More Reading
The Age of Cloning
By J. Madeleine Nash
Even now, a week after news of the achievement
first flew around the globe, traces of astonishment linger
in the air like a contrail. The landmark paper published late
last week in the journal Nature confirmed what the
headlines had been screaming for days: researchers at the
Roslin Institute near Edinburgh, Scotland, had indeed pulled
off what many experts thought might be a scientific impossibility.
From a cell in an adult ewe's mammary gland, embryologist
Ian Wilmut and his colleagues managed to create a frisky lamb
named Dolly (with apologies to Ms. Parton), scoring an advance
in reproductive technology as unsettling as it was startling.
Unlike offspring produced in the usual fashion, Dolly does
not merely take after her biological mother. She is a carbon
copy, a laboratory counterfeit so exact that she is in essence
her mother's identical twin.
What enabled the Scottish team to succeed where so many others
have failed was a trick so ingenious, yet so simple, that
any skilled laboratory technician should be able to master
it─and therein lies both the beauty and the danger: once Wilmut and his colleagues figured out how to cross that biological
barrier, they ensured that others would follow. And although
the Roslin researchers had to struggle for more than 10 years
to achieve their breakthrough, it took political and religious
leaders around the world no time at all to grasp its import:
if scientists can clone sheep, they can probably clone people
too.
Without question, this exotic form of reproductive engineering
could become an extremely useful tool. The ability to clone
adult mammals, in particular, opens up myriad exciting possibilities,
from propagating endangered animal species to producing replacement
organs for transplant patients. Agriculture stands to benefit
as well. Dairy farmers, for example, could clone their champion
cows, making it possible to produce more milk from smaller
herds. Sheep ranchers could do the same with their top lamb
and wool producers.
But it's also easy to imagine the technology being misused,
and as news from Roslin spread, apocalyptic scenarios proliferated.
Journalists wrote seriously about the possibility of virgin
births, resurrecting the dead and women giving birth to themselves.
On the front page of the New York Times, a cell biologist
from Washington University in St. Louis, Missouri, named Ursula
Goodenough quipped that if cloning were perfected, "there'd
be no need for men."
Scientists have long dreamed of doing what the Roslin team
did. After all, if starfish and other invertebrates can practice
asexual reproduction, why can't it be extended to the rest
of the animal kingdom? In the 1980s, developmental biologists
in Philadelphia at what is now Allegheny University of the
Health Sciences came tantalizingly close. From the red blood
cells of an adult frog, they raised a crop of lively tadpoles.
These tadpoles were impressive creatures, remembers University
of Minnesota cell biologist Robert McKinnell, who followed
the work closely. "They swam and ate and developed beautiful
eyes and hind limbs," he says. But then, halfway through
metamorphosis, they died.
Scientists who have focused their cloning efforts on more
forgiving embryonic tissue have met with greater success.
A simple approach, called twinning (literally splitting embryos
in half), is commonly practiced in the cattle industry. Coaxing
surrogate cells to accept foreign DNA is a bit trickier. In
1952 researchers in Pennsylvania successfully cloned a live
frog from an embryonic cell. Three decades later, researchers
were learning to do the same with such mammal as sheep and
calve. "What's new," observes University of Wisconsin
animal scientist Neal First, "is not cloning mammals.
It's cloning mammals from cells that are not embryonic."
Embryo cells are infinitely easier to work with because they
are, in the jargon of cell biologists, largely "undifferentiated".
That is, they have not yet undergone the progressive changes
that turn cells into skin, muscles, hair, brain and so on.
An undifferentiated cell can give rise to all the other cells
in the body, say scientists, because it is capable of activating
any gene on any chromosome. But as development progresses,
differentiation alters the way DNA─the double-stranded molecule
that makes up genes─folds up inside the nucleus of a cell.
Along with other structural changes, folding helps make vast
stretches of DNA inaccessible, ensuring that genes in adult
cells do not turn on at the wrong time or in the wrong tissue.
The disadvantage of embryonic cloning is that you don't know
what you are getting. With adult-cell cloning, you can wait
to see how well an individual turns out before deciding to
clone it. Cloning also has the potential to make genetic engineering
more efficient. Once you produce an animal with a desired
trait─a pig with a human immune system, perhaps─you could
make many copies.
In recent years, some scientists have speculated that the
changes wrought by differentiation might be irreversible,
in which case cloning an adult mammal would be biologically
impossible. The birth of Dolly not only proves them wrong
but also suggests that the difficulty scientists have had
cloning adult cells may have less to do with biology than
with technique.
To create Dolly, the Roslin team concentrated on arresting
the cell cycle─the series of choreographed steps all cells
go through in the process of dividing. In Dolly's case, the
cells the scientists wanted to clone came from the udder of
a pregnant sheep. To stop them from dividing, researchers
starved the cells of nutrients for a week. In response, the
cells fell into a slumbering state that resembled deep hibernation.
At this point, Wilmut and his colleagues switched to a mainstream
cloning technique known as nuclear transfer. First they removed
the nucleus of an unfertilized egg, or oocyte, while leaving
the surrounding cytoplasm intact. Then they placed the egg
next to the nucleus of a quiescent donor cell and applied
gentle pulses of electricity. These pulses prompted the egg
to accept the new nucleus─and all the DNA it contained─as though it were its own. They also triggered a burst of
bio-chemical activity, jump-starting the process of cell division.
A week later, the embryo that had already started growing
into Dolly was implanted in the uterus of surrogate ewe.
An inkling that this approach might work, says Wilmut, came
from the success his team experienced in producing live lambs
from embryonic clones. "Could we do it again with an
adult cell?" wondered Wilmut, a reserved, self-deprecating
man who likes gardening, hiking in the highlands and drinking
good single-malt Scotch (but who was practical enough to file
for a patent before he went public).
It was a high-risk project, and in the beginning Wilmut proceeded
with great secrecy, limiting his core team to four scientists
failed far more often than they succeeded. Out of 277 tries,
the researchers eventually produced only 29 embryos that survived
longer than six days. Of these, all died before birth except
Dolly, whose historic entry into the world was witnessed by
a handful of researchers and a veterinarian.
Rumors that something had happened in Roslin, a small village
in the green, rolling hills just south of Edinburgh, started
circulating in scientific circles a few weeks ago. It was
only last week, when the rumors were confirmed and the details
of the experiment revealed, that the real excitement erupted.
Cell biologists, like everybody else, were struck by the simple
boldness of the experiment. But what intrigued them even more
was what it suggested about how cells work.
Many scientists had suspected that the key to getting a donor
cell and egg to dance together was synchronicity─getting
them started on the same foot. Normal eggs and sperm don't
have that problem; they come pre-divided, ready to combine.
An adult cell, though, with its full complement of genes,
has to be coaxed into entering an embryonic state. That is
probably what Wilmut did by putting the donor cell to sleep,
says Colin Stewart, an embryologist at the U.S. National Cancer
Institute. Somehow, in ways scientists have yet to understand,
this procedure seems to have reprogrammed the DNA of the donor
cell. Thus when reawakened by the Roslin team, it was able
to orchestrate the production of all the cells needed to make
up Dolly's body.
Like most scientists who score major breakthroughs, Wilmut
and his colleagues have raised more questions than they have
answered. Among the most pressing are questions about Dolly's
health. She is seven months old and appears to be perfectly
fine, but no one knows if she will develop problems later
on. For one thing, it is possible that Dolly may not live
as long as other sheep. After all, observes NCI's Stewart,
"she came from a six-year-old cell. Will she exhibit
signs of aging prematurely?" In addition, as the high
rate of spontaneous abortion suggests, cloning sometimes damages
DNA. As a result, Dolly could develop any number of diseases
that could shorten her life.
Indeed, cloning an adult mammal is still a difficult, cumbersome
business─so much so that even agricultural and biomedical
applications of the technology could be years away. PPL therapeutics,
the small biotechnical firm based in Edinburgh that provided
a third of the funding to create Dolly, has its eye on the
pharmaceutical market. Cloning, says PPL's managing director
Ron James, could provide an efficient way of creating flocks
of sheep that have been genetically engineered to produce
mild laced with valuable enzymes and drugs. Among the pharmaceuticals
PPL is looking at is a potential treatment for cystic fibrosis.
Nobody at Roslin or PPL is talking about cloning humans. Even
if they were, their procedure is obviously not practical─not as long as dozens of surrogates need to be impregnated
for each successful birth. And that is probably a good thing,
because it gives the public time to find ways to prevent abuses
without blocking scientific progress. If the policymakers
succeed, and if their guidelines win international acceptance,
it may take a lot longer than the editorial writers and talk-show
hosts think before a human clone emerges─even from the shadows
of some offshore renegade lab. "How long?" asks PPL's James. "Hopefully, an eternity."
─With reporting by Helen Gibson/Roslin and
Dick Thompson/Washington
