Duke University Alumni Magazine


By researching the results of bad habits and other neurological villains, pharmacologist Ted Slotkin has discovered how certain chemicals insidiously damage the developing brain.

he drug is a viciously addictive poison, taken without prescription by about one-fourth of pregnant women in this country. Once in their bloodstream, it unerringly finds its way into the brains of their unborn children. There, among the tangle of rapidly growing nerve cells, it subversively masquerades as a natural chemical signal that normally instructs the neurons how to grow, organize, and connect themselves. The drug's pernicious campaign of misinformation kills many young neurons outright and permanently confuses the critical interconnections of many others. Its espionage also wreaks havoc outside the fetal brain, damaging the adrenal hormone system that alerts the infant's body to oxygen deprivation.

The drug's assault kills more than 100,000 babies a year in utero and many thousands more at birth. It leaves countless newborns clinging to fragile life in intensive care. Its tragic impact continues beyond the hospital, suffocating nearly 2,000 infants a year in their cribs. And still later in life, the permanent brain damage the drug has wrought leaves countless more children with learning disabilities, attention deficit/hyperactivity disorder, and other behavioral problems that will plague them their entire lives.

The drug is nicotine.

Disappointed? The letdown you likely experienced at this revelation--expecting perhaps a more exotic villain like cocaine or heroin--is no surprise to Duke Medical Center pharmacologist Ted Slotkin. He knows all too well that the public continues to accept the familiar horror of "cigarette babies," despite his decades of painstaking laboratory studies that have nailed nicotine as a key culprit in miscarriage and infant death.

We are not alone in our complacency, Slotkin asserts, for "both the press and the medical community continue to regard tobacco as separate from, and less serious than, illicit drugs of abuse." As evidence, he cites the fact that 80 percent of medical textbook pages on drug abuse concentrate on illicit drugs, compared to less than 5 percent on tobacco. Yet illicit drugs account for only a few thousand deaths each year, compared to 400,000 for tobacco. Also, cocaine is the subject of four times as many scientific research papers as nicotine, despite the fact that far more pregnant women smoke cigarettes than use crack cocaine.

"Nicotine exposure is likely to be the single most widespread prenatal chemical insult in the world, continuing unabated despite decades of educational and medical intervention," Slotkin wrote in a landmark paper-- "Fetal Nicotine or Cocaine Exposure: Which One is Worse?"--in the June issue of the Journal of Pharmacology and Experimental Therapeutics. (The text is available on the World Wide Web at http://www.dukenews.duke.edu/nicotine/slotkin.htm.)

Besides exposing the hazards of nicotine to the unborn, Slotkin's award-winning research--conducted at Duke since he first arrived as a research associate in 1970--has led him into a broad range of other startling explorations. He and his colleagues have revealed how pesticides affect the growing brain, why so-called "birth trauma" is good for newborns, and how depression in the elderly differs from that in the young. Lately, Slotkin is exploring what he calls an "off-the-wall" possibility of using certain drugs to persuade breast cancer cells to commit suicide.

Of mice and man: Slotkin holds a nicotine pump, which administers precise doses of chemicals into lab rats
Photo: Bruce Feeley

"The core of all our research is the question of how developing cells make decisions such as whether to divide and how to specialize," he says. "Everybody starts out as a single cell, and all the cells that come out of it have the same DNA. And yet, cells specialize--to become a brain cell, a heart cell, a skin cell. Since the information that tells cells what to become doesn't come just from their DNA, it has to come from how cells talk to each other, and how the environment talks to cells to enable them to make the right decisions. To an embryonic cell, it's critical who its neighbors are and what external cues it receives--such as stimulation, oxygen, or hormones." And these signals must appear at just the right time. "It's just as a child exposed to a different language within a very fixed period can learn to speak that language idiomatically and without an accent, and to think in that language, but loses that ability after a certain age. So, cells have a fixed period in which they must receive theproper inputs to assemble the machinery they need to respond to those inputs later on." Slotkin, a professor of pharmacology and cancer biology, can help society deal with issues such as pregnant women's cocaine or cigarette use by posing them as basic biology questions, since those drugs switch cell signals on or off at the wrong time.

Particularly disturbing, he emphasizes, is that fetal cells often react completely opposite from adult cells to outside signals such as "neurotransmitters"--chemical signals that plug into receptors on a neuron's surface to stimulate it. "In adults, if you flood the brain with a neurotransmitter, the receptors shut down to protect the cell from excessive stimulation," says Slotkin. "But when fetal cells are stimulated in the same way, they actually enhance their response. They're essentially saying, 'Whatever chemicals I'm exposed to now must be what I'm supposed to respond to later, so I'll turn on all the machinery I need to respond to that input.' " Slotkin's experimental manipulation of such signals has yielded some disconcerting results. When the Duke researchers denied fetal rats the chemical signals needed to stimulate their developing hearts, those hearts never "learned" to connect hard work with growth. No matter how much the treated rat exercised, its heart muscle never responded by strengthening. "It's as though you send yourself to the exercise room to develop an Arnold Schwarzenegger build and wind up looking like Woody Allen," says Slotkin.

In the researchers' animal studies, they use implantable mini-pumps to infuse precisely metered doses of a chemical--perhaps nicotine, a pesticide, or some other substance--into the bloodstreams of pregnant rats. Then, using meticulous biological analyses and microscopic studies, they measure the chemical's effects on the brains of the rats' unborn offspring. The techniques have proven to be a powerful approach to pinpointing the effects of nicotine on the growing brain, says Slotkin. "Until such studies, we had only statistical associations of the effects of women smoking during pregnancy on the outcomes of their children. But those kinds of associations didn't automatically connote a causal relationship. The picture was confused by all kinds of other factors in the smoking lifestyle--including lower socioeconomic status, which leads to poor prenatal care, as well as other risky behaviors, including use of other drugs of abuse and alcohol."

With animal research, Slotkin can test individual components of tobacco, determining which actually elicit such effects as brain damage or sensitivity to hypoxia after birth--a condition that can trigger Sudden Infant Death Syndrome (SIDS). Slotkin's studies revealed the damning details of the mechanisms of nicotine's damage to the fetal brain. The experiments showed that nicotine mimics a key brain neurotransmitter, acetylcholine, which is normally released in a precise sequence of signals that tell the sensitive growing brain cells how to "wire" their connections. Nicotine stimulates the same cell receptors as acetylcholine, but at the wrong time and with the wrong intensity, confusing the normal development process and causing the fetal brain to miswire itself permanently. Nicotine also kills brain cells outright by inducing them to "age" prematurely and die.

Slotkin's experiments have clearly implicated nicotine as the cause of one-third to two-thirds of cases of SIDS, the second leading cause of infant death after accidents. Nicotine damages the adrenal system, which the infant needs to "alert" its body to stress. The infant uses the adrenal system to boost heart rate and breathing during periods of hypoxia--during birth itself and after birth when some babies have an inherited predisposition to mild apnea, or breathing cessation, during sleep. In the newborn, the heart and respiratory systems are not yet fully wired with nerve cells to allow them to respond to hypoxia, as in adults. Instead, they rely on secretion of certain adrenal stress hormones, called catecholamines. In their experiments, the Duke pharmacologists first infused into pregnant rats doses of nicotine that mimicked blood levels found in typical human smokers. After the baby rats were born, the researchers exposed them to a low-oxygen environment, similar to what a human infant might encounter during birth, sleep apnea, or sleeping in a face-down position. The high-dose nicotine group of baby rats were far more likely to die during low-oxygen periods than those whose mothers had not received nicotine.

Besides pinpointing nicotine's role as a neurological villain, Slotkin's laboratory has yielded insights that will help pregnant women quit smoking more safely. The scientists have found that during the first trimester of pregnancy, women can more safely use nicotine patches, inhalers, and gum to quit smoking. This early-treatment strategy is contrary to the popular belief that drugs are most harmful to the fetus during early pregnancy, says Slotkin. "Nicotine works on a very specific set of proteins that, although they're present from early in pregnancy, aren't really there in very large numbers until the second trimester. This tells us that pregnant women have a 'window of opportunity' we didn't know about before." Nevertheless, he warns, use of nicotine therapy must be carefully circumscribed, and will power is by far the safest anti-smoking treatment.

The Duke pharmacologist's research has also shown the inadequacy of the U.S. Surgeon General's warning that links smoking-related fetal damage primarily to low birth weight. "We have fallen into the trap of thinking that if a baby is of normal weight, then no damage has been done," says Slotkin. "But in our animal studies--in which we could simulate smoking levels from two packs a day down to half a pack--we found that all the brain damage that occurs at growth-retarding levels of nicotine still shows up at doses that don't affect growth. The brain is much more sensitive than the rest of the body."

Slotkin's studies of the brain-damaging effects of pesticides have shown similar insidious effects at low dosages. Administering low doses of the widely used pesticide chlorpyrifos to pregnant rats, he and his colleagues have found evidence of disrupted brain development at doses below those typically identified as "toxic."

Although crack cocaine has received by far the most research media attention, Slotkin's studies show that cigarette babies are likely in more danger than crack babies. "Virtually all crack users also smoke cigarettes," he says. "So, in developing the statistical associations of crack-baby syndrome, researchers have generally not separated out the effects due to cigarette smoking. Many previously believed that crack cocaine caused SIDS, but when investigators began to look at the incidence of SIDS in the offspring of women who used crack cocaine, they found it to be no higher than in the offspring of women who smoke cigarettes. So cocaine itself might not actually cause SIDS, but rather the associated cigarette smoking." Also, he notes, cocaine use is typically episodic, with more transient effects than that of the constant flow of nicotine into the fetal brain from the smoking mother.

Slotkin's newest nicotine studies will strike at the very heart of the issue of teen smoking. His theory is that the still-developing adolescent brain may suffer permanent physical damage from smoking. "Most smokers begin smoking in adolescence," he says, "and it is quite possible that nicotine exposures in an adolescent brain also can cause irreversible changes in the development, structure, and function of specific nerve pathways. Such effects might explain why nicotine is often more viciously addictive in adolescents than it is in adults, and why the adolescent smoker becomes the lifelong smoker." He plans to expose adolescent rats to nicotine levels that mimic smoking and to use the lab's arsenal of powerful analytical techniques to search for signs of brain damage.

Like any good basic research, the work by Slotkin and his colleagues has opened other unexpected pathways to key discoveries with important clinical implications. More than a decade ago, he and his colleagues presented evidence that the oxygen deprivation the fetus usually experiences accompanying birth is actually a necessary signal for its development. "The fetus has to change its physiology drastically to adapt to life outside the womb," says Slotkin. "It turns out that getting asphyxiated is an important signal to the infant, even though it causes oxygen levels to fall to only 10 percent of 'normal.' While those levels would cause severe brain damage in the adult, such hypoxia is a normal condition for the newborn, since their cells work in a completely different way from adult cells. This low oxygen triggers the infant to restructure its respiration, heart function, and metabolism for its new environment." These findings have meant a rethinking of the need for the prevalent practice of performing Caesarean sections, says Slotkin. "We need to reduce the number of Caesarean sections, because they reduce a critical kind of stimulation the baby needs to live outside Mom."

Like his studies on the young, Slotkin's studies on depression among the elderly have importantly affected thinking about the other end of life's road. "You can ask similar kinds of scientific questions about the aging brain as in the newborn. We are exploring the signals sent to a brain cell to tell it to die. And we're asking whether the aging brain regulates its pathways differently from the brains of young people."

So far, Slotkin's work has found that elderly depression seems to be biologically different from depression in the young. "We're developing animal models of elderly depression that enable us not only to dissect out the biological differences, but possibly to come up with better drug therapies for elderly depression, since the standard therapies don't work very well."

As the graph indicates, research on cocaine use and its effects far outstrips that on nicotine, an area of study still lacking research funds. Yearly totals show primary papers and review articles; the bars on the far right reflect review articles.

To study elderly depression in rats, the pharmacologists create the same surgical lesions in older animals that cause depression in younger animals--removing the olfactory region that is so important to a rat's connection with the outside world. Besides this technique, the scientists plan to develop methods to create brain lesions that closely resemble the same brain deficits found in elderly humans. With such animal models, they can explore the resulting depression and the effectiveness of potential new treatments.

The most surprising new research direction for the Slotkin lab seems to be its foray into breast cancer research. "Cancer cells are those that have gone backwards in development, reverting to a more embryological form," he says. "And many breast cancer cells have similar molecular characteristics as nerve cells. We've found that these cancer cells start to make receptors, called beta adrenergic receptors, that switch on replication at certain development stages and switch it off at others. So, our idea, which might be totally off the wall, is to find drugs that manipulate these receptors. We might be able to either shut down replication of the breast cancer cells, or even tell them to age faster and die."

Such cancer therapy would be totally different from current drug therapies, which must penetrate cancer cells to attack their machinery directly. Cancer cells often become resistant to such drugs by evolving ways to pump them safely out of the cell. "Since the anti-cancer drugs we're thinking about affect receptors on the cells' surface, the cancer may not develop resistance. This research might give us a whole new set of drugs that would work on cancer cells after they've escaped standard chemotherapy."

As if nicotine, pesticides, depression, and cancer weren't formidable enough foes, Slotkin, like his fellow scientists, finds himself in a constant struggle to maintain his lab's funding. He is certainly thankful for his current support from the National Institutes of Health, the Department of Defense, andĐof all groups--the Smokeless Tobacco Research Council. Even with a positive funding climate in Washington, only 20 percent of grant proposals are accepted. "So, if you want one grant, you have to write five," he says. "The low funding rate also means we're throwing away 80 percent of the proposals, a lot of which constitute very worthy research ideas. But the major problem, even for a really good lab, is continuity. It's very hard to maintain a decent-sized laboratory with a sense of research mission and intellectual continuity when you're continually suffering uncertainties or interruptions in your funding. Graduate students need to have support for about five years to allow them to get Ph.D.s. But if grants only last three years, you can't guarantee a student that long-term support."

What's more, researchers often find themselves in a classic Catch-22 situation: "Given the limited grant periods, in the middle of a grant you've got to prepare additional grant proposals in order to guarantee continuity. But these new grants often suffer a reduced chance of being funded because agencies might take into account that you're already funded," he says. "Believe me, even senior researchers suffer plenty of anxiety attacks over these funding issues."

Slotkin likes to offer a reminder that basic scientific research offers a stunningly large return on dollar investment, citing economic studies that show a return of about 500 to one. But beyond the strict monetary measures, he also cites the extraordinary "quality-of-life return on investment" yielded by productive research--a humane dividend of lives saved and lives enhanced.


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