A Radical Notion

Animal studies have shown that a number of environmental triggers, such as poor nutrition or exposure to bisphenol A (a chemical found in plastic), alter the protein production of genes at critical times by turning them on, off, up or down; and that these “epigenetic” changes get passed down from mother to baby and even into the next generation. A striking example involves research using mice that, despite being genetically identical, are either small and brown, or obese and yellow (and prone to diabetes and cancer as adults), depending on whether or not a particular gene is activated by a simple change in their mother’s diet. Exposures in the womb get biologically embedded just when the developing nervous, immune and metabolic systems are most susceptible to being modified, essentially programming these systems early on.

These signals from the environment apparently echo far into the future, “which is why we’ve got to take seriously the public health aspects of food choices by girls and women,” says David Barker whose 1995 paper, “Fetal Origins of Coronary Disease” in the British Medical Journal, gave rise to the Barker Hypothesis.

A physician and professor at the University of Southampton Medical School in the U.K. and at the Oregon Health and Science University in Portland, Barker offers up a body of research suggesting that hundreds of millions of people need not have type 2 diabetes, for instance; that this and other chronic disease epidemics can be traced back to the placenta and are, he says, “unnecessary.” Prevention is simple but not easy, he explains: It requires improvement in the nutrition of girls and young women.

“Chronic disease isn’t about abnormal things happening to adults who then need fixing,” Barker says. “It’s about variations in key systems during development, which in turn cause wide variations in how well a baby is nourished. The ability of a mother to nourish her baby in the womb reflects her own lifetime nutrition, beginning when she herself was in the womb. To say ‘don’t drink, don’t smoke,’ is not enough. We’ve done that; we need to move on from merely limiting damage to building better people.”

Using good nutrition to build healthy people is hardly a new idea. (The Bloomberg School’s David Paige—decades before he taught Wang when she was a doctoral student here—developed a food voucher program in Baltimore that later served as the model for WIC.) What is news: the extent to which a developing baby’s or young child’s environment plays a role in chronic disease by silencing or activating genes. That’s why the heavy emphasis by Barker and his acolytes on birth weight: In addition to being a measure of pregnancy outcome, it’s an indicator of fetal nutrition, of whether an individual’s in utero experience was harsh or benign. Birth size implies potential in terms of metabolism, cognition and endocrine function.

If the early-origins framework that Barker built still rankles some scientists, it’s because the mechanisms remain elusive. Associating a prenatal exposure with the heart disease of a middle-aged man is one thing; directly linking the two is quite another. Lots of other potentially culpable stuff also happens in the intervening decades, muddying up the path between cause and effect. Which is why Wang is collaborating with a vast network of scientists and clinicians around the world as she leads comprehensive long-term studies into the early life precursors for pediatric and adult diseases including preterm birth, food allergy, obesity and metabolic syndrome. In Wang’s purview, the futile nature-versus-nurture debate morphs into verifiable questions with measurable answers: What environmental and social factors consort with which genetic factors; how, when and to what degree?  Is the net effect a risk for disease—or resilience?

Of many adverse influences that can pull a trigger cocked by genetics, poor nutrition is a biggie. But brutal neighborhoods also belong on that list, according to Wang, as well as vicious domestic situations: “Violence is to mental health as cigarette smoking is to cancer,” says Barry Zuckerman, MD, chief of pediatrics at the Boston Medical Center and a mentor of Wang’s since she was a resident there in the late 1990s. While Zuckerman and his protégé are focused on discovering those factors contributing to low birth weight, they also are keen to identify biologic interventions and social strategies that could preempt or at least buffer the detrimental effects of environmental influences. Zuckerman’s Reach Out and Read program, for instance, goes beyond the scope of conventional pediatric practice, using literacy as “medicine” to immunize kids against the power of poverty and violence; he says that primary care practitioners must encourage parents to read aloud to babies and preschoolers.

About the time when Xiaobin Wang was starting to read and ready to enter school, China’s educational system ground to a halt as a result of the Cultural Revolution.

While her classmates languished in illiteracy, Wang devoured state-approved biographies of great scientists like Marie Curie. Her parents, neither privileged nor wealthy, delighted in their daughter’s intellect. So did teachers who had few reasons to find joy in their profession. Her mastery of lessons elicited praise, which in turn accelerated Wang’s learning. She skipped the sixth grade; then the 12th. In 1978, China started reforming education just in time for Wang to distinguish herself on a national exam that landed her at Beijing University where she started medical school at the impressionable age of 16.

How had Wang mustered both physical and intellectual fortitude in an impoverished and corrosive environment while others around her withered? Posing that question—why does one baby, one child, one adult, have a markedly different outcome from most others despite all else appearing equal?—ultimately became central to her research.

First, she wanted to know why some women who smoke have low-birth-weight babies, while others who smoke have normal-sized babies. Next, she wanted to understand why so many minority women living in poverty have preterm births while others living and working next to them have healthy, full-term babies.

As she investigated what part genes contributed to the puzzle and what part environment, she became convinced that there is crosstalk among dozens if not hundreds of factors—nutrition and smoking and genetic variables, just to name a potent few. Each single threat to health and well-being is difficult enough to study on its own. A “real-world” assessment involves the complication of a multitude of other threats that may exacerbate that original threat. And an even more accurate measure involves accounting for buffers that may temper some threats. Not one to shy away from seemingly insurmountable challenges, Wang insists on considering all the in utero variables she can conceive of—whether bad or potentially beneficial—no matter that this exponentially complex task has required her to devise novel methods of research.

It’s good science that compels her to consider the oft-neglected protective factors that engender resilience in the face of harsh societal or environmental factors. And it’s something more, something personal. If you talk to Wang for any length of time, you’ll be impressed by the force of gratitude that gushes from her for her parents and school- teachers as well as the likes of Guyer and Zuckerman, whom she describes as lifetime mentors. “From my elementary school to now, I have been extremely fortunate to have so many wonderful teachers, mentors and role models,” she says. “Their vision, leadership, knowledge, guidance and encouragement have greatly influenced my pursuit for education, training and research in medicine and public health.”

The mentor who awaited Wang when she entered Beijing University was Professor Gongshao Ye, a preeminent pediatrician who established the field of maternal-child health in China and authored a definitive textbook used for 30 years. “She told me that one ounce of prevention was worth more than 10 ounces of treatment,” Wang says.

She also told Wang to head to the U.S. after med school for further training. That advice set the young woman on a trajectory that twice would land her at Johns Hopkins, first as a doctoral student of perinatal epidemiology in the 1990s with Bernie Guyer as her advisor; and now again in 2012 as a named professor and center director. Here and now, she’s poised to fully answer the question that has occupied her since her early days: What causes preterm birth?

When it first occurred to her that question needed answering, the Barker Hypothesis was simmering on a back burner; epigenetics was not yet commonplace in scientific discourse. She was a pediatric resident at the Boston Medical Center. By then, her parents’ mandate to Work Toward Hope had gestated for some 30 years.

Never in her life had Wang seen such a tiny baby.

Born at 26 weeks—three months early—the preemie’s reluctant first breath required intubation and chest compressions. If, because of the marvels of life-support technology and her colleagues’ considerable skills, this infant survived the week—and even if, in months to come, this fragile being was able to “graduate” from the neonatal intensive care unit and go home (likely with a feeding tube and oxygen)—its translucent skin seemed to Wang to be a window into a future of suffering. Prematurity is a challenge to the brain as well as the lungs. Common, chronic complications of preterm birth include brain bleeds, blindness, hearing loss and lung disease.

As a resident in a hospital that served a low-income minority population, among which almost 20 percent of births are preterm, Wang was keen on learning from the attending physicians how to rescue babies weighing in at just over a pound. But as the preemies kept on coming, she felt responsible, not only for them but also for their disenfranchised parents who were at a loss for how to care for such medically, emotionally and economically demanding newborns. Wang couldn’t imagine how even she, a trained pediatrician, would cope as the mother of such a preemie. Empathy and indignation moved her to tears and moved her to act. There had to be something she could do in addition to saving these lives, here and now. Something preventive.

The first thing she did was to author an elegant analysis that appeared in 1995 in the New England Journal of Medicine, demonstrating the finding that low birth weight and preterm birth repeated from one generation to the next.

The next thing she did was conceive the idea for the Boston Birth Cohort.

She sensed that the complex causes of preterm birth might begin to be teased apart if she could compare a sizable population of mother-preemie pairs against a population of healthy mother-baby pairs, with all coming from similar circumstances. Bleak as the NICU was, Wang recognized it as the ideal place to start to understand why some babies ended up here, connected to tubes and wires, while another group landed safely in the “happy” nursery down the hall. A multitude of risk factors necessitated a large number of cases (preterm births) as well as controls (full-term births). Mothers would need to agree to be interviewed, allow medical records to be scrutinized and contribute samples of maternal blood, cord blood and placental tissue.

With a small seed grant and encourage-ment from her professors Barry Zuckerman and Howard Bauchner, MD (currently editor-in-chief of JAMA), she set out on what now is a massive, 14-year-old project involving 7,600 mother-infant pairs, 60 percent of whom are black and 25 percent Hispanic. To date, analyses of the data have generated more than 30 publications; notably, Wang pioneered the genetic study of preterm birth. With a landmark article in JAMA in 2002, her group demonstrated how smoking mothers with certain genotypes had a 10-fold higher risk of preterm birth over smoking mothers with other genotypes, revealing a synergistic effect between a genetic and an environmental factor. A finding like this paves the way for “biologic hotspotting,” a strategy that identifies genetic vulnerabilities so that individualized interventions can be targeted at a particular behavior or specific biologic variable.

Wang’s Boston Birth Cohort comprises an extensive collection of epidemiological and clinical data as well as biospecimens housed in more than a dozen freezers near her new lab space in the Wolfe Street building. This rare resource allows Wang and her collaborators to investigate environmental, genetic and epigenetic influences on mothers, infants and children. Few, if any, prospective birth cohorts in the nation are so well positioned to answer “why” in the context of a minority, high-risk population bearing a disproportionately high burden of chronic conditions and diseases such as preterm birth, obesity and allergies. Because the study spans decades, researchers may check back with the subjects to ask new questions and look at disease progression.

With that cohort still actively re-cruiting, Wang and colleagues have built two more: The Chicago Family Cohort, focusing on food allergies, involves 4,000 subjects from 1,000 families; and the Chinese Twins cohort involves 2,000 pairs of twins and probes the precursors of obesity and metabolic syndrome. All three studies are churning out data.

“From the Boston Birth Cohort, we have data showing that by age 6, over 45 percent of the children in the study—no kidding!—are overweight/obese,” Wang says. “Fifty percent of the mothers were overweight/obese at the time of conception. Let’s not wait until these kids walk into the doctor’s office as obese adults.”

Statistics like that one are guiding Wang’s latest efforts to corral Johns Hopkins faculty from the schools of Public Health, Medicine and Nursing for investigations into the early life precursors of intergenerational obesity. One NIH grant application involves nutrition expert Laura Caulfield, PhD, and Mei-Cheng Wang, PhD, a biostatistician, both from SPH; Tina Cheng, MD, a professor of pediatrics in the SOM; and mental health expert Deborah Gross, PhD, and Sarah Szanton, PhD, a health disparities researcher, both from the SON. Among Szanton’s contributions is a “society-to-cells” resiliency model that provides a holistic context for understanding health differences and guiding interventions at six different levels. Each one of the levels, Szanton says—society, community, family, individual, physiological and cellular—represents an opportunity to exert positive change. It’s impossible to resist applying this framework to Wang: Given that she was a full-term baby nurtured by family and mentors, her ability to overcome the deleterious effects of the Cultural Revolution begins to make sense.

At a March 21 symposium on the Future of Child Health that marked the occasion of Wang’s assuming her named professorship, a dozen distinguished colleagues (many of them former teachers) gathered from around the country in Sheldon Hall to honor her achievement and give mandate—just as her parents had done a half-century earlier.

Joseph Brain, a professor of environmental physiology at the Harvard School of Public Health who mentored Wang when she was a research fellow there, sought to involve her in a couple of big, important topics: “The first,” he said, “has to do with children who grow up with exposure to toxic metals.”

He described his department’s efforts to develop a birth cohort focusing on early exposure to toxic metals: The group is collecting maternal and cord blood from mother-infant pairs in northeastern Oklahoma where families live next to mountains of mining waste containing lead and zinc. Brain’s related animal studies demonstrate that anemia (iron status) increases lead uptake. The take-home message: Treating anemia could reduce the risk of brain damage by lead poisoning.

“One of the things we’d like to talk to Xiaobin about,” he said, “is how can we use that birth cohort, and apply some of the methods, insights and technology that she has?”

Sitting primly in the front row, wearing a petite white suit and butter yellow top, Wang appeared a genial force of nature, as likely to sweep people up as to be swept up. (“After you talk to her,” asks a colleague, “don’t you feel like your hair has been blown straight back?”)

As is her habit, she smiled easily, often nodding in the affirmative. Hailed by all as an indefatigable researcher and frequently described as a doting mother of her twin teenage sons, Wang was ready to accept their challenge. Her agenda, big and broad, is inclusive, extending beyond one person, institution or discipline.

“We have heaped enormous expectations on her,” Bernie Guyer cautioned the crowd during an affectionate introduction of his former student. “As her colleagues, students and friends, how do we help her to be successful?”

Wang was reflective: “My most challenging and difficult periods turned out to be my most productive and creative periods. I don’t underestimate the challenges before me. With interdisciplinary colleagues down the hall, and collaborators across the street, this is the right place for me now to leverage all the tremendous resources for the best chances of success and for translation.

“That’s my big dream.”