A single study has the potential to reshape the future. Across the world, there are countless research projects brimming with untapped possibilities. The Stellar Science Foundation (SS-F), driven by the mission to “advance the world through the power of science,” is committed to exploring the essence of scientific research and pushing its impact to new heights.
In the “Invent Innovation” series, we spotlight groundbreaking research that serves as the key to driving forward innovation by interviewing leading scientists. Through these conversations, we delve into the background and process of generating innovative knowledge, exploring the potential and influence of each study in depth.
For the second installment, we spoke with Naoko Irie, whose research focuses on the early development of the human germ line, including reproductive cells, eggs, sperm, and early embryos, in pursuit of unlocking the mysteries of life. In January 2025, she was awarded the Japan Society for the Promotion of Science (JSPS) Prize for her outstanding contributions to the study of early human germ cell development. Her research has garnered attention for its potential applications in assisted reproductive technologies, such as in vitro fertilization, as well as its contributions to advancements in reproductive science.
Dr. Irie has long pursued a fundamental question: “When and how do reproductive cells, which carry human genetic information, arise?” In the course of her work, she encountered an unexpected, groundbreaking discovery—one that gave her goosebumps—guided by intuition. With a vision to create a world where people struggling with reproductive challenges have more choices, Dr. Irie continues to explore the profound mystery of reproductive cells—the very beginning of human life itself.
Unraveling the Mystery of “Life’s Continuity Across Generations”
— To begin with, could you briefly explain what the “Human Germ Line” is, which serves as the focus of your research?
In simple terms, the Human Germ Line refers to the human reproductive lineage. In this context, “reproduction” pertains specifically to reproductive cells, which, in humans, include eggs and sperm. The concept of the “germ line” also carries the profound meaning of “life’s continuity across generations.”
It is said that the human body is composed of approximately 37 trillion cells, yet only one type of cell is directly inherited from parents: the germ cells. These cells are passed down through generations—your parents inherited their germ cells from their own parents, and so on.
In essence, every generation, from newborns to the elderly, exists through the continuity of the germ line. The transmission of genetic information via germ cells, which leads to the formation of the next generation, is what we call the “germ line.”
— So, the Human Germ Line refers to the mechanism through which reproductive cells pass genetic information from one generation to the next?
Exactly. And this concept is not unique to humans—if we trace back far enough, all living organisms, including plants and animals, originate from a single common source of life. Over time, different germ lines have emerged, ultimately leading to the rich biodiversity we see today.
Approaching the Human Germ Line: Research Methods and Techniques
—What methods and approaches do you use in your research on the Human Germ Line?
We study the Human Germ Line using human pluripotent stem cells. There are two types of human pluripotent stem cells:
- Embryonic Stem (ES) Cells – Derived from the early-stage embryo shortly after fertilization.
- Induced Pluripotent Stem (iPS) Cells – Created artificially by reprogramming somatic cells.
In our research, we primarily use ES cells. While earlier studies predominantly relied on mouse cells, a major breakthrough came in 1998 when human ES cells were first successfully derived in the United States. Since then, human ES cells have become a crucial tool for studying early development in humans.
ES cells are derived from embryos at about four days post-fertilization, just before implantation in the uterus. By observing and manipulating ES cells, we can study the early stages of germ cell formation in humans.
There are specialized techniques for culturing ES cells. The process involves plating the cells on culture dishes, providing a nutrient-rich medium, and monitoring their development daily. The basic maintenance involves regularly replacing the culture medium to support cell growth. Over time, the cells form colonies, which can be carefully separated into smaller clusters, ultimately leading to the expansion of ES cell populations. This meticulous daily cell culture work is an essential part of our research process.
Figure: Created by Naoko Irie, Translated by SS-F
Do Germ Cells Form Even Before the Intestines? The Profound Mystery of Reproductive Cells
—Through your research, what fundamental questions have you been exploring?
From the very beginning of my research, my core ambition has been to capture the exact moment when germ cells first emerge.
Human germ cells begin to form around three weeks after fertilization. However, at this stage, the fetus does not yet have ovaries or testes—in fact, it is still far from resembling a human form. This means that the germ cells that eventually develop into eggs and sperm are already present before the formation of the reproductive organs.
After fertilization, the fetal body gradually takes shape within the mother’s womb. The single-cell zygote begins dividing repeatedly, forming different cell types. Broadly speaking, some cells will develop into the placenta, while others will become the body. The gut forms, followed by the brain at the head, then the limbs… This is the general developmental sequence. However, remarkably, germ cells are already present before the gut is even formed.
Reproduction is a highly specialized and fundamental function of human biology. This suggests that germ cells are prioritized and formed earlier than other body structures because of their essential role in sustaining life across generations.
—So in essence, your research focuses on the very starting point of human life—understanding how sperm and eggs, and ultimately human beings, come into existence?
Exactly. But when I first began my research, there were no established cell culture methods available to observe the early stages of germ cell formation. To even begin my work, I first had to develop a research framework for inducing germ cell differentiation from ES cells—laying the groundwork for future studies.
—How long has research on the Human Germ Line been conducted?
When it comes to the study of germ cells and fertilization, research on mammals advanced significantly in the 1980s, alongside the development of genetic manipulation techniques. In mice, germ cell development was first identified as early as the 1950s, and from the 1980s onward, research delved deeper into the underlying mechanisms.
Building on this foundation, I focused on the possibility that mice and humans might have key differences in germ cell development—which led me to conduct research using human ES cells, as I mentioned earlier. In 2015, I published the findings in my paper, “SOX17 is a critical specifier of human primordial germ cell fate.“ This research provided crucial insights into how human germ cells are specified, distinguishing them from mouse models.
Of course, there is still much that remains unknown. The human germ line is an unbroken continuum—it starts with the formation of primordial germ cells, which later develop into eggs and sperm that become functional during puberty, leading to fertilization, embryonic development, and the cycle repeating in subsequent generations. However, the exact timing, location, and mechanisms of germ cell formation, particularly during early development, are still unclear.
To fully understand these processes, researchers would need to observe human embryos during the first two weeks post-fertilization. However, due to ethical and technical constraints, studying human embryos at this stage is not feasible. These limitations make germ line research particularly challenging, leaving many unanswered questions in the field.
A Surprising Breakthrough—Unlocking the Key to Germ Cell Development
—So, there are still many unknowns regarding when exactly germ cells are formed?
Yes. Research on the early stages of human development is one of the most challenging areas in this field. It is often referred to as a “black box” because there is so little information available. While the blastocyst stage (the fertilized egg at day 5–6 post-fertilization) can be replicated in vitro through IVF, the process beyond implantation leading to fetal development remains largely uncharted territory. Due to the lack of available samples and knowledge, this stage is still a complete mystery.
To unlock this black box, researchers initially relied heavily on mouse models, assuming that germ cell development in mice closely mirrored that of humans.
However, as I reported in my 2015 paper, my research using human ES cells and fetal samples revealed a major difference between mice and humans in germline development.
—Your 2015 paper was groundbreaking for demonstrating the ability to generate human germ cells in vitro. Why was this such a revolutionary finding?
The biggest breakthrough was that we successfully replicated the moment of human germ cell formation in an experimental system.
Prior to this, protocols had been developed for differentiating pluripotent stem cells into various tissues and organs, but directing them toward the germline had been considered particularly challenging. In fact, just four years before our publication, a study had demonstrated that germ cells could be generated from mouse ES cells, leading to speculation on whether the same was possible in humans. My 2015 study provided the answer.
Another key breakthrough was that by establishing this in vitro differentiation system, we could investigate the molecular mechanisms behind human germ cell formation. This led to the discovery that the transcription factor SOX17 plays a crucial role in human germ cell specification—so much so that the title of our 2015 paper reflects this discovery.
This was an unexpected and groundbreaking finding, as SOX17 had not been considered a key player in germ cell development in mice. This research not only challenged assumptions based on mouse models but also opened up new avenues for understanding human reproductive biology.
──How Did You Discover the Importance of “SOX17”?
My intuition played a significant role in this discovery.
Interestingly, in mouse research, it had been reported that “SOX17” was not necessary for germ cell development. Researchers working with mice potentially dismissed its presence as an anomaly or an error, leading them to avoid further investigation into its role.
However, something about “SOX17” intrigued me. Despite the prevailing assumptions, I felt there was more to uncover about its potential significance in human germ cell development.
──Your Intuition Played a Major Role in This Discovery!
Yes, absolutely!
Alongside my research on germ cell development, I was also conducting studies on gene expression. As part of this work, I would routinely examine various genes—but, in secret, I made a point to quietly observe “SOX17” as well.
Something about it made me feel that it was worth investigating further.
As I continued to follow my intuition, I eventually discovered that SOX17 was a decisive factor in germ cell formation. It was completely unexpected, and I still remember getting goosebumps when I finally realized its true significance.
The Growing Importance of Research Ethics
— You mentioned getting goosebumps from your discovery. Hearing your story, I can see how your research touches on the very foundation of human life.
That’s true. Research on the germ line is deeply connected to concepts like “immortality” and “rejuvenation.”
For example, consider a simple but fascinating fact: when a child is born from an adult mother and father, the child is not an adult but starts at age zero.
This is quite mysterious when you think about it. The mother’s cells have aged, yet the fertilized egg starts from “zero.” This suggests that within human cells, some have the ability to return to an original, youthful state.
This raises fundamental questions like “Where does life truly begin?” It’s an incredibly romantic and intriguing field of study.
──At the same time, research related to reproduction is an extremely sensitive field, where research ethics become even more critical.
You are absolutely right. As a researcher involved in reproductive studies, I feel a strong sense of responsibility and believe that I must always consider these ethical implications carefully.
With technological advancements and further developments in techniques to induce reproductive cells, various future possibilities can be envisioned. For example, there have already been reports that skin cells can be reprogrammed into iPS cells, which can then be used to create eggs or sperm. Moreover, what once seemed like science fiction could become reality—for instance, someone picking up a strand of hair from a famous person and using it to create sperm or eggs to produce a child, or mass-producing millions of genetically identical individuals from a single person’s DNA. There are even ideas about using genetic engineering to freely design physical appearance and abilities.
On a global scale, such competition in this field is likely inevitable. That is precisely why it is crucial for ethically conscious nations and responsible researchers to take the lead in establishing clear rules while advancing these technologies. I believe that such a carefully guided approach is essential.
──If regulations vary from country to country, there is a risk that researchers may congregate in countries where restrictions are more lenient.
That’s right. For example, if Japan and Western countries were to completely ban such research, talented researchers might flock to other nations, potentially making the scenarios we just discussed a reality.
In fact, We are seeing more cases where outstanding international researchers gather in well-funded institutions, utilizing otherwise difficult-to-obtain biological samples to rapidly produce and publish high-quality research findings. Taking these facts and risks into account, we need to establish a proper framework. Instead of imposing an outright ban, it is crucial to clearly define the permissible scope of research and regulate the development of technologies in a controlled manner.
Toward a Society Where Those Struggling with Childbirth Have More Options
— Based on everything we’ve discussed so far, how do you hope to connect your research to the advancement of society?
I hope to create a society where the sensitive perceptions surrounding reproduction are gradually alleviated, allowing people to consider assisted reproductive technologies more naturally as part of their daily lives.
Assisted reproductive treatments, such as in vitro fertilization, were once met with criticism from society. However, it is also a fact that these advancements have brought happiness to many people. By contributing to advancements in reproductive technologies, I want to help those struggling with childbirth gain more options. I will continue my research in the hope that it can lead, even in a small way, to someone’s happiness.
— In that pursuit, is there anything in particular you are eager to challenge in the near future?
Until now, my research has focused primarily on the earliest stages of germ cell development and their initial migration into the gonads. Moving forward, I would like to explore even later stages of development. By comparing the process from fertilization to the formation of germ cells, I aim to further uncover the mysteries of the germline.
Additionally, germ cells are often considered “immortal” cells capable of rejuvenation. Interestingly, when compared to cancer cells—another type of cell that can achieve immortality within the body—there are similarities in certain aspects of gene expression. By studying and contrasting these mechanisms, I hope to shed light on the mysteries of cellular immortality, rejuvenation, and, conversely, the processes of aging and cell death. Ultimately, I want to deepen our understanding of how life perpetuates itself at the cellular level.
(Written by Tomohiro Kurimura, Photography by Kayo Sekiguchi, Interview & Editing by Masayuki Koike)
