Writing the Human Genome
S Krishnaswamy
A BOLD new project has been recently announced by a strong group of UK universities supported by the Wellcome Trust, which has more than £1 billion in funds. Its objective is to synthesise the human genome, or in other words, to write what is called the code of life. With an initial investment of £10 million, the Synthetic Human Genome Project (SynHG) aims to create the means to construct human chromosomes – and eventually entire genomes – from the ground up. Researchers from the University of Oxford, the University of Cambridge, Imperial College London, the University of Manchester, and the University of Kent are part of the consortium on this collaborative UK project.
The human genome comprises approximately 3 billion chemical "letters" (A, T, C, and G in humans). To fit inside almost every cell in our body, this code is organised into 23 pairs of chromosomes that are securely wrapped around proteins.
The SynHG initiative follows the J Craig Venter Institute's (JCVI) announcement in March 2024 of producing stable, single-copy Human Artificial Chromosomes (HACs), which had plagued synthetic biology for decades. Previous attempts to create HACs were thwarted by "multimerisation," an uncontrollable process in which the artificial chromosome would create numerous copies of itself inside a cell, rendering it useless for precise experimentation or therapy. The success of the JCVI team is a leap that provides synthetic biologists with a powerful, controllable tool for delivering large amounts of genetic information directly to the nucleus of a human cell.
It is this tool that makes the ambitions of the UK's SynHG project seem plausible. The promise is revolutionary: virus-resistant tissues, an end to inherited mitochondrial diseases, and cell therapies. Understanding that the application of science is never neutral, the question arises in the coming brave new world of synthetic biology: Who will this technology truly serve? The many, or the few?
READING THE GENOME: STRUGGLES INVOLVED
To understand the reason for the question, it is necessary to realise what is going to be synthesised. The chromosomes are not simple strings; they are complex structures with protective caps, called telomeres, on their ends, just like the plastic tips on shoelaces. The chromosome has a pinched central region called a centromere that acts as an anchor during cell division. For decades, the holy grail was just to read every letter in this library – or in technical language, 'sequence the genome'. This reading or sequencing effort began as a monumental public project. The International Human Genome Project (HGP) was launched in 1990 by the US Department of Energy and the National Institute of Health at a cost of approximately $3 billion. The participants comprised public research institutes from the US, UK, France, Germany, Japan and later China. It was a triumph of open, publicly-funded science. It operated under the Bermuda Principles, which mandated that all data be released freely within 24 hours – a radical commitment to collective ownership. Its progress was soon challenged by Craig Venter's private company, Celera Genomics, which aimed to sequence the genome faster and then patent hundreds of genes, locking humanity's common inheritance behind a paywall.
The race between the HGP and Celera ended in a tense, politically mediated truce. US President Bill Clinton and British Prime Minister Tony Blair announced in June 2000 that the international Human Genome Project and Celera Genomics Corporation had completed an initial sequencing of the human genome. Scientists working in the public and private sectors were congratulated on this landmark achievement. The International Human Genome Sequencing Consortium announced the completion of the Human Genome Project (HGP) in April 2003 with the generation of a highly accurate and publicly available reference sequence of the human genome. But the HGP's declaration of "completion" was a milestone, not a finish line. The technologies of the time could only read the "paragraphs" of the genome; the repetitive, complex "sentences" in the telomeres and centromeres remained unreadable gaps. The Human Genome Project was not able to complete the genome because nearly 8 per cent of it – some 200 million letters – was hidden in these repetitive, structurally complex regions. Finally, in March 2022, the Telomere-to-Telomere (T2T) Consortium, with core leadership and funding from public government sources, used advanced technologies to read every last base pair from one end of each chromosome to the other.
WHOSE GENOME?
This scientific triumph exposed a deeper, more insidious problem: the myth of the "average" genome. The original HGP reference was a patchwork of DNA from about 20 anonymous donors, with 70 per cent of it coming from a single individual of predominantly European ancestry. It was a single, incomplete story presented as the universal human narrative. This bias has had real consequences, skewing medical research and creating dangerous blind spots in global health.
There are efforts to overcome the bias at the international level. The Human Pangenome Reference Consortium is one of these initiatives whose goal is to do the inventory of the variety of human genomes. This effort acknowledges that our DNA is a record that has traces of the DNA inherited through migrations and mixings and holds our history. The representation of Indian ancestry in international genomic databases is still small. In 2019, CSIR's IndiGen project sequenced the genomes of 1029 healthy Indians. Another project, Genome India, has examined about 10,000 Indian genomes and found around 135 million genetic variations. Finding disease risks and medication responses specific to populations depends on these efforts. They still make up a tiny portion of the world's data, though. Many tribal or isolated groups are still unsampled, and their unique genetic architectures are absent from the global reference, meaning the benefits of precision medicine will continue to bypass them unless this is corrected.
This brings us back to the new project to synthesise a human genome. Led by Professor Jason Chin, the SynHG consortium, which comprises only researchers in the UK, is starting modestly by aiming to synthesise a single human chromosome. There are many profound potential benefits if it succeeds. It is possible to make synthetic mitochondria to prevent inherited mitochondrial diseases. Human cell lines grown outside the body can now be engineered and used in humans for therapies. It will provide a deeper scientific understanding of how genome structure dictates function. But the shadow of Celera and the inequities of past genomics loom large. Who will own these synthetic creations? Will they be patented? Will this technology, developed at immense cost, become a tool only for the wealthy, further entrenching global health disparities?
FOR WHOM?
Remarkably, embedded within the SynHG consortium is a social science program called "Care-full Synthesis" led by sociologist Professor Joy Zhang at the University of Kent. Its mandate is explicitly political and inclusive: to consider societal priorities from across the Global South, include diverse perspectives in knowledge production, and explore the policies needed to ensure this research is applied only if and when communities desire it. This is not a project imposing a technology on the world. It is, in theory, a project that will create tools and, simultaneously, institute a global framework for their equitable use. It is an attempt to bake ethics and justice into the effort from the very beginning.
With its dedication to "Care-full Synthesis," the SynHG project is an attempt in the right direction. But the consortium that has taken the lead for the synthesis needs to be expanded. It needs to include researchers from institutions in the Global South. The data and outcomes have to be part of the commons. The venture of synthesising artificial human genomes has great potential and benefits, but whether it will overcome the bias and grow to benefit all will depend on the outcome of the tremendous commercial and political pressures that will unavoidably arise.
