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 ºÚÁϳԹÏÍø 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¡ªcreating 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, ºÚÁϳԹÏÍø, (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, ºÚÁϳԹÏÍø
Email: jasmina@agr.nagoya-u.ac.jp

Media contact

Naomi Inoue
International Communications Office, ºÚÁϳԹÏÍø
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?

Hiroyoshi Nishikawa

Professor of the Department of Immunology, ºÚÁϳԹÏÍø 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.

Aortic aneurysms are characterized by abnormal enlargement of the aorta, the primary artery responsible for carrying blood from the heart. Rupture often leads to sudden death, and currently, no effective drug therapies are available to halt disease progression.

Researchers at ºÚÁϳԹÏÍø in Japan found that aortic aneurysms are associated with clonal hematopoiesis, an age-related process in which blood-forming stem cells acquire genetic mutations. Their findings, published in the , suggest that commonly used osteoporosis drugs could slow or halt aneurysm progression.

Currently, surgery is the only definitive treatment for aortic aneurysms. Surgical decisions are guided by the risk of rupture, which is assessed through imaging of aneurysm diameter, morphological features, and expansion rate.

It remains difficult to predict which patients will experience progressive aneurysm enlargement, highlighting the need for additional indicators to better stratify disease progression risk. Furthermore, developing drugs that slow disease progression is crucial for reducing mortality. Achieving both goals requires a clear understanding of the underlying mechanisms.

To address this challenge, Assistant Professor and graduate student Jun Yonekawa of the , along with their colleagues, conducted a comprehensive study.

The research team hypothesized that macrophages derived from clonal hematopoiesis accelerate the progression of aortic aneurysms. Although clonal hematopoiesis is recognized as a contributor to several age-related diseases, such as cardiovascular diseases and osteoporosis, its association with aortic aneurysms remains unclear.

Analysis of patient data

Researchers first conducted a clinical study to examine the relationship between clonal hematopoiesis and abdominal aortic aneurysms in 44 patients scheduled for aneurysm surgery.

Genetic analysis and retrospective clinical data showed that approximately 60% of patients had clonal hematopoiesis. These patients had a significantly faster aneurysm expansion rate compared to those without clonal hematopoiesis.

These results suggest that clonal hematopoiesis, which is detectable through routine blood sampling, may serve as a novel biological marker alongside conventional indicators.

Investigation of causal mechanisms in animal models

Researchers then used a mouse model of clonal hematopoiesis driven by Tet2 mutations. These mice exhibited more rapid aneurysm progression and greater increases in aortic diameter than control mice.

Histological analysis showed thinning and fragmentation of elastin fibers in the aortic wall, substantial macrophage infiltration, and degeneration of adjacent vascular smooth muscle cells.

Further analyses suggested that Tet2-mutant macrophages in affected mice exhibited increased expression of osteoclast-related markers, including TRAP. In vitro, these macrophages showed an enhanced propensity to differentiate into osteoclast-like cells and upregulated MMP-9 expression. These findings suggest a potential mechanism by which Tet2-mutant macrophages may contribute to extracellular matrix degradation and aneurysm progression.

The study also identified the RANK/RANKL signaling axis as a key driver of cellular differentiation. This axis is also involved in the pathogenesis of osteoporosis. Researchers found that inactivating the RANK gene in macrophages suppressed cellular transformation and abnormal aortic expansion.

Potential non-surgical approach

To assess clinical relevance, researchers treated affected mice with osteoporosis drugs¡ªanti-RANKL antibodies and alendronate. This intervention significantly reduced aneurysm progression.

“These drugs could potentially be repurposed for clinical use, as they are already FDA-approved and have established safety profiles,” said Yonekawa, the study’s first author. “Our findings provide a rationale for exploring drug-based therapeutic strategies for aortic aneurysms.”

Yura, the study’s corresponding author, concluded: “Our hypothesis that vascular diseases may result from blood aging enabled us to identify a mechanism underlying aortic aneurysms. We hope these results will improve the prediction of the disease and support the development of treatments to halt progression.”

Paper information:

Jun Yonekawa, Yoshimitsu Yura, Junmiao Luo, Katsuhiro Kato, Shuta Ikeda, Yohei Kawai, Tomoki Hattori, Ryotaro Okamoto, Mari Kizuki, Emiri Miura-Yura, Keita Horitani, Kyung-Duk Min, Takuo Emoto, Hiroshi Banno, Mikito Takefuji, Kenneth Walsh, Toyoaki Murohara (2026). Tet2-driven clonal hematopoiesis drives aortic aneurysm via macrophage-to-osteoclast-like differentiation, The Journal of Clinical Investigation.

DOI:

Expert contact:

Yoshimitsu Yura
ºÚÁϳԹÏÍø Graduate School of Medicine
Email: yura.yoshimitsu.z6@f.mail.nagoya-u.ac.jp

Medica contact:

Naomi Inoue
ºÚÁϳԹÏÍø International Communications Office
Email: icomm_research@t.mail.nagoya-u.ac.jp

Top image:

Graphical abstract of the study showing that Tet2-driven clonal hematopoiesis promotes aortic aneurysm progression through macrophage-to-osteoclast-like differentiation.

(Credit: ºÚÁϳԹÏÍø / Jun Yonekawa and Yoshimitsu Yura)

Nearly two thirds of participants held positive attitudes toward sexual and gender minorities, but most assumed others were less accepting

 
Coming out is known to have clear benefits for mental health and wellbeing, yet for many LGBTQ+ individuals in Japan, doing so remains a significant challenge. Researchers at ºÚÁϳԹÏÍø surveyed cisgender, heterosexual Japanese adults on their attitudes toward sexual and gender minorities and coming out. Their findings, published in , show that while most participants had positive attitudes toward LGBTQ+ people, they assumed the public was more negative than themselves¡ªa misperception that may be stopping people from showing their support.  
 
¡°For sexual and gender minority individuals, concealing their gender identity or sexual orientation can have a serious impact on their mental health, while being accepted after coming out is associated with improved quality of life,¡± Xianwei Meng, associate professor at ºÚÁϳԹÏÍø¡¯s , said.  
 
¡°In Japan, many sexual and gender minority individuals report feeling unable to come out. Much of the existing research has focused on the fear of discrimination and stigma, while the role of support from others has been overlooked, even though it¡¯s critical to whether someone feels safe enough to openly share their identity.¡± 

Measuring the gap between personal and estimated societal attitudes 

The online survey collected 370 responses and measured three things: participants¡¯ own attitudes toward sexual and gender minorities, their estimates of how accepting the Japanese public is toward them, and their willingness to support a friend who wished to come out. These were measured using numerical rating scales.  
 
The average personal attitude score toward sexual and gender minorities was 4.24 (on a 6-point scale), while the average estimated public attitude score was 3.83. This statistically significant gap shows that participants underestimated how accepting others were. ? 

Based on their responses, participants were divided into three main groups: those who were positive toward sexual and gender minorities and estimated others as positive (62%), those who were positive but estimated others as negative (17%), and those who held negative attitudes and estimated others as also negative (16%).  
 
These group differences had a notable impact on participants’ willingness to support coming out. The study found that participants who held positive attitudes but assumed others were negative scored significantly lower on willingness to support a friend coming out than those who held positive attitudes and believed others shared their views (3.93 vs. 4.43 out of 7). Their support level was closer to neutral, neither actively helping nor refusing. 

Impact on support for those who want to come out 

¡°Our findings suggest that attitudes toward sexual and gender minorities in Japan are more positive than commonly assumed. However, the misperception that others hold more negative views may discourage people from expressing support, making society appear less accepting than it actually is. Sharing the reality that many people are accepting could help create a more inclusive society,¡± said coauthor Yuka Mizuno, a master¡¯s student at ºÚÁϳԹÏÍø who specializes in social psychology. 
 
The findings carry important implications beyond individual attitudes. In workplaces and schools, raising awareness that acceptance is more widespread than people assume could help build more supportive environments. Media coverage also has a role to play, as reporting that focuses heavily on discrimination and exclusion may inadvertently reinforce a misperception that negative attitudes are the norm. ? ?

Paper information:

Yuka Mizuno and Xianwei Meng (2026). Misperceived Public Attitudes Undermine Support for Sexual and Gender Identity Disclosure in Japan, Psychology of Sexual Orientation and Gender Diversity. DOI: .  

Expert contact:  

Xianwei Meng  
Graduate School of Informatics   
ºÚÁϳԹÏÍø   
E-mail: meng@i.nagoya-u.ac.jp ? ? 

Media contact:  

Merle Naidoo   
International Communications Office   
ºÚÁϳԹÏÍø   
Email: icomm_research@t.mail.nagoya-u.ac.jp   

Top image:

How mistaken beliefs about society can silence support for coming out: A person who personally holds positive attitudes toward LGBTQ+ individuals but assumes society is negative may hesitate to encourage a friend to come out. Yuka Mizuno, ºÚÁϳԹÏÍø 

The origins of a debilitating muscle-wasting disease begin at birth, not in adulthood, ºÚÁϳԹÏÍø researchers have shown. A single treatment at this early stage significantly reduced nerve cell breakdown in adult mice. ? 

Spinal and Bulbar Muscular Atrophy (SBMA) is a rare inherited disease that causes progressive muscle weakness and wasting in men. Patients typically develop early symptoms such as hand tremors in their thirties, but diagnosis usually occurs around age 40 when muscle weakness becomes more evident. Because the disease is triggered by high levels of testosterone, only males are affected.  
 
Researchers at ºÚÁϳԹÏÍø have found that a natural burst of testosterone right after birth causes a mutant protein to overactivate the nerve cells that control muscles (motor neurons) in newborn mice carrying the SBMA mutation. This ongoing overactivation eventually causes those nerve cells to break down in adulthood. The findings, published in , showed that treatment given at birth significantly reduced this breakdown. 

While it is well established that abnormal protein accumulation in neurodegenerative diseases begins years or decades before symptoms appear, what actually happens in the body during this period remains poorly understood. This study focused on the earliest stage of SBMA, the first days after birth.  
 
A brief natural spike in testosterone known as the neonatal testosterone surge or ¡°mini-puberty¡± occurs in all newborn males and lasts approximately 10 days in mice and around 6 months in humans. Because the defective protein produced by the SBMA mutation¡ªmutant androgen receptor protein¡ªrequires testosterone to move into the nucleus of motor neurons and cause damage, the team suspected that this surge represented the earliest moment at which the disease could be triggered. 
 
¡°We confirmed that mutant protein accumulates in the nuclei of motor neurons in male SBMA mice within the first day of life, driven by the neonatal testosterone surge. Female mice with the same mutation showed no such effects, confirming that testosterone is the key trigger,¡± said lead author and assistant professor Tomoki Hirunagi from ºÚÁϳԹÏÍø¡¯s .

Additionally, genes responsible for activating nerve cells, especially glutamate receptors, were abnormally overactive in SBMA mice in the first week of life and caused motor neurons to become overactive. Importantly, the same abnormal overactivity was also observed in motor neurons grown in the laboratory from the cells of actual SBMA patients. This suggests that the disease process in humans may follow the same pattern.

?To test whether treating the disease at birth could help, the researchers administered two gene-silencing drugs to newborn mice with the SBMA mutation, one targeting the mutant protein directly, and one targeting REST4, a protein found to drive the abnormal nerve cell overactivity.  
 
The drug targeting the mutant protein temporarily reduced mutant protein levels and the drug targeting REST4 corrected abnormal gene activity in motor neurons. Both treatments improved survival and motor performance, and decreased motor neuron degeneration in mice assessed at 13 weeks of age.  

¡°Perhaps the most remarkable finding was that a drug given at birth to target the mutant protein continued to protect motor neurons months later, even though the drug effects  had worn off within two weeks. This suggests that intervening at the right moment early in life can have lasting consequences, long after the treatment is gone,¡± Dr. Hirunagi said. 
 
REST4, the protein found to drive the abnormal nerve cell overactivity in SBMA, represents a potential new target for future therapies. 

ºÚÁϳԹÏÍø has previously developed leuprorelin acetate, the only drug approved in Japan for SBMA treatment, making these discoveries part of a broader research legacy in tackling the disease. 
 
The research team identified the next priority as determining whether the same abnormal nerve cell overactivity occurs in human SBMA patients. ¡°This is currently very difficult to study directly, because examining newborn nervous system activity in living patients is not feasible. Our goal is to translate these findings into patient care,¡± Dr. Hirunagi said. The team also intends to evaluate the safety of gene-silencing drugs and the efficacy of repeated treatment. 

Paper information:  

Tomoki Hirunagi, Kentaro Sahashi, Madoka Iida, Kazunari Onodera, Satoshi Yokoi, Yosuke Ogura, Genki Tohnai, Kenji Sakakibara, Kentaro Maeda, C. Frank Bennett, Yohei Okada, Masahisa Katsuno (2026). Restoring early postnatal synaptic dysregulation rescues motor neuron degeneration in a mouse model of Spinal and Bulbar Muscular Atrophy, Nature Communications, 17: 2412. DOI: .??

Funding information: 

This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant numbers: JP20H00527, JP23H00420, JP24K18683, JP23K24249, JP24K18712, JP25K02585) and the Japan Agency for Medical Research and Development (AMED) (Grant numbers: JP22nk0101575, JP22am0401007, JP22bm0804020, JP25bm1423003).

Expert contact:  

Tomoki Hirunagi   
Graduate School of Medicine  
ºÚÁϳԹÏÍø  
E-mail: hirunagi.tomoki.k3@f.mail.nagoya-u.ac.jp 

Masahisa Katsuno 
Graduate School of Medicine  
ºÚÁϳԹÏÍø 
E-mail: katsuno.masahisa.i1@f.mail.nagoya-u.ac.jp

Media contact:  

Merle Naidoo?
International Communications Office?
ºÚÁϳԹÏÍø?
Email: icomm_research@t.mail.nagoya-u.ac.jp

Top image:

Microscopy images of spinal cord tissue from male (left) and female (right) SBMA model mice on the first day after birth. Brown staining indicates accumulation of the mutant androgen receptor protein in motor neuron nuclei. The protein accumulates extensively in male mice but shows little to no accumulation in female mice, confirming that testosterone drives the early accumulation of the mutant protein in motor neurons. Credit: Hirunagi et al., 2026 

Fumagillin has been investigated as a drug lead for more than 70 years, but its more potent relative ovalicin was never developed. Now, scientists have identified metabolic instability as the key barrier and have overcome it through chem-bio hybrid synthesis, yielding drug candidates for amebiasis, a parasitic infection affecting 50 million people annually. 

Amebiasis is a parasitic disease caused by the microscopic protozoan Entamoeba histolytica. Infection occurs through the ingestion of cysts from contaminated water or food. Worldwide, approximately 50 million symptomatic cases are estimated annually, mainly in tropical and subtropical regions.??
?
Fumagillin, a fungal natural product, has been studied for decades as a potential antiparasitic drug, but its more potent relative ovalicin was never developed. Now, a study published in the reveals why: although ovalicin is highly active against amebiasis, liver enzymes rapidly break it down in the body. Researchers ?used a chem-bio hybrid approach to turn that insight into metabolically stable drug candidates that worked in animal models of amebiasis, including liver infection with abscess formation.?
?
The research team, led by scientists from the at ºÚÁϳԹÏÍø, ?identified the liver cytochrome P450 enzymes responsible for ovalicin breakdown, with CYP 2B1 and CYP 2C6 emerging as the main drivers. Blocking these enzymes with a chemical inhibitor significantly prolonged ovalicin survival, providing strong evidence that rapid liver metabolism limits its effectiveness.?

Successfully curing infections in animals 

¡°We engineered fungi to build modified ovalicin molecules with a special attachment point that we could customize. We then clipped different molecular groups onto that point to create versions that the liver could not destroy,¡± explained senior author and associate professor Yuta Tsunematsu.  
 
Using genetically engineered filamentous fungi, the team produced gram-scale quantities of a non-natural ovalicin molecule. They then created about 30 derivatives and tested each one to find versions that killed parasites, survived liver breakdown, and were not toxic. 
 
The protozoan parasite depends on an enzyme called MetAP2 for its proteins to work properly and survive. Blocking MetAP2 kills it but does not harm humans because we have a backup enzyme that can perform the same function. 
 
Two of the new compounds, YOK24 and NS-181, blocked the parasite¡¯s MetAP2 enzyme and eliminated the parasitic infection in hamsters, causing liver abscesses to disappear entirely. 
 
These results are an important step toward testing these drug candidates in humans. Importantly, the compounds were effective after both injection and oral administration. Oral treatment would be especially valuable in low-resource settings, where amebiasis is most prevalent. 

A new drug development method 

Current amebiasis treatments, such as metronidazole, can cause side effects and face growing concerns about drug resistance. 
 
This study introduces Chem-Bio Hybrid Synthesis, a new method that combines genetic engineering of microbes and chemistry to transform natural compounds that worked in lab tests but failed in patients due to rapid breakdown or toxicity. The approach could address these challenges for amebiasis and be applied to develop treatments for other parasitic diseases, cancer, and obesity. 

Paper information:  

Yuki Okura, Yumiko Saito-Nakano, Andrii Balia, Nurul Syahmin Binti Suhaimi, Chika Ando, Namiko Ogata, Tomona Ikeda, Takumi Sato, Keiko Kano, Emi Mishiro-Sato, Masaki Kita, Noriyuki Miyoshi, Kenji Watanabe, Kouichi Yoshinari, Norio Shibata, Mihoko Mori, Seiki Kobayashi, Yuji Sumii, Ryota Shizu, Tomoyoshi Nozaki, Yuta Tsunematsu (2026). Chem¨CBio Hybrid Synthesis Enables Reengineering of Natural Product-Based Methionine Aminopeptidase 2 Inhibitors for Treating Amebiasis, Journal of the American Chemical Society, 148(7), 7189¨C7201. DOI: . 

Funding information:

This work was financially supported by the Japan Agency for Medical Research and Development (AMED) (Grant numbers: JP22wm0325020, JP23wm0325070, JP25jm0110022) and the Japan Society for the Promotion of Science (JSPS) (Grant number 24K02190). 

Expert contact: 

Yuta Tsunematsu 
Graduate School of Bioagricultural Sciences 
ºÚÁϳԹÏÍø 
E-mail: tsunematsu.yuta.p4@f.mail.nagoya-u.ac.jp 

Media contact:

Merle Naidoo?
International Communications Office?
ºÚÁϳԹÏÍø?
Email: icomm_research@t.mail.nagoya-u.ac.jp 

Top image:

Scientists genetically engineered the fungus Aspergillus nidulans to produce a modified ovalicin molecule. Although this molecule itself was still susceptible to liver breakdown, it provided a chemical handle that enabled the synthesis of metabolically stable drug candidates for amebiasis. Credit: Yuta Tsunematu, ºÚÁϳԹÏÍø?

Professor Hiroyoshi Nishikawa (Graduate School of Medicine) has been awarded the Japan Academy Prize.

This prize is awarded by for particularly outstanding academic papers, books, and other research achievements.

The research topic recognized under the award was ¡°Establishment of the Immuno-Genomic Cancer Evolution Hypothesis and its Application to Precision Medicine for Cancer Immunotherapy.¡±

Nishikawa developed a method for the precise analysis of live human cancer tissue. He demonstrated that genomic mutations in cancer cells both promote their own proliferation and induce an immunosuppressive environment, thereby causing tumor initiation and progression. Nishikawa named this mechanism the ¡°Immuno-Genomic Cancer Evolution Hypothesis.¡±

This concept is believed to have brought significant advancements to cancer immunology, as well as having opened up a new field in tumor biology. With this research, Nishikawa also established a new technical foundation that integrates molecular targeted therapies aimed at genomic mutations with cancer immunotherapy (immuno-genomic precision medicine), and he is currently pursuing its clinical application.

Researchers in Japan demonstrated, for the first time in animal models, that stem cell treatment can be effective even when initiated after motor deficits appear in cerebral palsy.

Mechanism of SHED-derived HGF in treating chronic perinatal brain injury (Credit: Yoshiaki Sato)

Cerebral palsy is a condition usually caused by brain damage before or during birth, resulting in impaired posture and movement. Early symptoms are typically subtle, which may delay diagnosis until more obvious signs appear as the child grows.

Recent animal studies show that stem cell therapy may help restore neurological function when initiated in the acute or subacute phase, typically within a few weeks after birth. While some clinical research suggests possible benefits even in later stages, confirmatory clinical trials have not yet been published.

Now, a Japanese research team has demonstrated in rat experiments that stem cells from human primary tooth pulp may help treat chronic-phase cerebral palsy.

“This is the first animal study to show that stem cell treatment works even after motor deficits have already appeared,” said Clinical Professor of , the study’s corresponding author. The findings were published in the journal .

Cerebral palsy affects two to three of every 1,000 live births, and there is currently no cure. The primary cause is hypoxic-ischemic encephalopathy (HIE), which results from reduced oxygen and blood flow to the brain.

“Our team is collaborating with S-Quatre, a Japanese biotechnology company, to develop a new therapeutic approach for HIE using stem cells from human exfoliated deciduous teeth (SHED),” Sato said. “These stem cells are collected from baby teeth that have naturally fallen out and would otherwise be discarded. This method avoids the ethical concerns associated with other stem cell sources.”

A research team led by Sato, Dr. Takahiro Kanzawa, and Professor at and ºÚÁϳԹÏÍø Hospital, in collaboration with S-Quatre, conducted an experimental study to determine whether SHED-based treatment remains effective in the chronic phase of cerebral palsy.

Animal model experiments

The researchers created cerebral palsy models by inducing unilateral hypoxic-ischemic brain injury in 7-day-old rats, resulting in one-sided motor impairment similar to hemiplegic cerebral palsy in humans. They tested the rats at 4 weeks of age using a horizontal ladder test and selected only those with significantly low scores for the study.

They administered SHED intravenously to the selected rats during the chronic phase at 5, 7, and 9 weeks of age¡ªroughly equivalent to pre-adolescence in humans.

The researchers compared motor and learning functions between SHED-treated and untreated rats. In the horizontal ladder test, where rats crossed a ladder with irregularly spaced rungs, the SHED group had a significantly lower number of slips than the control group at four months.

In the cylinder test, which measures forelimb asymmetry, the SHED group relied more on the impaired forelimb than the control group. In the shuttle avoidance test, the SHED group demonstrated significantly better avoidance rates in later sessions, suggesting improved learning and memory.

Using quantum dot-labeled SHED with in vivo imaging, the researchers tracked the cells’ migration and biodistribution, confirming that they migrated to the brain.

Cell culture experiments

The research team also performed cell culture experiments to evaluate SHED by comparing it with other stem cell types, such as bone marrow mesenchymal stromal cells and dermal fibroblasts.

In non-contact co-culture experiments, SHED promoted neural stem cell proliferation more effectively than the other cell types. The researchers attribute this effect to SHED’s high secretion of hepatocyte growth factor (HGF).

These results suggest that SHED treatment could improve motor and cognitive impairments in rat models of cerebral palsy, even in the chronic phase. This therapeutic effect appears to occur through the promotion of new nervous tissue growth via HGF and related biological pathways.

Looking ahead

ºÚÁϳԹÏÍø Hospital is conducting a clinical study to evaluate the safety and tolerability of a single intravenous dose of autologous SHED in children with cerebral palsy. Based on the results of this study, the team plans to conduct large-scale trials and long-term follow-up studies to confirm the treatment’s efficacy.

“Our ultimate goal is to establish this approach as a new treatment option for patients with cerebral palsy and their families,” Sato said.

Paper information:

Takahiro Kanzawa, Atsuto Onoda, Azusa Okamoto, Xu Yue, Ryoko Shimode, Yukina Takamoto, Sakiko Suzuki, Kazuto Ueda, Ryosuke Miura, Toshihiko Suzuki, Naoki Tajiri, Shinobu Shimizu, Saho Morita, Hiroshi Yukawa, Hiroshi Kohara, Noritaka Fukuda, Yasuyuki Mitani, Hideki Hida, Yoshiyuki Takahashi & Yoshiaki Sato (2026). Novel stem cell therapy for cerebral palsy using stem cells from human exfoliated deciduous teeth, Stem Cell Research & Therapy.
DOI:

Expert contact:

Yoshiaki Sato
ºÚÁϳԹÏÍø Hospital
Email: y.sato@nagoya-u.jp

Media contact:

Naomi Inoue
ºÚÁϳԹÏÍø International Communications Office
Email: icomm_research@t.mail.nagoya-u.ac.jp

Two bacteria working together to break down intestinal mucus are identified as a contributing factor to chronic constipation

Scientists at ºÚÁϳԹÏÍø in Japan have found two gut bacteria working together that contribute to chronic constipation. The duo, Akkermansia muciniphila and Bacteroides thetaiotaomicron, destroy the intestinal mucus coating essential for keeping the colon lubricated and feces hydrated. Their excess degradation leaves patients with dry, immobile stool. This discovery, published in , finally explains why standard treatments often fail for millions of people with chronic constipation.

Notably, the study shows that Parkinson’s disease patients, who suffer from constipation decades before developing tremors, have higher levels of these mucus-degrading bacteria. While constipation in Parkinson¡¯s disease has traditionally been attributed to nerve degradation, these findings suggest that bacterial activity also plays a crucial role in the development of their symptoms.

Why ¡°mucin¡± matters for digestion

Constipation is a very common digestive problem. Doctors have assumed it happens because of slow gut movement when our intestines are not moving food along fast enough. However, this explanation does not work for everyone.

Some people have constipation with no identifiable cause, referred to as chronic idiopathic constipation (CIC). Parkinson’s disease patients also face severe, treatment-resistant constipation, though it is clinically categorized separately from CIC. Many struggle with severe constipation for 20 or 30 years before they develop tremors and movement problems, but researchers did not know why until now.

Instead of focusing on nerve and muscle movement in the gut, the researchers examined the protective gel-like coating called colonic mucin, a substance in the large intestine that lines the intestinal walls and is found within stool. Colonic mucin keeps stool moist, helps it move smoothly through our digestive tract, and protects the intestinal wall from bacteria.

They found that two gut bacteria work in sequence to break down this mucin. B. thetaiotaomicron uses enzymes to remove protective sulfate groups from the mucin, and A. muciniphila then breaks down and consumes the exposed mucin.

Sulfate groups attached to colonic mucin molecules normally prevent bacteria from degrading them. When too much mucin is destroyed, stool loses moisture and becomes hard and dry, causing constipation. Because the problem is mucin loss, not slow gut movement, standard laxatives and gut motility drugs are often ineffective.

A new frontier for gut health treatment

¡°We genetically modified B. thetaiotaomicron so it could no longer activate the enzyme sulfatase that removes sulfate groups from mucin,¡± Tomonari Hamaguchi, lead author and lecturer from the Academic Research & Industry-Academia-Government Collaboration Office at ºÚÁϳԹÏÍø explained.

¡°We put these modified bacteria into germ-free mice together with Akkermansia muciniphila, and surprisingly the mice did not develop constipation; the mucin stayed protected and intact.¡±

The experiment proved that blocking the sulfatase enzyme prevents the bacteria from degrading mucin. Therefore, drugs that block sulfatase could treat bacterial constipation in humans.

For millions of patients with treatment-resistant constipation, including those with Parkinson’s disease, this discovery offers hope for new therapies that address the root microbial causes of their condition.

Paper Information:

Tomonari Hamaguchi, Noriaki Gibo, Misuzu Ohara, Mikako Ito, Tomoyuki Ogura, Jun-Ichi Takeda, Hiroshi Nishiwaki, Fei Zhao, Ryo Kinoshita-Daitoku, Masashi Hattori, Koji Nonogaki, Tetsuya Maeda, Kenichi Kashihara, Yoshio Tsuboi, Masaaki Hirayama, Mitsuhiro Fujishiro, Hiroki Kawashima, Kinji Ohno (2026). Bacterial constipation: Mucin-degrading intestinal commensal bacteria cause constipation, Gut Microbes, 18(1).

Funding information:

This work was supported by Grants-in-Aids from the Japan Agency for Medical Research and Development (AMED) (JP23ek0109678) and the Japan Society of the Promotion of Science (JSPS) (JP22K15394, JP22K17343, JP23H02794, JP23K18273, and JP23K06412), and by grants from the Hori Sciences and Arts Foundation and from Yakult Bio-Science Foundation.

Expert Contact:

Tomonari Hamaguchi
Academic Research & Industry-Academia-Government Collaboration
ºÚÁϳԹÏÍø
Email: hamaguchi.tomonari.r4@f.mail.nagoya-u.ac.jp

Media contact:

Merle Naidoo
International Communications Office
ºÚÁϳԹÏÍø
Email: icomm_research@t.mail.nagoya-u.ac.jp

Top image:

The two bacteria that cause bacterial constipation, seen under an electron microscope. Left: Bacteroides thetaiotaomicron (Top: Transmission Electron Microscopy (TEM) image; Bottom: Scanning Electron Microscopy (SEM) image; Right: Akkermansia muciniphila (Top: TEM; Bottom: SEM). They work in sequence to destroy the intestinal mucus coating that keeps stool moist. Credit: Tomonari Hamaguchi, ºÚÁϳԹÏÍø

Study finds floating ovarian cancer cells recruit mesothelial cells in abdominal fluid to create cancer clusters

Ovarian cancer kills more women than any other gynecological cancer. Most patients receive their diagnosis only after the disease spreads throughout the abdomen. Until now, scientists have never fully understood why this cancer advances so fast. 
  
A new study led by ºÚÁϳԹÏÍø explains why. Published in , the study shows that cancer cells recruit help from protective mesothelial cells that normally line the abdominal cavity. Mesothelial cells lead the invasion and cancer cells follow the pathways they create. These hybrid cell clusters resist chemotherapy better than cancer alone. 
 
Researchers examined abdominal fluid from ovarian cancer patients and found something unexpected. Cancer cells do not float alone in the abdominal cavity. Instead, they often grab onto mesothelial cells and form hybrid spheres. ºÚÁϳԹÏÍø 60% of all cancer spheres contain these recruited mesothelial cells. The cancer cells release a protein called TGF-¦Â1 that transforms the mesothelial cells and causes them to develop spike-like structures that cut through tissue. 

Invadopodia, spike structures that do the digging for cancer 

When ovarian cancer develops, cancer cells break off from the tumor. These cells enter the abdominal fluid and float freely. The fluid moves around as you breathe and move your body. This movement carries the cancer cells to different spots in the abdomen. 
 
Most other cancers spread differently. Breast cancer or lung cancer cells enter blood vessels. They travel through the bloodstream to reach distant organs. Doctors can sometimes track these cancers through blood tests because blood moves in predictable paths through vessels. 
 
Ovarian cancer cells avoid blood vessels entirely. They float in fluid that has no fixed path. This floating stage happens before the cancer cells attach to new organs. Scientists did not fully understand what happened during the floating period or how cells worked together to spread cancer so quickly. 
 
The research team discovered that cancer cells recruit protective mesothelial cells that have shed from the abdominal cavity lining during this floating stage. ?The two cell types stick together and form hybrid spheres. The mesothelial cells then grow invadopodia, spike-like structures that drill into surrounding tissue. The hybrid spheres resist chemotherapy drugs more effectively and invade tissues faster when they land on organs.

Outsourcing the hard work of cell invasion 

The researchers examined abdominal fluid from ovarian cancer patients using advanced microscopy to watch this process in real time. They confirmed their findings with mouse models and single-cell genetic analysis. 
 
Lead author Dr. Kaname Uno, a former PhD student and current Visiting Researcher at ºÚÁϳԹÏÍø¡¯s , explained that the cancer cells do not need to become more invasive themselves. ¡°They manipulate mesothelial cells to do the tissue invasion work. They undergo minimal genetic and molecular changes and just migrate through the openings that mesothelial cells create.¡± 
 
Dr. Uno worked as a gynecologist for eight years before he pursued research. One of his patients changed his career path. She had clear screening results just three months before doctors found advanced ovarian cancer. Current medical tools failed to detect the cancer early enough to save her life. This motivated Dr. Uno to investigate why ovarian cancer spreads so rapidly. 
 
This discovery opens new treatment possibilities. Current chemotherapy targets cancer cells but ignores the mesothelial accomplices. Future drugs could block the TGF-¦Â1 signal or prevent the formation of these dangerous partnerships. The research also suggests that doctors could monitor these cell clusters in abdominal fluid to predict disease progression and treatment response. 

Paper Information: 

Kaname Uno, Masato Yoshihara, Yoshihiko Yamakita, Kazuhisa Kitami, Shohei Iyoshi, Mai Sugiyama, Yoshihiro Koya, Tomihiro Kanayama, Haruhito Sahara, Satoshi Nomura, Kazumasa Mogi, Emiri Miyamoto, Hiroki Fujimoto, Kosuke Yoshida, Satoshi Tamauchi, Akira Yokoi, Nobuhisa Yoshikawa, Kaoru Niimi, Yukihiro Shiraki9, Jonas Sj?lund, Hidenori Oguchi, Kristian Pietras, Atsushi Enomoto, Akihiro Nawa, Hiroyuki Tomita, Hiroaki Kajiyama (2026). Mesothelial cells promote peritoneal invasion and metastasis of ascites-derived ovarian cancer cells through spheroid formation, Science Advances, 21(6).

?Funding information:

This study was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI Grants-?in Aid for Scientific Research grant numbers 20H03824, 21KK0157, 21KK0296, 21K16788, 23K18326, and 24K12529; JSPS Overseas Research Fellowships (202460603); JST FOREST Program (JPMJFR235L); and Lena W?ppling¡¯s Foundation (2025).

Expert Contact:  

Kaname Uno
Graduate School of Medicine
ºÚÁϳԹÏÍø 
Email: kaname.uno@med.lu.se

Media contact:

Merle Naidoo
International Communications Office
ºÚÁϳԹÏÍø  
Email: icomm_research@t.mail.nagoya-u.ac.jp 

Top image:

Cancer cells (red) stick to mesothelial cells (green) and form hybrid spheres that cut into surrounding abdominal tissue. Credit: Uno et al., 2026