Precisely how much of each vitamin or mineral should be in the human diet has long been a matter of research and discussion. In 1941, an official body of experts in the United States published a compendium of Recommended Dietary Allowances (RDAs) that has been updated periodically ever since. For each nutrient, this book lists the daily ingestion levels judged adequate to meet the standard nutritional requirements of a normal healthy person of given age, sex, and physical condition. The adult RDA for zinc is 15 mg, for example, and that for riboflavin (vitamin B2) is 1.7 mg. The lists were later expanded as a series of Dietary Reference Intakes (DRIs) that also include upper bounds on tolerable ingestion levels. These are important too, because there is circumstantial evidence that particular vitamins in large doses reduce the risk of cardiovascular disease and some cancers, or slow the aging process; and, on the other hand, that high-dose levels may also have some toxic effects.
One important nutrient is tocopherol (vitamin E), an antioxidant naturally synthesized only in the chloroplasts of photosynthetic organisms. The RDA for tocopherol is 7—9 mg, an amount readily obtained from a diet rich in leafy vegetables, grains, and vegetable oils. However, 10—100 times higher daily intakes of tocopherol have been associated in some scientific studies with decreased risks of various chronic disorders and degenerative diseases. Such massive quantities of tocopherol are well beyond what is consumed in a normal diet, but some scientists envision engineering food crops that will deliver these higher therapeutic levels of vitamin E.
Tocopherols come in several natural types that differ slightly in important chemical details. Two of these (a-tocopherol and g-tocopherol) are equally absorbed by the human gut, but the a form is preferentially retained and distributed throughout the body and delivers higher effective doses of vitamin E. Unfortunately, in oilseed crops (corn, soybean, canola, cottonseed, and palm) that are primary sources of vitamin E in the human diet, g-tocopherol is about 10 times more abundant than a-tocopherol. In the biosynthetic pathway for a-tocopherol in these and other plants, the final biochemical step involves the conversion of the g form to the a form by the enzyme g-tocopherol methyl-transferase (g-TMT). Thus, one notion is that if g-TMT expression could be elevated in oilseed or other edible plants, more of their g-tocopherol might be converted to a-tocopherol, thereby enriching human diets in useful vitamin E.
In 1998, one key research step toward this goal was achieved using an odd hodgepodge of organisms: a photosynthetic bacterium (Synechocystis), a microbe (Agrobacterium) that induces tumors in plants, a flowering mustard plant (Arabidopsis), and garden carrots. The following thumbnail sketch of technical events is intended merely to illustrate the molecular complexities as well as researcher ingenuity that often underlie transgenic experiments in agricultural genetic engineering.
First, the gene for g-TMT in Synechocystis was isolated and used to identify and characterize the mode of action of the counterpart gene in Arabidopsis. This knowledge proved useful in the design strategy for a genetically modified form of Arabidopsis that overexpressed g-TMT. The transgenic DNA consisted of a seed-specific promoter sequence isolated from the carrot, joined to the Arabidopsis gene for g-TMT, all cloned and delivered into Arabidopsis by the transformation vector Agrobacterium (see "Galls and Goals" in the appendix). Once in Arabidopsis, the promoter sequence did as intended; it stimulated high expression of the adjacent g-TMT gene, specifically in seeds. The net outcome was that much more of the g-tocopherol was converted to a-tocopherol, and the concentration of the latter increased dramatically. As a result, the effective vitamin E activity in the transgenic Arabidopsis seeds was elevated by approximately ninefold.
Tocopherols and other vitamins are organic compounds, the biological products of biosynthetic pathways that in principle are potentially subject to genetic manipulations of this sort. Does this mean that inorganic minerals (composing the other major class of dietary supplements) are unsuitable for bioengineering? Not necessarily, as the following example illustrates.
Most crop plants take up minerals from the soil, but the efficiency of the process and how and where the minerals are stored in various tissues are among the variables that influence the available concentrations of these dietary supple ments to humans. For example, spinach and leguminous crops are renowned for their high iron content, whereas the seeds of cereal grains are much poorer in this mineral. In an attempt to improve this latter situation, geneticists recently engineered a new strain of transgenic rice whose grains contain threefold more iron than normal rice.
The first step involved isolating the DNA sequence for an iron-storage protein (ferritin) from soybeans. Next, a regulatory DNA sequence was identified and isolated that promotes gene expression specifically in rice seeds. Then, using Agrobacterium as a transformation vector, this ferritin gene and its regulator were inserted into experimental rice plants. The transgenic rice has triple the iron content of its predecessor, meaning that even one meal-sized portion of the new cultivar would provide about 40% of the adult RDA for this essential mineral.
These experimental protocols for engineering the vitamin and mineral contents of plants pave intriguing paths leading to the nutritional enrichment of economically important food crops. Further research must establish whether such approaches are technically, socially, and economically feasible on commercial scales and also whether there are any possible effects harmful to human health. For example, too much vitamin D can be toxic. Also, a recent study published in the Journal of the American Medical Association concluded that too much vitamin A in the diet of older women may increase their risk of hip fractures significantly. One hypothesis is that too much vitamin A may inhibit the ability of vitamin D to help the body absorb calcium, a mineral needed for strong bones and for hormone production.
Another question must also be explored: Are the transgenic crops themselves negatively affected in any way by the genetic alterations? The metabolic pathways of living creatures, including those underlying the production, transport, or storage of vitamins and minerals, are marvelously tuned outcomes of millennia of evolutionary processes, so any precipitous alterations (such as the wholesale conversion of g- to a -tocopherol, or the tripling of iron content in seeds) might have some unexpected consequences for the plants.
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