Overall Research Goals:
My research interest over the past decade has focused on scaling up biochemical knowledge for gaining a deeper understanding of the molecular basis of neurodegenerative and neuropsychiatric disorders and finding ways to optimize their treatment. I have also made seminal contributions to the development of the metabolomics field and applications of metabolomics for the study of drug effects, establishing foundations for “Pharmacometabolomics”, a discipline that complements and informs pharmacogenomics and enables Precision Medicine initiatives. Over the next five years, I will continue to expand on these directions and applications of a systems biochemical approach, hoping to contribute in significant ways to President Obama’s Alzheimer’s Initiative as well as to Precision Medicine national and global initiatives. At the heart of my research is a deeper understanding of neuropsychiatric disease mechanisms, disease heterogeneity, and optimization of treatment for patients based on genotype, metabotype, microbiome activity and environmental influences and strategies for personalizing and optimizing treatment outcomes.
Biographical History and Educational Background:
With training in chemistry and biochemistry at the American University of Beirut during my PhD work, training in molecular biology during post-graduate training at Johns Hopkins (worked with Nobel Laureate Hamilton Smith) and with subsequent training in genetics and molecular biology at Massachusetts General Hospital (MGH) and the Massachusetts Institute of Technology (MIT), I have gained a strong foundation in basic research. This broad training has enabled me to use integrated approaches and tools to solve problems in biology and to build foundations for a “systems biology” approach for the study of neuropsychiatric diseases and a “systems pharmacology” approach for the study of drug effects. During my work at MIT and while working closely with Professor Paul Schimmel, who played a seminal role in the evolution of the biotechnology industry, I developed a strong appreciation for applications of basic research and realized the importance of translation research and paths to develop new therapies based on novel findings. I have cofounded three biotechnology companies toward achieving this goal, the most recent being Metabolon, a biotechnology company that has played a central role in developments and applications of metabolomics in the medical field. I joined the Duke Department of Psychiatry and Behavioral Sciences in 2005 as an Adjunct Associate Professor while transitioning out of Metabolon, then in 2006 became a full-time Associate Professor focusing on a deeper understanding of the molecular basis of neuropsychiatric diseases, and devoted significant time to the development of the metabolomics field and its applications. While at Duke, I have played scientific leadership roles nationally and internationally, led large consortia that created new scientific disciplines, made major contributions toward defining novel mechanisms in neuropsychiatric diseases and raised close to 20 million dollars for research funding (mainly NIH with not-for-profit and for-profit funding) in areas of precision medicine.
Academic Achievements and Scholarship:
Areas of research in which I have made significant contributions include:
- The study of metabolic impairments in neuropsychiatric diseases including depression, schizophrenia and Alzheimer’s disease.
- Metabolomics technologies and applications for the study of human disease and treatment outcomes; helped create a community of metabolomics researchers.
- Established foundations for “Pharmacometabolomics”, a new field for the application of metabolomics for the study of drug effects and variation of response to treatment as enabling tools for precision medicine. Contributed to the rapidly growing field of “Quantitative and Systems Pharmacology” by linking the metabolome and genome and drug response.
- Made several discoveries on the role of the gut microbiome in neuropsychiatric diseases and response to treatment.
- Helped move basic research from bench to clinic with discoveries concerning creatine kinase and energy impairment in neurodegenerative diseases.
Below I exemplify from work that was done through large consortia and networks that I have built with NIH funding.
Metabolic failures in neuropsychiatric diseases: Ground-breaking work was done in applying metabolomics and lipidomics tools for the study of neuropsychiatric diseases. More than twenty published papers have brought totally new insights about pathway and network changes in these disorders.
A. Studies in Schizophrenia - Using lipidomics technologies, we identified major changes in membrane structure and function that happen very early in the disease process. Lipid metabolism defects were noted both centrally and peripherally, suggesting that the disease is systemic and affects different organs. By using complimentary metabolomics platforms and focusing on neurotransmitters and related pathways, we provided new support to the idea that the different hypotheses of schizophrenia (dopamine, serotonin, glutamate) seem to be all part of one hypothesis due to interconnectedness within these pathways and have moved to evaluate failures within a metabolic network context. We provided the first lipidomics map for three atypical antipsychotic drugs and defined signatures that correlate with response to treatment.
B. Studies in Depression - Metabolomics studies in major depression revealed changes in mitochondrial beta oxidation, lipid metabolism and neurotransmission, with remission showing a unique metabolic state. For the first time, we mapped global changes related to the use of three antidepressants (selective serotonin reuptake inhibitors [SSRIs]) and defined pathways implicated in response and slow progressive metabolic changes that might explain delayed response to these medications. We defined metabolic changes correlated with response to placebo and compared that to response to SSRIs. We generated new hypotheses regarding the mechanism of action for the rapid-acting drug ketamine. Such studies, if validated, can provide powerful tools for patient sub-classification and the streamlining of clinical trials, as well as insights for novel drug discovery.
C. Studies in Alzheimer’s Disease - Over the past four years, we have assembled an interdisciplinary team of experts in metabolomics, genetics, biochemistry, bioinformatics, biomarker discovery and clinical trials, and have begun to define perturbations in interlinked biochemical pathways across the trajectory of Alzheimer’s disease (AD). Using non-targeted lipidomics platforms, we defined changes in phosphatidyl cholines (PC), plasmalogens and the sphingolipidome. These changes suggest alterations in membrane structure and function in AD. Using targeted and non-targeted metabolomics platforms, we have identified defects in the methionine (MET)/one carbon metabolism pathway – this pathway regulates fundamental cellular methylation processes, including steps in phospholipid biosynthesis. It also generates homocysteine, the elevation of which has been linked to neurotoxicity, oxidative stress, DNA damage, and increased risk for both stroke and dementia. Perturbation in the interconnected neurotransmitter systems norepinephrine (NE) and tryptophan (TRP) and the linked purine (PUR) pathway were also identified, reflecting failures in neurotransmission and mitochondrial dysfunction. Constructed metabolic networks linked perturbations in NE and PUR with elevated tau, and changes in TRP and MET to amyloid-beta42. In partnership with the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and with funding from the NIA, we established the Alzheimer’s Disease Metabolomics Consortium with the goal of creating a comprehensive metabolic database for ADNI linking metabolomics data to genomics and imaging data. This is in line with major recommendations and concepts we developed in the Alzheimer’s Summits of 2012 and 2015, and in response to President Obama initiative to prevent or treat AD by 2025. This consortium became part of Accelerating Medicines Partnership-Alzheimer's Disease (AMP-AD) program coordinated by FNIH for implementing the President mandate for accelerating treatments for AD.
Contributions to the emergence of a new field “Metabolomics”: Vision creation: In the year 2000 before the term “metabolomics” was used in the United States, and through a series of patent applications, I put forward an early vision about how metabolomics could radically transform our current understanding, monitoring and management of human disease. Together with a team of scientists, we put forward concepts that metabolic signatures could (1) provide diagnostic, prognostic and surrogate markers for a disease state; (2) enable the sub-classification of disease; (3) provide biomarkers for drug response phenotypes (pharmacometabolomics); and (4) provide information about mechanisms of disease. We provided some of the earliest support for these concepts. Creation of Metabolomics leading Biotechnology Company: At the early stages and while funding for metabolomics was not available through the NIH, I co-founded Metabolon Inc., a biotechnology company to explore concepts of metabolomics and applications in the medical field. The company has made substantial contributions to the evolution of the metabolomics field and its applications to the study of human disease. Established the Metabolomics Society: I recognized the need for a platform that can bring together researchers interested in the concept of metabolomics. I cofounded the Metabolomics Society, an international non-profit organization with the mission of promoting the field of metabolomics. During my presidency and from a modest beginning, the society grew to over 500 members from 25 countries within the first four years. I organized national and international meetings and workshops, and brought together a team to establish the first version of minimal standards for the field. I also helped with the creation and positioning of “Metabolomics”, the official journal for the Metabolomics Society.
Established Foundations for Pharmacometabolomics - A sub-field of metabolomics that complements and informs pharmacogenomics and enables precision medicine. With funding from the NIGMS (including large stimulus funding), I established the “Pharmacometabolomics Research Network (PMRN) that includes over thirty scientists from different disciplines. The goal was to integrate metabolomics with pharmacology and pharmacogenetics in partnership with the Pharmacogenomics Research Network (PGRN) as steps to enable a Quantitative and Systems Pharmacology approach towards precision medicine. Eight years later, pharmacometabolomics is an established field that determines the so-called “metabotype” or metabolic state of an individual as affected by environmental, genetic and enteric microbiome influences to study drug responses and to understand treatment outcomes. It provides tools for mapping the global effects of drugs on metabolism and for identifying pathways and networks implicated in mechanisms of action and mechanisms of variation in response to treatment. With over 30 publications, we lead this area of research; provided totally new insights about the molecular basis for on- and off-target effects of major classes of therapies including SSRIs, statin, antiplatelet and antihypertensive therapies. We also provided insights about treatment outcomes, ethnic and gender basis for variation of response and exemplified how metabolomics is an enabling tool for precision medicine.
Established support for the role of the gut microbiome in neuropsychiatric diseases and response to statins: Metabolic signatures for several neuropsychiatric diseases suggested changes related to gut microbiome host co-metabolism. Variation of response to statins was shown to involve, in part, gut microbiome activity and function.
Contributions that led to the Development of Creatine as a Potential Combination Therapy for Treating Neurodegenerative Diseases.Earlier in my career, I led research that resulted in unraveling a new role for the Creatine Kinase system in neuronal cell death. Along with Dr. Flint Beal, then at Harvard, we revealed neuroprotective properties of creatine analogs in animal models of Amyotrophic Lateral Sclerosis and Parkinson’s disease. I led creatine development from the bench to the clinic. Subsequent large investments made by the NIH to clinical teams resulted in testing the natural compound creatine in phase II and III studies for the treatment of Parkinson’s and Huntington’s diseases.