A 6-year-old boy wakes up in the night. He's vomiting
and has mild abdominal discomfort, lethargy and
fever. In the morning, his pediatrician tells the parents
their son has viral syndrome and sends them
home, but the boy's condition worsens throughout the day.
By the time he is taken to a local
emergency room that evening, he's dehydrated and developing
a rash. The doctor on call suspects
sepsis — an acute and highly contagious bloodstream
infection often mistaken for the flu. The hospital
begins aggressive antibiotic treatment, but it's too late
to turn things around. The child goes into
cardiac arrest and dies early the next morning.
It's a case that made an indelible impression on
Samuel Yang, assistant professor in
Emergency Medicine at Johns Hopkins, when he was just
beginning his medical career. After the fact, the
youngster's blood culture revealed that he had
meningococcemia, one of many causes of sepsis. More
than 4,300 children in the United States, and millions
around the globe, die every year from sepsis.
"It's a leading cause of death for children and
infants worldwide, and early diagnosis greatly
improves the chances of recovery," Yang said.
Unfortunately, the early symptoms, especially in
youngsters, are often mistaken for flu or other illnesses
that are not life-threatening, and a blood
culture to produce a diagnosis takes at least 18 hours,
which is too late in most cases to guide
treatment.
The Hartwell Foundation recently awarded Yang a grant
to support development of an innovative
"point of care" diagnostic tool that will tell caregivers
— within minutes — if sepsis is present and
also identify the specific pathogen.
To avoid the tragic consequences of delaying
treatment, many doctors order broad-spectrum
intravenous antibiotic therapy and inpatient observation
for all children with flulike symptoms. "This
conservative approach may sound like a good idea," Yang
said, "but it carries significant risks: Children
may suffer iatrogenic complications associated with
unnecessary treatment and hospitalization, and
overuse of antibiotics leads to the development of
increased rates of multidrug-resistant organisms.
It's also quite costly."
Yang's proposal has the potential to revolutionize
care for children with sepsis and save many
lives. Collaborating with colleagues at the Whiting School of
Engineering and the
School of Medicine,
he will use molecular and nano technologies to create a
"lab on a chip," a glass-and-silicon wafer about
the size of a microscope slide. "Ultimately," he said, "all
the physician will need to do is to load the
patient's blood sample onto the chip and, a few minutes
later, read the results."
The Hartwell Foundation selected Yang and 11 other
researchers nationwide for Hartwell
Individual Biomedical Research Awards. "We are honored to
provide financial support to these
exceptional researchers pursuing applied biomedical
research to advance children's health," said Fred
Dombrose, foundation president. "The Hartwell Foundation
seeks to inspire innovation and achievement
by funding early-stage, transformative ideas with the
potential to benefit kids in the United States,"
he added.
Advances in DNA testing for pathogen detection have
set the stage for improving sepsis
detection time and accuracy, Yang said. In a simple
"sample-in and answer-out" format, the proposed
chip will process a patient's blood sample, detect the
presence of any bacterial DNA and analyze the
sequence to identify and characterize the detected
pathogen. PCR (polymerase chain reaction) is a key
technique in molecular genetics that permits the analysis
of DNA without having to clone it, providing
very rapid results. His group has already developed a
"molecular triage tool," based on PCR technology,
that is capable of diagnosing life- or limb-threatening
bacterial infections in patients.
Yang proposes a sample processing system based on
electrokinetic forces, an innovation in the
relatively new field of lab chip technology. He said he
believes this approach will ensure not only
diagnostic accuracy but also efficiency; the latter has
been a problem with most sample processing
platforms so far developed because they are made up of a
collection of complex functional components
connected into a system in a piecemeal fashion. A variety
of electrokinetic forces, which are
generated based on the strategic arrangement of electrodes
embedded in Yang's chip, will allow cells
and biomolecules to be manipulated in microscale with high
precision and efficiency, he explained. In
addition, he and his collaborators will incorporate
nanoparticle quantum dots, which offer unique
photophysical properties that can dramatically enhance the
detection sensitivity and speed of chip-
based PCR. All the functional components will be
microfabricated on a single, disposable glass-and-
silicon wafer.
Yang's collaborators are Tza-Huei "Jeff" Wang,
associate professor in
Mechanical Engineering
and Biomedical
Engineering; Richard Rothman, associate professor in
Emergency Medicine and
Infectious Diseases; and Charlotte Gaydos, professor in
Infectious Diseases.
The Hartwell Foundation also has provided Johns
Hopkins with funding for a Hartwell
Fellowship, which the university has awarded to Nilay Shah.
A clinical fellow in Pediatric Oncology,
Shah is researching the genetic underpinnings of the
childhood cancer neuroblastoma. This is the
third consecutive year that Johns Hopkins has received
funding for a Hartwell Fellowship, which is
intended to foster the career development of a young
biomedical scientist whose work focuses on
improving children's health.
For more information, see the foundation's Web site:
www.thehartwellfoundation.org.
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