[Consideration on Academia Environments for Creating Medical Innovation].

The spread of COVID-19 has re-affirmed the crucial importance of the pharmaceuticals industry in improving the level of citizens' health and medical care, as well as the industry's importance in terms of contribution to economic growth and tax revenues. Although some time has passed since the importance of industry-academia collaboration was first raised in relation to the creation of innovative new drugs and the continuation of global competitiveness, conflicts between academia and companies have also been highlighted as barriers that hinder efforts to promote the practical realization of academia-initiated seeds. The authors have hypothesized that conflicts between academia and companies can be attributed to the vulnerability of innovation creation environments, including drug discovery, on the academia side, insufficient awareness concerning human resources that will undertake industry-academia operations, and inadequate development of structures. Consequently, we implemented fact-finding investigations in relation to universities and public research institutions in Japan, with the objective of ascertaining the actual status of innovation creation environments, including drug discovery, on the academia side. From the results of these investigations, we will clarify the issues that may present barriers to innovation creation, and consider policies, etc. for the enhancement of innovation creation environments.

[Consideration on Industry-Academia Partnering in Drug Discovery Development: Based on a Questionnaire Survey of Pharmaceutical Companies and Academia].

Japanese pharmaceutical products continue to experience a trade deficit, since import values exceed export values. In drug discovery development, given the pace of technological innovations, there has been a major shift from low-molecular-weight compounds to biomedicine. It is anticipated that industry, academia and government will work more closely together in support of the pharmaceutical industry. Drug discovery requires much time and vast resources before the results can be put to practical use, and evidence suggests that many newly approved drugs derive from university-sourced technology. Pharmaceutical companies keep a close eye on technology evolving in universities. However, some reports state that there is a substantial difference compared to the development costs of the major Japanese pharmaceutical companies. Therefore, the authors hypothesized that there may be some issues hindering industrial-academic partnerships in drug discovery. In order to understand the actual situation and barriers to promoting industrial-academic collaboration, the Japan Pharmaceutical Manufacturers Association (JPMA), Japan Agency for Medical Research and Development (AMED), and the Medical Industry-Academia Collaboration Network (medU-net) Council will work together in issuing questionnaires and conducting an awareness survey. This survey sought the personal opinions of individuals belonging to JPMA and medU-net. Based on the results of this survey, we will introduce the issues related to industrial-academic collaboration and partnerships, and any gaps between industry and academia. Furthermore, we suggest solutions to promoting drug discovery innovation in Japan.

[Conflict of interest and disclosures to academic meetings and journals].

In 2013, there were cases in which clinical research papers on antihypertensive drugs conducted at five universities in Japan were retracted. Based on this case, the clinical research system in Japan was reviewed, and it was particularly required to strengthen the conflict of interest (COI) management system. Clinical Trial Act effected in April 2017 imposed a conflict of interest management obligation on researchers conducting clinical research. Conflict of interest management is accountability for the society and patients and protection of the cutting-edge research. This reviews the necessity and purpose of conflict of interest management and introduces the types of research and the required management of conflict of interest.

Oscillatoxin I: A New Aplysiatoxin Derivative, from a Marine Cyanobacterium.

Cyanobacteria have been shown to produce a number of bioactive compounds, including toxins. Some bioactive compounds obtained from a marine cyanobacterium Moorea producens (formerly Lyngbya majuscula) have been recognized as drug leads; one of these compounds is aplysiatoxin. We have isolated various aplysiatoxin derivatives from a M. producens sample obtained from the Okinawan coastal area. The frozen sample was extracted with organic solvents. The ethyl acetate layer was obtained from the crude extracts via liquid-liquid partitioning, then separated by HPLC using a reversed-phase column. Finally, 1.1 mg of the compound was isolated. The chemical structure of the isolated compound was elucidated with spectroscopic methods, using HR-MS and 1D and 2D NMR techniques, and was revealed to be oscillatoxin I, a new member of the aplysiatoxin family. Oscillatoxin I showed cytotoxicity against the L1210 mouse lymphoma cell line and diatom growth-inhibition activity against the marine diatom Nitzschia amabilis.

'The industry must be inconspicuous': Japan Tobacco's corruption of science and health policy via the Smoking Research Foundation.

OBJECTIVE: To investigate how and why Japan Tobacco, Inc. (JT) in 1986 established the Smoking Research Foundation (SRF), a research-funding institution, and to explore the extent to which SRF has influenced science and health policy in Japan. METHODS: We analysed documents in the Truth Tobacco Industry Documents archive, along with recent Japanese litigation documents and published documents. RESULTS: JT's effort to combat effective tobacco control was strengthened in the mid-1980s, following privatisation of the company. While remaining under the protection of Japan's Ministry of Finance, the semiprivatised company lost its 'access to politicos', opening up a perceived need for collaboration with global cigarette makers. One solution, arrived at through clandestine planning with American companies, was to establish a third-party organisation, SRF, with the hope of capturing scientific and medical authority for the industry. Guarded by powerful people in government and academia, SRF was launched with the covert goal of influencing tobacco policy both inside and outside Japan. Scholars funded by SRF have participated in international conferences, national advisory committees and tobacco litigation, in most instances helping the industry to maintain a favourable climate for the continued sale of cigarettes. CONCLUSIONS: Contrary to industry claims, SRF was never meant to be independent or neutral. With active support from foreign cigarette manufacturers, SRF represents the expansion into Asia of the denialist campaign that began in the USA in 1953.

A controversial idea as a cultural resource: The Lysenko controversy and discussions of genetics as a 'democratic' science in postwar Japan.

The Japanese discussion of the theory of Soviet agronomist Trofim D. Lysenko began in the postwar years under the American occupation. Leftists introduced Lysenko's theory immediately after the war as part of a postwar scientists' movement. Unlike many American geneticists, who sharply criticized the theory, Japanese geneticists initially participated in the discussion in an even-handed way; their scientific interests in the roles of cytoplasm and the environment in heredity shaped their initial sympathetic reaction. As the Cold War divide deepened, however, Japanese scientists began expressing sharp anti-Lysenko criticisms that resembled the American criticisms. Interestingly, throughout the period, Japanese geneticists' overall aim in the discussion remained largely unchanged: to effectively reconstruct their discipline and maintain its proper image and authority. However, the shift in their reaction occurred due to an evolving sociopolitical context, especially the shift in the meaning of 'democratic' science from a science that employed democratic processes to a science of a liberal-democratic state. Regarding Lysenko's idea as a cultural resource could help to explain how and why it was treated differently in different places, and why a controversy emerged in certain contexts but not in others.

Practice and politics in Japanese science: Hitoshi Kihara and the formation of a genetics discipline.

This paper examines the history of Japanese genetics in the 1920s to 1950s as seen through the work of Hitoshi Kihara, a prominent wheat geneticist as well as a leader in the development of the discipline in Japan. As Kihara's career illustrates, Japanese genetics developed quickly in the early twentieth century through interactions with biologists outside Japan. The interactions, however, ceased due to the war in the late 1930s, and Japanese geneticists were mostly isolated from outside information until the late 1940s. During the isolation in wartime and under the postwar U.S. Occupation, Kihara adapted to political changes. During wartime, he developed a research institute focusing on applied biology of various crops, which conformed to the national need to address food scarcity. After the war, he led the campaign for the establishment of a national institute of genetics and negotiated with American Occupation officers. The Americans viewed this Japanese effort with suspicion because of the rising popularity of the controversial theory of the Russian agronomist, Trofim Lysenko, in Japan. The institute was approved in 1949 partly because Kihara was able to bridge the gap between the American and Japanese sides. With Kihara's flexible and generous leadership, Japanese genetics steadily developed, survived the wartime, and recovered quickly in the postwar period. The article discusses Kihara's interest in cytoplasmic inheritance and his synthetic approach to genetics in this political context, and draws attention to the relation between Kihara's genetics and agricultural practice in Japan.

PERK eIF2 alpha kinase is required to regulate the viability of the exocrine pancreas in mice.

BACKGROUND: Deficiency of the PERK eIF2 alpha kinase in humans and mice results in postnatal exocrine pancreatic atrophy as well as severe growth and metabolic anomalies in other organs and tissues. To determine if the exocrine pancreatic atrophy is due to a cell-autonomous defect, the Perk gene was specifically ablated in acinar cells of the exocrine pancreas in mice. RESULTS: We show that expression of PERK in the acinar cells is required to maintain their viability but is not required for normal protein synthesis and secretion. Exocrine pancreatic atrophy in PERK-deficient mice was previously attributed to uncontrolled ER-stress followed by apoptotic cell death based on studies in cultured fibroblasts. However, we have found no evidence for perturbations in the endoplasmic reticulum or ER-stress and show that acinar cells succumb to a non-apoptotic form of cell death, oncosis, which is associated with a pronounced inflammatory response and induction of the pancreatitis stress response genes. We also show that mice carrying a knockout mutation of PERK's downstream target, ATF4, exhibit pancreatic deficiency caused by developmental defects and that mice ablated for ATF4's transcriptional target CHOP have a normal exocrine pancreas. CONCLUSION: We conclude that PERK modulates secretory capacity of the exocrine pancreas by regulating cell viability of acinar cells.

Expansion and evolution of insect GMC oxidoreductases.

BACKGROUND: The GMC oxidoreductases comprise a large family of diverse FAD enzymes that share a homologous backbone. The relationship and origin of the GMC oxidoreductase genes, however, was unknown. Recent sequencing of entire genomes has allowed for the evolutionary analysis of the GMC oxidoreductase family. RESULTS: Although genes that encode enzyme families are rarely linked in higher eukaryotes, we discovered that the majority of the GMC oxidoreductase genes in the fruit fly (D. melanogaster), mosquito (A. gambiae), honeybee (A. mellifera), and flour beetle (T. castaneum) are located in a highly conserved cluster contained within a large intron of the flotillin-2 (Flo-2) gene. In contrast, the genomes of vertebrates and the nematode C. elegans contain few GMC genes and lack a GMC cluster, suggesting that the GMC cluster and the function of its resident genes are unique to insects or arthropods. We found that the development patterns of expression of the GMC cluster genes are highly complex. Among the GMC oxidoreductases located outside of the GMC gene cluster, the identities of two related enzymes, glucose dehydrogenase (GLD) and glucose oxidase (GOX), are known, and they play major roles in development and immunity. We have discovered that several additional GLD and GOX homologues exist in insects but are remotely similar to fungal GOX. CONCLUSION: We speculate that the GMC oxidoreductase cluster has been conserved to coordinately regulate these genes for a common developmental or physiological function related to ecdysteroid metabolism. Furthermore, we propose that the GMC gene cluster may be the birthplace of the insect GMC oxidoreductase genes. Through tandem duplication and divergence within the cluster, new GMC genes evolved. Some of the GMC genes have been retained in the cluster for hundreds of millions of years while others might have transposed to other regions of the genome. Consistent with this hypothesis, our analysis indicates that insect GOX and GLD arose from a different ancestral GMC gene than that of fungal GOX.

PERK EIF2AK3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis.

Mutations in PERK (EIF2AK3) result in permanent neonatal diabetes as well as several other anomalies that underlie the human Wolcott-Rallison syndrome, and these anomalies are mirrored in Perk knockout mice. To identify the cause of diabetes in PERK-deficient mice, we generated a series of tissue- and cell-specific knockouts of the Perk gene and performed a developmental analysis of the progression to overt diabetes. We discovered that PERK is specifically required in the insulin-secreting beta cells during the fetal and early neonatal period as a prerequisite for postnatal glucose homeostasis. However, PERK expression in beta cells is not required at the adult stage to maintain beta cell functions and glucose homeostasis. We show that PERK-deficient mice exhibit severe defects in fetal/neonatal beta cell proliferation and differentiation, resulting in low beta cell mass, defects in proinsulin trafficking, and abrogation of insulin secretion that culminate in permanent neonatal diabetes.

Learning from Philip Morris: Japan Tobacco's strategies regarding evidence of tobacco health harms as revealed in internal documents from the American tobacco industry.

Japan is in the midst of a rapid increase in tobacco-related disease mortality, following the rapid growth of smoking after WWII. Stomach cancer was the country's leading cause of cancer death for most of the 20th century, until lung cancer took over this position in 1993. Cigarettes are the major cause of lung cancer in Japan, but the country's leading manufacturer, Japan Tobacco, two thirds of which is owned by the Japanese government, continues to question whether tobacco is a major cause of disease and death. Japanese courts do not have the power to subpoena a company's internal records, which has made it difficult to document Japan Tobacco's strategies concerning tobacco and health. Our interpretation of online archives of internal documents from American tobacco companies, however, is that Japan Tobacco has long known about the potential health risks involved in smoking and has sought to obstruct effective tobacco control. Beginning in the mid-1980s, these efforts were often co-ordinated with American tobacco manufacturers. The documentary evidence shows that cigarette manufacturer Philip Morris in particular assisted with and sometimes also supervised Japan Tobacco's actions and statements on smoking and health. In one instance, data gathered for an article published by the Japan Public Monopoly Corporation (Japan Tobacco's predecessor) were deliberately altered to lower the reported value of a hazard indicator (nicotine concentration in the air). International collaboration has made it easier for companies such as Japan Tobacco to develop effective anti-antismoking strategies. Evidence of such global industry collaborations might grow as lawsuits begin to be filed in other nations.

Glucose dehydrogenase is required for normal sperm storage and utilization in female Drosophila melanogaster.

Female sperm storage is a key factor for reproductive success in a variety of organisms, including Drosophila melanogaster. The spermathecae, one of the Drosophila sperm storage organs, has been suggested as a long-term storage organ because its secreted substances may enhance the quality of sperm storage. Glucose dehydrogenase (GLD) is widely expressed and secreted in the spermathecal ducts among species of the genus Drosophila. This highly conserved expression pattern suggests that this enzyme might have an important role in female fertility. Here, we examine the function of GLD in sperm storage and utilization using Gld-null mutant females. The absence of GLD reduced the amount of sperm stored in the spermathecae and led to a highly asymmetrical sperm distribution in the two spermathecal capsules of the mutant females. The storage defect was especially severe when the mutant females were crossed to a Gld-mutant male that had previously mated a few hours before the experimental cross. Under this mating condition, the mutant females stored in the spermathecae only one-third of the sperm amount of the wild-type control females. In addition, the mutant females used stored sperm at a slower rate over a longer period compared with wild-type females. Thus, our results indicate that GLD facilitates both sperm uptake and release through the spermathecal ducts.

PERK eIF2alpha kinase regulates neonatal growth by controlling the expression of circulating insulin-like growth factor-I derived from the liver.

Humans afflicted with the Wolcott-Rallison syndrome and mice deficient for PERK (pancreatic endoplasmic reticulum eIF2alpha kinase) show severe postnatal growth retardation. In mice, growth retardation in Perk-/- mutants is manifested within the first few days of neonatal development. Growth parameters of Perk-/- mice, including comparison of body weight to length and organ weights, are consistent with proportional dwarfism. Tibia growth plates exhibited a reduction in proliferative and hypertrophic chondrocytes underlying the longitudinal growth retardation. Neonatal Perk-/- deficient mice show a 75% reduction in liver IGF-I mRNA and serum IGF-I within the first week, whereas the expression of IGF-I mRNA in most other tissues is normal. Injections of IGF-I partially reversed the growth retardation of the Perk-/- mice, whereas GH had no effect. Transgenic rescue of PERK activity in the insulin- secreting beta-cells of the Perk-/- mice reversed the juvenile but not the neonatal growth retardation. We provide evidence that circulating IGF-I is derived from neonatal liver but is independent of GH at this stage. We propose that PERK is required to regulate the expression of IGF-I in the liver during the neonatal period, when IGF-I expression is GH-independent, and that the lack of this regulation results in severe neonatal growth retardation.