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Science, Business Leaders Propose HGP 2.0 to Synthesize Entire Genomes

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NEW YORK (GenomeWeb) – Scientists from genetics, genome engineering, and synthetic biology along with business and technology advocates have proposed a new, large-scale, collaborative project to synthesize entire genomes, including a genome for a human cell line.

Pointing to the success of the Human Genome Project (HGP) in accelerating DNA sequencing and analysis, the 25 individuals positioned their project as the successor to that endeavor, a so-called "HGP-write" to naturally follow the completed "HGP-read."

Led by New York University Professor Jef Boeke, Harvard Medical School Professor George Church, Autodesk Research's Andrew Hessel, and New York City biotech mover-shaker and consultant Nancy Kelley, a total of 25 individuals attached their names to the proposal, which was published today in Science.

"Genome synthesis is a logical extension of the genetic engineering tools that have been used safely within the biotech industry for ~40 years and have provided important societal benefits," the authors wrote. "As human genome-scale synthesis appears increasingly feasible, a coordinated scientific effort to understand, discuss, and apply large-genome engineering technologies is timely."

The document is associated with a controversial closed-door meeting held last month at Harvard, sponsored in part by Autodesk, where more than 100 scientists and other invited attendees gathered to discuss synthesizing a human genome. The organizers also held a much smaller meeting on the topic at NYU in October 2015.

On the day of the May meeting, Stanford University bioengineering professor Drew Endy and Northwestern University religion professor and bioethicist Laurie Zoloth published an essay critical of the circumstances under which it was held. "The creation of new human life is one of the last human-associated processes that have not yet been industrialized or fully commodified," they wrote. "It remains an act of faith, joy, and hope. Discussions to synthesize, for the first time, a human genome should not occur in closed rooms."

Endy told GenomeWeb in an email that he and Zoloth were both "long-time supporters of synthetic biology," and that he was invited to the meeting but declined to attend.

For their part, the proposal's authors noted that it would require public involvement to discuss ethical, legal, and social implications of synthesizing a human genome, and that they would enable that discussion in advance of any implementation.

Despite several references to potential benefits from the project, the authors couched the reason for taking it up in economic terms. "The primary goal of HGP-write is to reduce the costs of engineering and testing large genomes in cell lines by over 1,000-fold within 10 years," they said.

"The perhaps much bigger payoff [of the HGP] was a smaller project to reduce the cost of sequencing, and that has led to the fact we now have $1,000 genomes and now have the 1000 Genomes Project and million-genome database that catalog the variation among humans," Boeke told GenomeWeb.

That variation is what researchers are ultimately interested in, and if whole-genome synthesis costs fall similarly, "it becomes easy to synthesize variation," he said. "Then testing of specific variants can become much more efficient and much more informative."

At the current price of double-stranded DNA synthesis (approximately $.03 per base pair for constructs up to 10,000 base pairs) fabricating a human genome would run up a bigger bill than the $3 billion it first took to sequence it; however, the authors suggested that falling prices would eventually lead the project to be cheaper than the HGP.

Technologies that could ultimately benefit from lower genome engineering costs and better understanding of human genomic variation might include organs grown for transplanting into humans, cell lines that are immune to viruses or resistant to cancer, and tools to accelerate pharmaceutical development such as organoid chips.

"We've also proposed that this not be limited to the human genome and have it also be initiated in other species as well," Boeke said.

In the shorter term, pilot projects including synthesizing genes and their non-coding regulatory regions or entire chromosomes could provide "substantial and useful innovations," even if they don't require constructing an entire genome. Scientists have already synthesized viral, bacterial, and mitochondrial genomes, and Boeke is leading an attempt to construct an entire yeast genome.

After reading the written proposal, Endy and Zoloth furthered their criticism. "We are heartened to see that the authors of 'The Genome Project-Write' are in favor of open and public discourse regarding developing capacities to 'write' human genomes," Endy and Zoloth said. "However, before launching into such a momentous project, with such enormous ethical and theological implications, basic questions still need to be asked — starting with, 'Whether and under what circumstances should we make such technologies real?', and 'Is developing capacities to synthesize human genomes now a good idea?'"   

"Boeke et al. fail to pose these essential questions," they said.  "In fact, in their proposal, [they] fail to pose any questions. Nor do they detail specific limits about what should not be done. Nor do they note the enormous theological issues raised by their proposal. Taken together these omissions should raise the added question of whether this group is well equipped to organize and lead such considerations."

Financial disclosures revealed several authors held close ties with companies that could benefit from the project as outlined. Church is a co-founder of DNA synthesizing firm Gen9, organ engineering firm eGenesis, and microbial engineering firm enEvolv, among others. Co-author and Yale University Professor Farren Isaacs is also a co-founder of enEvolv. Hessel owns stock in computer-aided design software and 3D printing firm Autodesk. Luhan Yang, a former Church lab member, is also a co-founder of eGenesis.

Endy is also a co-founder of Gen9, which has been seeking to increase demand for its high-throughput DNA synthesis platform.

To kick-start their plan, the authors said they are seeking $100 million from public, private, philanthropic, industry, and academic sources from around the world. "Most of it, we're still looking for," Boeke said.

While the authors suggested administrating the project using the National Human Genome Research Institute's Centers of Excellence in Genomic Sciences model, Boeke said the details of the project could depend on the funding sources that become involved. He also suggested that the synthetic yeast genome project could offer important lessons on how to run such a consortium.

There's plenty to learn from the HGP itself, he added. "One of the interesting lessons [we learned from the HGP] was that when it was first proposed, it was very controversial. I remember, as an assistant professor, sitting down at lunch with some of the senior faculty and there wasn't a lot of enthusiasm for it. People thought: one, it was impossible; two, it would cost a fortune; and three, it would be done at the expense of their personal research projects. Those ended up not being true," Boeke said.

"That's made us a little bit less concerned about some of the negative publicity that's come out. It's kind of inevitable when you throw a new idea out there," Boeke said.

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