Introduction to special issue

A Question of Dose

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Science  09 May 2003:
Vol. 300, Issue 5621, pp. 925
DOI: 10.1126/science.300.5621.925

Metals have been adopted by biological systems because of their catalytic versatility, but their reactivity can also make them toxic at low concentrations. Hence they are classified as nutrients or poisons. But this is a misleading division, because many enzyme catalysts have reaction centers with diverse and variable metal associates. Such flexibility is useful for organisms living in metal-poor environments that may have to take what they can get, but it is potentially dangerous. Thus, the availability of trace metals may govern an organism's nutritional strategy in a particular environment. This special issue explores the double-edged nature of metal chemistry, how it can be exploited for our benefit, and the consequences if it is not tamed.


Transition metals, such as iron and copper, with their multiple oxidation states are vital for the cascades of electron transfer reactions that are characteristic of cellular processes. Without iron, life on our planet would be unrecognizable. It is the key to oxygen transport, photosynthesis, nitrogen fixation, and respiration in most modern organisms. How the complexity and organization of these processes originated is a matter of conjecture, but the traces of these beginnings may lie in the modern preponderance of iron-sulfur clusters in key enzymes (Rees and Howard, p. 929). Normal, healthy cells may concentrate high levels of several metals, and to avoid poisoning, metals must be sequestered and transported by specific proteins. Ensuring easy and rapid transfer of such enveloped metals to their target proteins requires unusual coordination chemistry (Finney and O'Halloran, p. 931). Metals in cells are substantially influenced by cell signaling networks [see this week's STKE Focus issue (]. For example, nitric oxide affects the regulation of iron metabolism in response to inflammation (Bouton and Drapier in STKE). Zinc is also emerging as a transynaptic messenger, and zinc-sensitive dyes and imaging techniques have galvanized neurobiology (Li et al. and Frederickson in STKE).

Complexation in a larger nontoxic molecule is also the key to exploiting metal chemistry for therapeutic purposes (Thompson and Orvig, p. 936). But there is still a fine line between poisoning and salvation. Despite Paul Ehrlich's pioneering use of the arsenic-containing drug salvarsan to treat syphilis, arsenic is now more known for its contamination of borehole water supplies in southern and central Asia. Although those water supplies are no longer contaminated by pathogens, other bacteria capable of metabolizing arsenic appear to be involved in mobilizing the poison into the groundwater (Oremland and Stolz, p. 939). In contrast, the ubiquity of other metals in the environment sometimes makes it hard to discern their impact. For example, manganese is an essential trace element in the human diet, but when inhaled in mines it can trigger psychotic behavior and Parkinson's-like symptoms; it's unclear, however, whether low-dose exposures from car exhausts are harmful (see the News story by Kaiser, p. 926).

In the oceans, metals are vanishingly scarce. Despite this dearth, microscopic plankton are the source of more than half the planet's primary production via metal-driven reactions. To be productive in these metal “deserts,” special salvage molecules have to be employed by planktonic organisms, but identifying such agents in the vastness of the open ocean is challenging. In this environment, both microorganisms and scientists are operating at the limits of what is biologically and experimentally feasible (Morel and Price, p. 944). In the world of the “metallome,” it is indeed a narrow path between poison and nutrient.

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