Caryn Lerman and her colleagues at the Transdisciplinary Tobacco Use Research Center are hot on the trail of biological, psychological, and social means to counter tobacco’s addictive power.
By Samuel Hughes | Photo by Bill Cramer
Every now and then, when she’s hard against a deadline for some complex grant proposal involving genes and tobacco, Dr. Caryn Lerman will reach into her desk drawer and pull out a Chiclet-size piece of gum. It’s Nicorette, a gentle, legal, not particularly swell-tasting form of Nicotine Replacement Therapy. Like a hanging, it concentrates the mind. But its potency pales against the ultimate nicotine delivery device—a cigarette.
Lerman hasn’t smoked for years now, though she can speak first-hand to tobacco’s allure. And as director of the Penn/Georgetown Transdisciplinary Tobacco Use Research Center (TTURC), she knows better than almost anyone on the planet what smokers are up against.
“The more I learn, the more I realize that it’s extremely complicated,” she says quietly, sitting in her office in the TTURC complex, on the fourth floor of a generic office building at 36th and Market streets. “I realize how hard it will be, and how long it will take, to really get to the point where we have a very comprehensive understanding of addiction—and a sufficient understanding that we can actually be designing better prevention and treatment strategies based on that. It’s a long process.”
Call it the genetics of smoking. “Our goal is to obtain a more complete understanding of the role of specific genetic factors and bio-behavioral mechanisms that promote tobacco use,” the center’s mission statement explains, “in order to apply this knowledge to prevention, treatment, and reduction of harmful tobacco exposure.”
The Penn/Georgetown TTURC is actually one of seven such academic research centers around the country devoted to studying various aspects of tobacco use and nicotine addiction. As its name suggests, it crosses disciplines with wild abandon, delving into psychology, genetics, neuroscience, medicine, epidemiology, communications, and public policy. Lerman herself has appointments in the Abramson Cancer Center (where she’s associate director of the Cancer Control and Population Science program), the Department of Psychiatry, and the Annenberg School for Communication (where she holds the Mary Whiton Calkins Chair, which she herself named in honor of the first female president of the American Psychological Association and the American Philosophical Association).
Though the center has been at Penn for less than two years—ever since Lerman arrived from Georgetown, bringing her grants and many of her colleagues with her—the TTURC is already a major player. It has a full-time staff of some 35, and $10 million in federal grants from the National Cancer Institute (NCI) and the National Institute on Drug Abuse (NIDA)—not to mention some $400,000 from the Robert Wood Johnson Foundation to study the public-policy and communications pieces of the tobacco puzzle.
For those of us who aren’t accustomed to federal largesse, that seems an awful lot of money. But tobacco is no ordinary research subject. Consider these facts—some of which may be depressingly familiar—from TTURC’s Website:
• Some 43.5 million adults in the United States—23.3 percent of the adult population—smoke cigarettes.
• Nearly one in every five deaths in the U.S. is a result of smoking, making it the leading preventable cause of death.
• More than 440,000 deaths in the U.S. are attributable to tobacco use each year—more than those caused by AIDS, alcohol, motor-vehicle accidents, homicides, drugs, and suicides combined.
• The annual cost of smoking-related health care is $75.5 billion.
• Roughly 3,000 Americans die each year because of exposure to secondhand smoke, and more than 1,000 infants die because their mothers smoked during pregnancy.
Some might argue that cigarette addiction is really a matter of weakness (users), greed (sellers/producers), and venality (Congress and everyone else who conspire to keep it legal). But the story, and the science, are a lot more complicated than that.
“I’ve always had the desire to do work that was cancer-related,” Lerman is saying. “Most people in their lives know people or have people close to them who have died of cancer. In my case it was my aunt, who I was very close to.”
Her first deep interest in psychology was the mind-body connection—specifically the “impact of the mind or stress on physical illness.” She was a graduate student at USC in the late 1970s and early ’80s, when the field of behavioral medicine was getting underway, and her dissertation was on Type A Behavior Pattern—“Nothing that relates to me personally at all,” she deadpans. She doesn’t act like the Central Casting kind of Type A—too calm, and her sense of humor is too quietly subversive—but along the way she garnered the Society of Behavioral Medicine New Investigator Award (1989) and the American Psychological Association Award for Outstanding Contributions to Health Psychology (1995), and they tend not to give those things to navel-gazers.
She got hooked on cancer genetics while working in Fox Chase Cancer Center’s behavioral-research crew. “My initial work was on the psychological aspects of genetic testing—understanding how all this exciting research coming out of the human-genome project was actually going to impact on people’s lives, where people want to know their genetic futures,” she says. “How would they react to the information psychologically? Would they change their behavior?”
That, in turn, led to a deep interest “in the question of whether we could characterize the genetic underpinnings of different behaviors that relate to cancer,” she says. “And, of course, one of the most important cancer-risk behaviors is tobacco use.”
About seven years ago, by then at Georgetown, she and some colleagues at the National Cancer Institute began a series of studies to look for specific genetic effects on smoking behavior. That, she says, “provided the foundation for submitting the TTURC grant.”
One study examined the effects of giving smokers relevant information about their genetic susceptibility to lung cancer—to see “whether we could overcome a sense of invulnerability and motivate them to quit smoking,” she explains. “We discovered that we did motivate them a great deal by giving them biological feedback. However, despite a really high level of motivation and many quit-attempts, most people in the study were not able to quit smoking.
“That’s where I became more interested in the problem of addiction,” she adds. “Because it’s not just a matter of wanting to quit, knowing cigarettes are bad for you and that quitting will prevent cancer and other diseases—that’s not enough. There’s got to be some real core biology.”
It was the phone call from Dr. John Glick that got things moving. As director of the Abramson Cancer Center at Penn, he was already quite familiar with Lerman’s work at Georgetown. When he heard she wanted to make a move, he pounced.
“When I heard that Caryn Lerman was in play, we called her up, and said, ‘Don’t take any other jobs—come to Penn!’” Glick recalls. “She came up, and it was an immediate, charismatic relationship. She has a national and international reputation in tobacco research, and in other aspects of cancer control, including behavioral research. We said, ‘Caryn, design your dream job, and we’ll make it happen.’”
In addition to acting as a “catalyst between many faculty and scientists on campus,” Glick says that Lerman “has great leadership skills, she’s brilliant, she’s very collaborative, and she’s also one of the most interactive people I ever met. This is a home run for the Cancer Center, for Caryn, for the psychiatry department, and for Annenberg.”
And the Type A free agent sounds pretty happy, too. “Penn is an amazing place in terms of the depth and breadth of the scientific activity here,” says Lerman. “So many smart and creative people who are open and willing to collaborate—and who really challenge me to do things in different and better ways.” In addition to being able to upgrade the center’s genetics research, she notes, “we’ve expanded in the areas of behavioral pharmacology, animal studies—areas in which we did not have research activities before.”
For Dr. Joseph Cappella, professor of communication, Lerman’s expertise in the genetic basis of risky behavior and her research in communication about genetic risk are “complementary” to the expertise of Annenberg Public Policy Center faculty members working on health-related issues.
“Personally, from the first informal meetings we had with Caryn, I found immediate and exciting connections between her work in genetics and my own in persuasion in health and political contexts,” he adds. “For example, information about genetic dispositions to disease (or toward risky behavior) can invite feelings of fatalism—or the desire to take control of one’s life, depending on how the information is presented.”
Nicotine addiction is a kind of Gordian knot, comprised of intricately entwined genetic and environmental strands. Unraveling it requires many things, not the least of which is better scientific tools.
“One of the real barriers to understanding the genetic basis of tobacco use is that the measures used to define tobacco use are really not well refined,” says Lerman. “And one of the directions in which we want to go is to do studies that better characterize patterns of tobacco use.”
That premise underlies the research projects underway at the TTURC, which include:
• Genetic Influences on Smoking Cessation.
• The Georgetown Adolescence Tobacco Research (GATOR) study.
• Effects of Alcohol on Nicotine Responses in Smokers.
• Genetic Mediators of Smoking Cue Reactivity.
• Genetics and Nicotine Sensitivity NRT (Nicotine Replacement Therapy) Effect on Smoking Reinforcement by Genotype.
Lerman points to the GATOR study, in which principal investigator Janet Audrain-McGovern is trying to “define different trajectories or patterns of use, and understand, even create, typologies of smoking initiations.” Those phenotypes, she adds, “will provide much better measures for doing genetic studies.”
She wants to do the same thing for the science of kicking the habit—“Really understanding the relapse processes, not just doing a clinical trial and saying, ‘At six months or one year, how many people are abstinent and how many people aren’t?’” as she puts it. “So one key area is to better understand the phenotypes of addiction and use, and then to improve the way that we’re doing the genetic studies, taking advantage of the new advances in genomics. But if we were only using more advanced genomics techniques, but still dealing with the old crappy phenotypes, it wouldn’t be useful. So we’re trying to improve our genetic analysis and define much better phenotypes or ways to characterize tobacco use.
“We can certainly improve our ability to tailor treatments to individual smokers based on their biology, psychological background, and so forth,” Lerman adds. “But there will still be a great deal of error. So one of the challenges in translating this to actual clinical practice to the public is: What is the threshold of certainty for the tools that come out of this? And at what point are we ready to put this out in the clinic—knowing that it will never be 100 percent?
“Because it’s never going to be perfect,” she acknowledges. “It’s behavior, and behavior’s complicated. We’ll never have it completely figured out.”
“I knew it was going to kill me, either in the short term or the long term,” Randall Hardie was saying over coffee. “And it wasn’t going to be a nice way to go.”
Hardie, a 38-year-old business administrator in the neuropsychiatry section of Penn’s psychiatry department, tells a familiar story: Smoking regularly by the time he was 17. Tried to quit for 15 years. Never succeeded for more than a couple of months.
It’s an “insidious” drug, he says. “It invades your consciousness 24/7. As soon as you wake up, ‘Oh, I’d like to have some nicotine.’ It interrupts your thought process—you can’t think, can’t get anything done.” And the unfulfilled sense of craving, he adds, “definitely makes you ornery.”
About year and a half ago, he heard about a Quit for Health program at the TTURC, and signed up. It was free—helping people quit while studying the results of those efforts is part of the center’s research agenda—and it offered a combination of behavior modification and Nicotine Replacement Therapy (in Hardie’s case, a nicotine patch). It wasn’t easy, but it worked. Today Hardie is nicotine-free, and loving it.
In his view, his own addiction was a classic case of heredity and environment. Both his parents smoked, and he still has fond, Proustian memories of the first whiff of smoke drifting back from the front seat of their Chevrolet Impala each time one of them would light up.
“I’m genetically predisposed,” he says. “I don’t want to blame anyone else for my addiction, but I grew up in a household with cigarette smoke. It’s an addictive smoke. If you grew up in a house with smokers and you do try it, you’re going to get addicted.”
Well, yes and no. To get personal for a moment, both my parents smoked, too. (Both eventually quit.) So I probably have a genetic susceptibility myself, not to mention many years of second-hand smoke. But the outcome for me was an intense loathing of cigarettes and their foul exhaust, and—not to put too fine a point on it—a bafflement as to why anyone would take up such a stupid, self-destructive, foul-smelling habit.
Then again, I can’t even warm up to Nicorette, despite a secret longing for the mental lift and concentration-sharpening it’s said to provide. It’s a dull thud, I tell Lerman.
“People have different responses to nicotine,” she says quietly. “That’s part of why some people become addicted, and some people don’t.”
Right now, I’m pondering the mysteries of the CYP2B6 gene. It’s responsible for producing an enzyme that helps metabolize a variety of substances in the human body, including drugs. Two drugs in particular are relevant. One is an anti-depressant called bupropion, which goes by the brand name Zyban. The other is nicotine.
One of bupropion’s targets is the dopamine transporter, and the drug affects levels of the neurochemical dopamine in the brain.
“The genes that we had focused on as being related to addiction included dopamine-transporter and other genes in the dopamine pathway,” Lerman explains. By studying those genes and their relationship to the effectiveness of treatment, she and her colleagues thought they might be able to identify those who are likely to respond to bupropion—and those who aren’t.
“Instead of using a standard, one-size-fits-all model of smoking treatment” —in which, Lerman explains, “you try the patch, and if that doesn’t work, we’ll step you up and try Zyban—we thought that we could, through genetics research, develop a more rational way of tailoring treatment to an individual’s genetic profiles.”
There is also “evidence for a genetic mutation” in the CYP2B6 gene, she adds, and people who have that mutation do not appear to produce as much of the metabolizing enzyme. Less enzyme means they’ll be able to metabolize less nicotine into its inactive compound, cotonine—which, in turn, means their brains are being “bathed in more nicotine more chronically” than are those of people without the mutation. The result of those nicotine baths are the very changes in the brain’s dopamine receptors that maintain addiction.
“Then, when you try to quit, you don’t feel normal,” says Lerman, “because your brain has adapted to having the drug.”
In a recent paper, she sums it up: Smokers who have that genetic mutation “experience greater increases in cravings for cigarettes and are about 1.5 times more likely to relapse during the treatment phase than smokers who do not have the variant.”
Women, incidentally, tend to have higher rates of relapse than men, largely because of the negative moods brought about by quitting.
“There’s evidence that females may experience more withdrawal symptoms, more negative mood changes when they try to quit, and that increases the chance that females will relapse relative to males,” says Lerman. “In this study, the females who had the mutation and were treated with the placebo had really low quit rates of about 19 percent. But that same group, with the mutation treated with bupropion, had success rates of 54 percent. That’s as high as any group of males. So the drug seems to be able to overcome the gender difference and the genetic predisposition, particularly in the females.”
After examining the data provided by their smokers on moods, cravings, and other withdrawal symptoms, Lerman’s team found that bupropion did reduce certain withdrawal symptoms, such as cravings. While those “didn’t seem to predict people’s long-term quitting,” she says, “changes in negative mood symptoms did. So it really seems that one of the most important mechanisms of this drug is its ability to attenuate the negative mood effects of quitting.”
Freddie (Freda) Patterson is a smoking-cessation counselor at TTURC who counsels a lot of nicotine addicts and clearly takes her job seriously. She is also a high-spirited lass with an engaging sense of humor and a certain Northern Irish gift of gab.
“Sometimes when I’m sitting there, and I hear them talking about the stress relief, and how great it is, I’m like, ‘You know, that sounds really fantastic!’” she says with a musical laugh. “I know this sounds really weird, because I’ve never been a smoker, and I vowed I never would because of my parents—my Dad died from lung cancer—but when I’m in there, and I hear everyone telling me how great it is, and how much they miss it, I’m tempted! I’m like, ‘I’m missing out on something here, you know?’”
Her nicotine-envy is, of course, unlikely to be consummated. But it does testify to the power of the addiction.
“That’s something that I talk about in the groups,” she says. “When you have someone who’s really trying so hard, and you can see they’re just fighting—their life is miserable! So I say to them, ‘This is really hard. There’s a whole industry out there that’s doing its best to make you smoke, so don’t feel too bad.’”
“There are a lot of smart people working at the tobacco industry,” agrees Janet Audrain-McGovern. “They can make these ads so appealing—not only to teens that are into thrill-seeking, but also those that have a depressed mood.”
Audrain-McGovern, an assistant professor of psychology in psychiatry at TTURC who migrated north from Georgetown with Lerman, has been leading a four-year longitudinal study of adolescents and smoking—the GATOR study. It examines the role of social, psychological, and genetic factors in what they call “smoking adoption,” and with some 1,100 adolescents participating, it’s a big undertaking.
But the stakes are high. Each day, more than 5,000 American youth try their first cigarette—and more than 2,000 become daily smokers. Some 80 percent of adult smokers began smoking before age 18. And between 1991 and 1997, smoking among high-school students rose from 27.5 percent to 36.4 percent.
By the 12th grade, some 70 percent of the GATOR teens had taken at least a puff, while 29 percent qualified as “regular smokers.” While a regular smoker at age 18 may not fire up as often as a regular smoker at age 38, the habit and addiction are firmly in place. Of course, how many teenagers think they are—or ever will be—addicted?
“They’ll say, ‘Once I get out of high school, I’ll stop this nasty habit, because I’m going to college or to the workforce,’” says Audrain-McGovern. But few of them actually quit. (Another study will examine that next stage of life.)
Audrain-McGovern and her colleagues have found that risk-takers—“novelty-seekers”—are more receptive to tobacco advertising than their less adventurous counterparts, and that receptiveness often leads to lighting up. Yet depression and its attendant moods are also linked to smoking; many smokers “medicate” themselves with cigarettes. Hence Audrain-McGovern’s grudging respect for the ability of tobacco advertisers to touch so many different hearts.
But there are some proverbial ounces of prevention out there. One is exercise, which may represent an intersection of science and common sense. Turns out your old gym teacher was right: playing lots of volleyball can keep you out of all kinds of trouble. Including, it seems, smoking.
“A lot of cross-sectional studies have looked at physical activity and smoking and found that they’re negatively related—meaning that teens who are more active are less likely to smoke,” notes Audrain-McGovern. “But we don’t know what causes what.” Based on a recent study, she says, “We think—although our conclusions are tentative at this point—that physical activity may not only protect against starting to smoke, but also protect against progressing to greater and greater levels.
“We also controlled for depression in this study,” she adds, “because depression is not only linked to less physical activity but also to greater likelihood of smoking. Is that a mechanism by which physical activity could have its protective effects? Is it because it moderates the mood? If you’re cranking out dopamine, or something along the same reward pathway that smoking operates on, then maybe you won’t pick up a cigarette.”
In one study, they found that teens who have various “alternative reinforcers” to smoking—sports, school clubs, high academic achievement—are less likely to smoke. Teens who have reinforcers that “complement” smoking—alcohol, marijuana, peers who smoke—are more likely to light up.
On the flip side is what Audrain-McGovern calls “delayed discounting,” in which a person has trouble delaying gratification, and will “take a smaller reward right now over a larger reward later.” Teens who had higher levels of delayed discounting were more likely to smoke.
A similar finding could be described as a nuanced take on self-control. “You can have good self-control,” says Audrain-McGovern—ability to concentrate, calm yourself down, act responsibly—“and you can also have aspects of poor control, where you cope through anger or you have trouble problem-solving.”
While the road to Tobacco Hell can be bypassed by those with certain types of poor control, it’s harder if they “don’t have the good control to buffer them.”
Those skills need to be included in prevention programs, she says. “Because it’s not simply, ‘We need to learn how to refuse that cigarette. If Bobby offers you that cigarette, you’d better just say No.’ It’s not completely the ability to say No to an offer; it’s the ability to self-regulate in a number of different ways.”
Often, says Joe Cappella, researchers focus exclusively on the rational aspects of quitting, such as the health risks, and less on the emotional aspects of quitting or not quitting, such as feeling proud or disgusted. He and Lerman, with support from the Annenberg Public Policy Center, recently sampled a representative group of 450 18-to-25-year-old-smokers, asking about those rational and emotional factors associated with kicking the habit.
“Some preliminary analyses indicate that emotional factors play a significant role in intentions to quit beyond rational considerations,” Cappella says. “Within the next six months we will follow up [with] the participants to see if emotional factors help us predict actual quitting (or attempts to quit smoking) over the ensuing year.”
Researchers in the TTURC are also studying how certain brain-wave patterns may be a risk factor for nicotine addiction. It’s no secret that some people have trouble focusing their attention when other distractions are present—an attention deficit that can be revealed in brain-wave patterns. Nicotine has been shown to normalize these brain-wave patterns and thus reduce the attention deficit—but when the delivery device is a cigarette, it can come at a terrible cost.
I ask Lerman what all this says about the notion of willpower.
“Willpower is still alive and well,” she says quickly. “Some people are going to have more trouble quitting than others because of their biological makeup. But the genetic component of quitting is really just one component. You and I might have the same genotype, and if we were smokers it might be equally difficult for us to quit; however, I may be more successful because in the face of my predisposition, I may have more willpower than you.
“But the fact that we know that there is a biological basis of addiction, aside from the genetics research, does in a sense remove some degree of blame for people, because it’s not just an issue of people choosing to smoke,” she adds. “You can’t say that smoking is a choice, because once somebody becomes addicted and their brain changes, it’s not as easy as it might seem.”
Take a drag—a big, long one. Good. Then take another. Good. And another. Keep puffing. You might look a little silly, since the cigarette isn’t lit, but the only people who are watching you are scientists. And all they want to know is: Does it work for you?
Dr. Brad Collins, another assistant professor at TTURC (and another Georgetown emigre), has been examining the finer points of “smoking-cue reactivity.”
As smokers learn to associate the once-neutral cues or items in their environment with the pleasure of smoking, Collins explains, “these items or settings can cause an urge to smoke.” To undo that urge, a sort of behavioral exorcism, like puffing on an unlit cigarette, can be effective.
“We’re still at the preliminary stages of the research,” he cautions. A lot depends on the person, the substance, and the behavior. For some people, after three hours of repeated five-minute sessions with unlit cigarettes and other nicotine-junkie paraphernalia, “you can see their reactivity and their self-purported urge to smoke drop off.”
But it won’t work for everybody. “There are certain genes and gene formations that identify people who are at risk for having greater withdrawal, and also greater reactivity,” says Collins. “And those people probably are not the individuals who would do well in an exposure/response-prevention form of treatment.”
If you think it’s hard to quit smoking when you’re single, educated, and reasonably content with your job, try it when you’ve got a screaming baby on your hands and your hormones are all out of whack.
“The postpartum population is probably the most resistant to change for smoking,” says Collins. “Smoking might be one of the few things that they can do that actually feels good.”
Yet everyone knows second-hand smoke is bad news for infants and children, right? Wrong. Which is one of the motivations for the research program Collins is overseeing: a family-based intervention to decrease children’s exposure to second-hand smoke while at the same time decreasing parental smoking rates.
“The population that we’re recruiting for this study isn’t necessarily the best educated in terms of the dangers of smoking and second-hand smoke,” says Collins. “They also don’t have a lot of access to treatment because of low income, their education problems, and so on. And so their motivation is pretty low.
“Most moms, because of pretty successful campaigns, know of the dangers of smoking when they’re pregnant,” he adds. “But very few moms—particularly low-educated, low-income moms, know about the dangers of smoking around kids. Over 35 percent of moms who have infants in the West Philly community are smokers—around their kids.”
Obviously, they need to be educated. And even if they’re not ready to quit, they can learn to adjust when and where they smoke—protecting their child’s health if not their own. “From a behavioral-scientist point of view,” Collins says, “once you get your foot in the door—and the mom starts making some minimal gains through the process of continued contact with the health counselor and getting positive reinforcement for the little gains they’re making—you can kind of nudge them and increase their motivation to quit.”
There is a larger principle at work here, one not restricted to poor, uneducated mothers. “The truth of the matter is that preparing people for the possibility of relapse is better than promising them that the hard part’s over and they never have to worry about smoking again,” says Collins. “Because smoking is always going to be available—whether it’s legal or not. And they’re always, in the future, going to have a choice in every situation they’re in: ‘Do I remain an ex-smoker, or do I want a cigarette?’”
