Periodic Reporting for period 4 - NASCENT (Novel Approach to Systematically Characterize Exercise- and Nutrient- responsive genes in Type 2 diabetes and cardiovascular disease)
Reporting period: 2021-08-01 to 2024-01-31
Type 2 diabetes and cardiovascular disease are serious and increasingly common health problems globally, demanding urgent attention for better prevention and treatment methods. Lifestyle interventions have proven to be an effective way to prevent these diseases, surpassing the effectiveness of some medications, while being cost-efficient, safe, and of broad benefit. However, due to the complexity of human biology, not everyone responds in the same way to such interventions. This presents an important opportunity to personalize prevention and treatment approaches, based on individuals’ unique biological and behavioural characteristics.
The NASCENT project thus began with the aim of investigating how environmental factors and genes interacted with each other to gain greater understanding as to why there was such a wide range of individual responses to treatment and interventions. Through innovative techniques that turn off and on specific genes, we could deepen our understanding of such gene-environment interactions. The NASCENT project focused on integrating genetic and molecular epidemiology, machine learning, innovative clinical trial design, and functional genomics. This integrative programme of research afforded a rare opportunity to provide multiple orthogonal lines of evidence addressing key hypotheses. For example, some of the research in epidemiological studies and clinical trials conducted by our team implicated genes like PPARGC1A as a modifier of the effects of lifestyle on body adiposity and blood glucose and fat levels. Using a novel CRISPR-based approach, we were able to further define the functional basis to these interactions.
The rapid emergence of the SARS-Cov2 virus in late 2019, led me to redirect our efforts towards COVID-19 research. I worked with collaborators in Sweden and the UK to establish the COVID Symptom Study in Sweden; we enrolled 200,000 participants, generating valuable data on COVID-19 incidence and symptoms. By repurposing an app originally designed for tracking daily eating habits (used in one of our earlier ERC projects) to capture self-reported COVID symptoms, we collected data from the UK, US, and Sweden, aiding global public health efforts.
Despite its origins as a research project, the COVID Symptom Study played a crucial role in providing public health leaders with essential epidemiological data during the rapidly evolving pandemic. Our early findings, such as identifying loss of taste and smell as prominent COVID-19 symptoms, significantly contributed to understanding and managing the disease. We also investigated the impact of COVID-19 on specific populations, including healthcare workers, individuals with cancer, and those with diabetes and obesity.
Although the NASCENT project redirected to address the COVID-19 pandemic, and later paused due to the lead investigator's 24-month sabbatical, the work conducted has had a major global impact on precision medicine. This is perhaps most clearly illustrated in the International Consensus Report on Precision Diabetes Medicine (Nature Medicine, 2023), which was chaired by NASCENT’s lead investigator.
The NASCENT project thus began with the aim of investigating how environmental factors and genes interacted with each other to gain greater understanding as to why there was such a wide range of individual responses to treatment and interventions. Through innovative techniques that turn off and on specific genes, we could deepen our understanding of such gene-environment interactions. The NASCENT project focused on integrating genetic and molecular epidemiology, machine learning, innovative clinical trial design, and functional genomics. This integrative programme of research afforded a rare opportunity to provide multiple orthogonal lines of evidence addressing key hypotheses. For example, some of the research in epidemiological studies and clinical trials conducted by our team implicated genes like PPARGC1A as a modifier of the effects of lifestyle on body adiposity and blood glucose and fat levels. Using a novel CRISPR-based approach, we were able to further define the functional basis to these interactions.
The rapid emergence of the SARS-Cov2 virus in late 2019, led me to redirect our efforts towards COVID-19 research. I worked with collaborators in Sweden and the UK to establish the COVID Symptom Study in Sweden; we enrolled 200,000 participants, generating valuable data on COVID-19 incidence and symptoms. By repurposing an app originally designed for tracking daily eating habits (used in one of our earlier ERC projects) to capture self-reported COVID symptoms, we collected data from the UK, US, and Sweden, aiding global public health efforts.
Despite its origins as a research project, the COVID Symptom Study played a crucial role in providing public health leaders with essential epidemiological data during the rapidly evolving pandemic. Our early findings, such as identifying loss of taste and smell as prominent COVID-19 symptoms, significantly contributed to understanding and managing the disease. We also investigated the impact of COVID-19 on specific populations, including healthcare workers, individuals with cancer, and those with diabetes and obesity.
Although the NASCENT project redirected to address the COVID-19 pandemic, and later paused due to the lead investigator's 24-month sabbatical, the work conducted has had a major global impact on precision medicine. This is perhaps most clearly illustrated in the International Consensus Report on Precision Diabetes Medicine (Nature Medicine, 2023), which was chaired by NASCENT’s lead investigator.
One significant measure of the output from our research project is the number of peer-reviewed publications in high-impact scientific journals, such as Nature, Nature Medicine and The Lancet Diabetes & Endocrinology. Through this project, we have produced 60 such publications, all of which are freely accessible online.
Additionally, our project’s findings were disseminated at major international conferences. Our PhD students and postdoctoral researchers, funded by the ERC, had the opportunity to present their results at prestigious annual meetings, including the European Association for the Study of Diabetes (EASD) in Stockholm, Sweden (post-COVID), and the American Society for Human Genetics in Washington, D.C. USA.
The work undertaken on Covid-19, supported by the ERC, attracted a great deal of public attention. A four-part series of lay-language articles overviewing Sweden’s public health strategy, written by the principal investigator (Franks), were published in The Conversation. These articles were read ~3 million times. Franks undertook many media interviews discussing Covid-19 epidemiology for TV (e.g. Sky News, CNN, BBC), Radio (BBC, Radio Sweden), and newspapers (e.g. The Independent, Financial Times, The Times, The Daily Mail, Expressen, Aftonbladet). In May 2020, Franks participated in a panel debate for the Financial Times Global Boardroom with Dr. Soumya Swaminathan (Chief Scientist, WHO) and Dr. Peter Piot (Director, London School of Hygiene and Tropical Medicine). Other panellists included French president Francois Macon and former British prime minister Tony Blair.
Another measure of a project’s success is the number of PhD students successfully defended their ERC-funded work. In this case, we saw six PhD students graduate during the duration of the NASCENT project.
Additionally, our project’s findings were disseminated at major international conferences. Our PhD students and postdoctoral researchers, funded by the ERC, had the opportunity to present their results at prestigious annual meetings, including the European Association for the Study of Diabetes (EASD) in Stockholm, Sweden (post-COVID), and the American Society for Human Genetics in Washington, D.C. USA.
The work undertaken on Covid-19, supported by the ERC, attracted a great deal of public attention. A four-part series of lay-language articles overviewing Sweden’s public health strategy, written by the principal investigator (Franks), were published in The Conversation. These articles were read ~3 million times. Franks undertook many media interviews discussing Covid-19 epidemiology for TV (e.g. Sky News, CNN, BBC), Radio (BBC, Radio Sweden), and newspapers (e.g. The Independent, Financial Times, The Times, The Daily Mail, Expressen, Aftonbladet). In May 2020, Franks participated in a panel debate for the Financial Times Global Boardroom with Dr. Soumya Swaminathan (Chief Scientist, WHO) and Dr. Peter Piot (Director, London School of Hygiene and Tropical Medicine). Other panellists included French president Francois Macon and former British prime minister Tony Blair.
Another measure of a project’s success is the number of PhD students successfully defended their ERC-funded work. In this case, we saw six PhD students graduate during the duration of the NASCENT project.
The second phase of the project focused on functional studies using gene editing technologies and other cutting-edge cell biology methods to study the basis of gene-environment interactions in vitro. Several subprojects have been running in parallel. These included:
MATE1: Analysis of interactions between metformin and MATE1 variants in glucose metabolism. In summary, this suggests a functional role of a genetic variant in MATE1 expression, and thus in metformin retention in hepatocytes, which might explain and predict an improved metformin response in individuals with certain genotypes.
RAB3GAP2: Through a GWAS of muscle fibre phenotypes, we identified variants in RAB3GAP2 that appear to affect capillary density and coagulation. The study is of high relevance for the exercise-induced effect in muscle capillary formation and risk of thrombosis.
Using white and brown human adipose cells, we undertook CRISPR/Cas9 experiments involving allele-specific editing of target variants in PPARGC1A (Huang et al. Diabetologia, 2023), PPARGC1B (Huang et al. Diabetes, 2024), and MTIF3(Huang et al. EIife, 2023). Wild type vs. variant allele cell lines were exposed to a range of pharmacueticals and lifestyle mimetics to test gene-exposure interactions. These experiments provide novel functional evidence for each variant in a range of obesity-related basal and treatment-response phenotypes, and elucidate mechanistic pathways through which these genes regulate energy metabolism.
The third and final phase of NASCENT focused on performing new clinical trials. A major trial supported by NASCENT was the PREDICT trial. In this trial, we provided specific meals to 1,100 adults and monitored their blood sugar, cholesterol, and insulin levels after eating, both at the clinic and at home over two weeks. Our aim was to identify the factors influencing how our bodies process food after eating, with the goal of making personalized diet recommendations. The trial, aligned with NASCENT’s objectives, was performed through a public-private partnership (with Zoe Global Ltd).
MATE1: Analysis of interactions between metformin and MATE1 variants in glucose metabolism. In summary, this suggests a functional role of a genetic variant in MATE1 expression, and thus in metformin retention in hepatocytes, which might explain and predict an improved metformin response in individuals with certain genotypes.
RAB3GAP2: Through a GWAS of muscle fibre phenotypes, we identified variants in RAB3GAP2 that appear to affect capillary density and coagulation. The study is of high relevance for the exercise-induced effect in muscle capillary formation and risk of thrombosis.
Using white and brown human adipose cells, we undertook CRISPR/Cas9 experiments involving allele-specific editing of target variants in PPARGC1A (Huang et al. Diabetologia, 2023), PPARGC1B (Huang et al. Diabetes, 2024), and MTIF3(Huang et al. EIife, 2023). Wild type vs. variant allele cell lines were exposed to a range of pharmacueticals and lifestyle mimetics to test gene-exposure interactions. These experiments provide novel functional evidence for each variant in a range of obesity-related basal and treatment-response phenotypes, and elucidate mechanistic pathways through which these genes regulate energy metabolism.
The third and final phase of NASCENT focused on performing new clinical trials. A major trial supported by NASCENT was the PREDICT trial. In this trial, we provided specific meals to 1,100 adults and monitored their blood sugar, cholesterol, and insulin levels after eating, both at the clinic and at home over two weeks. Our aim was to identify the factors influencing how our bodies process food after eating, with the goal of making personalized diet recommendations. The trial, aligned with NASCENT’s objectives, was performed through a public-private partnership (with Zoe Global Ltd).