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Cloning and Stem Cell Science: Learning from Nature

By Nancy Touchette

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Stem Cells

Several weeks ago researchers from Korea cloned the first human embryos. The researchers had no intention of creating designer babies. Instead, they used cells from the cloned embryos to create embryonic stem cells, in a procedure known as therapeutic cloning.

Cloned human embryo at the two-cell (left), four-cell (center) and eight-cell (right) stage.

The first mammal to be cloned, Dolly the Sheep, was born seven years ago, and researchers have been cloning frogs and flies for decades. The fact that it has taken so long to clone a human underscores the hurdles—both technical and legal—that researchers around the world have faced in trying to achieve the same goal.

“The egg is unique in its capacity to specify all the cells needed for an organism to develop,” says Paul deSousa of the Roslin Institute in Edinburgh, Scotland, where Dolly was cloned. “You can take a nucleus out of a mature cell and put it in an egg. Every now and then the conditions are just right and that nucleus can now specify an entire organism. If that’s not remarkable, I don’t know what is.”

How Does the Egg Do It?

Researchers are interested in therapeutic cloning because it may enable them to create special cells that can be used to treat disease.

But researchers also just plain want to know how the egg does it. How does the egg, a single cell, know how to program the genome so that at the end a living, breathing person emerges with just the right number of fingers and toes, and the right kinds of cells, tissues, and organs?

The egg is the ultimate stem cell because it creates all the cells needed to make a person. Understanding how an egg’s genome is programmed may help researchers figure out how to take stem cells and coax them into becoming the kinds of cells and tissues they want for medical use.

Right now, stem cell researchers rely on eggs and embryos because that’s as far as the science has gotten. What they would really like is the ability to make therapeutically useful stem cells without using eggs or embryos.

DeSousa says that before devoting too much effort to using current cloning methods for creating new stem cells, it’s important to understand the how the egg successfully programs the genome.

“We should spend time understanding how the egg accomplishes this feat,” he says. “Once we understand this, then we talk about revolutionizing medicine.”

Under the best circumstances—even in experimental animals—cloning is extremely inefficient. Often, many embryos must be generated to yield a single clone. And even among the successful clones, some animals get sick and die.

How was the first human embryo cloned? Gently.

Scientists have made incremental advances in cloning by tweaking the system—making slight changes in technique and culture conditions. For example, researchers who cloned the first mules last year increased the concentration of calcium in the culture medium.

To successfully clone human embryos, researchers used a more gentle method for extracting the nucleus from the donor cell. They also increased the time between the transfer of the donor nucleus and the activation of the egg.

But most researchers believe that if stem cells or cloning technology are to be useful in someday treating disease, more drastic improvements are necessary.

The heart of the problem lies in the nature of the genome. In humans, the genome contains 30,000 genes nestled among 3 billion base pairs of DNA. As the embryo grows from a single fertilized egg, these genes must be exquisitely programmed to turn on and turn off at just the right time.

One way to understand how the appropriate genes are turned on and off is to figure out what happens when the nucleus of a specialized, or mature, cell is removed and placed in an egg with no nucleus.

“We really need to understand the difference between an embryonic cell and an adult or mature cell,” says Rudolf Jaensich of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts. “We need to know how the mature nucleus is reprogrammed. Right now, we know so little.”

Genes from Mother or Father May Hold Key

When a cell matures or becomes specialized, as a heart, liver, or skin cell for example, it only keeps a certain fraction of genes turned on—those genes needed to keep the cell functioning. But when nucleus of a mature cell, such as a liver cell, is taken out and placed into an egg, the slate is wiped clean. Something in the egg causes many of the liver genes to turn off and a new set of genes to turn on.

Scientists don’t know exactly what triggers the massive changes in the nucleus of the egg that determine how it develops. But they do know that to be properly programmed the genome needs to make certain genes active and accessible.

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This is accomplished in part by adding tags to genes or whole regions of DNA. But just which genes are marked and which are not remains a big mystery.

A critical part of the process is something called imprinting. A person inherits two copies of each gene—one from the mother and one from the father— but only one copy is active. A relative handful of genes—50 or so—are specially marked, or imprinted, so that only the maternal or paternal copy is used.

These imprinted genes seem to control how other genes in the genome are precisely regulated. If imprinted genes are altered, embryos cannot develop properly.

“We will never clone anything successfully until we understand imprinting,” says Jaenisch.

Most researchers understand the ethical implications of cloning and stem cell research and object to using the technology to produce babies. But they also believe that therapeutic cloning may provide the best way to learn the tricks nature uses. These same tricks, researchers hope, could enable them to create diverse cells that could be used to treat disease.

“Ultimately, we want to be able to reprogram somatic cells without having to resort to the egg,” says deSousa. “We don’t need to fear technology, but we need to move it forward in a responsible fashion.”

Rhind, S.M. et al. Human cloning: Can it be made safe? Nature Rev. Gen. 4, 855-864 (November, 2004).

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