History of the Center for Mitochondrial and Epigenomic Medicine (CMEM)

The Center for Mitochondrial and Epigenomic Medicine at the Children’s Hospital of Philadelphia (CHOP) is the product of over forty years of evolution in the field of Mitochondrial Medicine. Based on research from the Wallace laboratory beginning in the early 1970s which defined the rules of human mitochondrial DNA (mtDNA) genetics through studies in the 1980s on human mtDNA variation and its role in human evolution, the stage was set in 1988 for the report by the Wallace laboratory of the first maternally inherited mtDNA diseases: Leber Hereditary Optic Neuropathy (LHON) and Myoclonic Epilepsy and Ragged Red Fiber Disease (MERRF) (6, 7). At that juncture, a center was conceived and established that would bring patients, physicians, and scientists together to determine the role of bioenergetic dysfunction in causing both rare and common complex diseases and to develop new diagnostics and therapeutics to address these pressing clinical problems.

The first center was founded at Emory University by Douglas C. Wallace, director and Robert W. Woodruff Professor of Molecular Medicine, and called the Center for Molecular Medicine (CMM). CMM combined a strong basic research program in mitochondrial and germ cell biology with a robust clinical program encompassing a Mitochondrial Medicine Clinic and Mitochondrial Molecular and Biochemical Diagnostic Laboratory. Through this center, many “complex” diseases were shown to be the result of mitochondrial gene dysfunction and the nature and breadth mtDNA variation was used to reconstruct the origins and ancient migrations of women.

To increase global awareness of mtDNA variation and disease and to assure that accurate information would be available to global scientists, physicians, and patients, CMM developed the web-based, curated, mtDNA information service, MITOMAP. MITOMAP was complemented MITOMASTER, a compendium of mtDNA information analysis tools. MITOMAP and MITOMASTER have since become the definitive resources on global human mtDNA variation. With these innovations CMM soon became the world’s premier center in the emerging field of mitochondrial diseases.

In 2002, Dr. Wallace moved CMM to the University of California, Irvine (UCI) to bring the mitochondrial medicine and germ cell biology programs to Southern California. As the Donald Bren Professor of Molecular Medicine, Wallace reconfigured CMM as the Center for Molecular and Mitochondrial Medicine and Genetics (MAMMAG). At UCI MAMMAG encompassed four interrelated units: a Mitochondrial and Stem Cell research and educational unit (MITORES), a Mitochondrial Medicine Clinical Unit (MITOMED), a Mitochondrial Medicine Information Unit (MITOMAP), and a private sector Interface Unit (MITOCORP).

During the eight years that MAMMAG functioned in Southern California, broad progress was made in understanding the role of mitochondrial genetics and bioenergetics in human evolution and disease. Human evolution studies demonstrated that regional mtDNA variation was functional and relevant forhuman adaptation to different regional environments. Moreover, this ancient adaptive mtDNA variation was shown to be an important factor in the predisposition to a variety of common diseases.

Studies on complex diseases confirmed the central role of mitochondrial dysfunction in a broad range of diseases, both rare multisystem diseases and common complex diseases such as Alzheimer and Parkinson Disease, autism, diabetes and metabolic syndrome, cardiac and muscle diseases, renal dysfunction, endocrine disorders, cancer and aging. Studies on germ and stem cell biology revealed the profound importance of bioenergetics for developmental biology and implicated the mitochondrial regulation of the epigenome as central to a variety of diseases.

The fact that the mitochondrial genome encompasses between one and two thousand nDNA-coded mitochondrial genes plus the thousands of copies of the mtDNA necessitates a close interaction between the nucleus and its cytoplasm and the mitochondria. One important factor in this interaction is the mitochondrial modulation of high energy intermediates, metabolites, reactive oxygen species, and redox state, all of which impinge of the cellular signal transduction systems and the epigenome. The close affinity between mitochondrial bioenergetics and the epigenome were validated through experiments conducted within MAMMAG.

To solidify the center’s mission on mitochondrial bioenergetics and epigenomics, Wallace again relocated the center to the CHOP in 2010 and renamed the center the Center for Mitochondrial and Epigenomic Medicine (CMEM). In addition to directing the center, Wallace was appointed the Michael and Charles Barnett Chair in Pediatric Mitochondrial Medicine and Metabolic Disease. By focusing on the non-traditional forms of inheritance, CMEM has continued to clarify the etiology of both rare and common complex diseases using the newest biomedical technologies including next generation sequencing, advanced imaging, innovative animal disease models, and bioinformatic systems biology and complex data analysis. These new approaches are being applying to a broad range of clinically relevant problems ranging from the preimplantation embryo through the child to our oldest citizens. Special emphasis is being given to understanding the etiology of the diseases and developing effective preventative and interventional therapies.

REFERENCES

1. Wallace DC, Bunn CL, Eisenstadt JM (1975) Cytoplasmic transfer of chloramphenicol resistance in human tissue culture cells. J Cell Biol 67:174-188, 1975.
2. Giles RE, Blanc H, Cann HM, Wallace DC (1980) Maternal inheritance of human mitochondrial DNA. Proc Natl Acad Sci USA 77:6715-6719.
   Denaro M, et al. (1981) Ethnic variation in Hpa 1 endonuclease cleavage patterns of human mitochondrial DNA. Proc Natl Acad Sci USA 78:5768-5772.
3. Merriwether DA, et al. (1991) The structure of human mitochondrial DNA variation. J Mol Evol 33:543-555.
4. Wallace DC, et al. (1988) Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242:1427-1430.
5. Wallace DC, et al. (1988) Familial mitochondrial encephalomyopathy (MERRF): Genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease. Cell 55:601-610.
6. Shoffner JM, et al. (1990) Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNALys mutation. Cell 61:931-937.