£10 Million Project Will Try To Build Artificial Human Genome
Synthetic human genomes could change medicine and science forever.
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Toward the end of the 20th century, scientists developed tools that made it possible to read genomes, culminating in the release of the first draft of the human genome in 2003. This era of genomics has profoundly shaped research and society. As Human Geneticist Professor Richard Gibbs said, The Human Genome Project “changed the way people thought biology could be done.”
Alongside efforts to read genomes, scientists have been exploring the possibility of writing them – essentially constructing an entire genome from scratch.
The world’s largest medical charity – the Wellcome Trust – is continuing this exploration with its announcement of a new five-year collaborative research project, Synthetic Human Genome (SynHG). The project is dedicated to developing tools, technologies and methods for the synthesis of human genomes and has received £10 million in funding from the trust.
“Through creating the necessary tools and methods to synthesize a human genome we will answer questions about our health and disease that we cannot even anticipate yet, in turn transforming our understanding of life and wellbeing,” Dr. Michael Dunn, director of Discovery Research at Wellcome, said.
Why create synthetic genomes?
Physicist Richard Feynman’s “last blackboard” famously read: “What I cannot create, I do not understand.”
Though an organism’s genome can now be read in a matter of hours, much remains unknown about how that genome drives cellular function and life.
Professor Robin Lovell-Badge, principal group leader at the Francis Crick Institute, explained some of the key gaps in our current knowledge of the human genome: “The protein-encoding parts are fairly straightforward, but these comprise only a small fraction of the total,” he told the Science Media Centre. Protein encoding regions of the genome are primarily called exons, and can be sequenced using whole-exome sequencing (WES).
“There are segments, notably those that contain highly repetitive DNA at the ends of chromosomes (telomeres) and the centromeres, that play a role in segregating the chromosomes to each daughter cell when it divides, about which we know less. There are also huge numbers of repetitive elements, some remnants of viruses that have integrated into the genome or have been copied and moved around,” he continued.
When and where a gene will be activated within a cell is controlled by a regulatory region. “Some of these elements and the proteins with which they interact are also responsible for dynamic folding and generally organizing the genome, which in turn is thought to help not just tight packaging of the chromosomes when the cell divides but also efficient control of gene activity,” Lovell-Badge explained.
Though the function of these elements can be studied it is possible that some are “superfluous” or “evolutionary relics with no clear function”, making the process laborious, potentially expensive and ultimately “not rewarding”, Lovell-Badge noted.
Collectively, these knowledge gaps are motivating factors for constructing genomes from scratch. While genome-editing tools such as CRISPR-Cas9, zinc finger nucleases (ZFN) and transcription activator-like effector nucleases (TALENS) enable the introduction of edits to the genome, synthetic genomes would allow changes to be made at a much larger scale.
Synthetic genomics
Synthetic genomics generally refers to a branch of synthetic biology where research focus is on creating viruses, bacteria and eukaryotic cells that possess synthetic genomes. Synthetic genomes are created by designing and assembling DNA sequences that are then inserted into an organism’s cells.
History of synthetic genome creation
Early efforts to synthesize synthetic genomes focused largely on viruses or bacteria. In 2010. Researchers from the J. Craig Venter Institute synthesized the first synthetic bacterial genome, Mycoplasma mycoides JCVI-syn1.0. A four-megabase synthetic version of the bacterium Escherichia coli was published in Nature in 2019.
In 2023, synthetic biologists from The Synthetic Yeast Genome Project 2.0 (Sc2.0) consortium announced they had created a yeast strain comprising 50% synthetic DNA.
This was a major feat – synthesizing a yeast genome is more technologically challenging than synthesizing a bacterial genome. “It’s substantially bigger. It’s more repetitive than bacterial genomes, and it’s made up of many individual chromosomes, whereas most bacteria have only one,” Dr. Jef D. Boeke, professor in the Department of Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine, and leader of the consortium, told Technology Networks.
Because humans are more closely related to yeast than to bacteria, constructing synthetic yeast genomes from scratch could open up new possibilities for modeling human cells. Nonetheless, scientists have continued to pursue the ambitious goal of building larger, more complex genomes, such as those found in crops – or humans.
“Being able to build and redesign segments or entire human chromosomes will be important – after all you can only truly understand something if you can build it from scratch,” said Lovell-Badge. “And if you understand what is relevant and important, it may be possible to refine or improve aspects of its activity – for example, to more efficiently express gene products of medical value – or redesign it to make novel gene products.”
The technology needed to achieve this currently doesn't exist. The new SynHG project aims to tackle this challenge, though it is expected to take decades to complete.
A new project to create synthetic human DNA
SynHG is led by Professor Jason Chin from the Generative Biology Institute at Ellison Institute of Technology and the University of Oxford, and involves research teams from the Universities of Manchester, Cambridge, Kent, Oxford and Imperial College London.
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Over the next 5–10 years, Chin and his team plan to develop the foundational tools needed to construct the first synthetic human genome. As a proof of concept, they will focus on trying to create a fully synthetic human chromosome, according to the project website, and would like to develop methods for changing the sequence of a chromosome with minimal impact on the subsequent protein. This foundational work could take many years in itself.
“As for synthetic human chromosomes, although the current project is very unlikely to get that far, it may eventually be possible to make synthetic cells that can be grown in the lab with high efficiency,” said Lovell-Badge. “If these were to ever be used in humans, it would be important to design them carefully so that they can’t lead to tumors or produce novel infectious particles.”
SynHG recognizes the societal and ethical implications of synthetic genomes, which are complex and numerous. For instance, introducing synthetic DNA into living cells could result in unanticipated biological consequences with the potential to cause ecological imbalances. Scientists could also recreate known gene or genome sequences from an individual in a laboratory without even coming into contact with that person, raising genetic privacy questions and concerns.
Chin and colleagues have created a social science program – “Care-full Synthesis”, led by Professor Joy Zhang from the Centre for Global Science and Epistemic Justice at the University of Kent. It will run alongside the technical SynHG project to investigate the potential implications of synthetic DNA creation, working with academics, industry, civil society and policy partners.
“With Care-full Synthesis, through empirical studies across Europe, Asia-Pacific, Africa, and the Americas, we aim to establish a new paradigm for accountable scientific and innovative practices in the global age—one that explores the full potential of synthesizing technical possibilities and diverse socio-ethical perspectives with care,” said Zhang.
“The public must have a clear understanding of what this research entails, while researchers and funders must have a thoroughgoing understanding of where the public wants to go with this science,” Sarah Norcross, director of the Progress Educational Trust (PET), told the Science Media Centre. “We are therefore extremely pleased to see that a dedicated social science program has been incorporated into this work at the outset.”
Norcross cautioned that this work should not overshadow important developments in human genome sequencing and editing: “Although the Human Genome Project was ostensibly completed in 2003, the human genome was not actually sequenced in its entirety until the Telomere-to-Telomere Consortium concluded its work 20 years later. As for human genome editing, we have barely begun to explore the possibilities and consequences of that technology, and we have seen one appalling (and thankfully isolated) instance of its misuse.”
It’s imperative, she stressed, that these various ways of probing genomes are approached with “diligence” and with a “balance between ambition and humility”.
