Variation within genes has important implications for all biological traits. We identified 3899 single nucleotide polymorphisms (SNPs) that were present within 313 genes from 82 unrelated individuals of diverse ancestry, and we organized the SNPs into 4304 different haplotypes. Each gene had several variable SNPs and haplotypes that were present in all populations, as well as a number that were population-specific. Pairs of SNPs exhibited variability in the degree of linkage disequilibrium that was a function of their location within a gene, distance from each other, population distribution, and population frequency. Haplotypes generally had more information content (heterozygosity) than did individual SNPs. Our analysis of the pattern of variation strongly supports the recent expansion of the human population.

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Gross inequities in disease burden between developed and developing countries are now the subject of intense global attention. Public and private donors have marshaled resources and created organizational structures to accelerate the development of new health products and to procure and distribute drugs and vaccines for the poor. Despite these encouraging efforts directed primarily from and funded by industrialized countries, sufficiency and sustainability remain enormous challenges because of the sheer magnitude of the problem. Here we highlight a complementary and increasingly important means to improve health equity: the growing ability of some developing countries to undertake health innovation.

This paper highlights the growing capacity for innovation in some developing countries. To maximize the potential of this phenomenon for global health, countries and donors need to link two disparate schools of thought: (1) a search for technological solutions exemplified by global public-private product development partnerships, and (2) a focus on systemic solutions exemplified by health policy and systems research. A strong capacity for both technological and social innovation in developing countries represents the only truly sustainable means of improving the effectiveness of health systems. Local publicprivate research and development partnerships, implementation research, and individual leadership are needed to achieve this goal. [Health Affairs 26, no. 4 (2007): 1052-1061 10.1377/hlthaff.26.4.1052 I n c o ll o q u i a l us e , t h e t e r m " i n n ovat i o n " is often seen as synonymous with "invention." To the global health community, "innovation" may carry baggage associated with patents and the high cost of medicines. However, the definition used by economists is far broader than invention and is highly relevant to considerations of access: It encompasses the entire process-from idea to implementation-for new products, services, processes, practices, and policies. 1 Improving access to essential products and services requires three forms of innovation: technological, to ensure availability of products that are more cost-effective than existing interventions; social, to ensure the distribution of essential goods and services; and adaptive, involving both providers and communities, to contextualize the adoption of goods and services to local settings.2 Technological solutions in health include new drugs, devices, diagnostics, and vaccines. Social and adaptive solutions include new ways to organize human resources, information, and decision making in health systems. In all cases, innovation involves both the solution and its implementation.Unfortunately, "technological utopians" and "systems utopians" seem to speak 1 0 5 2 J u l y /A u g u s t 2 0 0 7 C o m m e n t a r y

Phenylalanine hydroxylase (PAH) is a tetrahydrobiopterin-dependent, nonheme iron enzyme that catalyzes the hydroxylation of L-Phe to L-Tyr in the rate-limiting step of phenylalanine catabolism. This reaction is tightly coupled in the wild-type enzyme to oxidation of the tetrahydropterin cofactor. Dysfunction of PAH activity in humans leads to the disease phenylketonuria (PKU). We have investigated two PKU-inducing mutants, Arg158Gln and Glu280Lys, using kinetic methods, magnetic circular dichrosim (MCD) spectroscopy, and X-ray absorption spectroscopy (XAS). Analysis of the products produced by the mutant enzymes shows that although both oxidize pterin at more than twice the rate of wild-type enzyme, these reactions are only approximately 20% coupled to production of L-Tyr. Previous MCD and XAS studies had demonstrated that the resting Fe(II) site is six-coordinate in the wild-type enzyme and converts to a five-coordinate site when both L-Phe and reduced pterin are present in the active site. Although the Arg158Gln mutant forms the five-coordinate site when both cosubstrates are bound, the Fe(II) site of the Glu280Lys mutant remains six-coordinate. These results provide insight into the PAH reaction and disease mechanism at a molecular level, indicating that the first step of the mechanism is formation of a peroxy-pterin species, which subsequently reacts with the Fe(II) site if the pterin is properly oriented for formation of an Fe-OO-pterin bridge and an open coordination position is available on the Fe(II).

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The tremendous potential of genomics to contribute to significant healthcare innovations in the developing world will not be realised without attention to governance. Governments, industries and citizens will encounter numerous ethical issues in achieving a balance between risk management and the promotion of the benefits of genomics. We need a governance mechanism that maintains a balance between the global public goods characteristics of genomics knowledge and the private goods nature of its application. Networks may well be an appropriate way of preventing a bleak future of increasing disparities between industrialised and developing countries. An informed debate that attempts to exchange the politics of polarisation with a truly participatory process would be worth pursuing. Consequently, this paper proposes a Global Genomics Initiative (GGI) that would provide such a forum.

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