91Ë¿¹ÏÊÓƵ

Check out recent PhD graduate Daniel J. Buss's two new papers just out on biomineralization of organic fiber networks - one about chicken eggshell, and the other about Achilles tendon insertion into bone:

Chicken eggshell:ÌýÌý(±ô¾±²Ô°ì)

Achilles tendon:ÌýÌý(±ô¾±²Ô°ì)

Check out also this recent paper by postdoctoral fellow Joseph Deering on the eggshell of the common leopard gecko: (link)

PROSPECTIVE STUDENTS

• Consider marveling at, and studying, BIOMINERALIZATION as a graduate student in the McKee lab.
• Does the term 'biorocks'Ìýintrigue you?
• Might you be fascinated by how geology, crystallography and biology all come together in biomineralization processes that form hard bones, teeth, inner ear otoconia, kidney stones and eggshells?
• Are you interested in multiscale microscopies that reveal 3D structures in biology all the way down to the nanoscale?
• Are you interested in bioimaging and how structure provides function in biomineralized hierarchical assemblies found throughout Nature?
• Might you be amazed by the fact that your proteins and small biomolecules can 'sculpt'Ìýthe same rocks you might find on the side of a trail during a hike, or in a gem display at a museum, to create and organize nano-structured biorocks within organisms?
• Would you like to study why bones and teeth are soft in some inherited rare skeletal and dental mineralization diseases, and what we can do about it?
• Are you fascinated by biology at large? Have you enjoyed the BBC's and Sir David Attenborough's Planet Earth and Blue Planet series and their other episodes? (you should)
• If these statements and questions have grabbed your attention, the McKee lab currently has openings for graduate students, and is seeking candidates with at least some degree of research experience in academia or industry.
• Join my international biomineralization research group of highly motivated, enthusiastic and curious students and staff who are interested in knowing how biology interfaces with mineralogy at the micro- and nano-scale.

Research in McKee's laboratory is primarily focused on mineralization (calcification) of extracellular matrices in bones and teeth, in mineralization pathologies, and in other biomineralizing systems such as inner-ear otoconia and eggshells.Ìý In particular, in addition to characterizing mineralization patterns in various tissues, he is investigating the role of mineral-binding proteins, peptides, amino acids, and small molecules – most notably a protein called osteopontin – and the enzymes that modify these biomolecules to influence their mineralization-regulating activities.Ìý His studies on pathologic mineralization include work on rare bone diseases where skeletal and dental mineralization is defective (osteomalacia / odontomalacia), and bones and teeth are soft and deform.Ìý His work also includes investigating the actions of regulatory molecules where debilitating mineral deposition occurs in soft tissues such as in the kidney (urolithiasis, kidney stones), in blood vessels (vascular calcification), and in tendon and ligament insertions (entheses).

McKee and 91Ë¿¹ÏÊÓƵ colleague Natalie Reznikov have developed the concept of theÌýStenciling PrincipleÌýfor extracellular matrix mineralization which describes that at very specific locations in extracellular matrices, enzymes precisely control the selective removal (stenciling) of inhibitory small molecules (pyrophosphate) and proteins (osteopontin) to regulate mineral crystal growth.Ìý The underlying notion of this principle derives from the original pivotal paradigm for double-negative regulation discovered by Francois Jacob and Jacques Monod in the late 1950s.Ìý The paradigm of "repressing a repressor" to induce an activation effect – originally explaining genetic regulation of enzyme expression in bacteria – continues until today and explains many processes in developmental biology, cancer biology, and even ecology.Ìý For bone, theÌýStenciling PrincipleÌýdescribes a double-negative "inhibiting an inhibitor" scenario for enzyme-substrate/inhibitor pairs that permits and regulates the growth of small mineral foci in the extracellular matrix.Ìý These mineral foci then enlarge to eventually form a tightly packed, 3D crossfibrillar (collagen) mineralization pattern at the microscale termedÌýcrossfibrillar mineral tessellation.Ìý This structural feature of bone is important for imparting micromechanical robustness to bone tissue – without it (as in osteomalacia), bones painfully bend and deform.Ìý Pertaining to theÌýStenciling Principle, McKee specifically focuses on the enzyme-substrate/inhibitor relationship betweenÌýtissue-nonspecific alkaline phosphataseÌý(TNAP, TNSALP, ALPL) andÌý±è²â°ù´Ç±è³ó´Ç²õ±è³ó²¹³Ù±ðÌý(PPi), and betweenÌýphosphate-regulating endopeptidase homolog X-linkedÌý(PHEX) andÌý´Ç²õ³Ù±ð´Ç±è´Ç²Ô³Ù¾±²ÔÌý(OPN).Ìý He also investigates what goes wrong with mineralization in the rare bone diseases hypophosphatasia (HPP) and X-linked hypophosphatemia (XLH) that have inactivating gene mutations in TNAP and PHEX, respectively.

In parallel to his calcium-phosphate mineralization work, McKee has a longstanding research program on calcium-carbonate mineralization (eggshells, otoconia, and synthetic helical/chiral crystal suprastructures).Ìý In past work, he examined extensively extracellular matrix organization and composition at cell-matrix and matrix-matrix interfaces (including at implantable biomaterial interfaces), and the tooth enamel maturation stage of amelogenesis.

Research methods

To study biomineralization processes and mineralized tissue hierarchical structure at the nano- and microscale, a variety of morphological, biochemical, immunochemical, cell biological and molecular techniques are used which include among others: electron microscopy and electron tomography, focused-ion beam milling (FIB-SEM serial-surface-view with 3D reconstruction and deep learning approaches), atomic force microscopy, micro-computed tomography and other X-ray analytical approaches, optical microscopies, immunocytochemistry,Ìýin vivoÌýexperimentation using normal and transgenic mice,Ìýin vitroÌýcell culture and crystal growth systems, standard biochemical and chemical assays, and computational simulations.

Research group/network affiliations

McKee is a member of the following research groups/networks: National Network for Canadian Oral Health Research, Québec FRQS Centre de Recherche en Biologie Structurale, Québec FRQS Réseau de Recherche en Santé Buccodentaire et Osseuse, 91Ë¿¹ÏÊÓƵ Centre for Bone and Periodontal Research, 91Ë¿¹ÏÊÓƵ Institute for Advanced Materials, 91Ë¿¹ÏÊÓƵ Sustainability Systems Initiative, and the 91Ë¿¹ÏÊÓƵ Regenerative Medicine Network.

Research areas:Ìý

Mineralized Tissues and Extracellular Matrix Biology

RECENT GRAPHIC ABSTRACTS & JOURNAL COVERS

ACTIVE GRANTS

• Identifying novel mechanisms for dentoalveolar mineralization defects in X-linked hypophosphatemia (Co-applicant; PI Brian Foster) National Institutes of Health (NIH, USA), R01 operating grant
• Molecular signaling in dentinogenesis and dental caries riskÌý(Co-applicant; PI is Mairobys Socorro)ÌýNational Institutes of Health (NIH, USA), R03Ìýoperating grant
• Protein mineral interactions at the organic-inorganic interface in biominerals (McKee Principal Investigator, no co-applicants) Natural Sciences and Engineering Research Council of Canada, Discovery operating grant
• Upsampling of low-resolution/large-volume 3D tomographic images using generative adversarial neural networks applied to biological anthropology, medical imaging and evolutionary biology (Co-applicant; PI Natalie Reznikov) NSERC/FRQNT NOVA joint funding program Quebec/Canada, operating grant; New Frontiers Research Fund (NFRF) – Exploration Program Canada, operating grant
• Mineralization mechanisms and osteopontin in bones and teeth (McKee Principal Investigator, no co-applicants) Canadian Institutes of Health Research, Project operating grant
• Canada Research Chair in Biomineralization (Tier 1) (McKee Principal Investigator, no co-applicants) Canada Research Chairs Program, operating and salary award grant
• Atomistics of engineering and natural materials (Co-applicant; PI Moutanabbir O) Canada Foundation for Innovation, Innovation Fund equipment infrastructure grant
• Correlative 3D nanoimaging and molecular mapping in situ of mineralized tissues (McKee Principal Investigator, no co-applicants) Canada Foundation for Innovation, JELF equipment infrastructure grant

  ---

  Ìý