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Therapeutic cloning gives silenced genes a second voice

As controversy continues on therapeutic experiments in Xenopus embryos, is the removal silencing may not be permanent.” cloning to create human embryos, applying the of methyl groups from specific regions of DNA. Jaenisch and his colleagues have also shown technique—also known as somatic cell nuclear This may be a necessary step in the epigenetic that nuclei from a skin cancer cell can be repro- transfer—in animals is generating important reprogramming of the nucleus, the researchers grammed to direct normal development of a insights into disease development. suggest in the October Nature Cell Biology. mouse embryo—meaning that removal of the Some scientists are using the approach to As cells differentiate, they accrue many epigenetic alterations is enough to restore cells study epigenetic alterations—chromosomal other types of epigenetic alterations, such as to normal (Genes Dev.18,1875–1885; 2004).An modifications that do not alter the DNA the addition of phosphates or removal of earlier study reported similar results with brain sequence—which can cause cancer. “A acetyl groups from histones, or chromosomal tumor cells (Cancer Res. 63, 2733–2736; 2003). principal question in cancer research is what proteins, and trigger changes in chromatin Based on such findings, pharmaceutical part of the cancer cell phenotype comes from structure. Defects in these processes have been companies are racing to develop and test ‘epige- genetic defects and what part is epigenetic,”says linked to cancer and other diseases. netic therapies’—for example, drugs that pre- http://www.nature.com/naturemedicine Rudolf Jaenisch, professor of biology at the Tumor suppressor genes are often vent the addition of methyl groups might Whitehead Institute for Biomedical Research. methylated in cancer cells, notes Peter Jones, reactivate silenced tumor suppressor genes. “Nuclear transfer experiments can tell us that.” professor of biochemistry at the University Some such drugs are already in use to treat dis- Therapeutic cloning involves injecting of Southern California. Methylation keeps orders such as myeloid dysplastic syndrome the nucleus of an adult cell into an egg these genes turned off, promoting tumor and sickle cell anemia and are being tested for that has had its own nucleus removed. growth, he says. “It has always been believed some types of cancer. Compounds that can pre- Scientists have found that when the nucleus that once a gene becomes methylated, vent histone deacetylation are also in early clin- of a cancer cell is introduced into an it is permanently silenced,” Jones adds. ical trials for cancer and rheumatoid arthritis. egg, the cell’s epigenetic features are “The [Xenopus] findings show that this Because many normal cells continuously stripped away—a process known as ‘nuclear undergo epigenetic modifications, these drugs reprogramming.’ “This is because epigenetic may have several toxic side effects. They are also alterations, unlike genetic alterations, are unlikely to be effective in cancers whose origin reversible,”says Jaenisch. is strictly genetic.

© 2004 Nature Publishing Group Once injected, the nucleus undergoes The primary benefit from these studies is in dramatic changes in structure and understanding disease mechanisms better, but protein composition that somehow reset the drugs hold some promise of therapeutic its genetic material and allow it to direct benefit. “If we can manipulate the human

embryonic development, says Emory Courtesy: Whitehead Institute epigenome,” says Wade, “we have the potential University geneticist Paul Wade. Reversing cancer: Scientists have cloned a normal to influence a large number of human diseases.” One such modification, as indicated by recent mouse from a melanoma cell. Kris Novak, San Francisco US panel recommends ‘black box’ warnings for antidepressants Advisors to the US Food and Drug many practitioners are convinced these drugs trial registry. On 8 September, the editors of Administration have asked the agency to add work,” said Thomas Newman, an 12 leading medical journals announced that tough warnings to antidepressant medications, epidemiologist and pediatrician at the trials published in their journals must be saying the drugs cause some children to University of California in San Francisco. registered at the outset in a public database. become suicidal. On 14 September, the committee voted 15 Their announcement came one day after The advisory committee said it was to 8 in favor of a so-called ‘black box’ warning the pharmaceutical industry trade concerned by data from 24 clinical trials that would inform patients and doctors about organization PhRMA said it plans to set up a showing that most antidepressant the risks. voluntary database where companies can post medications do not work in children. The Drug companies say the warning may scare results from clinical trials. At a congressional data, most of which has not been published in away children who need the treatment. But the hearing on 9 September, Eli Lilly executive peer-reviewed journals, also showed that these drugs’ critics claimed victory after the hearing, John Hayes explained why the pharmaceutical drugs as a class increase the risk of suicidal saying the episode underscores the need for industry is now eager to act:“There is clearly a thoughts and behaviors in children. full disclosure of data from clinical trials. societal crisis in terms of the credibility of “We have very strong evidence of harm and The controversy over antidepressant use in drug company results,”Hayes said. not good evidence of efficacy, and I know children has accelerated the push for a clinical Erika Check, Washington,DC

NATURE MEDICINE VOLUME 10 | NUMBER 10 | OCTOBER 2004 1005