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1. Biomodifying the 'natural': from Adaptive Regulation to Adaptive Societal Governance

Author

Mourby, M, Bell, J, Morrison, M, Faulkner, A, Li, P, Bicudo, E, Webster, A, Kaye, J, Mourby, M, Bell, J, Morrison, M, Faulkner, A, Li, P, Bicudo, E, Webster, A, and Kaye, J

Abstract

Biomodifying technologies-such as gene editing, induced pluripotent stem cells, and bioprinting-are being developed for a wide range of applications, from pest control to lab-grown meat. In medicine, regulators have responded to the challenge of evaluating modified 'natural' material as a therapeutic 'product' by introducing more flexible assessment schemes. Attempts have also been made to engage stakeholders across the globe on the acceptable parameters for these technologies, particularly in the case of gene editing. Regulatory flexibility and stakeholder engagement are important, but a broader perspective is also needed to respond to the potential disruption of biomodification. Our case-study technologies problematize basic ideas-such as 'nature', 'product', and 'donation'-that underpin the legal categories used to regulate biotechnology. Where such foundational concepts are rendered uncertain, a socially responsive and sustainable solution would involve exploring evolutions in these concepts across different societies. We suggest that the global observatory model is a good starting point for this 'Adaptive Societal Governance' approach, in which a self-organizing network of scholars and interested parties could carry out the multi-modal (meta)analyses needed to understand societal constructions of ideas inherent to our understanding of 'life'.

Published
2022

2. Governance of research consortia: challenges of implementing Responsible Research and Innovation within Europe

Author

Morrison, M, Mourby, M, Gowans, H, Coy, S, Kaye, J, Morrison, M, Mourby, M, Gowans, H, Coy, S, and Kaye, J

Abstract

Responsible Research and Innovation ('RRI') is a cross-cutting priority for scientific research in the European Union and beyond. This paper considers whether the way such research is organised and delivered lends itself to the aims of RRI. We focus particularly on international consortia, which have emerged as a common model to organise large-scale, multi-disciplinary research in contemporary biomedical science. Typically, these consortia operate through fixed-term contracts, and employ governance frameworks consisting of reasonably standard, modular components such as management committees, advisory boards, and data access committees, to co-ordinate the activities of partner institutions and align them with funding agency priorities. These have advantages for organisation and management of the research, but can actively inhibit researchers seeking to implement RRI activities. Conventional consortia governance structures pose specific problems for meaningful public and participant involvement, data sharing, transparency, and 'legacy' planning to deal with societal commitments that persist beyond the duration of the original project. In particular, the 'upstream' negotiation of contractual terms between funders and the institutions employing researchers can undermine the ability for those researchers to subsequently make decisions about data, or participant remuneration, or indeed what happens to consortia outputs after the project is finished, and can inhibit attempts to make project activities and goals responsive to input from ongoing dialogue with various stakeholders. Having explored these challenges, we make some recommendations for alternative consortia governance structures to better support RRI in future.

Published
2020

3. A reference map of potential determinants for the human serum metabolome

Author

Bar, N., Korem, T., Weissbrod, O., Zeevi, D., Rothschild, D., Leviatan, S., Kosower, N., Lotan-Pompan, M., Weinberger, A., Le Roy, C. I., Menni, C., Visconti, A., Falchi, M., Spector, T. D., Vestergaard, H., Arumugam, M., Hansen, T., Allin, K., Hong, Mun-Gwan, Schwenk, Jochen M., Häussler, Ragna S., Dale, Matilda, Giorgino, T., Rodriquez, M., Perry, M., Nice, R., McDonald, T., Hattersley, A., Jones, A., Graefe-Mody, U., Baum, P., Grempler, R., Thomas, C. E., Masi, F. D., Brorsson, C. A., Mazzoni, G., Allesøe, R., Rasmussen, S., Gudmundsdóttir, V., Nielsen, A. M., Banasik, K., Tsirigos, K., Nilsson, B., Pedersen, H., Brunak, S., Karaderi, T., Lundgaard, A. T., Johansen, J., Gupta, R., Sackett, P. W., Tillner, J., Lehr, T., Scherer, N., Dings, C., Sihinevich, I., Loftus, H., Cabrelli, L., McEvoy, D., Mari, A., Bizzotto, R., Tura, A., ’t Hart, L., Dekkers, K., Leeuwen, N., Slieker, R., Rutters, F., Beulens, J., Nijpels, G., Koopman, A., Oort, S., Groeneveld, L., Groop, L., Elders, P., Viñuela, A., Ramisch, A., Dermitzakis, E., Ehrhardt, B., Jennison, C., Froguel, P., Canouil, M., Boneford, A., McVittie, I., Wake, D., Frau, F., Staerfeldt, H. -H, Adragni, K., Thomas, M., Wu, H., Pavo, I., Steckel-Hamann, B., Thomsen, H., Giordano, G. N., Fitipaldi, H., Ridderstråle, M., Kurbasic, A., Pasdar, N. A., Pomares-Millan, H., Mutie, P., Koivula, R., McRobert, N., McCarthy, M., Wesolowska-Andersen, A., Mahajan, A., Abdalla, M., Fernandez, J., Holl, R., Heggie, A., Deshmukh, H., Hennige, A., Bianzano, S., Thorand, B., Sharma, S., Grallert, H., Adam, J., Troll, M., Fritsche, A., Hill, A., Thorne, C., Hudson, M., Kuulasmaa, T., Vangipurapu, J., Laakso, M., Cederberg, H., Kokkola, T., Jiao, Y., Gough, S., Robertson, N., Verkindt, H., Raverdi, V., Caiazzo, R., Pattou, F., White, M., Donnelly, L., Brown, A., Palmer, C., Davtian, D., Dawed, A., Forgie, I., Pearson, E., Ruetten, H., Musholt, P., Bell, J., Thomas, E. L., Whitcher, B., Haid, M., Nicolay, C., Mourby, M., Kaye, J., Shah, N., Teare, H., Frost, G., Jablonka, B., Uhlen, M., Eriksen, R., Vogt, J., Dutta, A., Jonsson, A., Engelbrechtsen, L., Forman, A., Sondertoft, N., de Preville, N., Baltauss, T., Walker, M., Gassenhuber, J., Klintenberg, M., Bergstrom, M., Ferrer, J., Adamski, J., Franks, P. W., Pedersen, O., Segal, E., consortium, The IMI DIRECT, Bar, N., Korem, T., Weissbrod, O., Zeevi, D., Rothschild, D., Leviatan, S., Kosower, N., Lotan-Pompan, M., Weinberger, A., Le Roy, C. I., Menni, C., Visconti, A., Falchi, M., Spector, T. D., Vestergaard, H., Arumugam, M., Hansen, T., Allin, K., Hong, Mun-Gwan, Schwenk, Jochen M., Häussler, Ragna S., Dale, Matilda, Giorgino, T., Rodriquez, M., Perry, M., Nice, R., McDonald, T., Hattersley, A., Jones, A., Graefe-Mody, U., Baum, P., Grempler, R., Thomas, C. E., Masi, F. D., Brorsson, C. A., Mazzoni, G., Allesøe, R., Rasmussen, S., Gudmundsdóttir, V., Nielsen, A. M., Banasik, K., Tsirigos, K., Nilsson, B., Pedersen, H., Brunak, S., Karaderi, T., Lundgaard, A. T., Johansen, J., Gupta, R., Sackett, P. W., Tillner, J., Lehr, T., Scherer, N., Dings, C., Sihinevich, I., Loftus, H., Cabrelli, L., McEvoy, D., Mari, A., Bizzotto, R., Tura, A., ’t Hart, L., Dekkers, K., Leeuwen, N., Slieker, R., Rutters, F., Beulens, J., Nijpels, G., Koopman, A., Oort, S., Groeneveld, L., Groop, L., Elders, P., Viñuela, A., Ramisch, A., Dermitzakis, E., Ehrhardt, B., Jennison, C., Froguel, P., Canouil, M., Boneford, A., McVittie, I., Wake, D., Frau, F., Staerfeldt, H. -H, Adragni, K., Thomas, M., Wu, H., Pavo, I., Steckel-Hamann, B., Thomsen, H., Giordano, G. N., Fitipaldi, H., Ridderstråle, M., Kurbasic, A., Pasdar, N. A., Pomares-Millan, H., Mutie, P., Koivula, R., McRobert, N., McCarthy, M., Wesolowska-Andersen, A., Mahajan, A., Abdalla, M., Fernandez, J., Holl, R., Heggie, A., Deshmukh, H., Hennige, A., Bianzano, S., Thorand, B., Sharma, S., Grallert, H., Adam, J., Troll, M., Fritsche, A., Hill, A., Thorne, C., Hudson, M., Kuulasmaa, T., Vangipurapu, J., Laakso, M., Cederberg, H., Kokkola, T., Jiao, Y., Gough, S., Robertson, N., Verkindt, H., Raverdi, V., Caiazzo, R., Pattou, F., White, M., Donnelly, L., Brown, A., Palmer, C., Davtian, D., Dawed, A., Forgie, I., Pearson, E., Ruetten, H., Musholt, P., Bell, J., Thomas, E. L., Whitcher, B., Haid, M., Nicolay, C., Mourby, M., Kaye, J., Shah, N., Teare, H., Frost, G., Jablonka, B., Uhlen, M., Eriksen, R., Vogt, J., Dutta, A., Jonsson, A., Engelbrechtsen, L., Forman, A., Sondertoft, N., de Preville, N., Baltauss, T., Walker, M., Gassenhuber, J., Klintenberg, M., Bergstrom, M., Ferrer, J., Adamski, J., Franks, P. W., Pedersen, O., Segal, E., and consortium, The IMI DIRECT

Abstract

The serum metabolome contains a plethora of biomarkers and causative agents of various diseases, some of which are endogenously produced and some that have been taken up from the environment1. The origins of specific compounds are known, including metabolites that are highly heritable2,3, or those that are influenced by the gut microbiome4, by lifestyle choices such as smoking5, or by diet6. However, the key determinants of most metabolites are still poorly understood. Here we measured the levels of 1,251 metabolites in serum samples from a unique and deeply phenotyped healthy human cohort of 491 individuals. We applied machine-learning algorithms to predict metabolite levels in held-out individuals on the basis of host genetics, gut microbiome, clinical parameters, diet, lifestyle and anthropometric measurements, and obtained statistically significant predictions for more than 76% of the profiled metabolites. Diet and microbiome had the strongest predictive power, and each explained hundreds of metabolites—in some cases, explaining more than 50% of the observed variance. We further validated microbiome-related predictions by showing a high replication rate in two geographically independent cohorts7,8 that were not available to us when we trained the algorithms. We used feature attribution analysis9 to reveal specific dietary and bacterial interactions. We further demonstrate that some of these interactions might be causal, as some metabolites that we predicted to be positively associated with bread were found to increase after a randomized clinical trial of bread intervention. Overall, our results reveal potential determinants of more than 800 metabolites, paving the way towards a mechanistic understanding of alterations in metabolites under different conditions and to designing interventions for manipulating the levels of circulating metabolites., QC 20211001

Published
2020
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4. Genetic studies of abdominal MRI data identify genes regulating hepcidin as major determinants of liver iron concentration

Author

Wilman, H. R., Parisinos, C. A., Atabaki-Pasdar, N., Kelly, M., Thomas, E. L., Neubauer, S., Jennison, C., Ehrhardt, B., Baum, P., Schoelsch, C., Freijer, J., Grempler, R., Graefe-Mody, U., Hennige, A., Dings, C., Lehr, T., Scherer, N., Sihinecich, I., Pattou, F., Raverdi, V., Caiazzo, R., Torres, F., Verkindt, H., Mari, A., Tura, A., Giorgino, T., Bizzotto, Froguel, P., Bonneford, A., Canouil, M., Dhennin, V., Brorsson, C., Brunak, S., De Masi, F., Gudmundsdóttir, V., Pedersen, H., Banasik, K., Thomas, C., Sackett, P., Staerfeldt, H. -H, Lundgaard, A., Nilsson, B., Nielsen, A., Mazzoni, G., Karaderi, T., Rasmussen, S., Johansen, J., Allesøe, R., Fritsche, A., Thorand, B., Adamski, J., Grallert, H., Haid, M., Sharma, S., Troll, M., Adam, J., Ferrer, J., Eriksen, H., Frost, G., Häussler, Ragna S., Hong, Mun-Gwan, Schwenk, Jochen M., Uhlén, Mathias, Nicolay, C., Pavo, I., Steckel-Hamann, B., Thomas, M., Adragni, K., Wu, H., Hart, L., Roderick, S., van Leeuwen, N., Dekkers, K., Frau, F., Gassenhuber, J., Jablonka, B., Musholt, P., Ruetten, H., Tillner, J., Baltauss, T., Bernard Poenaru, O., de Preville, N., Rodriquez, M., Arumugam, M., Allin, K., Engelbrechtsen, L., Hansen, T., Forman, A., Jonsson, A., Pedersen, O., Dutta, A., Vogt, J., Vestergaard, H., Laakso, M., Kokkola, T., Kuulasmaa, T., Franks, P., Giordano, N., Pomares-Millan, H., Fitipaldi, H., Mutie, P., Klintenberg, M., Bergstrom, M., Groop, L., Ridderstrale, M., Atabaki Pasdar, N., Deshmukh, H., Heggie, A., Wake, D., McEvoy, D., McVittie, I., Walker, M., Hattersley, A., Hill, A., Jones, A., McDonald, T., Perry, M., Nice, R., Hudson, M., Thorne, C., Dermitzakis, E., Viñuela, A., Cabrelli, L., Loftus, H., Dawed, A., Donnelly, L., Forgie, I., Pearson, E., Palmer, C., Brown, A., Koivula, R., Wesolowska-Andersen, A., Abdalla, M., McRobert, N., Fernandez, J., Jiao, Y., Robertson, N., Gough, S., Kaye, J., Mourby, M., Mahajan, A., McCarthy, M., Shah, N., Teare, H., Holl, R., Koopman, A., Rutters, F., Beulens, J., Groeneveld, L., Bell, J., Thomas, L., Whitcher, B., Hingorani, A. D., Patel, R. S., Hemingway, H., Franks, P. W., Bell, J. D., Banerjee, R., Yaghootkar, H., Wilman, H. R., Parisinos, C. A., Atabaki-Pasdar, N., Kelly, M., Thomas, E. L., Neubauer, S., Jennison, C., Ehrhardt, B., Baum, P., Schoelsch, C., Freijer, J., Grempler, R., Graefe-Mody, U., Hennige, A., Dings, C., Lehr, T., Scherer, N., Sihinecich, I., Pattou, F., Raverdi, V., Caiazzo, R., Torres, F., Verkindt, H., Mari, A., Tura, A., Giorgino, T., Bizzotto, Froguel, P., Bonneford, A., Canouil, M., Dhennin, V., Brorsson, C., Brunak, S., De Masi, F., Gudmundsdóttir, V., Pedersen, H., Banasik, K., Thomas, C., Sackett, P., Staerfeldt, H. -H, Lundgaard, A., Nilsson, B., Nielsen, A., Mazzoni, G., Karaderi, T., Rasmussen, S., Johansen, J., Allesøe, R., Fritsche, A., Thorand, B., Adamski, J., Grallert, H., Haid, M., Sharma, S., Troll, M., Adam, J., Ferrer, J., Eriksen, H., Frost, G., Häussler, Ragna S., Hong, Mun-Gwan, Schwenk, Jochen M., Uhlén, Mathias, Nicolay, C., Pavo, I., Steckel-Hamann, B., Thomas, M., Adragni, K., Wu, H., Hart, L., Roderick, S., van Leeuwen, N., Dekkers, K., Frau, F., Gassenhuber, J., Jablonka, B., Musholt, P., Ruetten, H., Tillner, J., Baltauss, T., Bernard Poenaru, O., de Preville, N., Rodriquez, M., Arumugam, M., Allin, K., Engelbrechtsen, L., Hansen, T., Forman, A., Jonsson, A., Pedersen, O., Dutta, A., Vogt, J., Vestergaard, H., Laakso, M., Kokkola, T., Kuulasmaa, T., Franks, P., Giordano, N., Pomares-Millan, H., Fitipaldi, H., Mutie, P., Klintenberg, M., Bergstrom, M., Groop, L., Ridderstrale, M., Atabaki Pasdar, N., Deshmukh, H., Heggie, A., Wake, D., McEvoy, D., McVittie, I., Walker, M., Hattersley, A., Hill, A., Jones, A., McDonald, T., Perry, M., Nice, R., Hudson, M., Thorne, C., Dermitzakis, E., Viñuela, A., Cabrelli, L., Loftus, H., Dawed, A., Donnelly, L., Forgie, I., Pearson, E., Palmer, C., Brown, A., Koivula, R., Wesolowska-Andersen, A., Abdalla, M., McRobert, N., Fernandez, J., Jiao, Y., Robertson, N., Gough, S., Kaye, J., Mourby, M., Mahajan, A., McCarthy, M., Shah, N., Teare, H., Holl, R., Koopman, A., Rutters, F., Beulens, J., Groeneveld, L., Bell, J., Thomas, L., Whitcher, B., Hingorani, A. D., Patel, R. S., Hemingway, H., Franks, P. W., Bell, J. D., Banerjee, R., and Yaghootkar, H.

Abstract

Background & Aims: Excess liver iron content is common and is linked to the risk of hepatic and extrahepatic diseases. We aimed to identify genetic variants influencing liver iron content and use genetics to understand its link to other traits and diseases. Methods: First, we performed a genome-wide association study (GWAS) in 8,289 individuals from UK Biobank, whose liver iron level had been quantified by magnetic resonance imaging, before validating our findings in an independent cohort (n = 1,513 from IMI DIRECT). Second, we used Mendelian randomisation to test the causal effects of 25 predominantly metabolic traits on liver iron content. Third, we tested phenome-wide associations between liver iron variants and 770 traits and disease outcomes. Results: We identified 3 independent genetic variants (rs1800562 [C282Y] and rs1799945 [H63D] in HFE and rs855791 [V736A] in TMPRSS6) associated with liver iron content that reached the GWAS significance threshold (p <5 × 10−8). The 2 HFE variants account for ∼85% of all cases of hereditary haemochromatosis. Mendelian randomisation analysis provided evidence that higher central obesity plays a causal role in increased liver iron content. Phenome-wide association analysis demonstrated shared aetiopathogenic mechanisms for elevated liver iron, high blood pressure, cirrhosis, malignancies, neuropsychiatric and rheumatological conditions, while also highlighting inverse associations with anaemias, lipidaemias and ischaemic heart disease. Conclusion: Our study provides genetic evidence that mechanisms underlying higher liver iron content are likely systemic rather than organ specific, that higher central obesity is causally associated with higher liver iron, and that liver iron shares common aetiology with multiple metabolic and non-metabolic diseases. Lay summary: Excess liver iron content is common and is associated with liver diseases and metabolic diseases including diabetes, high blood pressure, and heart di, QC 20191128

Published
2019
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