Audacious project plans to create human genomes from scratch

Scientists revealed on Thursday that they plan to launch a project to synthesize human and other complete genomes from off-the-shelf parts, a prospect that ignited a storm of controversy last month when a closed meeting to discuss such an undertaking was held.

The project, which will be launched this year, will be run by a nonprofit organization called the Center of Excellence for Engineering Biology. The organizers expect its very existence to drive down the cost of splicing together the strings of chemical “letters” that constitute DNA into whole genomes — eventually producing a man-made version of the complete genetic blueprint for a human being.

When biologist George Church of Harvard University helped organize last month’s closed-door meeting, it was described as a forum for discussing the technological hurdles to creating human and other genomes from scratch, and for airing ethical issues that such a project might raise. Church told STAT at the time that the meeting was “exploratory” and implied that any such project was only a tentative possibility.

The tone now is far from tentative. Although the two-page unveiling of the ambitious plan, published in Science by Church and 24 others, including business and policy experts, is sprinkled with phrases like “engineering cancer resistance” and “understanding of genetic blueprints,” what most stands out is one little word, frequently repeated: “will.”

The project is called “HGP-write”: HGP refers to the Human Genome Project, the decade-long effort to sequence the genome, and “write” stands in contrast to the “reading” that HGP did. The synthetic human genomes would be inserted into human cells whose natural DNA has been removed, potentially allowing scientists see which genetic sequences lead to which traits, disease processes, and physiological functions.

The project will also try to address human health challenges, the authors write, by creating human genomes immune to cancer and viruses, or building pig genomes that could allow the animals to serve as human organ donors.

“The goal is to launch HGP-write in 2016 with $100 million in committed support, from public, private, philanthropic, industry, and academic sources,” the authors write.

Because the very existence of the project should, like the original HGP, spur the development of technologies, such as those needed to assemble big chunks of DNA into a working genome, the whole thing would likely cost less than the HGP’s $3 billion, the HGP-write leaders said.

Ethical concerns persist

Scholars who raised concerns about last month’s meeting did not find the essay reassuring.

Biologist Drew Endy of Stanford and bioethicist Laura Zoloth of Northwestern University, who criticized last month’s meeting, said in a statement that they are “heartened to see” that the leaders of HGP-write “are in favor of open and public discourse regarding developing capacities to ‘write’ human genomes.” The announcement in Science, however, “fail[s] to pose … essential questions,” such as whether “developing capacities to synthesize human genomes [is] a good idea.”

The ethical issues range from more general concerns about researchers “playing God” to the question of who would own a synthetic genome and who could profit from it.

Attorney Nancy J. Kelley, an organizer of the May meeting who helped found the New York Genome Center, said last month’s meeting did inform the Science essay, though ethical concerns are given only passing mention. “The paper’s very short,” she said. “You can only introduce the concepts. You can’t really discuss them or raise a debate about them in the paper.”

But because of unresolved — in fact, not evenly publicly debated — ethical concerns about creating a human genome, Endy and Zoloth said, the “current proposal should be broadly rejected and not now pursued.”

The train has left the station, however. HGP-write has detailed plans and an umbrella institute, the Center of Excellence for Engineering Biology, which will oversee the project. California-based software company Autodesk has committed $250,000. Next steps include organizing working groups of scientists, and raising more money. Kelley said they will look for funding from public and private sources.

One obvious source, the National Institutes of Health, is not yet on board. Although its genome institute “has ongoing interest in funding the development of technologies for ‘writing’ DNA,” NIH director Dr. Francis Collins told STAT, “NIH has not considered the time to be right for funding a large-scale production-oriented ‘HGP-write’ effort.”

Plans come into focus

Despite the “H,” HGP-write “need not be restricted to human,” its leaders write. Also on the drawing board: mouse, fruit fly, roundworm, yeasts — all for basic biology experiments — and pig, because synthesizing its genome and tweaking it slightly could allow pigs’ organs to be transplanted into people whose hearts, livers, kidneys, or other parts are failing.

Church has already edited pig genomes for that purpose using the CRISPR-cas9 technique. But he told STAT at a conference in April that CRISPR is likely to be superseded, and soon, by whole-genome synthesis.

“If you want to make one change, or 10 changes, by all means do genome editing,” said Jef Boeke, director of the Institute for Systems Genetics at New York University and one of the “Gang of Four” leading HGP-write. “But if you want to make one change per 400 [DNA base pairs], it’s more efficient to create your genome from scratch.”

HGP-write will start by synthesizing 1 percent of the human genome and inserting those strings into human cells growing in labs, said Boeke. Its leaders are confident it will drive down the cost of synthesizing long strings of DNA into complete genomes — now 10 base pairs for $1 — by 1,000-fold within a decade, so that synthesizing a 10,000-letter-long strand of DNA will cost $1.

Looking ahead

It’s anyone’s guess whether HGP-write will succeed, let alone how long it may take. A project led by Boeke to create a yeast genome from scratch is halfway to its goal after about 10 years, and yeast has fewer than 1 percent the amount of DNA that people do.

One of HGP-write’s first targets could be constructing a human chromosome, perhaps chromosome 21, an extra copy of which causes Down syndrome. Ultimately, the project could produce a “reference genome” made up of the most common variants of humans’ 20,000 or so genes. For odd historical reasons, the current reference genome, from the Human Genome Project, comes mostly from a single individual, a man in Buffalo, N.Y. A true reference genome might better represent all of humanity.

Boeke emphasized that “we’re only talking about doing this in cell lines, not humans.” As for the risk that the technology to synthesize a bespoke genome and insert it into an early human embryo might get “into the wrong hands,” he said, “any proposed new technology has the potential to be misused, and this is one of them.”