• The Director’s Message

Message from the Director General

Hisao Masai Photo

Hisao Masai

In 2022, we witnessed the tragedy that an unjustified war brought to people on this earth. Watching the tremendous loss of human lives in Ukraine and Russia simply has made us speechless. As scientists working to benefit humanity, we strongly oppose this senseless war and hope this tragedy will end soon. On the bright side, the COVID pandemic finally seems to be abating somewhat. After nearly three years, face-to-face meetings have finally resumed, and many have started to attend meetings abroad. Although life in Japan has not completely returned to normal, we hope to soon return to a way of life where we are not living in constant fear of infection.

TMIMS 2022

In September, we had very good news. Dr. Masato Hasegawa, the leader of the Dementia Research Project was selected as a 2022 Clarivate Citation Laureate. Clarivate Citation Laureates are candidates considered likely to win the Nobel Prize in their respective fields. His paper on TDP-43, a causative factor for neurodegenerative diseases and dementia published in 2006, was cited more than 2000 times and is in the top 0.1% of high-impact papers. We are very pleased that his long-term research on the pathology and molecular basis of neurodegenerative diseases has been recognized. Dr. Hasegawa continues to uncover basic mechanisms of disease development and expansion, and applies these findings to the development of novel drugs and therapies for treating people with dementias (see also page 16).

We are currently in the third year of the 4th project term, and we have started a “Frontier Research Laboratory” program in which young researchers in the institute can conduct independent research projects. Dr. Shinobu Hirai has been selected to head the first Frontier Research Laboratory with a new research team, and we are eager to expand this program in the coming years.

The Coronavirus pandemic has prevented many activities and forced many events to be on-line. Scientific interactions with other institutes were limited, and we had not been able to invite outside visitors. However, the situation improved much in 2022, and many seminars and public lectures were conducted in a hybrid manner, allowing both in-person and on-line interactions (see page 60).

On December 6, 2022, we were able to host the 23rd TMIMS International Symposium, “New Frontiers in the Ubiquitin Proteasome System” (organized by Dr. Yasushi Saeki of the Protein Metabolism Project). We invited 7 prominent scientists from abroad who are leaders in the field. During the one-day meeting, these scientists as well as 6 invited speakers from within Japan and 7 in-house speakers gave talks in the auditorium. There were heated questions and answers for every talk, and the meeting was followed by a reception with much further discussion. It had been three years since the last TMIMS international symposium, and we all thoroughly enjoyed face-to-face interactions.

Two years ago, we created a program for inviting prominent foreign scientists to visit and work at the institute for up to one year. However, we had not been able to put this program into action because of the pandemic. For the first time in 2022, we decided to invite three foreign scientists through this program, and Dr. Gemma Knowles (King’s College London invited by Dr. Atsushi Nishida) visited our institute last year. Next year more scientists will visit us through this program.

We have continued to develop pan-vaccines against SARS-CoV-2 and conduct basic research to clarify mechanisms of infection and develop new drugs against infections. We have also contributed to policy-making by the Tokyo Metropolitan Government by providing social dynamics data.

Research achievements from our institute in 2022

We had numerous notable findings from this institute in 2022. Dr. Taku Miyagawa in the Sleep Research Project discovered an association between a genetic variant of the orexin gene and idiopathic hypersomnia. This genetic variation occurs at the cleavage site on pre-pro orexin, and the variant showed a significantly reduced cleavage rate. The uncleaved polypeptide is less functional than the cleaved peptide, thus reducing the signal transduction efficiency through the orexin receptor. This is the first time that a significant risk factor for idiopathic hypersomnia has been identified, and this work provides a breakthrough in clarifying the mechanism of this disease. The finding was reported in npj Genomic Medicine (page 12). The Circadian Clock project (led by Dr. Hikari Yoshitane) identified a mechanism that stabilizes the circadian timekeeping system in mammals through rhythmic transcription of Bmal1. These results were published in Nature Communications and show how circadian clock regulation may be maintained robustly. Dr. Kosuke Tanegashima of the Stem cell project (led by Dr. Takahiko Hara), in collaboration with Dr. Hitoshi Okamura’s group at Kyoto University, found that expression of CXCL14, a chemokine, is regulated in a circadian manner. They further found that CXCL14 regulates innate immunity and functions to protect animals from bacterial skin infections. Overall, their results demonstrate that CXCL14-controlled innate immune responses are more robust during circadian periods when animals are asleep or inactive compared to when they are awake and active. These findings were reported in the Proceedings of the National Academy of Science of the United States of America (PNAS), and are described in further detail in an interview article (page 14). Dr. Tsuyoshi Takahashi and Yuichiro Miyaoka in the Regenerative Medicine Project analyzed gene editing at a single-cell level. They found that gene editing either occurred in all alleles in a cell or in none. These findings revealed novel aspects of gene editing and were reported in iScience. Other interesting papers published this year are listed on our Home Page (https://www.igakuken.or.jp/topics/topics2022.html).

Science in 2022

The 2022 Nobel Prize in Physiology or Medicine was awarded to Swedish paleogeneticist Svante Paabo for his discoveries on the genomes of extinct hominins and in human evolution. Dr. Paabo sequenced the genome of Neanderthals, an extinct relative of Homo sapiens, and found that DNA sequences from Neanderthals were more related to sequences from present-day humans originating from Europe or Asia than to sequences from present-day humans from Africa. Dr. Paabo also discovered a previously unknown hominin, Denisova, from the Denisova cave in southern Siberia, whose genome is distinct from those of Neanderthals or Homo sapiens. He concluded that gene transfer took place from these now-extinct hominins to Homo sapiens. Homo sapiens are known to have first appeared in Africa around 300,000 years ago. They expanded out of Africa around 70,000 years ago, and coexisted with the Neanderthals in Eurasia for tens of thousands of years. During their millennia of coexistence, Homo sapiens interbred with both Neanderthals and Denisovans, and around 1% to 4% of the genome of present-day humans with European or Asian origins is derived from Neanderthals. How we, humans, have evolved on this planet earth is a mind-provoking question. With new technology, it has now become possible to experimentally examine the evolutional path of human beings.

Science in Japan

We hear much these days about the declining strength of scientific research in Japan. In 2000, Japan ranked 4th in countries with the most top 10% publications with 7.3%. In 2010, Japan ranked 7th with 5.5%, and in 2020, 12th with 4%. During this period, China moved from 13th to 3rd to first. In the last 20 years, government research support increased by 20-fold in China (60 trillion yen) and doubled in the USA (70 trillion yen), while it increased by only 20% in Japan (17 trillion yen). Besides problems with funding, it appears that in Japan, being a scientist is not a very attractive carrier choice. Many aspiring young scientists have a hard time getting by in temporary positions and are forced to give up their careers as researchers. Young graduate students in Japan cannot see much of a bright future in pursuing academic careers.

Japan has produced 27 Nobel laureates in the sciences and is ranked No.7 in the world. We’ve had 22 recipients since 2000 and are one of the top 3 countries in this regard. This achievement is mainly due to the strong support by the Japanese government for the basic sciences for last more than 40 years. The tree of science cannot grow without thick roots in the ground. The thick roots are the basic sciences that feed nutrients to the tree, which then produces ripe seeds. During hard times, the branches and leaves may be blown away, but the trunk will stay, as long as the roots are solid, and the tree will be able to yield seeds in the future. If the roots are fragile, the tree will not last, even though the seeds look ripe. We need to protect and expand the roots. Basic sciences need to be protected and grown even when seeds seem to be in the distant future. The current trend in Japanese science policy is to look for seeds instead of nurturing the basic sciences. Without watering the roots, the seeds will die, and the tree itself will wither away. I strongly urge the Japanese government to increase support for all aspects of the basic sciences. Only the basic sciences will uncover the mysteries of nature that will bring us solutions that will revolutionize our lives.

Outlook for 2023

In 2023, we will continue to strive for creative discovery in various biomedical fields including protein metabolism, genome maintenance, brain functions and neurodegenerative diseases, sleep disorders, circadian rhythms/aging, addiction, antibody therapy, gene editing, mental diseases, viral infections and so forth. Our findings should lead to improved prediction, diagnoses, and treatments for diseases.

With decreases in coronavirus severity and deaths, I hope our way of life will be more normal this year. That said, we will continue our efforts to develop more versatile vaccines that will respond even to new variants of COVID-19 and to other unpredictable emerging viruses/pathogens, and to establish a common platform for vaccine development. We will also continue to support the Tokyo Metropolitan Government by providing information and medical technology to aid in policy-making.

I hope that the atrocities and tragedies of 2022 will be mitigated in 2023 and we will be living on a more peaceful planet.

Legends to figure

TMiMS, located in the midst of the Tokyo Metropolitan Area, is devoted to improving the health and welfare of people in this mega-city. We study various diseases associated with longevity, stressful lifestyles, high diversity/social mobility of people, all of which are intrinsic to a metropolis.
We conduct cutting-edge basic science that will disclose fundamental basic mechanisms of biological processes and disease development. In collaboration with hospitals, we will apply our findings to the prediction/prevention/diagnosis of diseases, and to treatment of patients. We also conduct social medical research to understand the social and environmental factors associated with mental health, and improve patient welfare. These diverse approaches will be combined to improve medical care, and overcome the medical problems facing Tokyo.