Muse Transgenic Clones

Rcjohnsen rcjohnsen at aol.com
Mon Feb 14 17:52:45 EST 2000


EMBARGOED FOR RELEASE: 31 JANUARY 2000 AT 17:00 ET US
Contact: Seema Kumar
kumar at wi.mit.edu
(617) 258-6153
Whitehead Institute for Biomedical Research 
Scientists develop most efficient mouse cloning strategy to date, create
transgenic clone  
   Tetley is no ordinary mouse. And it's not just because he's a clone. Tetley
is special because he was created using a new technology that researchers say
has produced the most efficient results to date for cloning mice. He is also
the first mouse clone whose genetic material was modified in the laboratory
before cloning. The technology used to create Tetley, say researchers, will
have a major impact on improving the efficiency of cloning in general. 
   In the February issue of Nature Genetics, researchers, led by Dr. Rudolf
Jaenisch at the Whitehead Institute for Biomedical Research, report that they
have successfully used embryonic stem cells to clone mice with the highest
efficiency to date. Their study comparing clones generated by two different
donor strains suggests that the genetic make up of donor cells plays a key role
in determining the viability of clones. 
   In addition, the scientists show for the first time that it is possible to
modify the genetic material in embryonic cells before using these cells to
clone new animals. The scientists inserted a gene derived from the tetracycline
(tet) receptor into an embryonic stem cell and then transplanted the modified
genome into an egg cell whose genetic material had been removed. The result was
Tetley: a transgenic clone who now carries the tet gene. The new technology
will improve cloning efficiency by providing researchers the genetic tools
needed to understand why so few clones survive to term and grow into healthy
adults. 
   "Our technology will help scientists tackle one of the major challenges of
mammalian cloning‹the low numbers of viable clones," says Dr. Jaenisch. "Most
clones die during gestation or soon after birth, and there are many possible
reasons for this, including genetic make up of the donor, the cell-cycle stage
of the donor cell, loss of genetic information, or the inability of the egg
cell to reprogram the donor cell nucleus." 
   Assessing the impact of these factors on cloning efficiency has been
difficult because most cloning experiments have used somatic cells‹adult cells
that have specialized to perform specific functions in the body. Somatic cells
have a limited lifespan, and they are difficult to manipulate genetically. As a
result, they make poor tools for studying the genetic basis of cloning
efficiency. 
   The technology of cloning using embryonic stem cells removes that obstacle,
allowing researchers to study the various parameters that affect cloning
efficiency, says Dr. Jaenisch. Embryonic stem cells normally direct the
development of an entire animal. They can grow indefinitely in culture and can
also be genetically manipulated to carry extra genes or knock-out genes under
study. Thus they provide researchers the perfect genetic tool to study cloning.

   Although the Federal government and most scientists believe human cloning to
be unethical, experts agree that improving cloning technology could have real
benefits in agriculture and animal husbandry, as well as in biomedical research
designed to decipher the mechanisms of disease. The mouse, in particular, is
considered the best mammalian model system to study the genetic basis of human
disease. 
   In the Nature Genetics study, the Jaenisch lab and their collaborators at
University of Hawaii produced mouse embryos by transplanting genetic material
from embryonic stem cells of two different strains of donor mice into
enucleated egg cells. They then implanted these embryos into surrogate mice.
After the transfer, 7 of the 34 embryos‹21percent‹from the first strain
developed to term and grew into healthy adults. By contrast, only 8 of 76
embryos made from the second, more inbred strain developed to term. All 8 died
within 24 hours after birth, demonstrating that genetic make up of donor cells
may be a key to survival of clones. 
   "Embryonic stem cells from outbred mice created clones with better
efficiency than embryonic stem cells from inbred mice. Thus, the ability to
generate viable clones from ES cells might be correlated with their genetic
diversity," says Dr. William Rideout, a postdoc in the Jaenisch lab. 
   Scientists also found that the survival rate of transferred embryos was
higher with cloning using embryonic stem cells rather than somatic cells,
probably because embryonic stem cells need less reprogramming of gene
expression (i.e. turning back of the developmental clock) than somatic cells. 
   This and other information from ES cell cloning will help researchers
maximize cloning efficiency. 
Finally, this study points to a new way of making transgenic animals that could
be faster and more efficient, say scientists. "Transgenic science is an
important research tool because it allows us to insert mutations in a gene and
study how it affects the whole animal. If we know which gene is mutated in a
particular human disease, we can develop mouse models with the same mutation,"
says Dr. Rideout. 
   Today, mouse models of diseases such as epilepsy, colon cancer,
hypertension, and diabetes are providing new insights into the genetic basis of
these diseases, but transgenic animals are cumbersome to make and it takes
three to nine months for scientists to create a new strain. Scientists say that
using targeted ES cells to clone animals will cut down by one-third the time it
takes to create mouse models. 
### 
   The study was funded in part by the National Institutes of Health. 
The title of the Nature Genetics report is "Generation of mice from wild-type
and targeted ES cells by nuclear cloning." The authors are: 
William M. Rideout III, Whitehead Institute for Biomedical Research
Teruhiki Wakayama, University of Hawaii
Anton Wutz, Whitehead Institute for Biomedical Research
Kevin Eggan, Whitehead Institute for Biomedical Research
Laurie Jackson-Grusby, Whitehead Institute for Biomedical Research
Jessica Dausman, Whitehead Institute for Biomedical Research
Ryuzo Yanagimachi, University of Hawaii
Rudolf Jaenisch, Whitehead Institute for Biomedical Research




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