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Scientists report breaking barrier to efficient cloning

March 8, 2013
Courtesy of the RIKEN Center for Developmental Biology
and World Science staff

Bi­ol­o­gists say they’ve cre­at­ed nor­mal, healthy mouse clones with a new tech­nique that can pro­duce cop­ies of cop­ies, and so on, with no ap­par­ent lim­it.

The new meth­od seems to sweep aside bar­ri­ers to safe, ef­fi­cient cloning, said the re­search­ers. They used a var­i­ant of the tech­nique that in 1996 led to the first mam­mal cloned from an adult cell, Dolly the sheep. The pro­ce­dure, called so­mat­ic cell nu­clear trans­fer, in­volves put­ting a cell nu­cle­us con­tain­ing the ge­net­ic in­forma­t­ion of the crea­ture to be cloned, in­to a liv­ing egg with its own nu­cle­us re­moved.

Mouse clones said to be from the 24th and 25th gen­er­a­tions (Im­age cour­te­sy Riken Cen­ter)


Sci­en­tists have pre­vi­ously strug­gled with low suc­cess rates and lim­its on how many times mam­mals could be re­cloned. At­tempts at re­clon­ing cats, pigs and mice more than two to six times had failed. 

In the new work, Teru­hiko Wa­ka­ya­ma at the RIKEN Cen­ter for De­vel­op­men­tal Bi­ol­o­gy in Ko­be, Ja­pan, led a team that tweaked the tech­nique to make 581 clones of one orig­i­nal mouse through 25 con­sec­u­tive rounds of cloning. There was no vis­i­ble drop in the suc­cess rate, the re­search­ers said, re­port­ing their find­ings March 7 in the jour­nal Cell Stem Cell.

“One pos­si­ble ex­plana­t­ion for this [past] lim­it on the num­ber of re­clon­ing at­tempts,” Wa­ka­ya­ma said, “is an ac­cu­mula­t­ion of ge­net­ic or ‘epige­net­ic’ abnor­mal­i­ties” over genera­t­ions. Epige­net­ic changes are al­tera­t­ions to DNA func­tion that don’t in­volve a change in the DNA code it­self.

To pre­vent these aberra­t­ions, Wa­ka­ya­ma and his team added a sub­stance called tri­cho­statin to the cell cul­ture me­di­um used for the pro­cess. Tri­cho­statin is a his­tone de­acety­lase in­hib­i­tor, a com­pound that pre­vents chem­i­cal changes to DNA-associated struc­tures called his­tones. These changes in turn can cause epi­ge­net­ic abnor­mal­i­ties by af­fect­ing the way DNA is “pack­aged.”

Wa­ka­ya­ma and col­leagues said they in­creased cloning ef­fi­cien­cy by up to six­fold and im­proved each step of the pro­ce­dure. The 581 mice ob­tained through se­quen­tial cloning were all healthy, fer­tile, gave birth to healthy pups and lived about two years, like nor­mal mice, the sci­en­tists said.

“Our re­sults show that there were no ac­cu­mula­t­ions of epige­net­ic or ge­net­ic abnor­mal­i­ties in the mice, even af­ter re­peat­ed cloning,” wrote the au­thors. “This tech­nique could be very use­ful for the large-scale pro­duc­tion of superior-qual­ity an­i­mals, for farm­ing or con­serva­t­ion pur­pos­es,” added Wa­ka­ya­ma, who al­so made the news in 2008 when his team cre­at­ed clones from the bod­ies of mice fro­zen for 16 years.


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Biologists say they’ve created normal, healthy mouse clones with a new technique that can produce copies of copies, and so on, with no apparent limit. The new method seems to sweep aside barriers to safe, efficient cloning, said the researchers. They used a variant of the technique that in 1996 led to the first mammal cloned from an adult cell, Dolly the sheep. The procedure, called somatic cell nuclear transfer, involves putting a cell nucleus containing the genetic information of the creature to be cloned, into a living egg with its own nucleus removed. Scientists have previously struggled with low success rates and limits on how many times mammals could be recloned. Attempts at recloning cats, pigs and mice more than two to six times had failed. In the new work, Teruhiko Wakayama at the RIKEN Center for Developmental Biology in Kobe, Japan, led a team that tweaked the technique to make 581 clones of one original mouse through 25 consecutive rounds of cloning. There was no visible drop in the success rate, the researchers said, reporting their findings March 7 in the journal Cell Stem Cell. “One possible explanation for this [past] limit on the number of recloning attempts,” Wakayama said, “is an accumulation of genetic or ‘epigenetic’ abnormalities” over generations. Epigenetic changes are alterations to DNA function that don’t involve a change in the DNA code itself. To prevent these aberrations, Wakayama and his team added a substance called trichostatin to the cell culture medium used for the process. Trichostatin is a histone deacetylase inhibitor, a compound that prevents chemical changes to DNA-associated structures called histones. These changes in turn can cause epigenetic abnormalities by affecting the way DNA is “packaged.” Wakayama and colleagues said they increased cloning efficiency by up to sixfold and improved each step of the procedure. The 581 mice obtained through sequential cloning were all healthy, fertile, gave birth to healthy pups and lived about two years, like normal mice, the scientists said. “Our results show that there were no accumulations of epigenetic or genetic abnormalities in the mice, even after repeated cloning,” wrote the authors. “This technique could be very useful for the large-scale production of superior-quality animals, for farming or conservation purposes,” added Wakayama, who also made the news in 2008 when his team created clones from the bodies of mice frozen for 16 years.