More Doubt Cast on Cloning Safety
Strengthening the scientific case against human cloning, researchers have discovered that even apparently healthy clones may harbor unpredictable genetic abnormalities.
In experiments with laboratory animals, scientists at the Whitehead Institute at the Massachusetts Institute of Technology and the University of Hawaii discovered that clones created with embryonic stem cells develop apparently capricious errors in when and how their genes become active. Those errors can lead to premature death or serious abnormality in the resulting animals, the researchers said. The research also found that stem cells themselves are surprisingly unstable.
The findings bolster misgivings about the basic biology of cloning.
Developmental biologist Brigid Hogan of Vanderbilt University and the Howard Hughes 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 have targeted a U.S. laboratory where members of a religious sect allegedly were experimenting with ways to clone a human being. The group is led by a man who claims that he witnessed a UFO landing in 1973 and that humans must create new life through cloning because aliens created humanity. Members told a congressional committee in March that they had hired several researchers to work on cloning.
Two fertility experts also have recently announced their intent to try to clone a human being.
The new research also could influence the debate over a separate use of embryonic stem cells to create tissues for research on diseases and their treatments. The Bush administration is expected to decide soon whether researchers who take government money should be allowed to work on tissues derived from embryonic cells.
Medical researchers hope to use stem cells to produce perfectly matched tissues to replace or repair organs that have stopped functioning, thus treating diseases--including diabetes, heart problems and Parkinson’s--and perhaps allowing the replacement of body parts. The work is controversial because obtaining the stem cells requires the destruction of embryos.
“I am concerned that this [research] may feed those who want to ban the research,” said Robert Lanza, vice president of medical and scientific development at Advanced Cell Technology, which is researching human embryonic stem cells for the treatment of several diseases.
Clones May Not Be Normal
The scientists who conducted the new research, however, said their findings should not alter the potential of stem cell technology as a source of disease therapies. The problems discovered in the new research only arose when the cloned embryos were forced to develop into a mature animal, said Rudolf Jaenisch at the Whitehead Institute, the senior scientist on the project.
Those who support human cloning say the technique could be used as a means of human reproduction for childless couples unable to conceive with more conventional medical assistance, for those seeking to regenerate a loved one, or for people wanting to copy themselves. The new research calls into serious question the safety of all those ideas, cloning experts said.
“Our findings clearly argue against reproductive cloning,” said Jaenisch. “Even apparently normal clones may not be normal. We have the hard evidence now.”
The research suggests that there can be errors in a cloned embryo that even a conscientious infertility specialist could not detect in a screening procedure. That may be an insurmountable safety problem for reproductive cloning, said Alexander M. Capron, an expert on biomedical ethics at the USC Law School who is a member of a national bioethics commission.
“It undermines the claims of those who say that they will be able to select out good cloned embryos from those with abnormalities,” Capron said. “This is a false hope.”
Since 1997, when the first adult mammal was cloned, researchers around the world have successfully cloned sheep, cattle, mice, goats and pigs. A Korean team even reported cloning a human embryo. But researchers have been unable to clone 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 colleagues cloned generations of mice to study the behavior of six genes responsible for normal fetal growth and development. The activity of these genes normally varies depending on which parent they come from.
The researchers looked at embryonic stem cells, which can give rise on their own to all the tissues an organism requires, because they more readily produce clones that survive pregnancy and birth and live into adulthood.
To create genetically identical animals by cloning, researchers transfer the nucleus of an adult or embryonic cell into an unfertilized egg from which the nucleus has been removed. The newly constructed embryo cell contains a full set of chromosomes--much as a normal embryo would--but must revert to a more primal state in which it can recover the embryo’s ability to develop into a new organism.
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 and off at critical moments of development.
Chemical Cues Went Awry
In the research reported today, the scientists discovered that the genes themselves were normal enough in the cloned animals. But the chemical cues that orchestrate when the genes turn on and off went awry in a variety of almost random ways. The activity of the genes varied significantly in the placentas and kidney, heart and liver of cloned mice, compared to normal mice and mice created by in vitro fertilization.
The problems also cropped up when the mice were grown directly from the embryonic stem cells, without the extra step of cloning. The embryonic cells, themselves, seemed extremely unstable when grown in the laboratory, with even sister stem cells showing wide variations in when genes were active, the researchers reported.
The cloning process also appeared to be at fault.
“You don’t see these huge missing chromosomes or a chunk of DNA missing or a mutation,” said cloning expert Mark Westhusin at Texas A&M; University. “What you see is abnormal gene expression, and there is no way to predict it.”
“They are almost like environmental effects, where the environment is the cloning process itself,” Westhusin said.
Despite the genetic problems, many of the cloned mouse embryos survived into adulthood. That suggests that mammalian development is surprisingly tolerant of genetic mistakes, the researchers said.
The researchers studied clones made from embryonic stem cells, so their work does not directly address whether similar flaws may occur in clones made from more specialized stem cells that exist in adults or from adult cells from skin or other mature tissue. The use of adult cells to create a clone is the most common technique when duplicating genetically engineered livestock, but the practice 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 after birth. The placentas that nourish them in the womb often are abnormal. Even those that survive into adulthood frequently are larger than normal.
“So little is known about why cloning of mammals is so inefficient from a purely biological point of view,” Hogan said. “No one knows why the large majority of the clones don’t develop normally.”
Added Capron of USC: “It would certainly seem to me that the problem seen here needs a good deal more basic science exploration in animals before moving on to human beings.”
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