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It began with photosynthesis, when primeval algae-like
organisms took in atmospheric oxygen and discharged carbon dioxide
as a metabolic waste product. As organisms became more complex,
living became synonymous with breathing. Respiration became the
crux of life. From the first wailing gasp of birth until the final
silence of death, the lungs prime the pump of life, passing air
over capillaries in millions of tiny alveoli, where oxygen moves
into the bloodstream and toxic carbon dioxide moves out. Oxygen-rich
blood fuels each and every bodily function. It is essential, basic,
and elemental to life.
when something goes awry in the respiratory system, the result is
at the least crippling and more often life-threatening. Lung cancer
is the leading cancer killer in both the United States and worldwide,
according to the American Cancer Society, and cancer is only one
form lung disease takes. Chronic obstructive pulmonary disease (COPD),
cystic fibrosis, asthma, and others are included in a range of lung
disorders that often cause suffering for decades before people take
their last breath.
Yet the medical community in the United
States has had difficulty garnering the money and infrastructure—and
some say the will—to tackle lung health with the same vigor
as other more “politically correct” health problems
such as heart disease or stroke. Lung disease is a health condition
with a stigma, largely because this group of devastating disorders
is often related to smoking.
However, many lung diseases develop
whether people smoke or not. Among them are asthma (which affects
close to 20 million people), idiopathic pulmonary fibrosis (affecting
more than 100,000 people), sleep-related breathing disorders (which
affect 5% to 8% of the U.S. population), and
tuberculosis (with millions newly infected each year worldwide).
And of the 170,000 annual deaths attributed to lung cancer, 15%
are in nonsmokers—as was the case with Dana Reeve, a lung
cancer activist and the widow of Superman actor Christopher Reeve,
who herself died of lung cancer in 2006 despite never having smoked.
“There is a definite bias in
the scientific and medical community because many of the most prevalent
lung diseases are seen as ‘diseases of choice,’”
says Emory pulmonologist Kenneth Brigham. “But one could argue
that they are the result of tobacco companies marketing a very addictive
substance. The fact remains that a large number of people out there
have these diseases, and we are morally obligated as doctors to
Fadlo Khuri, a medical oncologist
who specializes in treatment of lung cancer, calls it “a modern
day plague. The number of deaths from tobacco-related disease exceeds
almost all other diseases worldwide. The consequences are heart-breaking,
especially when good people are sent a subliminal message that it’s
their fault. No one deserves the death sentence and suffering that
goes along with lung cancer. Survivors are severely incapacitated
by shortness of breath and fear of recurrence. And the odds of survival
are very poor after recurrence.”
A look at the allocation of cancer
research dollars underscores the underfunding for lung disease.
In 2005, the National Cancer Institute (NCI) spent $279.2 million
on lung cancer research out of a grand total of $4.78 billion on
research for all cancers. The Centers for Disease Control and Prevention
budgeted nothing for lung cancer research in 2005, while spending
$232.6 million for breast, cervical, and prostate cancer research,
according to the Lung Cancer Alliance. At the American Cancer Society
in 2004, of $130 million for research, $29 million went to breast
cancer and a disproportionate $12 million to lung cancer. And the
Department of Defense appropriated $150 million for breast cancer
research and $85 million for prostate cancer research in 2005, while
budgeting only $2.1 million for lung cancer.
Rather than following the national
reluctance to tackle lung disease, the Woodruff Health Sciences
Center (WHSC) is bringing it to the forefront. Physicians, nurses,
and public health researchers alike are engaged in basic science
and clinical trials, patient care, and programs to predict, treat,
and prevent all forms of lung disease. In the past five years, WHSC
has almost doubled the number of physicians and researchers involved
in work related to lung disease. It has expanded its research portfolio
with an eight-fold increase in funding, increased the number of
trainees in this area, and now has two NIH-funded programs to train
lung disease researchers. In short, Emory is working on several
fronts to change the paradigm.
“At Emory, we already are very
good at taking care of patients who have lung diseases like asthma,
cancer, and cystic fibrosis,” says Jesse Roman, director of
the Division of Pulmonary, Allergy, and Critical Care Medicine.
A growing number of clinical and research
programs that focus on lung disease are creating breathing room
for the primer of life. Roman gives a rundown of these specialty
areas including interstitial lung disease (a joint venture between
pulmonary medicine, thoracic surgery, radiology, and pathology),
adult cystic fibrosis (a collaboration between medicine and pediatrics),
interventional pulmonology (a partnership between thoracic surgery
and medicine), and acute lung injury (a collaboration between medicine,
physiology, and pediatrics). Additionally the Emory Sleep Center
(with support from neurology and medicine) is tackling lung-related
sleep disorders such as sleep apnea, and the Andrew McKelvey Lung
Transplantation Center is working on pulmonary hypertension.
The increasing prestige and prominence
of these initiatives has brought forward lung disease as a candidate
for one of the WHSC’s new centers of excellence, which seek
to upend the traditional model for treating disease. These centers
will bring together all the clinical physicians and basic science
researchers working on a disease, eliminating competition for patients
between specialities, minimizing inefficiences, and introducing
new financial and fundraising strategies.
As the familiar brown cloud of smog settles over metro Atlanta
on hot summer days, the number of asthmatic children and others
with chronic lung diseases in emergency rooms rises.
Several studies conducted by
researchers at Emory’s Rollins School of Public Health
(RSPH) during the past 10 years bear that out. The most recent
efforts include a $1 million study of emergency room visits
to 41 hospitals in metro Atlanta dating back to 1994. This
investigation compares daily air quality to daily emergency
room visits for cardio-respiratory problems.
“We have more than 10
million emergency room visits in our database,” says
Paige Tolbert, chair of environmental and
occupational health at RSPH and principal investigator of
the project. “These numbers give our current study far
greater power than similar research that has been done in
This study separates respiratory
outcomes into groups by asthma, chronic obstructive pulmonary
disease, upper respiratory infections, and pneumonia. Data
show a strong connection between ozone levels and asthma attacks.
The investigators are seeing associations of urban air pollutants
with several other respiratory conditions too.
Atlanta is an ideal place to
study the effects of air quality on health. According to Tolbert,
the city has the second highest number of vehicle miles driven
per day in the nation, which contributes along with the city’s
heat to high ozone levels. And prevailing wind patterns blow
emissions from coal-burning electrical power plants in North
Georgia toward Atlanta. Their practices governed by more lax
rules were grandfathered into EPA clean air regulations under
Gail Norton, the first secretary of the interior in President
Bush’s administration. These plants pollute the metropolitan
area with particulate matter.
by the National Institutes of Health, the National Institute
of Environmental Health Sciences, and the U.S. Environmental
Protection Agency (EPA)—is the largest to date to look
at the relationship of emergency room visits and air pollution.
It also uses some of the most refined and detailed air quality
data available anywhere, thanks to measurements taken with
sophisticated equipment by collaborators at the Georgia Institute
Results of the initial research
have appeared in the journal Epidemiology. But Tolbert
and colleagues are far from finished. The longer the study
runs, the stronger the conclusions will be, she says. Policy
makers at the EPA and in the state are keeping a close eye
on the results coming out of the study, with the findings
having direct relevance to standard-setting and pollution
control efforts. Ultimately, the researchers hope the impact
of their findings will be to help metro Atlantans breathe
water, air. All are essential building blocks of life, but of all
the organs in the body that pump and transport and mix and breathe,
the lungs are the most delicate. When it comes to transplanting
a lung or even two from one person to another, timing is especially
“Coordinating the arrival of
the organ with the patient can be the most difficult part of the
transplant process,” says Seth Force, surgical director of
the lung transplant program. When Force is notified that an organ
is available, the first step is a phone conversation to see if the
organ is the right size and in good condition for a person on Emory’s
transplant list. If it is, the lung transplant team moves into high
arranging to get the patient to Emory and to schedule an operating
A single transplant surgery takes
approximately four hours, while a double transplant takes twice
as long. Donor lungs can come from across the United States, but
problems can occur in the donor lung once it has been without blood
flow for more than seven hours. Therefore, the distance from the
donor to Emory can be a significant limiting factor. This makes
it difficult to take lungs from the West Coast, for example.
When Force joined Emory in 2003, Emory
surgeons were performing between nine and 11 lung transplants a
year. Since then, the WHSC has recruited three new pulmonologists,
a number of specialized nurses, transplant coordinators, and support
personnel to boost the number of transplants to 25 a year. Within
the next five years, the goal is to reach 50 per year.
The patients who come to Emory for
lung transplants run the gamut. Some need one lung, and some need
two. They suffer from cystic fibrosis, emphysema, pulmonary fibrosis,
and sarcoidosis. They have ranged in age from 17 to 70, with younger
patients suffering primarily from genetic cystic fibrosis, those
in their 50s most often with pulmonary fibrosis, and the older patients
“Out of the starting blocks
we started an aggressive approach to transplantation,” Force
says. “But we were limited by a short waiting list. We have
spent a great deal of energy in the past three years just trying
to build up the number of patients on our list.”
A rising star in the field doesn’t
hurt. As a fellow at Barnes Hospital at Washington University School
of Medicine in St. Louis, Force worked with Joel Cooper, who is
credited with performing the first successful lung transplant. During
his time in St. Louis, Force was trained by some of the best in
the field at one of the busiest lung transplant centers in the United
States. He estimates he participated in 40 lung transplants during
that period. Since Force came to Emory, Washington has even tried
unsuccessfully to lure him back, according to Alexander Patterson,
chief of cardiothoracic surgery there. Force’s “energetic
leadership has moved Emory’s lung transplant program into
the ranks of the busy and successful programs in the country,”
The Emory program in lung transplantation
got its start in 1993 when pulmonologist Clinton Lawrence joined
the faculty from Stanford, another well-known specialty center for
lung transplantation. That same year, cardiothoracic surgeon Kirk
Kanter performed first lung transplant at Emory. Thirteen years
later in 2001, the program was named the Andrew McKelvey Lung Transplantation
Center for the philanthropist and CEO of Monsterworldwide.com, who
donated $20 million to Emory’s effort. Last year, McKelvey
added $5 million more.
“His support has been remarkable
for us,” says Lawrence, who has been McKelvey’s friend
and medical adviser for more than 25 years. “These resources
have been a real catalyst. They primed the pump and helped us expand
The success of this program has been
a boon to the state of Georgia as well. “We’re the only
program in the state, and I don’t think there will ever be
another one because it’s too difficult to start from scratch,”
branches of the respiratory system divide downward from the trachea
into two major airways called bronchi, which subdivide like the
roots of a tree into a million smaller airways called bronchioles.
It is here, within the capillaries of millions of tiny air sacs
called alveoli that the crucial transfer of oxygen and carbon dioxide
occurs. Within the alveoli cells, the genes and the proteins they
produce direct the action.
Introduce tobacco smoke to the equation,
and a whole cascade of problems begins in the respiratory process.
The damage begins when smoke temporarily paralyzes the cilia (microscopic
hairs) that normally sweep irritants away. So smoking puts irritants
directly on lung tissue and then hinders its natural ability to
protect itself. When celia are irritated, proteins call in immune
cells, which cluster around the irritation. These immune cells often
repel an initial or occasional threat, but if they are called on
too often, scar tissue forms, making the lungs stiff and without
the elasticity required for efficient respiration. In emphysema,
the lung tissue disintegrates because of this persistent inflammatory
It is the role of these tiniest parts
of the lung that fascinate Ken Brigham, vice chair of research in
the Department of Medicine and director of Emory’s new Predictive
Health Initiative. He has tenaciously searched for new treatments
for COPD, which includes several lung conditions such as chronic
bronchitis and emphysema.
“There is simply not much out
there to treat these progressive diseases,” he says. “There
are no effective drugs at all for COPD that are directed at the
root of the problem.” Brigham leads GeneRx+, a small business
housed in an incubator run jointly by Emory and Georgia Tech.
“We’re attempting to find
novel therapies because the usual approaches have been ineffective,”
he says. “There has been considerable progress in developing
asthma drugs but much less with emphysema and COPD. They are slowly
progressing diseases that take a long time to study, thereby making
drugs for them expensive to develop.”
Brigham is developing gene- and protein-based
drugs that introduce therapeutic proteins into cells. This approach
is “gene-based therapeutics” rather than “gene
therapy” because the drugs under development do not permanently
alter patients’ genes. Instead, they operate outside the patients’
genome, directing cells to produce therapeutic proteins.
Brigham established GeneRx+ to bring
some basic discoveries he had made in the lab to the clinic. Two
products are now under development, one a gene-based protein called
alpha-1antitrypsin (AAt) and another that resembles a DNA inhaler
The AAt drug, a normal protein that
protects the lung against inflammation, has been under development
for several years. “Without enough of it, inflammatory diseases
like emphysema will develop,” Brigham says. “This protein
suppresses the consequences of unregulated inflammation, directly
protecting tissues from damaging enzymes.”
Enzymes made by inflammatory cells
digest lung tissue, damaging and eventually dissolving it completely
if the person’s defenses (including AAt) don’t neutralize
them. Scientists have found that smokers generate so many inflammatory
enzymes that they overwhelm the capacity of the lung to protect
itself with natural defenses like the protein AAt.
Brigham hopes to deliver the gene
for AAt directly to lung cells to make them generate the protein.
That’s where the DNA inhaler known as AuContrAer (short for
Automatic Controlled Aerosol) comes in. This aerosol-delivery device
delivers the gene responsible for producing AAt directly to the
lung. Brigham hopes this tool will deliver more of the drug to lung
tissue without damaging the drug in the process. He also hopes the
tool will ensure most of the drug ends up on lung tissue rather
than back out in the air. AuContrAer has been proven safe and effective
in animal trials, and Brigham hopes to start a phase 1 clinical
trial in humans soon. AAt has already passed through early phase
clinical trials that established “proof of principle”
and safety for the drug in humans, and a phase 2 clinical trial
for efficacy will be the next step.
Published in the journal Human
Gene Therapy, the initial study of AAt included patients with
genetically low levels of this protein so investigators could tell
whether the treatment increased the amount of protein. It did.
Like innocent bystanders in a bombing, the
lungs often are unexpected victims. Delicate and
vulnerable, the lungs of alcoholics face even greater risks
than healthy ones. In fact, more alcoholics may die from lung
injury than from liver damage.
As David Guidot,
director of the Emory Alcohol and Lung Biology Center at the
Atlanta Veterans Affairs Medical Center (VAMC), knows well,
acute respiratory distress syndrome (ARDS) is extremely severe.
The condition usually deteriorates until patients must be
placed on ventilators and monitored in intensive care. Even
then, approximately 50% of ARDS patients die.
The risk of dying from lung
disease is four times higher for alcoholics than non-alcoholics.
“And these alcoholics die young,” Guidot says.
“The average age of death from ARDS is approximately
30, even among healthy people. By contrast, the average age
of death from alcohol-related cirrhosis is 60 to 65.”
The deadly combination of alcoholism
and acute lung injury is thought to stem from a shortage of
the antioxidant compound glutathione in the lungs of alcoholics.“Glutathione
is found throughout the body, and certain parts of the body
need it more than others,” says Guidot. “The alveoli
and small airways are very dependent on it. They have 1,000
times the concentration of glutathione than is found in other
parts of the body. Chronic alcoholics have extremely low levels
of glutathione in the lungs.”
A former member of the center,
Marc Moss, and colleagues published a landmark study on the
relationship between chronic alcohol abuse and ARDS in JAMA
in 1996. Since then, Guidot and his team have continued the
research using animal models and clinical subjects. When they
fed alcohol to rats—the best way to control for smoking
and other contributors to lung disease—they saw glutathione
levels plummet within only four to six weeks.
“The alcohol itself doesn’t
cause these changes,” says Guidot. “It causes
oxidative stress, which lowers the amount of glutathione in
This work has been fruitful.
The center recently received a $1.8 million grant from the
National Institutes of Health for their research and a separate
grant to fund the associated training program, which supports
five fellows at any one time. The grant supplements a consistent
flow of funding to understand alcoholism’s relationship
to lung disease. Approximately 25 Emory faculty in fields
such as neonatology, physiology, and pulmonary and critical
care medicine are engaged in related research at Grady Memorial
Hospital, Emory University’s research laboratories,
and the VAMC.
“Emory is the hot spot
for the alcohol and lung disease connection,” Guidot
says. “When you make the discovery, when you invent
the field, you have a big head start. It’s an important
public health issue, and we put it on the map.”
Guidot and colleagues are seeking
ways to lessen the risk of ARDS for alcoholics suffering from
trauma. Goals include finding better ways to identify alcoholics
when they arrive in emergency departments and developing drugs
to increase glutathione levels in patients before they develop
ARDS. The researchers also are studying how alcohol abuse
intersects with asthma, pneumonia, HIV, and lung transplantation.
In terms of prevention, taking
extra doses of glutathione is not a cure because an acute
lung infection often is the first sign of damage. By then,
it’s too late.
As Guidot says, “If
your house is on fire, it’s too late to install a smoke
1.5 million people die of lung cancer each year worldwide, and the
disease kills many people during the prime of life. “The fact
that lung cancer survival is so low is a devastating indictment
of the quality of care in this country,” says Khuri, deputy
director of clinical and translational research at the Winship Cancer
Institute. “Lung cancer is an ominous disease that doesn’t
have many advocates because there are not enough survivors around
five years after their diagnosis.”
In the past, the NCI has shown little
interest in funding lung cancer research, Khuri says. “But
we hope that is changing. We’re making inroads.”
As an example of the turning tide,
the NCI recently awarded $7.9 million to Winship, representing one
of the largest lung cancer research grants in the country and the
largest ever for Emory. Khuri is director and co-principal investigator
for the project, along with Emory pharmacologist Haian Fu.
The grant is built around four scientific
projects and supported by three core laboratory facilities to target
cell signaling in lung cancer to enhance the success of therapy.
Forty researchers and clinicians from 10 departments throughout
the WHSC are involved in multiple studies, which are seeking new
drugs that interfere with cancer cell signaling. They hope to take
advantage of one of cancer cells’ fundamental characteristics.
“Cancer cells don’t know
when to die,” Khuri says. “Part of a healthy cell life
is death when it becomes too damaged to function properly. Cell
death—apoptosis—is usually programmed into a cell. But
cancer cells have a breakdown in the cellular communication system.
This breakdown helps them avoid apoptosis, and they proliferate.”
This team will study and try to exploit
the abnormalities of lung cancer cell signaling to develop new drugs
and therapies. “We hope to turn the strength of lung cancer
into its Achilles’ heel,” says Khuri.
Molecular signaling pathways within
normal cells follow a cascade of molecular reactions that emit proteins,
which turn on programmed cell death when the genes become too damaged
to work properly. But certain proteins called oncogenes interfere
with this cell death process in cancer cells. Targeting the specific
genes and proteins involved should make the cancers vulnerable to
specific compounds, particularly when those cancers are overly dependent
on those oncogenes for their survival. The Winship researchers are
searching for novel compounds that target an oncogene to battle
the proliferation of cancer cells. Similar approaches have proven
successful in other cancers, such as the drug Gleevec for leukemia
and Herceptin for HER2-positive breast cancer.
The research also will seek to better
predict which patients will benefit from chemotherapy. “Some
people will do poorly regardless of chemo,” Khuri says. “If
they would do just as well without it, we would like to spare them.
We need better predictors of chemo effectiveness in individuals,
and we need to know which kind of chemo will work.”
A better understanding of lung cancer
biology and genetics should help clinicians make more informed clinical
decisions. “It’s another step toward individualizing
therapy for cancer patients,” Khuri says.
The studies are important and could
prove groundbreaking, but they aren’t a search for a magic
bullet. The premise acknowledges that a single genetic mutation
doesn’t cause lung cancer. Instead there are many causes on
the cellular level, with many genetic mutations from many different
So the work continues, and more is
needed—not only in lung cancer but also in other lung diseases,
from asthma to pulmonary fibrosis, from sleep-related breathing
disorders to tuberculosis. Politically correct or not, Emory wants
to intervene in the cycle that leads from lung disease to death.
The vision of the WHSC is to transform health and healing for all
people. And in the area of lung treatment, its redoubled efforts
may yet yield fresh air and new life.
Valerie Gregg is a freelance writer in metro Atlanta. Ilustrations
by David Julian.
fibrosis—one of the most common hereditary
diseases that affects the entire body, causing progressive disability
and early death. Difficulty breathing, the most common symptom,
results from frequent lung infections.
chronic lung disease often caused by exposure to toxic chemicals
or long-term exposure to tobacco smoke. Symptoms include shortness
of breath on exertion, hyperventilation, and an expanded chest.
chronic obstructive pulmonary disease—an umbrella term for
a group of respiratory tract diseases such as chronic bronchitis
and emphysema characterized by airflow obstruction or limitation.
fibrosis—involves scarring of the lung.
Gradually, the air sacs of the lungs become replaced by fibrotic
tissue. When the scar forms, the tissue becomes thicker, causing
an irreversible loss of the tissue’s ability to transfer
oxygen into the bloodstream. Symptoms include shortness of breath,
a chronic hacking cough, fatigue and weakness, discomfort in the
chest, loss of appetite, and rapid weight loss.
interstitial lung disease—a
group of lung diseases, most of which involve fibrosis (see above)
apnea—a sleep disorder characterized by
pauses in breathing during sleep, which each last long enough
so one or more breaths are missed
modified gene, or a set of nucleotides that codes for a protein,
that increases the malignancy of a tumor cell
structures that take the form of hollow cavities. In the lung,
they are spherical outcroppings of the respiratory bronchioles
and the primary sites of gas exchange with the blood.
first airway branches that no longer contain cartilage. Smaller
than one millimeter in diameter, they divide until they become
terminal bronchioles. Respiratory bronchioles have sporadic alveoli
on their walls.
immune system disorder characterized by small inflammatory nodules.
It can have the appearance of tuberculosis or lymphoma in x-rays.