Going to the source
 |
Stem cell
research slated
to expand at
Children's |
If there's anything that represents pure potential, it's
the stem cell," says Leonard Zon, MD, the Children's
Hospital Boston researcher heading up the hospital's new
Stem Cell/ Developmental Biology research program.
Like the acorn from which an oak will grow, stem cells are the
starting point for a cell-division cascade that produces all the
billions of special cells in skin, muscle, blood, brain, eyes,
heart and other organs that make up the human body. The youngest
stem cells, derived from embryos that are only days old, have
the greatest creative potential. These so-called embryonic stem
cells, the acorns, can make everything else, the oak. From the
acorn, specialized stem cells arise to create the branches, and
further specialized stem cells create the twigs, leaves and even
more acorns. The same potential exists for the human body, raising
the possibility of growing stem cells to replace all types of
diseased human organs and tissues.
Embryonic stem cells are "pluripotent," meaning that
they're able to grow any type of cell. Stem cells from older
embryos or adults are "multipotent," meaning they
can still grow various kinds of cells, but are "committed"
to making cells of a specialized tissue such as the nervous system,
the vascular network, or muscle. In other words, multipotent cells
(also called "adult" stem cells) have somehow been
told—or have decided—what their identity is going
to be, and they proceed along that defined pathway to make a particular
tissue or organ—say, the cells of the blood system. As gestation
progresses, stem cells become more and more specialized.
Directly from the source
Because of their flexibility, embryonic stem cells are eagerly
sought after by researchers. Experiments already show that they
can be induced to grow into bone marrow, nerve cells, muscle and
other tissues. These successes raise the possibility of an entirely
new approach to treating disease, and research with embryonic
stem cells is exploding worldwide. In the United States, however,
federal rules prohibit using government money to create and experiment
with new embryonic stem cells because of their source: embryos
obtained from in vitro fertilization (IVF) procedures.
In IVF—made famous in 1978 with the birth of the first
test-tube baby—the parents' eggs and sperm are brought
together in the laboratory to optimize the chances of fertilization.
If successful, the cells of the fertilized egg begin dividing,
and the resulting mass of cells, now called an embryo, is implanted
in the mother's uterus in the hope of achieving pregnancy.
However, IVF often generates more viable embryos than are safe
to reimplant (due to the risks of a multiple pregnancy). Parents
then have the option to discard the unused embryos or freeze them
for potential use in the future. Some choose a third option and
donate the unused embryos to research. Many people object to such
studies for religious or moral reasons, since they destroy embryos
that have the biological potential to become human beings. As
a result, government-funded research can use only existing human
embryonic stem-cell lines—those created before President
Bush's doctrine, announced in 2001. But scientists note
that the government-approved lines have a number of limitations
(see sidebar on page 20). Having a greater number and variety
of lines will help ensure that scientists can successfully generate
a particular tissue they need.
Children's is among a handful of institutions pursuing
embryonic stem-cell research without federal funding, relying
on support from private donors. In April, Children's launched
its new interdisciplinary Stem Cell/Developmental Biology research
program, and tapped Zon to guide it. Along with being an expert
in blood diseases, he is one of Children's 10 Howard
Hughes Medical Institute investigators, and is president of
the International
Society for Stem Cell Research, a nonprofit organization that
promotes the dissemination of information and ideas relating to
stem cells.
The Children's stem cell program, housed in the hospital's
new Karp Family Research Laboratories, will consist of 35 to 50
dedicated researchers, plus over 30 associated faculty from other
departments who are doing related research. These numbers are
expected to grow over time. "We're trying to become
one of the first groups to use stem cell therapy to cure childhood
disease," Zon says. In addition to its own program, Children's
will be an active participant in the new Harvard University Stem
Cell Institute, whose executive committee Zon is chairing. "No
place can compare with the scientific firepower at Children's
and Harvard," he says.
At Children's, Zon is setting up a dedicated laboratory
for human embryonic stem cell work that can be used by researchers
throughout the hospital. The lab will provide resources for culturing
embryonic stem cells and developing new lines to work with. The
bigger goal, however, is to learn what genetic and molecular triggers
drive embryonic stem cells to develop into various tissues, such
as hormone-making cells, skin cells and muscle cells. Once these
triggers are understood, scientists may be able to push stem cells
to divide and form specialized tissues. Diabetes specialists,
for example, could get new sets of insulin-making beta cells that
could be added to the pancreas without being rejected. Neuroscientists
could get a supply of healthy new neurons that wire themselves
correctly into the brain, perhaps replacing those that die in
Alzheimer's, Parkinson's and Lou Gehrig's disease,
for example.
"We need to see what these cells can do," says Zon.
Lessons from blood
Children's researchers have long been probing the basic
biology of stem cells, including adult stem cells. Research has
shown that many mature tissues contain a residue of special adult
stem cells that stand ready, like a rescue squad, to repair damage
in case of injury. Bone marrow is the tissue best understood so
far, but there also seem to be adult stem cells in the nervous
system, skin, blood vessels and other organs. Research has even
suggested that adult stem cells from one organ, such as bone marrow,
can be coaxed into switching identity and growing cells for another
system, such as muscles. But much of this research was flawed
and has been discounted.
The current stem cell research program grew out of the hematology
program under David Nathan, MD, Children's physician-in-chief
from 1985 to 1995. As a result, Children's first expertise
is in hematopoietic stem cells, which give rise to the various
components of blood, such as red cells and immune-system cells.
Zon, for example, is working with young zebrafish, whose transparent
bodies let him watch as various blood components are put in place
and observe what happens when genetic mutations are introduced.
On the clinical side, Children's has an active Stem
Cell Transplantation Program, where blood stem cells taken
from donor bone marrow are being used to treat such diseases as
leukemia, other cancers of the blood system, severe aplastic anemia,
and severe combined immune deficiency (SCID), which makes children
vulnerable to every infection they meet. Unfortunately, using
donated bone marrow is problematic since many children can't
find a suitable donor that matches their tissue type. Without
a proper match, they can develop graft-versus-host disease (GVHD),
in which infection-fighting cells from the donor recognize the
patient's body as being different or foreign and attack
it. GVHD can be prevented by suppressing the immune system with
medication, but this can open the door to infection.
George Daley, MD, PhD, associate director of the Stem Cell/Developmental
Biology research program, is trying to avoid the need for donors
altogether by tapping the potential of embryonic stem cells. Daley,
who came to Children's in October 2003, is widely recognized
as one of the nation's foremost stem cell researchers. He
was one of the first four scientists to receive federal funding
for human embryonic stem cell studies, and did groundbreaking
work that paved the way for development of Gleevec, a drug that
has been highly effective in treating chronic myeloid leukemia
From the lab to the
patient
Work with embryonic stem
cells is in its infancy... |
He has a research group with about 20 people who are interested
in blood development. "We're trying to address this
problem of tissue donors by generating a line of universally transplantable
cells," he says. "We're focused on embryonic
stem cells and directing them into becoming adult blood stem cells."
A longer-term strategy is to customize stem cells so they exquisitely
match each recipient's tissue type. "We could make
a new stem cell line that is tailored to the patient," Daley
speculates. "We can already do that in mice." To create
such a line, the researchers would get a cell sample from a patient,
take the nucleus from one of these cells, and then implant that
nucleus into a stem cell from which the original nucleus had been
removed.
It may be possible to replace a faulty gene—one causing
sickle cell anemia, for example—with a normal, healthy copy
of the same gene, Daley adds. Then, the repaired stem cells could
be introduced into the body, allowed to divide, and used to reconstitute
the sick child's bone marrow. It's a treatment that
should last a lifetime.
"We are keenly interested in the genetic diseases of children,"
says Daley. "And the first zone of opportunity is going
to be the intractable immune deficiency diseases." Some
of these diseases are already treatable with gene therapy, but
major problems arose in France recently when a few children given
new immune-system genes—delivered by viruses—developed
leukemia. That news seriously slowed gene therapy research, and
has focused increasing interest on the idea of using stem cells
as a way of correcting genetic defects.
The genetics of stem cells themselves is another area of intense
study. The Children's program has a core laboratory dedicated
to stem cell genomics, headed by Yi Zhou, PhD, and is one of several
major centers participating in the large, NIH-funded Stem Cell
Genome Anatomy Project. The NIH project's goal is to purify
adult stem cells and find out what genes are expressed in stem
cells from blood, liver, kidney, the gastrointestinal tract and
bone. Zhou and colleagues are focusing on blood stem cells, comparing
what genes turn on in zebrafish and mice to guide development
of the different cells that make up blood.
Targeting diseases of young and
old
While the Stem Cell/Developmental Biology research program has
its roots in hematology, Zon plans to dramatically expand its
scope. "We're one of the best groups in the world
for blood stem cell research," Zon says. "We're
now developing programs to take our blood stem-cell knowledge
to other organs and other diseases."
Zon is currently conducting a search for two new faculty to join
the program. The goal is for one of the new recruits to have expertise
in either brain stem cells or pancreatic stem cells, while the
other will focus on cancer: certain tumor cells have stem-cell-like
characteristics, making them able to renew themselves endlessly;
this makes them able to perpetuate the cancer and form new malignant
tumors. Most other cancer cells lack this ability. Children's
researchers will explore what genes are being activated in the
self-renewing cancer cells, and make these the targets of therapy.
"We'll be looking at cancer in a unique way, envisioning
it as a stem-cell problem," says Zon.
Why are new embryonic
stem cells needed? In 2001, President
George W. Bush announced that the federal government would
provide funds for human embryonic
stem cell research, but... |
He is also building a network of collaborators from all corners
of the Children's research community. These researchers'
interests range from developing stem-cell therapies to rebuild
muscles ravaged by Duchenne muscular dystrophy to learning how
the kidneys are formed in the developing embryo. Indeed, many
developmental biologists, who study embryonic organ development,
are offering to share resources with the stem cell program. "A
lot of people are excited about the opportunities in having a
stem cell center here," Zon says.
Researchers studying tissue engineering and regenerative medicine
will also be tapped. Tissue engineers use stem cells to grow new
tissues in the laboratory by "seeding" the cells onto
scaffolds that give them shape and form, or getting them to implant
at the site in the body needing repair. Vascular biologists, for
example, are exploring the potential of certain adult stem cells
of the blood system to rebuild damaged blood vessels and heart
valves. Researchers in regenerative medicine are studying how
mature cells can be made to defy nature and revert to a primitive
state that resembles stem cells, and then re-specialize to regrow
injured tissues—just as newts can grow new limbs. Elsewhere
at Children's, neuroscientists are working to regenerate
injured nerves, and researchers in otolaryngology are trying to
treat deafness by regenerating hair cells in the inner ear.
These investigators' work has turned up many molecular
and genetic clues that are likely to advance stem cell research.
"The collaborations being forged at Children's Hospital
Boston and throughout Harvard will be critical to the success
of bringing stem cells into clinical medicine," says Zon.
"Our basic biology is set up to push the field forward and
ultimately translate the work to the clinic."
Children's is forging ahead into this new field of science,
despite funding barriers. In the process, its researchers are
working to meld stem cell biology into their ongoing studies of
molecular biology, cell biology and human genetics. As they do
so, they can be expected to play a defining role in stem cell
research as medicine is, perhaps, changed forever.
The philanthropy factor
Never before has philanthropy been so critical to a scientific
endeavor that has the potential to transform basic research into
therapies for millions. Stem cell research holds the promise of
helping patients suffering from illnesses as diverse as childhood
leukemia and Parkinson's disease. Yet traditional funding
sources are severely hindered, due to restrictions in federal
funding for embryonic stem cell research and significant cutbacks
for NIH grants. Moreover, prospects for industrial funding are
limited by restrictive license terms proposed by patent holders
for stem cell derivation. Visionary philanthropists can fill the
gap and help bring about a pivotal medical breakthrough.
For more information about supporting
stem cell research at
Children's Hospital
Boston, please contact Kathleen Corcoran at
(617) 355-2370 or at kathleen.corcoran@chtrust.org.
