ST 7 Jul 2001
Evenhealthy clones may have abnormalities
STRENGTHENING thescientific case against human cloning, researchers have discovered that evenapparently healthy clones may harbour unpredictable genetic abnormalities.
In experimentswith laboratory animals, scientists at the Whitehead Institute at theMassachusetts Institute of Technology and the University of Hawaii discoveredthat clones created with embryonic stem cells develop apparently capriciouserrors in when and how their genes become active.
Those errors canlead to premature death or serious abnormality in the resulting animals, theresearchers said.
The research alsofound that stem cells themselves are surprisingly unstable.
The findingsoffer new evidence to bolster misgivings about the basic biology of cloning.
The new research,published in Science yesterday, comes as federal investigators have targeted anAmerican laboratory where members of a religious sect were allegedlyexperimenting with ways to clone a human being.
Two fertilityexperts have also announced recently their intent to try to clone a humanbeing.
The new researchcould also influence the debate over a separate use of embryonic stem cells tocreate tissues for research on diseases and their treatments.
Medical researchershope to use stem cells to produce perfectly-matched tissues to replace orrepair organs that have stopped functioning - thus treating diseases includingdiabetes, heart problems, Parkinson's - and perhaps allowing the replacement ofbody parts.
The work iscontroversial because obtaining the stem cells requires the destruction ofembryos. The scientists who conducted the new research, however, said theirfindings should not alter the potential of stem-cell technology as a source ofdisease therapies.
The problemsdiscovered in the new research arose only when the cloned embryos were forcedto develop into a mature animal, said senior scientist Rudolf Jaenisch at theWhitehead Institute, who is on the project.
Those who supporthuman cloning say the technique could be used as a means of human reproductionfor childless couples unable to conceive with more conventional medicalassistance, for those seeking to regenerate a loved one or for people wantingto copy themselves.
The new researchcalls into serious question the safety of all those ideas, cloning expertssaid.
Los Angeles Times
MoreDoubt Cast on Cloning Safety
By ROBERT LEEHOTZ, Times Science Writer
Strengthening thescientific case against human cloning, researchers have discovered that evenapparently healthy clones may harbor unpredictable genetic abnormalities.
In experiments with laboratory animals, scientists at the Whitehead Instituteat the Massachusetts Institute of Technology and the University of Hawaiidiscovered that clones created with embryonic stem cells develop apparentlycapricious errors in when and how their genes become active. Those errors canlead to premature death or serious abnormality in the resulting animals, theresearchers said. The research also found that stem cells themselves aresurprisingly unstable.
The findings bolster misgivings about the basic biology of cloning.
Developmental biologist Brigid Hogan of Vanderbilt University and the HowardHughes Medical Institute called the research "a technical tour de force.This certainly is raising a flag."
The report, published today in Science, comes as federal investigators havetargeted a U.S. laboratory where members of a religious sect allegedly wereexperimenting with ways to clone a human being. The group is led by a man whoclaims that he witnessed a UFO landing in 1973 and that humans must create newlife through cloning because aliens created humanity. Members told acongressional committee in March that they had hired several researchers towork on cloning.
Two fertility experts also have recently announced their intent to try to clonea human being.
The new research also could influence the debate over a separate use ofembryonic stem cells to create tissues for research on diseases and theirtreatments. The Bush administration is expected to decide soon whetherresearchers who take government money should be allowed to work on tissuesderived from embryonic cells.
Medical researchers hope to use stem cells to produce perfectly matched tissuesto replace or repair organs that have stopped functioning, thus treatingdiseases--including diabetes, heart problems and Parkinson's--and perhapsallowing the replacement of body parts. The work is controversial becauseobtaining the stem cells requires the destruction of embryos.
"I am concerned that this [research] may feed those who want to ban theresearch," said Robert Lanza, vice president of medical and scientificdevelopment at Advanced Cell Technology, which is researching human embryonicstem cells for the treatment of several diseases.
Clones May Not Be Normal
The scientists who conducted the new research, however, said their findingsshould not alter the potential of stem cell technology as a source of diseasetherapies. The problems discovered in the new research only arose when thecloned embryos were forced to develop into a mature animal, said RudolfJaenisch at the Whitehead Institute, the senior scientist on the project.
Those who support human cloning say the technique could be used as a means ofhuman reproduction for childless couples unable to conceive with moreconventional medical assistance, for those seeking to regenerate a loved one,or for people wanting to copy themselves. The new research calls into seriousquestion the safety of all those ideas, cloning experts said.
"Our findings clearly argue against reproductive cloning," saidJaenisch. "Even apparently normal clones may not be normal. We have thehard evidence now."
The research suggests that there can be errors in a cloned embryo that even aconscientious infertility specialist could not detect in a screening procedure.That may be an insurmountable safety problem for reproductive cloning, saidAlexander M. Capron, an expert on biomedical ethics at the USC Law School whois a member of a national bioethics commission.
"It undermines the claims of those who say that they will be able toselect out good cloned embryos from those with abnormalities," Capronsaid. "This is a false hope."
Since 1997, when the first adult mammal was cloned, researchers around theworld have successfully cloned sheep, cattle, mice, goats and pigs. A Koreanteam even reported cloning a human embryo. But researchers have been unable toclone many species, such as rabbits, rats, cats and dogs.
In all species, success rates are low.
To better understand why so many cloned animals either die or are abnormal,Jaenisch and David Humphreys at the Whitehead Institute and their colleaguescloned generations of mice to study the behavior of six genes responsible fornormal fetal growth and development. The activity of these genes normallyvaries depending on which parent they come from.
The researchers looked at embryonic stem cells, which can give rise on theirown to all the tissues an organism requires, because they more readily produceclones that survive pregnancy and birth and live into adulthood.
To create genetically identical animals by cloning, researchers transfer thenucleus of an adult or embryonic cell into an unfertilized egg from which thenucleus has been removed. The newly constructed embryo cell contains a full setof chromosomes--much as a normal embryo would--but must revert to a more primalstate in which it can recover the embryo's ability to develop into a neworganism.
As part of the cloning process, within a few hours of the new cell's creation,its biological clock must be reset. That affects when and how genes turn on andoff at critical moments of development.
Chemical Cues Went Awry
In the research reported today, the scientists discovered that the genesthemselves were normal enough in the cloned animals. But the chemical cues thatorchestrate when the genes turn on and off went awry in a variety of almostrandom ways. The activity of the genes varied significantly in the placentasand kidney, heart and liver of cloned mice, compared to normal mice and micecreated by in vitro fertilization.
The problems also cropped up when the mice were grown directly from theembryonic stem cells, without the extra step of cloning. The embryonic cells,themselves, seemed extremely unstable when grown in the laboratory, with evensister stem cells showing wide variations in when genes were active, theresearchers reported.
The cloning process also appeared to be at fault.
"You don't see these huge missing chromosomes or a chunk of DNA missing ora mutation," said cloning expert Mark Westhusin at Texas A&MUniversity. "What you see is abnormal gene expression, and there is no wayto predict it."
"They are almost like environmental effects, where the environment is thecloning process itself," Westhusin said.
Despite the genetic problems, many of the cloned mouse embryos survived intoadulthood. That suggests that mammalian development is surprisingly tolerant ofgenetic mistakes, the researchers said.
The researchers studied clones made from embryonic stem cells, so their workdoes not directly address whether similar flaws may occur in clones made frommore specialized stem cells that exist in adults or from adult cells from skinor other mature tissue. The use of adult cells to create a clone is the mostcommon technique when duplicating genetically engineered livestock, but thepractice has had an extremely high failure rate.
Even in the most experienced hands, barely one in 100 cloned embryos survives,published data show. Many cloned animals die late in pregnancy or soon afterbirth. The placentas that nourish them in the womb often are abnormal. Eventhose that survive into adulthood frequently are larger than normal.
"So little is known about why cloning of mammals is so inefficient from apurely biological point of view," Hogan said. "No one knows why thelarge majority of the clones don't develop normally."
Added Capron of USC: "It would certainly seem to me that the problem seenhere needs a good deal more basic science exploration in animals before movingon to human beings."