Mice, made to order.
At laboratories across the country, biologists create mice with a
genetic makeup to assist colleagues hunting for the causes of human
The rodents are transgenic, meaning that scientists have taken a
gene - sometimes human, sometimes mouse - and transferred it, said Dr.
Pearson-White, director of the University of Virginia's Transgenic
"Transgenic is, you're adding something, a different color, activity
oncogene," which causes cancer, she said.
The U.Va. center, and a similar lab at Virginia Commonwealth
also creates so-called "knock-out" mice, which lack one or more of
80,000 or so genes.
The mouse is now one of the most frequently used mammals in medical
behavioral research. Early in the 20th century, its potential to shed
the genetic study of human diseases was recognized by scientists
established the Jackson Laboratory, based in Bar Harbor, Maine, which
a well-known mouse farm.
Not only is the mouse genome about the same size as the human
(approximately 3.1 billion base pairs), the two share virtually the
of genes. Because the DNA sequence of the mouse could help identify
human genes, the same federal project that sequenced the human genome
to do the same for the mouse, finishing up this spring.
"Because mice and humans share many of the same fundamental biological
behavioral processes, this animal is one of the most significant
models for human disease," the former director of the National
Health, Dr. Harold Varmus, has said.
Mice are valued "fuzzy test tubes" for their fecundity and relatively
maintenance costs. They come of age about eight weeks after birth, and
produce several pups in a single litter.
In recent years, their shared mammalian inheritance with humans has
particularly helpful in transgenic research, which allows scientists
human genes in action - or even inaction, when they've been knocked
specific groups of cells.
Recognizing that tremendous potential, VCU in January opened a
produce transgenic and knock-out mice. Directed by geneticist Dr.
Windle, the lab produces animals to reveal the actions of a wide array
genes, including those involved in lungs, bone and skin as well as the
"Of mice and men" takes on new meaning when a human gene that causes
cancer can be injected into mouse embryos and then studied by
specialists eager to uncover how the tumors begin and how to stop
"There's not a field in biomedical research where these tools can't
used," said Windle.
"These animals make it possible," Pearson-White said, to study
ailments in an animal model "as close to people as reasonably,
Dr. Tim Bender, a U.Va. microbiologist, says the transgenic mice
crucial to his work studying gene regulation of white blood cells
lymphocytes. Pearson-White's lab recently produced for him a line of
overexpress a cancer-causing gene called "myb."
Without the gene, mice can't make blood, and don't survive. Until
transgenic mice in which myb (pronounced "mib") was overexpressed
mice in whom myb was on all the time, killing the animals. New
allowing Pearson-White and Bender to make transgenic mice in which
expression is controlled "in space and time," Bender said.
With the new mice, Bender will be able to control when and where myb
turned on. The animal will develop normally with myb turned off, and
be given a drug that will act like a pharmaceutical remote control to
myb in certain lymphocytes.
"At this point, we don't know that it's going to work," Bender said.
the myb mice have the potential to shed new light on the gene's
human diseases such as colon cancer and breast carcinomas.
"Without Sonia's facility, that work can't be done," Bender
Pearson-White began the lab at U.Va. in 1992, when she realized
techniques allowing researchers to put genes of one species into
lend itself to her work studying genes that control skeletal
The technology was just a couple of years old, but Pearson-White knew
was incredibly powerful."
She went to the Cold Spring Harbor Laboratory in New York to learn how
inject foreign genes, called DNA constructs, into mouse embryos,
to surrogate mothers, and raise them in an environment free from
barking dogs or cats.
Since then, the U.Va. lab has created more than 500 "founder lines" of
from 181 DNA constructs for 32 Virginia investigators, she said. Each
about 40 mice.
In its freshman year, the VCU facility has provided mice for seven
and is working with more investigators on how to use the made-to-order
other research, Windle said.
"A lot of what we do is looking at gene regulation," Pearson-White
Cancer researchers need to understand how and what turns "on" an
may someday use that knowledge to guide them in developing gene
can treat patients.
Costs vary from lab to lab, but at U.Va., for about $3,405, the
receives some 30 to 50 mouse pups, of which about 15 percent are
Taking a mouse embryo and inserting new genes is not the same as a
company changing a part in its latest model. Biology, Pearson-White
particular and has its own rules.
"It is hard," she says. "There are so many steps that could all go
Too much foreign DNA, for example, can be lethal. And the chemicals
researcher uses to produce the foreign DNA also can be fatally
"The magic is you can do it at all," she says.
The process of creating transgenic mice is basically the same. At
DNA injection begins with a "starter" mouse from the Jackson Lab, a
is one-quarter black and three-quarters brown. The lab has a stable of
males, who despite vasectomies romance the female mice at night,
Eggs from the females, which have been given hormones, are harvested
morning from the fallopian tubes. The embryos are removed, and the
The embryos are transferred to a dish containing a soupy mixture
growth-promoting chemicals. Narrow-tipped pipettes, filled with
are attached to a microscope, and a technician viewing the dish
them, poking the embryos cautiously and releasing the DNA.
A single technician does this 200 to 300 times a day, in the
afternoon when the embryos are still young. The engineered embryos are
implanted into the oviduct of a white surrogate mouse, and the pups
in about three weeks.
Not all pups carry the transgene. A sliver of tail is taken from each
check its DNA to determine which are transgenic. Some will be merely
in which only a small subset of cells carry the transgene, which then
transmit to offspring.
Knock-out mice have a better success rate - about a third - in part
they are implanted in the uterus, rather than the fallopian
Three weeks after birth, after weaning, the mice are transferred
this time to the client-researcher elsewhere on the U.Va.
campus.INFORMATION U.Va. Transgenic Mouse Core Facility:
VCU Transgenic Mouse Core Facility:
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