Medical Biology - Research Publications
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ItemArtificial intelligence takes center stage: exploring the capabilities and implications of ChatGPT and other AI-assisted technologies in scientific research and education(WILEY, 2023-11)The emergence of large language models (LLMs) and assisted artificial intelligence (AI) technologies have revolutionized the way in which we interact with technology. A recent symposium at the Walter and Eliza Hall Institute explored the current practical applications of LLMs in medical research and canvassed the emerging ethical, legal and social implications for the use of AI-assisted technologies in the sciences. This paper provides an overview of the symposium's key themes and discussions delivered by diverse speakers, including early career researchers, group leaders, educators and policy-makers highlighting the opportunities and challenges that lie ahead for scientific researchers and educators as we continue to explore the potential of this cutting-edge and emerging technology.
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ItemMaternal gut microbiota during pregnancy and the composition of immune cells in infancy(FRONTIERS MEDIA SA, 2022-09-21)BACKGROUND: Preclinical studies have shown that maternal gut microbiota during pregnancy play a key role in prenatal immune development but the relevance of these findings to humans is unknown. The aim of this prebirth cohort study was to investigate the association between the maternal gut microbiota in pregnancy and the composition of the infant's cord and peripheral blood immune cells over the first year of life. METHODS: The Barwon Infant Study cohort (n=1074 infants) was recruited using an unselected sampling frame. Maternal fecal samples were collected at 36 weeks of pregnancy and flow cytometry was conducted on cord/peripheral blood collected at birth, 6 and 12 months of age. Among a randomly selected sub-cohort with available samples (n=293), maternal gut microbiota was characterized by sequencing the 16S rRNA V4 region. Operational taxonomic units (OTUs) were clustered based on their abundance. Associations between maternal fecal microbiota clusters and infant granulocyte, monocyte and lymphocyte subsets were explored using compositional data analysis. Partial least squares (PLS) and regression models were used to investigate the relationships/associations between environmental, maternal and infant factors, and OTU clusters. RESULTS: We identified six clusters of co-occurring OTUs. The first two components in the PLS regression explained 39% and 33% of the covariance between the maternal prenatal OTU clusters and immune cell populations in offspring at birth. A cluster in which Dialister, Escherichia, and Ruminococcus were predominant was associated with a lower proportion of granulocytes (p=0.002), and higher proportions of both central naïve CD4+ T cells (CD4+/CD45RA+/CD31-) (p<0.001) and naïve regulatory T cells (Treg) (CD4+/CD45RA+/FoxP3low) (p=0.02) in cord blood. The association with central naïve CD4+ T cells persisted to 12 months of age. CONCLUSION: This birth cohort study provides evidence consistent with past preclinical models that the maternal gut microbiota during pregnancy plays a role in shaping the composition of innate and adaptive elements of the infant's immune system following birth.
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ItemWeight Gain in Early Life Predicts Risk of Islet Autoimmuity in Children With a First-Degree Relative With Type 1 Diabetes(AMER DIABETES ASSOC, 2009-01)OBJECTIVE: In a prospective birth cohort study, we followed infants who had a first-degree relative with type 1 diabetes to investigate the relationship between early growth and infant feeding and the risk of islet autoimmunity. RESEARCH DESIGN AND METHODS: Infants with a first-degree relative with type 1 diabetes were identified during their mother's pregnancy. Dietary intake was recorded prospectively to determine duration of breast-feeding and age at introduction of cow's milk protein, cereals, meat, fruit, and vegetables. At 6-month reviews, length (or height) and weight, antibodies to insulin, GAD65, the tyrosine phosphatase-like insulinoma antigen, and tissue transglutaminase were measured. Islet autoimmunity was defined as persistent elevation of one or more islet antibodies at consecutive 6-month intervals, including the most recent measure, and was the primary outcome measure. RESULTS: Follow-up of 548 subjects for 5.7 +/- 3.2 years identified 46 children with islet autoimmunity. Weight z score and BMI z score were continuous predictors of risk of islet autoimmunity (adjusted hazard ratios 1.43 [95% CI 1.10-1.84], P = 0.007, and 1.29 [1.01-1.67], P = 0.04, respectively). The risk of islet autoimmunity was greater in subjects with weight z score >0 than in those with weight z score < or =0 over time (2.61 [1.26-5.44], P = 0.01). Weight z score and BMI z score at 2 years and change in weight z score between birth and 2 years, but not dietary intake, also predicted risk of islet autoimmunity. CONCLUSIONS: Weight gain in early life predicts risk of islet autoimmunity in children with a first-degree relative with type 1 diabetes.
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ItemFunctional Analysis of Mmd2 and Related PAQR Genes During Sex Determination in Mice.(S. Karger AG, 2022)INTRODUCTION: Sex determination in eutherian mammals is controlled by the Y-linked gene Sry, which drives the formation of testes in male embryos. Despite extensive study, the genetic steps linking Sry action and male sex determination remain largely unknown. Here, we focused on Mmd2, a gene that encodes a member of the progestin and adipoQ receptor (PAQR) family. Mmd2 is expressed during the sex-determining period in XY but not XX gonads, suggesting a specific role in testis development. METHODS: We used CRISPR to generate mouse strains deficient in Mmd2 and its 2 closely related PAQR family members, Mmd and Paqr8, which are also expressed during testis development. Following characterization of Mmd2 expression in the developing testis, we studied sex determination in embryos from single knockout as well as Mmd2;Mmd and Mmd2;Paqr8 double knockout lines using quantitative RT-PCR and immunofluorescence. RESULTS: Analysis of knockout mice deficient in Sox9 and Nr5a1 revealed that Mmd2 operates downstream of these known sex-determining genes. However, fetal testis development progressed normally in Mmd2-null embryos. To determine if other genes might have compensated for the loss of Mmd2, we analyzed Paqr8 and Mmd-null embryos and confirmed that in both knockout lines, sex determination occurred normally. Finally, we generated Mmd2;Mmd and Mmd2;Paqr8 double-null embryos and again observed normal testis development. DISCUSSION: These results may reflect functional redundancy among PAQR factors, or their dispensability in gonadal development. Our findings highlight the difficulties involved in identifying genes with a functional role in sex determination and gonadal development through expression screening and loss-of-function analyses of individual candidate genes and may help to explain the paucity of genes in which variations have been found to cause human disorders/differences of sex development.
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ItemMetabolite-based dietary supplementation in human type 1 diabetes is associated with microbiota and immune modulation(BMC, 2022-01-19)BACKGROUND: Short-chain fatty acids (SCFAs) produced by the gut microbiota have beneficial anti-inflammatory and gut homeostasis effects and prevent type 1 diabetes (T1D) in mice. Reduced SCFA production indicates a loss of beneficial bacteria, commonly associated with chronic autoimmune and inflammatory diseases, including T1D and type 2 diabetes. Here, we addressed whether a metabolite-based dietary supplement has an impact on humans with T1D. We conducted a single-arm pilot-and-feasibility trial with high-amylose maize-resistant starch modified with acetate and butyrate (HAMSAB) to assess safety, while monitoring changes in the gut microbiota in alignment with modulation of the immune system status. RESULTS: HAMSAB supplement was administered for 6 weeks with follow-up at 12 weeks in adults with long-standing T1D. Increased concentrations of SCFA acetate, propionate, and butyrate in stools and plasma were in concert with a shift in the composition and function of the gut microbiota. While glucose control and insulin requirements did not change, subjects with the highest SCFA concentrations exhibited the best glycemic control. Bifidobacterium longum, Bifidobacterium adolescentis, and vitamin B7 production correlated with lower HbA1c and basal insulin requirements. Circulating B and T cells developed a more regulatory phenotype post-intervention. CONCLUSION: Changes in gut microbiota composition, function, and immune profile following 6 weeks of HAMSAB supplementation were associated with increased SCFAs in stools and plasma. The persistence of these effects suggests that targeting dietary SCFAs may be a mechanism to alter immune profiles, promote immune tolerance, and improve glycemic control for the treatment of T1D. TRIAL REGISTRATION: ACTRN12618001391268. Registered 20 August 2018, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375792 Video Abstract.
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ItemWomen with type 1 diabetes exhibit a progressive increase in gut Saccharomyces cerevisiae in pregnancy associated with evidence of gut inflammation(ELSEVIER IRELAND LTD, 2022-02)AIMS: Studies of the gut microbiome have focused on its bacterial composition. We aimed to characterize the gut fungal microbiome (mycobiome) across pregnancy in women with and without type 1 diabetes. METHODS: Faecal samples (n = 162) were collected from 70 pregnant women (45 with and 25 without type 1 diabetes) across all trimesters. Fungi were analysed by internal transcribed spacer 1 amplicon sequencing. Markers of intestinal inflammation (faecal calprotectin) and intestinal epithelial integrity (serum intestinal fatty acid binding protein; I-FABP), and serum antibodies to Saccharomyces cerevisiae (ASCA) were measured. RESULTS: Women with type 1 diabetes had decreased fungal alpha diversity by the third trimester, associated with an increased abundance of Saccharomyces cerevisiae that was inversely related to the abundance of the anti-inflammatory butyrate-producing bacterium Faecalibacterium prausnitzii. Women with type 1 diabetes had higher concentrations of calprotectin, I-FABP and ASCA. CONCLUSIONS: Women with type 1 diabetes exhibit a shift in the gut mycobiome across pregnancy associated with evidence of gut inflammation and impaired intestinal barrier function. The relevance of these findings to the higher rate of pregnancy complications in type 1 diabetes warrants further study.
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ItemType 1 diabetes: a disease of developmental origins(WILEY-HINDAWI, 2017-09)The incidence of type 1 diabetes globally has increased dramatically over the last 50 years. Proposed environmental reasons for this increase mirror the modern lifestyle. Type 1 diabetes can be viewed as part of the non- communicable disease epidemic in our modern society. Meanwhile rapidly evolving new technologies are advancing our understanding of how human microbial communities interface with the immune system and metabolism, and how the modern pro-inflammatory environment is changing these communities and contributing to the rapid rise of non-communicable disease. The majority of children who present with clinical type 1 diabetes are of school age; however 80% of children who develop type 1 diabetes by 18 years of age will have detectable islet autoantibodies by 3 years of age. The evolving concept that type 1 diabetes in many children has developmental origins has directed research questions in search of prevention back to pregnancy and early life. To this end the world's first pregnancy to early childhood cohort study in at-risk children has commenced.
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ItemThe dark side of insulin: A primary autoantigen and instrument of self-destruction in type 1 diabetes(ELSEVIER, 2021-10)BACKGROUND: Since its discovery 100 years ago, insulin, as the 'cure' for type 1 diabetes, has rescued the lives of countless individuals. As the century unfolded and the autoimmune nature of type 1 diabetes was recognised, a darker side of insulin emerged. Autoimmunity to insulin was found to be an early marker of risk for type 1 diabetes in young children. In humans, it remains unclear if autoimmunity to insulin is primarily due to a defect in the beta cell itself or to dysregulated immune activation. Conversely, it may be secondary to beta-cell damage from an environmental agent (e.g., virus). Nevertheless, direct, interventional studies in non-obese diabetic (NOD) mouse models of type 1 diabetes point to a critical role for (pro)insulin as a primary autoantigen that drives beta cell pathology. SCOPE OF REVIEW: Modelled on Koch's postulates for the pathogenicity of an infectious agent, evidence for a pathogenic role of (pro)insulin as an autoantigen in type 1 diabetes, particularly applicable to the NOD mouse model, is reviewed. Evidence in humans remains circumstantial. Additionally, as (pro)insulin is a target of autoimmunity in type 1 diabetes, its application as a therapeutic tool to elicit antigen-specific immune tolerance is assessed. MAJOR CONCLUSIONS: Paradoxically, insulin is both a 'cure' and a potential 'cause' of type 1 diabetes, actively participating as an autoantigen to drive autoimmune destruction of beta cells - the instrument of its own destruction.
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ItemSimplifying prediction of disease progression in pre-symptomatic type 1 diabetes using a single blood sample(SPRINGER, 2021-11)AIMS/HYPOTHESIS: Accurate prediction of disease progression in individuals with pre-symptomatic type 1 diabetes has potential to prevent ketoacidosis and accelerate development of disease-modifying therapies. Current tools for predicting risk require multiple blood samples taken during an OGTT. Our aim was to develop and validate a simpler tool based on a single blood draw. METHODS: Models to predict disease progression using a single OGTT time point (0, 30, 60, 90 or 120 min) were developed using TrialNet data collected from relatives with type 1 diabetes and validated in independent populations at high genetic risk of type 1 diabetes (TrialNet, Diabetes Prevention Trial-Type 1, The Environmental Determinants of Diabetes in the Young [1]) and in a general population of Bavarian children who participated in Fr1da. RESULTS: Cox proportional hazards models combining plasma glucose, C-peptide, sex, age, BMI, HbA1c and insulinoma antigen-2 autoantibody status predicted disease progression in all populations. In TrialNet, the AUC for receiver operating characteristic curves for models named M60, M90 and M120, based on sampling at 60, 90 and 120 min, was 0.760, 0.761 and 0.745, respectively. These were not significantly different from the AUC of 0.760 for the gold standard Diabetes Prevention Trial Risk Score, which requires five OGTT blood samples. In TEDDY, where only 120 min blood sampling had been performed, the M120 AUC was 0.865. In Fr1da, the M120 AUC of 0.742 was significantly greater than the M60 AUC of 0.615. CONCLUSIONS/INTERPRETATION: Prediction models based on a single OGTT blood draw accurately predict disease progression from stage 1 or 2 to stage 3 type 1 diabetes. The operational simplicity of M120, its validity across different at-risk populations and the requirement for 120 min sampling to stage type 1 diabetes suggest M120 could be readily applied to decrease the cost and complexity of risk stratification.
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ItemType 1 diabetes in pregnancy is associated with distinct changes in the composition and function of the gut microbiome(BMC, 2021-08-06)BACKGROUND: The gut microbiome changes in response to a range of environmental conditions, life events and disease states. Pregnancy is a natural life event that involves major physiological adaptation yet studies of the microbiome in pregnancy are limited and their findings inconsistent. Pregnancy with type 1 diabetes (T1D) is associated with increased maternal and fetal risks but the gut microbiome in this context has not been characterized. By whole metagenome sequencing (WMS), we defined the taxonomic composition and function of the gut bacterial microbiome across 70 pregnancies, 36 in women with T1D. RESULTS: Women with and without T1D exhibited compositional and functional changes in the gut microbiome across pregnancy. Profiles in women with T1D were distinct, with an increase in bacteria that produce lipopolysaccharides and a decrease in those that produce short-chain fatty acids, especially in the third trimester. In addition, women with T1D had elevated concentrations of fecal calprotectin, a marker of intestinal inflammation, and serum intestinal fatty acid-binding protein (I-FABP), a marker of intestinal epithelial damage. CONCLUSIONS: Women with T1D exhibit a shift towards a more pro-inflammatory gut microbiome during pregnancy, associated with evidence of intestinal inflammation. These changes could contribute to the increased risk of pregnancy complications in women with T1D and are potentially modifiable by dietary means. Video abstract.
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