Reprogramming of Genes at Core of Cloning Debate
Panayiotis Zavos’ dispute with the country’s top cloning experts centers on the seemingly magical powers of the egg cell.
Cloning takes advantage of the fact that almost every cell in an animal contains all the genes needed to grow and operate that animal all over again. Those include the genes that control how a fertilized egg grows into an embryo and then into a fully developed baby.
But while fetal-growth genes exist within the cells of adult humans and animals, they have been silenced. Because they are not needed by a mature heart or brain or skin cell, the body has placed a kind of chemical lock on them so they cannot be turned on.
One hurdle in cloning is to remove the locks so these fetal-development genes can be activated. As it turns out, researchers have found something that can do the trick: the egg cell.
To clone a cow, to pick one example, scientists start with a cow egg cell. They remove the egg’s DNA--the material that contains its genes--and replace it with DNA from a different, live cow, often from its skin cells.
The egg removes the locks on the silenced genes, in a process called reprogramming.
Then, the egg divides and grows into a cow embryo, which can be transferred to a surrogate mother and grown to term.
The result is a calf that inherits all its genes from the cow that donated its DNA. By contrast, traditional reproduction involves both an egg and sperm, producing offspring with genes from a mother and father.
However, the cloning process often goes terribly awry. In cloning cows, mice and other animals, most scientists have been able to produce only three to five live animals in every 100 attempts, said Dr. Thomas Okarma, chief executive of Geron Corp., a leading biotechnology firm.
Most cloned embryos fail to grow, experts say, or they die shortly before birth. Others die soon after birth of lung or heart defects. And some that appear normal develop unexplained health problems in midlife.
Rudolph Jaenisch, a cloning expert at the Massachusetts Institute of Technology, said that most of the problems are because of errors committed by the egg cell in reprogramming adult genes. “There are 30,000 genes, and in principle any gene is a target for faulty reprogramming.”
What irks Jaenisch and many other cloning experts is that there is no known way to test an embryo for reprogramming errors. Today’s prenatal tests can find problems with chromosomes--a sign of Down’s syndrome and certain other diseases--or errors in the chemical sequence of a gene, which may suggest cystic fibrosis or other genetic disorders. But scientists are just beginning to understand how adult genes revert to a fetal state in cloning.
Zavos maintains that his team can avoid reprogramming errors. Instead of using adult skin or cheek cells, he said, it is working with special cells in the body known as stem cells, whose genes may carry fewer of the chemical “locks” that require reprogramming. The team is also working on methods to prompt an adult cell to reprogram its genes, even before it is inserted in an egg.
Zavos also says that his expertise in human fertility will allow him to reject faulty embryos and transfer only healthy ones to a patient. He acknowledges that he cannot test for malfunctions in all 30,000 genes and says, “It would be dishonest and irresponsible of us to say we can guarantee 100% success.” But he is confident that his team can produce healthy children.
Jaenisch and other experts say that Zavos’ team may be able to spot embryos that are obviously flawed but that those embryos would likely die on their own anyway.
“The worry is the fetus that appears normal but is not,” Jaenisch said. A subtle brain defect might mean little in an animal, he said, but it would be very important to a parent aching to have a healthy child.
