Mitochondria as chi.

WESTERN medicine is in crisis. Continually increasing resources are being expended to combat the age-related diseases that include diabetes and metabolic syndrome, Alzheimer’s disease, Parkinson’s disease, cardiovasculardisease, andcancer.Yet thecauses of these diseases remain a mystery, while their incidence and morbidity either remain constant or are increasing (Wallace 2005b). Huge investments in biomedical research in the recent past have resulted in some striking accomplishments, including the sequencing of the human chromosomal DNA (Lander et al. 2001; Venter et al. 2001), the identification of hundreds of thousands of human chromosomal single nucleotide polymorphisms (SNPs), and the identification of regional clusters of chromosomal SNPs (the HapMap) (International HapMap Consortium et al. 2007). However, these accomplishments have failed to reveal the anticipated genetic causes for the common age-related diseases. For example, a series of ‘‘whole-genome scans’’ encompassing hundreds of thousands of chromosomal SNPs and .32,000 subjects has revealed nine polymorphic loci associated with type II diabetes, yet the aggregate risk for all nine loci accounts for only a small proportion of the overall diabetes risk (Saxena et al. 2007; Scott et al. 2007; Sladek et al. 2007; Zeggini et al. 2007). Thomas Kuhn, in his book The Structure of Scientific Revolutions (Kuhn 1996), argued that when the scientific effort expended on a problem increases—yet productivity declines—then the difficulty may lie with the assumptions (paradigms) on which the research is based. For the past 100 years, Western biomedical science has stood on two philosophical pillars: the anatomical paradigm of medicine and the Mendelian paradigm of genetics. The anatomical paradigm of medicine has at its foundation the work of Vesalius, who first described the organs of the human body 450 years ago. Since then, physicians and medical scientists have specialized in individual organs and their associated disease manifestations, leading to the fields of neurology, ophthalmology, nephrology, cardiology, endocrinology, etc. The organ-specific compartmentalization of medicine has also led to several generally accepted corollaries: organ-associated symptoms are the result of organspecific problems, organ-specific problems are the result of tissue-specific protein and gene defects, and tissuespecific protein defects should be treated with chemicals that specifically interact with the defective tissue-specific protein. The Mendelian paradigm of genetics argues that genetic traits are transmitted across generations according to the laws of Gregor Mendel. The associated medical corollary is that if a clinical trait is transmitted in a Mendelian fashion, it is genetic, but if it is not, then the trait must be the consequence of environmental factors. This corollary is formalized through the estimation of heritability by dividing the frequency that a phenotypic trait is shared by identical twins with the frequency that it is shared by fraternal twins. However, since Mendelian genetics is the result of chromosomal dynamics, the Mendelian paradigm is specific for nuclear DNA (nDNA) genes. While the anatomical paradigm of medicine and the Mendelian paradigm of genetics have been powerful predictors of medical relationships for the past century, they are failing to direct us toward solutions for the common age-related diseases. According to Kuhn, when a prevailing paradigm fails to make productive predictions, then hypothesis-based research begins to fail. To resolve the crisis and return to productive ‘‘normal science,’’ a new paradigm must be generated that encompasses the strengths of the previous paradigm but Address for correspondence: Center for Molecular and Mitochondrial Medicine and Genetics, Hewitt Hall 2014, University of California, Irvine, CA 92697-3940. E-mail: [email protected]