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