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Thursday, November 23, 2000

By Dennis Oda, Star-Bulletin
Ryuzo Yanagimachi watches as Hidenori Akutsu picks out
one of their cloned mice. Their research using cloned mice
can help explain how genes are imprinted. Their breakthrough
discoveries is being published in the upcoming journal Science.

UH team
breaks new ground
in genetics

The famed mouse-cloners
think their new work will
improve cloning efficiency

By Helen Altonn

The University of Hawaii's famed "Team Yana" has contributed another first to biology textbooks.

Working with mainland colleagues, the UH researchers are using their famed mouse-cloning technique to answer fundamental genetic questions.

University of Hawaii

"It is only the beginning," said Dr. Ryuzo Yanagimachi, professor of anatomy and reproductive biology and director of the Institute for Biogenesis Research, John A. Burns School of Medicine.

The pioneering development, reported in tomorrow's issue of the journal Science, has enormous implications for understanding basic developmental mechanisms and genetic abnormalities.

Research on clones provides the opportunity to work with different combinations of chromosomes.

Yanagimachi and Dr. Hidenori Akutsu, research fellow in the biogenesis research institute, collaborated in the project with scientists at Whitehead Institute, Massachusetts Institute of Technology.

They included Kevin Eggan, who did some work at UH while Akutsu went to MIT; Konrad Hochedlinger, William Rideout and Rudolf Jaenisch.

Their paper is entitled: "X-Chromosome Inactivation in Cloned Mouse Embryos."

Work stimulates other labs

Yanagimachi's team captured international attention two years ago with the historic cloning of generations of mice. However, the "Honolulu Technique" did not work after the sixth generation.

He believes the latest research findings will improve cloning efficiency and explain "what Mother Nature is doing -- the natural process" in biological development.

Other projects are under way at the laboratory using cloning to study blood and brain development, Yanagimachi said in an interview. "The work can stimulate other laboratories worldwide into thinking about how to use cloning to understand basic genetic principles," he said.

Akutsu, a doctor in the department of obstetrics and gynecology at Fukushima Medical University in Japan, said the research will lead to better understanding of molecular mechanisms of normal embryo development and the causes of some forms of cancer.

Another benefit, he said, will be "improvement of cloning technology aiming at the cell replacement therapy."

Associate professor Steve Ward, a new faculty member on Yanagimachi's team, said, "This work is significant because this is one of the first descriptions of how the mother's chromosomes and father's chromosomes normally work together to form a child."

Genetic 'battle of sexes'

There are two copies of each of 140,000 genes in the body -- one from the mother and one from the father, the scientists pointed out.

Most genes are used randomly, but early in the embryonic stage the body gets a signal to use either a maternal or paternal gene. This is called imprinting.

"If they mess up, it causes trouble," Yanagimachi said, noting it can lead to abnormalities.

If the egg were making a cake using genes as a recipe, Ward said, "it could read the father's recipe for chocolate cake or the mother's for pecan pie."

In effect, he said, "it's a genetic battle of sexes in the embryo."

Nature can sort it out

The male has X and Y chromosomes, while the female has two X chromosomes.

But the new study shows nature has a way of ensuring an equal number of X-linked genes, the scientists said.

The egg can reverse a female adult cell to embryonic state, then undergo an X-inactivation process in which one of the chromosomes is silenced.

The reprogramming begins early in development, and the process is random. "We don't know which chromosome is inactivated -- maternal or paternal," Yanagimachi said.

To begin with, "everybody gets half the chromosomes from the mother and half from the father," he said.

The chromosomes must work collaboratively to produce a child, or the embryo will develop abnormally, he said.

Ward noted the "dosage phenomenon," which occurs when there are extra copies of genes instead of only two.

For instance, in Down syndrome, he said, the only genetic defect is one extra 21 Chromosome, second to the smallest chromosome, resulting in mental retardation.

'Dolly' debate is history

The new study settled a debate about Dolly, the cloned sheep that preceded "Team Yana's" historic cloned mouse Cumulina.

The question was whether she has random X-inactivation as normal females do or the same X chromosome in all her cells that was inactive in the mammary cell nucleus from which she was cloned.

The answer: X-inactivation is random in the cells of cloned animals.

The scientists expect that genes on other chromosomes also are reprogrammed in the egg's embryonic stage.

If the egg couldn't fix defective marks on the genes of the X-chromosomes or other chromosomes in the cloned cell, they said, it would result in abnormal development and the embryo's death.

"This is very cutting-edge science," said Yanagimachi, who is also distinguished for his work in in-vitro fertilization and dried sperm technology. "We are just building up."

University of Hawaii

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