Can Old Cells Learn New Tricks?

Rcjohnsen rcjohnsen at
Tue Feb 29 02:25:55 EST 2000

                                                        Can Old Cells Learn New

Gretchen Vogel

Stem cells found in adults show surprising versatility. But it's not yet clear
whether they can match the power of cells from embryos

    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 lab-grown
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
    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
    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
    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.

Related articles in Science:

In Search of Stem Cell Policy.

Mark S. Frankel 
Science 2000 287: 1397. (in Editorial) [Full Text] 

The Business of Stem Cells.

Eliot Marshall 
Science 2000 287: 1419-1421. (in News) [Summary] [Full Text] 

Fetal Neuron Grafts Pave the Way for Stem Cell Therapies.

Marcia Barinaga 
Science 2000 287: 1421-1422. (in News) [Summary] [Full Text] 

Patients' Voices: The Powerful Sound in the Stem Cell Debate.

Daniel Perry 
Science 2000 287: 1423. (in Viewpoints) [Abstract] [Full Text] 

A Time for Restraint.

Frank E. Young 
Science 2000 287: 1424. (in Viewpoints) [Abstract] [Full Text] 

Europe Confronts the Embryonic Stem Cell Research Challenge.

Noëlle Lenoir 
Science 2000 287: 1425-1427. (in Viewpoints) [Abstract] [Full Text] 

Out of Eden: Stem Cells and Their Niches.

Fiona M. Watt and and Brigid L. M. Hogan 
Science 2000 287: 1427-1430. (in Review) [Abstract] [Full Text] 

Stem Cells in Epithelial Tissues.

J. M. W. Slack 
Science 2000 287: 1431-1433. (in Review) [Abstract] [Full Text] 

Mammalian Neural Stem Cells.

Fred H. Gage 
Science 2000 287: 1433-1438. (in Review) [Abstract] [Full Text] 

Why Stem Cells?.

Derek van der Kooy and and Samuel Weiss 
Science 2000 287: 1439-1441. (in Review) [Abstract] [Full Text] 

Translating Stem and Progenitor Cell Biology to the Clinic: Barriers and

Irving L. Weissman 
Science 2000 287: 1442-1446. (in Review) [Abstract] [Full Text] 

Regulation of Cell Fate Decision of Undifferentiated Spermatogonia by GDNF.

Xiaojuan Meng, Maria Lindahl, Mervi E. Hyvönen, Martti Parvinen, Dirk G. de
Rooij, Michael W. Hess, Anne Raatikainen-Ahokas, Kirsi Sainio, Heikki Rauvala,
Merja Lakso, José G. Pichel, Heiner Westphal, Mart Saarma, and Hannu Sariola 
Science 2000 287: 1489-1493. (in Reports) [Abstract] [Full Text] 

Volume 287, Number 5457 Issue of 25 Feb 2000, pp. 1418 - 1419 
©2000 by The American Association for the Advancement of Science. 

Copyright © 2000 by the American Association for the Advancement of Science.   

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