Morgan Craig
- Professeure adjointe
-
Faculté des arts et des sciences - Département de mathématiques et de statistique
André-Aisenstadt, room 5243
Profile
Research expertise
Neutrophil and hematopoietic stem cell dynamics
Neutrophils are the most abundant white blood cell in the body and are front-line fighters against bacterial and fungal infections. Neutropenia, or a lack of neutrophils, can have serious implications for people's health, including an inability to ward off infection or life-threatening sepsis. All blood cells are derived from pluripotent hematopoietic stem cells, that self-renew and differentiate to maintain cell counts in the bone marrow and in circulation.
Our approach to study how hematopoiesis/granulopoiesis occurs is to delineate the mechanisms required for the control of hematopoiesis in the body and to use physiology to determine pharmacokinetic and pharmacodynamic relationships and drug models to understand how hematopoiesis normally proceeds and how disruptions/treatments affect the system. Using delay differential equations, we model the hematopoietic system in a physiologically-complete way to study the impact of different endogenous proteins/drugs.
Blood cell production is regulated by a variety of small proteins called cytokines that modulate the total number of cells by controlling the differentiation, proliferation, maturation, and/or the storage of cells in the marrow and circulation. Granulocyte colony-stimulating factor (G-CSF) is the principle cytokine responsible for the regulation of neutrophil counts, and acts in a negative feedback loop with circulating neutrophil numbers to maintain basal concentrations in the blood. During chemotherapy, patients frequently experience neutropenia due to the non-selective cytotoxicity of anti-cancer agents, so exogenous G-CSF is administered to boost cell counts on the system. We study the optimization of exogenous G-CSF treatment with specific reference to the physiological mechanisms of neutrophil production. We are also interested in the rare disease of cyclic neutropenia (and its platelet-analogue cyclic thrombocytopenia), a condition where patients experience continuously oscillating neutrophil (platelet) counts.
My work also combines stochastic approaches to hematopoiesis, specifically with reference to the HSCs, to understand how clones are generated in a variety of normal and pathological conditions.
Reconstructing immune networks
Disordered hematopoietic conditions, like cyclic neutropenia and cyclic thrombocytopenia, give us a window into the multitiude of control networks that regulate the production of blood cells. Using data from individuals with perturbed hematopoieisis and applying dynamical systems and statistical techniques like convergent cross mapping and periodogram analysis, we reconstruct immunological networks of cytokines and blood cells. Clustering and threshold measures allow us to zoom in on the "hubs" that control hematopoiesis to give us a clearer picture of how hematopoiesis is regulated at homeostasis.
PBPK modelling of antiretrovirals to study new drug delivery systems
Though the development of combination antiretroviral (ARV) treatment (highly active antiretrovial therapy, or HAART) has transformed the management of HIV and the prognosis of those living with the infection, several factors account for why ARV treatment cannot be discontinued and why an HIV cure remains elusive. The selection of resistant HIV can be brought about by, for example, imperfect adherence leading to resistant HIV, imperfect drug penetration in HIV sanctuaries or transmission sites, the persistence of latent virus in memory cells.
To study how readily ARV drugs reach crucial sites, and the impact of that penetration on imperfect drug taking patterns, we use physiologically-based pharmacokinetic (PBPK) modelling, which takes into account the many elements affecting the disposition of ARVs in the body. Our hope is that a better understanding of how HIV resistance is impacted by the pharmacokinetics in the whole body will lead to better drug delivery systems and suggestions for HIV cure techniques.
Biography
Adjunct Professor
Department of Physiology
McGill University, Montréal, QC
Postdoctoral Research Fellow, 2016-2018
Organismic and Evolutionary Biology
Harvard University, Cambridge, MA
Université de Montréal, Montréal, QC Canada
Ph.D. (Sciences pharmaceutiques), 2016
Titre : Improving the use of G-CSF during chemotherapy using physiological
mathematical modelling: a quantitative systems pharmacology approach
Directeurs de recherche: Fahima Nekka (Université de Montréal), Michael C Mackey (McGill University)
University of Manitoba, Winnipeg, MB Canada
M.Sc. (Mathematics), 2011
Titre : Incorporating stochastic influences in assembly models: application to intermediate filament polymerisation
Directeur de recherche : Stéphanie Portet (University of Manitoba)
Collège universitaire de Saint-Boniface, Winnipeg, MB Canada
B.Sc. (Mathématiques et Chimie), 2006
Awards and recognitions
- Lee A. Segal Prize for Best Student Paper in the Bulletin of Mathematical Biology, awarded by the Society for Mathematical Biology (2018).
Affiliations and responsabilities
Research affiliations
Professional titles and affiliations
Titles: corporations and professional organizations
Teaching and supervision
Teaching
Courses taught (current session only)
Programs
Student supervision
Theses and dissertation supervision (Papyrus Institutional Repository)
Mixed effects modelling for biological systems
Cycle : Master's
Grade : M. Sc.
Optimizing doxorubicin-G-CSF chemotherapy regimens for the treatment of triple-negative breast cancer
Cycle : Master's
Grade : M. Sc.
Projects
Research projects
Centre de recherches mathématiques (CRM)
Centre de recherches mathématiques (CRM)
Plasmonic optophysiology optogenetics
La médecine quantitative au service de la personnalisation thérapeutique en oncologie
La médecine quantitative au service de la personnalisation thérapeutique en oncologie
Characterization of disrupted hematopoiesis by mathematical modelling
Characterization of disrupted hematopoiesis by mathematical modelling
One Health Modelling Network for Emerging Infections (OMNI)/RÉseau UNe seule santé sur la modélisation des InfectionS (REUNIS)
One Health Modelling Network for Emerging Infections
La médecine quantitative au service de la personnalisation thérapeutique en oncologie
Réseau Québécois de Recherche sur les Médicaments (RQRM) / Integrated quantitative approach to novel targets in triple negative breast cancer.
La médecine quantitative en appui à la personnalisation des thérapies.
Supplément COVID-19 CRSNG_Characterization of disrupted hematopoiesis by mathematical modelling
Quantitative Approaches to Understand Differential Immune Responses in COVID-19
Outreach
Publications and presentations
Publications
1. T. Cassidy, M. Craig. Determinants of combination GM-CSF immunotherapy and oncolytic virotherapy success identified through in silico treatment personalization. Submitted to: PLOS Computational Biology, Special Issue on Targeted Anticancer Therapies and Precision Medicine in Cancer. 2019 (in print).
2. M. Craig, K. Kaveh, S. Chen, E. Eton, A. Dhawan, D. Goldman, A. Kazuya, M. Rahman, M.A. Nowak, A. Goldman. Cooperative adaptation to therapy (CAT) confers resistance in heterogeneous tumors. PLOS Computational Biology 15(8):e1007278. 2019. Journal cover (August 2019).
3. T. Cassidy, M. Craig, A.R. Humphries (2019). Equivalences between age structured models and state dependent distributed delay differential equations. Mathematical Biosciences and Engineering16(5):5419-5450. 2019.
4. N. Pillai, M. Craig, A. Dokoumetzidis, S.L. Schwartz, R. Bies, I. Freedman. Chaos synchronization and Nelder-Mead search for parameter estimation in nonlinear pharmacological systems: Estimating tumor antigenicity in a model of immunotherapy. Progress in Biophysics and Molecular Biology, 139:29-30. 2018.
5. A.R. Kirtane, O. Abouzid, D. Minaham, T. Bensel, A.L. Hill, C. Selinger, A. Bershteyn, S.S. Mo, M. Craig, H. Mazdiyasni, C. Cleveland, J. Rogner, Y-A. Lee, L. Booth, F. Javid, T. Grant, A.M. Bellinger, B. Nikolic, A. Hayward, L. Wood, P.A. Eckhoff, M. A. Nowak, R. Langer, and G. Traverso. Development of an oral once-weekly drug delivery system for HIV antiretroviral therapy. Nature Communications, 9(1):pp. 12. 2018.
6. Transit and lifespan in neutrophil production: implications for drug intervention. Journal of Pharmacokinetics and Pharmacodynamics, 45(1):59-77. 2018. [*=Co-first authors]
7. G.P. Langlois, M Craig, A.R. Humphries, M.C. Mackey, J.M. Mahaffy, J. Bélair, T. Moulin, S.R. Sinclair, and L. Wang. 2017. Normal and pathological dynamics of platelets in humans. Journal of Mathematical Biology, 75(6-7):1141-1462. 2018.
8. M. Craig. Towards quantitative systems pharmacology models of chemotherapy-induced neutropenia. CPT: Pharmacometrics & Systems Pharmacology, 6(5):293-304. 2017.
9. M. Craig, A.R. Humphries, and M.C. Mackey. An upper bound for the half-removal time of neutrophils from the blood. Blood, 128(15):1989-1991. 2016.
10. M. Craig, M. González-Sales, J. Li, and F. Nekka. Approaching pharmacometrics as a paleontologist would: Recovering the links between drugs and the body through reconstruction. CPT: Pharmacometrics & Systems Pharmacology, 5(3):158-160. 2016.
11. M. Craig, A.R. Humphries, and M.C. Mackey. A Mathematical model of granulopoiesis incorporating the negative feedback dynamics and kinetics of G-CSF/neutrophil binding and internalization. Bulletin of Mathematical Biology, 78(12):2304-2357. 2016.
12. M. Craig, M. González-Sales, J. Li, and F. Nekka. Impact of pharmacokinetic variability on a mechanistic physiological pharmacokinetic/pharmacodynamic model: a case study of neutrophil development, PM00104, and filgrastim. In Mathematical Sciences with Multidisciplinary Applications, edited by B. Toni, p. 91-112. New York: Springer Science + Business Media. 2016.
13. M. Craig, A.R. Humphries, F. Nekka, J. Bélair, J. Li, and M.C. Mackey. Neutrophil dynamics during concurrent chemotherapy and G-CSF administration: mathematical modelling guides dose optimisation to minimise neutropenia. Journal of Theoretical Biology, 385:77-89. 2015.
Disciplines
- Applied Mathematics
- Physiology
- Pharmacy
Areas of expertise
- Modelization and Simulation
- Immune Mediators: Cytokines and Chemokines
- Leukocytes
- Stem Cells and Organogenesis
- Pathology
- Immune System
- Platelets
- Differential Equation
- Cell Signaling (Circulatory and Respiratory Health)
- Cell Signaling and Infectious and Immune Diseases
- AIDS / HIV
- Antivirals
- Chemotherapy
- Immunotherapy
- Apoptosis and Cancer
- Leukemia
- Viral Infections
- Bacterial Infections
- Drug Metabolism
- Infectious Diseases
- Physiology
- Cell Signaling and Cancer
- COVID-19
- COVID19