Life, death and stem cells
Both sides of the debate on therapeutic cloning
are fighting for life and against death. It's probably
the only thing they have in common.
Your doctor has some bad news. Turns out your heart
isn’t working right. In fact, due to deterioration
in the muscle tissue, it’s only operating at 10
percent capacity. That explains your chest pains, difficulty
breathing, and inability to exert yourself without getting
winded. Unfortunately, you know what the diagnosis means:
getting on a donor list, staying at home, and waiting
for the hospital beeper to go off if a donor organ becomes
available. And even if that does happen—and the
chances are slim—you’ll always be wondering
how long the transplant will last, worrying that your
immune system will wise up to this foreign mass of muscle
and attack it with everything it’s got.
But your doctor has another idea. He will collect cells
from the surface of your skin and put them in a dish.
You’ll go home, with orders to stay in bed and
rest. About six weeks later, you will arrive at the
hospital and be wheeled into the operating room. The
last thing you’ll remember is the anesthesiologist
placing a mask on your face and asking you to count
backward from 10. When you wake up in recovery, groggy
and achy, your doctor will say that you’re going
to be fine. Even as the two of you speak, your heart
muscle will be renewing itself. Tissue will have been
engrafted into your heart—tissue created from
your very own DNA. No red flags to alert your immune
system. In a few weeks, you’ll be completely restored.
For now, the above scenario is speculative fiction—highly
controversial speculative fiction. Politicians, lawyers,
ethicists, religious leaders, United Nations delegates,
and scientists are embroiled in a debate over whether
the process used to “heal your heart” is
morally flawed.
For that new heart tissue to be created, researchers
would need to remove the nucleus from one of your skin
cells and implant it into a donor egg cell from which
the nucleus had been removed. They would coax the egg
cell to divide into a blastocyst, a mass of about 100
cells. In the center of that mass they’d find
the payload—embryonic stem cells, microscopic
dots with nothing but pure potential. The cells are
able to form any type of cell in the human body, including
those from which scientists could conceivably grow your
heart tissue. Or liver tissue. Or pancreatic tissue.
Or brain tissue. Or spinal cord tissue. And so on. To
do that, they would need to destroy the cloned blastocyst,
and that’s where it gets messy.
If, rather than harvesting it for stem cells, scientists
instead placed that blastocyst, grown from your skin
cells, inside a human uterus, it would have the potential
to develop into a fetus. Nine months later, if all went
well, a baby would be delivered. But not just any baby.
It would be a carbon copy of you, cell for cell. It
would be your clone, the “twin” you never
had.
Just the prospect of creating a human being in this
way is an ethical minefield in and of itself. But so
is destroying the blastocyst. And so is creating it
in the first place. To make matters worse, for researchers
today to learn how to create “your” heart
muscle tomorrow, they need to experiment on human embryonic
stem cells. Until now, scientists in the field have
used leftover blastocysts that stock the freezers of
fertility clinics for their studies. These blastocysts
are fertilized embryos that have the potential to develop
into healthy babies.
Welcome to the ethical bouillabaisse known as embryonic
stem cell research, where issues related to religion,
abortion, cloning, and human disease are dumped together
into a single scientific stew. Rarely has an issue of
basic science been so hotly debated on every imaginable
front, from family dinner tables to political platforms.
The Bush administration remains firmly behind
the stem cell research policy announced in 2001, which
restricted federally funded embryonic stem cell research
to existing stem cell lines. But last May, Nancy Reagan,
Republican icon and wife of the late President Ronald
Reagan, asked the sitting president to change his policy
on embryonic stem cell research, calling it the best
hope for people with Alzheimer’s disease, the
illness that plagued her husband in his final years.
And in July, the Reagans’ son, Ron, carried the
same message to the Democratic National Convention.
But behind all the political sparring, where is the
science? Critics claim that embryonic stem cell advocates
are inflating their case; advocates say it is the most
exciting development in biology in decades. Still, fundamental
questions remain: How advanced is the research? Can
therapeutic cloning actually work, delivering on its
promise to cure the incurable? And what of the arguments
both camps cite to prove their points? Do the current
findings somehow manage to achieve a weird combination
of ambiguity and promise in such a way that both sides
can claim science is on their side?
The monster in the gonad
In 1953, cancer researcher Leroy Stevens discovered
teeth and hair in mouse testicles, and the field of
stem cell biology was born. A major tobacco company
had awarded a grant to Jackson Laboratory in Bar Harbor,
Maine, where Stevens was a scientist, for a study the
company hoped would prove that the paper in cigarettes—not
tobacco—caused cancer. After exposing mice to
large amounts of cigarette ingredients, Stevens noticed
that a few were developing gigantic scrotums. When he
dissected the scrotums, he was taken aback by what he
found inside: a hodgepodge of random tissue, including
cartilage, teeth, and hair.
This particular type of tumor is called a teratoma,
taken from the Greek word “teraton,” which
means monster. It’s a tumor that originates from
a germ cell (precursors for both egg and sperm cells),
hence its ability to form such a bizarre array of tissue.
Stevens quickly abandoned his tobacco research and spent
the next few decades studying these teratomas, trying
to get at their cellular roots. Eventually he came across
what he called a “pluripotent embryonic stem cell,”
that is, a cell that can give rise to a variety of tissues.
Stevens’ work was limited in that the cell lines
he discovered always maintained the potential to form
these monster-like cancers.
Nearly 30 years after Stevens’ initial discovery,
scientists in the United States and the United Kingdom
iso-lated embryonic stem cells from a mouse blastocyst,
a find that energized the field. Still, research in
the area remained safely cloistered in the walls of
academic study. Then, in 1998, two groups independently
announced that they had isolated human embryonic stem
cells. One group from the Wisconsin Regional Primate
Research Center had used leftover blastocysts from a
fertility clinic. The second team, from Johns Hopkins
University School of Medicine, harvested their stem
cells from aborted fetuses.
For researchers, this was a watershed discovery. For
opponents of embryonic stem cell research, it was a
call to arms. The ethical and political question of
“should we find therapies this way?” came
head to head with the scientific question “can
we find therapies this way?” The stew began to
bubble.
Of cloned mice and men
Whitehead Institute’s Rudolf Jaenisch knows
a thing or two about mice. Years ago he was among the
first scientists to incorporate foreign DNA into a mouse’s
genome in such a way that the new genetic information
could be passed down to subsequent generations. Called
“transgenics,” this procedure is now commonplace
in labs around the world. For well over a decade, Jaenisch,
who also is a professor of biology at MIT, has cloned
thousands of mice, trying to decipher all the factors
involved in what he calls “reprogramming”—the
process by which the host egg cell reactivates the entire
genome of the donor nucleus. While much of the basic
biology of how cloning works remains a mystery, one
thing is clear to Jaenisch: There is no such thing as
a normal clone.
“The vast majority of cloned embryos die in utero,”
he says. “Others are stillbirths.” The slim
percentage that grow to adulthood “are ridden
with all sorts of genetic-related health conditions.
They’re obese; they die young. I suspect many
have neurological damage which is hard for us to detect.
Out of all the animals ever cloned, I’m not sure
whether any normal clone has yet been produced.”
The problem, Jaenisch says, is that it’s impossible
for an egg cell to reactivate every single gene in the
donor nucleus. Something inevitably goes wrong. “This
isn’t a technical issue,” he maintains.
“It’s not like the early days of in vitro
fertilization, where we simply needed to improve the
techniques. This is a principal biological issue.”
For this reason, he and most other scientists in the
field believe that human reproductive cloning should
be universally—and permanently—banned. “Human
reproductive cloning would be the conscious and willful
creation of a grossly malformed person. The very thought
of doing it is reprehensible.”
While the fetus created from a cloned blastocyst is
not normal, the embryonic stem cells derived from it
are. In 2002, Jaenisch collaborated with George Daley,
then a Whitehead Fellow, on a study of a mouse that
had no functional immune system due to a genetic defect—for
all intents and purposes, a “bubble boy.”
The team removed a cell from the tip of the mouse’s
tail, extracted the nucleus, and placed it into a de-nucleated
egg cell. It became a blastocyst from which they culled
embryonic stem cells. The stem cells, because they were
taken from the diseased mouse, contained that same genetic
flaw. The scientists corrected the defect in the stem
cells and grew them into mature blood stem cells, which
they then injected into the mouse. It was, essentially,
the same kind
of procedure used in the hypothetical repair of your
damaged heart. And it had the same outcome: The mouse
was cured.
This study, published in the journal Cell,
was “the first proof-of-principle experiment proving
that therapeutic cloning can work,” says Jaenisch.
Last summer, Mayo Clinic scientists reported in the
American Journal of Physiology that they used
embryonic stem cells to repair damaged heart tissue
in rats.
Obviously, neither mice nor rats are men. Still, “Human
cells are no more complex than mouse cells,” says
Lawrence Goldstein, a professor of cellular and molecular
medicine at the University of California, San Diego.
“It’s like a Cadillac versus a Volkswagen.
The parts don’t necessarily go in the same places,
but the principles are the same.”
But figuring out which “parts” go where
requires a steep learning curve.
“We know a tremendous amount about mouse embryonic
stem cells and how to culture and differentiate them,”
says Daley, now a professor at Harvard Medical School.
“But for now, our understanding of how to do the
same in human embryonic stem cells is much more primitive.
There are issues of cell viability and engraftability
that have yet to be explored in greater detail. I’m
sure there are challenges that we don’t even know
yet.”
Still, researchers have begun to see some success in
creating mature tissue from human embryonic stem cells.
So far, they’ve derived heart cells called cardiomyocytes,
blood precursors (which can become either red or white
blood cells), and certain classes of
neurons. Goldstein is using human embryonic stem cells
to create Alzheimer’s cells. “Our goal is
to make human embryonic stem cells that carry the mutations
that cause hereditary Alzheimer’s disease and
use those cells to test hypotheses that we’ve
gotten from animal models of the disease,” says
Goldstein. Using funding from Howard Hughes Medical
Institute allows him to take advantage of human embryonic
stem cells outside the limited number approved for federal
funding in 2001 by President Bush.
But what about human therapeutic cloning, performing
in a person the same kind of procedure Jaenisch and
Daley performed in a mouse?
The first—and so far only—breakthrough
here occurred earlier this year when Woo Suk Hwang and
Shin Yong Moon of Seoul National University reported
in the journal Science that they had successfully
cloned a human blastocyst and removed viable embryonic
stem cells from it. Notes Jaenisch, “This paper
proves that human therapeutic cloning is possible.”
The American Medical Association, the National Academy
of Sciences, and such publications as the New England
Journal of Medicine have issued statements supporting
this work, creating the impression that all scientists
stand united against those trying to prevent embryonic
stem cell research on moral and religious grounds.
But first impressions can be deceiving.
A dissenting voice
James Sherley is blunt. “I do not subscribe to
the majority view at all,” the MIT associate professor
says. “I’m just one of many scientists who
feels this way. Ask yourself, ‘What are we destroying?’
It really is nonsensical to debate the whole question
of when life begins. We know that embryos are alive.
With therapeutic cloning, we’re talking about
destroying one human being for another human being’s
gain. That’s something that we as a society must
not do.”
This argument essentially is the same as the one posed
by the anti-therapeutic-cloning, anti-embryonic-stem-cell
research faction: Whether the blastocyst is cloned or
taken from a fertility clinic, they claim, acquiring
embryonic stem cells destroys a human life. (Jaenisch
counters by pointing out that a cloned blastocyst has
little, if any, chance of ever developing into a normal
baby.)
But Sherley has another problem with this area of research,
one that his fellow critics seldom, if ever, mention.
A researcher at MIT’s Biological Engineering
Division, Sherley works with adult stem cells. Unlike
embry-onic stem cells, adult stem cells are generally
thought to become only the type of tissue from which
they’ve been taken. A familiar example: bone marrow
transplants in which the adult stem cells from the donor
marrow help the cancer patient. Ideally, a person’s
own adult stem cells could be used in treatment. A cancer
patient could have adult stem cells taken from his blood
samples, multiplied in a dish, and administered without
any danger of rejection.
Adult stem cell researchers have hit two significant
roadblocks: These cells are hard to identify and difficult
to grow. But according to Sherley, embryonic stem cell
researchers soon will face the same obstacles.
“You have to ask, ‘What do you need in
order to produce tissue for long-term replacement therapy?’
The answer is, ‘You need adult stem cells,’”
Sherley says. “If these embryonic stem cell therapies
will be successful, they must produce adult stem cells.
So these researchers will soon have the same problems
that we have. They’ll have to figure out ways
to locate and then multiply the adult stem cells from
the tissue cultures that they created using embryonic
stem cells.”
Sherley says that mature tissue alone won’t suffice
for long-term replacement therapy. Even with bone marrow
transplants, if the marrow doesn’t contain adult
stem cells, the procedure fails.
The solution, as he sees it, is to bypass altogether
the moral quagmire of experimenting with human blastocysts
and focus exclusively on adult stem cells. Besides,
“I just can’t accept that reproductive clones
are unhealthy but stem cells from reproductive clones
are fine,” he says. “The data aren’t
convincing.”
But many of his fellow scientists aren’t persuaded.
“The real issue,” says Jaenisch, “is
that so far, it’s impossible to propagate and
grow adult stem cells. And adult stem cells haven’t
been shown to have therapeutic value, except for blood
cells.”
What’s more, Daley notes, not every tissue has
adult stem cells. “For the pancreas, the heart,
and much of the brain, there does not appear to be active
regeneration from adult stem cells. For these tissues,
embryonic stem cells are likely to be the best source
of replacement cells.”
As for the moral question regarding when life begins,
“I just spent the other day working with a number
of ethicists and philosophers discussing this very issue,”
says Goldstein, “and very smart, experienced people
with different viewpoints confront the issue differently
and arrive at different answers. This sort of debate
is a standard thing to happen when we have new technologies
that test our conceptions of who we are and what we’re
about.”
Toward a public-policy train wreck
In 2002, Bernard Siegel was channel surfing when he
stumbled on a press conference in which spokespersons
for the UFO cult the Raelians announced that they had
cloned the first human baby. Siegel, an attorney, decided
that the manner in which the cult members were manipulating
this alleged baby was evidence for a child abuse investigation.
So, he filed for guardianship.
“Then came the media firestorm,” he says.
(Because of this case, the Raelians refused to do a
DNA test on the child—who Siegel is certain does
not exist.)
Even after the case was dropped, Siegel noticed how
the Raelians had affected the world of stem cell research.
Rael, their leader, had testified in a congressional
hearing and appeared before the National Academy of
Sciences to make his case in favor of human reproductive
cloning. Conservatives seized on his testimony and used
it as evidence that all forms of cloning—including
therapeutic cloning—should be banned.
“There was no single, unified group of scientists
that could answer to this,” says Siegel. And so
he founded the Genetics Policy Institute (GPI), a Coral
Gables, Florida-based science advocacy group whose membership
includes many top stem cell researchers.
This fall will mark the first real test of the group’s
effectiveness.
Toward the end of this year, delegates with the United
Nations will renew a debate on two competing treaties
that were tabled last year. The first, the Costa Rican
treaty—which is supported by the U.S.—bans
all forms of cloning, including therapeutic. The second,
the Belgium treaty, would allow therapeutic cloning
while banning the procedure for reproduction.
It is too early to tell how the vote will go. If delegates
adopted the Costa Rican treaty, “it would cast
a pall on the research, declaring it an affront to human
dignity and morally reproachable,” Siegel says.
But what he fears most is that it would breathe life
in the Brownback Bill, a bill authored by United States
senator Sam Brownback (R-Kan.), that proposes to make
the very process of nuclear transfer with human cells
a criminal offense, punishable with mandatory jail time
for any scientist who attempts it.
This fall, “we’re heading straight toward
a public-policy train wreck,” says Siegel. Coming
to a head are the U.N. vote, a U.S. presidential election
in which embryonic stem cell research has been a key
issue, and a California initiative that would provide
up to $295 million annually for embryonic stem cell
research. “These will all, in one fell swoop,
influence the landscape of stem cell research,”
he says.
Meanwhile, both scientists and the public must be patient.
It will be many years before we see whether therapeutic
cloning will ever treat, for example, “your”
heart muscle. And there still is the possibility that
researchers will find ways to cure myriad diseases in
mice and rats, yet never apply those techniques successfully
in people. Until someone does, in fact, make the transition
to humans, the debate will rage on, forcing scientists
to work under a cloud of public controversy.
But researchers push forward, confident that this field
eventually will deliver on some of its promises.
Goldstein, for one, is optimistic that his efforts
one day will yield treatments to rid the body of cancer,
diabetes, and other ailments. “Sure, it’s
possible for this to be a huge failure, but I don’t
see that,” he predicts. “The science and
the data are sound enough so that a guy like me, who’s
done this for 25 years and has a reasonably good scientific
track record, is willing to put substantial resources
and energy into this. I’m willing to take risks,
but I wouldn’t do this if I thought there was
a high likelihood it would fail.”
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