Walter Kahr

I received my MD and PhD (Biochemistry) from the University of Toronto in 1994. Following post-graduate training in Internal Medicine at the University of Toronto (1994-1997), I completed a hematology fellowship in the Department of Medicine (1997-1999) and a post-doctoral fellowship in the Department of Pathology and Molecular Medicine (1999-2002) at McMaster University in Hamilton. During my post-doctoral fellowship I discovered that bleeding problems in patients with the rare inherited Québec platelet disorder arose from the abnormal expression of urokinase in their platelets. This information aided the effective treatment of this bleeding disorder. As a clinician-scientist at the Hospital for Sick Children I follow children with bleeding and clotting disorders. My research is focused on understanding the structure and function of platelets – the smallest cells in the blood – and how they develop from megakaryocytes, the largest cells in the bone marrow.

Blood Coagulation in Health and Disease

Our research is aimed at understanding the development and function of blood platelets. These tiny, numerous cells initiate and co-ordinate blood clotting (i.e. hemostasis) at wound sites by adhering, aggregating and secreting a wide assortment of molecules. Platelets are also involved in the formation of arterial plaques and pathological clots such as the thrombi that cause heart attacks and strokes, major causes of mortality in the modern world. Many of our insights into the mechanisms of platelet development and function have come from studies of patients with inherited platelet disorders. Our particular interest is alpha granules, secretory vesicles that platelets use to transport and secrete several hundred different kinds of protein. We have identified several proteins and cellular pathways involved in the development of alpha granules in the cells that produce platelets, the bone marrow megakaryocytes.

Blood Platelets in Health and Disease

Each of us releases 100 billion platelets into our bloodstream every day. These tiny disk-shaped cells, only about 3 microns across, play vital roles as they patrol blood vessels for signs of injury. When they detect a breach they adhere, aggregate and activate formation of a clot that seals the wound and limits blood loss. Thus individuals lacking platelets or having dysfunctional cells experience abnormal bleeding. In addition to their key role in blood clotting, platelets are also involved in inflammation, immunity and wound healing, and in the formation of atherosclerotic plaques and pathological clots (i.e. thrombi) that trigger heart attacks and strokes. The many roles of platelets in health and disease are linked to their unique ability to store and release a wide range of biomolecules. These include a wide gamut of proteins stored within and released from secretory αgranules, and studies of the development and function of these granules is a major focus of my research group.

Platelets and Megakaryocytes

Platelets are produced by megakaryocytes, cells that develop within the bone marrow until they reach enormous sizes of up to 100 microns across. At that point they generate extensions that protrude into blood vessels and shed platelets into circulation by the thousands. We study megakaryocyte development in a variety of different ways using cells derived from humans and mice. This allows us to monitor gene expression, protein localization and trafficking, as well as the development of alpha granules, using advanced methods such as high-resolution fluorescence and electron microscopy. The ability to manipulate megakaryocytes in vitro has allowed us to study their development in detail, and examine aspects such as the trafficking of proteins destined for alpha granules, some of which are synthesized by megakaryocytes, while others are taken up from the bloodstream.

Hereditary Platelet Disorders: Bedside to Bench and Back Again

Much of the recent progress that has been made in understanding platelet production, structure and function has come from studies of hereditary conditions where one or more of these aspects are affected. Patients with arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome have platelets that lack α-granules. In a series of studies we identified that the root cause of this defect is loss of one of two proteins: VPS33B and VPS16B, which we showed using yeast two-hybrid screens and mass spectrometry form a functional protein complex. Ongoing studies are extending this work in several directions, including determining the structure of the functional VPS33B/VPS16B complex. This work recently culminated in the discovery that the VPS33B/VPS16B complex represents the first bidirectional SEC/MUNC complex with the potential to bind up to 4 SNAREs simultaneously (see Liu et al. J Biol Chem 2023 Jun;299(6):104718).

In another project we used classical genetics and platelet mRNA expression analysis to reveal the cause of gray platelet syndrome (GPS), where patients have platelets containing some alpha granule components, but normal granules fail to form. We found that GPS is caused by loss of function of NBEAL2 (neurobeachin-like 2), a large protein with several potential functional domains about which little is known. We have explored NBEAL2 function using Nbeal2-knockout mice that recapitulate many aspects of GPS pathology. These studies have allowed us to observe that loss of NBEAL2 function leads to impaired megakaryocyte development and affects their ability to package and retain protein cargo into alpha granules. Current studies are focused on elucidating the cellular mechanisms whereby NBEAL2 facilitates maturation and stability of alpha granules.

A recent example where the expertise of my group and our collaboration with others proved highly productive involved solving a mystery concerning a patient with a puzzling set of symptoms involving platelets and the immune system. We discovered the root of these problems was loss of expression of ARPC1B, a component of the Arp2/3 complex that generates branched actin filaments in blood cells. This work received considerable media interest and was recognized by the inaugural Janet Rossant Research innovation Prize, and it has stimulated further exploration of ARPC1B deficiency by us and others. A novel technical aspect of this project was the generation of gene knockout human megakaryocyte precursor (imMKCL) cells using CRISPR/Cas9 gene editing, which were used to model megakaryocyte development in the absence of ARPC1B function.

Courses Taught

BCH449H Medical Biochemistry
BCH374Y1 Research Project in Biochemistry
BCH473Y Advanced Research Project in Biochemistry

Awards and Distinctions

2023, 2018, 2017 — Platelet Journal Cover Competition - Winner for 2018, 2023  
2018 — The Janet Rossant Research Innovation Prize, The Hospital for Sick Children, Research Institute
2006-2009 — Heart and Stroke Foundation of Ontario, Phase II Clinician Scientist Award