Designer Genes Using resurrected 700-million-year-old genes, biomedical scientists have shown that molecular tools from ancient single-cell organisms older than animals themselves can transform animal cells into pluripotent stem cells, contributing to viable mice. HKU Bulletin | Nov 2025 Research 20 21 In so doing, the team have not only revealed the evolutionary origins of genes critical to stem cell biology but also overturned a long-held belief that such transformative capabilities are only found in animal genes. The team, which was led by Dr Ya Gao, Dr Daisylyn Senna Tan and Professor Ralf Jauch from the School of Biomedical Sciences at HKUMed, carried out the research in collaboration with Dr Alex de Mendoza of Queen Mary University of London, and Dr Mathias Girbig and Dr Georg Hochberg at the Max Planck Institute for Terrestrial Microbiology in Germany. “The most striking outcome of the research,” explained Professor Jauch, “is that when the protist SOX gene was used to create stem cells, they could successfully contribute to healthy mice despite hundreds of millions of years of independent evolution. The molecular tools we use to make stem cells have much deeper roots in our evolutionary past. “Stem cells are critical for multicelled life and can form all the hundreds of cell types of the animal body, and are essentially immortal as they can indefinitely propagate. It seems that nature used a pre-existing set of molecular tools and repurposed them rather than inventing new tools to make animal stem cells. “The research revealed that ancestral ‘Ur-SOX’ proteins which we predicted to exist in a ‘great-greatgreat-grandmother of all cells’ that we share with our unicellular relatives, can reprogramme mouse cells into pluripotent stem cells, challenging the belief that animal genes are unique and highlighting nature’s enduring ability to inspire innovation with a preexisting set of tools. It also shows that SOX and POU factors are older than stem cells and animals.” Our bodies consist of about 200 cells with special properties, each playing a critical role in maintaining overall health. “These are fit for their specialised job but cannot do the job of other cells,” explained Professor Jauch. “Pluripotent stem cells can make unlimited copies of themselves and can be nudged to form all of the 200 human cell types.” that normally regulates organ development — such as the gut and the liver — into a very powerful inducer of pluripotency with a single point mutation. “It has captivated me that we can drastically alter the function of molecules that parted ways, in evolutionary terms, hundreds of millions of years ago,” he said. “I want to know when and why these two molecules split up. This led me to travel back in time into our evolutionary past and to my surprise, I had to go much further back than I initially thought.” While the team’s work has largely concentrated on therapeutic medical applications, tangential uses are also possible, including the potential for preserving endangered species. “Preserving our genetic heritage is a mission of humanity – wildlife extinction is progressing at an alarming speed,” said Professor Jauch. “What we can do as biotechnologists is to preserve the stem cells of endangered animals. This will preserve their genetic blueprints within a living cell and could allow us to preserve critically endangered species such as the northern white rhino, even restore a species that we lost, such as the dire wolf. “Yet, for most animals we are currently not able to make stem cells. Enhanced and re-designed factors optimised based on evolutionary principles can help democratise stem cell generation across animals.” Endangered species The work paves the way for new protein designs in novel therapies for regenerative medicine and disease studies to combat health issues related to ageing. Custom-designed proteins are already used in the healthcare industry to turn regular cells into stem cells for therapeutic applications, and currently the field is developing ChatGPT for protein to design purpose-built proteins for biomedical applications. “These algorithms stand on the shoulders of natural evolution and the beauty of life,” said Professor Jauch. “We expect our findings will further help train AI algorithms to optimise molecules that we can use to engineer the properties of cells to study diseases in the laboratory, to regenerate damaged tissues with newly-made cells and even to reverse ageing.” This translational work will be driven by Dr Gao and Dr Tan, co-first authors of the study, at HKU’s Centre for Translational Stem Cell Biology at the Hong Kong Science and Technology Park. “We can use designer genes to transform blood into mature neural cells, which can help us understand what goes wrong when neurons degenerate and neurological diseases develop.” Professor Jauch’s interest in ancient proteins began years ago with the discovery that he could turn a gene Novel protein designs From left: Dr Daisylyn Senna Tan, Dr Ya Gao, Professor Ralf Jauch, and Dr Alex de Mendoza. It seems that nature used a pre-existing set of molecular tools and repurposed them rather than inventing new tools to make animal stem cells. Professor Ralf Jauch
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