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Bench to Bedside
Heparin is an inexpensive "blood-thinning" drug that doctors use to stop
blood from clotting. The medicine is widely prescribed to treat dozens
of health conditions in which blood clotting can be especially dangerous,
such as stroke and many heart disorders. Now, NIGMS grantee Ram Sasisekharan
of the Massachusetts Institute of Technology in Cambridge has unearthed
a brand-new potential use for heparin: treating cancer. Sasisekharan is
a biochemist who studies the sugar molecules, or carbohydrates, that coat
the surfaces of cells. To investigate the potential importance of a cell's
sugar "coat" in the development of cancer, he and his coworkers injected
an enzyme called heparinase into mice with tumors. Heparinase is an enzyme
that cuts up complex sugars, generating molecules of heparin. The researchers
found that one particular heparinase treatment slowed the growth of skin,
lung, and prostate tumors in the mice. Surprisingly, however, a chemical
cousin of heparinase actually accelerated tumor growth in mice, indicating
that slightly different forms of this family of molecules can have very
different effects on cell growth and cancer. Heparin and molecules like
it cloak the surfaces of nearly all the cells in our bodies, and Sasisekharan
suspects that these sugary molecules interact with cancer-controlling
proteins circulating in the blood and on the surfaces of other cells.
If the findings can be repeated in people, heparin could be put to use
quickly, since it is already an FDA-approved medicine and as such has
been demonstrated to be safe for human use.
Few would argue that the ability to accurately predict the course of
disease outbreaks and other serious health problems affecting millions
of people would be worthwhile. Two NIGMS grantees — Simon Levin
and his group at Princeton University in New Jersey and Martin
Blaser of New York University in New York City — have used entirely
different approaches to mathematically model the behavior of infectious
microorganisms that impact large populations of people. In the first case,
Joshua Plotkin and Jonathan Dushoff, working with Levin, analyzed the
gene sequences of flu strains from the last 16 years and discovered patterns
that researchers may be able to use to predict which particular strain
of flu will emerge in the coming season. If accurate, such a prediction
would be a helpful tool to avoid misery and save many lives by permitting
the makers of the following year's flu vaccine to better target the precise
variants of flu likely to be the most prevalent. Levin and his coworkers
delved into a computer database containing DNA sequences representing
560 samples of different flu viruses. The researchers discovered that
the many strains separated naturally into a small number of distinct clusters,
and they showed that clustering could be useful in predicting how the
flu virus evolves over time. In the second case, infectious disease specialist
Blaser teamed up with mathematician Glenn Webb of Vanderbilt University
in Nashville to pursue a different line of research addressing another
issue of widespread health concern. Blaser, who models the infectious
behavior of the ulcer-causing bacterium Helicobacter pylori, applied
his knowledge to produce a model of how the deadly bacterium Bacillus
anthracis could be spread through the U. S. postal system. The researchers
simulated the outbreak of mail-borne anthrax in the fall of 2001 and concluded
that all the known cases of infection could be traced back to contamination
through the mail from only six original envelopes. The researchers also
concluded from their mathematical model that the rapid and widespread
use of antibiotics probably averted many additional potentially deadly
infections from this outbreak.
Many people are surprised to learn that medicines may only work properly
in a percentage of those who take them. What's more, whether or not people
develop side effects — and if they do, which ones they'll get —
varies widely. While many factors such as diet, environment, and the amount
of exercise a person gets can help account for this variability in drug
response, a key determinant is genes. So-called pharmacogenetics research
aims to unravel some of the biological reasons why people react so differently
to medicines. In recent years, pharmacogenetics scientists have found
many examples where a change in one or a few of the DNA "letters" that
spell out genes can cause people to have different responses to medicines.
For example, NIGMS grantee Mark Ratain of the University of Chicago
has identified a group of cancer patients who have a bad reaction to a
chemotherapy drug called irinotecan, which is used to treat a variety
of solid tumors. Ratain and his research team have found that some patients
have two extra letters in the gene that instructs the body to make a protein
that metabolizes irinotecan and other drugs. Because of this genetic difference,
these people have much higher levels of irinotecan than most patients
given the same dose. When administered this medicine, patients with extra
letters in the gene experienced dramatic drops in their white blood cell
counts, making these patients more likely to develop a potentially life-threatening
infection. The same patients also experienced severe diarrhea, which can
cause dangerous fluid loss in people who are already very sick. Ratain
predicts that future genetic screening of patients may help avoid toxic
side effects and help determine the precise dose of chemotherapy needed
to treat their cancer.
Your body may be better at protecting you from microbial invaders than
you thought. Recently, NIGMS grantee Charles Serhan of Brigham
and Women's Hospital in Boston, Massachusetts, made the surprising observation
that naturally occurring molecules in the body that help fight inflammation
also appear to protect tissue linings of the mouth, intestines, and airways
from infection. While doing experiments to study the roles white blood
cells normally play in controlling inflammation, Serhan and his coworker
Sean Colgan unexpectedly discovered something new.
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| Photo credit: Beth McCormick and James Casanova,
Harvard Medical School |
In the process of policing epithelial cells (the cells that line the
organs of the body and skin), white blood cells shoot a chemical signal
to the epithelial cells telling them to manufacture a microbe-killing
substance, the research team found. This chemical likely protects the
cell from a potentially dangerous infection by eliminating bacteria on
contact. To verify the observation, the scientists infected epithelial
cell cultures growing in plastic lab dishes with the bacterium Salmonella
typhimurium and then added a chemical that provokes inflammation in
the body. In earlier experiments, the researchers showed that in response
to the inflammation-prompting substance, epithelial cells boost their
production of a "molecular shield" component called BPI.
Serhan's research team found that as BPI levels in the cells increased,
more and more Salmonella in the culture dishes died, whereas using
a "dummy" chemical had no effect. The results are significant in describing
a new defense mechanism in the body, but also, as Serhan states, in pointing
to new strategies to thwart difficult-to-treat infections of the mouth,
intestines, and esophagus.
The body-wide infection called sepsis is the leading cause of death in
critically ill patients nationwide, striking
750,000 people every year and killing over 210,000. Sepsis occurs when
bacteria leak into the bloodstream, causing widespread damage all over
the body. Blood pressure plunges dangerously low, the heart has difficulty
pumping enough blood, and body temperature climbs or falls rapidly, in
many cases causing multiple organs to fail. In recent years, researchers
have come to realize that the gut, or intestinal tract, plays an important
role in sepsis. Scientists have found that after a severe infection or
injury, cells in the intestinal lining die off. This form of cell death,
called apoptosis, isn't always a bad thing — for example, nerve cells
require apoptosis during development to form a healthy brain. However,
researchers suspect that blocking apoptosis in the intestines of critically
ill patients may help to prevent death from sepsis. NIGMS grantee Craig
Coopersmith of Washington University in St. Louis, Missouri, reports
experiments in mice that suggest this strategy may someday be effective
in people. Coopersmith and his coworkers genetically engineered lab mice
to produce large amounts in their intestines of a cell-death-blocking
protein called bcl-2. The researchers exposed the experimental mice to
the bacterium Pseudomonas aeruginosa, which can be deadly to people,
and discovered that 40 percent of the mice escaped infection and survived,
compared to only 4 percent of mice without bcl-2. The results suggest
that stopping intestinal cell death may someday be an effective treatment
for sepsis.
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