Berlin, Germany:  Disturbed sleep is very common in almost all neuropsychiatric and neurodevelopmental conditions (NDPCs), such as autism, attention deficit and hyperactivity disorder, schizophrenia, and bipolar disorder. While it is understandable that the symptoms of such conditions would lead to sleep disruption and also that sleep disruption would worsen symptoms in these conditions, Irish researchers have now found new genetic associations between some of these conditions and chronotype, the behavioural manifestations of an individual’s circadian rhythm (“night owl” or “early bird)”.  These findings may point the way to the development of new therapies for patients.

Presenting the results of the study to the annual conference of the European Society of Human Genetics today (Tuesday), Dr Laura Fahey, a postdoctoral researcher in the Family Genomics Research Group, Maynooth University, Republic of Ireland, will say that sleep disturbances are known to predate the onset of major depressive disorder and bipolar disorder, and that polygenic score analysis can identity whether these conditions and sleep traits share genetic variation. The researchers therefore used polygenic risk score analysis on large-scale genetic studies of NDPCs to test their ability to predict chronotype and insomnia in over 409,000 participants in the UK Biobank.

Their findings strengthen known genetic correlation results in that they show that polygenic scores for autism and schizophrenia are associated with an evening chronotype, while polygenic scores for attention-deficit/hyperactivity disorder, schizophrenia, and bipolar disorder are associated with insomnia. “We also identified novel associations between bipolar disorder and chronotype, as well as insomnia and autism,” says Dr Fahey. “These are interesting insights into the genetic basis of sleep disruption, and may open new research avenues for the treatment of sleep and circadian rhythm disturbances in these patients.”

“The finding that shared genetic variation between bipolar disorder and chronotype was enriched (overrepresented) in a pathway* called NRF2-KEAP1 was interesting to us, as the NRF2 pathway was previously linked to the pathology of bipolar disorder and schizophrenia. Additionally, NRF2 has previously been shown to be rhythmically regulated by circadian clock genes.

“However, it was surprising that there was no enrichment of shared genetic variation in any biological pathway for the other sleep-NDPC phenotype pairs investigated. This was particularly surprising for ADHD and insomnia, as we found these two phenotypes to have the strongest genome-wide correlation. A reason for this could be that the shared genetic variation is highly polygenic, affecting all biological pathways somewhat equally. It could also be that this shared genetic variation is enriched in cell- or tissue-specific pathways, which we did not explore”, Dr Fahey says.

The researchers also intend to test polygenic scores from more diverse populations, the UK Biobank data used in their study being on individuals of white British ancestry. “We need to know whether this work can be applied to other population groups,” says Dr Fahey, “since we hope that our work may contribute to the development of predictive and preventive interventions in the future.”.

Further research could also investigate the impact of the genetic variation found in the biological pathways identified by the scientists as influencing circadian rhythm; for example, whether there are specific subsets of patients with these changes where it would be useful to look for differences in gene expression. “However, the next stage of my research project will take a broader perspective and aim to better understand the genetic architecture using different methods and investigating both rare and common genetic variations underlying sleep and circadian rhythm disturbances in NDPCs,” Dr Fahey says.

Professor Alexandre Reymond, from the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, and chair of the conference, said: “It is interesting to see that perturbations of the same molecular pathways are associated with distinct phenotypes (bipolar disorder/schizophrenia and chronotype), a phenomenon called pleiotropy. It is tantalising to think that, if we are in presence of “direct pleiotropy” where one trait influences the other trait, we may have some hints about possible treatments”.

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* Gene-regulation pathways turn genes on and off. Such action is vital because genes provide the recipe by which cells produce proteins, which are the key components needed to carry out nearly every task in the body.

The Family Sleeps programme is funded by the European Research Council under the European Union’s Horizon 2020 research and innovation programme (grant no. 950010) awarded to Dr Lorna Lopez at Maynooth University. Dr Fahey’s visit to the conference was sponsored by the Irish Society of Human Genetics as part of a prize for “best postdoctoral presentation” at the society’s conference in September 2023.

Abstract no. C30 Shared genetic links between sleep, neurodevelopmental, and neuropsychiatric conditions: a genome-wide and pathway-based polygenic score analysis

Berlin, Germany:  While influenza infection is a significant public health threat, causing serious illness in between three and five million people worldwide per year and leading to about up to 650,000 deaths, the effectiveness of influenza vaccines varies considerably between individuals depending on vaccine types and individual circumstances. A person’s ability to resist infection (host immunity) plays an important role in this. Now, researchers have developed a way of classifying host immunity in individuals, which may lead to the early identification of those who will not respond well to a regular vaccine schedule and therefore allow them to receive different vaccine regimes to provide them with long-lasting immunity. This will not only reduce influenza-related illness but also reduce the logistical and financial burden it causes to healthcare systems, they say.

Presenting the results of their study to the annual conference of the European Society of Human Genetics today (Monday), Dr Nhan Nguyen, a postdoctoral researcher at Professor Yang Li’s group, from the Centre for Individualised Infection Medicine, a joint venture of the Helmholtz Centre for Infection Research and Hannover Medical School, Hannover, Germany, and colleagues will describe how they took blood samples from 286 healthy donors aged 18-81, 45% of whom were women, during four influenza seasons in order to try to identify those who would be unprotected against influenza after vaccination.

“After examining their pre- and post-vaccination antibody status, we used multiomics¹ technology to identify proteins and metabolites that could serve as predictive markers for the identification of individuals who have low levels of protection even after vaccination’”, says Dr Nguyen. “This is a more sophisticated way of identifying such people than that which is used at present, where protection is assessed solely by changes in the number of antibodies in the blood pre- and post-vaccination.”

The influenza vaccine is updated every year in response to variations in the virus, and this means that the pre-vaccination antibody level can differ in individuals due to previous infection or their vaccination history. The current vaccine response calculation may therefore not provide host-specific information that is sufficiently accurate to estimate a person’s immune response and/or vulnerability to future infections, since some people already have high antibody levels at pre-vaccination that do not change significantly after they have received a vaccine.

The results were consistent over the four flu seasons and the four different updates of the flu vaccines. “Each seasonal influenza vaccine is designed to protect against three or four different flu viruses, so a lot of factors are involved in an individual’s vaccine response. We aimed to identify the robust signals of response that spanned across different influenza seasons and were consistent despite the variations in the response of the same individual to different flu viruses,” says Dr Nguyen.

The researchers hope that the biomarkers they have identified as being related to an individual’s vaccine response will enable the development of personalised influenza vaccine administration, for example, higher dose vaccines, repeated vaccinations, or vaccines including an adjuvant to boost response. These biomarkers in turn will reduce the cost of vaccine response screening, as well as increasing protection against infection. They believe that their research could lead to the development of individualised adapted strategies for the administration of influenza vaccines.

“We are now testing a molecule that could act potentially as a predictive biomarker as well as a modulator of influenza vaccine response. We are also exploring the possibility of developing a market product such as a diagnostic test based on our results. And we hope to further explore the idea of personalised influenza vaccination based on the biomarkers we have identified in this study,” Dr Nguyen concludes.

Professor Alexandre Reymond, from the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, and chair of the conference, said: “Personalised health is all about identifying the fraction of individuals of the population who are at risk in order to be able to treat them specifically. Importantly, this will benefit these individuals and decrease the burden on the health system, which in turn will benefit everybody.”

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1.Multiomics is an approach to biological analysis that combines various ‘ome’ datasets, which are high-throughput measurements from genome, proteome, transcriptome, epigenome, and metabolome.

The work was funded by the European Research Council Starting Grant (ERC-StG, 948207) – Cross-omics integration to identify modulators for improving vaccine efficacy (ModVaccine) to Prof Yang Li at the Helmholtz Centre for Infection Research

Abstract no. C24.4 A collective influence of genetic background on influenza vaccinees responses

Berlin, Germany:  Aneuploidy (the presence of an abnormal number of chromosomes) in embryos is a major cause of impaired embryo development, leading to conditions such as Down syndrome, as well as to pregnancy loss. The transfer of such embryos in women undergoing IVF is therefore usually avoided because of unfavourable pregnancy outcomes. But mosaic embryos, comprising both genetically normal and abnormal cells, can result in perfectly normal babies. Now, researchers have been able to understand how these mosaic embryos self-correct to develop normally. This understanding will improve the numbers of embryos suitable for transfer in women undergoing IVF, they say.

Presenting their results to the annual conference of the European Society of Human Genetics today (Monday), Ms Sheila Kwok, a PhD candidate in the Physiology Department of the University of Toronto, Toronto, Canada, will explain how the existence of a self-correction mechanism in mosaic embryos is consistent with the results of a large-scale clinical study of over 3500 pregnancy outcomes from mosaic embryo transfers from the International Registry of Mosaic Embryo Transfers (IRMET)* - where only 1.2% of preimplantation mosaicism persisted throughout pregnancy or postnatally. These findings, in turn, will reduce the stress on patients who have only mosaic embryos available for transfer, they say.

There has been an increasing number of women postponing motherhood over the past two decades. As they age, they become more likely to produce genetically abnormal embryos, due to higher error rates during egg development. This poses a challenge for women wishing to balance reproductive health with motherhood, since in IVF genetically normal embryos are prioritised for transfer to shorten time to pregnancy and reduce miscarriage and abnormal pregnancies. In older women, this can be very limiting, and therefore mosaic embryos are often the only available choice. Understanding how and which mosaic embryos will develop normally is therefore of ultimate importance.

“From earlier work carried out at the CReATe Fertility Centre, Toronto by Drs Clifford Librach and Mitko Madjunkov, we knew that mosaic embryos could result in ongoing pregnancies and live births at a rate of around 30%, which is lower than those from embryos with normal number of chromosomes (euploid embryos). This enabled us to start using mosaic embryos for transfer where no euploid embryos were available, but we still did not fully understand the process by which they self-corrected,” says Ms Kwok.

All pregnancies, natural or assisted, have around 3% risk of having an abnormal child. The 1.2% persistence of mosaicism therefore does not exceed this risk but prompts researchers to continue searching for answers. “We will expand our research to look at embryos with specific chromosomal aberrations to understand if this clearance mechanism is specific to the chromosome being affected,” says Ms Kwok. And, for all women who have a mosaic embryo transfer, current recommendations are prenatal testing and close pregnancy monitoring.”

By utilising advanced single-cell transcriptomic analysis¹ and post-implantation embryo culturing systems, the researchers have now been able to address how two cell populations with differential fitness levels are able to co-exist in the same environment, and what are the mechanisms inducing the depletion of the abnormal cells. Their findings pointed to the fact that abnormal cells were less able to survive than normal cells, which had higher fitness. They now plan to use gene editing technology with stem cell-derived embryo models to validate the importance of the genes and molecular functions they have identified in these processes. In the future, they will apply small molecule treatments² on mosaic embryos to try to facilitate this self-correction process.

“Embryology and assisted reproductive technologies have come a long way from the initial success rates of around 10-20%. In the last 10 years with advanced genetic tests for embryo selection rates have been close to 50-60%”, says Dr Svetlana Madjunkova MD, PhD, Head of Reproductive Genetics at CReATe Fertility Centre, the senior author of this work and the founder of IRMET. “But we still need to improve our understanding of which embryos to prioritise for transfer, to optimise patient treatment, help patients achieve their family goals and prevent the waste of time and resources, not to mention patient emotional and psychological stress, involved in transferring embryos that are not viable, and the complications associated with multiple embryo transfer. Our results, elucidating some of the mechanisms controlling normal embryo development, are providing strong evidence to believe that we have made an important step down this path.”

Professor Alexandre Reymond, from the Center for Integrative Genetics at the University of Lausanne, Lausanne, Switzerland, and chair of the conference, said: “Juggling career and parenthood is difficult and often induces couples to become parents are an older age. While this increases genetic risk, we are now beginning to understand how to mitigate it.”

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*www.irmet.net

1. Single-cell transcriptomics examines the gene expression level of individual cells in a given population.

2.Small molecules are chemical compound that target specific biological processes or pathways in cells without introducing genetic modifications.

Abstract no. 5084 Single-cell transcriptomics of post-implantation embryos: unveiling aneuploidy effects and lineage dynamics.

The study was funded by the CReATe Fertility Centre, Toronto.

Berlin, Germany:  Differences in socioeconomic status (SES) are known to be linked to differences in the risk of developing disease. While people with lower SES are more likely to develop complex diseases such as diabetes and cardiovascular disease, those with a higher SES are at increased risk of developing certain types of cancer. Using biobank and national register data, researchers from Finland have now found that people with lower SES (educational achievement and occupation) have a greater genetic susceptibility to develop many other complex diseases such as rheumatoid arthritis, lung cancer, depression, and alcohol use disorder, as well as Type 2 diabetes, whereas those with a higher SES are more at risk of developing breast, prostate, and all cancers.

Dr Fiona Hagenbeek, a postdoctoral researcher at the Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland, who will present her group‘s work at the annual conference of the European Society of Human Genetics today (Sunday), says that these promising initial results mean that it is likely that polygenic risk scores, which measure an individual‘s risk of a particular disease based on genetic information, could be added to the screening protocols for multiple diseases and in several countries. “Understanding that the impact of polygenic scores on disease risk is context-dependent may lead to further stratified screening protocols,“ she says. “For example, in the future, screening protocols for breast cancer may be adapted so that females with a high genetic risk and who are highly educated receive earlier or more frequent screening than females with lower genetic risk or less education.”

The researchers used genomics, SES, and health data from approximately 280,000 Finnish individuals in the FinnGen study, a research project in genomics and personalised medicine that aims to understand the genetic basis of diseases. The participants were aged 35 – 80 at the time of entry into the study. The study aimed to systematically assess the evidence of gene-environment interaction (GxE) through the differing genetic susceptibility to disease in diverse socioeconomic groups. While previous studies have shown the presence of such a difference in risk, this is the first to systematically assess GxE for SES in 19 complex diseases that have a high burden in high-income countries.

“Most clinical risk prediction models include basic demographic information such as biological sex and age, recognising that disease incidence differs between males and females, and is age-dependent,“ says Dr Hagenbeek. “Acknowledging that such context also matters when incorporating genetic information into healthcare is an important first step. But now, we can show that the genetic prediction of disease risk also depends on an individual’s socioeconomic background. So while our genetic information does not change throughout our lifetime, the impact of genetics on disease risk changes as we age or change our circumstances.“

The researchers hope that the study will be followed up to see whether further differences can be identified when looking at more specific aspects of educational and professional achievement. While their current results for profession generally mirror those for education, they do not match completely, indicating that each can provide unique information on the interplay of socioeconomic status and genetics on disease risk. Expanding the list of socioeconomic indices to be studied may bring about new insights into how the overlapping aspects of a person’s socioeconomic environment may, together with genetic information, influence their disease risk.

They will also compare their results across biobank studies from Finland, UK, Norway, and Estonia through the INTERVENE* consortium, allowing them to determine whether there are country or biobank-specific issues involved. “Our study focused solely on individuals of European ancestry, and it will also be important in the future to see whether our observations concerning the interplay of socioeconomic status and genetics for disease risk are replicated in people of multiple ancestries in higher and lower-income countries,“ says Dr Hagenbeek. “As the overall aim of incorporating genetic information into healthcare is to facilitate personalised medicine, we should not treat genetic information as ‘one size fits all‘. Rather, we should investigate and then include the circumstances that modify genetic risk when carrying out disease prediction.“

Professor Alexandre Reymond, from the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, and chair of the conference, said: “To really move to personalised health it will be essential to gauge both genetic and environmental risks. We should commend our Finnish colleagues for their part in spearheading this effort.”

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* INTERVENE is the 'International consortium of integrative genomics prediction’,  (https://www.interveneproject.eu/), a Horizon 2020 funded collaboration between 17 organizations from nine European countries and the USA. The overarching aim of the consortium is to develop tools for disease prevention, diagnosis, and personalised treatment by integrating human genetics and artificial intelligence. To this end, the INTERVENE consortium links human genetic data to electronic health records and registry data for over 1.7 million individuals from eight European and US biobank studies (FinnGen, Estonian Biobank, HUNT, Network for Italian Genomes, Partners Biobank, HUS Helsinki Biobank, UK Biobank, and Genomics England).

The research was funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement No 101016775.

Abstract no. CO9.3  Gene-environment interplay of socioeconomic indices and complex diseases

Berlin, Germany: Polygenic risk scores (PRSs) are estimates of an individual’s susceptibility to a specific complex trait obtained by aggregating the effects of dozens, thousands, and potentially millions of genetic variants associated with that specific trait into a single figure. Some private companies now market PRS embryo screening to prospective parents through the use of in vitro fertilisation and pre-implantation genetic testing. While PRS has great potential for prediction in live-born (mostly adult) individuals, its accuracy is still far from perfect. And this is even truer for its use in the selection of pre-implantation embryos (PGT-P), say the Japanese scientists who have discovered just how inaccurate and inconsistent the outcomes can be. Their results will be presented at the annual conference of the European Society of Human Genetics today (Saturday).

Using large-scale computational simulations and data from BioBank Japan, Dr Shinichi Namba, from the Department of Genome Informatics, Graduate School of Medicine, University of Tokyo, Japan, and colleagues, constructed PRSs for PGT-P to predict adult height, as well as the risk for Type 2 diabetes (T2D). They selected randomly 500 males and 500 females from whom they simulated couples. From each of these couples they simulated ten embryos, and then applied the six most widely-used PRS methods to predict height and diabetes data for these embryos.

When they evaluated the ‘best’ embryos, i.e. those predicted to be the tallest and those with the least diabetes risk selected by each method, they were surprised to find that there was little or no concordance between them. “We had not been expecting such a lack of robustness. No combination of two PRS methods selected the same embryo over half the time. The lowest-ranked embryo ranked using one method could be the top-ranked in another. Even worse, simply repeating the same method produced a different embryo rating each time, and this pattern was the same when screening for both height and T2D.

“There is no single state of the art method, and individual researchers use the one they prefer, but our results were so conclusive that we can say confidently that PRS scores in embryos are basically worthless at present,” says Dr Namba. “There is little point in following up this research until the technology improves.”

Many conditions are caused by a combination of genetics and environment, and PRSs are only able to capture parts of any of the relevant genetic component, which is itself likely to be highly complex and difficult to analyse. Using PRS screenings in order to select a ‘suitable’ embryo means that many embryos would have to be discarded, perhaps unnecessarily, and this would be unethical. In the context of fertility treatment there are usually very few embryos to choose from to begin with, so it is important that the choice of one over another be based on sound evidence.

”While pre-implantation testing for conditions with a single genetic cause is evidence-based, this is not the case for PRSs. I believe that companies selling this service to prospective parents should clearly state its limitations and acknowledge the inaccurate and inconsistent nature of the results,” says Dr Namba. “And while we understand the desire to have a healthy baby, should we ever arrive at a stage where the accuracy of this technology is much improved it should not be made widely  available without a society-wide debate taking place.”

Professor Alexandre Reymond, from the Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland, and chair of the conference, said: “These results align perfectly with the ESHG recommendation regarding the use of polygenic risk scores in pre-implantation genetic testing, i.e. that it is at the moment both unproven and unethical”.

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Abstract no. C02.4 Pre-implantation genetic testing by polygenic risk scores selects different embryos across score construction methods with randomness

Related literature:

Forzano, F., Antonova, O., Clarke, A., de Wert, G., Hentze, S., Jamshidi, Y., Moreau, Y., Perola, M., Prokopenko, I., Read, A., Reymond, A., Stefansdottir, V., van El, C., Genuardi, M., Executive Committee of the European Society of Human Genetics, Public and Professional Policy Committee of the European Society of Human Genetics, The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice, Eur J Hum Genet, 2021, doi: 10.1038/s41431-021-01000-x.

Berlin, Germany:  Cancer is the leading cause of disease-related death in children in most developed countries, and at least a quarter of these patients are diagnosed with aggressive high-risk or relapsed cancers, with an expected five-year survival rate of less than 30%. Accurate diagnosis can be difficult, and survivors often suffer life-long side effects because of the toxic treatments needed to cure them. Now, researchers from Australia have shown that, by using precision medicine*, it is possible not only to obtain more accurate diagnoses, but also that using precision-guided, targeted treatments earlier improves the two year progression-free survival in young cancer patients. Their results will be presented to the annual conference of the European Society of Human Genetics today (Saturday).

Associate Professor Vanessa Tyrrell, Director of the Zero Childhood Cancer National Precision Medicine Program (ZERO), a joint initiative of Children’s Cancer Institute, and Kids Cancer Centre, Children’s Hospital, Randwick, Australia, and colleagues at the nine child cancer centres around Australia, have enrolled over 1600 children into the program since 2017.  Previously ZERO was limited to children with high-risk cancers, but recently expanded to be open to all children diagnosed with cancer in Australia, a trial the team are calling ZERO2. “Having found that over 70% of children with high-risk cancers were able to benefit from personalised medicine, we felt that we needed to see whether this benefit could be applied to other childhood cancers, too,” says Prof Tyrrell. “To date we have recruited over 700 children to this second trial, which we are aiming to continue for at least another four years.”

ZERO’s first national clinical trial, which ran from 2017 to 2022, has already produced results related to a child’s predisposition to cancer through gene variants in their germline (child genomic cancer risk). These variants were found in around 16% of children with high-risk cancer. Utilising whole genome sequencing (WGS) was more sensitive for the detection of germline cancer predisposition variants than standard clinical testing pathways; more than half had not been previously identified through standard clinical care, because the patients did not meet the testing criteria. Paired tumour-germline molecular profiling increased the germline cancer predisposition diagnosis rate and aided in genetic counselling for the families receiving these results. The findings of cancer risk led to high (nearly 67%) referral rates to cancer genetic services and, subsequently, the detection of relatives at risk of cancer.  All first-degree relatives took up testing where it was recommended.

 “This is not surprising to me, given that these children have developed cancer so young,” says Prof Tyrrell, “We also found that close to 70% of these germline variants were not previously known to be associated with the cancer type the patients presented with. This, together with the fact that over half the genetic cancer risk findings conferred a higher susceptibility to developing second cancers after chemotherapy, has significant implications for both treatment choices and ongoing surveillance.”

Of the newly identified variants, 80% had cancer surveillance/risk reduction implications for relatives, too. This is a much higher yield than is found in standard clinical practice and has significant implications for both patients and families, the researchers say. They now aim to continue to improve the application of precision medicine over time, focusing on the identification of new targets that drive an individual cancer; matching those targets to more effective, less toxic treatments and working out more effective, less invasive ways of monitoring how a child’s cancer is behaving; accelerating access to clinical trials as the ability to identify and match more targets to treatments is expanded; and transitioning precision medicine from research into standard health care systems.

“Only seven years ago, these aims seemed implausible to most people, and it was challenging in the beginning to encourage enrolment of children into ZERO. Today, clinicians and families are demanding this precision medicine model as standard of care for all their high-risk, relapsed, rare, and undiagnosable patients,” says Prof Tyrrell.

As well as identifying treatable cancers, ZERO aims to identify new genomic features, molecular targets and biomarkers that can lead to the development of more effective treatments. The researchers have already been able to characterise new cancer drivers and identify targeted drugs that may be effective in specific patients with specific alterations in their tumours. “Further, there have been cases where we have shown that novel alterations were also sensitive to another targeted drug that we did not expect, therefore potentially offering more therapeutic options to the patient.

“The tools needed to implement precision medicine more widely are not cheap, but its unquestionable promise in better stratifying the diagnosis and identifying the most likely effective targeted treatments for an individual’s cancer, together with the reduction in costs as technologies, computational capabilities, and automation improves leads me to believe that, in the future, multiomic profiling driving research-guided clinical care will be the gold standard, not just in cancer, but in many other diseases too,” Prof Tyrrell concludes.

Professor Alexandre Reymond, chair of the conference, said: “Sequencing our genome in its entirety allows us to do much more than looking under the proverbial lamp post. As a human genetic society, ESHG should aim to make this standard clinical care”.

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* Precision medicine optimises efficiency and therapeutic benefit for individual patients by using genetic and/or molecular profiling (“multiomics”) of their disease to enable the choice of the best treatment for them.

Abstract no. PL3.1 Zero Childhood Cancer National Precision Medicine Program: Improving outcomes for children with high risk cancer cancer utilising comprehensive, integrated multiomic profiling

The research is funded by a joint initiative from the Australian Department of Health and Aged Care’s Medical Research Future Fund and the Minderoo Foundation.