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V o l u m e 7, N o . 8
April 20, 2015
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Shing Center
on campus.
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Study pinpoints how X chromosome silenced
By Krista Conger
G
arfield has a dark secret. The cartoon cat is a genetic anomaly, not because of his insatiable lasagna cravings, but because of his coat color.
Outside the world of the Sunday comics, orange and
black cats are almost invariably female.
This truism is due to a curious biological phenomenon called X inactivation, which ensures that females
of all species have only one active X chromosome in
every cell. Early in development, when embryos have
just few cells, one X chromosome is shut down or silenced in each cell. This chromosome remains inactive
in all of that cell’s progeny throughout the life of the
animal. In cats and many other species, the selection
of the chromosome to be inactive is random; in some
other species, the X chromosome inherited from the father is always chosen.
X inactivation is necessary to ensure that females,
who have two X chromosomes, and males, who have
only one, end up with roughly the same dosage of genes
that occur on that chromosome.
The “orange or black fur” gene is on the X chromosome, so a female cat can have a calico coat with both
colors if “orange” and “black” remain active in different
cells, but because a male cat has just one X chromosome
it can be only one of these colors.
Scientists have known about X inactivation for
decades. Recently they learned that an RNA molecule called Xist is responsible. But it’s not been as
clear exactly how Xist works to silence genes on the X
chromosome.
Now researchers at the School of Medicine have
outlined the molecular steps of inactivation, showing
that it occurs in an orderly and directed fashion as early
embryonic cells begin to differentiate into more specialized tissues. They’ve identified more than 80 proteins
in mouse cells that bind to Xist to help it do its job.
They hope their findings will shed light on conditions
in humans that are typically more severe in one gender
than the other.
Gender differences in diseases
“We see some very interesting phenomena with X-
linked diseases in humans,” said Howard Chang, MD,
PhD, professor of dermatology. “Often, when the faulty
gene is on the X chromosome, the condition is more severe in boys. This happens in hemophilia, for example.
In contrast, women are far more likely than men to suffer from autoimmune diseases, for reasons we don’t yet
understand. This research opens the door to possibly
understanding the biological basis for these differences.”
A paper describing the research findings was pub-
Chris s Ha igh t Pag a ni
A genetic phenomenon called X inactivation is the reason that most calico cats are female. Now researchers have outlined the molecular
steps of inactivation, showing that it occurs in an orderly and directed fashion as early embryonic cells begin to differentiate.
Researchers identify major
cellular culprit in scarring
By Krista Conger
A skin cell responsible for scarring,
and a molecule that inhibits the cell’s activity, have been identified by researchers
at the School of Medicine.
The molecule slowed wound healing
in mice but alleviated scarring, the researchers said.
The researchers also found that the
cell may play a role in the growth of melanoma and in skin damage caused by rada m ato / shu t t erstock
Scars are comprised mainly of collagen, a fibrous
protein secreted by a type of cell found in the skin.
lished in the April 9 issue of Cell. Chang is the senior
author, and former graduate student Ci Chu, PhD, is
the study’s lead author. The research required an entirely new technique, which was developed by Chu, to
identify proteins interacting with Xist.
“Usually people start with a protein of interest and
look for RNA molecules that might associate with that
protein. We wanted to start with the RNA and find
out what proteins Xist is See chromosome, page 6
diation. A drug that acts in the same way
as the inhibitory molecule is already approved for use in humans as a treatment
for type-2 diabetes, so it could potentially move quickly into clinical trials for
the treatment of scarring and melanoma.
“The biomedical burden of scarring
is enormous,” said Michael Longaker,
MD, co-director of Stanford’s Institute
for Stem Cell Biology and Regenerative
Medicine. “About 80 million incisions
a year in this country heal with a scar,
and that’s just on the skin alone. Internal
scarring is responsible for many medical
conditions, including liver cirrhosis, pulmonary fibrosis, intestinal adhesions and
even the damage left behind after a heart
attack.”
A paper describing the researchers’
findings was published April 17 in Science. Longaker, a professor of surgery,
and institute director Irving Weissman,
a professor of pathology and of developmental biology, are the senior authors.
Postdoctoral scholar Yuval Rinkevich,
PhD, and graduate student Graham
Walmsley share lead
See scar, page 7
Scientists decipher brain’s noise
the brain gobbles glucose (the fuel our
brain cells run on) barely budges when
By directly recording electrical activity we cease performing a physical or menfrom the human brain, neuroscientists tal activity. Even at rest, the brain seems
at the School of Medicine have shown engaged in a blizzard of electrical activity,
that distinct, distant groups of brain which neuroscientists have historically
viewed as useless “noise.”
areas that support memory
“Increases in brain activretrieval act in concert, even
ity during conscious thoughts
during sleep.
and actions represent only the
The findings, described
tip of the iceberg,” said Josef
in a study published online
Parvizi, MD, PhD, associate
April 8 in Neuron, confirm
professor of neurology and
for the first time that speneurological sciences and the
cific electrical patterns of
senior author of the Neuron
coordinated neural activstudy. “The vast amount of
ity in widely separated huenergy consumption by our
man brain structures during
Josef Parvizi
brain is due to its spontanememory retrieval persist
throughout our cycles of waking and ous activity at all times when we are not
sleeping. The findings confirm indirect consciously involved in a specific task.”
What, then, is all this spontaneous
observations made in previous studies
that used brain imaging. They also shed noise for?
light on why the brain paradoxically appears to exhaust so much of the body’s At rest, but not resting
energy in what, at first glance, seems akin
Over the past decade, neuroscientists
to the idling of a car’s engine.
using brain-imaging methods like funcThe human brain is a greedy organ. tional MRI scans, which track blood
Accounting for only 2 percent of the flow in the brain (believed to be a good
body’s weight, it consumes 20 percent of stand-in for local neural activity), have
the body’s energy. Yet the rate at which started to reveal
See noise, page 7
By Bruce Goldman
Director of Center for Population Health Sciences appointed
By Kris Newby
Mark Cullen, MD, cut his teeth on
large population data sets in 1997, when
he partnered with Alcoa, America’s largest aluminum producer, to research ways
to improve its employees’ health. Back
then, it took his Yale University-based
team five years to create data bridges
between the company’s hundreds of
thousands of fragmented health, employ-
overall health of society.
This evidence can come from a variety
of sources — electronic medical records,
genomic sequences, biospecimen repositories, insurance records, wearable sensors and social and environmental data.
The challenge is to create methods to deliver this information to researchers and
care providers in relevant and privacyprotected formats.
“This isn’t rocket science, but there
norbert von der groeben
Mark Cullen has been named the first director of the Center for Population Health Sciences, whose
mission is to use population-level evidence to improve bedside care and the overall health of society.
ment, injury and environmental records.
“Our goal was to understand factors
that undermine worker health, then to
develop prevention and treatment strategies,” said Cullen. “This research led to
groundbreaking occupational health reforms, including environmental controls
and new strategies to reduce injury and
illness. It was eye-opening to discover
that other aspects of work and life — not
just toxins and bad behavior — conspire
to produce positive and negative outcomes. When I witnessed how multidisciplinary teams could unlock knowledge
hidden within population data, I was
hooked.”
Now Cullen, professor of medicine
and chief of the Division of General
Medical Disciplines at Stanford, is bringing his experience and enthusiasm to the
Stanford Center for Population Health
Sciences as its first director.
“Backed by Stanford’s research and
computational engines, the Center for
Population Health Sciences is poised to
harness the power of big data to improve
health here and around the world,” said
Lloyd Minor, MD, dean of the School
of Medicine. “Mark Cullen is the right
person to bring together clinicians and
researchers in social, biologic and data
sciences to meet these challenges.”
Population health science mission
inside
Launched in 2012 by Spectrum, the
Stanford Center for Clinical and Translational Research and Education, the center’s mission is to use population-level
evidence to improve bedside care and the
were no financial incentives to develop
these tools until the Accountable Care
Act came along,” said Cullen.
The 2010 Patient Protection and
Affordable Care Act includes cost-reduction and quality-improvement incentives that health-care institutions
can take advantage of through the wise
use of population-health data. There
are incentives for hospitals that show
improved outcomes for heart failure,
pneumonia and surgery. And there are
incentives for clinicians and hospitals to
set up accountable care organizations to
lower annual per-capita growth on health
spending and improve health for large
populations.
Population-health scientists can be instrumental in creating the tools to more
effectively and efficiently help institutions take advantage of these qualityfocused incentives, said Cullen.
During the last year, Lorene Nelson, PhD, associate professor of health
research and policy and the center’s associate director, helped lay the foundation for the center, engaging more than
200 faculty members in a series of meetings and symposia. With the assistance
of Spectrum staff, she also organized
a distinguished lecture series to bring
new ideas to the Stanford community,
launched a website and Twitter feed to
foster collaborations, and expanded the
pilot grant program.
To date, the center has awarded 26
project teams with grant awards ranging from $20,000 to $50,000. Funded
by Spectrum’s Clinical and Translational
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Inside Stanford Medicine is
published monthly in July and
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Science Award from the National Institutes of Health and by Stanford Health
Care, many of these projects are focused
on developing a “learning health system,”
in which clinical data can be linked to
external information relevant to patient
health, such as neighborhood locations
and environmental conditions. Representative projects include:
•Design of an electronic clinical-decision support system to improve emergency care for children.
•Development of a personalized
medicine practice using genomic data.
•Methodologies for using Google
Street View to assess neighborhoods for
population health research.
“Today’s electronic medical records
are like MapQuest a decade ago — they
provide a snapshot of a chart without
much added value,” said Cullen. “We
want to add intelligence to medical records in the same way that smartphone
navigation apps have added real-time
traffic alerts and alternate routes. For example, when an asthmatic child comes to
the emergency department, a physician’s
dashboard might include information on
air quality, viral outbreaks in the patient’s
neighborhood and the child’s vaccination
record.”
In addition to large data sets, the
center is developing easier access to
clinical, volunteer and demographically
segmented study populations. As with
the databases, center staff will work with
investigators to identify and facilitate
connections with population groups that
could be of importance to their research.
Nationwide clinical data access
Population-health researchers can
also look forward to enhancements to
STRIDE, the Stanford Translational
Research Integrated Data Environment,
a comprehensive warehouse of de-identified clinical notes, diagnoses and prescriptions for nearly 2 million patients
treated since 1994 at Stanford Hospital
& Clinics, now called Stanford Health
Care, and Lucile Packard Children’s Hospital Stanford.
Michael Halaas, chief information
officer for the School of Medicine, has
led the effort, initiated by Spectrum and
other member institutions in the CTSA
consortium, to connect STRIDE to a nationwide, scalable informatics framework
called i2b2. When this project is complete, Stanford researchers will be able
to access anonymized clinical data from
participating health-care systems around
the country for research and clinical trial
Access to new data, populations
recruitment. The i2b2 framework is
To better support the efforts of pop- based on the Research Patient Data Regulation-health scientists, the center is istry developed at Massachusetts General
working on providing centralized access Hospital. It has a number of advantages,
to a variety of U.S. and international including extensive testing by the Boshealth databases. Stanford population ton-based Partners Health System and
scientists say they are particularly excited Harvard faculty; an easily understood
about the pending acquisition of several database schema; release under an openlarge insurance-claims data sets from source license; an organized user group
for sharing information and applications;
public and private insurers.
“To understand the complex finan- and the capacity to share translational
cial, social and regional incentives that research data with collaborators across
drive health-care delivery in the United other i2b2 institutions.
“I couldn’t be more pleased with the
States, researchers need easier access to
detailed information on what types of tremendous progress that all the facservices patients are using, where they are ulty who have worked on this initiative
accessing these services and how much have made over the last two years,” said
they cost,” said Kate Bundorf, MBA, Harry Greenberg, MD, senior associate
MPH, PhD, associate professor of health dean of research for the medical school
research and policy. “Developing a large and director of Spectrum. “With the aprepository of insurance claims will enable pointment of Mark Cullen, the center is
Stanford researchers to examine these poised to take the next step in becoming the hub for research and educational
types of questions.”
The center plans to make these data activities related to population health
sets available at very low cost to Stan- across the university. Perhaps most excitford trainees and investigators at every ing to me, with all the marvelous talent
level. But even more important, center we have at Stanford, we will be able to
provide muchstaff will provide
technical support “This isn’t rocket science, needed guidance to
investigators, clinito help users get
but there were no
cians and policyaccess to the data
makers concerning
needed to answer
financial incentives to
the very difficult
their research
develop these tools until task of drawing acquestions. Other
inferential
data sets the centhe Accountable Care Act curate
conclusions from
ter hopes to make
the great wealth
available over time
came along.”
of new data now
include those from
the Google X Baseline Study and In- available at our fingertips. This data has
the potential to improve the health and
depth Network.
The Google study is a five-year pilot well-being of local, national and even
study in which daily health information global populations.”
The Stanford Center for Population
is being collected from healthy people
in Southern California via a Google- Health Sciences is supported by Specdesigned web portal and with biomet- trum, which is funded by the National
rics devices, such as glucose-measuring Center for Advancing Translational Scicontact lenses and activity-measuring ac- ences at the NIH; Stanford Health Care;
celerometers. The study’s objective is to the dean’s office; and various clinical deprovide researchers with a comprehensive partments. Under the umbrella of Stanpicture of human health and the transi- ford’s Biomedical Data Science Initiative,
tion to disease. Collaborators include the this funding aims to help fuel transforStanford School of Medicine and Duke mations in human health and scientific
University School of Medicine. Baseline discovery by fostering innovative collaborations among medical researchers,
studies have just begun.
Indepth Network is a coalition of computer scientists, statisticians and
health and demographic surveillance physicians.
Information on the center is available
systems in 23 low- and middle-income
countries in Africa and Asia. Negotia- at http://med.stanford.edu/phs.html. ISM
tions are underway to enable Stanford
researchers to initiate collaborative stud- Kris Newby is the communications manies on geographically defined groups un- ager for Spectrum, the Stanford Center for
der regular surveillance by local scientific Clinical and Translational Research and
teams.
Education.
April 20, 2015
Inside Stanford Medicine
Few mutations involved in transmission of drug-resistant HIV
By Ruthann Richter
In the largest study of its kind to date, researchers at
the School of Medicine and their colleagues have found
that worldwide only a limited number of mutations
are responsible for most cases of transmission of drugresistant HIV.
HIV, the virus that causes AIDS, can mutate in the
presence of antiviral drugs, and these mutations can be
transmitted from one person to the next.
In the new study of more than 50,000 patients in
111 countries, the researchers found a small group
of mutations accounted for a majority of the cases of
transmission-related resistance to the HIV drugs used
to treat infections in resource-limited settings. The results suggest the levels of transmission of drug-resistant
strains have not increased globally as much as once
feared, said Robert Shafer, MD, professor of medicine
and principal investigator for the study.
“What we are showing is that the rates of transmitted drug-resistant HIV in the low- and middle-income
countries most affected by HIV have increased modestly. The rate of increase in sub-Saharan Africa has
been low, and an increase has not been detected in
south Asia and Southeast Asia. That’s good news,” Shafer said.
However, there continues to be an increase in drug
resistance because the regimens used by HIV patients in
lower-income countries are often not as robust as those
used in upper-income countries, and strict adherence to
a daily, lifetime regimen of taking the pills is challenging, particularly for people in the poorest parts of the
world, he noted.
“It is inevitable that transmitted drug resistance
will increase further, so we need to continue ongoing
monitoring to ensure successful, long-term treatment
outcomes for the millions of people on therapy worldwide,” Shafer said.
He said the findings could have important implications for treatment in these hard-hit regions, leading
to the possible development of an inexpensive test for
key mutations to help determine which drugs should be
given to previously untreated patients.
The study was published online April 7 in PLoS
Medicine.
Halting the spread of HIV
To gauge the extent of the problem of transmitted
resistance to HIV drugs, Shafer and his colleagues reviewed HIV sequencing data on 50,870 individuals
across the globe, taken from 287 studies published between 2000 and 2013. Nearly 60 medical institutions
on five continents contributed data for the study. The
researchers analyzed each virus sequence for the presence of 93 mutations previously shown to be indicators
of drug resistance.
They found the overall prevaNorbert von der Groeben
lence of transmitted drug resistance ranged from 2.8 percent in
sub-Saharan Africa to 11.5 percent
in North America. In south Asia
and Southeast Asia, the prevalence
of transmitted resistance remained
unchanged during the decade
of expansion in drug treatment.
However, many studies from subSaharan Africa have shown the
prevalence of resistance to be more
than 5 percent in recent years, Shafer noted. He said the inevitable
increase in transmitted drug resistance could undermine confidence
in the ability to treat HIV in lowincome regions and potentially dissuade new patients from seeking
care.
To avoid that prospect, the
study points to the possibility of
creating a simple, inexpensive test
Researchers Vici Varghese, Robert Shafer and Soo-Yoon Rhee are co-authors of a paper that for the key resistance-related mutafound that a small group of mutations accounted for a majority of the cases of transmission- tions, which could help clinicians
related resistance to HIV drugs used to treat infections in developing countries.
pinpoint the drugs likely to be most effective for individual patients. In both Africa and Asia, the researchers
identified four specific resistance-related mutations that
were associated with the drugs nevirapine and efavirenz.
These are among an older, less-expensive class of drugs
known as non-nucleoside reverse transcriptase inhibitors, typically used in the developing world as part of a
standard, daily regimen.
“The idea of an inexpensive test for key mutations
is attractive because if it were used in conjunction with
a viral load test [a measure of the amount of virus in a
patient’s blood], it would allow physicians to know if
therapy should be changed and where adherence counseling should be given,” Shafer said. Patients who show
signs of these mutations could be switched to newer,
albeit more costly, drugs known as protease inhibitors,
which are less susceptible to resistance, he said.
“You could therefore shut off the flow of drug resistance by using regimens that are less vulnerable to the
development of drug resistance in the first place,” he
said.
Unrelated strains
The study also found that the drug-resistant strains
did not come from a single line of resistant viruses,
but were distinctly different from each other, suggesting they had been acquired independently and not as
a result of a single transmission chain. That contrasts
with patterns of resistance in other microbes, such as
malaria and tuberculosis, where resistant strains tend
to move rapidly among populations, Shafer said. It also
contrasts with an emerging pattern of drug resistance in
many upper-income countries, where 20 years of HIV
therapy have spawned the spread of many highly drugresistant strains.
“We are finding that the strains being detected in
low-income countries are pretty much unrelated to one
another. So that suggests these have not yet gained a
foothold in the population, and are less often being
transmitted among people who have never received the
drugs before,” Shafer said.
Other Stanford co-authors are Soo-Yon Rhee, MA,
a research associate and first author of the study; John
Ioannidis, MD, DSc, professor of medicine and of
health research and policy; Jonathan Taylor, PhD, professor of statistics; David Katzenstein, MD, professor
emeritus of medicine, and Vici Varghese, PhD, a research associate.
The work was funded by the National Institutes of
Health, the Bill & Melinda Gates Foundation and the
Center for AIDS Research.
Stanford’s Department of Medicine also supported
the work. ISM
Study: Encountering a wall corrects ‘GPS’ cells in mouse brains
By Kim Smuga-Otto
By analyzing the activity of “GPS”
neurons in mice, researchers at the
School of Medicine have discovered that
the mental maps created by these cells
accumulate errors, which are corrected
when the animal encounters a wall.
The findings support the theory that
these cells, called grid cells, use an animal’s perceived speed and direction to
help it navigate familiar places.
Thus, as you stumble through your
pitch-black kitchen in the middle of
the night for a glass of water, your body
knows how many steps to take and when
to turn to get to the sink. Scientists believe grid cells are responsible for constructing the internal, GPS-like map
that keeps you from colliding with the
refrigerator.
But grid cells can make small errors,
the Stanford researchers assert, taking
you to the dishwasher instead of the
sink, at which point other nearby neurons, called border cells, assist in reorienting the grid cells to correctly map
your current position.
How the brain integrates this sensory
and motion data is one of the big open
questions of spatial navigation. A paper
that helps to answer that question was
published April 16 in Neuron. Lisa Giocomo, PhD, assistant professor of neurobiology at Stanford, is the senior author;
the lead author is graduate student Kiah
Inside Stanford Medicine
April 20, 2015
Hardcastle. This work was done in close
collaboration with the theory lab of
Surya Ganguli, PhD, assistant professor
of applied physics at Stanford, who is the
other co-author on the study.
Learning from Nobel laureates
A decade ago, grid cells were identified in the entorhinal cortex of the
brain by Norwegian scientists May-Britt
Moser, PhD, and Edvard Moser, PhD,
who were among the winners of last
year’s Nobel Prize for the discovery of
the neurons involved in self-location and
navigation. They found individual cells
that fired consistently when a mouse
wandered past certain places in both
light and dark enclosures. At each of
these places, a unique set of grid cells activated, presumably signaling to cells in
the hippocampus the mouse’s location.
“You can think of them as a neurological longitude and latitude system,” said
Giocomo, who did postdoctoral work
with the Mosers at the Kavli Institute of
Systems Neuroscience/Centre for Neural
Computation at the Norwegian University of Science and Technology.
It was there that she collected data
from 11 mice, each outfitted with a
microdrive. The device, surgically implanted in the mice’s brains, contained
numerous microelectrodes, each with the
ability to record from several neurons,
including grid cells, so researchers could
monitor the firing of several cells simul-
taneously. During the 40- to 50-minute its speed or turned too much, or not
session that each mouse spent exploring enough. These small mistakes would aca dark, 1-square-meter space, a particular cumulate the more it traveled, explained
set of grid cells would activate in its brain Hardcastle, and lead to larger errors.
when it arrived at certain place within
The research “represents an importhe enclosure.
tant step forward in understanding how
But when Hardcastle, a graduate spatial cues from the outside world influstudent in Giocomo’s lab,
ence spatial representations
analyzed specific paths where
inside the brain,” said neuthe mouse spent a long time
roscientist Ila Fiete, PhD,
far away from the border, she
of the University of Texas
found that the grid cells began
at Austin, who was not infiring when the animal was
volved in the study.
not quite in the place where
Giocomo and her stuthe cells usually fired. Over
dents have gathered an even
time, the cells would lose aclarger data set from mouse
curacy and begin to fire when
studies in her Stanford lab
Lisa Giocomo
the mouse was at an increasing
and are planning to study
distance from that place. But
grid cells in rats, as well.
encountering a wall corrected this dis- Giocomo is interested in investigating
crepancy. Giocomo suspects border cells how more complex visual information,
are responsible for this correction.
as well as touch and smell, is used to correct grid cells, and for that, they need to
Rapid rate of errors
be able to sample more neurons.
The study was supported by grants
The speed at which the grid cells acquired errors surprised her. “Within two from Burroughs-Wellcome, the James
minutes, the maps started to drift,” she S McDonell Foundation, the Simon’s
said. “We thought it would take 30 to 40 Foundation, the Alfred P. Sloan Foundation and Stanford’s Bio-X Interdisciplinminutes.”
However, a particular set of grid cells ary Initiatives Program.
Stanford’s Department of Neurobiolwouldn’t fire when the mouse was a long
way from the place where those cells were ogy also supported the work. ISM
supposed to fire. This supports the theory that grid cells use speed and direction Kim Smuga-Otto is a science-writing into calculate the animal’s location; errors tern for the school’s Office of Communicacould creep in if the mouse misestimated tion & Public Affairs.
3
Pilot project aims to help heart-failure patients self-manage
By Grace Hammerstrom
Earl Shook knew he was in trouble. He couldn’t
walk five feet without losing his breath and stopping to
rest. He couldn’t carry his dog’s 35-pound bag of food
without dropping it to the floor. And he couldn’t cook
for the Fifty Plus Club at the Menlo Park Presbyterian
Church, where he worked.
For weeks, Shook, 74, had been experiencing shortness of breath, which his physician treated as pneumonia. As his condition worsened, he returned to the
doctor, but needed a wheelchair to get from his car
to her office. She knew immediately there was something else going on, and sent him to a cardiologist for
a consultation. Shook was diagnosed with congestive
heart failure with atrial fibrillation, and was told that
he should be hospitalized. Shook resisted, convincing
his doctor to let him cook for the Fifty Plus Club that
Friday night. But when he could barely stand without holding onto a table, he and everyone around him
knew he needed help.
He was transported via ambulance to Stanford Hospital from his cardiologist’s office the following Monday, and spent a week in the hospital.
At discharge, Shook became one of the first people
be enroll in a pilot project that monitors heart-failure
patients at home. Launched earlier this year, the project
is a joint effort of Stanford Health Care’s heart failure
team and Aging Adult Services Program. Nursing &
Rehab at Home, an SHC community partner, and Philips Healthcare, a corporate partner, are collaborating on
the project. The goal is to teach these at-risk patients
self-management of their chronic condition, and keep
them from being admitted to the hospital.
“There is abundant evidence in the literature that
suggests home monitoring can improve patient outcomes,” said Rita Ghatak, PhD, director of Aging Adult
Services. “It can improve survival, days out of the hospital, quality of life, and it provides an extra measure of
psychosocial support.”
According to project leader Dipanjan Banerjee, MD,
clinical assistant professor of cardiovascular medicine,
Stanford has employed a number of interventions to
reduce heart-failure readmissions over the past three
years, but they have all been inpatient, hospital-based
interventions, such as scheduling follow-up appointments prior to discharge, making discharge phone calls,
educating patients about managing their condition at
home, and reconciling medications before discharge.
“All of these are great interventions, but they don’t
speak to what happens to the patient at home,” said Banerjee, who is also director of SHC’s Mechanical Circulatory Support Program. “There’s a big opportunity
to use home monitoring or home-based approaches to
improve patient care.”
Bringing care home
A day after arriving home, Shook received a digital scale, a blood pressure cuff, a pulse oximeter and a
hub station and was trained on using the devices by the
Nursing & Rehab at Home staff. For 30 days, Shook
weighed himself daily and took his blood pressure
and oxygen saturation. His readings were automatically transmitted to a central monitoring portal. If he
skipped a day, the home health agency would call to
remind him. If his vital signs were out of the normal
range, the agency would contact the Stanford nurses to
intervene.
“A key focus in heart failure management is prompt
symptom recognition and knowing what action to
take when early signs of decompensation emerge,” said
Christine Thompson, RN, clinical nurse specialist for
the heart failure team, who helped develop the pilot
norbert von der groeben
ria, as well as daily self-assessment of symptoms, Ghatak
said.
“Heart failure doesn’t end when patients leave the
hospital,” said Angela Bingham, RN, nurse coordinator for the heart failure team. “A big part of managing
heart failure is teaching self-management for patients
with chronic disease. The home monitoring pilot really
supports patients doing that.”
“There’s a big opportunity
to use home monitoring or
home-based approaches to
improve patient care.”
Providing peace of mind
Earl Shook enrolled in a Stanford Health Care pilot project that
monitors heart-failure patients at home.
project. “Daily monitoring of vital signs, in addition to
assessment of subjective symptoms, is a tool that may
particularly benefit some of our high-risk patients.”
As part of the project, patients also receive a home
visit by one of four Aging Adult Services nurses —
Pauline Marchon, RN; Terese McManis, RN; Candace Mindigo, RN; or Lourina Co, RN. In addition
to ensuring that patients are using the monitoring
equipment correctly, the home visit allows the nurses
to reinforce messages about diet, exercise and medications. On more than one occasion, these visits uncovered a potential health problem that could be addressed
immediately.
When McManis conducted a home visit with Shook,
she noticed something was awry. His blood pressure
readings were abnormal, she said, and his diastolic
number, at 110, was very high. The nurse was concerned enough to call Thompson. “We got him in to
see his cardiologist the next day,” said McManis. His
medications were adjusted immediately, bringing his
blood pressure back into a normal range within two
days.
Heart failure is a complex syndrome requiring lifelong adherence to medications and certain dietary crite-
The pilot project plans to enroll 30 patients with
heart failure from the inpatient and clinic settings,
and provide them with home monitoring equipment
for 30 days free of charge. To date, it has enrolled 22
patients. Not every heart failure patient is a candidate,
Bingham said. Patients must live within Santa Clara
and San Mateo counties, and be well enough to conduct the self-monitoring or have someone in the home
available to help them. At this time, patients must also
speak English or have someone who can interpret for
them in their home. At the end of the 30-day monitoring period, a nurse conducts a phone survey to evaluate
the program’s impact on the patient’s health and quality
of life.
For Shook, being sent home after a week in the hospital was unnerving. “When you’re cared for at the hospital by good nurses and doctors, and you’re sent out
from the hospital, there’s a void,” he said. The home
monitoring was reassuring, he added. “It let me know
there was somebody there still caring for me.”
Shook has completed the 30 days of being monitored, but still chooses to monitor himself daily with
equipment he acquired on his own. A lifelong chef who
cooked for the airlines at San Francisco International
Airport for much of his career, Shook has had to learn a
“whole new way to cook,” he said, cutting back dramatically on salt to help manage his high blood pressure,
and using herbs, lemon and mustard to season his food.
“Seeing those numbers every day helped me change
my diet, and I do a little more walking with my dog,”
he said. “It gave me a sense of discipline. Now I make
sure to take all my pills. Before I would skip them
sometimes.” ISM
Grace Hammerstrom is a freelance writer for Stanford
Health Care.
P l e as e giv e bloo d
Blood type needed:
O-, ABTo request an appointment, call 723-7831
or you can make an appointment online.
3373 Hillview Ave., Palo Alto
445 Burgess Drive, Menlo Park,
515 South Dr., Mountain View
http://bloodcenter.stanford.edu
Big Data in Biomedicine Conference set for May 20–22 a
By Bruce Goldman
The 2015 Big Data in Biomedicine
conference, to be held May 20-22 at
the School of Medicine’s Li Ka Shing
Center for Learning & Knowledge, will
bring together hundreds of participants
from several continents. Their common focus: how best to apply today’s
massive computational power to the
mountains of data steadily accumulating in biomedical databases, Internet
search engines, social-media archives
and wearable sensors.
“The Big Data in Biomedicine Con-
4
ference brings together the industry
experts, thought leaders and researchers who will help transform the way we
diagnose, treat and prevent disease in
our own community and around the
world,” said Lloyd Minor, MD, dean
of the School of Medicine. “The ideas
and connections generated at this event
will be catalysts in widespread transformation in human health.”
The annual three-day conference
debuted in 2013, thanks to a grant
from the Li Ka Shing Foundation. Last
year, nearly 500 participants, including
dozens of speakers and panelists from
academia, information-technology and
biotechnology corporations, venture
capital firms, the U.S. government,
hospitals and foundations convened
on campus to discuss ways of harnessing the power of big data to improve
human health. More than 1,000 others watched the event online via livestreamed video.
Topics to be highlighted this year
will include genomics, population
health, mHealth (the application of
data obtained from mobile devices to
medical practice and public health),
neuroimaging, crowdsourcing, statis-
tics, ethical and legal issues, immunology and “learning” health systems.
The research of one of the keynote
speakers, Michael Levitt, PhD, professor of structural biology at Stanford, exemplifies the revelations made possible
through the application of computer
power to biomedical problems. Levitt
shared the 2013 Nobel Prize in Chemistry for his development of multi-scale
models elucidating the conformations
of huge, unwieldy biomolecules.
Other keynote speakers will be Sharon Terry, CEO of Genetic Alliance;
Kathy Hudson, PhD, deputy direc-
April 20, 2015
Inside Stanford Medicine
Adherence to blood thinner best with pharmacist management
By Tracie White
Patients are more likely to take a new
type of blood thinner correctly and without missing doses when they are managed by pharmacists, rather than only by
doctors or nurses, according to a study
co-authored by a researcher at the School
of Medicine.
Mintu Turakhia, MD, assistant professor of medicine, and fellow researchers studied a new treatment for atrial
fibrillation, a dangerous heart disorder that increases the risk of stroke and
blood clots. The treatment, a drug called
dabigatran, is one of a new class of twicedaily oral medications. A paper describing the findings was published April 14
in the Journal of the American Medical
Association.
Researchers found that Veterans
Health Administration patients who got
their prescriptions for the medication
filled by VHA pharmacists who educated
them about the drug and checked their
adherence on a regular basis were 80 percent more likely to follow medication
guidelines than those who didn’t receive
this kind of support.
“The new oral anticoagulants, such as
dabigatran, represent the biggest medical change in in the delivery of care for
a-fib patients,” said Turakhia, the senior
author of the study. “Before, the only option we had for patients was warfarin,
which is cumbersome and requires blood
testing once or more per month.”
What leads to better adherence
Because these new drugs come in
fixed doses and patients taking them
don’t need to undergo regular blood
tests, health-care professionals assumed
that the drugs wouldn’t need to be monitored. What this study shows is that
when the drug was delivered by pharmacists who provided an increased level
of patient support, patient adherence
greatly improved.
“Although pharmacist-led management of these new drugs is uncommon
in the U.S., the findings make the case
that it is still important and can ultimately impact clinical outcomes,” Turakhia said.
Since the first of the new drugs was
approved by the Federal Drug Administration in 2010, physicians have been
increasingly prescribing them in place
of warfarin, an anticoagulant that has
been used to treat a-fib for 50 years,
Turakhia said. Evidence shows that the
new drugs work at least as well as warfarin, and cause less bleeding — but only
when taken correctly. “This is important
because even missing a few doses can
lead to acute events such as stroke,” he
said. “How well you take
the new drugs largely determines your treatment
benefit.”
The new oral anticoagulants are popular with
many patients because they
require no monthly lab visits to measure their levels
in the blood. Patients are
instead simply sent home
from the pharmacy with
the pills.
norbert von der groeben
Alternative to warfarin
“Among my patients,
I used to get asked about
alternatives to warfarin a
dozen times a week,” Turakhia said. “Many of them
were unhappy with the
need for regular, often lifelong blood testing.”
Atrial fibrillation, a
type of heart arrhythmia,
is a common and grow- Mintu Turakhia and his colleagues have found that patients who receive guidance from pharmacists are better at taking a
ing problem in the United new class of anticoagulants as prescribed.
States that affects at least 3
million people. Due to rising rates of obesity and hypertension, ford Health Care and the Veterans Af- tients no longer make routine visits to a
that number is increasing, and more fairs Palo Alto Health Care System. “We laboratory that may have offered similar
people at a younger age are developing didn’t expect to see that much variation patient support, Turakhia said.
“This finding challenges the entire
the disorder. A-fib may result in symp- by site.” Next, researchers conducted
toms such as palpitations, racing heart, in-depth telephone interviews with the framework of health-care delivery of
shortness of breath and fatigue. An ir- managers, usually pharmacists, at 41 of these new agents,” Turakhia said. “These
medicines were pitched as easier for paregular heartbeat leads to poor blood these pharmacy sites.
“We rolled up our sleeves and looked tients and for health-care providers.”
flow, which puts patients at a high risk
at what each site was doing,” Turakhia Since patients are no longer required to
of stroke.
visit labs regularly, as with warfarin, in
The introduction of these new blood said.
most cases the physician alone, or with
thinners has been a major change in
the help of practice nurses, is now solely
the treatment plan for many of these Benefits of supportive pharmacist
patients.
At the sites with the highest patient responsible for checking on adherence.
Most doctors and their offices don’t
According to the FDA, from its ap- adherence, there was usually a pharmaproval in October 2010 through August cist actively educating patients on medi- have a system in place to verify how well
2012, about 3.7 million prescriptions cation adherence, reviewing any possible patients take their medication and to anfor dabigatran (Pradaxa) were dispensed, drug interactions, and following up to ticipate refills and get patient their refills
and approximately 725,000 patients make sure patients were taking the medi- promptly before medications run out.
“We’re suggesting that greater strucreceived a dispensed prescription from cation when they were supposed to and
U.S. outpatient retail pharmacies.
that prescriptions were being refilled on tured management of these patients,
beyond the doctor just prescribing
Heart researchers became concerned time.
when studies began showing that paThe sites with patients who had medications for them, is a good idea,”
tients were not adhering as well to treat- the highest adherence levels had some Turakhia said. “Extra support, like that
ment guidelines with this new blood key features in common, among them provided in the VA anticoagulation clinthinner, in some cases crippling the treat- this type of “pharmacist-led patient ics with supportive pharmacist care,
greatly improves medication adherence.”
ment’s effectiveness, Turakhia said.
management.”
The lead author of the study, Supriya
Puzzled by this, researchers set out to
“We determined there was a high level
determine if this lack of adherence could of scrutiny and review to make sure pa- Shore, MD, is a cardiologist at Emory
be explained by where patients were fill- tients were getting the drugs,” Turakhia University.
Turakhia is a consultant for Precision
ing their prescriptions for the medica- said. “There was a lot of consideration of
tion. They looked at Veterans Health the dose, interaction with chronic kidney Health Economics, Medtronic Inc., and
Administration sites where 20 or more disease and review to make sure that pa- St. Jude Medical Inc.
The project was supported by grants
outpatients had dabigatran prescriptions tients should be getting these drugs.”
filled between 2010 and 2012.
The study’s results suggest that an from Veterans Affairs Health Services
“Surprisingly, we found that treat- unintended side effect of a-fib patients Research and Development Office and
ment adherence varied not by individual, switching to the new blood thinner the American Heart Association.
Stanford’s Department of Medicine
but by site,” said Turakhia, who is also medications may be poorer adherence to
a cardiac electrophysiologist with Stan- medication guidelines because most pa- also supported the work. ISM
at Li Ka Shing Center
tor of the National Institutes of Health;
France Cordova, PhD, director of the National Science Foundation; Brook Byers,
PhD, partner at Kleiner Perkins Caufield
and Byers; and William King, CEO of
Zephyr Health.
Stanford scientists who will speak at
the conference include Laura Carstensen,
PhD, professor psychology and director
of the Stanford Center on Longevity; bioethicist Mildred Cho, PhD, professor of
pediatrics; Mark Cullen, MD, professor
of medicine and director of the Stanford
Center for Population Health Sciences;
crowdsourcing-game developer Rhiju
Inside Stanford Medicine
April 20, 2015
Das, PhD, assistant professor of biochemistry; neuroimaging pioneer Michael
Greicius, MD, MPH; and Lester Mackey,
PhD, assistant professor of statistics.
The conference is part of Stanford
Medicine’s Biomedical Data Science Initiative, which strives to make powerful
transformations in human health and scientific discovery by fostering innovative
collaborations among medical researchers, computer scientists, statisticians and
physicians.
To learn more or register for the conference, visit http://bigdata.stanford.edu.
ISM
5
Patient views on research participation surprise, bioethicists say
boost er shot medi a
By Kris Newby
on medical practices, or ROMP, ethics
While a debate was raging between project, which was launched in the afterscientists and government regulators on math of a controversial research-consent
how best to explain to patients the risks form used in a study that compared two
of participating in clinical research stud- oxygen-delivery levels for extremely preies, a team of bioethicists boldly went mature babies. While many researchers
where no experts had gone before — to and bioethicists argued that the research
was done in an appropriate fashion, oththe patients themselves.
What the patients said surprised ers disagreed.
Even though these at-risk infants were
them: Keep it simple, but always ask
permission, even when the research only randomly assigned to one of two staninvolves gathering data from anonymized dard treatment options, some people felt
that the clinical risks of standard pracmedical records.
“We didn’t anticipate that patients tices should be disclosed as research risks.
would want to grant permission for med- Researchers, the public and the bioethics
ical record searches, a research method community were deeply divided about
that involves much less risk than most whether the consent form adequately
randomized studies that compare stan- warned parents about participation risks.
dard treatment options,” said Mildred The ROMP ethics study was designed to
Cho, PhD, professor of pediatrics and gather evidence on patient attitudes toof medicine at the School of Medicine. ward risks and how to best ask for per“The good news was that most patients mission to conduct this type of research.
“Creating burdensome consent regusaid they would forgo documented
consent or accept simple approaches to lations for minimal-risk research may
granting permission, even verbal permis- impede the collection of valuable medisions, if requiring written agreements cal evidence without actually increaswould hinder this type of comparative- ing the protection of participants,” said
David Magnus, PhD, a co-author of the
effectiveness research.”
A paper describing the findings of the study and the director of the Stanford
patient survey was published April 14 in Center for Biomedical Ethics.
Cho, Magnus and other rethe Annals of Internal Medisearchers involved in the projcine. Cho, who is also assoect began collecting data in
ciate director of the Stanford
August 2013 through a WebCenter for Biomedical Ethbased survey of 1,095 adults.
ics, is the lead author of the
The survey included quespaper. Benjamin Wilfond,
tions about attitudes toward
MD, professor and chief of
research, doctors and health
pediatric bioethics at the
systems, as well as questions
University of Washington
to assess understanding of reSchool of Medicine, is the
search concepts, such as variasenior author.
Mildred Cho
tions in prescribing patterns
The findings will be used
to inform the U.S. Office of Human among physicians, randomization and
Research Protections and the Food and informed consent. The survey also asked
Drug Administration as they develop questions about patients’ preferences for
regulations on how to structure patient being notified about studies, and their
permissions for research conducted dur- perceptions of risk and willingness to
ing mainstream clinical care and through participate in the context of three scenarios. The three scenarios were presented
mobile devices.
in videos, which are available at http://
The patient perspective
spectrum.stanford.edu/romp-videos.
During the process of developing and
The survey was the work of a research
Chromosome
continued from page 1
talking to,” said Chang. “Ci’s new technique allowed us to discover the RNA
and protein complexes responsible for X
chromosome silencing.”
The genes for orange and black fur
are on the X chromosome in cats. Therefore, a female cat can have a patchwork
of both orange and black fur depending
on which chromosome was randomly inactivated in each ancestor cells. A male,
however, can be orange or black, but not
both. (An exception would be a male cat
that had somehow inherited an extra X
chromosome along the way, making it an
XXY animal likely to have other significant genetic problems.)
Chu’s technique, which the researchers call CHIRP-MS for “comprehensive
identification of RNA-binding proteins
by mass spectrometry,” allowed the researchers to identify the sequential interaction of over 80 proteins with Xist
during X inactivation. Many of these
proteins have never before been associated with that process. It’s thought that
they may help target and anchor Xist to
active genes along the length of the X
chromosome like burrs on a shoelace after a hike in the woods.
Elaborate genetic machinery
“If you lay all the copies of Xist in a
cell end to end, they are not long enough
to coat the entire X chromosome,” said
Chang. “Instead, Xist spreads judiciously,
6
finding active
genes and shutting them down.
It also must stay
anchored to the
chromosome and
not float over to
any other chromosomes in the
nucleus. This reHoward Chang
quires an elaborate set of machinery that we believe acts
in a sequential fashion.”
Specifically, the researchers suspect
that some proteins help Xist locate and
silence active genes, while others work to
maintain that silencing once it has been
established.
“We’re interested in really understanding this process, including how the inactivation of a specific X chromosome is
maintained during DNA replication and
cell division,” said Chang. “We and others are really excited by this research.”
Other Stanford co-authors of the paper are postdoctoral scholar Qiangfeng
Zhang, PhD, graduate student Ryan
Flynn, and undergraduate student Maheetha Bharadwaj.
The research was supported by the
National Institutes of Health, the California Institute for Regenerative Medicine, the Howard Hughes Medical
Research Institute, the Institut Curie in
Paris and EpiGeneSys.
Stanford’s Department of Dermatology also supported the work. ISM
Bioethicists produced videos to explain key clinical research concepts to participants in their study on
the public’s attitudes toward comparative effectiveness research in medical practices.
testing the videos and survey, the bioethicists learned a great deal about the
best way to educate patients on medical research, Magnus said. “One of our
first challenges was to dispel the ‘doctors
know best’ myth. Doctors don’t always
know which treatments are best for individual patients,” he said. “In the absence
of good evidence, these choices are often
influenced by advertising, insurance coverage and local preferences. Busting this
myth was essential in explaining why
comparative-effectiveness research is so
important.”
Hearing it from their doctors
One interesting survey finding was
that patients preferred that their doctors, rather than medical researchers, ask
them whether they’d like to participate in
research. This runs counter to conventional wisdom in the research community, where the participation of doctors
in the recruiting process can be viewed as
a potential conflict of interest.
For supporters of comparative research in clinical settings, it was encouraging to learn that 97 percent of the
respondents agreed that health systems
should conduct this type of research.
“I think that patients really want us to
make it easier for them to participate in
research,” said Magnus. “As medical research evolves, the ways that we engage
and inform patients must evolve, too.”
Some of the ROMP team members
were recently awarded a grant from the
National Institutes of Health to continue
researching the ethics of informed consent. Next, they will be translating their
educational videos into Spanish and
Mandarin, and developing strategies and
tools for educating patients from diverse
ethnic groups about research that makes
use of electronic medical records and
stored biological samples.
The project is supported by the NIH
National Center for Advancing Translational Sciences’ Clinical and Translational Sciences Award to the Institute of
Translational Health Sciences at the University of Washington and to Spectrum,
the Stanford Center for Clinical and
Translational Research and Education.
The Office of Human Research Protections guidance on patient disclosure
can be reviewed at http://www.hhs.gov/
ohrp/newsroom/rfc/draftstandardreseach.html. ISM
Kris Newby is the communications manager for Spectrum, the Stanford Center for
Clinical and Translational Research and
Education.
Registration open for Health Matters, a community event
A community event that explores
the latest in advancements in medicine and health at Stanford Medicine
will take place from 9 a.m. to 2 p.m.
May 16 at the Li Ka Shing Center
for Learning and Knowledge.
The event, Health Matters, is free
and open to the public. It will feature
educational programs about health
for the entire family, including lectures by Stanford Medicine faculty
members on maintaining cognitive
health and preventing dementia,
preventing heart disease, reducing
the risk of infectious disease, understanding breast cancer biology, and
staying healthy and injury-free when
exercising, as well as on new genetics
research on longevity and aging.
“One thing we truly appreciate on
the Stanford campus is having colleagues a few steps away who work
in different disciplines,” said Lloyd
Minor, MD, dean of the Stanford
University School of Medicine. “The
opportunity to collaborate with
so many top experts in an array of
fields enriches your own work and
accelerates the speed at which new
knowledge about how disease works
can be transformed into better, safer
treatments. Likewise, collaborating
with our local community deeply
matters.”
In celebration of the 25th anniversary of the Stanford Health Library,
medical librarians will be on hand
to answer health questions and help
visitors research health-related topics.
High school students can take part in
a “mini medical school” program.
Event-goers can also visit the
health pavilion, a collection of exhibits featuring interactive, hands-on attractions and activities for the whole
family: Climb aboard the Stanford
LifeFlight helicopter; play with cutting-edge robotic and 3-D technologies; cuddle up with canines from
the pet-assisted wellness (PAWs) program; get answers to health questions
from a variety of Stanford experts;
and watch cooking demonstrations
with Stanford nutrition experts.
Seating at the talks is limited and
pre-registration is strongly suggested.
The online registration deadline is 5
p.m. May 11. After that time, you
can register for the event onsite
For more information and to register online, visit http://healthmatters.stanford.edu. ISM
April 20, 2015
Inside Stanford Medicine
Noise
cuitry within two key nodes of a very important network in these patients. Known as the default mode
continued from page 1
network, this set of widely distributed brain structures
may consume more energy than any other network in
hidden patterns within this spontaneous neural noise, the brain. It is most active when an individual is nomipatterns that might provide a window into the organi- nally at rest — lying still with eyes closed or just starzation of the brain. Dozens of networks — distributed ing off into space or is retrieving an autobiographical
clusters of brain regions dedicated to various mental ac- memory (“What did I eat for breakfast?”). As soon as
tivities from solving math problems to recalling what that same person is asked to perform any of a number
one ate for breakfast — have now been identified, sim- of other specific mental tasks (for example, solving the
ply by grouping together brain regions with similar pro- equation, “How much is 32 times 5?”), this network
files of neural-noise activity. Numerous task-dedicated shuts down. Previously, Parvizi and colleagues were
brain networks’ constituent nodes appear to retain their the first to use direct brain recordings to confirm this
shared activity (albeit at a slow, drifting rate) when at unique property of the default mode network.
For the present study, Parvizi, who is director of
rest — that is, when their particular expertise isn’t being called upon — or even when an individual is com- Stanford’s Human Intracranial Cognitive Electrophysipletely unconscious, such as when sleeping or under ology Program, recruited three patients — two women
and a man — for whom the ideal
anesthesia.
locations to place the electrodes
But brain imaging provides
only indirect assessments of elec- “Increases in brain activity covered both a region called the
angular gyrus, near the outer
trical activity in various brain regions, and critics have suggested during conscious thoughts surface of the brain’s left parietal
that “resting” network patterns and actions represent only lobe, and another region called
the posterior cingulate cortex, on
of activity may be an artifact. In
the tip of the iceberg.”
the inside surface of the left paaddition, while fMRI scans can
rietal lobe, in the narrow space
map activity in the brain panwhere the brain’s two hemispheres nearly meet. In peooramically, their temporal resolution is imperfect.
Parvizi and his colleagues directly addressed these ple, the angular gyrus and posterior cingulate cortex,
concerns and limitations by eavesdropping on the ac- both known to be key components of the default mode
tivity of distinct populations of nerve cells in the hu- network, are several inches apart — a vast expanse, neuman brain. The technique they used, called intracranial rologically speaking.
Beyond the medical procedure already performed,
electrophysiology, provides resolution at a scale of milliseconds and millimeters, letting researchers obtain the new study imposed no further invasive action. Usmeaningful results from inspecting a single individual’s ing intracranial electrophysiology, the researchers found
that electrical activity in these two distant regions of
brain.
the default mode network responded with surprising
Spying on the brain
simultaneity when the experimental subjects were asked
Intracranial electrophysiology’s precision comes from to contemplate various statements of past personal
making direct brain recordings in individuals who have events shown on a computer, such as “I ate a banana for
undergone an invasive procedure for medical purposes. breakfast this morning” (which requires autobiographiThe subjects involved in the Neuron study were patients cal memory retrieval and engages the default mode
with frequent epileptic seizures who had checked into network).
“There was effectively zero time lag” in the response
Stanford Hospital for about a week, during which time
their brains were monitored in an effort to detect the of these regions, said the study’s lead author, Brett Fosexact spot — unique in each different patient’s brain — ter, PhD, a postdoctoral scholar in Parvizi’s lab.
The technique’s temporal precision allowed the rewhere the recurring seizures are being initiated.
In a continuous experiment lasting several days, the searchers to plot the sequence of subjects’ responses
researchers were able to spy, simultaneously, on the cir- to autobiographical-memory queries, which triggered
Scar
electrical activity in, first, the brain’s vision centers;
next, the angular gyrus and posterior cingulate cortex;
then, the brain’s decision centers; and finally, as subjects
pushed a “True” or “False” key on the computer before
them, the motor area.
Similar patterns of activity
Strikingly, the pattern of coordinated electrical activity observed in the default mode network regions when
patients were performing an autobiographical-memory
task persisted even when those individuals were at rest
or asleep. Foster and Parvizi discovered this similarity
by recording activity from these regions while subjects
were resting with their eyes closed during the day and
throughout the night while they slept.They then asked
if the pattern of activity during these states was similar.
What they found, hidden within the idling brain
noise, were slow, drifting activity patterns during rest
and sleep that directly matched those seen during effortful memory retrieval. Importantly, to show that
such electrical patterns reflect those previously observed
by brain-imaging researchers, they also performed
fMRI scans in the same individuals, and confirmed
that network activity patterns for electrical activity and
blood flow were closely aligned.
The findings put one debate to bed — the coordinated resting-state network activity visualized by neuroimaging is real — but raise another: What advantage
might an organism derive from the immense energy
expenditure needed to keep all that activity going even
during sleep? Parvizi and Foster speculated that this
may be the brain’s way of maintaining relationships
within its network organization — tuning itself up in
preparation for future action.
Sounding a word of caution, Parvizi said that referring to network organization should not mislead the
reader into thinking the brain is some kind of computer. “The brain is much more than a bunch of ones
and zeroes,” he said.
Additional Stanford study co-authors were research
assistant Vinitha Rangarajan and medical student William Shirer.
The study was funded by the Stanford NeuroVentures Program, the National Institute of Neurological
Disorders and Stroke, the National Science Foundation
and the National Institute of Mental Health.
Stanford’s Department of Neurology and Neurological Sciences also supported the work. ISM
authorship.
Scars are comprised mainly of collagen, a fibrous protein secreted by a type
of cell found in the skin called a fibroblast. Collagen is one of the main components of the extracellular matrix — a
three-dimensional web that supports and
stabilizes the cells in the skin.
diphtheria toxin, which would allow the
researchers to assess how wounds healed
in the absence of EPF cells.
The researchers found that the proportion of EPF cells, compared to the
overall number of fibroblasts in the skin
on the backs of the animals, increased
dramatically from less than 1 percent in
10-day-old embryos to about 75 percent
in mice that were 1 month old.
an area of only
about 5 percent
of the original
wound. In contrast, untreated
skin formed scars
that covered over
30 percent of the
original wound
area.
An early observation
Role of cell type in scarring
Twenty-five years ago, Longaker observed that prior to the third trimester
of pregnancy, human fetuses heal without scarring after surgery. Furthermore,
many animals heal without scarring.
“We are the only species that heal
with a pathological scar, called a keloid,
which can overgrow the sight of the original wound,” said Longaker. “Humans
are a tight-skinned species, and scarring
is a late evolutionary event that probably
arose in response to a need as huntergatherers to heal quickly to avoid infection or detection by predators. We’ve
evolved for speedy repair.”
In late 2013, a study led by researchers
at King’s College London showed that fibroblasts in the skin of mice arise as two
distinct lineages. One, in the lower layer
of the skin, mediates the initial steps of
repair in response to wounding.
Longaker, Rinkevich and Walmsley
wondered whether this fibroblast type,
which expresses a protein called engrailed, could be responsible for the collagen deposition that leads to scarring.
They generated genetically engineered
mice in which the cells, called EPF cells
for “engrailed-positive fibroblasts,” were
labeled with green fluorescent protein to
allow tracking of the cells’ location during
the animals’ development. The cells were
also engineered to carry a “kill switch”
that could be activated by the presence of
The researchers also found evidence
pointing to a major role for EPF cells in
scarring. After diphtheria toxin was applied to wounds on the backs of mice,
the wounds healed with less scarring.
“The EPF cells are clearly responsible
for the vast majority of scarring,” said
Longaker. Complete healing in the diphtheria toxin-treated wounds required an
additional six days compared to controls,
but much of the repaired skin looked
and appeared to function normally. In
contrast, scarred skin is frequently less
flexible and weaker than uninjured skin.
When the researchers analyzed the
EPF cells more closely, they found that
they express a protein called CD26 on
their surface. CD26 activity has been
implicated in the metabolism of many
hormones, including insulin, and the human version of the protein is a target for
inhibitors such as sitagliptin (distributed
by Merck under the trade name Januvia)
and vildagliptin (distributed by Novartis) that are marketed for treating low
blood sugar levels in people with type-2
diabetes.
The researchers found that a small
molecule that blocks the activity of
CD26 also reduced the amount of scarring in a manner similar to that seen
when EPF cells were eliminated. In particular, scars that formed on wounds
treated with the CD26-inhibitor covered
Radiation damage, melanoma and
EPF cells
continued from page 1
Inside Stanford Medicine
April 20, 2015
Michael Longaker
In addition to examining the role
played by EPF cells in scarring, the researchers investigated skin damage
caused by radiation, as well as the growth
of melanoma cancer cells. Radiation
therapy for cancer frequently causes
damage to the skin it must pass through
to reach the inside of the body. Eliminating the EPF cells in the mice also
eliminated much of the fibrosis caused
by radiation exposure, the researchers
found. Furthermore, melanoma cancer
cells transplanted onto the backs of the
laboratory mice grew more slowly when
EPF cells were eliminated.
“I’ve been obsessed with scarring for
25 years,” said Longaker. “Now we’re
bringing together the fields of wound
healing and tumor development in
remarkable new ways. It’s incredibly
exciting.”
Additional
Stanford authors
are postdoctoral
scholars Michael Hu, MD,
Zeshaan Maan,
MD, and Aaron
Newman, PhD;
Irving Weissman
research associate Micha Drukker, PhD; and graduate student Michael
Januszyk.
The research was conducted as a collaboration with scientists from Weissman’s laboratory and the laboratories
of H. Peter Lorenz, MD, and Geoffrey
Gurtner, MD, both professors of plastic
and reconstructive surgery at Stanford.
The research was supported by the
National Institutes of Health, the California Institute for Regenerative Medicine, the Smith Family Trust, the Hagey
Laboratory for Pediatric Regenerative
Medicine, the Oak Foundation, a gift
from Ingrid Lai and Bill Shu in honor of
Anthony Shu, the Gunn/Olivier fund,
the Human Frontier Science Program,
the Machiah Foundation, the Siebel
Foundation and the Plastic Surgery
Foundation.
Stanford’s Department of Medicine
also supported the work. ISM
Fundraising walk to focus awareness on suicide prevention
A Stanford campus walk to focus awareness on suicide prevention will take
place May 3 starting at 9:30 a.m. at PAC-12 Plaza next to the football field.
Check-in time is 8:30 a.m. The event, a fundraiser for the American Foundation for Suicide Prevention, is organized by the Omicron Chi chapter of Delta
Sigma Theta sorority and sponsored by the Department of Psychiatry and Behavioral Sciences.
To register for the Out of the Darkness walk at Stanford, visit http://afsp.
donordrive.com/event/stanford. ISM
7
Karl Deisseroth wins Albany Medical Center Prize
By Bruce Goldman
Karl Deisseroth, MD, PhD, will receive the Albany Medical Center Prize
in Medicine and Biomedical Research
for his pioneering work in optogenetics.
Deisseroth is a professor of bioengineering and of psychiatry and behavioral sciences at Stanford University.
He also holds the D.H. Chen Professorship. He will share the $500,000
prize with Sunney Xie, PhD, a professor of chemistry and chemical biology
at Harvard, who is a pioneer of singlemolecule biophysical chemistry and its
application to biology.
The two will be presented with the
prize at a ceremony and press conference in Albany, New York, on May 15.
“Dr. Deisseroth’s groundbreaking
work in optogenetics presents enormous potential in this young and
emerging field,” said Lloyd Minor,
MD, dean of the School of Medicine.
“Optogenetics offers great hope for
basic research and future clinical applications to improve human health. We
congratulate Dr. Deisseroth on this impressive and well-deserved honor.”
Optogenetics involves positioning
photosensitive proteins on the surfaces
of nerve cells in particular brain tracts
or circuits. This enables scientists to
study the brains of living animals with
high precision.
Funded by a $50 million gift from
New York City philanthropist Morris
Silverman, the Albany Prize has been
awarded since 2001 to encourage and
recognize extraordinary and sustained
contributions to improving health care
and promoting biomedical research
with translational benefits for better
patient care. It is the largest cash prize
given in biomedicine nationwide.
“It’s a great honor to receive this
prize,” Deisseroth said. “The recognition of optogenetics is not only a tes-
of note
repor ts on significant honors and awards
for faculty, staf f and students
Jason Batten , a medical student, has been
awarded a Fellowship at Auschwitz for the Study of
Professional Ethics. He is among 62 students from
seminaries and from schools of business, journalism, law and medicine to be accepted to the twoweek, interdisciplinary program, which focuses on
investigating ethical issues. Batten conducts clinical ethics research at the Stanford Center for Biomedical Ethics.
Kristen Ganjoo , MD,
was promoted to associate professor of medicine, effective Feb. 1. She
is working to establish a
world-class multidisciplinary sarcoma center at
the Stanford Cancer Institute. Her research focuses
on developing new therapies for sarcoma.
Kristen Ganjoo
Tirin Moore , PhD, was
promoted to professor of
neurobiology, effective Feb.
1. He studies the neural basis of cognition by examining the activity of neurons
in visual and motor structures within the brain.
Sherri Sager , chief government and community
relations officer at Lucile
Packard Children’s HosTirin Moore
pital Stanford, has been
named one of the 100
most influential women in
Silicon Valley by the Silicon Valley Business Journal.
Sager has represented the
hospital to government
agencies and community
groups, and she has advocated for the well-being
of children and expectant
Sherri Sager
mothers through work on
policy issues. She serves
as chair of the San Mateo
County Economic Development Association’s board
of directors and as a board
liaison on the Ravenswood
Family Health Center’s
board of directors. She is
involved in many other
health and community
Hua Shan
organizations.
Hua Shan , MD, PhD,
was appointed professor of pathology, effective
April 1. Her research focuses on international
blood safety and availability. She directs the Transfusion Medicine Service and is a co-director of the
Transfusion Medicine Program. ISM
8
tament to the creativity and vigor of
everyone in the lab and our collaborators over the last decade or more, but
also a signal to the world beyond the
scientific community regarding the
importance of basic science research
to understanding the biology of health
and disease.”
Developed over the last 10 years,
optogenetics mixes optics, genetic engineering and several other disciplines. It
uses light to control the messages traveling along our nerves. The key to its
efficacy is the use of genetic-engineering techniques to insert the genes for
photosensitive proteins called microbial opsins into specified nerve cells in
living animals. As a result, these opsins
wind up coating the surfaces of the designated nerve cells, whose signaling can
then be activated or inhibited by pulses
of laser light transmitted by a hair-thin
optical fiber.
Scientists can then observe the ef-
norbert von der groeben
Karl Deisseroth pioneered optogenetics, a technology that uses light and genetically altered
microbial proteins to activate or inhibit the firing
of neurons in animal brains.
fects of these manipulations on animals’ behavior and deduce the role
played by particular nerve cells, relays
and circuits. ISM
Medical students awarded 2015 Soros Fellowships
Three Stanford medical students are among the 30 recipients of the 2015 Paul and Daisy Soros Fellowships for New
Americans, which support graduate studies for immigrants to the United States and their children.
Each of the Soros Fellows, selected from a pool of 1,200 applicants, can receive as much as $90,000 for tuition and
living expenses in support of graduate education. Cecil Benitez , PhD, a medical student,
was born in Mexico and moved to the
United States with her family when she
was 9 years old. She earned a PhD in developmental biology at Stanford studying
the transcriptional networks of the development of insulin-producing cells in the
pancreas. Her work led to numerous publications, including a chapter in a biology
textbook.
Cecil Benitez
Paras Minhas
Gerald Chunt-Sein Tiu
Paras Minhas is a student in the MD/
PhD program and is working toward a PhD
in neuroscience. He is the son of Sikh immigrants and program and is working toward a PhD in genetics. He
grew up in Maryland. He attended the University of Pitts- is the son of Burmese-Chinese parents who emigrated to
burgh, where he conducted research on Parkinson’s and California from Myanmar. He graduated summa cum
Alzheimer’s diseases, which led to several scientific pub- laude in chemical and physical biology from Harvard
lications. He recently co-managed Stanford’s Pacific Free University. Then, he was awarded a Michael C. RockeClinic in east San Jose. He currently works in the labora- feller Fellowship to study the social, political and cultural
tory of Katrin Andreasson, MD, studying the inflamma- dynamics of HIV in China and Myanmar. He works in
tion and bioenergetics of neurodegenerative disorders.
the laboratory of Maria Barna, PhD, on RNA-mediated
Gerald Chunt-Sein Tiu is a student in the MD/PhD gene regulation in mammalian development. ISM
Detecting lymphoma relapse by monitoring cell-free tumor DNA
By Krista Conger
Circulating tumor DNA in the blood of patients
treated for non-Hodgkin lymphoma can be used to identify those who are relapsing earlier, and with greater accuracy, than conventional monitoring, according to a study
by researchers at the School of Medicine.
The finding is important because it will allow clinicians
to quickly identify patients who need additional treatment. It also further validates the use of circulating tumor
DNA as a means to detect or monitor cancers.
“Diffuse large B-cell lymphoma is the most common
blood cancer,” said Ash Alizadeh, MD, PhD, an assistant
professor of medicine and a member of Stanford’s Cancer
Institute. “This disease is curable in most patients, but a
significant minority of these patients will relapse. Right
now we don’t have a good way to identify those who fall
into this category.”
The current standard for detecting the cancer in these
patients is imaging with combined PET and CT scans.
However, imaging is limited by its specificity; not every
positive PET scan means a patient has truly relapsed.
A paper describing the new research was published
April 16 in Blood. Alizadeh is the senior author, and postdoctoral scholar David Kurtz, MD, and former postdoctoral scholar Michael Green, PhD, share lead authorship.
The researchers studied 75 patients diagnosed with
diffuse large B cell lymphoma. They identified the DNA
sequence unique to each patient’s tumor and then used
high-throughput sequencing to look for the sequence in
the patient’s blood, both in the plasma (the straw-colored,
cell-free liquid in which blood and immune cells circulate), and in the patient’s circulating immune cells.
The researchers found that, in patients known to be
relapsing, they could reliably detect the tumor DNA in
the plasma. In contrast, when they examined the circulating cells in the blood they could detect the disease in only
30 percent of the relapsing patients. They then compared
their plasma-based method with PET/CT scans. Studying
patients who would go on to relapse, they found their new
method identified all patients at the time of their relapse,
and often was able to detect disease prior to relapse. Furthermore, the test was positive only in those patients who
truly had relapsed. In contrast, a positive PET/CT scan
was correct only 56 percent of the time.
Alizadeh cautions that it’s not yet possible to identify
the unique cancer-specific DNA sequence in every patient. About 20 to 30 percent don’t have enough circulating tumor DNA to do so. “This is all about sharpening
the tool,” Alizadeh said, “but the specificity of this new
approach is very promising.”
Other Stanford co-authors are postdoctoral scholars
Scott Bratman, MD, PhD, and Florian Scherer, MD;
research associate Chih Long Liu, PhD; research fellow
Christian Kunder, MD, PhD; former postdoctoral scholar
Kazuhiro Takahashi, MD, PhD; clinical trials assistant
Cynthia Glover; research assistant Shingo Kihira; assistant
professor of surgery Brendan Visser, MD; data manager
Karen Corbelli; assistant professor of medicine David
Miklos, MD, PhD; professor of medicine Ranjana Advani,
MD; professor of medicine Ronald Levy, MD; and assistant professor of radiation oncology Maximilian Diehn,
MD, PhD. The research was supported by the Stanford
Cancer Institute Innovation Fund Award, the Stanley
Hack Family Foundation, the Evelyn Leung Memorial
Foundation and the Lymphoma Research Foundation.
Stanford’s Department of Medicine also supported the
work. ISM
April 20, 2015
Inside Stanford Medicine