As the president of the Japan Society for Bioscience, Biotechnology, and Agrochemistry (JSBBA), I would like to congratulate Dr. Satoshi Ōmura, who has been awarded the 2015 Nobel Prize in Physiology or Medicine for his “disscoveries concerning a novel therapy against infections caused by roundworm parasites.”Citation1) This issue (Biosci. Biotechnol. Biochem. vol. 1, 2017) is being published to commemorate this special occasion.
JSBBA was founded in 1924 as an academic organization called the Agricultural Chemical Society of Japan, by Dr. Umetaro Suzuki, who discovered aberic acid (later called oryzalin or vitaminB1) from rice bran as an active factor in the cure for beriberi.Citation2) He also proposed the novel concept that food contains unknown essential nutritional substances other than carbohydrates, amino acids, and lipids, which are now known as vitamins. By establishing this society, he aimed to stimulate the development of science and technology in the field of agricultural chemistry and to use the newly acquired knowledge for social development. Dr. Ōmura, an honorary member of the JSBBA, has mentioned in his Nobel lecture titled “A splendid gift from the earth: the origins and impact of the avermectins”Citation3) that he has profound respect for nature and micro-organisms. We at JSBBA wholeheartedly share this view.
Ivermectin and its parental compound avermectin are both extremely broad-spectrum agents. The main targets for these agents are glutamate-gated chloride channels, but they also have minor effects on gamma-aminobutyric acid (GABA)-gated chloride channels. These agents are effective against nematodes, arthropods, insects, ticks, and possibly several other invertebrates due to the presence of glutamate-gated chloride channels and the lack of a blood-brain barrier in these organisms; ivermectin and avermectin function to open these channels, causing muscle paralysis that kills the parasite. However, in vertebrates, glutamate-gated chloride channels are not found and GABA-gated chloride channels are expressed only in the central nervous system, which is protected by the blood–brain barrier that restricts the entry of ivermectin, making it very safe for vertebrates.
I have a personal connection to ivermectin and Dr. Ōmura. After obtaining a degree based on research into the mechanism of action of the anticancer agent mitomycin C, which Dr. Ōmura’s predecessor Professor Tōju Hata had discovered at the Kitasato Institute, I moved to the United States to study cancer multidrug resistance at the National Cancer Institute. There, in 1986, I discovered a human gene, MDR1, which is highly expressed in multidrug-resistant cancer cells.Citation4,5)
MDR1 (also known as P-glycoprotein or ABCB1) is a unique membrane protein that exports various structurally unrelated lipophilic compounds from the cell, and this protein is important for human health.Citation6) To elucidate the physiological role of this protein, in 1994, Dr. Borst’s group in the Netherlands established a mouse model lacking this gene.Citation7) MDR1-deficient mice appeared healthy but when they were sprayed with ivermectin to treat a mite infestation, they were killed.
Through this serendipitous discovery, the essential role of MDR1 in the blood–brain barrier was revealed. The blood–brain barrier had previously been thought to be only a physical barrier composed of endothelial cell tight junctions of blood capillaries. MDR1, expressed in endothelial cells of blood capillaries, efficiently exports ivermectin to prevent it from reaching the central nervous system. Therefore, the central nervous system of mammals, including that of humans, is highly protected against toxic chemicals. Only some inbred dogs of the collie breed, which have defects in MDR1, and mice lacking MDR1 are severely poisoned by ivermectin.
Ivermectin is a revolutionary and useful drug, and has been improving the health and welfare of hundreds of millions of individuals. Furthermore, Dr. Ōmura has discovered almost 500 novel bioactive compounds, many of which have important applications in medicine or industry or are used as important reagents. The awarding of the Nobel Prize in Physiology or Medicine to Dr. Ōmura has imbued me with a renewed sense of awe towards his passion and continued efforts. I wish him the very best, and I hope that Dr. Ōmura’s future contributions to science will further improve the lives of many around the world.
Disclosure statement
No potential conflict of interest was reported by the author.
Kyoto University, Kyoto, Japan
[email protected]
References
- The Nobel Assembly at Karolinska Institutet. Press Release, October 5 2015.
- Suzuki U, Shimamura T. An active factor in rice bran (in Japanese). Tokyo Kagaku Kaishi. 1911;32: 4–16.
- Ōmura S. Nobel Lecture “A splendid gift from the earth: the origins and impact of the avermectins”. December 7, 2015.
- Chen C-J, Chin JE, Ueda K, et al. Internal dupilication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistance human cells. Cell. 1986;47:381–389.10.1016/0092-8674(86)90595-7
- Ueda K, Cardarelli C, Gottesman MM, et al. Expression of a full-length cDNA for the human “MDR1” gene confers resistance to colchicine, doxorubicin, and vinblastine. Proc Natl Acad Sci USA. 1987;84:3004–3008.10.1073/pnas.84.9.3004
- UEDA K. ABC proteins protect human body and maintain optimal health. Biosci Biotechnol Biochem. 2011;75:401–409.10.1271/bbb.100816
- Schinkel AH, Smit JJM, van Tellingen O, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994;77:491–502.10.1016/0092-8674(94)90212-7