Building a chromosome from scratch may sound like science fiction, but scientists have actually done it—and made it work. In an ambitious effort, researchers created a completely synthetic chromosome for yeast, a common organism found in baking and brewing. The real surprise? After carefully fixing some flaws, the lab-made chromosome allowed the yeast to grow just like normal, even under stressful conditions like heat and nutrient shortages. This achievement is part of the Synthetic Yeast Genome Project version 2.0, which explores how custom-built genes could reshape our understanding of biology and lead to powerful new technologies.
Researchers at Macquarie University, including Professor Isak Pretorius, Professor Ian Paulsen, Dr. Hugh Goold, and Dr. Heinrich Kroukamp, along with teams from Johns Hopkins University and the University of Edinburgh, led this research. Their results, shared in the journal Nature Communications, describe how they built and then repaired this synthetic chromosome to help the yeast grow and behave like the original. The improvements were based on earlier lessons from the same project and involved clever new methods to fine-tune the design and performance of the synthetic DNA.
Creating the synthetic chromosome followed a step-by-step approach. Segments were produced separately in different yeast strains and then joined through mating and natural DNA mixing. Initially, the artificial chromosome caused the yeast to grow poorly, especially in tough conditions like high temperatures or when provided with limited food sources. Scientists used a method that relies on a modern gene-editing tool called DNA-Based Upgrading of Genomic Systems to identify which parts of the synthetic chromosome were responsible for the problems. One major issue was found in a gene responsible for moving copper into cells. Changes in the region that controls how this gene is activated interfered with the yeast’s ability to survive. Another problem came from a gene linked to cell division, where design changes disrupted its normal function.
Restoring the original control sequences and reintroducing certain helper RNA molecules, known as transfer RNA, helped solve the growth issues. According to Professor Pretorius, “We identified key errors caused by placing recombination sites near gene regulatory regions, which had unintended consequences on gene expression and cellular fitness.” These corrections allowed the yeast to regain healthy growth even in challenging conditions, making it behave much more like the natural strain.
These corrections led to valuable insights. Many of the problems were traced back to small DNA tags that had been placed too close to regions controlling important genes. The team responded by developing a cleaner version, called synthetic chromosome sixteen version 2.0. This updated version removed the problematic areas, improved gene stopping signals, and reduced the number of added DNA tags. These steps helped the synthetic chromosome function more effectively and gave scientists a more dependable model for building artificial chromosomes in other organisms.
Committed to a gradual improvement process, the researchers followed a cycle of designing, testing, and refining. They found that although yeast can tolerate many changes to its genetic material, some parts—particularly those outside protein-coding areas and genes with few substitutes—require special attention. Adding back all the missing transfer RNA on a small, separate DNA circle significantly improved the yeast’s health, especially under stressful growth conditions.
These lessons from synthetic chromosome sixteen, now applied to a stronger working version, offer the scientific community a solid example of how to build artificial chromosomes that truly work. These findings could help guide the design of tailor-made chromosomes not just for yeast, but for plants and animals too—where it is even more essential to preserve genetic balance. Ultimately, this improved chromosome design highlights what can be done with today’s genetic tools and provides a useful roadmap for building complex genetic systems that are stable, effective, and ready for future innovations.
Journal Reference
Goold H.D., Kroukamp H., Erpf P.E., et al. “Construction and iterative redesign of synXVI a 903 kb synthetic Saccharomyces cerevisiae chromosome.” Nature Communications, 2025. DOI: https://doi.org/10.1038/s41467-024-55318-3
About the Authors
Professor Isak Pretorius is a leading figure in synthetic biology and biotechnology, best known for his work in yeast genetics and genome engineering. Based at Macquarie University in Australia, he has played a central role in global efforts to design and construct synthetic eukaryotic genomes, including the landmark Synthetic Yeast Genome Project. With a background in microbiology and a passion for reprogramming biological systems, Professor Pretorius has made significant contributions to the development of custom-built genetic tools for both industrial and research applications. His leadership bridges fundamental science and applied innovation, particularly in fields like winemaking, fermentation, and bioengineering. He is also recognized for mentoring emerging researchers and fostering international collaboration in genome-scale projects.
Professor Ian Paulsen is a renowned microbial genomics expert at Macquarie University, where he focuses on systems biology, synthetic biology, and the environmental applications of microbial science. His research has spanned the study of microbial physiology, metabolic networks, and the genetic engineering of microorganisms for biotechnological purposes. A key contributor to the Synthetic Yeast Genome Project, Professor Paulsen brings a data-driven approach to understanding and redesigning microbial genomes. His work often integrates computational modeling and functional genomics to address global challenges in sustainability and industrial biotechnology. With a strong commitment to interdisciplinary research, he is recognized for bridging the gap between computational biology and experimental science.
Dr. Hugh Goold is a senior scientist recognized for his expertise in molecular biology and genome engineering. He is affiliated with the New South Wales Department of Primary Industries and has worked extensively on synthetic biology applications in yeast and other microbial systems. As one of the key contributors to the design and debugging of synthetic chromosome XVI, Dr. Goold has helped advance the frontiers of genome-scale engineering. His work focuses on improving genetic stability, functionality, and performance in synthetic organisms. With a practical background in applied biology, Dr. Goold’s research often translates into tools and strategies with broad industrial and agricultural relevance, including biosecurity and sustainable biotechnology.
Dr. Heinrich Kroukamp is a microbial biotechnologist known for his work in synthetic genome construction and cellular engineering. Based in Australia and associated with MicroBioGen and Macquarie University, he has contributed to major international efforts to develop synthetic yeast chromosomes. Dr. Kroukamp’s expertise lies in strain development, fermentation optimization, and resolving biological bottlenecks in engineered organisms. In the Synthetic Yeast Genome Project, he has played a key role in testing, debugging, and refining synthetic DNA to ensure robust growth and performance. His research bridges molecular design with practical outcomes, contributing to innovations in areas such as industrial fermentation, renewable bioproducts, and microbial physiology.
