Despite having its statehood established relatively recently in 1867 and hosting a relatively small population of just over 40 million inhabitants, Canada has an illustrious history of major contributions to science and medicine.  Perhaps most well-known among Canadian contributions to medicine is the discovery of insulin and associated methods for its purification by Frederick Banting and Charles Best at the University of Toronto in 1921. Only 29 years later in 1950, Dr. John Hopps developed the first external pacemaker, and conceptualized its insertion via venous catheters – an administration technique still in use today. During the same year, oncologist Dr. Vera Peters made the seminal discovery that Hodgkin’s disease – previously considered incurable – was highly treatable with high-dose radiation therapy. Her work in this regard guides current treatment plans for patients with cancer worldwide. Canada’s innovative research culture extends even further into all spheres of science in technology, and perhaps nowhere else is this more apparent than in the field of immunology.

1963 – Discovery of stem cells and hematopoiesis: Drs. James Till and Ernest McCulloch

Stem cells are long-lived cells that have the unique properties to self-renew and give rise to more specialized (“differentiated”) progeny. While the theoretical concept of such cells had been hypothesized in the 19th century, there had been a lack of experimental evidence to prove their existence. Two Canadians, James Till, a biophysicist, and Ernest McCulloch, a hematologist, collaborated on pioneering experiments at the University of Toronto that examined the reconstitution of blood (i.e. hematopoietic system) in irradiated mice; work inspired by fears of worldwide nuclear disaster during the Cold War. Their experiments involved injecting bone marrow cells into mice which had lost their hematopoietic systems because of experimental irradiation. After transplantation of the bone marrow cells, Till and McCulloch noticed the appearance of nodules within the spleens of the recipient mice. These nodules contained cells of the 3 main blood cell lineages and rare cells that had the ability to self-renew. The results of their work were published in 1964, and not only provided bona fide proof of the existence of stem cells, but also of hematopoiesis – the development of functional blood cells and of the immune system. The findings of Drs. Till and McCulloch have been instrumental for the development of stem cell and bone marrow transplant therapies used today to treat certain hematological cancers.

1984 – Cloning of the TCR: Dr. Tak Wah Mak

Throughout the 1960s, immunologists began to recognize that specific cells in the blood, termed lymphocytes, were responsible for protection against infectious disease. Furthermore, during this time, there was considerable appreciation that antibodies produced by lymphocytes are important in providing protection against a myriad of different pathogens. A conundrum remained, however, that individuals with agammaglobulinemia (a disease causing an absence of antibody-producing B cells) were able to efficiently control viral infections. These observations led to the discovery of another class of lymphocytes –T cells – that can efficiently control infections even in the absence of antibodies. Whereas B cells were recognized to be the producers of antibodies that could bind fragments of foreign infectious agents, the ways in which T cells mediated clearance of infections remained unclear and was the subject of intense investigation throughout the 1970s and early 1980s. During this period, it was hypothesized that antibody-like molecules, termed the “T cell receptor (TCR)”, present on the surface of T cells formed a means for T cells to mediate clearance of infection. However, the exact genes contributing to the elusive TCR were not yet identified, which made the study of T cell function extremely difficult. This problem was termed the “holy grail of immunology” until 1983, when the laboratory of Dr. Tak Mak at the University of Toronto devised a method for screening thousands of potential candidate genes that could potentially form the human TCR. In the summer of 1983, Dr. Mak noticed gene sequences present in human T cells that resembled those of antibodies produced by B cells. Thus, the lab had successfully discovered the genetic elements encoding for the TCR. The work was confirmed in parallel by the laboratory of Dr. Mark Davis at Stanford University who had used a similar method to devise the genetic elements underlying the mouse TCR. It is hard to overstate the importance of the findings of Drs. Mak and Davis. Notably, new strategies to treat various forms of cancer involve the use of chimeric antigen receptor (CAR) T cells, which heavily rely on the findings of our Canadian discovery.

1973 – Discovery of Dendritic Cells: Dr. Ralph Steinman

Today, dogma in immunology dictates that adaptive (T and B cell) responses to infection are orchestrated by dendritic cells (DCs). DCs take up infectious particle (bacteria, fungi, viruses) and “show” them to T and B cells so that these cells can mediate clearance of the infection. Today, immunologists appreciate DCs to have even broader roles for mediating anti-cancer immune responses as well. Much of immunologists’ understanding of these critical cells is based on the extensive work done by the late Canadian Dr. Ralph Steinman who discovered DCs in 1973 at the Rockefeller University in New York City – a discovery for which he won the Nobel Prize in Medicine or Physiology in 2011. Despite the current acceptance of the centrality of DCs to immunity, Steinman’s initial characterization of these cells was met with skepticism from the scientific community. At the time, it was accepted that there was an “accessory cell” that was required for T and B cell-mediated immunity, and it was known that this cell would stick to microscope slides, whereas lymphocytes would not. An expert in microscopy, Steinman had set out to characterize these glass-adherent accessory cells by employing a variety of microscopy techniques. Throughout his experiments, Steinman noted a rare cell that had peculiar dendrite-like projections and organelle structures that were quite distinct from those seen from macrophages (another candidate for the “accessory” cell). Steinman coined this rare cell as the dendritic cell. Intriguingly, Steinman’s work on the characterization of DCs and their function did not come out as one singular mechanistic paper. In fact, the various functions of DCs that we now appreciate as being central to immunity were gradually unravelled one-by-one through his laboratory’s many subsequent publications. Indeed, when reading of Steinman’s resilience, creativity, and immeasurable excitement for science, we cannot help but feel inspired.

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