Pioneering interdisciplinary research at the intersection of developmental biology, chemistry, and physics
In the rapidly evolving world of regenerative medicine, where biology converges with materials science, one Japanese visionary has been quietly reshaping what's possible in stem cell research. Professor Norio Nakatsuji, founding director of Kyoto University's Institute for Integrated Cell-Material Sciences (iCeMS), stands at the intersection of multiple scientific disciplines, weaving together developmental biology, chemistry, and physics to create breakthroughs that might one day revolutionize how we treat disease.
Nakatsuji's work exemplifies the tremendous potential of interdisciplinary research, demonstrating that the most profound scientific advances often occur at the boundaries between established fields.
From establishing critical human embryonic stem cell lines to pioneering novel approaches in biomaterials, Nakatsuji's career offers a fascinating window into both the present and future of biomedical science—a future where damaged tissues might be repaired, degenerative diseases conquered, and the very process of scientific discovery transformed through collaboration across traditional scientific silos 1 .
Norio Nakatsuji's scientific odyssey began with a fascination for developmental biology, where he sought to understand the miraculous process through which a single fertilized egg develops into a complex organism.
Earned his Doctor of Science degree from Kyoto University
Encountered mouse embryonic stem (ES) cells at the MRC Mammalian Development Unit in London—a critical awakening to their potential
Established monkey embryonic stem cell lines
Succeeded in creating human embryonic stem cell (hESC) lines (KhES1–5)
Founded the Institute for Integrated Cell-Material Sciences (iCeMS) at Kyoto University
"My interests in mammalian development led me to mouse embryonic stem cells. After returning to Japan and establishing my own laboratory, our ES cell-related research extended to monkey and human ES cells, which further expanded my interests to include biomedical applications of such wonderful cell lines."
This expansion of focus would prove tremendously fruitful. Five of Nakatsuji's hESC lines became workhorse tools for researchers throughout Japan, distributed to accelerate discovery across the country's scientific community 1 .
At the heart of Nakatsuji's research lies a fundamental biological concept: pluripotency. Unlike specialized cells with fixed identities, pluripotent stem cells possess the remarkable ability to differentiate into any cell type in the body—from neurons to heart cells to pancreatic cells.
Derived from early-stage embryos, these cells represent the gold standard for pluripotency but come with ethical considerations regarding embryo use.
First developed by Shinya Yamanaka, these are adult cells reprogrammed back to an embryonic-like state, offering an ethical alternative to ESCs.
The field has experienced explosive growth, with stem cell research expanding at 7% annually—more than twice the world average growth in research (2.9%). The most dramatic growth has occurred in iPSC research, which has seen an astonishing 77% annual growth rate since 2008 .
| Research Area | Annual Growth Rate | Field-Weighted Citation Impact |
|---|---|---|
| Overall Stem Cell Research | 7.0% | 1.50 |
| Embryonic Stem (ES) Cells | Moderate growth | 1.80 |
| Human Embryonic Stem (hES) Cells | Declining growth | 2.08-2.35 |
| Induced Pluripotent Stem (iPS) Cells | 77.0% | 2.93 |
Nakatsuji recognized earlier than most that realizing the full potential of these remarkable cells would require overcoming significant technical challenges—particularly in learning to grow them reliably at scale and direct their differentiation efficiently. This insight would lead him toward the unconventional approach of integrating materials science with biology 1 .
While Nakatsuji has contributed to numerous important studies throughout his career, his team's 2003 success in establishing human embryonic stem cell lines represents a particularly crucial achievement that deserves closer examination.
The experiment yielded five stable, pluripotent human embryonic stem cell lines (designated KhES-1 through KhES-5) that demonstrated all the hallmark characteristics of authentic hESCs 1 :
| Cell Line | Passages Tested | Pluripotency Markers | Karyotype Stability | Differentiation Potential |
|---|---|---|---|---|
| KhES-1 | 20-40 | Positive (Oct4, Nanog, SSEA-3/4) | Normal (46, XY) | Three germ layers |
| KhES-2 | 20-40 | Positive (Oct4, Nanog, SSEA-3/4) | Normal (46, XX) | Three germ layers |
| KhES-3 | 20-40 | Positive (Oct4, Nanog, SSEA-3/4) | Normal (46, XX) | Three germ layers |
| KhES-4 | 20-40 | Positive (Oct4, Nanog, SSEA-3/4) | Normal (46, XY) | Three germ layers |
| KhES-5 | 20-40 | Positive (Oct4, Nanog, SSEA-3/4) | Normal (46, XY) | Three germ layers |
These cell lines quickly became invaluable tools for the Japanese research community, enabling studies that would have been impossible otherwise. Perhaps more significantly, the methodological advances developed during their establishment contributed to improved protocols for working with pluripotent stem cells more generally 1 .
Nakatsuji's work, like all cutting-edge stem cell research, relies on a sophisticated array of biological reagents and materials. Here we highlight some of the most crucial tools enabling advances in this field:
| Reagent/Material | Function | Application in Nakatsuji's Research |
|---|---|---|
| Feeder Cells | Provide physical support and secrete essential growth factors | Mouse embryonic fibroblasts used to support hESC growth |
| Culture Media Formulations | Precisely balanced solutions of nutrients, hormones, and growth factors | Custom formulations to maintain pluripotency or direct differentiation |
| Extracellular Matrix Components | Synthetic or natural substrates that mimic the stem cell niche | Laminin, fibronectin, or synthetic polymers for feeder-free culture |
| Small Molecule Inhibitors/Activators | Chemical compounds that modulate specific signaling pathways | ROCk inhibitors to prevent apoptosis in single cells; Wnt activators |
| Cytokines and Growth Factors | Proteins that influence cell fate decisions through receptor binding | FGF2 to maintain pluripotency; BMP4 to induce differentiation |
| Characterization Antibodies | Immunological tools for detecting stem cell markers | Antibodies against Oct4, Nanog, SSEA-3/4 for pluripotency assessment |
| Gene Expression Tools | Methods for manipulating and monitoring gene expression | Lentiviral vectors for genetic modification; RNA-seq for profiling |
"Biological or synthetically designed materials can now be used to create powerful tools and resources for biomedical research and applications."
This toolkit has evolved significantly throughout Nakatsuji's career, with increasingly sophisticated biomaterials playing a growing role 1 .
The ultimate goal of much stem cell research is to translate basic discoveries into clinical applications that can help patients. Nakatsuji has maintained this translational perspective throughout his career, noting that his interests extend to "connecting basic research in universities to innovative applications in industry and society" 1 .
Developing technologies for large-scale 3D-culture production of quality-controlled human pluripotent stem cells for therapeutic applications.
Building networks among scientists in different fields to create new research frontiers through iCeMS.
Contributing to research infrastructure through initiatives like the Cross-Disciplinary Journal Club and international conferences.
This commitment to translation is evident in several aspects of his work. At the time of his 2012 interview, Nakatsuji was leading a "government-supported project of developing novel stem cell technologies which will enable large-scale 3D-culture production of quality-controlled human pluripotent stem cells, followed by differentiation into a number of cell lineages using various chemical compounds" 1 .
He has also played an important role in international conferences and dialogues, including appearing as a plenary speaker at the World Stem Cell Summit 2011, where he joined representatives from other leading institutions in discussing "strategies for advancing regenerative medicine" 2 .
One of the most fascinating concepts that Nakatsuji has championed is the importance of mesoscopic science—a domain that exists in the crucial space between the nanoscopic (atoms and basic molecules) and the bulk (everything larger than one micron) 1 .
In cellular mesoscopic spaces, handfuls up to several dozen biopolymers are in constant motion while forming multi-molecular architectures such as cell membranes and other organelle structures.
These structures robustly execute intricate cellular functions despite their constant dynamic reorganization.
The mesoscopic domain consists of "complex, dynamic, multi-part components built up from nanoscopic building blocks consisting of handfuls of atoms and molecules."
This realm is so promising that the United States Department of Energy has identified it as a priority exploration area.
"Mesoscopic domains, lying between 1 nm and 1 µm, are a realm where materials become life, and life inspires materials."
This focus on the mesoscale represents both a scientific frontier and a powerful metaphor for Nakatsuji's entire approach—working at the intersections between scales, disciplines, and applications to create new possibilities 1 .
Looking toward the future, Nakatsuji offers thoughtful guidance for young researchers considering their path:
"Young researchers should explore multiple fields of science during the early phase of their scientific careers, before it becomes necessary to specialize. Your scientific ability to examine and observe the target from multiple vantage points—and ultimately make the correct decision—will be considerably broader and more robust."
This encouragement of broad exploration is complemented by an admonition to appreciate the difficulty of true achievement, quoting Song Dynasty scholar Zhu Xi: "Youth quickly turns to old age, but achieving learning is fraught with difficulty" 1 .
When asked what he might have done had he not become a scientist, Nakatsuji points to architecture and music—fields that, like his scientific work, involve creating structure, harmony, and innovation within constraints 1 .
Norio Nakatsuji's career offers a powerful model for how science might evolve in the 21st century—moving beyond traditional disciplinary boundaries to create integrated approaches that tackle complex challenges. From his early work in developmental biology to his groundbreaking establishment of human embryonic stem cell lines and his leadership in building cross-disciplinary research institutions, Nakatsuji has consistently anticipated and helped shape the future of biomedical research.
His work reminds us that the most profound breakthroughs often occur at the intersections between fields—where biology meets materials science, where basic research meets clinical application, and where traditional approaches meet innovative perspectives. As regenerative medicine continues to advance, the cross-disciplinary foundation that Nakatsuji has helped build will undoubtedly play a crucial role in realizing the field's promise to transform how we treat disease and injury.
"Recent progress in molecular investigation of living cells and also in the synthesis of various functional smart materials has created unlimited opportunities for the integration of both fields, resulting in an innovative breakthrough opportunity on many frontiers."
Perhaps most importantly, Nakatsuji's career demonstrates that scientific progress depends not only on individual discoveries but also on building the collaborative infrastructures—both institutional and intellectual—that make future breakthroughs possible. Through his work, Nakatsuji has done as much as anyone to help realize this immense potential 1 .