Stem Cells Frustrate Scientists, Politicians

                  By Rick Weiss
                  Washington Post Staff Writer
                  Saturday, October 9, 1999; Page A1

                  It has been a year since researchers announced they
had discovered in
                  human embryos and fetuses a unique type of cell with
the potential to
                  treat a host of ailments, including diabetes,
Parkinson's disease and
                  even paralysis caused by spinal cord injury.

                  Now, in the final weeks of bargaining over a new
federal budget, a
                  divided Congress is struggling to decide whether the
medical promise
                  of these "human embryonic stem cells" is great enough
to justify the
                  use of taxpayer money to study them, despite the fact
that embryos
                  and fetuses must be destroyed to get them.

                  Congress has blocked federal funding of human embryo
research for
                  the past four years, but the discovery of stem cells
has upped the ante
                  in the embryo research debate. The research ban, which
is attached to
                  the appropriations bill for the departments of Labor
and Health and
                  Human Services, underwent several radical changes
while the Senate
                  addressed the bill last week, at various times
containing prohibitions
                  far stronger or weaker than in previous years. On
Monday, the House
                  will begin action on the issue.

                  For many lawmakers, it is largely a question of whom
they least wish
                  to alienate: highly motivated and perhaps overly
optimistic members
                  of patient groups who believe that stem cells may soon
save their lives
                  or the lives of their loved ones, or equally
passionate antiabortion
                  activists who believe it is unethical to experiment on
embryonic and
                  fetal tissues.

                  But for the many publicly funded scientists who want
to investigate
                  the cells, the issue is a no-brainer: The nation ought
to enlist their
                  help, they say, because it is becoming increasingly
clear that it will not
                  be easy to turn stem cells into cures.

                  Among the more frustrating problems is how to get the
cells to grow
                  into the specific kinds of cells needed by patients,
such as heart cells to
                  be given to a heart attack victim or pancreas cells to
be given to a
                  diabetic. Today the cells behave as though they have a
mind of their
                  own, becoming whatever kind of cell they choose, and
for no
                  apparent reason.

                  "You smile at them and they become heart, you frown
and they
                  become brain," complained Tom Okarma, president and
chief
                  executive officer of Geron Corp. of Menlo Park,
Calif., which has
                  funded most of the human embryonic stem-cell work in
this country.
                  The challenges ahead, he said, "are formidable."

                  Indeed, while Okarma and others still hold high hopes
that stem cells
                  will lead to medical breakthroughs, ongoing studies by
privately
                  funded scientists at Geron and elsewhere have lent an
air of sobriety
                  to a field that a year ago seemed almost drunk with
promise.

                  For example, it is still difficult to keep stem cells
alive in the
                  laboratory, and it has been impossible to grow them in
numbers large
                  enough to be medically useful. Moreover, scientists
still don't know
                  how to engineer the cells so they won't be rejected by
patients.

                  "The only way we're going to figure all this out is to
roll up our sleeves
                  and do the nitty-gritty research," said Harvard
University cell biologist
                  Evan Snyder. "There's such a clamor in the stem-cell
field, but we
                  should not let the clamor or the substantial promise
seduce us into
                  thinking we can do this quickly."

                  Embryonic stem cells are the basic, "plain vanilla"
cells present at the
                  core of newly developing animals. During prenatal
development, they
                  differentiate into more specialized cells, such as
those that form the
                  skin, liver, kidneys and brain.

                  What makes them unique is their ability to multiply
indefinitely in
                  laboratory dishes, where they can give rise to
offspring cells that also
                  have the ability either to blandly reproduce or, under
the right
                  influence, specialize into any of the body's tissue
types. Doctors hope
                  they will be able to grow a smorgasbord of replacement
tissues from
                  stem cells, for transplantation into people who need
them.

                  After years of funding from Geron, two research teams
announced
                  simultaneously last fall that they had finally
isolated human
                  embryonic stem cells. One team retrieved them from
young human
                  embryos and the other from the immature sex organs of
aborted
                  fetuses.

                  The best news so far is that the cells seem to be as
immortal as
                  advertised, said James Thomson, the University of
Wisconsin
                  researcher who isolated human stem cells from leftover
fertility clinic
                  embryos. After almost two years of living and dividing
in laboratory
                  dishes, every new generation of cells seems just as
young and full of
                  potential as the previous one.

                  To prove that, Thomson has injected into mice freshly
grown human
                  stem cells that are more than 300 generations removed
from the
                  parent cells he isolated from his original human
embryo. Stem cells
                  that have retained their full potential should, when
they are injected
                  into mice, differentiate into all the many kinds of
tissues that they can
                  become. And these 300th-generation cells have done so
with exquisite
                  creativity, Thomson said, with some of them becoming
hair, others
                  teeth, and still others little masses of cardiac cells
that soon begin to
                  beat in unison like a miniature heart.

                  In fact, it is not difficult to get stem cells to
differentiate into various
                  tissues. The hard part is growing them into the
specific kind of tissue
                  you want – and keeping them from specializing until
you are ready.
                  Scientists will have to grow huge vats of stem cells
in their
                  undifferentiated state if they are ever to
commercialize them.
                  Currently, however, the only way to keep the cells in
this "primordial"
                  state is to grow them in small dishes along with a
special type of
                  mouse cell.

                  The mouse cells – known as "feeder cells" – somehow
keep human
                  stem cells from spontaneously following their urge to
specialize. But
                  despite valiant efforts, Thomson and others have
failed to identify
                  how the feeder cells do that. It is a bottleneck
scientists will need to
                  get through if the research is ever going to become
useful for patients,
                  because the mouse-cell system is too cumbersome to
scale up to
                  commercial levels.

                  It's not an impossible task. Several years ago,
researchers working with
                  mouse embryonic stem cells were in the same bind:
Those cells only
                  retained their full potential when grown with finicky
feeder cells.
                  Then researchers found that a compound secreted by the
feeder cells,
                  called leukocyte inhibitory factor, or LIF, was the
magic substance that
                  was keeping the stem cells vital. Since then,
scientists have just had to
                  add some LIF to their dishes of stem cells,
eliminating the need for
                  feeder cells.

                  "After that, the mouse studies took off," recalled
Roger Pederson, a
                  Geron-supported researcher of human stem cells at the
University of
                  California at San Francisco. Unfortunately, LIF does
not do for
                  human stem cells what it does for mouse stem cells,
Pederson said.
                  "Someone has to discover the LIF counterpart for human
stem cells."

                  Perhaps even more daunting is the task of learning how
to prod
                  batches of stem cells to mature into specific kinds of
cells for
                  transplantation into people, such as liver cells for
patients with
                  cirrhosis or specific kinds of brain cells for
patients with Alzheimer's
                  or Parkinson's disease.

                  Scientists have had some small successes in
encouraging stem cells to
                  turn into desired types, such as blood cells and nerve
cells.

                  Last December, for example, Johns Hopkins University
researcher
                  John Gearhart stood before a Senate subcommittee and
unveiled a
                  poster-size photograph of spidery living cells with
branched,
                  outreaching arms. These appear to be healthy human
brain cells, said
                  Gearhart, grown in a laboratory dish from a starter
batch of stem cells
                  by feeding them a special recipe of nutrients. He
plans to inject some
                  into the brains of rodents this fall, to start
assessing their potential as
                  a treatment for brain diseases.

                  But Gearhart's method is far from foolproof. Many stem
cells treated
                  with the same nutrients do not become neurons, and
retain the
                  potential to become bone, muscle or other cells later
on – cells that
                  would not be welcome in a patient's brain.

                  Even less is known about how to spur stem cells to
grow with
                  assuredness into other kinds of cells, such as the
insulin-secreting
                  pancreas cells that, given the prevalence of diabetes
in this country,
                  are foreseen by Geron as the first "blockbuster"
moneymakers.
                  Somehow, researchers will have to overcome stem cells'
apparently
                  fickle nature.

                  Finally, there is the problem of immune-system
rejection. Researchers
                  want to figure out which molecules on stem cells are
recognized as
                  foreign by a patient's immune system. In theory,
researchers could
                  genetically engineer the cells to lack those molecules
– a
                  simple-sounding strategy that scientists concede will
probably take
                  many years to implement.

                  Depending on who is talking, problems such as these
add up to an
                  argument either for, or against, a quick infusion of
federal funds.

                  To some on Capitol Hill, including Sen. Arlen Specter
(R-Pa.), the
                  many difficulties scientists face suggest that federal
funds are needed if
                  cures are to be developed within the next decade.
Federal funding also
                  would ensure a level of public oversight not possible
when research is
                  left to private concerns.

                  But others, including Rep. Jay Dickey (R-Ark.), say
that given the vast
                  number of unanswered questions in the field, the
government could
                  satisfy itself by funding basic studies on animals and
less controversial
                  human cells, without venturing into the ethical
minefield of embryo
                  research.

                  Further complicating the political problem,
preliminary evidence
                  from mice suggests that stem cells retrieved from
embryos may have
                  medical advantages over those isolated from aborted
fetuses. That
                  revelation, described in the Oct. 1 issue of the
journal Science, is
                  problematic for legislators such as Dickey. Last week,
he sought to
                  reword the ban in a way that would have precluded
research on
                  embryo cells while allowing studies on aborted
fetuses. Fetal research
                  is less controversial than embryo research, because
the former can be
                  done on fetuses already aborted but the latter
involves the direct
                  destruction of embryos. Dickey later withdrew the
proposal.

                  In the end, Congress may manage to duck the issue.
During the past
                  few months, the National Institutes of Health has
created a set of
                  guidelines and ethical standards that publicly funded
scientists wishing
                  to study human embryonic stem cells would have to
follow.

                  The guidelines would preclude researchers from
retrieving stem cells
                  from embryos directly, because that act causes the
destruction of live
                  embryos. But researchers would be allowed to study
stem cells from
                  embryos that someone else had destroyed or from
aborted human
                  fetuses.

                  Many in Congress see the guidelines as a good
compromise – and as a
                  way to eliminate at least one controversial element
from a bill that is
                  already making waves with provisions relating to
abortion and birth
                  control. On Thursday, the Senate passed its version of
the HHS bill
                  with no restrictions on stem-cell research.

                  On Monday, the House will take up its version of the
bill. And if
                  representatives decide they can live with the NIH
guidelines – a far
                  from foregone conclusion – they too may drop the ban.

                  But the suspense might not end there. Many
Congress-watchers
                  predict that the House and Senate versions will defy
congressional
                  consensus on other counts, and ultimately will get
folded into a huge
                  omnibus spending bill.

                  Omnibus spending bills are negotiated outside the
usual committee
                  circles and are famed for ending up with unexpected
changes – the
                  result of horse-trading efforts in the wee hours of an
already extended
                  budget process. That means that, for all the lobbying
on both sides of
                  the issue, the legislative resolution to this year's
biggest biomedical
                  controversy may not become clear until the dust
settles at the end of a
                  frantic, closed-door session.

                              © 1999 The Washington Post Company



--
Charlotte Mancuso
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