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In this section:
» Understanding Life Processes
» Basic Studies Illuminate Disease Mechanisms
» New Approaches to Therapeutics
» Promising Technologies
These science advances convey the breadth and significance of
NIGMS-supported research in such areas as cell biology, biophysics,
genetics, developmental biology, pharmacology, physiology, biological
chemistry, bioinformatics, and computational biology. Although only
the lead scientists are named, coworkers and collaborators contributed
substantially to the achievements.
Understanding Life
Processes
MicroRNAs Debut as Key Actors in Health and Disease
One of the dogmas of biology has been that proteins, the cellular
workhorses of our bodies, perform the critical job of controlling
gene activity. But a series of recent discoveries is painting a
strikingly different picture.
A newly identified kind of RNA, called microRNA for its tiny size,
appears to control a third of our genes. Scientists are finding
that microRNAs play starring roles in a remarkably wide range of
biological processes.
Two studies in 2005 implicate microRNAs in cancer. Using microscopic
roundworms, Frank Slack, Ph.D., of Yale University in New Haven,
Connecticut, discovered that one particular microRNA can quiet Ras,
a protein known to be central to tumor formation when it is mutated.
In a separate study, Gregory Hannon, Ph.D., of Cold Spring Harbor
Laboratory in New York identified other microRNAs linked to the
severity of B-cell lymphoma in mice. These findings open promising
new avenues for preventing, diagnosing, and treating cancer.
In a third study, Richard Carthew, Ph.D., of Northwestern University
in Evanston, Illinois, and Hannele Ruohola-Baker, Ph.D., of the
University of Washington in Seattle uncovered telltale signs of
microRNA involvement in stem cell growth. Unlike most cells, stem
cells have the ability to continuously renew themselves, yet scientists
do not understand how this happens. The new research, done in fruit
flies, revealed that stem cells need certain microRNAs to maintain
their ability to divide endlessly.
Research on microRNA is still in the early stages, but the recent
discoveries linking microRNAs with cancer and stem cell biology
are fueling excitement about the potential therapeutic uses of these
multitalented molecules.
Human Growth Factors Maintain Stem Cells’ Clean
Slate
Human embryonic stem cells (hESCs) have the remarkable ability
to turn into any type of cell in the body. For this reason, these
cells give basic researchers an ideal model for studying early human
development and advancing regenerative medicine. Typically, scientists
grow hESCs in the laboratory by culturing them on a layer of mouse
cells that prevents the hESCs from changing into other cell types
too soon. Although stem cell therapy is still years away, scientists
have searched for a way to get rid of this step because it poses
a risk of contamination from animal cells.
New results from two basic researchers working independently may
solve this problem. One of the two researchers who originally discovered
hESCs, James Thomson, V.M.D., Ph.D., of the WiCell Research Institute
in Madison, Wisconsin, discovered that adding a human protein, basic
fibroblast growth factor, to a stripped-down version of cell-culture
broth kept the hESCs in an undifferentiated state. It did this,
he found, by stopping molecular signals that provoke the cells to
mature into other cell types. Thomson also learned that by using
his method, mouse cells were no longer needed. In related work,
Ali Hemmati-Brivanlou, Ph.D., of the Rockefeller University in New
York City discovered that turning on the production of yet another
human growth factor also helped to maintain the human stem cells’
clean slate and did not require mouse cells either.
The findings are a critical step forward in the quest to understand
the basic biology of hESCs. What’s more, by simplifying the
procedure for growing hESCs in the absence of animal cells, the
researchers pave the way for future scientists aiming to develop
stem-cell therapies to replace diseased or injured cells.
Cell Death Discovery Has Healing Power
Decades of research have taught scientists that cells have two
ways to die. The first, necrosis, is a nonspecific response to an
overwhelming stress such as a heart attack or exposure to poison.
Researchers have viewed the other kind of cell death, known as apoptosis,
as a normal, programmed process that helps shape organs and rid
the body of potentially harmful or unneeded cells. Recently, however,
scientists have begun to suspect that apoptosis may also have a
dark side, potentially contributing to neurodegenerative diseases
such as Alzheimer’s and Parkinson’s.
New work from Junying Yuan, Ph.D., of Harvard Medical School may
help settle the issue by defining a third way cells can perish.
Necroptosis, as the name suggests, shares characteristics with both
necrosis and apoptosis, and Yuan has found that it can occur in
healthy cells. Under the microscope, a cell dying by necroptosis
looks a lot like a cell dying by necrosis—it swells up and
bursts, spewing its contents on neighboring cells. However, as a
cell dies this way, it proceeds through a series of chemical steps
resembling apoptosis. Yuan found that necroptosis contributed to
delayed brain injury in mice suffering a stroke-like event. In further
work, she identified a molecule, necrostatin-1, that significantly
lessened necroptosis-induced brain damage.
Yuan’s research highlights the value of exploring basic cellular
function to uncover new knowledge about health and disease. The
findings may also help scientists learn how to develop necrostatin-1
or similar molecules as medicines for stroke or other medical conditions
that involve necroptosis.
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Basic Studies Illuminate
Disease Mechanisms
Genes Could Help Predict Trauma Outcome
Each year, doctors treat millions of trauma victims without being
able to predict how each person is likely to fare. Even people with
nearly identical injuries can have dramatically different outcomes,
with some inexplicably developing life-threatening complications
like multiple organ failure or body-wide inflammation.
Thanks to an NIGMS “glue grant” that brought clinicians
and basic researchers together to attack this problem, doctors are
one step closer to knowing how best to treat trauma patients. A
multidisciplinary group of scientists led by trauma surgeon J. Perren
Cobb, M.D., of the Washington University School of Medicine in St.
Louis, Missouri, scanned genetic material from trauma patients and
healthy volunteers. The researchers were looking for differences
in gene activity that might be associated with the most deadly effects
of severe trauma. They found that, compared to healthy people, the
trauma patients’ white blood cells showed dramatic differences
in the activity of certain genes. Because white blood cells are
involved in inflammation, these results shed light on inflammation’s
role in injury response.
This study is one of the first to standardize “gene chip”
experiments across several medical centers and show that such a
genetic test can give informative results in a clinical setting.
The work is an early, but significant, step toward the researchers’
goal of using genetic information to guide trauma treatment.
RNA Cut-and-Paste Makes an Adult Heart
Much like we mix and match shirts, pants, and shoes to put together
different outfits, a cell can shuffle segments of its genetic material
to produce thousands of different, but related, proteins. This process,
called alternative splicing, acts on RNA molecules that carry information
from DNA to the cell’s protein-making machinery. In many cases,
cells use alternative splicing to make particular proteins according
to the circumstances: Just as you might choose to wear a raincoat
on a soggy day, a cell can make a protein variant to suit its needs.
Now, basic researchers have discovered that alternative splicing
appears to play a key role in the development of a healthy heart.
Xiang-Dong Fu, Ph.D., of the University of California, San Diego,
used genetic engineering technology to create mice that could not
produce ASF/SF2, a protein known to be involved in cutting and pasting
RNA. Although these experimental mice looked normal at birth, within
a few weeks their hearts could not pump blood very well and they
died soon thereafter. Fu discovered that, without the proper ASF/SF2
splicing tool, the mice made the wrong version of an important heart
enzyme that helps transform a juvenile mouse heart into that of
an adult. The enzyme, the scientists learned, has also been linked
to heart attacks.
Fu’s findings may lead to a deeper understanding of alternative
splicing in the normal development of body organs. The research
may also shed light on why heart attacks occur and could suggest
strategies to prevent them.
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New Approaches
to Therapeutics
Scientists Find New Ways to Resist Resistance
When scientists discovered penicillin’s antibacterial properties
in the early 20th century, medicine was transformed. But just a
few years after people began using this drug, penicillin-resistant
bacteria started to appear. Today, antibiotic resistance remains
a public health challenge, making it increasingly hard to treat
tuberculosis, pneumonia, and many other infections. Scientists continue
to struggle to develop a fail-safe plan, but in 2005, basic researchers
made progress on two fronts.
First, using a hardy microorganism isolated from the Dead Sea,
Thomas Steitz, Ph.D., and Peter Moore, Ph.D., both of Yale University,
determined the protein structures of drug-resistant and drug-sensitive
bacterial ribosomes physically attached to different antibiotics.
This strategy is revealing because many antibiotics kill bacteria
by binding to the RNA components of their protein-making ribosomes.
The new structures show why a single genetic change prevents many
antibiotics from tightly gripping onto ribosomes and explains why
these versions can only weakly block bacterial protein production.
Researchers at a biotechnology start-up company that Steitz and
Moore helped to establish are using this structural information
to develop new antibiotics.
In the other study, Marcus W. Feldman, Ph.D., of Stanford University
in California investigated the role humans play in spreading antibiotic
resistance. He created a simple mathematical model comparing people
who tend to seek medical treatment with those who generally avoid
taking medicines, including antibiotics. The model suggested that
when people avoid antibiotics, resistance does not develop. But
when people do take these drugs, resistant bacteria quickly gain
footing and may even flourish as the antibiotic-sensitive bacteria
die off. Feldman’s findings point to an important link between
patterns of antibiotic use and the emergence of drug-resistant bacteria.
Although these studies were widely different in scope, they both
suggest new research directions for battling the increasingly urgent
problem of antibiotic resistance.
Brain’s Fear Center Affects Memory During Anesthesia
Despite the fact that general anesthetics have been used since
the 1800s, scientists still do not have a thorough understanding
of how these powerful drugs work in the brain. In addition to relieving
pain and causing loss of consciousness, anesthetics are known to
induce amnesia during the surgical period. A recent study has shed
light on this aspect of anesthetic action.
Using rats as a research model, Michael T. Alkire, M.D., of the
University of California, Irvine, has uncovered the role of the
amygdala—a brain region involved in fear, anxiety, and emotion—in
memory loss caused by the anesthetic sevoflurane. He placed two
groups of rats, one mildly anesthetized and the other untreated,
in a lighted chamber facing a dark tunnel. If the rats entered the
dark area, an environment rodents prefer, Alkire gave them a brief
electrical shock.
The unanesthetized animals remembered this shock until the next
day and quickly learned to stay in the safer, lighted environment.
However, those treated with sevoflurane behaved differently: Unable
to remember the bad experience, these animals continued to enter
the tunnel and receive a shock. When Alkire incapacitated the amygdalas
of the anesthetized rats, he observed that they could then remember,
and avoid, the shock. He concluded that sevoflurane could erase
a rat’s memory during the training session, but only if the
rodent’s amygdala was working properly.
By pinpointing the amygdala’s role in memory function during
anesthesia, this research adds to the growing body of knowledge
about how anesthetics exert their effects. It has particular relevance
to the relatively rare situations in which patients experience episodes
of awareness—and sometimes also pain—during anesthesia,
but are unable to move or report the problem. In some people, the
experience can trigger post-traumatic stress disorder. A better
understanding of how anesthetics interact with the brain to cause
amnesia could help reduce or eliminate episodes of awareness. The
study also provides new insights into memory formation, especially
those related to unpleasant or emotional events.
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Promising Technologies
State-of-the-Art Sensors Find Traces of Zinc and Mercury
Metals in the body keep us healthy, but they can also make us sick.
While small amounts of iron, copper, and zinc help proteins carry
out their regular functions, metals in the wrong amount or the wrong
place can cause trouble. Recent research implicates zinc in the
development of Alzheimer’s and Parkinson’s diseases
as well as strokes, seizures, and head injuries. Exposure to mercury,
which is harmful in any amount because the body can’t get
rid of it, can also cause neurological damage. Techniques that reliably
locate small amounts of metals in the body are key to understanding
the progression and treatment of these brain disorders as well as
the roles that metals play in normal processes. Some detection methods
currently exist, but most are either imprecise or difficult to implement.
Stephen Lippard, Ph.D., of the Massachusetts Institute of Technology
in Cambridge may have a new way. He has developed sensors that reveal
tiny amounts of zinc and mercury in cells, tissues, or water. When
Lippard applied these chemical sensors to biological samples and
then shone light on them, molecules of zinc or mercury in the samples
lit up. Lippard tested the zinc sensors on brain tissue from rodents
with head trauma or seizures and found that the sensors precisely
identified zinc in damaged nerve cells. Lippard has also fashioned
a sensor that selectively pinpoints even low levels of mercury in
water.
The fluorescent chemosensors may offer new tools for imaging metals
in the body and for studying the role of these molecules in health
and disease. The technology may also prove useful for monitoring
environmental quality in water, soil, and elsewhere.
Supports HHS Goal 2, Objective 2.2: Improve the safety of food,
drugs, biological products, and medical devices
Chicken Eggs Offer Better Way to Produce Important
Drugs
In recent years, a new class of drugs called monoclonal antibodies
has become an important treatment for cancer and other illnesses.
Therapeutic monoclonal antibodies, such as the breast cancer therapy
Herceptin®, work the same way natural antibodies work: They
identify and attach to receptors on cell surfaces to block unhealthy
molecular interactions or to alert other cells in the immune system
to launch an attack. Currently, monoclonal antibody drugs are manufactured
by inserting the genes encoding these proteins into cultured animal
cells. But the high cost of installing and operating cell-culture
production facilities has prompted scientists to look for a better
method.
With funding from a small business innovation grant, Lei Zhu of
Origen Therapeutics in Burlingame, California, figured out how to
make monoclonal antibody drugs in chicken eggs. She and her coworkers
inserted genetic instructions into the chicken genome, directing
the production of antibodies in egg whites. Extracting the protein
drugs was straightforward and efficient, and laboratory tests showed
that the antibodies were even more effective at killing cancer cells
than were antibodies made by traditional means.
This work is a technical milestone that could ease the development
of other therapeutic antibodies. In addition to the 17 approved
antibodies currently marketed as medicines to treat cancer, arthritis,
multiple sclerosis, and inflammatory bowel disease, dozens more
are currently in the development pipeline. Streamlined approaches
to make therapeutic monoclonal antibodies efficiently and economically
may mean less expensive—and potentially more effective—medicines
in the not-too-distant future.
Supports HHS Goal 4, Objective 4.2: Accelerate private sector
development of new drugs, biologic therapies, and medical technology
Computer Models Simulate Flu Epidemic, Could Guide
Response
When a type of flu found in poultry and other fowl started infecting
people in Southeast Asia, scientists and policymakers around the
world began to worry. By the fall of 2005, more than 100 cases of
avian, or “bird,” flu had been documented in humans
and about half of these had resulted in death. Researchers are concerned
that bird flu could provoke a worldwide outbreak. Because most people
have no prior immunity to this flu virus strain, a bird flu pandemic
could potentially kill millions.
Early progress in preparing for a possible outbreak emerges from
scientists involved in the Models of Infectious Disease Agent Study,
a research network designing simulations of disease spread with
the goal of identifying effective control strategies.
A multidisciplinary team including Neil M. Ferguson, D.Phil., of
Imperial College in London and Ira Longini, Ph.D., of Emory University
in Atlanta, Georgia, used computer models to simulate a human outbreak
of avian flu in Southeast Asia and to test what intervention measures
could contain it. The models were based on extensive population
data from Thailand and information about past flu outbreaks. As
the first hypothetical cases showed up in each modeling scenario,
the researchers introduced various intervention strategies, such
as giving antiviral drugs, vaccinating before an outbreak, quarantining,
or a combination of these methods. The models differed in many ways,
but each suggested that a carefully chosen combination of public
health measures along with the quick implementation and large-scale
use of antiviral drugs could stop the spread of an avian flu outbreak
at its source.
As the researchers continue to refine and test their models, they
are also developing preliminary models for the United States. Although
the simulations are still in progress, the MIDAS models offer new
knowledge that scientists and policymakers are considering as they
prepare for a possible outbreak.
Supports HHS Goal 2, Objective 2.1: Build the capacity of the
health care system to respond to public health threats in a more
timely and effective manner, especially bioterrorism threats
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