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About Us

The Current Status and Structure of MAMMAG

MAMMAG’s basic and translational research programs fall into two inter-related programs: (1) Mitochondrial and Molecular Medicine and Genetics and (2) Germ Cell and Stem Cell Biology. Both programmatic areas encompass basic laboratory research, preclinical research using primarily mouse models of human disease, and translational research to convert MAMMAG’s basic science discoveries into new diagnostics and therapeutics. To advance this agenda, the Center must maintain top flight molecular, cellular and biochemical genetics facilities, advanced barrier research facilities for manipulating the mouse, and avant garde clinical and diagnostic programs.

The translational research efforts of the Mitochondrial and Molecular Medicine group include investigation of the role of mitochondrial dysfunction in the pathophysiology of a variety of in-born errors of metabolism, with particular emphasis on those in which the defective protein is either located in the mitochondrion (i.e. defects in fatty acid oxidation and in the urea cycle) or the abnormal protein interacts with the mitochondrion and inhibits a mitochondrial function and/or mitochondrial turnover (i.e. Amyotrophic Lateral Sclerosis (ALS), Parkinson Disease (PD), Alzheimer Disease (AD), etc.). A major clinical genetic objective of the Center is to establish human nuclear transplantation within MAMMAG for use in establishing HLA-matched human embryonic stem cells for therapeutics. This same methodology may also be used to rid the zygotes of women harboring deleterious mtDNA mutations of the tainted mtDNA, a concept that Dr. Wallace enunciated almost 20 years ago. The translational research efforts of the germ and stem cell biology program includes developing protocols for the environmental and genetic manipulation of mouse and human stem cells to generate differentiated cells including oocytes, development of nDNA and mtDNA technologies to generate individualized tissue replacement cells, development of protocols to stimulate tissue regeneration, and perfecting tissue cell replacement strategies.

Clinical Mitochondrial Medicine Program (MITOMED)

The Center’s Mitochondrial and Molecular Medicine Clinical Unit (MITOMED) has established functioning Biochemical and Molecular Genetic Diagnostics Laboratories with special emphasis on the analysis of mitochondrial diseases. Clinic patients are seen within the General Clinical Research Center on the first floor of Hewitt Hall.To integrate the Center’s clinical, biochemical and molecular findings, the Center sponsors a Tuesday morning monthly clinical round. The Center’s clinical rounds have already served to expand the horizons of all of the participants and have resulted in our making molecular diagnoses for several patients that have defied explanation in the Orange County medical community for years. Some of these discoveries include identifying patient mtDNA mutations which cause diabetes, dystonia and various other complex pediatric and adult phenotypes; identifying mtDNA polymerase γ mutations in patients with Alper’s Syndrome and Autosomal Dominant Ophthalmoplegia; discovering that mutations in the β-actin gene can cause dystonia; characterizing various mutations in the mitochondrial ORNT1 gene associated with the HHH Syndrome, etc. All of these successes have been accomplished on an entirely research basis. However, since Dr. Wallace pioneered the development of molecular diagnostic tests for mtDNA disease and he and his colleagues hold many of the seminal patents in this area, and these same tests were provided as standard-of-care billable service in our CMM diagnostics laboratory in Georgia for many years, the Center’s faculty and staff have worked diligently to get the Center’s Molecular and Biochemical Diagnostics Laboratories CLIA-certified. This permits us to officially report the results of our standard-of-care tests and research investigations to our patients and subjects (MITOMED).

Bioinformatics and Information Science (MITOMAP)

Our Center is best known for our web-based mitochondrial information service, MITOMAP (www.mitomap.org). MITOMAP was established by Dr. Wallace and Ms. Marie Lott, M.S. in the early 1990s to assemble and make available all information about the human mtDNA including its sequence, the functions it encodes, population variation, clinical mutations, somatic and cancer mutation, and pseudogene variation. The MITOMAP database is directed by Dr. Wallace, managed by Ms. Lott, and curated by Ms. Lott, Dr. Vincent Procaccio and Dr. Wallace.

A major research component of MITOMAP is the development of MITOMASTER. MITOMASTER is based on a mtDNA sequence database of 2455 complete mtDNA sequences collected from around the world. Within MITOMASTER, all of the human mtDNA variation has been arranged within a sequential mutational tree that has placed every sequence variant in sequential order back to the first human mtDNA in Africa about 200,000 YBP. MITOMASTER uses this wealth of information plus the clinical information available in MITOMAP to interpret the genetic variation that is found in each new mtDNA sequence. In our current version of MITOMASTER a potential user can input a clinical mtDNA sequence and our system will determine if the sequence is contaminated by nDNA pseudogene sequence, define the mtDNA lineage (haplogroup) and relevant ancient adaptive polymorphisms, factor out potential tissue-specific somatic mutations, identify all potential pathogenic mutations, determine if any of the mutations have been identified previously, and assess the potential pathogenicity of the remaining mutations. We are close to releasing MITOMASTER version 1 which will be linked directly with MITOMAP into an integrated web based mtDNA query system.

MAMMAG’s Affiliation with the Center for Stem Cell Biology

Drs. Donovan, Lock and Wallace all serve on the UCI Human Stem Cell Steering Committee. Together with Dr. MacGregor and Ms. Waymire, these faculty members are committed to building an internationally ranked program in Germ Cell and Stem Cell Biology at UCI and within MAMMAG. A key component that must be included in the Human Stem Cell Laboratory Program is the capacity to perform somatic cell nuclear reprogramming by nuclear transplantation into enucleated oocytes.