HKUMed used the ancient choanoflagellate SOX protein to create stem cells and implanted them into mice, successfully contributing to healthy mice. The research team members included (back row, from left) Dr Daisylyn Senna Tan, Professor Ralf Jauch, Dr Alex de Mendoza (Queen Mary University of London, UK) and (front) Dr Gao Ya.
A research team from the School of Biomedical Sciences, LKS Faculty of Medicine at the University of Hong Kong (HKUMed), in collaboration with Queen Mary University of London and the Max Planck Institute for Terrestrial Microbiology, has unearthed the ancient evolutionary origins of genes critical to stem cell biology, dating back over 700 million years. Drawing on insights from evolutionary processes, this discovery reveals that tools borrowed from ancient single-celled organisms—and even recreated proteins from life's earliest days—can transform mouse somatic cells into pluripotent stem cells capable of developing into any cell type in multicellular animals. This breakthrough challenges the longstanding belief that only animal genes possess this transformative ability, paving the way for new protein designs in novel therapies for regenerative medicine and disease studies to combat ageing and related health issues. The findings were recently published in Nature Communications [link to the publication].
Background
The leap from single-celled organisms to complex multicellular animals was a pivotal evolutionary transition. The earliest ancestor of all animal cells, sitting at the base of the animal tree of life, may have resembled modern pluripotent stem cells. These stem cells might have played a crucial role in the rise of multicellular life, including early branching sponges, because they can replicate themselves indefinitely and differentiate into specialised cell types that perform specific roles in the body. Most multicellular animals have stem cells, suggesting their deep evolutionary importance.
Life's molecular machinery, from the genetic code to DNA replication, is remarkably similar across species, pointing to a shared evolutionary origin. Finding the evolutionary innovations that enabled the formation of new life forms holds the key to understanding our natural history. The HKUMed research team sought to identify the genetic 'switches' that made multicellular life possible by comparing genes in modern species and reconstructing ancestral ones to infer their properties. Key genes for cell fate determination, like the stem cell regulators SOX and POU factors, were thought to exist only in animals. But the research team found that these genes also exist in some single-celled relatives. This unexpected finding challenges the current understanding of SOX and POU gene evolution, prompting a deeper look into these ancestral genes, which may provide insights into the molecular toolkit that underlies the origins of multicellularity.
Research methods and findings
The research team worked with experts in evolution and biochemistry, using SOX and POU factors, to recreate genes from tiny water-dwelling organisms, known as choanoflagellates. They even used a molecular time-travel machine to rebuild the sequences of a 700-million-year-old version of a key protein called 'Ur-SOX'. Experimental tests revealed that these ancient proteins functioned similarly to the SOX proteins found in mammals like mice, which can transform ordinary cells into pluripotent stem cells that can develop into any cell type in the body. Remarkably, the Ur-SOX protein also works perfectly, proving that its potential existed long before the emergence of complex animals. Most strikingly, when the ancient choanoflagellate SOX protein was used to create stem cells, which were implanted into mice, this successfully contributed to healthy mice, illustrating how studying evolution's oldest genetic tools may unlock revolutionary medical advances.
Although another gene family, POU factors, did not work the same way as its counterpart, its presence in early life suggests that it was gradually refined over millions of years to support stem cell development.
Significance of the study
The discovery that ancient SOX proteins retain pluripotency-inducing power uncovers an evolutionary 'toolkit' full of potential. Scientists can now use these ancient proteins—or AI-designed versions—to develop safer, more efficient ways to transform cells. By using evolution-inspired methods, creating mutations and testing which versions of the protein work best for specific tasks (like medicines or enzymes), researchers can engineer and refine proteins in the laboratory over time. These custom-designed proteins are now widely used in healthcare to efficiently turn regular cells into stem cells for therapeutic applications. This breakthrough also enables better disease modelling, creating stem cells and guiding them into mature, functional cells to accurately study illnesses and test drugs.
Professor Ralf Jauch, Associate Professor in the School of Biomedical Sciences, HKUMed, explained, 'Ur-SOX was a preadaptation—a ready-to-use molecular tool. This research shows how molecular tools from unicellular protists, including the reconstructed ancestral "Ur-SOX" proteins, can reprogramme mouse cells into pluripotent stem cells. This challenges the long-held belief that animal genes are unique and highlights nature's enduring ability to inspire innovation.'
Dr Gao Ya, the lead author and Postdoctoral Fellow in the School of Biomedical Sciences, HKUMed, added, 'Nature perfected SOX's DNA-binding ability hundreds of millions of years ago. By studying these ancient blueprints, we can design artificial proteins that work even better than natural ones.'
Moving beyond disease modelling, the HKUMed research team plans to use engineered proteins for cell programming to help conserve endangered species (such as producing lab-grown gametes), produce higher-quality stem cells for regenerative medicine, and so forth. Overall, this research connects deep evolutionary history with cutting-edge solutions for medicine, ageing and associated illnesses, as well as ecological challenges.
About the research team
The research was led by Professor Ralf Jauch, Associate Professor, School of Biomedical Sciences, HKUMed, and Principal Investigator at the Centre for Translational Stem Cell Biology (CTSCB), in collaboration with Dr Alex de Mendoza, Queen Mary University of London, UK. The first authors were Dr Gao Ya and Dr Daisylyn Senna Tan from School of Biomedical Sciences, HKUMed; and Dr Mathias Girbig and Dr Georg Hochberg at the Max Planck Institute for Terrestrial Microbiology, Germany.
