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- Deficiencies in iron and zinc are global health issues, which are currently addressed by supplements and fortification programmes. In the developing world, iron supplements are an integral part of aid programmes and combatting anaemia is a major priority of the World Health Organization. Closer to home, low serum iron levels are prevalent in ~5% of females aged 11 - 64 (National Diet and Nutrition Survey 2012) correlating with low iron intake. To combat iron deficiency, all flours milled in the UK are chemically fortified with iron salts or iron powder up to 16.5 mg/kg (UK Flour Regulations 1998). The natural variation of iron in modern bread wheat is limited within the range of 6 - 13 mg/kg in white flour. Fertilization experiments have shown that extra iron is not taken up by plants. Therefore, increasing iron and zinc levels using genetic methods, known as biofortification, is the most sustainable approach to increase mineral levels in our diet which is dominated by a few staple crops. The limited variation in iron levels in bread wheat has been attributed to a number of factors. Over centuries, crop varieties have been selected for yield, at the cost of micronutrient content. Moreover, polyploid crops such as wheat are genetically buffered: gene variants that could change a certain trait are masked by other copies of the same gene, which makes it hard to select novel traits. In addition, iron levels are tightly regulated by plants to prevent over-accumulation of this metal that is toxic in its free ionic form. And last but not least, cereals have not evolved to put large amounts of minerals into the starchy endosperm, the part of the grain that we prefer to eat. In a very successful collaboration between the Balk and Uauy labs, we have recently found that, against expectations, iron and zinc levels in white flour from wheat or barley can be increased 3- and 2-fold, respectively. Element analysis showed that the iron levels of white flour were 16 - 17 mg/kg, similar to the legal requirement for fortification, and higher still in wholemeal flour. This was achieved by a cis-genics approach: wheat plants were genetically modified but the sequences are from wheat itself. We placed an endosperm-specific regulatory sequence in front of a wheat iron transporter. Our results show that, in principle, plants can direct much more iron and zinc to the endosperm than they do naturally. Moreover, there does not seem to be any major negative effect on growth. While the timely overexpression of the vacuolar iron transporter works remarkably well in boosting iron and zinc levels in grain, we do not yet understand why this strategy is so successful. After all, the up-regulated gene is a simple transporter and not a regulator. If we draw an analogy to traffic flow, increasing the number of lanes on the M25 does not per se improve traffic flow. Access roads, junctions and so on all need to be widened to increase traffic and prevent congestion. Also, we found that the transporter is specific for iron and cannot transport zinc. So why are zinc levels increased? To exploit our findings for biofortification, we will investigate the molecular and cell biological changes that underlie increased mineral transfer in the high-iron wheat line. We will also investigate what the source of iron and zinc is, for example if the plants take up more iron from the soil or whether the iron is more efficiently remobilized from other parts of the plant. We will then use this information to develop non-GM strategies to increase iron and zinc in wheat and other cereals. The bioavailability of the iron and zinc will be tested by offering digested white flour and bread to cultured intestinal cells. Taken together, these studies will greatly enhance our knowledge on nutrient transport, provide us with novel and non-GM strategies to increase the nutritional quality of wheat and give us a way to assess their impact on human nutrition.