Table Of ContentStem Cells:
Scientific Progress and
Future Research Directions
© 2001 Terese Winslow
STEM CELLS:
SCIENTIFIC PROGRESS
AND FUTURE
RESEARCH DIRECTIONS
June 2001
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TTAABBLLEE OOFF CCOONNTTEENNTTSS
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i
Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ES-1
Chapter 1: The Stem Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Chapter 2: The Embryonic Stem Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Chapter 3: The Human Embryonic Stem Cell
and The Human Embryonic Germ Cell . . . . . . . . . . . . . . . . . . . . . . . . . 11
Chapter 4: The Adult Stem Cell . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
Chapter 5: Hematopoietic Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Chapter 6: Autoimmune Diseases and the Promise
of Stem Cell-Based Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
Chapter 7: Stem Cells and Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Chapter 8: Rebuilding the Nervous System with Stem Cells . . . . . . . . . . . . . . . . . . . 77
Chapter 9: Can Stem Cells Repair a Damaged Heart? . . . . . . . . . . . . . . . . . . . . . . 87
Chapter 10: Assessing Human Stem Cell Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Chapter 11: Use of Genetically Modified Stem Cells in
Experimental Gene Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
Appendix A: Early Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A-1
Appendix B: Mouse Embryonic Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B-1
Appendix C:Human Embryonic Stem Cells and Embryonic Germ Cells . . . . . . . . . . C-1
Appendix D: Stem Cell Tables
i. Published Reports on Isolation and Differentiation of Mouse
Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D-2
ii. Published Reports on Isolation and Differentiation of Human
Fetal Tissue Germ Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D-13
iii. Published Reports on Isolation and Differentiation of Human
Embryonic Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D-14
iv. Published Reports on Isolation and Differentiation of Human
Embryonic Carcinoma Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . D-16
v. Published Reports on Isolation and Differentiation of Human
Adult Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D-18
vi. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D-22
Appendix E: Stem Cell Markers
i. Markers: How Do Researchers Use Them to Identify Stem Cells? . . . . . E-1
ii. Commonly Used Markers to Identify Stem Cells and
Characterize Differentiated Cell Types . . . . . . . . . . . . . . . . . . . . . . . E-5
Appendix F: Glossary and Terms
i. Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F-1
ii. Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . F-11
Appendix G:Informational Resources
i. Persons Interviewed . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G-1
ii. Special Contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G-4
iii. Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G-5
OPPORTUNITIES AND CHALLENGES:
A FOCUS ON FUTURE STEM CELL APPLICATIONS
Brain The makings of future news headlines about
tomorrow’s life saving therapies starts in the
Blood biomedical research laboratory. Ideas abound; early
vessels successes and later failures and knowledge gained
from both; the rare lightning bolt of an unexpected
Lungs breakthrough discovery — this is a glimpse of the
behind the scenes action of some of the world’s
Heart most acclaimed stem cell scientists’ quest to solve
Pancreas some of the human body’s most challenging
mysteries.
Liver
Kidney
Stem cells — what lies ahead? The following chapters
explore some of the cutting edge research featuring
stem cells. Disease and disorders with no therapies or
at best, partially effective ones, are the lure of the
pursuit of stem cell research. Described here are
Cartilage examples of significant progress that is a prologue to
an era of medical discovery of cell-based therapies
that will one day restore function to those whose lives
Bone are now challenged every day — but perhaps in the
future, no longer.
Muscle
REPORT PREPARED BY THE NATIONAL INSTITUTES OF HEALTH
Ruth Kirschstein, M.D.
Acting Director
Office of Science Policy
Lana R. Skirboll, Ph.D.
Director
PPRREEFFAACCEE
On February 28, 2001, Tommy G. Thompson, How and whether stem cells derived from any of
Secretary of Health and Human Services, requested these sources can be manipulated to replace cells
that the National Institutes of Health prepare a in diseased tissues, used to screen drugs and toxins,
summary report on the state of the science on stem or studied to better understand normal development
cells. This report was developed in response to his depends on knowing more about their basic proper-
request. It provides the current information about the ties. In this respect, stem cell research is in many
biology of stem cells derived from all sources— ways no different than many other areas of modern
embryo, fetal tissue, and adult. biology; it is advancing because new tools and new
knowledge are providing the opportunities for new
Since 1998, when human pluripotent stem cells were
insights. Like all fields of scientific inquiry, research on
first isolated, research on stem cells has received
stem cells raises as many questions as it answers. This
much public attention, both because of its extraordi-
report describes the state of the science of stem cell
nary promise and because of relevant legal and
biology and gives some clues as to the many and
ethical issues. Underlying this recent public scrutiny is
varied questions that remain to be answered.
decades of painstaking work by scientists in many
fields, who have been deciphering some of the most
WHAT IS THE SCOPE OF THE
fundamental questions about life with the goal of
REPORT?
improving health.
The report is a review of the state of the science of
In the last several decades, investments in basic
stem cell research as of June 17, 2001. Included in
research have yielded extensive knowledge about
this report is subject matter addressing stem cells
the many and complex processes involved in the
from adult, fetal tissue, and embryonic sources.
development of an organism, including the control
Because so much of the progress made to date was
of cellular development. But many questions remain.
dependent on animal models, a significant emphasis
How does a single cell—the fertilized egg—give rise
is placed on understandings gained from mouse
to a complex, multi-cellular organism? The question
models of development and mouse stem cell
represents a fundamental challenge in develop-
research. The report also devotes substantial attention
mental biology. Researchers are now seeking to
to scientific publications on the characterization of
understand in greater detail the genetic factors that
specialized cells developed from embryonic stem
regulate cell differentiation in early development.
cells and the plasticity of adult stem cells. A general
Put simply, stem cells are self-renewing, unspecial- overview of early development is provided in the
ized cells that can give rise to multiple types all of Appendix to assist the reader in understanding the
specialized cells of the body. The process by which key events in formation of cells, tissues, and the whole
dividing, unspecialized cells are equipped to per- organism.
form specific functions—muscle contraction or nerve
Both scientific and lay publications use a variety of
cell communication, for example—is called differen-
terms to describe stem cells and their properties. For
tiation, and is fundamental to the development of
this reason, this report adopts a lexicon of terms and
the mature organism. It is now known that stem cells,
it is used consistently throughout. To aid the reader, a
in various forms, can be obtained from the embryo,
glossary and terms section is provided. In several
the fetus, and the adult.
i
Preface
places in the report, discovery timelines are provided. HOW WAS THE REPORT
The various sources of stem cells are described, as
DEVELOPED?
are the techniques used to isolate and develop
them. A comprehensive listing of various stem cell The report was prepared under the auspices of the
isolation and characterizations is also included. Office of Science Policy, Office of the Director, NIH.
Several approaches were taken to obtain relevant
In order to ensure the reader is provided information
scientific information for the report. A thorough review
both about the basic biology of stem cells, and their
of the extant literature, including more than 1200
therapeutic potential, the report contains several
scientific publications was conducted. Scientific
chapters focused on particular diseases which might
experts (both domestic and international) from all
benefit from stem cell research. These chapters on
areas of relevant biomedical research in stem cells
the use of hematopoietic stem cells, followed by
were interviewed in depth. While the majority of the
focus features on specific nervous system diseases,
work presented in this report emanates from
diabetes, heart disease, and autoimmune diseases
investigators in academic laboratories, extensive
serve merely as examples of the many applications
discussions were held with scientists in the private
of stem cells that are being pursued. Also included
pharmaceutical and biotechnology sectors. Thus, the
are features that review aspects of stem cells as
report makes every effort to encompass what is
therapeutic delivery tools for gene therapy and,
known and not known about stem cell biology and is,
importantly, the safety considerations for developing
therefore, not limited to research that is or has been
stem cell-based therapies.
funded by the NIH.
WHAT IS NOT IN THE SCOPE OF In recent months, there have been many reports in
the lay press regarding scientific discoveries on
THE REPORT?
various types of stem cells. The science represented
NIH recognizes the compelling ethical and legal in this report focuses exclusively on scientific
issues surrounding human pluripotent stem cell publications or public presentations. In cases where
research. Because extensive discussions regarding technical or logistical information key to the under-
these issues have been presented in various forums standing of the details of science was needed,
elsewhere, they are not part of this review of the state personal communications with the information
of the science. Also, the report does not make sources were cited.
recommendations pertaining to the policies govern-
ing Federal funding of such research.
ii
EEXXEECCUUTTIIVVEE SSUUMMMMAARRYY
INTRODUCTION At about the same time as scientists were beginning
to explore human pluripotent stem cells from
A stem cell is a special kind of cell that has a unique embryos and fetal tissue, a flurry of new information
capacity to renew itself and to give rise to specialized was emerging about a class of stem cells that have
cell types. Although most cells of the body, such as been in clinical use for years—so-called adult stem
heart cells or skin cells, are committed to conduct a cells. An adult stem cell is an undifferentiated cell
specific function, a stem cell is uncommitted and that is found in a differentiated (specialized) tissue in
remains uncommitted, until it receives a signal to the adult, such as blood. It can yield the specialized
develop into a specialized cell. Their proliferative cell types of the tissue from which it originated. In the
capacity combined with the ability to become spe- body, it too, can renew itself. During the past decade,
cialized makes stem cells unique. Researchers have scientists discovered adult stem cells in tissues that
for years looked for ways to use stem cells to replace were previously not thought to contain them, such as
cells and tissues that are damaged or diseased. the brain. More recently, they reported that adult
Recently, stem cells have received much attention. stem cells from one tissue appear to be capable of
What is “new” and what has brought stem cell bio- developing into cell types that are characteristic of
logy to the forefront of science and public policy? other tissues. For example, although adult
hematopoietic stem cells from bone marrow have
Scientists interested in human development have
long been recognized as capable of developing into
been studying animal development for many years.
blood and immune cells, recently scientists reported
This research yielded our first glimpse at a class of
that, under certain conditions, the same stem cells
stem cells that can develop into any cell type in the
could also develop into cells that have many of the
body. This class of stem cells is called pluripotent,
characteristics of neurons. So, a new concept and a
meaning the cells have the potential to develop
new term emerged-adult stem cell plasticity.
almost all of the more than 200 different known cell
types. Stem cells with this unique property come from Are human adult and embryonic stem cells equiva-
embryos and fetal tissue. lent in their potential for generating replacement cells
and tissues? Current science indicates that, although
In 1998, for the first time, investigators were able to
both of these cell types hold enormous promise,
isolate this class of pluripotent stem cell from early
adult and embryonic stem cells differ in important
human embryos and grow them in culture. In the few
ways. What is not known is the extent to which these
years since this discovery, evidence has emerged that
different cell types will be useful for the development
these stem cells are, indeed, capable of becoming
of cell-based therapies to treat disease.
almost all of the specialized cells of the body and,
thus, may have the potential to generate replace- Some considerations are noteworthy regarding this
ment cells for a broad array of tissues and organs, report. First, in recent months, there have been many
such as the heart, the pancreas, and the nervous discussions in the lay press about the anticipated
system. Thus, this class of human stem cell holds the abilities of stem cells from various sources and pro-
promise of being able to repair or replace cells or jected benefits to be realized from them in replacing
tissues that are damaged or destroyed by many of cells and tissues in patients with various diseases. The
our most devastating diseases and disabilities. terminology used to describe stem cells in the lay
ES-1
