The Mouse shall show the way
amazing research is being done in two different labs, but
with one common thread: the mouse. What these two research
groups learn may greatly affect world health.
also: Of Mice and Men
By Charlotte Crystal
live fast lives. They generally are born, grow old and die within
two years, their limited longevity making them ideal for medical
using mice in experiments, you can speed up your studies, seeing
effects in a month that would take years to show up in people,
said Stuart Berr, an assistant professor of radiology and biomedical
also serve as good proxies for humans in medical research since
about 99 percent of the approximately 30,000 genes in humans and
mice are essentially identical, inherited from a common ancestor
some 75 million years ago. So genetically engineered mice, in
which individual genes either have been added as in transgenic
mice or subtracted as in knock-out mice
have become an important tool for scientists studying how
human genes work.
why an estimated 25 million mice now are used in research laboratories
around the world. One of the largest suppliers, The Jackson Laboratory
in Bar Harbor, Maine, alone sold 1.9 million mice in its most
recent fiscal year to research labs, including many at U.Va.,
said Joyce Peterson, a Jackson spokeswoman. And demand for the
nonprofit institutes 3,000 strains of mice is rising by
10 percent a year, she said.
studying mice that have survived heart attacks or a myriad
of other human ailments researchers can identify new avenues
for treatment of human disease, said Fred Epstein, an associate
professor of radiology and biomedical engineering who works with
to the American Heart Association, cardiovascular disease affects
more than 61 million Americans and is the leading cause of death
in the United States, claiming more than 900,000 lives a year.
researchers in the U.S. and around the world are seeking new treatments
for cardiovascular disease. But the labor is long and paths are
many, some of which lead nowhere. How can researchers identify
the most promising approaches?
Thats where Berrs expertise comes in. Berr helps researchers
analyze the results of their experiments by adapting medical imaging
tools to make the measurements they need.
helps U.Va. researchers with three different methods of medical
imaging that have been adapted for use with small animals:
A magnetic resonance imaging, or MRI, system that has been adapted
to show an image of a tiny mouse heart beating very fast.
A system developed by Mark Williams, associate professor of radiology,
that combines high-resolution, three-dimensional X-ray scans with
images of radioactively labeled compounds that travel to specific
targets (e.g., the lungs, a tumor, etc.).
A bioluminescence scanner that allows researchers to track cells
that have been labeled with light-emitting proteins, such as firefly
luciferase. The images of firefly light are superimposed onto
regular photographs to identify the regions of interest.
1999, Brent French, a molecular biologist and associate professor
of biomedical engineering, has worked closely with Berr to adapt
MRI to mouse research at U.Va. Since then, the cardiac MRI team
has developed several MRI methods for mouse cardiac research that
enable investigators to better understand what happens during
a heart attack and explore ways to minimize the damage after a
member of the team, Zequan Yang, assistant professor of research
in biomedical engineering, is studying the role of inflammation
in heart attacks. By studying the response to heart attack
in transgenic and knock-out mice, we can learn what
role individual genes play in the process, Yang said.
technical barriers are high. Unlike human hearts, which beat 60
to 80 times a minute in an average adult, a mouse heart beats
about 500 times a minute. And at 7 millimeters long about
the size of Thomas Jeffersons head on a nickel a
mouse heart is about a 1,000th the size of a human heart. So,
the equipment must be sensitive, accurate and fast.
team is working to acquire and display data so that particular
measurements of a pumping heart can be made and shown as two-dimensional
of the questions Berr is exploring with French and Epstein is
the effect that a small heart attack has on the rest of the heart.
Not only does the heart attack itself kill and damage muscle tissue,
but the gene expression of the muscle also changes, causing further
loss of muscle function.
mouse heart images show baseline cardiac function.
researcher, Chris Kramer, associate professor of radiology and
director of cardiac MRI for the U.Va. Health System, is working
on a related question. After a heart attack, the left ventricle,
which pumps the oxygenated blood to the rest of the body, remodels
itself. Kramer is trying to understand how the heart knows to
change its shape.
MRI technology that Berr has adapted allows researchers to see
differences in hearts after heart attacks.
weve seen is that there are three areas of impact
the immediate area, in which the tissue has been killed outright;
the adjacent area; and the area remote from the dead muscle tissue,
said Wesley Gilson, a graduate student studying with Epstein and
French. Gilson is measuring the impact of a heart attack on the
motion of the nearby heart muscle wall in genetically manipulated
mice. Epstein said Once we understand which genes are involved,
we can go on to develop targeted drugs for use in humans.
Of Mice and Men
By Elizabeth Kiem
scientific contribution of the laboratory mouse just got even
years after the celebrated breakthrough of the human genome project,
scientists now have something to compare it with: a working draft
of the genome of the common mouse.
impact comes from being the second one. With the human one, we
had nothing to compare it with, said Sonia Pearson-White,
director of U.Va.s Transgenic
Mouse Core Facility.
the two genetic maps turned up only about 300 genes, or 1 percent,
that are unique to either species. Many portions of the genome
show identical ordering, allowing geneticists to fill in holes
in the human map.
there is a big area that is known to be syntenic [falling on the
same chromosome] they can use the sequences to align and help
close the gap, said Pearson-White.
the portions of the sequencing that diverge allows biologists
insight into evolutionary processes. Pearson-White noted that
many of the genes found in mice but not humans serve olfactory
functions that humans have discarded.
researchers will focus more closely on the shared genotypes. As
many as 90 percent of the genes implicated in human diseases like
cancer, hypertension and diabetes appear to be shared. This validates
the role of the transgenic mouse in medical experiments.
key to all this is understanding all the genetics in the mouse,
because You can do a lot of breeding studies in mice, said
Dr. Jerry Nadler, chief of endocrinology and metabolism. Nadlers
work is in understanding the gene or genes that are responsible
for the destruction of cells that produce insulin, resulting in
the Transgenic Mouse Core Facility, Pearson-White assists U.Va.
researchers in creating models of human diseases in mice. The
process, known as a knock-out, involves injecting
mutated embryonic stem cells into mice embryos, which will transmit
the mutation into subsequent generations. No other species will
pass on the mutation through the germ lines.
dont understand why we cant do it in other species.
Nor is it understood why it works in the mouse, said Pearson-White.
Genome all the genetic material in the chromosomes
of a particular organism; its size is generally given as its
total number of base pairs.
Syntenic two genes that occur on the same chromosome;
syntenic genes may or may not be linked.
Transgenic containing foreign DNA. Transgenic mice
contain foreign (e.g. human) DNA in addition to the complete
last month, when the mouse genome became publicly available, biologists
had to clone large portions of DNA in order to narrow down the
mutation target. That is slow and painstaking legwork.
what you can do is go on-line and have the sequence. Then all
you have to do is a couple of quick experiments to verify it,
said Pearson-White. I would say its taken six months
to a year off of approaching a knock-out, and that is just incredibly
The working draft of the mouse genome is currently 2.5 billion
DNA letters long and has codes for 30,000 genes. Researchers
hope to complete the map by 2005.
human genome also contains about 30,000 genes, but fewer
appear to be active as in the mouse genome.
99 percent of human genes have a corresponding gene in the
the mouse and human genomes reveals 1,200 new human and
9,000 new mouse genes.
addition to running the Core Facility for genetic research on
mice, Pearson-White is head of a team that is studying a gene
that regulates growth and differentiation of stem cells. For her
work, the most important revelation of the mouse genome was the
evidence that much of the genetic coding shared by mice and humans
dictates regulatory function, as opposed to cell building.
was one of the surprises, that there were so many things that
werent just coding for proteins that were conserved,
she said. What are these conserved regions? What are they
telling us about what is important for the regulation of a gene?
mouse genome, published in Nature magazine, is available on-line
It joins fruit flies and roundworms on the list of mapped genetic