Scientists often face unexpected observations that lie tangentially to their original hypotheses. In the pursuit of unravelling the unexpected, scientist’s can sometimes make the monumental discoveries that push science forward. Amongst the well-known serendipitous discoveries of penicillin and x-rays also rests vinblastine, one of the world’s essential chemotherapeutic agents and first discovered by Canadians Robert Noble and Charles Beer (Figure 1) while investigating a treatment for diabetes.
Figure 1: Drs. Robert Noble (left) and Charles Beer. Sketches by Irma Coucill and the Canadian Medical Hall of Fame.
In 1952, while serving as the assistant director of the Collip Medical Research Laboratory at the University of Western Ontario, Robert Noble received a package from his brother Clark Noble, a doctor who had made notable contributions towards the discovery of insulin. The package contained leaves from the Catharanthus roseaus plant (formerly Vinca rosea), commonly known as the Madagascar periwinkle (Figure 2), that was sent to Clark by a patient from Jamaica, where it is sometimes made into tea and used as a remedy for diabetes. Clark, no longer active in research, sent the plant to Robert who was at the time working under James Collip, a biochemist famous for isolating clinically-viable insulin.
Robert Noble investigated the purported anti-diabetic effects by giving extracts of the periwinkle orally to diabetic mice and rabbits, but failed to observe any decreases in blood sugar levels. After additional investigations by his colleagues also failing to observe an anti-diabetic effect, Noble directly injected sterilized extracts of the periwinkle into mice, hoping for greater efficacy. Unexpectedly, this caused the mice to rapidly develop abscesses in their livers and kidneys, a sign of bacterial infection. Since the extracts were sterile, Noble and his colleagues deduced that the extracts might dampened the mice’s immune system, resulting in infection. Indeed, subsequent experiments indicated that the periwinkle extract destroyed the mice’s bone marrow, where immune cells are generated.
Robert Noble investigated the purported anti-diabetic effects by giving extracts of the periwinkle orally to diabetic mice and rabbits, but failed to observe any decreases in blood sugar levels. After additional investigations by his colleagues also failing to observe an anti-diabetic effect, Noble directly injected sterilized extracts of the periwinkle into mice, hoping for greater efficacy. Unexpectedly, this caused the mice to rapidly develop abscesses in their livers and kidneys, a sign of bacterial infection. Since the extracts were sterile, Noble and his colleagues deduced that the extracts might dampened the mice’s immune system, resulting in infection. Indeed, subsequent experiments indicated that the periwinkle extract destroyed the mice’s bone marrow, where immune cells are generated.
In light of these results, Noble became interested in applying the periwinkle extracts to blood cancers such as lymphomas and leukemias. However, such an experiment would require the isolation of the specific active compound out of the crude extracts. In 1954, Charles Beer joined Noble’s group on a fellowship from the British Empire Cancer Campaign. Beer had received his PhD in chemistry from Oxford University and brought with him the skills required to isolate biologically active compounds. While Beer was devising procedures for isolating the active compound from the extracts, Noble and others were struggling to gather sufficient periwinkle leaves to extract from. Noble relied on shipments of periwinkle leaves from Jamaica until a drought diminished the supply. Noble and Beer attempted to grow the plant in southern Ontario, which proved difficult as it only grew annually and could not survive the harsh Canadian winter.
Despite the difficulty in acquiring the necessary raw material, in 1958 Noble and Beer successfully isolated a highly-active component of the extract. The compound is known today as vinblastine, but was originally named vincaleukoblastine for the plant it is isolated from and its effect on white blood cells. Soon after the publication of their work into vinblastine (Figure 3), Noble and Beer entered into a productive partnership with Eli Lilly, a pharmaceutical company who would go on to research Vinca-derived alkaloids intensively. Together they tested vinblastine at the Princess Margaret Hospital in Toronto and successfully demonstrated its efficacy in human patients.
Figure 3. 2D-3D Fused structure of the Vinca alkaloid, Vinblastine, a world's essential medicine for the treatment of cancer.
Vinblastine was the first molecule to be discovered that belongs to the Vinca alkaloid family of chemicals, so named after the plant genus from which they can be extracted. During the isolation of vinblastine, Beer also isolated another Vinca alkaloid named vincristine that was present in lower amounts but had similar activity to vinblastine. When administered, these Vinca alkaloids bind tubulin, a major structural component of the cell that is required for cells to divide and proliferate. Vinca alkaloids inhibit the ability of tubulin to form the necessary structural components for cell division and drive them towards cell death. Cancers are highly reliant on tubulin to sustain their uncontrolled division and Vinca alkaloids inhibit their growth through disrupting tubulin polymerization.
Vinblastine, vincristine, and other Vinca alkaloids have been crucial in cancer chemotherapy worldwide. They are frequently used in chemotherapeutic regimens to treat a wide range of cancers, including testicular cancer, both Hodgkin’s and non-Hodgkin’s lymphomas, lung cancers, breast cancers, and many more. Many Vinca alkaloids are maintained on the World Health Organization’s Model List of Essential Medicines due to their safety and cost-effectiveness. Though it was serendipity that led Noble onto the tracks of discovering Vinca alkaloids, it was his and Beer’s continued efforts that led to the discovery of one of the world’s most essential cancer chemotherapeutic and for that, Cyclica honours the contributions of Robert Noble and Charles Beer to the treatment of cancers. A timeline of their lives is provided below in Figure 4.
Figure 4. A timeline of significant events in Robert Noble and Charles Beer's lives.
Stay tuned for our next blog outlining other great discoveries by Canadian scientists or check out our other blog posts for Canada150 found here.
References
1. Noble, R. L., Beer, C. T., & Cutts, J. H. (1958) Role of chance observations in chemotherapy: Vinca rosea. Ann NY Acad Sci 76, 882-894.
2. Noble, R. L. (1990) The discovery of the vinca alkaloids - chemotherapeutic agents against cancer. Biochem Cell Biol 68(12), 1344-1351.
3. Warwick, O. H., Darte, J. M. M., Brown, T. C., Beer, C. T., Cutts, J. H., & Noble, R. L. (1960) Some biological effects of vincaleukoblastine, an alkaloid in Vinca rosea Linn in patients with malignant disease. Cancer Res 20, 1032-1041.
4. Moudi, M., Go, R., Yien, C. Y. S., & Nazre, M. (2013) Vinca Alkaloids. Int J Prev Med 4(11), 1231-1235.
5. World Health Organization. (2000) WHO Model List of Essential Medicines (19th List). Geneva, Switzerland.
This blog was written by Tonny Huang, a graduate student at the Princess Margaret Cancer Center. Tonny has a deep interest in the applications of protein science for the betterment of human health. You can find him here on LinkedIn.
