FY 2000

Program Reannounced                 FY 1999

Project Period (Second Competition) FY 2001 to FY 2005

Letter to SCOR Directors            FY 2002 (midway through
regarding SCOR evaluation plans     year 02 of 2nd project
                                    period)

SCOR Evaluation Meeting             FY 2003 (late in year 02
                                    of 2nd project period)

Notification of SCOR Directors      FY 2003 (midway through
of NHLBI Decision                   year 03 of 2nd project
                                    period)

Number of Applications

The NHLBI does not limit the number of SCOR applications in a given
SCOR program from one institution provided there is a different SCOR
principal investigator for each application and each application is
self-contained and independent of the other(s).  This does not
preclude cooperation planned or possible among participants of SCORs
after awards are made.  Scientific overlap among applications will
not be accepted.  If more than one application is envisioned from an
institution, the institution is encouraged to discuss its plans with
the NHLBI SCOR Program Administrator.

FUNDS AVAILABLE

Applicants may request up to $1,125,000 in direct costs, not
including indirect costs for collaborating institutions, in the first
year with a maximum increase of no more than four percent in each
additional year requested in the application.  Award of grants
pursuant to this RFA is contingent upon receipt of funds for this
purpose.  It is anticipated that at least two SCOR grants will be
funded. NHLBI's FY 1996 plans for this initiative include a maximum
of $4.4 million.  The specific amount to be funded will, however,
depend on the merit and scope of the applications received and on the
availability of funds.

Equipment is included in the budget limitation.  However, requests
for expensive special equipment that cause an application to exceed
this limit may be permitted on a case-by-case basis following staff
consultation.  Such equipment requires in-depth justification.  Final
decisions will depend on the nature of the justification and the
Institute's fiscal situation.

Consortium Arrangements

If a grant application includes research activities that involve
institutions other than the grantee institution, the program is
considered a consortium effort.  Such activities may be included in a
SCOR grant application, but it is imperative that a consortium
application be prepared so that the programmatic, fiscal, and
administrative considerations are explained fully.  The published
policy governing consortia is available in the business offices of
institutions that are eligible to receive Federal grants-in-aid.
Consult the latest published policy governing consortia before
developing the application.  If clarification of the policy is
needed, contact Ms. Jane Davis, Grants Operations Branch, NHLBI,
301-594-7436. Applicants of SCOR grants should exercise great
diligence in preserving the interactions of the participants and the
integration of the consortium project(s) with those of the parent
institution, because synergism and cohesiveness can be diminished
when projects are located outside of the group at the parent
institution.  Indirect costs paid as part of a consortium agreement
are excluded from the limit on the amount of direct costs that can be
requested.

RESEARCH OBJECTIVES

Background

The production of blood cells, or hematopoiesis, takes place in the
bone marrow.  Hematopoiesis begins with the most primitive,
pluripotent hematopoietic stem cell, which has a frequency of less
than one per 10,000 nucleated bone marrow cells.  The stem cell can
either replicate and remain a stem cell or differentiate into myeloid
or lymphoid stem cells, which in turn can further proliferate and
mature, ultimately giving rise to all the circulating blood cells.
Each of these complex hematopoietic pathways is under the influence
of one or more hematopoietic growth factors or other cytokines that
enhance cellular proliferation and maturation, as well as inhibitory
activities that prevent proliferation.  These activities are
generated and act within the marrow microenvironment.

Currently, allogeneic bone marrow transplants are recognized as a
treatment of choice for chronic myelogenous leukemia, acute leukemias
failing initial treatment, aplastic anemia, and several lethal
disorders of the immune system and hematopoiesis.  Allogeneic bone
marrow transplantation has become increasingly used as a cure for a
variety of genetic defects of the hematopoietic and immune systems,
and for lipid storage diseases.  Genetic diseases that have been
successfully cured by bone marrow transplantation include Cooley's
anemia, sickle cell anemia, severe combined immunodeficiency,
Wiskott-Aldrich syndrome, Fanconi anemia, Blackfan-Diamond anemia,
ataxia telangiectasia, infantile agranulocytosis, Chediak-Higashi
disease, chronic mucocutaneous candidiasis, mucopolysaccharidosis,
cartilage-hair hypoplasia, Gaucher's and other lipid storage
diseases.  Some of these diseases, such as Cooley's anemia
(beta-thalassemia) and sickle cell anemia, are major worldwide public
health problems.  Others are devastating orphan diseases that are
extremely costly to treat.  Collectively, these genetic diseases
occur in tens-of-thousands of births per year.

It is also recognized that several malignant disorders are sensitive
to agents that have, as their dose-limiting toxicity, myelo-ablation.
This knowledge, along with the initial success of marrow and
peripheral blood-derived autografts administered after myelo-ablative
therapy, has clearly defined the rationale for the use of
hematopoietic stem and progenitor cells in the treatment of several
non-hematopoietic malignancies, including breast cancer, which occurs
with alarming frequency.

At present, over 5,000 HLA-matched marrow allografts are performed
annually.  Only about 35 percent of transplant candidates have a
suitably matched sibling marrow donor.  However, the development of a
national registry of volunteer marrow donors (National Marrow Donor
Program) and improvements in histocompatibility testing have provided
the alternative of marrow transplants from unrelated donors.  About
40 percent of patients who activate or formalize their searches for
an unrelated donor are now able to be transplanted.  Hence, about 60
percent of patients with transplantable disorders are able to get a
transplant.  The significant cost of the procedure, which could be as
much as $200,000 not including the possible long-term care for
chronic graft-versus-host disease, may preclude many from benefiting
from this form of treatment.

Recent Advances in Basic Science

Over the past five years, research into the biology of hematopoiesis
in animal models and in man have led to significant advances in the
phenotypic and functional characterization of stem cells.  We have
recently seen improvements in stem cell purification and in vitro
expansion (1,2).  These observations have increased our appreciation
of the complexity of the genetic and cellular events required for
homing, engraftment, growth, and development of stem cells within an
allogeneic or autologous microenvironment.  The advent of new
molecular technology that allows analysis of gene expression in small
numbers of cells makes it possible finally to address molecular
events associated with stem cell function.  A multitude of cloned and
purified hematopoietic growth factors and cytokines are now available
to facilitate stem cell research.  In most cases, receptors for these
activities have also been cloned, and studies are underway to define
intracellular signaling pathways.  Additionally, interacting
accessory cells have been identified that, in concert with cytokines,
may regulate or promote stem cell growth, self-renewal, and
differentiation.  Progress in the ability to define and isolate
functional subsets of these marrow stromal cells provides an
opportunity to control regulatory events in the marrow.  Advances in
these areas have served to spark an interest in the application of
modern cellular and molecular biological techniques to the study of
stem cells.  Many of these areas are now ready for investigation.

Gene Therapy

Progress in the gene therapy area may no longer be impeded for lack
of purified populations of stem cells, which are the ideal target for
gene transfer.  They can be easily obtained, manipulated in vitro,
reinfused into a patient, and are capable of repopulating the bone
marrow.  Theoretically, if appropriately manipulated, they will
self-renew, differentiate, and express the inserted normal gene for
the life of the patient.  Precisely how to manipulate the stem cell
to achieve efficient gene transfer without compromising the
functional potential required for long-term hematopoiesis remains a
critical area of research.  Nevertheless, the success of whole marrow
transplantation for the correction of several genetic disorders has
focused attention on the hematopoietic stem cell as a target for gene
therapy for the correction of several genetic disorders of
hematopoiesis and metabolism.  While encouraging results have already
been achieved with infusions of genetically modified autologous
lymphocytes for the correction of immune function in children with
ADA-deficient SCID, there remain major obstacles to the achievement
of efficient, stable, and long-term genetic correction of marrow stem
and progenitor cells and their mature progeny.  Nevertheless, these
early results signal the potential of this approach for correction of
a variety of genetic disorders, such as thalassemia, Fanconi anemia,
Sickle cell anemia, lethal genetic disorders of immunity, and
potentially severe autoimmune disorders and diseases of metabolism.

Stem Cell Therapy

Research in hematopoietic stem and progenitor cells has brought about
a new and fascinating therapeutic opportunity.  The advances
described above should permit more widespread application of stem
cell enriched transplants for genetic and acquired diseases in both
children and adults.  The congenital and acquired marrow failure and
dysfunction syndromes may soon be swiftly and completely treated by
the infusion of autologous stem cells rendered normal by gene
insertion, homologous replacement with the cloned wild-type allele,
or the transplantation of foreign normal stem cells rendered
compatible by manipulations of surface antigens.  This exciting
prospect, which will massively reduce the overwhelming cost and
inefficient efforts to maintain the lives of afflicted patients, will
finally offer a definitive cure for patients with rare disorders of
marrow function such as those with Fanconi's Anemia,  Wiskott-Aldrich
syndrome, and Kostmann syndrome.  It will also offer real hope to
patients with acquired aplastic anemia and the large numbers of
patients with various forms of thalassemia and sickle cell anemia who
must now struggle with incomplete therapies.

Recent studies indicate that either allogeneic donors or genetically
modified autologous marrow stem cell grafts may also be used to
correct several disorders in utero, early in the course of embryonal
development.  In animal models (3) and in humans (4,5) donor fetal
liver hematopoietic stem cells can also be transplanted with varying
degrees of success into an unrelated pre-immune recipient fetus.
These procedures have been performed without tissue matching, without
marrow ablation, without immunosuppressive drugs, and without the
development of graft-versus-host disease.  This suggests that the
fetus is both an ideal recipient and donor of hematopoietic stem
cells.

Other Areas

We are now in an excellent position to make significant progress in
other areas that are of importance to stem cell therapy.  For
example, the recent intriguing report (6) of a single cell capable of
reconstituting the bone marrow stroma and multilineage hematopoiesis
has potential major implications and is in need of extensive
investigation.  Additional areas include the interaction of stem
cells with adhesive proteins in the marrow stroma, the manipulation
and enhancement of the stem cell homing receptor (7), and research on
alternate sources of hematopoietic stem cells such as fetal liver
(3-5), cord blood (8), and peripheral blood (9).

The SCOR as a Mechanism for Supporting Stem Cell Biology Research

A spectrum of research, ranging from basic molecular and cellular
biology through clinical applications of this newly acquired
knowledge, is now feasible.  Stem cell biology research is ideally
suited to a multidisciplinary approach.  The collaboration of
molecular and cell biologists, hematologists, immunologists,
transplantation biologists, and clinicians will not only enhance, but
is probably required for, the transfer of landmark advances in basic
research into clinical applications.  The SCOR mechanism may
facilitate the development of skilled multidisciplinary teams.  The
SCOR mechanism is uniquely designed to support this spectrum of
multidisciplinary basic and clinical research in a synergistic
fashion such that major therapeutic advances will be realized in the
next decade in both gene therapy and stem cell transplantation.


Areas to be Addressed by this Initiative include, but are not limited
to:

o  Basic stem and progenitor cell biology, evaluating a variety of
sources including marrow, peripheral blood, cord blood, fetal liver,
and embryonic stem cells.

o  Stem cell identification, isolation, purification, and in vitro
(ex vivo) expansion.

o  In vivo and in vitro assay systems for human stem cells.

o  Manipulation of stem cell self-renewal and commitment.

o  Role of growth factors, cytokines, receptors, transmembrane
signaling, marrow stroma and microenvironment, and adhesive proteins
in stem cell interactions and hematopoiesis.

o  Interaction of stem cells and stromal cells with viruses such as
parvovirus, HIV, and CMV.

o  Stem cell transplantation and expression in animal models.

o  Histocompatibility and allo-interactions, mechanism of induction
of transplant tolerance, minimizing the GVH effect and graft
rejection, and maximizing the graft versus leukemia effect.

o  Enhancing stem cell engraftment through manipulation of stem and
progenitor cell homing receptors in the marrow stroma and on stem
cell surfaces.

o  Stem cell therapy to correct genetic diseases and congenital and
acquired marrow dysfunction.

o  Gene therapy using hematopoietic stem cells as targets for gene
insertion and long term expression of normal genes, using retroviral
vectors, adeno-associated viral vectors, and other sources of gene
transduction.

The primary focus of the overall SCOR grant application should be on
non-malignant hematologic diseases.

Biennial Research Meetings

Upon initiation of the program, the NHLBI will sponsor periodic
meetings to encourage exchange of information among investigators who
participate in this program and to stimulate collaboration.
Applicants should request additional travel funds for a two-day
meeting every other year, most likely to be held in Bethesda,
Maryland.  Applicants should also include a statement in their
applications indicating their willingness to participate in these
meetings.

STUDY POPULATIONS

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990. The new policy contains some
provisions that are substantially different from the 1990 policies.

All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 9, 1994 (FR 59 11146-11151) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.

Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 31, 1994, a letter
of intent that includes a descriptive title of the proposed research;
the name, address, and telephone number of the principal
investigator; the identities of other key personnel and participating
institutions; and the number and title of the RFA in response to
which the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NHLBI staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung and Blood Institute
Westwood Building, Room 557A
Bethesda, MD  20892

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Information, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone 301-435-0714.

The RFA label available in the PHS 398 application form must be
affixed to the bottom of the face page of the application.  Failure
to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review.  In addition, to identify the application as a response
to this RFA, check "YES", enter the title "Specialized Centers of
Research in Hematopoietic Stem Cell Biology" and the RFA number
HL-94-010 on line 2a of the face page of the application.

Send or deliver a signed, typewritten original of the application,
including the checklist, and three signed photocopies, in one package
to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

Send two additional copies of the application to the Chief, Review
Branch at the address listed under LETTER OF INTENT.  It is important
to send these two copies at the same time as the original and three
copies are sent to the Division of Research Grants (DRG), otherwise
the NHLBI cannot guarantee that the application will be reviewed in
competition for this RFA.

Applications must be received by September 15, 1994.  If an
application is received after that date, it will be returned to the
applicant.  DRG will not accept any application in response to this
announcement that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending
application.  DRG will not accept any application that is essentially
the same as one already reviewed.  This does not preclude the
submission of substantial revisions of applications already reviewed,
but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by NIH staff for
completeness and responsiveness.  Incomplete applications or
applications deemed not responsive to the RFA will be returned to the
applicant without further consideration.

Crucial to the initial scientific review will be a triage process
that will eliminate all applications that are deemed not
scientifically competitive within the goals and criteria of the RFA.
Those applications that are complete, responsive, and competitive
will be further evaluated for scientific and technical merit by an
appropriate peer review group convened by the NHLBI.  The second
level of review will be provided by the National Heart, Lung, Blood
Advisory Council.

Factors to be considered in the evaluation of each application will
be similar to those used in review of traditional research grant
applications and, in addition, will include overall proposed
interactions among basic and clinical research projects.  Major
factors to be considered in the evaluation of applications include:

o  Scientific merit of the proposed basic and clinical research
projects including significance, importance, and appropriateness of
the theme; innovation, originality, and feasibility of the approach;
and adequacy of the experimental design.

o  Leadership, scientific stature, and commitment of the program
director; competence of the investigators to accomplish the proposed
research goals and their time commitment to the program; and the
feasibility and strength of consortium arrangements.

o  Collaborative interaction among basic and clinical research
components, the balance between them, and plans for transfer of
potential findings from basic to clinical studies.

o  Adequacy of the environment for performance of the proposed
research including clinical populations and/or specimens; laboratory
facilities; proposed instrumentation; quality controls;
administrative structure; institutional commitment; and, when needed,
data management systems.

o  Appropriateness of the budget for the proposed program.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program needs and
balances, and the availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.  Special supplemental instructions for the
preparation of large, multi-project grant applications for the NHLBI
can be obtained by contacting the Stem Cell Biology SCOR Program
Administrator, as indicated below.

Direct inquiries regarding scientific issues to:

Alan S. Levine, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 5A12
Bethesda, MD  20892
Telephone:  (301) 496-5911
FAX:  (301) 496-9940

Direct inquiries regarding fiscal and administrative matters to:

Ms. Jane Davis
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A15C
Bethesda, MD  20892
Telephone:  (301) 594-7436
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.839, Blood Diseases and Resources.  Awards will be
made under the authorization of the Public Health Service Act, Title
IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42
USC 241 and 285) and administered under PHS grants policies and
Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirement of Executive
Order 12372 or Health Systems Agency review.  All current policies
and requirements that govern the research grant programs of the NIH
will apply to grants awarded under this RFA.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.


REFERENCES

1.  Spangrude GJ, Heinifeld S, Weissman IL:  Purification and
characterization of mouse hematopoietic stem cells. Science 240:58,
1988.

2.  Brandt J, Srour E, Besien K, Briddell RA, Hoffman R:
Cytokine-dependent long term culture of highly purified precursors of
hematopoietic progenitor cells from human bone marrow.  J. Clin.
Invest. 86:932, 1990.

3.  Harrison MR, Slotnick RN, Crombleholm TM, et al: In utero
transplantation of fetal liver haematopoietic stem cells in monkeys.
Lancet 2:1425, 1989.

4.  Raudrant D, Touraine JL, Rebaud A: In utero transplantation of
stem cells in humans: technical aspects and clinical experience
during pregnancy.  Bone Marrow Transplantation 9(suppl 1):98, 1992.

5.  Touraine JL, Raudrant D, Rebaud A, et al: In utero
transplantation of stem cells in humans: immunological aspects and
clinical follow-up of patients.  Bone Marrow Transplantation 9(suppl
1):121, 1992.

6.  Huang S, Terstappen LWMM: Formation of haematopoietic
microenvironment and haematopoietic stem cells from single human bone
marrow stem cells.  Nature 360:745-749, 1992.

7.  Tavassoli M, Hardy C:  Molecular basis of homing of intravenously
transplanted cells to the marrow.  Blood 76:1059, 1990.

8.  Gluckman E, Broxmeyer HE, Auerbach AD, et al. Hematopoietic
reconstitution in a Fanconi's anemia patient by means of umbilical
cord blood from an HLA-identical sibling.  New Engl J Med
321:1174-1178, 1989.

9.  Kessinger A, Armitage JO.  The evolving role of autologous
peripheral stem cell transplantation following high-dose therapy for
malignancies (Editorial).  Blood 77:211-212, 1991.

.

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