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 help them.”
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.
in the Air
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
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.
Tolbert’s study—funded 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 of Technology.
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 easier.
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 critical.
“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 gear, arranging to get the patient to Emory and to
schedule an operating room (OR).
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
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 with emphysema.
“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,” Patterson says.
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 dramatically.”
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,” Lawrence says.
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
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 of sorts.
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
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 the lung.”
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 detector.”
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 sources.
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
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
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.
level—inside the cell
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)
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.