Science, 25. Feb 2000, Vol 287, No. 5457, page 1418
Can Old Cells Learn New Tricks?
Stem cells found in adults show surprising versatility. But
it’s not yet clear wether they can match the power of cells from embryos.
Gretchen Vogel
Stem cell biologist Margaret Goodell has never seen her work on muscle and blood
development as particularly political, so she was surprised when last month the Coalition
of Americans for Research Ethics (CARE), a group that opposes the use of embryos in
research, invited her to speak at a congressional briefing in Washington, D.C. She was
even more astonished to find herself quoted by conservative columnist George Will a few
weeks later.
Goodell gained this sudden notoriety because her work, and that of other teams around the
world, just might provide a way around the moral and political quagmire that has engulfed
stem cell research to date. Since their discovery in 1998, human embryonic stem cells have
been one of the hottest scientific properties around. Because these cells can
theoretically be coaxed to differentiate into any type of cell in the body, they open, up
tantalizing possibilities, such as lab-grown tissues or even replacement organs to treat a
variety of human ills, from diabetes to Alzheimer's. Politically, however, human stem
cells have been a much tougher sell, as they are derived from embryos or fetuses. Indeed,
most research is on hold as policy-makers grapple with the ethics of human embryo
research.
Enter Goodell, whose work suggests that stem cells derived from adults, in this case, from
mouse muscle biopsies, can perform many of the same tricks as embryonic stem (ES) cells
can-but without the ethical baggage. Both CARE and George Will seized upon her work as an
indication that research on ES cells could remain on hold with no appreciable loss to
medicine. "There's a lot less moral ambiguity about the adult stem cells," says
bioethicist and CARE member Kevin Fitzgerald of Loyola University Medical Center in
Chicago.
But can adult stem cells really fulfill the same potential as embryonic stem cells can? At
this stage, the answer is by no means clear. Indeed, scientists caution that it is too
early to know if even ES cells will produce the cornucopia of new tissues and organs that
some envision. "It is still early days in the human embryonic stem cell world:' says
stem cell biologist Daniel Marshak of Osiris Therapeutics in Baltimore, which works with
adult-derived stem cells.
From a scientific standpoint, adult and embryonic stem cells both have distinct benefits
and drawbacks. And harnessing either one will be tough. Although scientists have been
working with mouse ES cells for 2 decades, most work has focused on creating transgenic
mice rather than creating labgrown tissues. Only a handful of groups around the world have
discovered how to nudge the cells toward certain desired fates. But that work gained new
prominence in late 1998, when two independent teams, led by James Thomson of the
University of Wisconsin, Madison, and John Gearhart of The Johns Hopkins University,
announced they could grow human stem cells in culture. Suddenly the work in mouse cells
could be applied to human cells-in the hope of curing disease.
The beauty of embryonic stem cells lies in their malleability One of their defining
characteristics is their ability to differentiate into any cell type. Indeed, researchers
have shown that they can get mouse ES cells to differentiate in lab culture into various
tissues, including brain cells and pancreatic cells.
Studies with rodents also indicated that cells derived from ES cells could restore certain
missing nerve functions, suggesting the possibility of treating neurological disorders.
Last summer, Oliver Brüstle of the University of Bonn Medical Center and Ronald McKay of
the U.S. National Institute of Neurological Disorders and Stroke and their colleagues
reported that they could coax mouse ES cells to become glial cells, a type of neuronal
support cell that produces the neuron-protecting myelin sheath. When the team then
injected these cells into the brains of mice that lacked myelin, the transplants produced
normal-looking myelin (Science, 30 July 1999, p. 754). And in December, a team led by
Dennis Choi and John McDonald at Washington University School of Medicine in St. Louis
showed that immature nerve cells that were generated from mouse ES cells and transplanted
into the damaged spinal cords of rats partially restored the animals' spinal cord function
(Science, 3 December 1999, p. 1826). Although no one has yet published evidence that human
ES cells can achieve similar feats, Gearhart says he is working with several groups at
Johns Hopkins to test the abilities of his cells in animal models of spinal cord injury
and neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson's
disease.
While Gearhart and his colleagues were grappling with ES cells, Goodell and others were
concentrating on adult stem cells. Conventional wisdom had assumed that once a cell had
been programmed to produce a particular tissue, its fate was sealed, and it could not
reprogram itself to make another tissue. But in the last year, a number of studies have
surprised scientists by showing that stem cells from one tissue, such as brain, could
change into another, such as blood (Science, 22 January 1999, p. 534). Evidence is
mounting that the findings are not aberrations but may signal the unexpected power of
adult stem cells. For example, Goodell and her colleagues, prompted by the discovery of
blood-forming brain cells, found that cells from mouse muscle could repopulate the
bloodstream and rescue mice that had received an otherwise lethal dose of radiation.
Bone marrow stem cells may be even more versatile. At the American Society of Hematology
meeting in December, hematologist Catherine Verfaillie of the University of Minnesota,
Minneapolis, reported that she has isolated cells from the bone marrow of children and
adults that seem to have an amazing range of abilities. For instance, Verfaillie and
graduate student Morayma Reyes have evidence that the cells can become brain cells and
liver cell precursors,
plus all three kinds of muscle-heart, skeletal, and smooth. "They are almost like
ES cells , " she says, in their ability to form different cell types.
These malleable bone marrow cells are rare, Verfaillie admits. She estimates that perhaps
1 in 10 billion marrow cells has such versatility. And they are only recognizable by their
abilities; the team has not yet found a molecular marker that distinguishes the unusually
powerful cells from other bone marrow cells. Still, she says, her team has isolated
"a handful" of such cells from 80% of the bone marrow samples they've taken.
Although the versatile cells are more plentiful in children, Verfaillie's team has also
found them in donors. between 45 and 50 years old.
Verfaillie's work has not yet been published nor her observations replicated. Even so,
many researchers are excited by the work. The cells "look extremely
interesting," says hematologist and stem cell researcher Leonard Zon of Children's
Hospital in Boston. Stem cell biologist Ihor Lemischka of Princeton University agrees..
"I'm very intrigued," he says, although he cautions that data from one lab
should not outweigh the decades of research on mouse ES cells.
Besides skirting the ethical dilemmas surrounding research on embryonic and fetal stem
cells, adult cells like Verfaillie's might have another advantage: They may be easier to.
manage. ES cells tend to differentiate spontaneously into all kinds of tissue. When
injected under the skin of immune-compromised mice, for example, they grow into teratomas
- tumors consisting of numerous cell types, from gut to skin. Before applying the cells in
human disease, researchers will have to learn how to get them to produce only the desired
cell types. "You don't want teeth or bone in your brain. You don't want muscle in
your liver," says stem cell researcher Evan Snyder of Children's Hospital in Boston.
In contrast, Verfaillie says her cells are "better behaved." They do not
spontaneously differentiate but can be induced to do so by applying appropriate growth
factors or other external cues.
Adult stem cells have a drawback, however, in that some seem to lose their ability to
divide and differentiate after a time in culture. This short life-span might make them
unsuitable for some medical applications. By contrast, mouse ES cells have a long track
record in the lab, says Goodell, and so far it seems that they "are truly infinite in
their capacity to divide. There are [mouse] cell lines that have been around for 10 years,
and there is no evidence that they have lost their 'stem cell-ness' or their
potency," she says.
For these and other reasons, many researchers say, adult-derived stem cells are not going
to be an exact substitute for embryonic or fetal cells. "There are adult cell types
that may have the potential to repopulate a number of different types of tissues,"
says Goodell. "But that does not mean they are ES cells. Embryonic stem cells have
great potential. The last thing we should do is restrict research." Right now, she
says, stem cell specialists want to study both adult and embryonic stem cells to find out
just what their capabilities might be.
That may be difficult. At the moment, human ES cells are unavailable to most researchers
because of proprietary concerns (see next story) and the uncertain legal status of the
cells. Internationally, most research on human ES cells is on hold while legislatures and
funding agencies wrestle with the ethical issues. In the United States, the National
Institutes of Health is the government agency that would fund the research, and currently,
researchers are not allowed to use NIH funds for work with human ES cells. Many European
countries, too, are still developing new policies on the use of the cells (see Viewpoint
by Lenoir, p. 1425).
The final version of NIH's guidelines for use of embryonic and fetal stem cells will not
appear before early summer, says Lana Skirboll, NIH associate director for science policy.
The draft guidelines would allow use of NIH funds for ES cell research as long as the
derivation of the cells, by private institutions, met certain ethical standards (Science,
10 December 1999, p. 2050). But several members of Congress are considering legislation
that would overrule the guidelines and block federal funding of ES cell research. At least
some of that debate is likely to focus on whether adult stem cells do in fact have the
potential to do as much as their embryonic precursors.