is remarkable that the stomach produces such a vicious reagent, it is even
more remarkable that a healthy stomach is unharmed by the acid it secretes.
Understanding the mechanisms of this
and other digestive tract mechanisms at the cellular level is the research
goal of Marshall H. Chip Montrose, professor of physiology and
biophysics at the IU School of Medicine.
Why doesnt the stomach digest
itself? For a few centuries now, that has been an active question,
Montrose says. Our work tries to answer a very old question about
how the stomach defends itself from the acid it secretes.
Montrose has made a career of studying the
structure and functions of epithelial cells in the gastrointestinal tract,
first at Johns Hopkins University and, since 1998, at IU. His research
on stomach acid secretion is causing a rethinking of the way the stomach
defends against acid.
Were learning new facts about
the basic process of digestion, Montrose says. Did you know
your stomach can convert to an alkali-secreting organ, as opposed to an
acid-secreting one, when you fast?
His team has discovered, through microscope
studies of cells in vivo, that there is an unusually reactive pH microdomain
on the surface of cells lining the stomach. This microdomain responds to
its environment, changing the pH from acidic to alkaline and back again,
according to conditions of feasting or fasting. The presence of this dynamically
responsive microdomain was previously unknown. Now, any scientific account
of stomach function must take this newly observed function into account.
Montrose researches the cellular and subcellular
mechanisms of colonic absorption as well. The stomach sends partially digested
food to the small intestine, where nutrients are absorbed into the body.
Undigested food is sent to the colon, the bodys last chance to scavenge
nutrients before the food is removed as waste.
The colon absorbs about 20 percent
of our daily salt and water needs, Montrose explains. If it
fails to claim enough nutrients, we go into a negative electrolyte balance.
Bacteria in the colon produce compounds
that not only stimulate sodium absorption in the colon, but are themselves
then absorbed and metabolized. Montroses laboratory team has discovered
that these compounds stimulate sodium absorption by regulating the pH outside
the absorptive cells, another case of a surprising microdomain that is altering
ideas about gastrointestinal function.
Its really a symbiotic relationship,
mutually beneficial, between colon bacteria and ourselves, Montrose
Montroses research on cell-level mechanisms
in the gastrointestinal tract has potential implications for treatment of
stomach and colon cancer, inflammatory bowel disease, and gastric and duodenal
ulcers. In another new and highly experimental research area, Montrose is
seeking to understand the endogenous
fluorophores of cancerous cells. Natural fluorescence of cells (the mechanism
of absorbing light energy and re-emitting light of a different color) can
change during carcinogenesis. It may be possible, Montrose theorizes, to detect
cellular aberration, even before tumors become visible to endoscopic imaging,
by comparing wavelengths of light.
To do this, Montrose and his laboratory team
are developing a spectroscopy approach, aimed at analyzing the spectral fingerprint
of subcellular organelles in human colon biopsies. This will give researchers
better information about what and where the fluorophores (molecules emitting
fluorescence) are and which wavelengths are best for detection and possible
All of the research conducted by Montrose
and his lab partners relies on access to imaging techniques and the quantitative
interpretation of pictures of living cells and tissues. In part, it is this
application that sets biophysics apart from other fields.
Biophysics defines areas of quantitative
biology and physiology that use the methods derived from modern physics
to answer questions, Montrose explains. Our domain has been
the use of high-resolution imaging and optical methods applied to complex
|Marshall H. "Chip" Montrose, professor of physiology and biophysics at the IU School of Medicine, relies on this recently installed two-photon microscope in his research. Photo Tyagan Miller.|
Confocal microscopy is a mainstay of Montroses
laboratory work. This special microscope device mitigates a problem encountered
when a sample has fluorescent molecules present throughout: light from nontarget
areas interferes with or obscures light from the target area.
This device records fluorescent images
after discarding the out-of-focus light that is always present, Montrose
Techniques such as confocal microscopy minimize
out-of-focus light, but a new imaging technique called two-photon microscopy
may completely eliminate out-of-focus light interference. With the two-photon
system, fluorescence is generated only at the precise target focus, using
two low-energy photons instead of one high-energy photon to excite fluorophores.
Because neither of the two photons has sufficient power alone to excite fluorescence
of the target, only the exact focal spot where photons are abundant has sufficient
energy (photon density) to fluoresce. All two-photon fluorescence originates
from the constrained areas.
Two-photon fluorescence gives us huge
improvements inhigh-resolution imaging when focused deep into thick specimens
like living organs, Montrose says. It should cause a revolution
in in vivo imaging over the next few years.
The two-photon system has an added
advantage, Montrose continues. Conventional fluorescent microscopy
causes bleaching of the entire target, which is often toxic to the living
tissues we study. The two-photon approach limits bleaching to the focal
point only, so damage is reduced. In late April, Montrose and his
laboratory installed a new multiphoton microscope, only the second such
unit on the IU Medical Center campus.
Montrose currently teaches masters,
doctoral, and medical students and is graduate
adviser in the IUPUI Department
of Physiology and Biophysics. His research has clearly changed what he
teaches about the gastrointestinal tract.
Every textbook in the world says that the stomach protects itself from acid by trapping bicarbonate at the surface as a protective layer, Montrose says. Our research disagrees. I avoid teaching the party line on that. I want to change the textbooks.
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