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Life is unfair, says Joanna Holbrook, introducing her research interests by highlighting the interplay between genetics and the environment that influences each infant’s start in life. She is working to tackle some of this unfairness by investigating factors that affect how a child develops in the womb and soon after birth, while also considering how pregnancy and childbirth affect the mother’s health. The complex interaction between mother and child — part of the ongoing nature-versus-nurture debate — is also the focus of Mary Chong’s research, which looks at the role of nutrition. Holbrook and Chong belong to different research groups at the A*STAR Singapore Institute for Clinical Sciences (SICS), but their work shares a dependence on data from a comprehensive study of mothers and infants before and after birth, called Growing up in Singapore Towards Healthy Outcomes (GUSTO).

“The GUSTO study is very deep,” says Holbrook. She points out that while other studies elsewhere in the world monitor more individuals, GUSTO is probably the broadest and most intensive study, analyzing genetics, nutrition, metabolic factors and neurocognitive state, as well as many other indicators of health and development. “The data collection points of GUSTO are much closer together than those of other studies,” adds Chong, “and so GUSTO captures the in-between data that other studies miss.” Minister Heng Swee Keat, in the Ministry of Education FY2015 Committee of Supply debate, described GUSTO as “a nationwide birth cohort study on how mothers’ diets and lifestyles during pregnancy affect their babies’ growth after birth. It is a study with great national impact for preventing and managing diseases like diabetes and obesity.”

Probing the microbiome

One area that Holbrook and her colleagues focused on was the developing population of microbes in an infant’s gut, reflecting the growing interest in the significance of the ‘microbiome’ on health and disease. Previous studies had suggested that variations in the acquisition of gut microbes can considerably affect future health and disease susceptibility. Using data from the GUSTO study, the SICS team discovered that the acquisition of gut microbes is strongly influenced by environmental factors, including the method of delivery and length of gestation. Babies delivered by cesarean section develop their microbial profile later than normal, as do those born after a shorter gestation time in the womb. The researchers also found that the rate at which microbial profiles develop can be used to predict body fat levels in an infant at 18 months, and so may be useful for predicting the risk of obesity later in life. The use of microbial populations to predict potential problems for a child could eventually be used to allow appropriate intervention. This explains the significant involvement of infant food producers in collaborating with and funding this A*STAR research.

Epigenetic biomarkers

Holbrook’s main focus of research, however, is at the deeper and more molecular level of ‘epigenetics’ — chemical modifications of DNA that can be influenced by the environment. It turns out that epigenetic modifications can be affected by the specific metabolic, nutritional and even emotional circumstances of an infant and its mother. One of the most important epigenetic changes is the acquisition of methyl (CH₃) chemical groups by specific parts of the DNA double helix.

The deep genetic analysis that is part of GUSTO has allowed Holbrook’s team to identify differences in the pattern of this ‘methylation’ process in infants and to correlate the differences with specific environmental influences. They found that up to 75 per cent of the variability in the methylation patterns of individuals can best be explained by the interaction of environmental factors (including the birth weight, gestational age and birth order of the infant and maternal smoking, depression and body mass index) with the infant’s genotype. That maternal depression can alter the modification of a child’s DNA indicates a profound interaction between one person’s mental health and another’s physical make-up and possible future health.

While the work mainly focused on identifying and classifying epigenetic variations and what they are correlated with, Holbrook explains that its ultimate aim is to offer practical clinical assistance. “We are trying to develop the DNA methylation patterns as biomarkers that will give us more sensitive and earlier indications that a child is at risk of developing problems,” says Holbrook. “This would allow appropriate intervention at an earlier stage.”

Nutrition for nurture

Chong is also using the GUSTO study to uncover interesting links between nutrition and emotional states, including depression and anxiety. Women participating in the GUSTO study were assessed for depression by questionnaire both during pregnancy and after giving birth. Their responses were then matched against measurements of plasma levels of folate (vitamin B9) and vitamin B12 during pregnancy. Low folate levels were found to be associated with depression during pregnancy, but not with post-natal depression. No association was found between depression and vitamin B12.

In a study due to be published in mid-2015, Chong and co-workers also discovered that low omega-3 fatty acid levels during pregnancy are associated with higher anxiety levels in mothers. Chong points out that the results do not currently indicate the ‘direction of causation’ in these nutritional correlations. “Are the women anxious because of low levels of omega-3 fatty acids, for example, or is their anxiety causing them to neglect their diet and not take their supplements?” Chong asks. This issue will be addressed by the Singapore Preconception Study of Long-term Maternal and Child Outcomes (S-PRESTO), beginning in early 2015, which will include assessment of women before they become pregnant. “S-PRESTO will really help us to identify the direction of association between nutritional and emotional states, and other problems, and to plan the most suitable interventions,” says Chong.

Both Holbrook and Chong report significant benefits in working at the A*STAR SICS Institute and collaborating with GUSTO to advance this crucial area of research. Chong comments that as the first such study in Asia, GUSTO offers a unique opportunity to fill gaps in our knowledge about the local influences on infant development. Holbrook says that a great advantage of working at SICS is its close interaction between clinicians and academic researchers, which was one of the key incentives for her moving to SICS from previous positions in Europe and the United States.

About the A*STAR Singapore Institute for Clinical Sciences

The Singapore Institute for Clinical Sciences (SICS) was established in 2007 within the Agency for Science, Technology and Research (A*STAR). As A*STAR’s key initiative to develop world-class clinical sciences programs, SICS seeks to build better lives for the future through their firm scientific understanding of existing, emerging and potential healthcare challenges all across Asia’s dynamic landscape. SICS distinguishes itself through a focus on clinical sciences and the use of innovative approaches and technologies, enabling efficient and effective study of human health and diseases. Research by their clinical scientists span the full ‘bench to bedside’ spectrum of activities in metabolic diseases, (including obesity, diabetes and insulin resistance), pathways to normal growth and development (cognitive development, behavioral and clinical psychology among others), as well as nutritional sciences (functional food studies, satiety regulation, sensory and taste perception).

About the GUSTO study

The GUSTO study is a collaborative effort between the National University Health System (NUHS), KK Women’s and Children’s Hospital (KKH), and A*STAR’s SICS. This research is supported by the Singapore National Research Foundation (NRF) under its Translational and Clinical Research (TCR) Flagship Programme and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC).