Of mice and genes
Molecular biologist Brian Popko takes
a close look at neurologically challenged mice—hoping to help
humans with peripheral nerve diseases.
Every week or so Chicago molecular biologist
Brian Popko goes mouse hunting on the Web. He scans the databases
of a half-dozen mouse mutagenesis centers across the country, searching
for lab mice with intriguing neurological problems—say, shaky
hind legs or weak forepaws. When one catches his eye, Popko turns
to his research team: is this a mouse worth studying?
Photo by Dan Dry
Popko tests a mouse’s grip to learn which genes govern
the cellular processes behind muscle movement.
The researchers in Popko’s lab need mice
whose dysfunctions parallel those of humans who have diseases of
the peripheral nervous system—the system carrying signals
from the brain and spinal cord to the limbs, skin, and internal
organs. Peripheral nerve diseases are associated with problems ranging
from hand numbness in carpal tunnel syndrome to loss of sensation
in the feet of diabetics. Peripheral neuropathies are also linked
to leprosy, malnutrition, autoimmune diseases such as lupus, exposure
to poisons including insecticides, medications for cancer and AIDS,
and infections such as Lyme Disease.
Popko finds mice fascinating for the window
they provide into molecular biology—a discipline that won
his devotion when, as a 14-year-old, he read The Double Helix
by James D. Watson, SB’47—but the researcher is also
driven by the hope that his work will help those with peripheral
“It’s a disease that is intellectually
challenging, but it’s also clinically important,” says
Popko, the Jack Miller professor in neurological diseases. Physicians
who study peripheral nerve disorders don’t know precisely
how widespread they are because the causes are diverse and misdiagnosis
is frequent; a common estimate is that 20 million Americans are
In Popko’s lab researchers use neurological
problems in mice as models for human ailments. By tracking down
the gene(s) behind a mouse’s leg tremor or the frailty of
its grip, the team hopes to learn how particular genes govern the
cellular processes that allow mice to move muscles or regenerate
nerves, to sense heat or feel pressure. Understanding basic functions
in the mouse sheds light on the nervous system of humans, who, despite
appearances, share a great deal genetically and physiologically
with the mice delivered to Popko’s lab.
Once a mouse arrives, the researchers make sure
it’s worth their time: finding the mutant gene among the 30,000
to 50,000 normal mouse genes is a one- to two-year process, and
the lab only studies six to ten mutant mouse strains at a time.
As Popko explains, “Doing a detailed phenotypic analysis on
an individual strain, as well as finding a single mutant base-pair
out of 3 billion nucleotides, is a considerable task.” The
team begins by confirming that a mouse’s neurological problems
mirror those of humans, examining the mouse much as a neurologist
would examine a person: measuring muscle strength, testing reactions
to heat and cold, looking for abnormal gait, and evaluating nerve
If the candidate proves clinically interesting,
Popko and his colleagues breed the mouse and its offspring with
normal mice from another strain with a distinct genetic background.
Of the scores of mice born, about one in four will show physical
or behavioral signs of the mutation. Using the genetic differences
between the two parental strains, Popko’s group links the
mutation first to one of the mutant mouse’s 20 chromosomes,
then to a particular region of the mouse genome, eventually narrowing
the field down to a single gene.
Meanwhile, not far from the lab, the Medical
Center offers clinical care for people with peripheral nerve disorders.
The clinic, in the Duchossois Center for Advanced Medicine, is another
division of the Jack Miller Center for Peripheral Neuropathy, which
provides patient care and education while supporting basic research.
The clinic recorded 500 patient visits in 2002–03, and the
center’s Web site (millercenter.uchicago.edu/index.shtml)
drew 5,700 visitors in August, just three months after it was launched.
Established in May 2001 with a grant from Jack
Miller, a Chicago businessman who suffers from peripheral neuropathy,
the center is headed by Popko, whom Miller helped to recruit in
January 2002 from the University of North Carolina at Chapel Hill.
The patients being treated in the clinic understand
the importance of basic research, says Popko, who occasionally reports
new findings to patient-support groups. “Surprisingly, they
have embraced our approach. They know they have a disease that we
don’t know a lot about and that you don’t hear a lot
about. You don’t see the cover of Newsweek devoted
to peripheral neuropathy, although there are a large number of people
who have it.”
While he cautions that “we are in the
early stages,” the pace of discovery has been fantastically
accelerated by newly developed technologies and databases. These
include techniques for sampling and characterizing the genes of
mice (using cells taken from tail snips); the sequencing of the
human and mouse genomes, both completed in the past two years; and
gene microarrays, in which a computer simultaneously displays expression
patterns of tens of thousands of genes from two mice, illuminating
differences between patterns in mutant and normal mice.
Though the discovery process remains painstaking,
the progress of the past few years was unimaginable when Popko completed
his doctoral research at the University of Miami School of Medicine
19 years ago. “If it were 1984 and I told you I was looking
for mutant genes in eight mouse strains, or even two,” he
says, “you would think I was overly ambitious—or even
insane.” Now, aided by mutant mice, Popko’s team may
help point the way to treating humans with similar peripheral nerve
diseases. The prospect, Popko says, is “exhilarating.”—Cathy