Thursday, July 5, 2001

University of Hawaii

Cloning unsafe,
UH team warns

They've found hidden problems
among mice that they've
cloned at the university

By Helen Altonn

University of Hawaii researchers who pioneered a mouse-cloning technique warn that cloning humans and animals with embryonic stem cells isn't safe.

They've discovered in their work with mice that cloned pups have hidden problems.

"Even if a cloned animal looks normal, it may have a dormant problem," said Ryuzo Yanagimachi, professor of anatomy and reproductive biology, who directs the Institute for Biogenesis Research in the John A. Burns School of Medicine.

He also urges caution in potential use of embryonic stem cells to treat degenerative illnesses because of tissue culture problems.

"We must be careful, but don't give up," said Yanagimachi, who has long been interested in converting embryonic stem cells into specialized cells and tissues to treat diseases.

He participated in two studies expected to create waves among scientists seeking to clone animals or use embryonic stem cells for therapeutic reasons.

"Many people studying DNA might be shocked," Yanagimachi acknowledged.

The findings are the latest in a controversial research area. President Bush supports a bill that would prohibit creation of cloned embryos for research use despite scientific arguments about the lifesaving potential.

Yanagimachi's team works only with mice but some mainland scientists are culturing stem cells from surplus embryos donated by fertility clinics or from aborted fetal tissue.

Other researchers are working on techniques to use stem cells from skin tissue, bone marrow or umbilical cord blood.

Yanagimachi and Dr. Hidenori Akutsu, a "Team Yana" member, collaborated with Rudolf Jeanisch and scientists at Whitehead Institute, Massachusetts Institute of Technology, in research being reported in tomorrow's issue of Science.

"A few years ago people dreamed of fantastic cell beauty in the future," said Akutsu, research fellow in the biogenesis institute and a doctor in the Department of Obstetrics and Gynecology at Fukushima Medical University in Japan .

"Our paper shows we must be more careful. Cloning will never make a correct copy. Especially in the beginning stage, it is very unstable."

Related work led by Yanagimachi and Professor Kunio Shiota of the University of Tokyo was reported in the June issue of Genesis.

Steve Ward, associate professor in the biogenesis institute, and Stefan Moisyadi, research coordinator, joined Yanagimachi and Akutsu in discussing the two papers in an interview.

The UH scientists are among those across the country excited about the potential of embryonic stem cells to advance medical science.

"Medically, it is a very promising area," Yanagimachi said, describing the possibility of using embryonic stem cells to replace dysfunctional cells and tissue causing Alzheimer's disease, Parkinson's disease, heart disease, diabetes and other illnesses.

For example, he said, if embryonic stem cells could be converted to nonworking pancreatic cells, an insulin-dependent person with diabetes no longer would need insulin.

However, he said the recent investigations raise a warning flag, "regardless whether cloning is used for reproductive or therapeutic purposes, including cell, tissue and organ replacement therapies."

Cloned mice aren't perfect copies of the original mice, the researchers found.

They reported in Genesis that many cloned animals have abnormal symptoms at birth, such as "overgrown placentas, increased body weight and respiratory problems."

Some die of hematological or immunological problems before reaching adulthood, they said.

They believe the problem lies in the DNA methylation pattern.

Methylation is the process of molecularly flagging a cell's genes so they are expressed in the right place at the right time to do what they are supposed to do, the researchers explained. Aberrant DNA methylation also can turn off genes and cause defects, according to research by Ohio State University scientists published in the journal Nature Genetics.

Yanagimachi and Akutsu and their colleagues found the methylation pattern isn't stable in clones of embryonic stem cells and can cause health problems. Both research papers indicate methylation patterns change, mainly in the tissue culture even before cloning, Moisyadi noted.

The researchers examined DNA of the placenta and skin of cloned mouse fetuses right before birth and several were incorrectly methylated. Each animal had different abnormalities. Molecular changes occur even in clones from normal cells, Ward said.

"No matter what you do, cloning changes these methylation flags. That's the important thing about cloning," he said. "The first problem was that somehow the mice were fat. That was the first hint that there was change.

"The second change that we suspected, and has been proven twice, is there are many changes in methylation, which is the way DNA is regulated by the cell."

The cloning technique is very inefficient now, with 98 percent of embryos dying, Yanagimachi said.

"It is very likely that the vast majority of cloned embryos die of extensive errors in DNA methylation.

"The one born is an exception, and even with one we may see some problems. It may not be perfectly normal.

"We don't know if we can ever make this cloning safe," Yanagimachi added. "We don't know. We're hoping. Even if cloning becomes safe, it is not for humans. Even for animals, it is not safe."

"A mouse only lives two years; humans 80 years," Ward pointed out, emphasizing the potential of dormant defects in cloned animals.

Since abnormal DNA methylation is known to cause developmental abnormalities and diseases, Yanagimachi said, "It is of primary importance to find a way to eliminate or minimize faulty DNA methylation in cloned offspring, regardless whether cloning is used for reproductive or therapeutic purposes, including cell, tissue and organ replacement therapies."

"Team Yana" has been trying to improve the efficiency of cloning since making international headlines in 1998 with the historic cloning of five generations of female mice.

But the "Honolulu Technique" didn't work after the fifth generation.

The team cloned the first male mouse, Fibro, and has made advances in understanding fundamental questions about biological development.

Yanagimachi also is noted for his work in in-vitro fertilization and freeze-dried sperm technology. He was recently elected to membership in the elite National Academy of Sciences in recognition of his achievements.

University of Hawaii

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