About Sickkids
About SickKids

Jason Maynes, MD, PhD

The Hospital for Sick Children
Staff Anesthesiologist
Anesthesia and Pain Medicine

Research Institute
Scientist
Molecular Structure & Function

University of Toronto
Biochemistry
Adjunct Professor


Phone: 416-813-5934
e-mail: jason.maynes@sickkids.ca

Brief Biography

  • PhD and MD, University of Alberta, 2006
  • Clinical training in paediatrics and anaesthesia, Barnes-Jewish Hospital/St. Louis Children's/Washington University in St. Louis, 2006 to 2011 
  • Post-doctoral fellowships at the Los Alamos National Laboratory, Washington University in St. Louis, 2006 to 2011

Research Interests

The research in my lab focuses on three main areas that attempt to combine my clinical training in paediatrics and anaesthesia with my research training in biophysics: (1) the mechanism of anaesthetic action and anaesthetic off-targets, (2) proteins involved in mitochondrial dynamics and, (3) high-content imaging and image analysis.

Anaesthetic agents (both intra-venous and inhalational gases) have poor affinities for the receptors associated with their clinical use/utility. This leads to potential off-target interactions on the cellular level and side-effects for the patient. Accumulating clinical evidence shows that anaesthetic agents administered before the age of four can have adverse long-term neuro-cognitive and neuro-behavioral effects on children. The exact mechanism of this effect is unknown but our lab has shown that all pharmaceuticals used in a common paediatric anaesthetic (inhalational agents isoflurane/sevoflurane, propofol, morphine, midazolam and ketamine) all cause (to varying degrees) mitochondrial membrane potential alterations, adverse mitochondrial morphology changes and damage to the mitochondrial genome. This can lead to persistent mitochondrial dysfunction and may lead to the neurological effects of anaesthetics on children, along with delayed wound healing and post-operative recovery. We are continuing to investigate the effect of anaesthetics mitochondrial function, agents that can mitigate these effects and other potential ways to deliver anaesthetic safely to paediatric patients.

Mitochondrial dynamics is an important cellular process where damaged mitochondrial components can be discarded, new functional mitochondrial units generated and the mitochondrial genome repaired. The mitochondrial processes of fusion and fission are also involved in autophagy and apoptosis. We are investigating the structural basis of mitochondrial fission and fusion using X-ray crystallography, surface plasmon resonance, fluorescence spectroscopy, among other biophysical techniques. Our current interest is focused on the role of the proteins Mitochondrial Fission Factor (Mff) and Dynamin-related Protein-1 (Drp-1) in mitochondrial fission and how post-translational modification affects the function of these two proteins.

To study mitochondria and other cellular processes we employ high-content imaging. Unlike traditional confocal microscopy, we image thousands of cells at a time using 96- or 384-well plates and use automated image processing algorithms to determine specified metrics from every cell in every image. This removes the traditional bias associated with manual characterization of confocal images. We have developed machine learning algorithms that automatically identify, quantify and then classify mitochondrial shape and function in a cell population of interest. We have also extended these techniques to other disease phenotypes of relevance to paediatric anaesthesia including pulmonary stenosis, dilated cardiomyopathy and chemotherapy-induced cardiac dysfunction. Using custom assays, we are able to perform high-throughput drug screening to look for agents that attenuate or eliminate the disease phenotype observed.

External Funding

  • Rare Diseases Foundation
  • Foundation for Anesthesia Education and Research

Publications

Maynes, JT, Luu, HA, Cherney, MM, Andersen, R., Williams, D., Holmes, CFB, James, MNG. 2006. Crystal Structures of Protein Phosphatase-1 Bound to Motuporin and Dihydromicrocystin-LA: Elucidation of the Mechanism of Enzyme Inhibition by Cyanobacterial Toxins. J. Mol. Biol. 356(1):111-120.

Maynes, JT, Cherney, MM, Qasim, MA, Laskowski, M. Jr, James, MNG. 2005. Crystal structure of the subtilisin carlsberg:omtky3 complex reveals two different ovomucoid conformations. Acta Cryst D. May;61(Pt 5):580-8.

Maynes, JT, Perreault, KR, Cherney, MM, Luu, HA, James, MNG and Holmes, CFB. 2004. Crystal structure and mutagenesis of a protein phosphatase-1:calcineurin hybrid elucidate the role of the β12-β13 loop in inhibitor binding. J. Biol. Chem. 279(41):43198-206.

Lamoureux JS, Maynes JT, Glover JN. 2004. Recognition of 5'-YpG-3' sequences by coupled stacking/hydrogen bonding interactions with amino acid residues. J. Mol. Biol. 335(2):399-408.

Maynes JT, Garen C, Cherney MM, Newton G, Arad D, Av-Gay Y, Fahey RC, James MNG. 2003. The crystal structure of 1-D-myo-inosityl 2-acetamido-2-deoxy-alpha-D-glucopyranoside deacetylase (MshB) from Mycobacterium tuberculosis reveals a zinc hydrolase with a lactate dehydrogenase fold. J. Biol. Chem. 278(47):47166-70.

Holmes CF, Maynes JT, Perreault KR, Dawson JF, James MNG. 2002. Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins. Curr. Med. Chem. 9(22):1981-9.

Maynes, JT, Bateman, KS, Cherney, MM, Das, AK, Luu, HA, Holmes, CFB and James, MNG 2001. Crystal structure of the tumor-promoter okadaic acid bound to protein phosphatase-1 J. Biol. Chem. 276(47):44078-44082.

Maynes, JT, Yuan, RG, Phipps, BM, Litster, SA, Leung, K and Snyder, FF 2000. Further refinement on the engineering of adenosine phosphorylase from purine nucleoside phosphorylase. Adv. Exp. Med. Biol. 486:107-110.  

Maynes, JT, Yuan, RG and Snyder, FF 2000. Identification, expression and characterization of E. coli guanine deaminase. J. of Bacteriology, Aug: 4658-4660.

Maynes, JT, Yam, YT,  Jenuth, JP, Yuan, RG, Litster, S, Phipps, B and Snyder, FF 1999. Design of an adenosine phosphorylase by active-site modification of murine purine nucleoside phosphorylase. Enzyme kinetics and molecular dynamics simulation of Asn-243 and Lys-244 substitutions of purine nucleoside phosphorylase. Biochem. J., Dec. 1, 344(2):585-592.