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Scientific Pitfalls Complicate Cloning Debate

Ben Harder
For National Geographic News
May 31, 2002
 
In an awe-inspiring scene from Episode II: Attack of the Clones, a mass-produced legion of identical men appears to march off an assembly line like so many Ford Model T's. The cloned soldiers look, think, and act alike, and their performance in battle proves beyond a doubt that they are hearty and hale members of the human race.

But scientific theory and experience in the lab show that cloning—either people or animals—may not be as easy as science fiction makes it look. Scientists are still struggling to understand whether it's even feasible to reliably coax molecules of DNA extracted from a single cell to develop into a living genetic replica of an entire organism.

"Cloning is as much an art as it is a science," said Robert Lanza of Advanced Cell Technology in Worcester, Massachusetts.



So while politicians, ethicists, and voters grapple with the vexing questions that surround the morality of cloning, scientists are struggling with a biological rather than an ethical problem: Cloning people might not be safe.

Success—and Many Failures

After years of experiments involving frogs, salamanders, and simpler organisms, cloning hit the big time in February 1997. That month, scientists reported the first successful attempt to reproduce a large, adult mammal through cloning. Nicknamed Dolly, the cloned sheep became an instant media darling and a symbol of the scientific promise of cloning.

Since Dolly, cows, pigs, monkeys, an adorable kitten, and even rare and endangered animals have all been produced through cloning. Some of these have survived to be adults and even reproduced.

But other clones have experienced terrible health problems, and many cloned embryos don't even survive to birth. Not everyone realizes that Dolly was the final success story at the end of a string of unsuccessful attempts and spontaneous abortions. Scores of sheep embryos died before they had even developed to a stage at which scientists could insert them into a live female.

A Complex Process

Cloning an animal is a complex process that can go fatally wrong at any stage. The process, also called nuclear transfer, begins when a nucleus is removed from an egg cell. This DNA-containing packet is discarded.

Next, a nucleus with a complete set of DNA is meticulously extracted from a single cell, itself removed painlessly from the skin or body of the living organism that's to be cloned. That nucleus is transferred by a delicate operation into the nucleus-deprived egg.

The egg then needs to be tricked into behaving as though it has been fertilized, a process that is usually triggered when a sperm fuses with the egg during sexual reproduction.

The pseudo-fertilized egg, containing the DNA of the clone subject, begins to multiply. Once it has grown to a certain size, the tiny embryo must be implanted into the uterus of a female that can nourish it and carry it to term.

"All those steps are critically important," Lanza said. "It's not surprising that you can screw it up." Research teams that have practiced the technique numerous times can get a good success rate, Lanza said. But the process can and often does go disturbingly awry, and there are some situations where practice could be morally unacceptable.

Casualties of Cloning

In late November of last year, Lanza and his colleagues reported the first successful effort to coax a human egg containing DNA from another human cell into beginning the process of developing into an embryo. Eggs containing the inserted DNA began to replicate, but they died after growing to just four or six cells each.

(Several secretive groups of scientists claim to be close to cloning a live human baby, but they have released little information to the public, and their claims have not been verified.)

If animal cloning experiments are any guide, attempts to clone people may face a high rate of failure. Often many nuclei must be transferred from cell to egg for each one that succeeds in developing into an embryo. This so-called wastage is much higher in cloning than in other reproductive technologies, such as in vitro fertilization, said Don Wolf, a researcher working to clone rhesus monkeys at the Oregon Regional Primate Research Center.

Furthermore, Wolf said, "there are suggestions that animals produced by nuclear transfer may not be as healthy as we first expected."

Cloned animals have been subject to an array of health and developmental problems, including oxygen shortage in the womb, infections after birth, ill-formed lungs, and liver damage.

It isn't clear which of these problems are intrinsically tied to cloning, and which may have resulted from poor execution of relatively unpracticed techniques—or even sheer bad luck.

"Our lack of knowledge is grossly apparent, Wolf said. We really don't have much of a clue" about why cloning so often goes wrong, he said.

Fortunately, we do have some guesses. Cloning requires taking a nucleus from an adult cell that is developed for a particular function in a particular part of the body. To properly specialize, nuclei of adult cells turn off certain genes, or certain copies of genes, and turn on others.

But transferring that nucleus out of that cell and into an egg doesn't necessarily guarantee that it will forget its past and revert to the uncommited state of an embryo nucleus, Wolf said.

That inescapable nuclear memory could lead to activation of the wrong genes at the wrong times—and might therefore lie at the root of cellular programming problems that kill many clones.

A study in the journal Nature Genetics, published online on May 28, supports this idea. Jerry Yang of the University of Connecticut, Storrs, and his colleagues reported that cloned cows that die shortly after birth have unusual patterns of inactivated DNA on their X-chromosomes. Cloned cows that lived, on the other hand, have normal patterns of DNA inactivation.

Weighty Problems

Other studies have suggested that cloned mice are much more likely to become obese in middle age. Why this happens is unclear.

Clones can also be excessively large at birth. That might not necessarily be bad for the clone, but the process of giving birth could harm the mother. So-called "large-calf syndrome" affects cows and sheep in particular, Wolf said.

There are also problems with the structure that links the mother to her fetus, called the placenta, which provides the lifeline on which the growing organism depends.

Even when a cloned animal survives to birth and health problems aren't immediately evident, it may suffer developmental problems. Some could crop up years after their birth.

"There could be subtle differences that creep up later on," Lanza acknowledged. But, he said, many animals that survive the first few days of their lives appear to develop normally and healthfully.

Lanza and his colleagues have reported that cloned cows do not typically develop abnormal body weight when they reach middle age. The mid-life obesity phenomenon could be a problem limited to specific breeds of mice, he suggested.

Not Immune?

Hoping to help rescue an endangered cow-like animal called a gaur from extinction, the researchers at Advanced Cell Technology recently cloned one and inserted the embryo into a cow. The cloned gaur survived birth, but the precious animal died from an infection three days later.

Whether the gaur's fatal susceptibility to the infection had anything to do with it being a clone is unknown, but there are some hints that cloned animals could have unnaturally weak immune systems.

One recent study of cloned mice found that the majority of them died within 800 days of birth, apparently of pneumonia. Just one in seven non-cloned mice died so prematurely under the same lab conditions.

Other cloned animals react abnormally to immunizations, perhaps because they don't acquire some of the immune antibodies that fetuses typically inherit from their mothers through the placenta.

Facing the Risk

No one knows whether the difficulties that plague animal cloning will render human cloning impossible or, at any rate, unacceptably risky. But if the only way to find out is to try, and perhaps to try again, the emotional and moral costs could be substantial.

"There's no reason to think biologically that humans would be any [more difficult] than other animals we've cloned," Lanza said. "But each species requires going up a learning curve." Producing Dolly, he noted, required scores of unsuccessful attempts.

When it comes to making copies of organisms, humans aren't experimental subjects on which most scientists are willing to try unreliable procedures. So regardless of how the ongoing ethical debate unfolds, science may hold off on trying to replicate people until it's entirely clear how the process of cloning works—and why it sometimes doesn't.

To put in the terms a certain wise old organism might have used: "Do, or do not. There is no try." But then again, Yoda was one of a kind.

National Geographic EXPLORER's new documentary Clone! presents an in-depth look at the cloning controversy that surrounds how we might one day resurrect extinct species, grow replacement organs, and even make duplicates of ourselves. It premieres Sunday, June 2, at 8:00 p.m. ET/5:00 p.m. PT on MSNBC.

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