Quitting cigarettes may not improve smokers' lung function if they have already begun to develop chronic obstructive pulmonary disease, according to new research from Weill Cornell Medicine. The findings illustrate how cigarettes affect the lungs on a cellular level — which, the investigators hope, will help persuade smokers to stop as early as possible.

"The addiction to nicotine is very powerful," said senior author Dr. Ronald Crystal, chairman of the Department of Genetic Medicine, the Bruce Webster Professor of Internal Medicine and a professor of medicine at Weill Cornell Medicine. "But the earlier you can stop smoking before developing COPD, the better chance you will have at healthy lungs."

Endothelial cells, which form the lining of blood vessels, shed small bubble-like particles of plasma membrane called circulating endothelial microparticles, or EMPs. This process becomes accelerated when programmed cell death — called apoptosis — occurs; researchers can identify apoptotic EMPs by looking for specific antibody markers in the blood.

Weill Cornell Medicine investigators previously found that smokers have elevated levels of apoptotic EMPs coming from pulmonary capillaries compared to nonsmokers. To determine what happens to a smoker's apoptotic EMP levels after they cease smoking, researchers in the new study, published July 26 in Thorax, assessed the total and apoptotic EMP levels of a group of 138 nonsmokers, healthy smokers and COPD smokers. After baseline EMP levels were recorded, 17 healthy smokers and 18 COPD smokers successfully quit smoking. All subjects' EMP levels were then collected after three, six and 12 months.

Researchers found that both healthy and COPD smokers had elevated levels of apoptotic EMPs compared to nonsmokers, but only healthy smokers were positively impacted by smoking cessation. "When healthy smokers stopped smoking, their levels of apoptotic EMPs dropped back down to normal levels. But for COPD smokers, their EMP levels did not," Dr. Crystal said.

COPD, which causes partially irreversible airflow obstruction, is the third most common cause of death in the United States. Once a person develops the disease, lung function declines at an accelerated rate. "Studying the mechanisms by which COPD occurs, particularly very early on, is important so that we can target drugs that may be effective in terms of stopping the progression of the disease," said Dr. Crystal, who is also a pulmonologist at NewYork-Presbyterian/Weill Cornell Medical Center.

The Global Initiative for Chronic Lung Disease has set the standard for diagnosing COPD and determining its progression. Out of GOLD's four classifying stages of COPD, which range in intensifying severity from GOLD I to IV, most COPD participants were at GOLD I and II. "We purposely looked at people with the mildest form of the disease because it gives better insight into the mechanism," Dr. Crystal said. "When the disease is more severe, there are many pathological mechanisms, so it's harder to sort out what's going on."

Dr. Crystal added that this research is also important when it comes to developing COPD biomarkers, which are substances in the blood that provide doctors with insight into how certain organs, such as the lungs, are doing.

Smoking tobacco — even lightly — through water pipes significantly affects lung function and biology in young adults, a new study by Weill Cornell Medicine researchers shows.

A water pipe consists of a bowl that holds burning charcoal and tobacco. The smoke creates bubbles through water in the bottom of the pipe and is inhaled through a hose. Water pipes, also known as hookahs, have been used for smoking fruit-flavored tobacco for centuries in the Middle East. More recently, however, water pipe smoking has become popular in the United States, with at least 20 percent of young adults reporting having smoked this way.

Many users believe water pipes to be a safe alternative to cigarettes. But in their study, published March 23 in the American Journal of Respiratory and Critical Care Medicine, investigators found that hookah smoking is, in many ways, more dangerous than cigarette smoking.

"The fact that the smoke bubbles through water has led to the perception that the toxins in the tobacco are filtered out," said Dr. Ronald Crystal, chairman of Genetic Medicine and the Bruce Webster Professor of Internal Medicine at Weill Cornell Medicine. "But the fact is, water pipe users are inhaling smoke into their lungs just like cigarette smokers do.

"We found evidence of multiple lung abnormalities in water pipe smokers," he added. "It is clear that even casual water pipe use is not safe."

One water pipe bowl holds the same amount of tobacco as a pack of cigarettes. Smoking that in one session exposes smokers to at least twice the amount of nicotine, seven to 11 times the amount of carbon monoxide, 100 times more tar, and 17 times the amount of formaldehyde in a pack of cigarettes, the study found. Those toxins have a measurable physical effect on young smokers, said Dr. Crystal.

The study looked at so-called light-use water pipe smokers – those who smoked no more than three bowls a week — whose average age was 24. The researchers evaluated both their clinical symptoms, such as coughing and production of phlegm, as well as biologic signs of lung damage.

They found that water pipe users had increased cough and sputum compared to non-smokers of a similar age, as well as reduced lung capacity. In addition, the hookah smokers showed significant abnormalities in the cells lining the airways in their lungs, suggesting that their lungs are being damaged.

"These results are concerning," Dr. Crystal said. "They suggest that, as these young people continue to smoke water pipes, they will develop clinical lung function abnormalities that can result in serious lung diseases."

Water pipe use is currently unregulated in the United States. More research is needed to determine the exact effects of inhaling water pipe smoke on long-term health, Dr. Crystal said.

"We need large-scale, epidemiologic studies, akin to the ones focused on cigarette smoking in the '70s and '80s," he said. "But for now, if I was advising a young person whether he should smoke a water pipe, I would say no."

With 'vaping' on the rise, a health economist explores e-cigarette use

The increasing popularity of e-cigarettes — known in academic parlance as ENDS, for electronic nicotine delivery systems — has policymakers in something of a quandary, as they struggle to understand the products' pros and cons. That debate, as the World Health Organization noted in a report to an international tobacco control convention in September 2014, has become increasingly divisive. One underlying challenge is that, with e-cigarettes invented only about a decade ago, their long-term health implications remain unclear — compared with vast amounts of research on the dangers of conventional smoking. For example, while some studies have found that the devices deliver just a tenth of the carcinogenic compounds of regular cigarettes, others have found them to contain higher levels of potentially harmful metals such as nickel and chromium. "Whereas some experts welcome ENDS as a pathway to the reduction of tobacco smoking, others characterize them as products that could undermine efforts to denormalize tobacco use," the WHO stated, adding that e-cigarettes "represent an evolving frontier, filled with promise and threat for tobacco control."In mid-April, the Centers for Disease Control and Prevention reported a startling statistic: in just a single year, the use of electronic cigarettes among middle and high school students more than tripled. The numbers, from the 2014 National Youth Tobacco Survey, mean that some 2.5 million teens nationwide are using the devices, which turn liquid nicotine into an aerosol that's inhaled — a process commonly known as "vaping." "This is the first time since the survey started collecting data on e-cigarettes in 2011 that current e-cigarette use has surpassed current use of every other tobacco product overall," the agency noted in its Morbidity and Mortality Weekly Report, "including conventional cigarettes." Among high schoolers, the vaping rate was 13.4 percent; by contrast, 9.2 percent reported smoking cigarettes and 5.5 percent used smokeless tobacco.

Health economist Dr. Michael Pesko has long focused his research on tobacco use. He has investigated such topics as how smokers stymie public health efforts by dodging higher cigarette prices, and documented a costly rise in smoking rates in response to the psychosocial stresses of 9/11 — work that earned him a spot on Forbes's 2014 list of "30 Under 30 Who are Changing the World in Science and Healthcare."

Increasingly, Dr. Pesko is turning his attention to e-cigarettes, with a variety of research projects exploring how and why people use them. "There are a lot of interesting questions relating to e-cigarettes in terms of their impact on overall public health," says Dr. Pesko, an assistant professor of healthcare policy and research and the Walsh McDermott Scholar in Public Health. "On one hand, there's legitimate concern that the devices themselves are harmful, or that they can be a gateway into regular cigarette use for adolescents. But on the other hand — within an adult smoking population, for example — there is evidence that they're risk-modifying products. If a smoker is going to use one or the other, you'd rather have them use the e-cigarettes, because while they're not harmless, they're less harmful and potentially could be used for smoking cessation."

In a study that's under journal review, Dr. Pesko is exploring how age restrictions on ENDS purchases affect tobacco use. Currently, he notes, 40 states prohibit anyone under 18 from buying vaping products. "Surprisingly, there are still 10 states where a 12-year-old can legally walk into a 7-Eleven and buy an e-cigarette," Dr. Pesko says, "but the FDA has proposed a law that would apply that under-18 purchasing restriction nationwide."

However, such rules could have unintended consequences, by driving youths to regular cigarettes when they can't obtain the electronic version. That's what Dr. Pesko has found, at least among high schoolers who describe themselves as infrequent smokers. "When the restriction is the same as accessing traditional cigarettes in terms of age, it can cause a substitution effect," Dr. Pesko says. "If e-cigarettes are equally hard to get, some people on the margins will use a regular cigarette — whereas before, maybe they wanted a regular cigarette, but an e-cigarette was so easy to buy, why jump through all the hoops?"

Dr. Michael Pesko

In another upcoming study, Dr. Pesko and colleagues conducted a national survey of 1,200 adult smokers, presenting them with hypothetical purchasing options: either their regular cigarettes, a vaping device (with a variety of prices, flavors, and health warnings), or nicotine replacement therapy. They conducted half the research in late 2014 and half in early 2015, to capture the effect of New Year's resolutions to stop smoking. "If adult smokers are trying to quit, what are they reaching for — nicotine replacement or e-cigarettes?" Dr. Pesko wonders. "We found some evidence that they're reaching for the e-cigarette as a quitting device more frequently."

Still another project is focusing on teens. In a collaboration with adolescent medicine specialist Dr. Lisa Ipp '96, Dr. Pesko is surveying patients in NewYork Presbyterian/Weill Cornell Medical Center's Adolescent Medicine Program about their vaping habits. The team began collecting data in January; participants will be rescreened at six months and one year. While preliminary numbers indicate that use of ENDS is "quite a bit lower" among the program's patients than the national average — for reasons that aren't entirely clear — Dr. Ipp is still concerned. Like many anti-smoking advocates, she points out that vaping products don't have the same rigorous regulation as traditional cigarettes, can be advertised on television and radio, and are available in a variety of kid-friendly flavors that the government bans from conventional tobacco products. "We're basically making nicotine an attractive, appealing option for teenagers who are particularly impressionable," says Dr. Ipp, an associate professor of clinical pediatrics. "I worry greatly that they're going to be addicted to tobacco down the road."

— Beth Saulnier

A version of this story first appeared in Weill Cornell Medicine, Vol. 14, No.2.

Could a process that's normally essential to life be a root cause of COPD?

Known as autophagy, it's a mechanism in which cells conserve energy and nutrients by consuming damaged or unneeded organelles — the tiny structures that perform various functions within each cell. "When people are starving, autophagy is critical," Dr. Choi explains. "But it also regulates inflammation, cell growth and many other processes." For example, in 2010 Dr. Choi and his team reported in Nature Immunology that autophagy confers a potent anti-inflammatory effect in acute inflammatory conditions. "The complexity of this," he notes, "is highlighted by the fact that in some other diseases of the lung, like pulmonary hypertension, autophagy is a good thing."Chronic obstructive pulmonary disease (COPD) kills some 130,000 Americans every year — including, in February, the actor Leonard Nimoy, beloved by millions for playing Mr. Spock on TV's "Star Trek." While the disease — the third-leading cause of death in the United States — is strongly associated with smoking, its underlying causes have never been clear, and effective treatments have proven elusive. "Right now, all you can do is mitigate it," says Dr. Augustine Choi, the Sanford I. Weill Chairman of the Weill Department of Medicine. "There's no cure." But Dr. Choi may have found an important clue to how COPD happens—and surprisingly, it's a process that is normally fundamental to our survival.

But that is not the case in chronic pulmonary disease. Dr. Choi and his team had previously found higher rates of autophagy in the lungs of people with COPD, and they have demonstrated that this leads to cell death that ultimately affects pulmonary function. In a paper published last fall in the Journal of Clinical Investigation, they explained that when cigarette smoke enters the air sacs in a smoker's lungs, it harms their mitochondria, the organelles that serve as cellular power plants. The cells are prompted to destroy their damaged mitochondria, but then they become unstable and are killed off. "The obvious question then is, can we block autophagy with new chemical inhibitors or drugs?" Dr. Choi says. "This has significant therapeutic implications, for sure, but we have to be cautious and systematic about how and when to target the autophagy in COPD."

Autophagy was first described in the 1960s, and for the next few decades it was the province of cell biologists, who studied the process in yeast. It was only within the last 10 to 15 years, Dr. Choi says, that scientists began to investigate autophagy in humans. And since 2008, when his team first published findings about autophagy in lung tissue from COPD patients, other researchers have begun to investigate its role in a host of other human diseases. "We got into the game a bit earlier than most people," Dr. Choi says. "Now you can't pick up a journal without seeing a paper on autophagy. The cancer guys have been doing a lot of autophagy work. Alzheimer's, Parkinson's, infectious disease—I could go on and on." At Weill Cornell Medicine alone, researchers have found links between autophagy and gynecologic cancers, female genital tract infection, pancreatic cancer, metabolic diseases, and kidney failure.

Autophagy investigators: Dr. Augustine Choi (center) with research fellows (left) Dr. Ilias Siempos and Dr. Mitsuru Imamura. Photo credit: John Abbott

Over the years, Dr. Choi has seen attitudes toward COPD shift significantly. It was once considered hopeless, he says, and research funding was limited in part because patients with diseases linked to smoking were not seen sympathetically. But while COPD patients may be haunted by the stereotype of the unrepentant lifelong smoker, the disease can develop decades after people quit, as in Nimoy's case. It can also strike non-smokers, for reasons that are still unknown. "The incidence of COPD not related to cigarette smoking is increasing," Dr. Choi says "Whether it's pollution, particulate matter in the environment, infections or a virus— we don't know." And that's just one of the many questions Dr. Choi and his colleagues are working to answer. They are also looking into how protective mechanisms in the lungs could offset autophagy, and they're trying to find a way to detect COPD with a simple blood test rather than a CAT scan.

Among the Weill Cornell Medicine researchers working on autophagy is Dr. Choi's wife, Dr. Mary Choi. An associate professor of medicine in the Division of Nephrology and Hypertension, she is leading investigations into its role in diseases of the kidney. She has found that impaired autophagy could lead to kidney fibrosis, a common feature in kidney failure and diabetic nephropathy — which means that therapies targeting autophagy could potentially restore kidney function. The couple came to Weill Cornell Medicine in 2013 from Boston, where both were on the faculty at Harvard Medical School and he was chief of pulmonary and critical care medicine at Brigham and Women's Hospital. There, as at Weill Cornell Medicine, patient care was a major aspect of his work. "Seeing patients gives you focus, and it helps you identify the questions that we need to address," Dr. Choi says. "Patients are what it's all about — you're trying to make an impact on human disease."

— Amy Crawford

This story first appeared in Weill Cornell Medicine, Vol. 14, No.2.

A mutation in a gene that helps prevent cellular damage contributes to a chain of events supporting the growth of non-small cell lung cancer, Weill Cornell Medicine researchers discovered. The finding may lead to the development of new targeted medications for the disease and potentially other cancers that often do not respond to chemotherapy or radiation.

The classic role of the gene nuclear factor erythroid-2-related like 2, or NRF2, is to promote the production of the body's natural antioxidants, or chemicals that help prevent cell damage. In a study published Oct. 19 in Nature Genetics, Weill Cornell Medicine scientists discovered that the mutated gene plays a crucial role in lung cancer cells' metabolism — how the cancer converts sugar, or glucose, into amino acids that act as building blocks for proteins and other molecules — driving tumor growth. They say this discovery could offer a new target to effectively treat the disease.

"We could potentially treat this with an inhibitor that targets the pathway," said lead author Dr. Gina DeNicola, a research fellow and member of the lab of Dr. Lewis Cantley, the Meyer Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine. "This would be a big boost for non-small cell lung cancer, which typically has a poor prognosis. Patients are often resistant to traditional chemotherapy and radiation treatments, and so far few therapies have really shown much promise."

Non-small cell lung cancer is a disease widely associated with smoking and exposure to other pollutants and chemicals such as radon and asbestos. It accounts for 85 to 90 percent of all lung cancers, which cumulatively kill about 158,040 Americans each year.

In their study, Dr. DeNicola, Dr. Cantley — who owns equity in, receives compensation from and serves on the Board of Directors and Scientific Advisory Board of Agios Pharmaceuticals — and colleagues Edouard Mullarky and David Wu discovered that mutations in the NRF2 gene and an associated gene called KEAP1 (Kelch-Like ECH-Associated Protein 1, which in normal cells inhibits antioxidant production) lead to increased production of several enzymes, including phosphoglycerate dehydrogenase (PHGDH).

These enzymes boost production of the amino acid serine and its conversion to glycine, another important building block. Together, serine and glycine are critical to producing proteins and other molecules, including an antioxidant, that help NSCLC to thrive. The series of events involved in this process is called the serine/glycine biosynthetic pathway.

While directly targeting the NRF2 gene with drugs would be challenging, developing drugs that interrupt other points of the serine/glycine biosynthetic pathway may be possible, Dr. DeNicola said.

"Targeting the pathway could be a way of attacking these cells that have NRF2 and KEAP1 mutations," she said.

Developing drugs that inhibit PHGDH may be promising because the enzyme is one of the first on the pathway and would stop subsequent actions promoting cancer. To test this theory, Dr. DeNicola and the research team silenced PHGDH in NSCLC cells in cultures and in mice, and found that the cells did not grow or multiply.

About four years ago, the Cantley Lab found that PHGDH enzyme levels are high in melanoma and triple negative breast cancer. Unlike NSCLC, these high levels were due to the large number of PHGDH gene copies in cancer cells. However, the PHGDH enzyme also contributed to events on the serine/glycine biosynthetic pathway.

While the ways in which the serine/glycine biosynthetic pathway are turned on in NSCLC and melanoma and triple negative breast cancer differ, finding a way to target the pathway could be beneficial for all of these diseases, Dr. DeNicola said. The findings may also be applicable to other malignancies in which NRF2 levels are high, such as pancreatic cancer.

A non-invasive and quick lung function test frequently used to evaluate whether or not a smoker is at risk for developing pulmonary disease is likely mislabeling a significant percentage of smokers as healthy, a research team led by Weill Cornell Medicine investigators suggests.

A more specialized but still non-invasive test can more accurately represent this risk, the researchers found in a new study, published Nov. 5 in the European Respiratory Journal. If used more widely, doctors will be able to better predict who will develop chronic obstructive pulmonary disease, which is a condition defined by obstruction to expiratory airflows that makes breathing difficult. COPD, which includes smoking-induced emphysema, chronic bronchitis and non-reversible asthma, is the third-leading cause of death in the United States and affects more than 20 million people nationwide. While it is a condition caused by smoking, only 20 percent of smokers develop it. Based on this information, investigators sought to determine a way to better predict who might be affected.

"We wanted to figure out an accurate way to detect who is most at risk so that doctors can intervene earlier," said Dr. Ronald Crystal, chairman of the Department of Genetic Medicine and the Bruce Webster Professor of Internal Medicine at Weill Cornell Medicine. "We found that a more comprehensive test works better, and using it will ensure that doctors aren't giving smokers a false sense of confidence that their lung function is normal."

The conventional lung function test, called spirometry, is widely available and can be performed in about one minute at a general practitioner's office. To take it, patients are instructed to inhale deeply and then blow out as hard as they can into a tube-like instrument. If less than 70 percent of air is blown out in that first second, and this ratio cannot be corrected by drugs that open up the airways, called bronchodilators, then the patient has COPD.

Dr. Ronald Crystal

"The problem with the spirometry test is that it doesn't give you the whole picture of lung function," Dr. Crystal said. Which is where the second, more comprehensive capacity diffusing test, which measures the function of a patient's air sacks, comes into play.

"If you think of the lung like an upside down tree, the trachea, or windpipe, is the trunk, the branches are the airways and the leaves are the air sacks," Dr. Crystal explained. "With smoking, those air sacks can be destroyed, and the diffusing capacity test measures their function."

Although it is similarly non-invasive, the diffusing capacity test is less portable, more expensive, and more difficult to run. For this reason, it is typically only used by pulmonologists.

To find out whether low-diffusing capacity levels correlated with an increased risk for developing COPD, investigators compared two groups of smokers — one with normal diffusing capacity levels and one with low diffusing capacity levels — all pulled from a larger pool of 1,570 New York City-based smokers with normal spirometry measures. Once divided into these groups, researchers randomly selected 59 people with normal diffusing capacity and 46 people with low diffusing capacity and followed them for about four years. Throughout this time, investigators ran sporadic lung function tests. All participants continued to smoke throughout the study, and most were about 50 years old, the typical age at which symptoms of lung disease appear.

While the vast majority of participants — 97 percent — with both normal spirometry tests and normal diffusing capacity stayed COPD-free over the four-year term, the researchers found that nearly one-quarter, or 22 percent, of people with the low diffusing capacity developed COPD during the study.

"This shows that smokers with normal spirometry results but low diffusing capacity are at significant risk for developing this serious and fatal disease," Dr. Crystal said.

It also means that many people who have normal spirometry results but never see a specialist or receive the diffusing test are being falsely told not to worry and that they're okay, Dr. Crystal continued. "Even with a normal spirometry test, patients and their doctors still have to worry that they may be at significant risk for developing COPD."

CT scans lower lung cancer deaths, according to NIH study

NEW YORK (July 2, 2014) — In response to a recent national study showing that CT scans in a select high-risk population lower lung cancer deaths, NewYork-Presbyterian/Weill Cornell Medical Center has launched a lung cancer screening program for those at risk for developing the disease. The program uses low-dose CT scans to detect cancer in its earliest stages, giving patients a significantly better chance to survive the disease. Lung cancer is the leading cause of cancer death for men and women in the United States and current data shows that most lung cancers are diagnosed at an advanced stage.

For many years, doctors relied on chest X-rays to identify tumors, but their limited sensitivity and clarity made diagnosis difficult as symptoms of lung cancer usually do not appear until the disease is already in an advanced stage. In 2011, the National Cancer Institute’s National Lung Screening Trial — the first national multicenter study on the efficacy of low-dose CT scans — established low-dose helical CT as the first validated screening test that can reduce mortality due to lung cancer. The nearly decade-long study found a 20 percent lower lung cancer death rate among current or former heavy smokers who were screened with low-dose helical CT compared to those screened by chest X-ray. Low-dose CT scans detected twice as many Stage 1A cancers as chest X-rays. In addition, advances in CT technology have led to new equipment that can deliver less than 20 percent of the radiation dose used in an average diagnostic chest CT exam, while still providing clear images.

As a result of the trial, the United States Preventative Services Task Force (USPSTF) updated its guidelines in 2013 to recommend annual screening for lung cancer with low-dose CT in adults age 55 to 80 who have a 30 pack-year smoking history (the equivalent of smoking one pack a day for 30 years) and currently smoke or have quit within the past 15 years.

About the Program

In addition to those meeting the USPSTF criteria, screening may be appropriate for individuals who are otherwise at high risk for lung cancer. For example, individuals with a first-degree relative (parent, sibling or child) who was diagnosed with lung cancer at an early age may be at increased risk. The program can provide an individualized assessment of risk to help guide decision-making about whether to undergo a screening. Patients receive an exam and a specialized low-dose CT scan. The exam and scan take only a few minutes, and the results are reviewed and shared with the patient within 24 hours by a team of doctors including pulmonologists, oncologists and radiologists.

Led by Dr. Bradley Pua, an interventional radiologist at NewYork-Presbyterian/Weill Cornell Medical Center and assistant professor of radiology at Weill Cornell Medical College, the program incorporates a variety of services aimed at preventing and treating cancer, including smoking cessation counseling, support groups for patients and families, and follow-up services for treatment. While low-dose CT scans are the most accurate way to screen for lung cancer, the technology is not perfect. Abnormal findings are common, but the vast majority do not represent cancer. Nearly one in five patients screened will test positive, but cancer is confirmed in only 3 percent of all screenings.

"As these CT scans will show things that do not necessarily represent cancer, joining a comprehensive center for screening where multidisciplinary teams of physicians can meet on a routine basis to discuss and continue to refine screening guidelines is imperative," said Dr. Pua. "Accessibility to this team of physicians with expertise in every aspect of diagnosis to treatment will allow for more coordinated care, minimizing any screening harms."

While NewYork-Presbyterian/Weill Cornell Medical Center has used low-dose CT scans to screen some patients for lung cancer, the dedicated screening program launches July 1. Patients do not require a referral and most insurances are accepted. For more information, call 646-697-LUNG (5864).

NewYork-Presbyterian/Weill Cornell Medical Center

NewYork-Presbyterian/Weill Cornell Medical Center, located in New York City, is one of the leading academic medical centers in the world, comprising the teaching hospital NewYork-Presbyterian and Weill Cornell Medical College, the medical school of Cornell University. NewYork-Presbyterian/Weill Cornell provides state-of-the-art inpatient, ambulatory and preventive care in all areas of medicine, and is committed to excellence in patient care, education, research and community service. Weill Cornell physician-scientists have been responsible for many medical advances — including the development of the Pap test for cervical cancer; the synthesis of penicillin; the first successful embryo-biopsy pregnancy and birth in the U.S.; the first clinical trial for gene therapy for Parkinson’s disease; the first indication of bone marrow’s critical role in tumor growth; and, most recently, the world’s first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. NewYork-Presbyterian Hospital also comprises NewYork-Presbyterian/Columbia University Medical Center, NewYork-Presbyterian/Morgan Stanley Children’s Hospital, NewYork-Presbyterian/Westchester Division, NewYork-Presbyterian/The Allen Hospital, and NewYork-Presbyterian/Lower Manhattan Hospital. NewYork-Presbyterian is the #1 hospital in the New York metropolitan area and is consistently ranked among the best academic medical institutions in the nation, according to U.S.News & World Report. Weill Cornell Medical College is the first U.S. medical college to offer a medical degree overseas and maintains a strong global presence in Austria, Brazil, Haiti, Tanzania, Turkey and Qatar. For more information, visit www.nyp.org and weill.cornell.edu.

It has long been a mystery: Why do breathing difficulties develop in one out of five smokers? What puts these smokers at risk for development of chronic obstructive pulmonary disease (COPD), the third-leading killer of Americans, while 80 percent seem to be protected against the damaging effects to airways of trillions of oxidants and chemicals in each cigarette puff?

Genetics plays a role, but one that has remained enigmatic — until now. In a study in the Feb. 3 issue of PLoS ONE, a team of researchers at Weill Cornell Medical College has discovered a biological link between genes known to be associated with COPD and lung function that may explain both the development of the disease and the disparate respiratory effects of cigarettes on their users.

They found, when comparing genetic expression between healthy smokers and non-smokers, that four genes previously associated with COPD are being abnormally expressed in the airway basal cells, the progenitor cells critical to airway function. These genes were among the 676 genes the researchers found were either being over- or under-expressed in the basal cells lining the airways in smokers. These basal cells are crucial to the health of the lung, and the first cells that show damage from smoking.

"This is the first demonstration of COPD risk genes to an actual mechanism within cells that are critical for the maintenance of lung health," says Dr. Ronald G. Crystal, chairman of genetic medicine at Weill Cornell Medical College. "We doubt these four genes are completely responsible for COPD. They are likely part of the story — we believe they play a central role in the very early events that lead to COPD, but they act within a very complex genetic-environment interaction."

A biological link between four genes known to be associated with COPD and lung function may explain the development of the disease. Image courtesy of Dr. Ronald Crystal

The researchers also found that not every smoker had the same level of abnormal expression in the four COPD risk genes (as well as in many of the other genes whose expression differed), which may explain inherited susceptibility to COPD.

"We believe that smoking reprograms basal cells, making some smokers with a certain genetic variant more susceptible to COPD, but we don't know the details yet," Dr. Crystal says. "We are now studying how the basal cells are disordered by smoking."

Basal cells make up 5 to 15 percent of the cells that line the branching airways of the lungs, as well as the windpipe. They contain the critical stem cells that produce the other three kinds of cells that make up, and clean, that protective sheath. "The basal cells replace cells in that lining that are injured or that die, so without them, your lungs will become sick," Dr. Crystal says.

"These abnormal biologic changes are going on in the lungs of smokers who appear to be healthy, but whose lungs show evidence of massive reprogramming," says the study's senior investigator," Dr. Crystal adds.

Dr. Ronald G. Crystal

For this study, the researchers studied 10 non-smokers as well as 10 smokers. Both groups were judged to have healthy lungs, based on chest X-rays, lung function tests and the lack of symptoms of breathing difficulty. Using fiberoptic bronchoscopy — a thin, tube-like instrument threaded through the nose or mouth into the lungs — the scientists sampled the lining of the airway in both groups, retrieving basal cells deep in the lungs.

They then sequenced the genome of these cells, looking at genetic expression of messenger RNA — the molecule each gene makes to produce proteins. The researchers found 676 genes that produced aberrant levels of messenger RNA in smokers. "Smoking essentially reprograms basal cells to have an output of messenger RNA that is different from that of non-smokers," Dr. Crystal says.

To their surprise, they found that 166 genes (25 percent) were found in chromosome 19, known to be home to genes linked to COPD. And in the precise location of these risk genes — an area known as 19q13.2 — 13 aberrantly expressed genes were discovered. Four of these genes were previously linked to development of COPD.

When the science is further defined, the researchers may be able to find targets for potential drug therapy that could protect at-risk smokers against COPD.

"It may be possible to protect basal cells from the toxic effects of cigarette smoke if you shield them in some way, perhaps by shutting off, or modifying the output, of certain genes," Dr. Crystal says.

More Americans will be diagnosed with cardiovascular disease in the coming decades in spite of plummeting smoking rates and a growing reservoir of effective treatments, according to a new Weill Cornell Medical College research study.

The study, published Oct. 7 in Health Affairs by lead author Dr. Ankur Pandya, assistant professor of public health from Weill Cornell Medical College, and researchers from Brigham and Women's Hospital and Harvard University, highlights the implications for health and cost burdens that will result from increasing obesity levels and an aging population.

Cardiovascular disease, which includes heart disease and stroke, is the leading cause of death and among the costliest health problems facing the United States. And this is not likely to change, the researchers say, especially if the obesity epidemic does not improve.

Fewer Americans are smoking and there are more effective treatments on the market to control blood pressure and cholesterol, changes that over the past few decades have led to fewer cardiovascular disease-related deaths, the researchers say. But despite gains in these areas, cardiovascular disease is and will continue to be a national scourge for decades because there will be more Americans who will live longer with the disease.

Using data from 1973 to 2010 reported in the National Health and Nutrition Examination Survey, the researchers project that, unless obesity becomes less prevalent, the number of Americans diagnosed with cardiovascular disease will continue to skyrocket through 2030. This will result in increasing health care costs, disability and reductions in patients' quality of life, researchers say.

Study Shows that Even if X-Rays and Other Exams are Normal, Airway Cells Show Early Damage by Activating Genes Seen in Embryos and Aggressive Lung Cancer

NEW YORK (July 16, 2013) — Smokers who've received a clean bill of health from their doctor may believe cigarettes haven't harmed their lungs. However, researchers at Weill Cornell Medical College have found that even smokers who seem healthy have damaged airway cells, with characteristics similar to cells found in aggressive lung cancer.

The study, published today in the journal Stem Cell, compared cells that line the airway from healthy nonsmokers with those from smokers with no detectable lung disease. The smokers' cells showed early signs of impairment, similar to that found in lung cancer — providing evidence that smoking causes harm, even when there is no clinical evidence that anything is wrong.

"The study doesn't say these people have cancer, but that the cells are already starting to lose control and become disordered," says the study's senior investigator, Dr. Ronald G. Crystal, chairman and professor of genetic medicine at Weill Cornell Medical College. "The smoker thinks they are normal, and their doctor's exam is normal, but we know at the biologic level that all cigarette smokers' lungs are abnormal to some degree."

The researchers found that in the cells lining the airways of the smokers's lungs, human embryonic stem cell genes had been turned on. These are genes that are normally expressed in developing embryos — soon after eggs are fertilized — before cells are programmed with their specific assignment. This gene is also "on" in the most aggressive, hard-to-treat lung cancers.

"We were surprised to see that the smokers were expressing these very primitive human embryonic stem cell genes," Dr. Crystal says. "These genes are not normally functioning in the healthy lung."

Healthy lung cells, like all of the body's cells, have very specific assignments. Although all of the body's cells contain the same genes, genes are only "turned on" for each cell's defined task. Therefore, healthy lung cells only express genes related to lung function, while brain cells express brain-specific genes. "Healthy cells are very tightly controlled. Normal cells have rules and only do certain things," says Dr. Crystal. "In cancer, that control is lost."

This loss of control allows cancerous cells to multiply without restraint and enables them to migrate to other organs because the genetic programming that keeps them on task is in disarray. The study found that smokers' cells were in the very early stages of losing this control.

"When you smoke a cigarette, some of the genetic programming of your lung cells is lost," says Dr. Crystal. "Your cells take on the appearance of a more primitive cell. It doesn't necessarily mean you will develop cancer, but that the soil is fertile to develop cancer."

In the study, 21 healthy nonsmokers were compared to 31 smokers who had no lung disease symptoms and had normal X-rays as well as normal chest examinations. All individuals were evaluated at Weill Cornell's Clinical and Translational Science Center and Department of Genetic Medicine Clinical Research Facility. By sending a thin tube called a bronchoscope and a fine brush into the lungs, investigators gently brushed the inside of the airways to collect cells from the airway's lining. Researchers examined these cells, called the airway epithelium, which come into contact with cigarette smoke and are where cancer begins, Dr. Crystal says.

Routine checkups can mislead smokers into thinking cigarettes aren't hurting their bodies. However, these results paint a different picture. "Physical examinations, lung function tests and chest x-rays are not sensitive enough to pick up these very early changes," Dr. Crystal warns doctors and smokers. "The take-home message is: Don't smoke. Smoking is bad and if you smoke, you're at risk."

Additional studies are needed to determine why exposure to smoke causes these changes, so that researchers can pinpoint particular areas for designing treatments. "This study gives us clues about how cells look on the way to developing lung cancer, which can help us develop therapies," Dr. Crystal says.

Beyond treatments, Dr. Crystal also hopes the research can lay the foundation for lung cancer prevention. Smoking is an addiction, he says, and despite high taxes and ads describing the dangers, 20 percent of the population continues to smoke. "Eventually, the goal is to develop therapies to protect the airways from cigarettes and other pollutants," Dr. Crystal says. "Understanding these very early events will give us clues and help us develop ways to protect the lungs."

Co-authors of the study include Dr. Renat Shaykhiev, Dr. Rui Wang, Rachel K. Zwick, Dr. Neil R. Hackett, Dr. Roland Leung, Dr. Malcolm A. S. Moore, Dr. Camelia S. Sima, IonWa Chao, Yael Strulovici-Barel and Jacqueline Salit from Weill Cornell Medical College; and Dr. Robert J. Downey from Memorial Sloan-Kettering Cancer Center.

The study was funded by the National Heart, Lung and Blood Institute of the National Institutes of Health.

Weill Cornell Medical College

Weill Cornell Medical College, Cornell University's medical school located in New York City, is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine, locally, nationally and globally. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research from bench to bedside, aimed at unlocking mysteries of the human body in health and sickness and toward developing news treatments and prevention strategies. In its commitment to global health and education, Weill Cornell has a strong presence in places such as Qatar, Tanzania, Haiti, Brazil, Austria and Turkey. Through the historic Weill Cornell Medical College in Qatar, Cornell University is the first in the U.S. to offer a M.D. degree overseas. Weill Cornell is the birthplace of many medical advances — including the development of the Pap test for cervical cancer, the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., the first clinical trial of gene therapy for Parkinson's disease, and most recently, the world's first successful use of deep brain stimulation to treat a minimally conscious brain-injured patient. Weill Cornell Medical College is affiliated with NewYork-Presbyterian Hospital, where its faculty provides comprehensive patient care at NewYork-Presbyterian Hospital/Weill Cornell Medical Center. The Medical College is also affiliated with the Methodist Hospital in Houston. For more information, visit weill.cornell.edu.