systems biology

Systems Biology of Early Atopy: Role of Human Milk (SunBEAm-Milk)

Surprisingly little is known about the effect of breastfeeding (BF) on infant immune system development besides an effect on the gut microbiome, but its impact on metabolites and Tregs could support protection against food allergy (FA). BF is currently recommended to prevent the development of allergic diseases, especially asthma/recurrent wheezing and AD in early childhood, but firm conclusions could not be drawn regarding FA due to high heterogeneity and low quality of studies. Reverse causation, recall bias and the poor accuracy of outcome assessment are significant limitations. Most are inadequately powered to specific FA; however, a recent study showed that exclusively BF infants had lower odds of egg, sesame, and peanut allergies. Importantly, immunomodulatory composition of HM varies between mothers, which has not been taken into consideration. For over two decades we have been developing methods to assess immunomodulatory factors in the complex matrix of HM and their association with infant FA. We have shown that high levels of HM total and specific IgA are associated with protection against cow’s milk allergy, but it is unclear whether HM IgA is responsible for or is a biomarker of the vertical transfer of protection. Infant fecal and systemic IgA levels during breastfeeding and after weaning are also elevated in infants at low risk for atopic disease raising the question of whether HM factors such as cytokines can promote IgA production in infants. Consistent with this, we showed that HM cytokines, such as APRIL, induce IgA production in naïve infant B cells, and infants receiving HM with higher levels of APRIL had lower incidence of allergic disease. Finally, lower levels of several HM fatty acids including short-chain fatty acids and DHA were associated with FA. While some these factors were are associated with maternal atopic disease, several of them are not and suggest a role for diet instead. The System Biology of Early Atopy (SunBEAm) population-based cohort of 2500 mother-infant pairs is >50% recruited and provides an unprecedented opportunity to assess association of HM feeding and immune factors in HM with development of infant immune system and FA/AD. The Common Sample comprises a subset of 100 dyads with FA, 100 with FA+AD, 100 with AD, 100 with no FA or AD and more extensively profiled biological data. Utilizing all 2-month HM samples available in the Common Sample, we will assess levels of immune factors in HM and their association with maternal/infant characteristics (Aim 1). Utilizing data from the whole cohort, we will assess the association between HM vs formula feeding on well-defined FA/AD further adjusted based on high vs low levels of HM immune components in the Common Sample (Aim 2b). Finally, we will examine the immune cell and epithelial effects of HM on infant immune markers and intestinal organoids (Aim 3). Key findings will be validated in an independent birth cohort. The ultimate goal is to uncover protective properties of BF and HM in FA and subsequent design of policies and prevention strategies to address the increasing rates of FA.

Towards Human Systems Biology of Sleep/Wake Cycles: Phosphorylation Hypothesis of Sleep

The field of human biology faces three major technological challenges. Firstly, the causation problem is difficult to address in humans compared to model animals. Secondly, the complexity problem arises due to the lack of a comprehensive cell atlas for the human body, despite its cellular composition. Lastly, the heterogeneity problem arises from significant variations in both genetic and environmental factors among individuals. To tackle these challenges, we have developed innovative approaches. These include 1) mammalian next-generation genetics, such as Triple CRISPR for knockout (KO) mice and ES mice for knock-in (KI) mice, which enables causation studies without traditional breeding methods; 2) whole-body/brain cell profiling techniques, such as CUBIC, to unravel the complexity of cellular composition; and 3) accurate and user-friendly technologies for measuring sleep and awake states, exemplified by ACCEL, to facilitate the monitoring of fundamental brain states in real-world settings and thus address heterogeneity in human.

Feedback control in the nervous system: from cells and circuits to behaviour

The nervous system is fundamentally a closed loop control device: the output of actions continually influences the internal state and subsequent actions. This is true at the single cell and even the molecular level, where “actions” take the form of signals that are fed back to achieve a variety of functions, including homeostasis, excitability and various kinds of multistability that allow switching and storage of memory. It is also true at the behavioural level, where an animal’s motor actions directly influence sensory input on short timescales, and higher level information about goals and intended actions are continually updated on the basis of current and past actions. Studying the brain in a closed loop setting requires a multidisciplinary approach, leveraging engineering and theory as well as advances in measuring and manipulating the nervous system. I will describe our recent attempts to achieve this fusion of approaches at multiple levels in the nervous system, from synaptic signalling to closed loop brain machine interfaces.

A Systems Biology Methodology to Drug Discovery for Neurotropic virus Infection with Clinical Corroboration

From systems biology to drug targets: ATP synthase subunit upregulation causes mitochondrial dysfunction in Shank3Δ4-22 mouse model of autism

FENS Forum 2024