3552, Blue Zone, Duke South, Durham, NC 27710
Box 3903 Med Ctr, Durham, NC 27710
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:
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.
Acylcarnitine metabolomic profiles inform clinically-defined major depressive phenotypesRead Full Text
Quantitative Systems Pharmacology for Neuroscience Drug Discovery and Development: Current Status, Opportunities, and Challenges.
Sets of coregulated serum lipids are associated with Alzheimer's disease pathophysiology.
Untargeted metabolomic profiling identifies disease-specific signatures in food allergy and asthma.
Bile acids targeted metabolomics and medication classification data in the ADNI1 and ADNIGO/2 cohorts.
Biobanking for Metabolomics and Lipidomics in Precision Medicine.
Systematic Error Removal Using Random Forest for Normalizing Large-Scale Untargeted Lipidomics Data.
Altered bile acid profile in mild cognitive impairment and Alzheimer's disease: Relationship to neuroimaging and CSF biomarkers.
Metabolic dysfunctions in the kynurenine pathway, noradrenergic and purine metabolism in schizophrenia and bipolar disordersRead Full Text
Expert insights: The potential role of the gut microbiome-bile acid-brain axis in the development and progression of Alzheimer's disease and hepatic encephalopathyRead Full Text
Altered bile acid profile associates with cognitive impairment in Alzheimer's disease-An emerging role for gut microbiome.
Pilot Study of Metabolomic Clusters as State Markers of Major Depression and Outcomes to CBT Treatment.
Generation and quality control of lipidomics data for the alzheimer's disease neuroimaging initiative cohort.
Mapping depression rating scale phenotypes onto research domain criteria (RDoC) to inform biological research in mood disorders.
Augmentation of Physician Assessments with Multi-Omics Enhances Predictability of Drug Response: A Case Study of Major Depressive Disorder.
Pharmacometabolomics Informs About Pharmacokinetic Profile of Methylphenidate.
Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression.
The inhibition of the kynurenine pathway prevents behavioral disturbances and oxidative stress in the brain of adult rats subjected to an animal model of schizophrenia.
Beta-defensin 1, aryl hydrocarbon receptor and plasma kynurenine in major depressive disorder: metabolomics-informed genomics.
Brain and blood metabolite signatures of pathology and progression in Alzheimer disease: A targeted metabolomics study.
Sphingolipid Metabolic Pathway Impacts Thiazide Diuretics Blood Pressure Response: Insights From Genomics, Metabolomics, and Lipidomics.
Targeted metabolomics and medication classification data from participants in the ADNI1 cohort.
Data-driven longitudinal modeling and prediction of symptom dynamics in major depressive disorder: Integrating factor graphs and learning methodsRead Full Text
Metabolic network failures in Alzheimer's disease: A biochemical road map.
The steroid metabolome in women with premenstrual dysphoric disorder during GnRH agonist-induced ovarian suppression: effects of estradiol and progesterone addback.
Ketamine potentiates oxidative stress and influences behavior and inflammation in response to lipolysaccharide (LPS) exposure in early life.
Nomenclature for alleles of the human carboxylesterase 1 gene.
Pharmacometabolomic signature links simvastatin therapy and insulin resistanceRead Full Text
Pharmacometabolomic signature links simvastatin therapy and insulin resistance.
TSPAN5, ERICH3 and selective serotonin reuptake inhibitors in major depressive disorder: pharmacometabolomics-informed pharmacogenomics.
Metabolomics enables precision medicine: “A White Paper, Community Perspective”Read Full Text
Metabolomic signatures of drug response phenotypes for ketamine and esketamine in subjects with refractory major depressive disorder: new mechanistic insights for rapid acting antidepressants.
A Genetic Response Score for Hydrochlorothiazide Use: Insights From Genomics and Metabolomics Integration.
Novel plasma biomarker of atenolol-induced hyperglycemia identified through a metabolomics-genomics integrative approach.
Pharmacometabolomics informs pharmacogenomicsRead Full Text
Pharmacometabolomic assessment of metformin in non-diabetic, African AmericansRead Full Text
Investigating the impact of missense mutations in hCES1 by in silico structure-based approachesRead Full Text
A METFORMIN METABOLOMIC EXPRESSION PROFILE STUDY UTILIZING AN ELECTRONIC HEALTH RECORD (EHR)-LINKED BIOREPOSITORY AND INTEGRATIVE MOLECULAR EPIDEMIOLOGY APPROACHESRead Full Text
Genetic Influences on Plasma Homocysteine Levels in African Americans and Yoruba Nigerians.
Standardizing the experimental conditions for using urine in NMR-based metabolomic studies with a particular focus on diagnostic studies: a reviewRead Full Text
Pharmacometabolomic Assessments of Atenolol and Hydrochlorothiazide Treatment Reveal Novel Drug Response Phenotypes.
Oxylipid Profile of Low-Dose Aspirin Exposure: A Pharmacometabolomics Study.
Genetic studies of quantitative MCI and AD phenotypes in ADNI: Progress, opportunities, and plans.
Metabolomic Signatures for Drug Response Phenotypes: Pharmacometabolomics Enables Precision Medicine.
Synthetic cannabimimetic agents metabolized by carboxylesterases.
Associations between central nervous system serotonin, fasting glucose, and hostility in African American females.
Standardizing the experimental conditions for using urine in NMR-based metabolomic studies with a particular focus on diagnostic studies: a review.
Module-based association analysis for omics data with network structure.
Individualization of treatments with drugs metabolized by CES1: combining genetics and metabolomics.
Quality assurance of metabolomics.
Pharmacometabolomics reveals that serotonin is implicated in aspirin response variability.
Is diabetes mellitus-linked amino acid signature associated with β-blocker-induced impaired fasting glucose?
Pharmacometabolomics: implications for clinical pharmacology and systems pharmacology.
Integration of pharmacometabolomic and pharmacogenomic approaches reveals novel insights into antiplatelet therapy.
Pharmacometabolomics of statin response.
Purine pathway implicated in mechanism of resistance to aspirin therapy: pharmacometabolomics-informed pharmacogenomics.
Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical AntipsychoticsRead Full Text
Comparing metabolomic and pathologic biomarkers alone and in combination for discriminating Alzheimer's disease from normal cognitive aging.
Associations between purine metabolites and monoamine neurotransmitters in first-episode psychosisRead Full Text
Correction: Enteric microbiome metabolites correlate with response to simvastatin treatment (PLoS ONE)Read Full Text
Alterations in metabolic pathways and networks in Alzheimer's disease.
Pharmacometabolomic mapping of early biochemical changes induced by sertraline and placebo.
Pharmacometabolomics reveals racial differences in response to atenolol treatment.
Pharmacometabolomic signature of ataxia SCA1 mouse model and lithium effects.
Pharmacometabolomics of response to sertraline and to placebo in major depressive disorder - possible role for methoxyindole pathway.
Purine pathway implicated in mechanism of resistance to aspirin therapy: Pharmacometabolomics-informed pharmacogenomicsRead Full Text
Enantioselective determination of methylphenidate and ritalinic acid in whole blood from forensic cases using automated solid-phase extraction and liquid chromatography-tandem mass spectrometry.
Impaired plasmalogens in patients with schizophrenia.
Interest in metabolomics continues to grow within US National Institutes of Health (NIH)Read Full Text
Merging pharmacometabolomics with pharmacogenomics using '1000 Genomes' single-nucleotide polymorphism imputation: selective serotonin reuptake inhibitor response pharmacogenomics.
Plasma omega-3 polyunsaturated fatty acids and survival in patients with chronic heart failure and major depressive disorder.
Cerebrospinal fluid metabolome in mood disorders-remission state has a unique metabolic profile.
Associations between purine metabolites and clinical symptoms in schizophrenia.
Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment.
3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia.
Associations between Purine Metabolites and Clinical Symptoms in SchizophreniaRead Full Text
Metabolomic changes in autopsy-confirmed Alzheimer's disease.
GLYCINE AND A GLYCINE DEHYDROGENASE (GLDC) SNP AS SSRI RESPONSE BIOMARKERS IN DEPRESSION: PHARMACOMETABOLOMICS-INFORMED PHARMACOGENOMICSRead Full Text
GLYCINE AND A GLYCINE DEHYDROGENASE (GLDC) SNP AS SSRI RESPONSE BIOMARKERS IN DEPRESSION: PHARMACOMETABOLOMICS-INFORMED PHARMACOGENOMICSRead Full Text
Glycine and a glycine dehydrogenase (GLDC) SNP as citalopram/escitalopram response biomarkers in depression: pharmacometabolomics-informed pharmacogenomics.
Metabolomics in early Alzheimer's disease: identification of altered plasma sphingolipidome using shotgun lipidomics.
Enteric microbiome metabolites correlate with response to simvastatin treatment.
Pretreatment metabotype as a predictor of response to sertraline or placebo in depressed outpatients: a proof of concept.
Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia.
Stable isotope-resolved metabolomic analysis of lithium effects on glial-neuronal metabolism and interactions.
Metabolomic differences in heart failure patients with and without major depression.
Lipidomic analysis of variation in response to simvastatin in the Cholesterol and Pharmacogenetics Study.
Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with schizophrenia.
Metabolomics: A global biochemical approach to the discovery of biomarkers for psychiatric disordersRead Full Text
Opioid use affects antioxidant activity and purine metabolism: preliminary results.
Alterations in tryptophan and purine metabolism in cocaine addiction: a metabolomic study.
Metabolomic Mapping of Atypical Effects in SchizophreniaRead Full Text
Metabolomics tools for identifying biomarkers for neuropsychiatric diseases.
Abnormalities in Inflammatory Lipid Levels in First Episode Schizophrenic Patients are Modulated by RisperidoneRead Full Text
Homeostatic Imbalance of Purine Catabolism in First-Episode Neuroleptic-Naive Patients with SchizophreniaRead Full Text
Metabolomics: A Global Biochemical Approach to the Study of Neuropsychiatric DisordersRead Full Text
3-HYDROXYKYNURENINE AND COGNITIVE IMPAIRMENT IN FIRST-EPISODE NEUROLEPTIC-NAIVE PATIENTS WITH SCHIZOPHRENIARead Full Text
Metabolomics: a global biochemical approach to the study of central nervous system diseases.
Metabolomic mapping of schizophrenic patients treated with atypical antipsychotics discloses drug-specific differences in global lipid changesRead Full Text
Metabolomics and lipidomics of neuropsychiatric disorders: Emerging dataRead Full Text
Discriminative tryptophan pathway in first-episode neuroleptic-naive patients with schizophreniaRead Full Text
Metabolomics: a global biochemical approach to drug response and disease.
Inflammatory changes in schizophrenia with antipsychotic treatmentRead Full Text
Metabolomics: Concepts and potential neuroscience applicationsRead Full Text
Metabolomic mapping of atypical antipsychotic effects in schizophrenia.
The metabolomics standards initiative (MSI)Read Full Text
ANYL 288-Metabolomics for mapping disease signatures and drug response phenotypesRead Full Text
The metabolomics standards initiative.
A preliminary metabolomic analysis of older adults with and without depression.
Metabolomic mapping of schizophrenia and atypical antipsychotic effectsRead Full Text
Metabolomics in the study of aging and caloric restrictionRead Full Text
High-performance liquid chromatography separations coupled with coulometric electrode array detectors: a unique approach to metabolomics.
Metabolomics in the study of aging and caloric restriction.
A preliminary metabolomic analysis of older adults with and without depressionRead Full Text
Metabolic profiling of patients with schizophrenia.
Metabolomics Standards Workshop and the development of international standards for reporting metabolomics experimental results.
Biomarkers for amyotrophic lateral sclerosis.
Identification of metabolic and protein biomarkers for amyotrophic lateral sclerosisRead Full Text
Establishing reporting standards for metabolomic and metabonomic studies: a call for participation.
Metabolic profiling of patients with schizophrenia.Read Full Text
Metabolomics: A new approach towards identifying biomarkers and therapeutic targets in CNS disordersRead Full Text
Metabolomic analysis and signatures in motor neuron disease.
Increases in cortical glutamate concentrations in transgenic amyotrophic lateral sclerosis mice are attenuated by creatine supplementation.
Creatine and creatinine metabolism.
Neuroprotective effects of creatine in a transgenic mouse model of Huntington's disease.
Neuroprotective effects of creatine administration against NMDA and malonate toxicity.
Amyotrophic lateral sclerosis: Transgenic model and novel neuroprotective agentRead Full Text
The neuroprotective properties of creatine in animal models of neurodegenerative diseasesRead Full Text
Creatine and cyclocreatine attenuate MPTP neurotoxicity.
Neuroprotective effects of creatine in a transgenic animal model of amyotrophic lateral sclerosis.
Cyclocreatine inhibits stimulated motility in tumor cells possessing creatine kinase.
Antitumor activity of creatine analogs produced by alterations in pancreatic hormones and glucose metabolism.
Neuroprotective effects of creatine and cyclocreatine in animal models of Huntington's disease.
Synthesis and creatine kinase inhibitory activity of nonhydrolyzable analogs of phosphocreatineRead Full Text
Specific targeting of tumor cells by the creatine analog cyclocreatineRead Full Text
Depletion of energy reserve via the creatine kinase reaction during the evolution of heart failure in cardiomyopathic hamsters.
The synthetic phosphagen cyclocreatine phosphate inhibits the growth of a broad spectrum of solid tumors.
Creatine and phosphocreatine analogs: anticancer activity and enzymatic analysis.
Antiproliferative effects of cyclocreatine on human prostatic carcinoma cells.
Microtubule stabilization and potentiation of taxol activity by the creatine analog cyclocreatine.
Enhancement of cardiac function by cyclocreatine in models of cardiopulmonary bypass.
Erratum: Microtubule stabilization and potentiation activity by the creatine analog cyclocreatine (Anti-Cancer Drugs (1995) 6 (419-426))Read Full Text
Cyclocreatine in cancer chemotherapy.
Cell cycle studies of cyclocreatine, a new anticancer agent.
Evaluation of creatine analogues as a new class of anticancer agents using freshly explanted human tumor cells.
Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) inhibits the replication of human herpes viruses.
Enhancement of the recovery of rat hearts after prolonged cold storage by cyclocreatine phosphate.
Cyclocreatine (1-carboxymethyl-2-iminoimidazolidine) inhibits growth of a broad spectrum of cancer cells derived from solid tumors.
Induction of a cellular enzyme for energy metabolism by transforming domains of adenovirus E1a.
Isolation of a functional human gene for brain creatine kinase.
Activation and repression of mammalian gene expression by the c-myc protein.
Purification of the HhaII restriction endonuclease from an overproducer Escherichia coli clone.
Catalytic properties of the HhaII restriction endonuclease.