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Biology and Beyond

Interdisciplinary scholars are decoding complex social impacts on genes, exploring new models of human development

The comparison between the genes of a human and those of a tomato indicates the subtle complexity of gene-environment interplay.

When the Human Genome Project got underway in 1990, experts believed that people carried an estimated 100,000 or more genes. Since then, the overall count has been revised downward to fewer than 25,000 genes, or about 7,000 fewer than a fleshy tomato. Does this mean that a human being is less complex than a salad ingredient?

No, says IPR anthropologist Thomas McDade, who directs Cells to Society (C2S): The Center for Social Disparities and Health at the Institute for Policy Research. Still, the comparison indicates the subtle complexity of gene-environment interplay.

In McDade’s view, one of the most significant achievements of human genome sequencing, completed in 2003, was pinning down the number of human genes. Gene mapping, however, only points to an organism’s inherited information; it cannot shed light on how genes “enter into conversation” with their environment to shape gene expression. In other words, genes are part of the conversation but don’t dictate the entire discussion with respect to human outcomes.

Thomas McDade

“We spent more than $3 billion to unlock the human genome and discover its secrets,” says McDade, “yet we still haven’t seen the initially promised breakthroughs in cures for diseases.”

That’s because these promises were based on what McDade calls an “overly simplistic model” of human biology. For example, even though a woman might have a mutation in a BRCA gene — responsible for tumor suppression — her chances of developing breast or ovarian cancer, while higher than those of the general population, are still not 100 percent. Similarly, humans all carry genes for inflammation that can contribute to diseases of aging, but how often or intensely these genes are expressed depends on environmental factors. McDade emphasizes the importance of moving beyond nature-versus-nurture or DNA-as-destiny metaphors. Doing so encourages us to reconceptualize the human genome as a dynamic substrate that incorporates information from the environment to alter function, with implications for well-being over a lifetime.

Creating complex biopsychosocial models requires new methods that cut across many disciplines. Such circumstances help explain why C2S, now approaching its 10th anniversary, has become an interdisciplinary knowledge hub. The center brings together anthropologists, sociologists, physicians, economists, epidemiologists, psychologists, and other social and biomedical scientists to answer a foundational question: How do socioeconomic, racial, and other types of disparities “get under our skin” to affect human health and development?

Inflammation and Early Environments

Considerable C2S research examines how early life experiences and environments affect the regulation of inflammation in later life. Inflammation is a necessary component of human development, but a tricky one. Too little inflammation at certain stages can cause harm. So can too much. Inflammation is a culprit implicated in a variety of illnesses, including cardiovascular disease (CVD), type 2 diabetes, and psychosocial conditions, such as depression and anxiety.

Emma Adam

IPR developmental psychobiologist Emma Adam is an innovator in collecting and testing saliva, particularly to detect the presence of cortisol — a hormone that mediates a body’s reaction to stress. McDade has led the development and validation of dried blood spots (DBS), which are collected on filter paper. Both are relatively easy to collect and transport in a variety of communities.For most researchers, studying human inflammation has involved drawing blood in a laboratory or other medical setting and then analyzing these draws for the presence of biomarkers — biological measures such as C-reactive protein (CRP) and cortisol. C2S faculty have devised easier, faster, and less costly ways to collect such information.

“For $1, we can collect a blood sample with a finger prick, a method commonly used by diabetics to monitor their blood sugar,” McDade says of the DBS method. No laboratory is needed, and researchers have the means to collect “hundreds, if not thousands, of samples” during site visits.

Now, McDade and others are refining these tools to allow researchers to collect data on “end-point” proteins, such as CRP and inflammatory cytokines, as well as to capture DNA methylation, an epigenetic mechanism that affects how genes are expressed.

He is working on a project with IPR health psychologist Greg Miller to do just that. A pioneer in the study of inflammatory gene expression, Miller has long collected molecular data through blood draws in laboratories, but these collections typically involve small samples. They also require study participants who are willing to undertake an often costly commute to a lab to provide a blood sample. The two researchers are conducting a study that will compare the results of gathering epigenetic and gene expression information from DBS with those from a traditional venipuncture blood draw. If the DBS 
and venipuncture results prove consistent, this could lead to many other applications in a range of research settings. The project has received funding from the National Science Foundation and the National Institutes of Health.

Stress and Disadvantage

In addition to studying early-life influences, C2S researchers are exploring how adolescent and adult experiences shape outcomes. A particular focus is examining impacts for those from disadvantaged backgrounds. One of Adam’s major research streams is targeting stress, especially the stress of racial discrimination, as one explanation for why minority groups tend to have worse health than whites.

One way Adam charts stress exposure is by measuring diurnal cortisol rhythms — levels of cortisol in saliva throughout the day. “You want to have high levels upon waking, because that helps to prepare you to meet the demands of the day,” she explains. “You want a strong decline across the day, then low levels at night.” When cortisol levels are lower than expected on waking and higher than expected at bedtime, the resulting “flattened” diurnal cortisol profile can indicate chronic stress and be a precursor to illnesses such as CVD.

In early work, Adam and her colleagues discovered that black and Hispanic adolescents generally had flatter diurnal cortisol profiles than their white counterparts. Socioeconomic status or overall life stress could not explain these patterns. The researchers hypothesized that discrimination may play a role.

She and her colleagues measured “concurrent discrimination” — discrimination currently happening — in young people from majority and minority backgrounds. When minority youth experienced discrimination, their cortisol slopes flattened, indicating chronic stress levels; when majority youth experienced discrimination, their cortisol slopes remained the same. “It seemed like the minority youth, in particular, were sensitive to the impact of racial and ethnic discrimination on their physiology,” says Adam.

Concurrent discrimination still did not account for all of the racial or ethnic differences in cortisol slopes, so Adam also investigated past incidences of discrimination. She analyzed 20 years of longitudinal data from 120 adults who had experienced discrimination from seventh grade through their early 30s. This led to a remarkable discovery: Blacks who say they experienced high levels of discrimination as adolescents had flatter diurnal cortisol slopes and dramatically lower overall cortisol levels as adults.

This finding reveals that “subtle discriminatory acts matter for your biology, and also for your health,” says Adam. “It’s a costly societal problem that really needs to be addressed.”

She and her colleagues continue to explore the topic. One of their recent research projects is the first to examine racial and ethnic differences in cortisol rhythms longitudinally. Their five-year Chicago-based study of 229 white, black, and Hispanic adults, 50 and older, reveals that older black adults, like their younger counterparts, were more sensitive to stress than whites.

“We were able to watch the flattening of the slopes unfold in response to chronic stress,” says Adam, “revealing a potential pathway for flattening of these slopes in racial or ethnic minorities.”

Disparities and Adaptations across Generations

Another area where C2S faculty have broken ground is in using biomarkers to trace how health disparities can transfer from one generation to the next.

Since his days as a doctoral student, IPR anthropologist Christopher Kuzawa has been interested in British epidemiologist David Barker’s Fetal Origins Hypothesis, which posits that CVD in adults can be traced to undernutrition in the womb.

Christopher Kuzawa

While writing his doctoral thesis in the late 1990s, Kuzawa traveled to Cebu, the second largest city in the Philippines, to research how such patterns might become manifest in adults. To test this idea, he implemented biomarkers from the Cebu Study, a project that began in 1983 with more than 3,300 mothers. Its original aim was to examine how using formula or breastfeeding affected their newborns’ subsequent development.

Since then, Kuzawa and the Cebu Study team have continued to collect data on subsequent generations, including reams of biomarker data and DNA samples. This rich data source has led to many important findings by Kuzawa and others. One recent example from their study indicates that women with high stress-hormone levels give birth to smaller babies. Similarly, when a baby is born premature, indicating a prenatal stressor, that child goes on to have altered stress-hormone levels as an adult. These findings point to long-term impacts of the mother’s stress levels on her offspring’s growth and health.

Kuzawa is working on additional data collection with both Miller and McDade to examine adult outcomes of the study’s first cohort of infants, now in their 30s. The researchers have remained in contact with them throughout their lives and are now following the cohort’s women as they have children of their own — collecting data on their pre- and postnatal states of mental and physical health and adult environments. They plan to use the data to see which factors in the mother’s experience predict birth outcomes and long-term health in their offspring.

A second focus of Kuzawa’s research aims to clarify how humans evolved as a species. For example, his team has explored why fathers’ testosterone levels might drop after the birth of a child as an evolutionary response to male caregiving. More recently, he has documented the energetic costs of human brain development and how this varies across the life cycle.

“Humans managed to pull off an interesting trick,” says Kuzawa. “Although we evolved a large and energetically costly brain, our body’s resting energy expenditure is the same as predicted for a mammal of our size. How was this achieved?”

As part of an NSF-funded study, Kuzawa and his colleagues used PET and MRI brain scan data to estimate how much energy the brain consumes across different developmental stages. Their results explain why, after a certain age, it becomes difficult to guess the age of a toddler or young child by physical size. By childhood, the brain has become “an energy monster,” nearly halting body growth and using twice as much energy as an adult’s brain.

“Our findings suggest that our bodies can’t afford to grow faster during the toddler and childhood years because a huge quantity of resources are required to fuel the developing human brain,” says Kuzawa, indicating why adequate nutrition is critical in childhood. “As humans we have so much to learn, and that learning requires a complex and energy-hungry brain.”

Biology and Policy Relevance

Looking over the last decade of C2S’s growth and development, McDade says it was crucial for the center to be situated within IPR. Yet at the beginning, when faculty discussed launching the center, they raised a lot of questions about how it would fit within IPR’s framework.

“We were at the very early stages of investigation about how social environments and social policy may matter to biology and health,” McDade recalls. There were no easy answers for how C2S was going to realize its aim of policy-relevant research. Yet he says C2S faculty also recognized that even if they were not doing policy research immediately, they would get there a lot faster by being part of IPR and collaborating with colleagues who do policy work.

“And we have gotten there,” he says. “It’s a unique intellectual moment, when the population sciences can make important contributions to our understanding of human biology and its complex, multilevel determinants.”

Thomas McDade is professor of anthropology, director of Cells to Society (C2S), and an IPR fellow. Emma Adam is professor of human development and social policy and an IPR fellow. Greg Miller is professor of psychology and an IPR fellow. Christopher Kuzawa is professor of anthropology and an IPR fellow.

This story originally appeared in the Spring 2015 issue of Centerpiece, here.