Nature or Nurture? How much genes determine our fate and how much they are influenced by the environment is a key question of our times and central to the advent of personal genomes and precision medicine. The two times 23,000 genes in the human genomes (a set each from mother and father) are regulated in space and time during the development from fertilized egg to full organism and in all the organs dependent on internal gene circuits integrated with extracellular clues like hormones, nutrients, cell-cell interactions as well as extrinsic influences such as light, music, stress, exercise etc. There are many gene regulatory layers and modes that determine the level of activity of any given gene in the gene “concert”. Epigenetic mechanisms (all mechanisms that are not primarily dependent on the gene sequence itself) are particularly interesting in the dialog with the environment as they carry a “memory” effect that can be passed on to daughter cells and can thus contribute to establish cellular “states” in which cells have adopted a particular function by interpretation of the various external clues (Jaenisch and Bird, 2003).
One major source of such clues is nutrition and, more generally, chemical exchange between our body and the environment (Corthesy-Theulaz et al., 2005). The minimal entity of life is the cell and cells represent the building blocks of multicellular organisms such as humans. All cells are surrounded by a lipid bilayer representing a “greasy seal” between the aqueous inside of the cell and the outside. Yet the cells require to import nutrients, water, ions to sustain their internal metabolism to produce energy and the building blocks required to safeguard and replicate the genetic material and the rest of the cellular infrastructure. While only a few molecules are thought to be able to pass through the fat membrane surrounding cells, the vast majority of molecules require transporters to enter cells (Giacomini et al., 2010). Sugars, amino acids, nucleotides, vitamins, water, ions but also “strange” molecules from other organisms or man-made, such as natural and synthetic drugs, dyes, food additives, molecules from cosmetics: all appear to require transporters encoded by our genomes (Hediger et al., 2013; Kell et al., 2011). So, our genome encodes for the proteinaceous entities that regulate access to the environment. What are these entities? What do they transport? Transporters comprise solute carriers, ion channels, water channels, and ATP-driven pumps, including ABC transporters(Hediger et al., 2013). Solute carrier proteins (SLCs), form the largest group, with some 400 genes, divided in some 50 families that can be further phylogenetically grouped. Solute carriers are membrane integral proteins localized on the cell surface and on organelles and comprise facilitative transporters and secondary active transporters (symporters and antiporters). SLCs are the second largest family of genes in the human genome after the GPCRs. Many of them are drug targets or associated with developmental and metabolic disorders. Others are known to transport drugs (fortuitously, see for example (Winter et al., 2014)). Yet we do not know the function of the vast majority of these and what these transport. Some speak directly to the molecular complexes that regulate metabolism in the cell (Rebsamen et al., 2015; Wang et al., 2015). Overall, these transporters must be highly active. It is said: You are what you eat. Every year, some 98% of your body is estimated to be renewed, consisting of new atoms, from the 26 or so elements that constitute the human body (Gibney et al 2013). Another rough estimate is that on average, humans take in some 1 ton of food every year. While part of it is secreted, processed one way or the other, the rest is mainly taken up through dedicated transporters, mainly of the SLC family. As there are SLC-corresponding/equivalent genes in all living species, also the bacteria in our guts that help with food processing and metabolism use them to transport molecules. Bacterial communities undergo chemical exchanges with each other to regulate communal growth and balance (Straight and Kolter, 2009). The food that humans have taken in likely has involved transport of chemical matters through transporters, typically the transport of nutrients from the soil into plant roots and the body and fruits. So, it can be argued that a lot of chemical matters, literally tons and tons, travels through membranes across the ecosphere and through our cells and yet we are quite oblivious of what determines the rate and the quality of the transport and how it may affect human health. Our genomes is bathed in this imported and transformed chemical matters, in fact it consists of it. Yet we know very little of the relationships between the human genomes, with it variants and the environment, with its supply of nutrients and chemicals but also an object of human intervention (through effects of humans on their environment). If a monsoon is delayed in its seasonal onset or a war rages somewhere creating disruption of agriculture or large amounts of refugees, it all can affect the nutrition of many people world-wide. One can argue, that it will also change the pattern of gene expression in a great variety of people. As disease can be considered the successful perturbation of cellular and organismic homeostasis, and therefore of gene expression, one can continue the argument saying that these global effects will affect the individual gene expression pattern in people. For all these reasons, it appears important to consider the effect of the individual variants in genomic sequence of individual humans as determined also by the environment. Personalized or precision medicine will be dependent on both, the genes and the environment. We are far away from understanding the molecular basis for individual interactions with the environment, apart from food and drug intolerance.
Surely the day will come when we will look at the current gene-centric, organ-centric and anthropo-centric view of health sciences era as short-sighted. Extrapolating from what we start understanding only in very rough terms now, it is clear that medical sciences in the future will have to be medical environmental sciences. The health of the human individual will only be possible within the health of the environment. Ultimately on a global, planetary level and certainly, through food production and parameters such as hygiene education, with society at large.
These are some of the questions worth discussing in Lindau:
• How can all of the above view be challenged?
• How can we start measuring and modeling the flow of chemical matter in and out of our bodies?
• How can we identify the mechanism and specificity of all transporters in the human genome?
• How can we measure chemical dependencies across organisms (plant, animal, microbes, humans)?
• How can we predict effects based on the sequence of genomes of individuals?
• How can we measure the long-term effect of chemical (broadly speaking) exposure to our genes?
• How can we measure the chemical impact/footprint of humans on their environment?
Corthesy-Theulaz, I., den Dunnen, J.T., Ferre, P., Geurts, J.M., Muller, M., van Belzen, N., and van Ommen, B. (2005). Nutrigenomics: the impact of biomics technology on nutrition research. Ann Nutr Metab 49, 355-365.
Giacomini, K.M., Huang, S.M., Tweedie, D.J., Benet, L.Z., Brouwer, K.L., Chu, X., Dahlin, A., Evers, R., Fischer, V., Hillgren, K.M., et al. (2010). Membrane transporters in drug development. Nat Rev Drug Discov 9, 215-236.
Gibney, M.J., Lanham-New, S.A., Cassidy, A., Vorster, H.H. (2013). Introduction to human nutrition. Wiley-Blackwell. 2nd edition.
Hediger, M.A., Clemencon, B., Burrier, R.E., and Bruford, E.A. (2013). The ABCs of membrane transporters in health and disease (SLC series): introduction. Mol Aspects Med 34, 95-107.
Jaenisch, R., and Bird, A. (2003). Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat Genet 33 Suppl, 245-254.
Kell, D.B., Dobson, P.D., and Oliver, S.G. (2011). Pharmaceutical drug transport: the issues and the implications that it is essentially carrier-mediated only. Drug Discov Today 16, 704-714.
Rebsamen, M., Pochini, L., Stasyk, T., de Araujo, M.E., Galluccio, M., Kandasamy, R.K., Snijder, B., Fauster, A., Rudashevskaya, E.L., Bruckner, M., et al. (2015). SLC38A9 is a component of the lysosomal amino acid sensing machinery that controls mTORC1. Nature.
Straight, P.D., and Kolter, R. (2009). Interspecies chemical communication in bacterial development. Annu Rev Microbiol 63, 99-118.
Wang, S., Tsun, Z.Y., Wolfson, R.L., Shen, K., Wyant, G.A., Plovanich, M.E., Yuan, E.D., Jones, T.D., Chantranupong, L., Comb, W., et al. (2015). Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347, 188-194.
Winter, G.E., Radic, B., Mayor-Ruiz, C., Blomen, V.A., Trefzer, C., Kandasamy, R.K., Huber, K.V., Gridling, M., Chen, D., Klampfl, T., et al. (2014). The solute carrier SLC35F2 enables YM155-mediated DNA damage toxicity. Nat Chem Biol 10, 768-773.