Bovine Telomere Length Reprogrammed News Release

Bovine Telomere Length Reprogrammed News Release

September 21, 2000

Cloned Animals Are Not As Old As Their DNA

Telomeres in Cloned Cows Found NOT SHORTER, NOT LONGER but JUST RIGHT

FOR MORE INFORMATION:

Jerry Yang, Professor 860-486-2406
David Bauman, media office 860-486-5627
Website: (includes photos): http://www.oocities.org/uconnyanglab/

[Note: Nature Genetics has lifted the embargo on this article. Direct further queries to:
Dr. Bette Phimister, Editor. Tel: 212-726-9314 Email:B.PHIMISTER@NATURENY.com]

STORRS, Conn. - Professor Xiangahong (Jerry) Yang and his research team at the University of Connecticut studying the way clones age, have produced 10 cloned calves from a 13-year-old cow and found that all the clones have cells of normal calves the same age, and a normal "genetic age" life expectancy.

The findings, reported in the upcoming issue of the journal Nature Genetics,comes a year after a study on Dolly the cloned sheep showed that her cells appeared prematurely old. That study raised serious questions about whether cells from adult animals could become young again through cloning and threatened the hope that future medical treatments could be developed based on cloned cells.

Yang, head of the Transgenic Animal Facility at UConn, compared the telomere lengths in the cloned calves, age matched controls, and donor cells from the aged cow with and without culture. He found:

That cloned cattle have normal telomere lengths
That shortened telomeres of donor cells are restored by the cloning procedure
That cell culture in vitro reduces telomere length
That telomerase activity in cloned embryos is indistinguishable from in vitro produced embryos

Concerns over cellular aging in clones centers on telomeres, lengths of DNA on the ends of chromosones. When a cell divides, chromosones replicate so that each new cell carries the same chromosones. Telomeres act as a molecular clock for cells, and get progressively shorter every time a cell divides. As cells age and telomeres shorten to a certain length, cells can no longer divide entering a stage known as senescence. Eventually the cells die. Because telomeres shrink throughout our lives, many scientists believe that the symptoms of old age are caused in part by these shortened telomeres.

To learn how cellular aging might affect aging of animals cloned from cells, Yang and his UConn research team generated 10 identical calves cloned from the somatic cells of an aged cow. These clones are Dolly's equivalent and created by a similar process. Six of the clones died shortly after birth and the remaining four are now 14 to 15 months of age, appearing healthy and indistinguishable from their naturally produced peers.

Yang asked the question whether Dolly's short telomeres are a singular exception or a general rule for the adult somatic cell clones.

"We compared the telomere lengths of 10 calves cloned from an old cow with those of control calves produced naturally from conventional reproduction," said Yang. "We found that the control and cloned calves have indistinguishable telomere lengths, while the donor cow has significantly shorter telomeres.

"We conducted our telomere assays on these clones back in September to December 1999," Yang continued, "but could not believe our results that our clones had normal telomere lengths, indistinguishable from the controls. We repeated the assays several times and the results were the same. We are very happy that after a lengthy peer review, our paper is finally published in this prestigious journal Nature Genetics."

Yang explained the discrepancy between his study and Dolly's short telomeres to: 1) different species, 2) availability of adult-derived clones for analysis (one vs. ten), and 3) different sources of DNA were used for
analysis (blood cells vs skin cells).

Yang's study also examined the telomere shortening during in vitro culture.They found that the aged donor cow has shorter telomeres and the telomeres were further shortened by in vitro culture. Yet, cloned animals have normal telomere lengths characteristic of their species, suggesting that the cloning procedure restores the telomeres to normal lengths. They further examined the telomerase, which is the enzyme responsible for the elongation of telomeres, in fertilized and cloned embryos. They found that telomerase activity is indistinguishable between the two types of embryos, suggesting that telomere elongation occurs during embryo development for the clones.

Yang's new findings differ from those of another recent study that received extensive coverage in the public press, suggesting that clones from fetal cells aged in vitro are born with genetically "younger" cells than conventionally produced calves.

In April, researchers at Advanced Cell Technology, a Massachusetts-based company interested in using cloning to treat human disease and extend life, announced they had reversed the aging process in six cloned cows they produced with cells that appeared to be younger than the cells of normal cows the same age. They produced the clones from in vitro aged fetal cells. They found that animals cloned from those cells with restored telomeres even
longer than those of normally reproduced newborn cows. This suggested that cloning could expand the life span of cells which in turn would translate into longer life spans in animals.

Referring to his new study, Yang emphasized: "These clones and the aged donor cow provided the opportunity for systematic study to examine whether the shortened telomeres of the aged donor are restored to normal lengths or not in cloned 'offspring'." He also noted that while the cells used to clone the cows in the ACT study were taken from fetal tissue, the cows in their study were cloned using somatic cells taken from an old adult cow.

"Our finding addressed the scientific as well as the public concerns about the 'genetic age' of adult somatic cell-derived clones, the equivalent of Dolly," Yang said. "This is obviously important because this is what
clone-based cell/tissue therapy is all about for diseased adults, particularly aged ones.

"They (ACT scientists) found that their fetal clones had longer telomeres than aged-matched control (cows) whereas we found normal telomere lengths in our adult-derived clones," said Yang. "The differences are likely due to different sources of the donor cells (fetus vs adult) and different culture conditions. The donor cells in our study were cultured only briefly whereas those in the ACT study were cultured to near senescence. Over-compensation in telomere reprogramming is a possibility when near-senescent cells were used for cloning because they are near the limit of telomere shortening."

For more information contact:

Dr. Xiangzhong (Jerry) Yang, Professor in the Department of Animal Science and Head of the Transgenic Animal Facility at the University of Connecticut Biotechnology Center. He can be reached at: Tel: 860-486-2406; e-mail:jyang@canr.uconn.edu

Additional comments may be requested from the following external experts:

Dr. Robert H. Foote
Professor Emeritus, Department of Animal Science; Cornell University,
Ithaca, NY 14853
Tel: 607-255-2050; e-mail: dgb1@cornell.edu

Dr. Thomas Wagner
Professor of Molecular Biology; Director of Oncology Research, Greenville
Hospital System,
Clemson University; Greenville, SC 29605-5601
Tel: 864-455-1565; e-mail: thomaswagner@home.com

Dr. Gary Anderson
Professor and head, Department of Animal Science; University of California
at Davis
Tel: 530-752-1682

Dr. Caird Rexroad
Senior Scientist, USDA; Beltsville, MD 20705
Tel: 301-504-7050; e-mail: Cer@ars.usda.gov

George Seidel, Jr.
Animal Reprod/Biotech Lab; Colorado State University; Fort Collins, CO 80523
Tel: 970-491-5287; e-mail: gseidel@cvmbs.colostate.edu

Dr. Jose Cibelli
Vice President, Advanced Cell Technology; Worcester, MA 01605
Tel: 508-756-1212