Scientists Show Cloning Leads to Severe Dysregulation of Many Genes

September 11, 2002

Tags: Jaenisch LabStem Cells + Therapeutic Cloning

CAMBRIDGE, Mass. — New results from Rudolf Jaenisch’s lab at the Whitehead Institute for Biomedical Research confirmed that the cloning process jeopardizes the integrity of an animal’s whole genome. Scientists had suspected this based on studying a mere dozen genes, but the current study, which will be reported online in the Proceedings of the National Academies of Science this week, expansively surveyed 10,000 genes for abnormalities.

Using DNA arrays, the researchers found that approximately one in every 25 genes were abnormally expressed in placentas from cloned mice, and to a lesser extent, the livers of cloned mice exhibited abnormal gene expression. “Recent studies showing premature death, pneumonia, liver failure, and obesity in aging cloned mice could be a consequence of these gene expression abnormalities,” says Jaenisch.

This study establishes unequivocally that the normalcy of surviving cloned animals should not be based on superficial clinical examinations but rather on detailed molecular analyses of tissues from adult cloned animals. In other words, even seemingly “normal-looking” clones may have serious underlying epigenetic abnormalities. Epigenetic defects are not mutations but are caused by faulty reprogramming of the donor nucleus leading to an atypical conformation that results in abnormal gene expression. Thus, cloning for the purpose of producing another human being, known as reproductive cloning, is completely unsafe and unethical.

The data suggest that many factors may contribute to abnormal gene expression in cloned animals including the cloning procedure itself and epigenetic errors inherited from the cell used in cloning. Epigenetic errors can occur in all genes and lead to dysfunction. Currently it is impossible to test for epigenetic errors during pregnancy, since they don’t affect the base sequence of a gene. This work was done in collaboration with Eric Lander at the Whitehead Center for Genome Research.

The cloning procedure, however, can be safely used to create embryonic stem cells to treat diseases such as Alzheimer’s, diabetes, and autoimmune diseases. The procedure, often called therapeutic cloning, involves removing the nucleus, which contains the DNA, from an egg and replacing it with the nucleus from an adult. For instance, the nucleus from the skin cell of an Alzheimer’s patient can be transferred into an emptied egg. The egg resets the developmental clock of the transferred nucleus and the reprogrammed cell starts developing into an embryo that is genetically identical to the patient.

At the stage when the embryo develops into a hollow ball of approximately a hundred cells it is explanted into a petri dish and can give rise to embryonic stem (ES) cells. These cells have the potential to become any cell in the body, including new neurons, muscle cells, and blood cells. Because the ES cells are derived from the patient, they can be used to treat the patient without the complications associated with foreign donor tissue such as immune rejection.

“It is important to remember that embryonic stem cells when combined with normal cells—as is the case with cell therapy—may function fine. Embryonic stem cells used to make whole animals by nuclear cloning, however, will most likely produce organisms that are abnormal, since many of the abnormally expressed genes have defined roles in fetal development,” says Jaenisch.

Earlier this year Whitehead scientists used a mouse model to establish for the first time that a combination of therapeutic cloning, gene therapy, and embryonic stem cell differentiation could be used to create custom-tailored cellular therapies for genetic disorders.

by Nadia Halim

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