About

Professor Michael C. Reed focuses on mathematical models of metabolic systems with implications for human health. His research addresses the complex causal mechanisms by which genetic and environmental variables influence the molecular biology of cells, particularly in the context of human diseases. Over the past seventy years, studies have revealed correlations between diet and diseases such as cancers, heart disease, diabetes, and neuropsychiatric disorders, as well as between genetic mutations and these diseases. However, these correlations are often weak and vary between populations, making it difficult to develop reliable health policy recommendations. Professor Reed's work emphasizes the importance of understanding the dynamic and intricate interactions among thousands of genes and their products, which govern cell biochemistry, metabolism, and signaling processes that lead to growth, development, and senescence. His research highlights the complexity of these dynamical systems, which are never at equilibrium and differ from cell to cell, as central to understanding the origins of disease.

Research topics

• Internal medicine
• Medicine
• Neuroscience
• Pharmacology
• Genetics
• Endocrinology
• Biology
• Psychology

Selected publications

• Elevated Homocysteine is Associated With Liver Fibrosis in Metabolic Dysfunction–Associated Steatotic Liver Disease in a Sex- and Menopause-Specific Manner

  Gastro Hep Advances · 2025-09-11 · 4 citations

  articleOpen access

  Background and Aims: Elevated hepatic homocysteine (Hcy) contributes to hepatic inflammation and fibrogenesis in metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to evaluate the association between serum Hcy levels and the risk of MASLD and hepatic fibrosis in a large, diverse population, accounting for clinical confounders and effect modifiers such as sex and reproductive status. Methods: We analyzed 1999-2006 National Health and Nutrition Examination Survey data for 8253 adults (≥18 years) without hepatitis B/C, excessive alcohol use, or pregnancy. MASLD was defined using the fatty liver index (≥30), and fibrosis risk was assessed using age-adjusted Fibrosis-4 and nonalcoholic fatty liver disease fibrosis score among MASLD subjects (N = 5328). Associations between serum Hcy and MASLD/fibrosis risk were evaluated using multivariable linear regression adjusting for confounders, with stratification by sex and menopausal status. Results: Serum Hcy levels were higher among those with MASLD (fatty liver index ≥30), though the association was attenuated after covariate adjustment. Among MASLD individuals, those at higher fibrosis risk (based on Fibrosis-4 or nonalcoholic fatty liver disease fibrosis score) had significantly elevated Hcy levels. This association remained significant in men and postmenopausal women, but not in premenopausal women. Conclusion: Elevated serum Hcy is independently associated with hepatic fibrosis risk in MASLD, particularly in men and postmenopausal women. These findings underscore the importance of accounting for sex and menopausal status in future Hcy-lowering interventions targeting MASLD.

  PublisherDOI

• Differential effects of synthetic estrogen on serum homocysteine levels before and after menopause

  PLoS ONE · 2025-12-10

  articleOpen access1st authorCorresponding

  Homocysteine (Hcy), a sulfur-containing amino acid, is produced in prodigious quantities by the methionine cycle in the liver. Hcy is the major biomarker for cardio-vascular disorders and is associated with many other diseases. In previous work, we have explained why menstruating women have lower serum homocysteine than men due to higher concentrations of estradiol. In this study, we first present epidemiological evidence from NHANES data that synthetic estradiol supplementation lowers serum Hcy in post-menopausal women, but raises Hcy in pre-menopausal women. Secondly, we give an explanation of this puzzling phenomenon using previously developed mathematical models of one-carbon and glutathione metabolism. The simulation analysis demonstrated that the non-monotonic response of glutathione to rising estradiol levels may account for the differing Hcy responses to estradiol supplementation in postmenopausal versus premenopausal women, through activation of cystathionine β-synthase, a key enzyme regulating tissue homocysteine levels. Our findings further highlight the importance of considering menopausal status and synthetic hormone use when evaluating the health effects of homocysteine.

  PublisherDOI

• A mathematical model of melatonin synthesis and interactions with the circadian clock

  Mathematical Biosciences · 2024-09-06 · 5 citations

  article
  PublisherDOI

• Serotonin as a biomarker of toxin-induced Parkinsonism

  Molecular Medicine · 2024-03-01 · 15 citations

  articleOpen access

  BACKGROUND: Loss of dopaminergic neurons underlies the motor symptoms of Parkinson's disease (PD). However stereotypical PD symptoms only manifest after approximately 80% of dopamine neurons have died making dopamine-related motor phenotypes unreliable markers of the earlier stages of the disease. There are other non-motor symptoms, such as depression, that may present decades before motor symptoms. METHODS: Because serotonin is implicated in depression, here we use niche, fast electrochemistry paired with mathematical modelling and machine learning to, for the first time, robustly evaluate serotonin neurochemistry in vivo in real time in a toxicological model of Parkinsonism, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). RESULTS: Mice treated with acute MPTP had lower concentrations of in vivo, evoked and ambient serotonin in the hippocampus, consistent with the clinical comorbidity of depression with PD. These mice did not chemically respond to SSRI, as strongly as control animals did, following the clinical literature showing that antidepressant success during PD is highly variable. Following L-DOPA administration, using a novel machine learning analysis tool, we observed a dynamic shift from evoked serotonin release in the hippocampus to dopamine release. We hypothesize that this finding shows, in real time, that serotonergic neurons uptake L-DOPA and produce dopamine at the expense of serotonin, supporting the significant clinical correlation between L-DOPA and depression. Finally, we found that this post L-DOPA dopamine release was less regulated, staying in the synapse for longer. This finding is perhaps due to lack of autoreceptor control and may provide a ground from which to study L-DOPA induced dyskinesia. CONCLUSIONS: These results validate key prior hypotheses about the roles of serotonin during PD and open an avenue to study to potentially improve therapeutics for levodopa-induced dyskinesia and depression.

  PublisherOA PDFDOI

• Lower hepatic <i>CBS</i> and <i>PEMT</i> expression in advanced NAFLD: inferencing strategies to lower homocysteine with a mathematical model

  Metabolism and Target Organ Damage · 2024-05-30 · 6 citations

  articleOpen access

  Aim: Hepatic homocysteine (Hcy) accumulation promotes inflammation and fibrosis in experimental nonalcoholic fatty liver disease (NAFLD), while vitamin B12 and folate reduce hepatic Hcy and protect animals from nonalcoholic steatohepatitis. This suggests clinical implications for preventing/treating patients with NAFLD. Given the known sex-specific regulation of one-carbon metabolism (OCM), the response to various OCM cofactors may vary by sex and reproductive status. We aimed to strategize an effective Hcy-lowering treatment in broader NAFLD patients while discerning disparities in treatment responses. Methods: We analyzed existing hepatic microarray data relevant to Hcy metabolism with clinical and histologic data from patients with NAFLD (N = 82), while considering potential age/sex disparities. Additionally, we performed computer simulation analyses using a mathematical model of OCM to predict hepatic Hcy-lowering effects of OCM cofactors by sex. Results: Of 82 patients with NAFLD, 98% had at least one metabolic feature [i.e., metabolic dysfunction-associated steatotic liver disease (MASLD)]. Lower hepatic gene expressions of cystathionine-beta synthase (CBS ) and phosphatidyl- ethanolamine N-methyltransferase (PEMT ) were associated with more severe fibrosis in NAFLD, while sub-analysis suggested possible variations by age and sex. The simulation analysis demonstrated sex differences in the Hcy-lowering effects of the OCM cofactors (vitamins B6 and B12, folate, and betaine), with the combination of these cofactors consistently showing the maximum Hcy-lowering effect in both sexes. Conclusion: We theorize that the combination of OCM cofactors would maximize Hcy-lowering effects in the broader MASLD population. Our findings also underscore the importance of considering sex and age in designing future studies on homocysteine metabolism.

  PublisherOA PDFDOI

• Sex differences in glutathione metabolism and acetaminophen toxicity

  Metabolism and Target Organ Damage · 2024-04-07 · 5 citations

  articleOpen access

  Aims: Clinical and experimental evidence has shown that females in humans and other mammals have higher glutathione (GSH) levels than males, which are caused by higher levels of estradiol. Understanding how hepatic GSH level and synthesis velocity depend on the sex hormones is an extremely important question since oxidative stress contributes to the risk for heart disease and cancer, and oxidative stress is reduced by GSH. Our aim is to develop a systems approach to understanding GSH metabolism and use this to explain the causes of GSH differences in males and females, how GSH changes during the menstrual cycle, and why women may be less susceptible to acetaminophen toxicity. Methods: We use mathematical models for hepatic glutathione metabolism, including one-carbon metabolism and acetaminophen detoxification, to investigate how the activation of certain enzymes by estradiol leads to dramatic changes in reaction velocities and metabolite concentrations. Results: The models explain why women of childbearing age have higher glutathione than men, and that this is caused by the balance of activation of glutamyl cysteine synthetase (GCL) and glutathione peroxidase (GPX) by estradiol. The steady-state concentration of glutathione in women depends on the strength of the activation of GCL and GPX and is quite homeostatic over a wide range of activations. Conclusions: During the menstrual cycle, the GSH concentration changes daily but over a relatively narrow range. We explain how this dynamic homeostasis depends on the biochemical network that produces GSH. The model is also consistent with published results that show that female mice are less susceptible than males to hepatotoxicity due to acetaminophen overdose and suggests that this might also be true for humans, though the human epidemiological data are contradictory.

  PublisherOA PDFDOI

• Modulation of serotonin transporter expression by escitalopram under inflammation

  Communications Biology · 2024-06-08 · 12 citations

  articleOpen access

  Selective serotonin reuptake inhibitors (SSRIs) are widely used for depression based on the monoamine deficiency hypothesis. However, the clinical use of these agents is controversial, in part because of their variable clinical efficacy and in part because of their delayed onset of action. Because of the complexities involved in replicating human disease and clinical dosing in animal models, the scientific community has not reached a consensus on the reasons for these phenomena. In this work, we create a theoretical hippocampal model incorporating escitalopram's pharmacokinetics, pharmacodynamics (competitive and non-competitive inhibition, and serotonin transporter (SERT) internalization), inflammation, and receptor dynamics. With this model, we simulate chronic oral escitalopram in mice showing that days to weeks are needed for serotonin levels to reach steady-state. We show escitalopram's chemical efficacy is diminished under inflammation. Our model thus offers mechanisms for how chronic escitalopram affects brain serotonin, emphasizing the importance of optimized dose and time for future antidepressant discoveries.

  PublisherOA PDFDOI

• Serotonin is a Common Thread Linking Different Classes of Antidepressants

  Research Square · 2023-03-28 · 2 citations

  preprintOpen access

  Depression pathology remains elusive. The monoamine hypothesis has placed much focus on serotonin, but due to the variable clinical efficacy of monoamine reuptake inhibitors, the community is looking for alternative therapies such as ketamine (synaptic plasticity and neurogenesis theory of antidepressant action). There is evidence that different classes of antidepressants may affect serotonin levels; a notion we test here. We measure hippocampal serotonin in mice with voltammetry and study the effects of acute challenges of antidepressants. We find that pseudo-equivalent doses of these drugs similarly raise ambient serotonin levels, despite their differing pharmacodynamics because of differences in Uptake 1 and 2, rapid SERT trafficking and modulation of serotonin by histamine. These antidepressants have different pharmacodynamics but have strikingly similar effects on extracellular serotonin. Our findings suggest that serotonin is a common thread that links clinically effective antidepressants, synergizing different theories of depression (synaptic plasticity, neurogenesis and the monoamine hypothesis).

  PublisherOA PDFDOI

• Dynamical questions in volume transmission

  Journal of Biological Dynamics · 2023-10-24 · 1 citations

  articleOpen accessSenior authorCorresponding

  In volume transmission (or neuromodulation) neurons do not make one-to-one connections to other neurons, but instead simply release neurotransmitter into the extracellular space from numerous varicosities. Many well-known neurotransmitters including serotonin (5HT), dopamine (DA), histamine (HA), Gamma-Aminobutyric Acid (GABA) and acetylcholine (ACh) participate in volume transmission. Typically, the cell bodies are in one volume and the axons project to a distant volume in the brain releasing the neurotransmitter there. We introduce volume transmission and describe mathematically two natural homeostatic mechanisms. In some brain regions several neurotransmitters in the extracellular space affect each other's release. We investigate the dynamics created by this comodulation in two different cases: serotonin and histamine; and the comodulation of 4 neurotransmitters in the striatum and we compare to experimental data. This kind of comodulation poses new dynamical questions as well as the question of how these biochemical networks influence the electrophysiological networks in the brain.

  PublisherOA PDFDOI

• Serotonin is a common thread linking different classes of antidepressants

  Cell chemical biology · 2023 · 14 citations

  • Pharmacology
  • Psychology
  • Neuroscience
  PublisherOA PDFDOI

Recent grants

• Analysis of Mechanisms of Biochemical Homeostasis

  NSF · $391k · 2006–2010

• EMSW21-RTG: Enhanced Training and Recruitment in Mathematical Biology

  NSF · $2.1M · 2010–2017

• Hyperacuity in the Auditory System

  NSF · $501k · 2001–2007

• NIH Grant R01NS025191

  NIH · $363k · 1993

Frequent coauthors

• H. Frederik Nijhout

  Duke University

  115 shared

• Cornelia M. Ulrich

  University of Utah

  78 shared

• Jesse F. Gregory

  University of Florida

  71 shared

• S. Jill James

  University College London

  67 shared

• Marian L. Neuhouser

  Fred Hutch Cancer Center

  66 shared

• Barry Shane

  University of California, Berkeley

  66 shared

• Amy Liu

  Georgetown University

  64 shared

• Janet Best

  The Ohio State University

  38 shared

Awards & honors

• Arts and Sciences Distinguished Professor of Mathematics (20…
• Bass Fellow (2008 - Present)