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Life. 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.
     So 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.
Seth Force, Jesse  Roman, Ken Brigham, Fadlo Khuri
  Something 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 the past.”
     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.
     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.
Transplanting fresh air  
Blood, 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 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 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, 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.
  A DNA inhaler  
The 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 process.
     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 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.
  ARDS Anonymous

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.”
Individualized cancer care  
About 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 Julian.

cystic 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.

emphysema—a 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.

intracellular level—inside the cell

pulmonary 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)

sleep apnea—a sleep disorder characterized by pauses in breathing during sleep, which each last long enough so one or more breaths are missed

oncogenes—a modified gene, or a set of nucleotides that codes for a protein, that increases the malignancy of a tumor cell

alveoli—anatomical 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.

bronchioles—the 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.

sarcoidosis—an immune system disorder characterized by small inflammatory nodules. It can have the appearance of tuberculosis or lymphoma in x-rays.



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