Joëlle Rüegg is a professor in environmental toxicology at Uppsala University, Sweden, and coordinator of Re-MEND. Her research focuses on endocrine disruptors and their impact on brain function and development. Prof. Rüegg is driven by working on issues that have a major societal impact. She is hopeful that Re-MEND will be able to unveil critical factors that influence a person’s mental health and their susceptibility to illness.
What is the main aim of Re-MEND?
“Healthcare today is largely focused on treating symptoms, not preventing them. So Re-MEND takes a different approach. We are interested in what makes mental illness happen and how to prevent that. “ Prof. Rüegg explains.
“The main aim of our research is to better understand how genes and environment interact and how that is manifested in an individual's psychological well-being. Society needs to become better at prevention. We need to advance our knowledge on mental health and illness, especially understanding the underlying biological factors,” she says.
What are critical life stages?
“There are few stages in life that are more sensitive than others. This includes periods when hormone signalling is particularly active. In RE-MEND, mental health is studied in relation to four life stages: early life, puberty, the period around childbirth and ageing. These sensitive life stages can lay the foundations for developing or not developing mental illness later in life. Some individuals are more vulnerable and susceptible to mental illness than others. We aim to get a better understanding of why that is so and also learn how to increase resilience, as this is a complex picture,” adds Prof. Rüegg.
How do you study this?
“Re-MEND integrates data from large population-based studies and experimental studies. There simply does not exist a population study that covers a whole life course. Hence, we combine several different studies to analyse all four life stages and try to identify key environmental factors that influence brain development and function, such as stress, food/diet and chemicals that we are exposed to. This is translated then into an experimental design as the project includes also many experimental studies. To research behavioural effects, the research team will conduct experiments on mice whereas with the help of brain organoids, i.e. cell models that mimic brain development in 3D, it is possible to study factors that influence vulnerability and resilience in early development. The project also incorporates machine learning and artificial intelligence to integrate and exploit the vast amount of data,” she explains.
How about reducing stigma around mental illnesses?
“One way to reduce stigma is understanding better underlying biological explanations and how we also communicate about these explanations as well as in general about mental health and illness. One of the focus areas in Re-MEND is the communication sciences to study effective ways of communication as well as engage with stakeholders and patients to understand multiple perspectives and perceptions on the issue,” Prof. Rüegg says.
“I believe collaboration is the key, across disciplines and across different actors in society, as mental health is affected by a variety of factors, and we need to work together to reverse the current development of rising mental health problems,” she summarises.
Philipp Antczak is a computational biologist at the University Hospital Cologne and Vice Coordinator of RE-MEND. Since early childhood he was interested in biology as well as computer science and thus, decided to study and specialise in bioinformatics. Scientifically he is interested in the application and development of computational techniques to answer biological questions of various kinds, and he has developed a key expertise in data integration and cross species analysis.
Could you tell us about the intersection between mental health and computational biology and how it is being explored in your research in Re-MEND?
“The intersection between mental health and computational biology is quite an interesting one. Usually science works with hard endpoints such as death or diseases that are very different to healthy individuals like cancers or infections. Mental health is different as I consider it more of a soft endpoint, so an endpoint where there is a large amount of variation and, to some extent, may have an aspect of individual subjectivity. Analysing the molecular data from such individuals is therefore a challenge and extremely interesting as we still know very little about these disorders,” Dr. Antczak explains.
How do you collaborate with other disciplines or address the interdisciplinary aspects in your work in Re-MEND?
“All of my work tends to be interdisciplinary as it really depicts how my daily work looks like. I like to take the approach that I first look at the data in depth and then use the knowledge that I have gathered to interact with experts and experimentalists for the specific dataset or question. I find that this enables me to better provide interpretations and answers and fosters a much easier discussion between the different partners within the project. With my background I can also cultivate some discussion around the experimental work and try to optimise the project as a whole,” he adds.
What are the biggest challenges in applying computational biology to the study of mental health, and how are you solving them in your work?
“As I mentioned earlier, I consider mental health more of a soft endpoint which comes with its own challenges on the computational side. Soft endpoints usually require a very large amounts of data, because the variation that we are trying to identify is quite small and to get significance one needs larger data sizes. Of course, with larger data sizes come challenges with their analysis. For example, when analysing DNA methylation data based on microarray technology we have to process the data altogether to align the data distributions to each other. A standard computer however generally does not come with sufficient memory to be able to load all of this data and normalise it together. In addition to this increased capacity requirement, analysing the data can also take longer as the datasets increase. In our analyses the increase in time is even often exponential and we need to find elegant ways to analyse the large datasets,” Dr. Antczak says.
How does your research contribute to better understanding of mental health disorders and development of new treatments or interventions?
“As we use so called unbiased approaches to characterize the individuals, we often identify genes, regions, or other molecular features that are relevant to the disease or endpoint that we are studying. These identified molecular states can then be used to develop a predictive model, i.e. looking to see whether we can build an early prediction model for example, or to improve stratification of individuals, or even find new subtypes within a disease. The same molecular state can of course be used to identify potential targets that may be targeted using pharmaceuticals. Here we can even make use of large databases that screen the effect of pharmaceuticals and identify potential novel compounds that could be used for treatment. These are of course very preliminary and will require many more tests to ensure that they are effective,” he explains.
How do you envision the future of computational biology in advancing our understanding and better prevention and treatment of mental health disorders?
“I think we can really make a difference in understanding mental health disorders and provide a more objective measure to stratify patients that are unwell. Stratification and treatment success are a key component for medical professionals and being able to provide the right treatment for the right person is not always that easy. With the work that we are doing here, I hope we can make this much simpler and at the same time establish a better understanding of the molecular state of the disease which can foster the development of new treatment strategies,” Dr. Antczak summarises.
Carl-Gustaf Bornehag is an environmental epidemiologist and professor in public health sciences at Department of Health at Karlstad University, Sweden, and adjunct professor at Icahn School of Medicine at Mount Sinai, New York, USA.
His research focuses on early life exposure for environmental risk and resilience factors for children´s health and development. Exposures in focus are endocrine disrupting chemicals (EDCs), food and nutrition, stress and life styles in interaction with genes and epigenetics. He is highly interested in bridging epidemiology with experimental studies in cell and animal models in order to learn more about underlying biological mechanisms.
Could you describe the main objectives of RE-MEND in the field of epidemiology, especially related to the SELMA study?
“We are focusing on the importance of environmental exposures such as endocrine disrupting chemicals (EDCs), stress, nutrition etc. for health and development in early life up to puberty with a general focus on mental illness. We will further examine how the environment may interact with genes in order to identify both risk and a resilience factors. Finally, we will try to identify biological mechanism explaining how the environment is related to mental illness in children. This is done by including epigenetic factors (such as DNA-methylation) that may act as mediators, and by bridging human data in SELMA with experimental studies in in-vitro studies,” Prof. Bornehag explains.
How will the RE-MEND project contribute to our understanding of mental health at population level?
“We have to understand that mental illness among children and adolescents has increased dramatically during the last decade in many countries including the US, Australia, the UK, and Sweden. Recent reports show increasing proportions of Swedish children reporting mental illness and contacting the public psychiatry service (BUP). The proportion increases with age, peaking among 15 to 17-year-olds where around 18 % had at least one BUP contact during 2022. We will in RE-MEND examine the importance of the environment, which is not very much studied, as well as the roles of genes and epigenetics,” he adds.
What specific research methods or approaches are you applying in the project to study the relationship between environmental factors and mental health outcomes?
“One approach, which is based on the fact that we always are exposed to complicated mixtures of environmental chemicals, is to use advanced statistical models in order to examine the importance of mixtures of EDCs rather than single chemicals. Further, we will together with the RE-MEND partner Human Technopol, bridge human SELMA data to in-vitro experiments, by identifying resilient and vulnerable SELMA children to generate brain organoids to identify molecular and cellular of risk and resilience during human neurodevelopment,” Prof. Bornehag explains.
Can you elaborate on any specific environmental factors or exposures that the RE-MEND and SELMA study focus on, and their potential impact on mental health?
“The focus in SELMA has mainly been on endocrine disrupting chemicals. However, we understand more and more that diet/nutrition play an important role when it comes to risk and resilience. Diet/nutrition can play both a beneficial role (good nutrition) but also a risk factor when food items is a source for human intake of dangerous chemicals (e.g., PFAS from fish consumption),” he adds.
In your opinion, what are the main challenges or gaps in current epidemiological research related to mental health from the environmental health perspective, and how does the RE-MEND project address them?
“There is a general gap in the knowledge regarding the role of environmental factors for mental illness where RE-MEND can contribute with important knowledge. Another major shortcoming in environmental epidemiology is that this approach usually don´t focus on biological mechanisms, it is normally a matter of associations between an exposure and an health outcomes. However, in order to develop better risk assessment of hazardous environmental factors we need more information on biological mechanisms. In RE-MEND we are bridging epidemiological and experimental approaches with one focus on epigenetic factors that may increase the knowledge on biological mechanisms,” he explains.
How does the collaboration between researchers from different disciplines enhance the research conducted in the RE-MEND project?
“Collaboration between different disciplines is of the greatest importance for gathering new knowledge, especially when experimental studies can confirm and explain what we find in environmental epidemiology. In RE-MEND, we have a highly interdisciplinary approach to study these issues in an integrated and novel manner,” Prof. Bornehag summarises.
What could be some of the potential implications or applications of the research conducted in the RE-MEND project for public health and mental health policies or interventions in your view?
“Better understanding of the role of the environment for mental illness both from a risk and resilience perspective, a scientific area with major knowledge gaps. Also, increased understanding of biological mechanisms for how the environment impacts mental illness is badly needed,” he adds.
Doreen Reifegerste is a professor in health communication at the School of Public Health at Bielefeld University, Germany. Her research focuses on mental health and health topics in media coverage. Within the RE-MEND projects she and her team want to unveil factors that influence public perceptions and media report about mental illness and their causes in different European countries. She is especially interested in ways to destigmatize people of different genders and ages with depression.
Could you explain the main objectives of your work in the context of the RE-MEND project?
“We are focusing on the mental health literacy among stakeholders and citizens. We will examine how we can inform them understandably about the interactions of environmental and genetic risk factors of mental illnesses. At the same time, we want to make sure that this information does not increase stigmatization of people with mental illnesses but rather increases their social acceptance,” Prof. Reifegerste explains.
What gap in research does RE-MEND aim to address in terms of mental health and communication research?
We already know from other projects and existing research that media content in the news and in social media which reports about the risk factors of mental illnesses can contribute to stigmatization of people with such illnesses. So, for example, we know that there are some reports about the lifestyle being a cause of depression. This attribution of responsibility to an individual can increase stigmatization and blaming of people with depression, while attributions of responsibility to genetic causes often result in reduced blame of patients with depression, but still increase stigmatization and the desire to keep social distance from people with depression.
In contrast, attributing responsibility to the environment, e.g., to stressful circumstances, can reduce stigmatization. However, there is broad agreement among researchers and experts that an interaction of environmental and genetic factors causes depression. So far, we do not know whether news coverage about such an interaction of environmental and genetic risks is understandable for the audience and how it influences stigmatization,” she adds.
Could you describe the interdisciplinary approach taken in the RE-MEND project and how it contributes to better understanding mental health communication?
“We look at the ways the neurologists, biologists, and psychologists in RE-MEND can communicate their results without increasing stigmatization. Thus, our research could not only be understood as a preparation for responsible public relations and of the science communication of the neurological, psychological, medical and biological results of RE-MEND researchers but also beyond.”
What methodologies are being employed within the RE-MEND project to investigate communication and mental health, especially around effective communication strategies?
“Our research is done with multiple methods. By surveys with citizens in different European countries we want to compare the different levels of mental health literacy and stigmatization. With experiments we want to test whether various forms of media reports can contribute to (de-)stigmatization. Then, we also want to find out about effective ways to communicate about mental health in personal conversations with health experts. For this, we use interviews with health personnel and patients of the different populations at higher risk of depression,” explains Doreen Reifegerste.
We are still in the early phases of the project but can you discuss any preliminary findings or insights gained thus far, particularly regarding the impact of communication on mental health perceptions and behaviors?
"From a secondary analysis of a survey on responsibility attributions in Germany and the U.S., we already know that, although responsibility attributions to social contexts were highest in both countries, they were more pronounced in Germany. In contrast, attributions to the individual were higher in the U.S.
From our literature search on stigmatization in European countries, we already learned that stigmatization of mental illnesses varies a lot between them. While it is very high in countries such as Lithuania and Italy, it is rather low in countries such as Germany and Sweden (This is according to a study from 2019 using data from 2005-2006, we now want to research with our survey, whether this is still the case and what are relevant determinants of this stigmatizing attributions)," she summarises.
Are there any specific challenges or opportunities that have emerged during the implementation of the project that you would like to highlight?
“So far, everything runs smoothly. At the moment, my colleague Angelika Augustine prepares the survey. It might be difficult to find participants for each study, because we want to recruit participants in different countries. But we think this is also an opportunity to compare the countries and detect ways to learn from each other.”
In what ways do you envision the findings of the RE-MEND project influencing mental health communication strategies and practices? And who could benefit from these?
“Medical and therapeutic measures have to undergo a long process of testing before patients receive them to minimize the risky side effects. This is barely the case for effects of communication. While there already exist guidelines on how to report on suicides or stigma-free media portrayals of people with addictions, there is a lack of media guidelines for other mental health topics.”
How do you see the RE-MEND project contributing to advancing both scientific knowledge and societal understanding of mental health communication dynamics?
“I hope that our results can contribute to deeper understanding for the responsibility of those communicating about mental illnesses. Thus, I hope that scientists, journalists, health experts or patients on social media reflect on the consequences of the potential media effects before they publish anything, just as a doctor or pharmacist reflects on the side effects of medical and therapeutic measures.”
Alkistis Skalkidou is a Professor at Department of Women's and Children's Health, leading the Obstetric and Reproductive Health research group in Uppsala University, Sweden. She also works as a senior consultant in Uppsala's University Hospital and has been the President of the Nordic Marcé Society. Her research activities focus on peripartum (onset during pregnancy) depression and its effects on the offspring.
She is very interested in the possibility to accurately predict the development of depression in the perinatal period (around the time of birth) and has worked with sizable longitudinal clinical cohorts of mothers and babies. She is also trying to unravel some of the complex pathophysiological mechanisms behind perinatal mood disorders and to identify subgroups of perinatal depression. In parallel, she is highly interested in research methods; having completed a PhD in Epidemiology, she tried to follow advances in the field of statistics and machine learning.
Could you describe your research in the context of the RE-MEND project?
“We are focusing on the importance of epigenetic and transcriptomic markers, as well this of proteins and metabolites in the development of depressive symptoms perinatally. Our work takes the field a bit further, as it takes into consideration differences in the onset and persistence of these symptoms through this very critical period,” Skalkidou explains.
How will this work contribute to our understanding of mental health and increase public health? If we are successful in identifying some biomarkers that can predict the development of depression, we could early identify women who need extra support and help. These or other biomarkers might also be important in explaining the pathophysiology of the disorder, so they can be treatment targets in the future. Lastly, by taking into consideration the presence of subgroups of perinatal depression, we can suggest different treatment and prevention strategies for different women, contributing to precision medicine efforts.
What specific research methods or approaches are you applying in the project to study the relationship between environmental factors and mental health outcomes?
“One approach that we use is considering environmental factors and stressors as possible confounders or mediators in our statistical modelling. Sometimes, these needs to be included in interaction terms in the same models. Some other approaches, when we have possible effect modification, we stratify our analyses. Through advanced collection methods such as the Mom2B app, we have access to a plethora of possible environmental factors that we take into account when considering the effect of biological factors on depression risk”, Prof. Skalkidou explains.
Can you elaborate on any specific environmental factors that your research in RE-MEND addresses, and their potential impact on mental health?
“We focus for example take into account early life trauma, partner support or complications during the delivery process” she adds.
In your opinion, what are the main challenges or gaps in current mental health research and how does the RE-MEND project address them?
“I think that there is a gap in defining mental ill-health; our classification system of course supports treatment strategies, but it would need to be much more defined, given that most patients with a psychiatric disorder have often psychiatric comorbidities. These disorders are often very complex and overlap with each other. In RE-MEND we will tackle this issue partly, but I think that as a research community we should try to use more advanced, data-driven techniques, to try to understand these complexities and interactions better”, she explains.
How does the collaboration between researchers from different disciplines enhance the research conducted in the RE-MEND project?
“Interdisciplinary collaboration is very demanding and must be based in trust. Within REMEND we try to openly communicate and build good foundations for working together. We learn so much from each other as we bring the different expertise and backgrounds together,” she adds.
What could be some of the potential implications or applications of the research that you are addressing in RE-MEND project?
“I hope that our results will help increase knowledge about mood disorders, especially among women, and that they will be instrumental in decreasing stigmatisation”, she highlights.
Nicolò Caporale works as a researcher at the University of Milan, in the lab of Prof. Giuseppe Testa, in the Neurogenomics Center of Human Technopole, in Italy. His research focuses on the genetic and environmental causes of neurodevelopmental disorders, with particular attention to endocrine regulation on brain development, through the use of stem cells and organoids. By integrating data from clinical cohorts with experimental molecular biology activities and computational analyses, his work is foundational for precision medicine approaches.
Could you describe your research in the context of the RE-MEND project?
“We are focusing on the importance of gene-environment interactions for neurodevelopment. In particular we will leverage cortical brain organoids to study in vitro the developmental trajectories of resilient and vulnerable individuals selected from the two cohorts of the project,” Dr. Caporale explains.
How will this work contribute to our understanding of mental health at individual and population level?
“Our work will link prenatal exposure in humans and genetic predispositions with neurodevelopmental effects. Performing organoid modelling from individuals with different levels of resilience and vulnerability, we aim to identify the molecular mechanisms that are key for developmental trajectories across the distribution of neurodiversity, overcoming the limitations of diagnostic categories, and understanding mental health on both individual and population levels,” he summarises.
What specific research methods or approaches are you applying in the project to study the relationship between environmental factors and mental health outcomes?
“We employ molecular atlases generated from organoid modelling, which involves systematically exposing cerebral cortical brain organoids (CBOs), three-dimensional experimental models that can be differentiated from human pluripotent stem cells in vitro to recapitulate and study early stages of neurodevelopment. During the differentiation of the organoids, we expose them to compounds that can either activate (agonists) or block (antagonists) hormone signalling pathways, as well as to endocrine disrupting chemicals (EDCs). This approach helps establish a molecular and cellular atlas of the impact of endocrine modulators on human neurodevelopment. The integration of molecular data from organoid modelling with human clinical data will allow us to define the role of environmental factors for mental health outcomes,” Dr. Caporale explains.
Can you elaborate on any specific environmental factors or exposures that your research in RE-MEND addresses, and their potential impact on mental health?
“We focus on the interplay between prenatal exposure to endocrine disrupting chemicals and metals, and genetic factors, to understand how they affect early brain development. Starting from epidemiological evidence of neurodevelopmental adverse outcomes we study their mechanism of action through experimental neurobiology approaches,” he adds.
In your opinion, what are the main challenges or gaps in current mental health research from the environmental health perspective, and how does the RE-MEND project address them?
“There is a clear gap in understanding the interplay between genetic and environmental factors in neurodevelopment, and how this contributes to mental health outcomes. Most research focuses on either genetic or environmental factors in isolation, neglecting the crucial interactions between them. We directly address this gap by studying the differential impact that environmental exposures can have on different individuals, recognising that not everyone responds in the same way to environmental insults,” Dr. Caporale highlights.
How does the collaboration between researchers from different disciplines enhance the research conducted in the RE-MEND project?
“Multidisciplinary collaboration is really the key to our research. By integrating data from clinical cohorts with experimental models and advanced computational analyses, we aim to bridge this gap and provide a more comprehensive understanding of the complex interplay between genes and environment in mental health,” he adds.
What could be some of the potential implications or applications of the research that you are addressing in RE-MEND project?
“Better understanding the interplay between genes and environment in shaping brain development and mental health could lead to improved diagnostic tools, personalised interventions, and preventive strategies. This knowledge could also inform public health policies aimed at reducing exposure to harmful environmental factors and promoting healthier environments for all,” Dr. Caporale concludes.