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June 3, 2016

Let’s Synthesize the Human Genome, Says HGP-Write

  • It is said that a goal is a dream with a deadline. Such thoughts appear to have inspired scientists who share a big dream—the synthesis of the human genome—and who are prepared to accept a tight deadline—just 10 years.

    The scientists hesitated to announce their goal until they could present it properly. It appeared June 2 in the journal Science, in an article entitled “The Genome Project–Write.” A couple of weeks before the publishing the article, the scientists discussed their plans at closed-door meeting at Harvard Medical School, and they conducted their deliberations with such discretion that they managed to arouse both curiosity and consternation. For example, Drew Endy, a bioengineer at Stanford University, and Laurie Zoloth, a professor of medical ethics and humanities at Northwestern University, openly called for more open proceedings to ensure that bioethical concerns would receive due consideration.

    Now that the Human Genome Project–Write (HGP-write) is out in the open, observers and potential participants may better judge whether it is realistic and responsible. HGP-write proposes to build on the knowledge gained by the original Human Genome Project, which could be called, with the benefit of hindsight, HGP-read. Whereas HPG-read “read” DNA to understand its code, HGP-write will use the cellular machinery provided by nature to “write” code, constructing vast DNA chains.

    “Although sequencing, analyzing, and editing DNA continue to advance at breakneck pace, the capability to construct DNA sequences in cells is mostly limited to a small number of short segments, restricting the ability to manipulate and understand biological systems,” wrote the authors of the Science article. “Further understanding of genetic blueprints could come from construction of large, gigabase (Gb)–sized animal and plant genomes, including the human genome, which would in turn drive development of tools and methods to facilitate large-scale synthesis and editing of genomes.”

    Among the authors of the Science article were leaders of the HGP-write team including as Jef Boeke, Ph.D., a researcher at NYU Langone Medical Center, George Church, Ph.D., a researcher affiliated with Harvard and MIT, and Andrew Hessel, a researcher at Autodesk, a software company. They indicated that HGP-write would be coordinated by the Center of Excellence for Engineering Biology, an independent nonprofit organization headed by Nancy J. Kelley, another co-author of the Science article.

    HGP-write has received a leadership gift of $250,000 from Autodesk to seed its planning and launch. But HGP-write anticipates much more generous support.

    “The goal is to launch HGP-write in 2016 with $100 million in committed support, from public, private, philanthropic, industry, and academic sources from around the world,” the authors continued. “The costs of the project lie not only in obtaining de novo synthesized DNA but in the assembly, integration, and functional assays required to evaluate and understand the modified genomes. Total project costs are difficult to estimate but would likely be less than the $3 billion cost of HGP-read.”

    “This grand challenge is more ambitious and more focused on understanding the practical applications than the original Human Genome Project, which aimed to ‘read’ a human genome,” said Dr. Church. “Exponential improvements in genome engineering technologies and functional testing provide an opportunity to deepen the understanding of our genetic blueprint and use this knowledge to address many of the global problems facing humanity.”

    Another proposed benefit of the project is the development of new genomics analysis, design, synthesis, assembly, and testing technologies, with the goal of making them more affordable and widely available. “Writing DNA code is the future of science and medicine, but our technical capabilities remain limited,” said Hessel. “HGP-write will require research and development on a grand scale, and this effort will help to push our current technical limits by several orders of magnitude.”

    Perhaps anticipating criticism from those who would accuse HGP-write of going a genome too far, the authors of the Science article outlined a number of “stepping stone” projects:

    1. Synthesizing “full” gene loci with accompanying noncoding DNA to help explain still-enigmatic roles of noncoding DNA variants in regulating gene expression.
    2. Constructing specific chromosomes—such as chromosome 21—or complex cancer genotypes to model human disease more comprehensively.
    3. Producing specialized chromosomes encoding one or several pathways.
    4. Advancing gene therapy by introducing the freedom to deliver many genes and control circuits to improve safety and efficacy, provided delivery challenges can be met.
    5. Using induced pluripotent stem cells to construct an “ultrasafe” human cell line via comprehensive recoding of protein-coding regions, and deletion of corresponding genome features to increase safety of such a cell line.
    6. Developing a homozygous reference genome bearing the most common pan-human allele (or allele ancestral to a given human population) at each position to develop cells powered by “baseline” human genomes.

    Also, HGP-write explicitly states that it is not interested in creating artificial humans. Instead, it insists it is focusing on human cell lines. Finally, one of HGP-write’s chief goals is ambitious but, ultimately, conservative—a 1000-fold reduction in the costs of engineering and testing large genomes.

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