Their SMART method accelerates enzyme evolution by reducing the selection period for superior variants from several weeks to a few days, and decreases overall enzyme engineering campaign costs by eliminating the need for specialized equipment.

Enzymes are proteins that catalyze chemical reactions in living organisms. They are widely applied in industries such as food production, detergents, pharmaceuticals, and chemicals. However, for commercial use, natural enzymes often need improved stability, substrate specificity, or catalytic efficiency.

Directed evolution is a Nobel Prize-winning strategy for improving proteins. It introduces artificial mutations into their genes and then selects superior variants. This approach mimics natural evolution over several weeks instead of millions of years.

A significant challenge of this approach is that artificially induced mutations can generate up to 100 trillion candidate variants, which renders the screening process extremely time-consuming and expensive.

To address this challenge, researchers at 菜創郭肱利 and their colleagues have developed SMART (Single-Molecule Assay on Ribonucleic acid by Translated product), an in vitro selection platform.

Their study demonstrated that SMART identifies improved enzyme variants much more rapidly and cost-effectively than conventional methods. The findings were published in the journal .

The SMART system was developed by a research group led by Associate Professor and Professor of the , in collaboration with researchers from the Institute of Science Tokyo and Saitama University. This approach successfully combines mRNA display, next-generation sequencing, and bioinformatics.

Key features of the SMART system

Typically, proteins and genes are physically separate, making it difficult and time-consuming to identify which gene encodes a discovered enzyme.

In the SMART system, puromycin acts as a chemical bridge, linking the enzyme protein to its corresponding blueprint, messenger RNA (mRNA). This mRNA display technique enables precise tracking of the relationship between individual proteins and their encoding genes at the single-molecule level.

Nakano emphasized, “In principle, there is no method for enzyme screening that is more efficient than this system. Screening enzymes at the single-molecule level has rarely been attempted before.”

SMART also incorporates an auxiliary unit for detecting enzyme activity. This study used engineered ascorbate peroxidase 2 (APEX2) as the auxiliary enzyme for oxidase screening. When the target oxidase is active and releases hydrogen peroxide (H?O?), APEX2 attaches a biotin marker to nearby molecules, enabling their isolation and capture.

Enzyme screening experiments using SMART

The researchers chose a yeast oxidase, SpDAAO, as a model enzyme because it has great potential for drug synthesis and diagnostics. The selection prioritized D-amino acids as enzyme substrates due to their growing relevance in medical applications.

The SMART method consists of several steps！creating a DNA library of enzyme variants, synthesizing enzymes in vitro, forming an mRNA display library, labeling catalytically active enzymes, isolating them with magnetic beads, and using sequencing data to guide subsequent rounds.

To assess the method, the team tested it on a simulated library with different ratios of active and inactive variants. After a single selection round, active variants were highly enriched, confirming SMART’s effectiveness.

In practical experiments, the team generated a mutant library by substituting the essential 232nd amino acid with each of the 20 other amino acids. Next-generation sequencing analysis showed that the wild-type (original form) Y232 was clearly selected (p < 0.001), reinforcing the method’s selectivity.

Initially, genetic analysis indicated selection of several variants, in addition to the original form. However, further statistical analysis identified these as experimental noise with minimal practical significance, supporting the method’s specificity.

Conclusion and future perspectives

The experiments showed that SMART selection is highly effective. At the same time, the team recognized the need for rigorous statistical analysis and careful experimentation, rather than relying solely on initial results.

The researchers expect SMART to be applicable beyond oxidases. They aim to facilitate the integration of novel enzymes into industry, establishing the system as a foundation for future enzyme development and practical biocatalytic solutions.

Publication

Kalhari Munaweera, Nana Odake, Hannah Patricia Halim, Kakeru Ikeda, Bo Zhu, Maurizio Camagna, Tomokazu Ito, Tetsuya Kitaguchi, Naoto Nemoto, Hideo Nakano, and Jasmina Damnjanovi? (2026). Harnessing the Power of SMART Single-Molecule Display for Enzyme Evolution: A Focus on Oxidase, ACS Synthetic Biology. DOI:

Funding

This work was supported by Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Early-Career scientists [grant number JP18K14387 and JP22K14828] and Grant-in-Aid for Transformative Research Areas (A) (Publicly Offered Research) [grant number JP25H02263], the Collaborative Research Program by Network Joint Research Center for Materials and Devices (Ministry of Education, Culture, Sports, Science and Technology -Japan: MEXT), and Retention, Development, and Promotion Program Program Aiming at Maximizing the Career Potential of Female Researchers, 菜創郭肱利, (MEXT’s Initiative for Realizing Diversity in the Research Environment, Leadership training type for women) awarded to Jasmina Damnjanovi?, and in part by Pre-Research Unit System of the Institute of Integrated Research, Institute of Science Tokyo and JSPS Grant-in-Aid for Transformative Research Areas (A) (Publicly Offered Research) [grant number JP24H01123] awarded to Bo Zhu.

Expert contact

Jasmina Damnjanovi?
Graduate School of Bioagricultural Sciences, 菜創郭肱利
Email: jasmina@agr.nagoya-u.ac.jp

Media contact

Naomi Inoue
International Communications Office, 菜創郭肱利
Email: icomm_research@t.mail.nagoya-u.ac.jp

Top image

The SMART single-molecule display model, predicted by Alphafold3, shows SpDAAO (red) linked to a puromycin linker (magenta) through puromycin incorporation into the growing polypeptide. The mRNA (gray) is hybridized and chemically joined to the linker, connecting it to its protein, SpDAAO. An auxiliary unit is added using ORC hairpin DNA (blue) with APEX2-scCro fusion protein (green).
Credit: Hideo Nakano and Jasmina Damnjanovi?

Launching a startup creates momentum！but sustaining it is another challenge altogether. The real work of bringing research into society often begins after the company is founded.

In 2022, Dr. Toshihira Irisawa (associate professor at Gifu University and researcher at the 菜創郭肱利 Institutes of Innovation for Future Society) founded , a startup rooted in his research on carbon fiber and polymer materials. Working closely alongside him has been?Ichiro Oda, Lead Research Administrator, who has supported Irisawa¨s journey as a startup founder.

Startup support can be hard to grasp. How far do institutional programs reach！and how are gaps filled when systems fall short? This conversation traces how that support actually works.

�ぉ� What led you to start fff fortississimo?

Irisawa: I often saw technologies developed with companies fail to reach commercialization. I started to think, ＾It would be faster if we did this ourselves.￣ So I decided to launch a university startup to bring our tennis strings to market.

�ぉ� When I first heard the company name, I thought it sounded musical. Was that intentional?

Irisawa: I hear that a lot. Fortississimo is a musical term meaning ＾very strong,￣ and the idea of strength and forward motion really fit what we wanted to do. The name also connects to , a carbon fiber manufacturing hub at Gifu University.

�ぉ� How did the support around your startup begin?

Irisawa: It began around 2021, when we were selected for the . After a staff change, Mr. Oda took over and helped connect us with advisors, companies, and fundraising opportunities.

Oda: I had just started at 菜創郭肱利 then. From our early conversations, I could tell right away that Dr. Irisawa was serious about building a startup.

�ぉ� What was it like after you launched the company?

Irisawa: The first year was tough. Support before founding！like the GAP Fund！was very generous, and I was grateful for that. But after launching the company, we quickly ran into funding limits. Many startups begin with 10 million yen in capital, and it runs out faster than you expect！making even basic investments, like equipment, difficult.

�ぉ� So there was a kind of ＾gap￣ in support after founding.

Irisawa: Exactly. After founding, many grants require matching funds, which means you have to pay a significant portion upfront. For startups trying to stay financially cautious, that can feel risky！almost like taking on debt.

�ぉ� In that situation, how did you support him?

Oda: My role is not to focus on technical details, but to connect people to opportunities for growth. When I see someone with strong momentum like Dr. Irisawa, I try to accelerate that by linking them to the right programs and people. In 2024, I encouraged him to apply to , a startup growth support program that offers funding and mentoring.

Irisawa: That¨s right. I applied because Mr. Oda recommended it, and we were accepted. The funding mattered, but the mentoring has been especially valuable. With monthly sessions, ideas that were once overlooked are now taken seriously, and things are moving in a much better direction.

�ぉ� What I¨m hearing is that the support has become a continuous line, not just isolated points.

Irisawa: Absolutely. From the beginning, I planned the business in three stages: HOP, STEP, and JUMP. HOP focuses on building a stable base with tennis string products. STEP expands into multiple applications and carbon fiber businesses. JUMP aims for an IPO by 2030. Things are progressing as planned, and I feel we are now entering the JUMP phase.

Oda: When I first saw the plan, I honestly thought it was a stretch. At the time Dr. Irisawa founded the company, most support programs only covered the HOP stage！the initial step of getting a startup off the ground.

�ぉ� Looking back, what kind of support system would you have wanted at that time?

Irisawa: Just one more push after founding！especially financial support in the first year！would have made a big difference.

Oda: That was a common challenge at the time. Recently, support has expanded to cover the post-founding phase！for example, for R&D after launch, as well as cross-institutional support through the Startup Promotion Office, , and .

�ぉ� What would you like to say to researchers considering a startup?

Irisawa: Starting a company is tougher and quieter than it may look from the outside. But if you are clear about what you want to do, you can get through it. Support systems matter, of course, but just as important is having people who are willing to move forward with you.

Oda: I see my role as supporting researchers who want to keep challenging themselves. When I feel that someone is serious about moving forward, I will do everything I can to connect them with the right opportunities.

Yuko Iida

Professor, Japanese Culture Studies, Graduate School of Humanities, 菜創郭肱利 / Director, Center for Transregional Culture and Society, Graduate School of Humanities, 菜創郭肱利

She has published many works, including Kanojotachi no bungaku: Katariniku-sa to yomareru koto 泳溺たちの猟僥�砕Zりにくさと�iまれること (single-authored); Josei to t┃s┃: Zasshi “Nyoningeijutsu” to 1930-nen zengo no bunka seisan 溺來と�L尸�埼j�I仝溺繁椰�g々と匯湘眉��定念瘁の猟晒伏�b (authored and compiled); and Kea o ekaku: Ikuji to kaigo no gendai sh┃setsu ケアを宙く�采��垢判蛆oの�F旗弌�h (co-authored).

Her new work, Puroretaria bungaku to jend─: Kaiky┗ naratibu int─sekushonariti プロレタリア猟僥とジェンダ�`�埼A��?ナラティブ?インタ�`セクショナリティ (authored and compiled), was published on October 24, 2022. She presently works in a wide variety of fields, as indicated by her serving as the Director of the Center for Transregional Culture and Society and organizing the international symposium The Ethics of Care and the Humanities on January 28 and 29, 2023. She specializes in modern and contemporary Japanese literature and gender studies.

What is the silent power that controls us? The pursuit of research to find the answer

We live with various social labels attached.

• Students of the natural sciences are good at thinking logically. Students of the humanities have high-level communication skills.
• Stable jobs with lifetime employment are popular. Starting a business and working freely is also good as a modern style.

Although we are not sure if they are true or not, we often hear many other similar examples. These labels affect us as norms for living even before we realize it. Professor Iida describes it in the following way:

＾We all live in ignorance of norms. I feel that it is important to visualize and be conscious of norms. If they are correct, we should maintain them, and if they are incorrect, we can disregard them.￣

However, how should we perceive norms, which can be described as ＾implicit dynamics￣? One of the approaches is analysis from the perspective of literature research.

In the late 1980s, a cultural research approach began to be incorporated into Japanese literature research. For example, a novel by a writer is read by many people, such as the editor, critics, and general readers, while influencing society and undergoing evaluation, which in turn influences the writer. Novels are therefore creations not only based on the writer¨s own views, but also based on the influence of society as a whole. Called the ＾literature field,￣ this entire process is acknowledged as an element that forms culture. A close analysis of the literature field enables a complex entanglement of the norms in society to be unraveled and visualized.

What is the ＾literature field,￣ which reflects and forms society?

Let¨s take a look at proletarian literature, which is one of Professor Iida¨s research areas and a major trend in modern literature.

The Meiji (1868-1912), Taisho (1912-1926), and Showa (1926-1989) eras saw dramatic progress in the modernization of Japan. Textiles, mining, shipbuilding, and many other industries supported the development of Japan in those days, but at the time, they required a large amount of cheap labor. Consequently, the structure of economic disparities became conspicuous, as expressed by the terms ＾bourgeoisie of the capitalist class￣ and ＾proletariat of the wage-earning class.￣ Under these circumstances, proletarian literature emerged with the theme of the harsh working environment of the proletariat and invited empathy from many people. This literature gained momentum especially in the 1920s and the 1930s, including the renowned work The Crab Cannery Ship (Kani k┃sen 亰垢巻) by Takiji Kobayashi.

Proletarian literature has been a popular research theme. Professor Iida, who has incorporated the perspective of gender into the research, says:

＾For gender research, it is important to look not only at gender, but also at connections with other elements.￣

Gender refers to the socially and culturally formed sex, rather than the biological sex. A gender perspective has been woven into each of education, work, public service, etc. The structure and true problems of gender will remain obscure if the relevant elements are simply identified and categorized. They will become explicit only after holistic consideration is given to their backgrounds and surroundings. Prof. Iida has given such consideration in Puroretaria bungaku to jend─: Kaiky┗ naratibu int─sekushonariti,⁽¹⁾ authored and compiled by her and other literature researchers.

Those who challenged capitalism and fought for socialism and communism in those days were subject to imprisonment as ＾thought￣ criminals. Among them were some proletarian writers, including Takiji Kobayashi. Some citizens tried to provide relief to such imprisoned fighters by, for example, providing them with relief items, visiting them in prison, and offering support for their families.

For these relief efforts, women played the main role in a practical sense. However, public documents only record that men took the lead in the relevant relief organizations, almost without reference to the women¨s efforts. In this regard, literature research first highlights the reality hidden in the male gender norms of the time. For example, proletarian writers Shigeharu Nakano and Rintaro Takeda, who authored By┃ki naoru 押�櫃覆曚� and 京┃姻霞看一顎 羽薦, respectively, depict women engaged in relief efforts in their novels. In one of her works, Professor Iida says:

＾Based on the gap between the public record and reality, I would like to indicate that unlike the public record, the relief narrative represented by proletarian literature features women as the main players in the relief efforts. […] Women, who do not appear in the public record, are portrayed in literature.￣ ⁽²⁾

In the structure of reality, there were gender norms of the ＾fight￣ as the central part played by men and of the ＾relief￣ as the peripheral part played by women. This theory is supported by the description of Tefu Watanabe, the ＾mother￣ of the relief efforts, as the symbol of the efforts. She is described in Nokosareta zen’ei no kazoku wa d┃shiteiru ka? 火された念�lの社怛はどうしてゐるか? by Misao Hata, published in the issue of March 1930 of the literature magazine Senki �蘰�, along the following lines:

＾She always smiles as if she had completely forgotten about the sadness of her son having been XX. She is working as hard as the young, big Seki-san. She is exactly like the mother of Pavel in Mother by Gorky. She is the mother of the proletariat. […] If any of you are about to feel depressed or intimidated even slightly, you should go there quickly and have a bowl of ramen noodles.￣⁽³⁾

Tefu Watanabe, who worked hard and made every effort to support the imprisoned fighters and their families, was often featured in proletarian literature magazines. Meanwhile, interestingly, she was at first described as a victim who had lost a family member in the midst of the fighting, namely a person to be relieved. A message to her was published in D┃shi xno kara ok─san e 揖崗〜勸からお銚さんへ in the July 1929 issue of Senki:

＾Ms. Watanabe, please don¨t cry when you come to see me. […] There are a lot of things to be done, including those that you can do. I hope that you will visit everyone and console them. Please do not think only about yourself but about everyone.￣⁽⁴⁾

Tefu Watanabe, a mother in deep sorrow due to the loss of a family member, was gradually becoming transformed from a person to be relieved to the key player in the relief efforts. In one of her works, Prof. Iida discusses this transformation along the following lines:

＾Due to these dual features, the family grief and predicament served as rhetoric that mobilized citizens to be engaged in the relief efforts. Tefu Watanabe played a symbolic role in this process. ⁽⁵⁾

To add momentum to the gender norm of the ＾fight￣ as the central part played by men, women placed in the peripheral were depicted differently depending on the purpose. To emphasize the necessity of relief, women were sometimes described with the focus on their family members who should be relieved and the women¨s predicament. At other times, women were depicted to encourage others to become committed as backup supporters. Professor Iida says:

＾Literature, especially novels, are based on a framework of thought which includes views about the family and society. Literature reflects and also forms society. ￣

The views described here are only a small part of her work Puroretaria bungaku to jend─, which we strongly recommend to you.

(1) Puroretaria bungaku to jend─: Kaiky┗ naratibu int─sekushonariti. Yuko Iida (auth. and comp.), Izumi Nakatani (auth. and comp.), and Kayo Sasao (auth. and comp.), Seikyusha, released at bookstores on October 24, 2022. ISBN978-4-7872-3514-5

(2) Ibid., p. 87 and p. 89

(3) Misao Hata, Nokosareta zen’ei no kazoku wa d┃shiteiru ka?, Senki, March 1930 issue Senkisha, p. 179 (Note: Primary citation from Puroretaria bungaku to jend─)

(4) D┃shi xno kara ok─san e, Senki, July 1929 issue, Senkisha, p. 127 and p. 129 (Note: Primary citation from Puroretaria bungaku to jend─)

(5) Authored by the same persons as (1), p. 85

How should we behave when norms are continuing to change?

From the modern era to the contemporary era, many literature works present the norms of each period. For such norms, Professor Iida feels something through her research. She says:

＾History shows that norms have always been changing, and I feel that they will surely continue to change.￣

Gender norms will also surely change in line with the times. Today, people have begun to search for their ideal selves as men and women, and even various identities that cannot be simply categorized as men or women. If there are old-fashioned systems and approaches that disregard this trend, they need to be changed. Professor Iida says:

＾I don¨t feel that the framework of gender will or should cease to exist. However, I believe that discrimination caused by the framework should be eliminated. It would be nice if we could just accept diverse people as they are. People have traditionally fallen into various categories, such as age, origin, class, ethnicity, and race. Among these, gender figures very strongly. I feel that it would be good if gender were diluted by many other attributes.￣

On April 14, 2026, 菜創郭肱利 hosted Her Excellency B└atrice Le Fraper du Hellen, Ambassador of France to Japan, for a commemorative ceremony marking the launch of IRL GlycoMIRAI. The event, held at Common Nexus on the Higashiyama Campus, also brought together senior CNRS leadership, including Andr└ Le Bivic, director of CNRS Biology, alongside 菜創郭肱利 President Naoshi Sugiyama and other representatives of the Tokai National Higher Education and Research System (THERS).

IRL GlycoMIRAI ！ short for Multidisciplinary International Research for Advancing Innovation in Glycosciences ！ is a new International Research Laboratory (IRL) jointly established by 菜創郭肱利 and the French National Centre for Scientific Research (CNRS). Working in close partnership with the Institute for Glyco-core Research (iGCORE), the lab brings together researchers from French and Japanese institutions to pursue cutting-edge glycoscience: the study of sugar chains that coat the surface of virtually every living cell.

For more on the laboratory and its research themes, see the related article from April 13, 2026.

In her remarks, Ambassador Le Fraper du Hellen noted that the ceremony came just days after French President Emmanuel Macron’s visit to Japan, during which scientific cooperation between the two countries took center stage. Coinciding with this visit, President Sugiyama and CNRS Chairman and CEO Antoine Petit met in Tokyo to sign the agreement underpinning GlycoMIRAI.

The Ambassador situated the new laboratory within a broader vision, pointing to the “One Health” approach as a framework especially well suited to the kind of research GlycoMIRAI will pursue. “Glycosciences also offer opportunities to face global challenges, from improving health and ensuring food security,” she said, noting that the timing was fitting given that the One Health Summit had been held in Lyon, France, on April 7.

President Sugiyama also spoke at the ceremony, expressing his hopes for the laboratory’s growth in the years ahead. 菜創郭肱利¨s spirit of free and creative thinking has nurtured six Nobel laureates, and Sugiyama suggested that the international collaboration fostered by GlycoMIRAI could one day produce another.

Following the ceremony, Ambassador Le Fraper du Hellen met separately with President Sugiyama. Discussions focused on strengthening student mobility and research collaboration between 菜創郭肱利 and French institutions, with particular attention to expanding study abroad opportunities in France. The two sides also reflected on an already active relationship: 菜創郭肱利 maintains inter-university agreements with 11 French institutions and runs ongoing exchange programs, including a long-standing partnership with the University of Strasbourg that has facilitated researcher visits and short-term language programs for undergraduate students.

These awards commend individuals who have achieved success in research and development, as well as in the promotion of public understanding of science and technology. Through this recognition, the program seeks to inspire those engaged in the field and contribute to the overall advancement of science and technology in Japan. The awards include the Awards for Science and Technology (Development Category, Research Category, Science and Technology Promotion Category, Technology Category, Public Understanding Promotion Category), the Young Scientists¨ Award, the Award for Creativity, and the Outstanding Support for Research Award.

Awards for Science and Technology

Research

• Tomoo Ogi (Professor, Research Institute of Environmental Medicine)
• Hiroyasu Tajima (Professor, Institute for Space-Earth Environmental Research)

Development

• Kensaku Mori (Professor, Graduate School of Informatics)

Young Scientists¨ Award

• Wang Qian (Professor, Graduate School of Engineering)
• Asuka Suzuki (Associate Professor, Graduate School of Engineering)
• Ryoya Tanaka (Lecturer, Graduate School of Science)
• Eisuke Yamamoto (Assistant Professor, Institute of Materials and Systems for Sustainability)

Outstanding Support for Research Award

• Kentaro Takahama (Manager, Technical Center)
• Yoshiharu Sawada (Deputy Manager, Technical Center)
• Fumitaka Yoshimura (Technical Specialist, Technical Center)
• Mayumi Nishimura (Technical Specialist, Technical Center)
• Shintaro Goto (Technical Specialist, Technical Center)

Related links

Some of these articles and posts contain language that, in citing 菜創郭肱利¨s name and the research publications of its researchers, may create the misleading impression that 菜創郭肱利 and its researchers were involved in the development of the Apps, etc. We wish to state clearly that 菜創郭肱利 and its researchers have had no involvement whatsoever in the development, manufacture, or sale of the Apps, etc.

Furthermore, the research conducted by 菜創郭肱利 researchers on the alleviation of motion sickness represents foundational findings obtained under specific experimental conditions. 菜創郭肱利 and its researchers do not evaluate or endorse the efficacy or safety of the Apps, etc. as commercialized products. We ask that the public take note of this distinction.

菜創郭肱利

Assistant Professor Chang researches 19th-century debates surrounding Mitogaku �C a school of thought in Japan that emerged in the 17th century �C and theories of civilization. By comparing thinkers who sought to preserve Japan’s traditions and morals (the Mitogaku scholars) with theorists of civilization who advocated learning Western civilization, Chang found that, contrary to the conventional view that these groups were adversaries, they in fact exerted an influence on one another.

Chang’s research was evaluated highly for its reexamination of Japanese thought in the late Edo period (1603-1868). At the award ceremony, Chang said ＾Going forward, I want to compare the intellectual histories of Japan and China, deepen my understanding of Western thought, and be able to grasp the movement of ideas at the global level.￣

Chang says that when she was an undergraduate in China, she wanted to be a physics teacher. While doing a teaching placement in a rural area, she noticed how it differed socially from the city, which sparked her interest in the foundational role of thought and philosophy in society. This led her to study philosophy at graduate school. ＾My advisor recommended that, in order to understand China, it¨s good to see it from abroad, so I came to Japan for my PhD.￣

At the award ceremony, 菜創郭肱利 President Naoshi Sugiyama expressed his high expectations for Assistant Professor Chang¨s future research, saying, “I hope that you become a researcher like Professor Mizuta himself, who was a ‘giant of knowledge.'” Professor Emeritus Takaho Ando, who served on the selection committee, commented, “It is very significant that, in the 14th year, we have, for the first time, a recipient of foreign nationality.”

Originally published in Japanese on March 19, 2026.

On April 17, 2026, Kakhramon Kuranbaev, Chairman of the Association of Mahallas of the Republic of Uzbekistan, visited 菜創郭肱利 to deliver a keynote address and participate in a roundtable hosted by the Center for Asian Legal Exchange (CALE).

The roundtable, titled “From Tradition to Institution: Evolution of the Mahalla System in Contemporary Uzbekistan,” explored how the “mahalla,” a traditional neighborhood self-governance institution rooted in Central Asian urban civilization, has been transformed under President Mirziyoyev’s reforms into a modern pillar of Uzbekistan’s social administration.

The event drew faculty from the Graduate School of Law and the Graduate School of Education and Human Development, as well as students from various programs. Expert commentary was provided by Dr. Aktam Jalilov, a 菜創郭肱利 alumnus and Director of the Institute for the Study of Youth Problems.

Kuranbaev later met with 菜創郭肱利 President Naoshi Sugiyama and Vice President Yoshiyuki Suto, who highlighted 菜創郭肱利’s longstanding partnership with Uzbekistan dating to the early 2000s. Both sides expressed their intention to deepen academic and research cooperation going forward.

Hiroyoshi Nishikawa

Professor of the Department of Immunology, 菜創郭肱利 Graduate School of Medicine, and also Chief of the Division of Cancer Immunology, Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center

In 2022, Dr. Nishikawa was honored as one of the Highly Cited Researchers 2022 by Clarivate Analytics for a third consecutive year, following his recognition in 2020 and 2021. He continues to be a leader in the field of cancer immunology.

Don¨t pretend to understand what you don¨t understand.

Dr. Nishikawa said that his early work, conducted more than 20 years ago, still serves as the cornerstones of his current research.

＾I was lucky to have experienced that work at the beginning. When something happens that I never expected, I can think that there¨s only so much wisdom I can have, and there¨s still so much I have yet to learn,￣ he said.

Our body¨s immune system plays a crucial role in not only fighting against bacteria and viruses but also eliminating cancer. Dr. Nishikawa started his research in the field of cancer immunology in the late 1990s, when the focus was mainly on the study of killer T cells, which directly attack cancer cells.

At that time, he thought that immunity was not so simple and decided to focus his research on helper T cells, which were recognized as coordinating the immune response. However, at the time, it was believed that helper T cells only assisted killer T cells in their fight against cancer, although much remained to be understood. He divided mice with cancer into several groups and treated them in different ways:

1. Activation of killer T cells only
2. Activation of helper T cells only
3. Activation of both killer and helper T cells
4. No treatment

He expected that mice with activated killer T cells and/or helper T cells would have better prognoses although to varying degrees; but unexpectedly, mice with only activated helper T cells showed cancer progression.

Why? Though he later noticed the fact during the days of research, CD4-positive T cells, to which helper T cells belong, can actually be further classified. In reality, in addition to helper T cells supporting killer T cells in fighting cancer, another subset of CD4-positive T cells called ＾regulatory T cells￣ also exist. They play a different role by putting the brakes on killer T cells¨ attacks. Immunity is such a powerful mechanism that once it gets out of control, it may cause excessive immune responses in the body. Regulatory T cells constantly monitor and control the immune system to prevent immune responses from getting out of hand.

Cancer can manipulate and exploit immune suppressive cells including regulatory T cells as a clever mechanism to evade attacks by the immune system. This mechanism may explain the results of his early research described above, in which treatment intended to activate helper T cells also activated regulatory T cells, unexpectedly leading to the protection of cancer cells. In fact, the two types of T cells work in balance with each other. CD4-positive T cells should not be lumped together as helper T cells only. The expected outcome would not be seen unless the two subsets of CD4-positive T cells are activated differently.

Dr. Shimon Sakaguchi, specially-appointed professor of the University of Osaka, discovered regulatory T cells in 1995. At the time, Dr. Nishikawa struggled with mysterious results, turned to Dr. Sakaguchi¨s research on regulatory T cells, thinking that it could be the key. Thus, he found the key to the solution and eventually paved the way for cancer immunology research.

He said, ＾Actually, immunology was my least favorite subject as a medical student. The theory at that time seemed like a patchwork of disconnected information that was being forced together. I couldn¨t understand it very well.￣

There are significant factors, such as one¨s position as a researcher and research trends at the time, that determine one¨s research theme. At the time, it must have taken courage for Dr. Nishikawa to focus on studying helper T cells.

＾It is important for researchers to sincerely face the occurring phenomena. We should not pretend to understand what we don¨t understand,￣ he said.

When you cannot explain well a phenomenon you are seeing or when you do not feel fully convinced, there is surely something wrong. An attitude of not running away from such dissatisfaction can lead to new findings.

A saying of his boss serves as his driving force: ＾If you see one phenomenon, continue to sit in front of it until you have written five papers on it.￣

The research of Dr. Tasuku Honjo, who is the Nobel Prize laureate in Physiology or Medicine 2018, has opened up a new field of cancer treatment known as ＾cancer immunotherapy,￣  particularly, ＾PD-1 blockade therapy￣. One drug used in this therapy is nivolumab (Opdivo).

Killer T cells typically do not attack unless they can recognize and identify other cells as their attack targets. This is another mechanism that prevents excessive immune response, and cancer cells can also take advantage of this mechanism to suppress the attackers. Cancer cells provide a ＾certificate￣ that they are not the attack targets as another means of escape. Killer T cells are slowed down and cannot show their ability to attack in the presence of this certificate. PD-1 blockade therapy including Opdivo has the function of nullifying this certificate, allowing killer T cells to attack cancer cells.

Cancer immunotherapy is a relatively new field of medicine. Unfortunately, PD-1 blockade therapy is only effective in 20% to 30% of eligible cancer cases, for some reasons not entirely explained. Dr. Nishikawa has proven one of the reasons.

＾The immune system works properly in a positive and negative balance. I realized the phenomenon I encountered 20 years ago commonly underlied the results of my current work,￣ he said.

It has been shown that PD-1 blockade therapy activates not only killer T cells but also regulatory T cells surrounding cancer. Therefore, the key to the efficacy of the drug is the balance between the two types of T cells. If regulatory T cells in the periphery of cancer are strong, the killer T cells will eventually be outcompeted by them.

Dr. Nishikawa¨s research progressed further, and the next step was to demonstrate exactly what determines the balance between killer and regulatory T cells. He turned his attention to cancer metastases in the liver, which are particularly resistant to PD-1 blockade therapy.

The liver is a metabolically active organ that receives abundant nutrients supplied from the digestive system such as the large and small intestines. The liver consumes a large amount of glucose to generate energy for metabolism, which results in the release of lactic acid. Cancer cells also consume high amounts of glucose to grow and divide. Metastatic cancer tissues in the liver are richer in lactic acid than other tissues.

＾What I keep in my mind during my research on cancer immunology is to have both the viewpoints of cancer and immunity. I¨ve noticed that regulatory T cells can utilize lactic acid, which hasn¨t received attention in previous studies,￣ said Dr. Nishikawa.

Killer T cells and most other types of immune cells use glucose as an energy source for their activities, but they cannot use lactic acid. In an area where a large number of immune cells are accumulating and actively working, glucose levels decrease while lactic acid levels increase. In such an environment, regulatory T cells, which can utilize lactic acid, would not have any trouble obtaining an energy source, allowing them to constantly monitor and control immune responses.

Furthermore, Dr. Nishikawa has demonstrated that high levels of lactic acid slow down the activity of killer T cells; this suggests that metastatic cancer in the liver may be a more favorable environment for regulatory T cells than for other immune cells.

This series of discoveries has provided new insights into the study of cancer immunology, and has significantly impacted clinical practice. It is a great advance to identify patients who are not expected to respond to PD-1 blockade therapy, considering their cost and potential side effects.

Dr. Nishikawa has accomplished many studies, and describes himself as ＾being persistent￣ when it comes to his research, while attributing much of his success to advances in science and technology and to superior researchers who have supported him. His research attitude can be traced back to the time when he was a researcher at the Memorial Sloan-Kettering Cancer Center in New York, U.S., from 2003 to 2006. His boss at the time, Dr. Lloyd J. Old, was a renowned leader in the field of cancer immunology.

＾He told me that when you see one phenomenon, continue to sit in front of it until you have written five papers on it. It¨s pretty hard to write five papers, but I learned from him the attitude of doing as much as I can to solve a series of things,￣ said Dr. Nishikawa.

The immune system is purposeful, interesting, and beautiful.

When and how does the immune system find and recognize cancer cells? Does the judgment of whether or not something is foreign depending on the situation? Can we create killer T cells that can utilize lactic acid?

Questions arise in his mind one after another. The immune system is very complex, and much of it is still a mystery. Therefore, efforts may not yield fruitful results. ＾It¨s daunting, and there¨s so much I don¨t understand yet, but that¨s what makes it exciting,￣ Dr. Nishikawa stated. Each of his words sounds as if it conveys a spark of curiosity.

＾While study immunology, I sometimes feel thrilled at such a complex but sophisticated mechanism present in our bodies, and the more I study, the more I am amazed and can only stand in awe of it. When I think something is wrong and research it again, I get exactly the results I was looking for. The immune system is so amazing that it makes me realize that human understanding is so far behind,￣ he said.