To anyone who trusted the old cigarette advertising — and millions did — smoking was not only pleasant and glamorous, it was also perfectly healthy. "Just what the doctor ordered," proclaimed one L&M ad. "More doctors smoke Camels than any other cigarette," added another, while a rival brand declared that "20,679 physicians say Luckies are less irritating."

Amid this devil's brew of dubious claims and pseudoscience, real scientists were busy establishing a biological fact: Smoking is dangerous, even deadly. We now know that smoking causes 87 percent of deaths from lung cancer, including 3,000 each year from second-hand smoke; it also triggers esophageal, bladder, kidney, pancreatic and cervical cancers. Further, it increases the risk for such non-cancerous problems as heart disease, stroke, emphysema and cataracts.

For decades, pioneering Washington University researchers have been working to understand, and combat, the blight of smoking. Today, they have a range of projects underway — both biologically and genetically based — that target aspects of this problem. At the same time, the medical school is working to help smokers quit. Faculty and staff have long held smoking cessation programs on campus and in the community. In 2007, the school established a "tobacco free" campus.

A Biologically Based Project: COPD

Today, the medical school has smoking-related projects in nearly every department. Recent studies, for example, have examined the impact of smoking in delaying tendon or ligament healing; others are looking at chemotherapeutics to prevent lung cancer among former smokers. A strong focus is on chronic obstructive pulmonary disease (COPD), and a year-old, $14.9 million grant from the National Heart, Lung and Blood Institute currently is giving a group of scientists, headed by Michael J. Holtzman, MD, the chance to understand how COPD develops.

Senior scientist Eugene V. Agapov, PhD, and Michael J. Holtzman, MD, study slides related to their work on chronic obstructive pulmonary disease.

Smoking is the major risk factor for developing COPD, a progressive and ultimately fatal condition that now ranks as the fourth-leading cause of death in the United States and "the only top-10 cause of death that continues to increase," says Holtzman, the Selma and Herman Seldin Professor of Medicine and director of the Division of Pulmonary and Critical Care Medicine.

In 2007, Holtzman's grant established a Specialized Center for Clinically Oriented Research (SCCOR), aimed at translating research findings quickly into clinical solutions. Their research indicates that a susceptible genetic make-up, combined with an early-in-life viral infection and smoking later on, may trigger COPD. Now the researchers hope to develop earlier and more precise ways of diagnosing COPD, as well as improved treatments, since few are available today.

Smoking and ADHD

The hazards of smoking are not limited to the smoker's own health. As a 2007 study by Rosalind J. Neuman, PhD, and Richard D. Todd, MD, PhD, the Blanche Ittleson Professor of Psychiatry and professor of genetics, shows, prenatal smoking can seriously affect unborn children who carry one or more candidate genes for attention deficit hyperactivity disorder (ADHD). With one of these genes, their risk triples; with two, it goes up ninefold; and with three, it rises to 16 times the normal level.

Rosalind J. Neuman, PhD, sitting, and programmer analyst Lingwei Sun review data showing that prenatal smoking can seriously affect unborn children who carry one or more candidate genes for attention deficit hyperactivity disorder.

The researchers studied children from nearly 800 Missouri families, asking mothers about their alcohol intake and smoking during pregnancy. Although only 5 percent reported drinking, 24 percent admitted to smoking — with 75 percent of the smokers having done so through at least two trimesters.

"Our study highlights the potential harm that children may incur because parents use substances with unknown consequences," says Neuman, research professor of mathematics in psychiatry and of genetics.

Psychiatry, Genetics and Smoking

In another major area, psychiatric researchers are investigating the genetic roots of smoking. Washington University is one of the leading centers worldwide in the genetic research of smoking-related behaviors.

Pamela A. Madden, PhD, received her first grant for smoking-related research in 1995 before others were conducting research in this area. But she believed it was important. "Smoking is the top public health problem in the world," says Madden, associate professor of psychiatry. "People who smoke throughout their lives can lose up to 10 years due to smoking-related factors."

She began by looking at the combination of smoking and alcohol problems, discovering that heavy smokers often need to drink more to become intoxicated — which puts them at greater risk for alcohol dependence. In other work, she focused on nicotine withdrawal, finding a strong association with psychiatric problems, especially depression. Michele L. Pergadia, PhD, research assistant professor of psychiatry, works closely with Madden and is expanding on her earlier work by examining symptoms of nicotine withdrawal through laboratory studies.

With twin data from other countries, she examined the importance of genetics in smoking. One study involved international gene mapping, in which she and her team found a strong signal that chromosome 22 is implicated in heavy smoking. Next, they will use data from male Finnish smokers to isolate the genes involved.

Ultimately, they hope to "better define what puts someone at risk for having difficulty quitting and flag risk factors for persistence of smoking that might be used to develop better treatments," Madden says.

In separate studies, psychiatry researchers Laura J. Bierut, MD, left, and Pamela A. Madden, PhD, are investigating the genetic roots of smoking. Madden's current research isolates genes in an attempt to identify those people most at risk for having difficulty in quitting smoking and to develop better treatments; Bierut studies nicotine dependence and the possibility of using advances in pharmacogenetics to guide treatment.

Genes and the Environment

In 2007, Madden's colleague, Laura J. Bierut, MD, published two articles on groundbreaking work that she and her team had done: the first large-scale genetics studies of nicotine dependence, which showed that genetic differences can determine a person's risk for becoming addicted. Specifically, they pinpointed several genes as culprits, especially the alpha-5 nicotinic cholinergic receptor gene (CHRNA5).

"The best thing to do is to prevent smoking," says Bierut, professor of psychiatry. "But for those who do smoke and are nicotine dependent, this may lead to pharmacogenetic advances that can guide treatment."

Bierut and co-principal investigator John Rice also received NIH funding for Washington University's piece of the Genes, Environment and Health Initiative, a national collaboration between geneticists and environmental scientists aimed at unraveling the mysteries of addiction. In other research, she is trying to understand how genetic variants differ across racial and ethnic groups. For example, one amino acid change in a smoking-related receptor is common among those of European descent but not among those of African descent. This may mean that there are different risks in the two populations.

"Smoking is still one of the leading causes of death," she says. "One quarter of our population continues to smoke. We need to decrease that figure and reduce this terrible burden."