Sudarshan Pinglay: 'The potential benefits of a synthetic minimal human genome are substantial.'
[EDITOR'S NOTE: BBI's Sudarshan Pinglay, Ph.D., leads a research lab affiliated with BBI, the University of Washington Department of Genome Sciences, and the Seattle Hub for Synthetic Biology. This commentary was published June 3 in the Journal Nature.]
Ten years ago, when I was a first-year graduate student, my PhD adviser smuggled me into a private meeting at Harvard Medical School in Boston, Massachusetts. I listened in thrall as participants from academia, industry and government debated the ethics, promise and pitfalls of an ambitious project: building a copy of the human genome from scratch using synthetic DNA.
A synthetic genome is built by replacing, piece by piece, a cell’s natural genome with DNA made in the laboratory. The artificial sequences can be copies of their natural counterparts or designed to give the cell properties that aren’t found in nature.
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When the synthetic human genome project was made public in June 2016, it had two main goals. First, to slash the cost of engineering large genomes by 1,000-fold within a decade. And, second, to produce a cell line with an ‘ultrasafe’ synthetic genome that was engineered to, for instance, make the cells less prone to viral infection.
But efforts never really got off the ground. At the time, the technological landscape was not ready to support the project’s ambitions and, failing to gather enough funding, the project remained a series of pilot research proposals and meetings rather than the centralized programme it set out to be. That no longer needs to be the case.
DNA synthesis and assembly methods have improved enough to reliably produce long genomic sequences. Scientists can insert synthetic DNA into cells — although this remains a bottleneck in research. Artificial-intelligence models can help scientists to predict how changes to DNA will affect cell biology. And there are signs that funders are starting to take the idea of a synthetic human genome seriously. For example, UK researchers are aiming to build the first fully synthetic human chromosome through a £10-million (US$13-million) project launched in 2025.
As such work begins, it’s time for synthetic biologists, ethicists and others to revisit a genome-scale project. However, such a project should follow a different path from the original plan.
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The goal to produce an ultrasafe modified cell line, although worthwhile, was arguably of limited scientific value. Broad, genome-wide resistance to viruses would require rewriting the genetic code across thousands of sites in an organism’s DNA. Such work would mainly use existing knowledge of genetic-code redundancy rather than uncover new biology. In many cases, targeted strategies — such as blocking viral entry or modifying a smaller set of genes — can provide adequate resistance without the need for whole genome recoding.
A more ambitious and potentially transformative goal would be to define the minimal human genome — stripping it down to the smallest set of genetic elements required for a cell to function. The focus would switch from large-scale editing to gaining a deeper understanding of which elements are essential.
The human genome is roughly three billion bases long, but only about 2% of it encodes genes. The rest is a sprawling, partly characterized mix of sequences required for gene regulation, genome structure and other as-yet-unknown functions. Much of the genome is plausibly dispensable, although we do not yet know how much.
The potential benefits of a synthetic minimal human genome are substantial.
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First, it could transform our understanding of human biology by revealing which combinations of genetic elements are sufficient for a cell to function. Each time a sequence is removed, researchers would learn whether it was needed, and seeing what breaks when a segment is missing provides a starting point for working out what it does. We’ve seen this in bacteria: researchers who reduced the genome of Mycoplasma mycoides from 901 genes to 473 found a class of ‘quasi-essential’ genes that seem dispensable in isolation but are needed for healthy growth (C. A. Hutchison III et al. Science 351, eaad6253; 2016).
Second, cells with minimal genomes could be useful in biomedicine, for instance, to improve chimeric-antigen-receptor (CAR) T-cell therapies. Much of the genome is a liability — it can promote unwanted gene expression, among other hazards. Minimal genomes reduce such risks.
Third, smaller genomes are cheaper and easier to synthesize than larger ones are. This would benefit both the initial project, and any work that builds on it.
Critics might argue that it’s hard to tell whether a rewritten genome is truly minimal. But even if it works only in one cell line or under specific culture conditions it would still be useful. Some might rightly have ethical concerns. The methods used to write a synthetic human genome might also be used to write pathogen genomes, for example.
Proactive governance will be key. There are precedents to learn from. Researchers voluntarily set safety norms for recombinant DNA at the 1975 Asilomar conference. And the Human Genome Project’s ELSI programme funded ethical and legal studies alongside genetic research. An oversight committee that includes scientists, ethicists and the public, with the ability to stop funding, could be established to guide what gets built and what does not.
Ten years from now, I want a first-year graduate student in biology to have genome-scale engineering as part of their toolkit. I wonder what genome they would build?
Nature 654, 10 (2026)
doi: https://doi.org/10.1038/d41586-026-01725-z