On the website of Ken Cadwell,
PhD, assistant professor of
microbiology, a four-paneled
Japanese screen serves as a
visual metaphor for the
serious inflammatory
intestinal disorder known
as Crohn’s disease. In
three panels, a cherry
branch teeming with
pink blossoms represents
a healthy intestinal tract.
The fourth panel, however,
shows a branch stripped of its
flowers, highlighting a potential
breakthrough in how scientists are
viewing the murky mechanisms of a disorder that
afflicts an estimated one in 500 people.
As some of Dr. Cadwell’s recent studies have suggested, a gene mutation
that promotes susceptibility isn’t sufficient to cause the disease, a notion that’s
suggested by the undisturbed cherry blossoms in the second panel. Nor is a
viral infection enough to disrupt the intestinal status quo, as illustrated by the
third panel. In combination, however, the virus and mutation could strip away a
patient’s protection, as pictured by the bare branch in the fourth panel, and trigger
Crohn’s. The consequences can be devastating. “Many victims of the disease end
up having pieces of their intestines surgically removed,” notes Dr. Cadwell, whose
recruitment was supported by funds from the Helen L. and Martin S. Kimmel
Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine.
“That tells you how crude the treatment options are right now.”
The idea that an external virus or other environmental factor might combine
with an internal gene disruption to spur Crohn’s disease isn’t entirely new. Dr.
Cadwell’s research, however, is among the first to provide experimental evidence
that links specific gene mutations with cell abnormalities that might help explain
the disorder’s tremendous variability. Among its many unexplained quirks,
Crohn’s primarily affects the lower small intestine in some patients and the colon
in others. “We try to paint this disease with a broad brush and say that it’s all
the same disease,” says Dr. Cadwell, “but we’re really talking about a group of
diseases that have certain similarities.”
One of his key findings has come from mice with a mutation in a gene called
ATG16L1, which is genetically associated with Crohn’s disease susceptibility but
extremely common in humans. Clearly, something more is required to trigger
the disease. In the genetically altered mice, Dr. Cadwell and colleagues noticed
a specific abnormality in a cell type that secretes antimicrobial molecules to
control the intestinal flora. The research group then saw the same cell defect in
intestinal samples taken from human patients with the ATG16L1 variant. “The
mice actually told us what to look for in the humans,” says Dr. Cadwell, “and it
turned out to be true.”
To his surprise, mice that had the ATG16L1 mutation but were raised in
a virus-free facility did not have the intestinal defect. When the researchers
deliberately infected the mice with a virus related to one that causes
gastrointestinal infections in humans, the abnormality reappeared. Treating these
mice with antibiotics, however, prevented their Crohn’s-like symptoms.
Nipping Crohn’s
Disease in the Bud
New Procedure Offers Elderly
Patients with Aortic Stenosis a
New Lease on Life
For many elderly people diagnosed with severe aortic stenosis, a progressive narrowing of the aortic heart valve, the situation is a catch-22. While a procedure to
replace their faulty valve is available, as many as one-third—mostly in their 80s
or 90s—are too sick or frail for the surgery. Without a replacement valve, few of
them will survive more than a year or two. But their future may soon be brighter,
thanks to a new procedure called transcatheter aortic valve replacement.
One of these valves is currently being investigated in clinical trials at 41
sites nationwide, including NYU Langone Medical Center. “The first four people
we treated left the hospital within five days and were discharged not to a rehab
facility but to their homes,” reports James Slater, MD, professor of medicine and
director of the Cardiac Catheterization Laboratory. “This could be a tremendous
breakthrough.” Dr. Slater is a consultant to the device manufacturer that sponsors the trial.
Vivian Bell, a pert 91-year-old who once aspired to be an opera singer, is
among those with a new lease on life. Not long after her surgery, she was back attending the opera and taking walks around her Midtown Manhattan neighborhood, her new aortic valve working without a glitch. “I’m happy and I feel good,”
she says.
NYU Langone pioneered cardiothoracic valve replacement through a
minimally invasive surgical approach. Even this technique, however, requires an
incision between the ribs and use of a heart-lung machine—sometimes too taxing
for the infirm. Transcatheter aortic valve replacement is a promising alternative.
Typically, a one-inch-long incision is made in the groin, and a catheter is snaked
through the femoral artery to the aortic valve,
nestled between the aorta and the heart’s
left ventricle. Compressed inside the
catheter is a new valve made of
porcine tissue attached to a frame.
With the help of three-dimensional angiographic
imaging, a sheath is removed,
and the valve expands. The
procedure takes roughly
half the time required for a
standard valve replacement.
“It’s remarkable to see
the valve flower in place,” says
Dr. Slater, “and suddenly a heart
that had been laboring to push blood
through a narrowed valve is obstructed no more. A lot of people
with severe aortic stenosis now
die of the disease rather than
have surgery,” Dr. Slater
notes. “Many of them may
have an alternative if this
new, less invasive treatment
option becomes widely
available. It’s a potential
game-changer.”
A Gas with a Foul Reputation May Hold the Key to Better Antibiotics
Hydrogen sulfide (H2S), the gas that gives a rotting egg its noxious stench, has long
been thought to be a mere by-product when bacteria digest organic matter. A study
by researchers at NYU Langone Medical Center, however, reveals that microbes
make the gas to survive one of the major hazards of cellular life: a storm of reactive
oxygen molecules known as oxidative stress. A normal immune response induces
oxidative stress in bacteria, and most antibiotics do so even more powerfully as part
of their bacteria-killing effect. “Taking away their H2S leaves bacteria much
more sensitive to antibiotics than they would be otherwise,” says Evgeny
Nudler, PhD, the Julie Wilson Anderson Professor of Biochemistry and
senior author of the study, published in the November 2011 issue of
Science.
Drugs that inhibit bacterial H2S production could thus
be a potent addition to the physician’s toolkit, and with so
many bacteria evolving resistance to antibiotics, they are
sorely needed. Researchers recently have found that humans
and other higher organisms actually produce H2S in small
quantities because, at low doses, it has positive effects. “We
now know that H2S, among other things, signals blood vessels
to relax and protects heart cells from injury after an arterial
blockage,” explains Dr. Nudler, whose research is supported by
Timur Artemyev.
Another simple gas, nitric oxide (NO), has similar positive
effects in our bodies. In a landmark study that appeared in Science
in 2009, Dr. Nudler and his colleagues reported that NO helps some
bacterial species survive DNA-damaging surges of oxidative stress.
Alas, only a handful of bacterial species produce NO, so the blocking of bacterial NO
during antibiotic treatment, for example, would be of limited use. But what about H2S?
“Since H2S has beneficial effects like NO’s in higher organisms, we reasoned that it
might have such effects in bacteria, too,” says Konstantin Shatalin, PhD, assistant
professor of biochemistry and lead author of the new study. Searching databases, Dr.
Shatalin found that virtually all bacteria have genes for enzymes that produce H2S—
from plague and anthrax bacilli to the tiny mycobacteria that cause tuberculosis.
Using genetic and chemical techniques to shut down H2S-producing
enzymes in four representative bacterial species, Dr. Shatalin found
that the bacteria did indeed become more vulnerable to oxidative
stress and thus to antibiotics. “Blocking H2S production made
them all highly sensitive to the antibiotics,” he notes, “and
restoring H2S reversed the effect.” The findings, which are likely
to lead to better medicines, also support a fundamental new
concept in microbiology: different classes of bacteria-killing
drugs, which attack bacteria by different routes, all induce
potentially lethal oxidative stress along the way.
Dr. Nudler is reaching out to the pharmaceutical industry
to help him develop drugs that will inhibit H2S-producing
enzymes in bacteria without harming their counterpart
enzymes in human cells. In principle, such drugs would be
administered along with antibiotics to turbocharge their bacteria-
killing effect, even for strains currently considered multidrug
resistant. With this strategy, he says, “we should be able to increase
the efficiency of virtually every class of antibiotic now in clinical use.”
research & clinical spotlight
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