William George MacCallum

While he was studying in Baltimore, MacCallum used to spend his summer vacation at home in Dunville, where he and his father had, what he referred to as "a makeshift laboratory in the woodshed." They would study specimens of all sorts collected from the country side. It was during his last year at Johns Hopkins Medical School, in the summer of 1896 that he made a pivotal discovery in malariology. It was the period of intense research to unravel the mode of transmission of malarial parasite, for which the leading contenders were British and Italian physicians.[11][12][13] One day MacCallum collected blood sample far from his home, and in his home laboratory he observed active parasites called Halteridium columbae (but now considered as Haemoproteus columbae) among the blood cells. He went back to procure the bird itself and later found that the blood sample contained highly active malarial parasites. His reported his findings before the Medical Society of Johns Hopkins Hospital in November 1896, was published in 1897 in the Bulletin of the Johns Hopkins Hospital and more complete form in The Lancet.[14] He diagnosed in the next summer research that protozoan infections such as Halteridium and Proteosoma were symptomatically similar, and produced pathogenic lesions as in human malaria.[15] He further discovered that there were two groups of the parasite, one which are non-motile "granular" (now called microgametocytes) and one motile "hyaline" (macrogametocytes); and that the motile groups were flagellated cells having four or more arms that could fuse with the non-motile forms (the process of fertilisation) to form non-motile bodies called vermicule (but now called ookinete). This was the first description of sexual dimorphism and reproduction in the life cycle of prorotozoans. In his 1898 paper he gave a critical deduction that the motile forms were male gametes, the non-motile female gametes, and the vermicule the zygote (which were later proven to be true). He concluded with foresight that "This is a process which we might have expected and which I am confident will be found to occur in the case of the human malaria parasites... It is evidently for the human being what is foreshadowed by the organism of the bird.[16][17] This was almost a Nobel Prize-winning work because the next year Ronald Ross of the Indian Medical Service demonstrated the transmission of bird malarial parasite (then Proteosoma but now Plasmodium relictum) by a mosquito (then Culex fatigans, but now Culex quinquefasciatus),[18][19][20] for which Ross won the Nobel Prize for Physiology or Medicine in 1902.[21]

In 1899 MacCallum and T.W. Hastings described a new species of pathogenic Gram-positive bacterium which they named Micrococcus zymogenes.[22] The bacterium was discovered to be the causative agent of heart infection (acute endocarditis). The bacterium was a very small, occurred mainly in pairs, sometimes in short chains, and developed in small, pale, grayish-white colonies. It was uniquely capable of fermenting milk, hence, the name zymogenes.[23][24]

At the University of Leipzig in 1900 MacCallum studied the lymphatic system from the skin of pig embryo, and completed the work in Baltimore after two years. At the time the connection between lymphatic system and connective tissues was not known, and there were many speculations, of which the dominant idea was that they were directly linked. MacCallum showed that most of the prevailing hypotheses were wrong (such as connection through stomata, pores or canaliculi) and that the tissues had no special interconnecting link. Instead, solid particles are transported between them through cell transfer (phagocytosis). The lymphatic vessels were made up of endothelial lining structurally similar to normal blood vessels.[25][26][27]

In 1903 MacCallum started investigating thyroid and parathyroid secretions, for which there were confusion and uncertainty at the time. He discovered that the endocrine glands were of completely independent functions. He found that muscle seizure (tetany) thought to be due to surgery on thyroid was actually due to injury or removal of parathyroid glands; parathyroid contained no iodine in contrast to popular belief; and that injection of calcium salt could completely restore all the symptoms of tetany. His findings were published in 1905.[28][29] In 1909, with Carl Voegtlin he finally established the direct importance of calcium in tetany, and thereby muscle contraction.[30][31][32]

From 1909 MacCallum investigated a unique tetanic condition called gastric tetany, in which parathyroid glands are normal. The disease was due to obstruction at the pylorus region (near the intestine) of the stomach. He found in dogs that under gastric tetany, gastric hydrochloric acid was lost, and the chlorine in the blood plasma was reduced causing severe electrolyte imbalance. This further caused increased electrical excitability of neurons leading to increased muscle twitching. In most severe cases violent convulsion occurred and the dogs die. These effects could be easily reversed by injecting chloride salts. His findings were reported before the American Society for Pathology in 1917, and published in full form in 1920.[33][34][35]