One score and six years ago, humanity embarked upon the Human Genome Project (HGP), sequencing all 3 gigabases of our genetic instruction manual. More than 1000 human genomes later, a consortium of synthetic biology heavy-hitters has proposed a new grand challenge. Appending “-Read” to the first project, they now propose Human Genome Project-Write, a quest to invert the process and synthesize the entire human genome from scratch.
The project got off to a somewhat rocky start when a closed meeting at Harvard was leaked to the press, prompting public concern as to what mad science these biologists were secretly up to. Not long after, a journal-imposed embargo lifted on a perspective piece detailing the proposal.
Foreseeing potential ethical concerns, the proposal suggests several ways to ensure the project goes forward in a responsible manner:
- Public conversation should precede any work on the project.
- Some percentage of research funds could be devoted to ethical, legal, and social implications.
- Strong biosafety standards would be followed, and regulations could be considered, possibly using human stem cell regulation as a template.
- Potential benefits from the project should be shared broadly, possibly through patent pooling.
Potential Benefits Of Synthetic Human Genomes
The major goal of the project is to reduce the cost of synthesizing and testing long DNA sequences. Just as with genome sequencing, the ultimate benefits of improved technology can’t be known until they happen, but the proposal tossed out a few ideas:
- A human reference genome, homozygous for the most common alleles, would provide a standardized point of comparison for research.
- The technology could help to develop transplantable organs and/or help drug discovery and testing.
- Longer constructs for gene therapy could be synthesized.
- Virus-proof cell lines could be made by recoding them to eliminate one or more codons and then deleting corresponding tRNAs.
- Stem cells could be made cancer-resistant by
- Removing transposons, retroviruses, and other genetically unstable elements.
- Adding multiple copies of tumor-suppressor genes.
- Recoding genes to remove mutation hotspots.
- Designer baby concerns could be alleviated by synthesizing genomes that cannot form germ cells.
- While not in the Science piece, Rob Carlson points out that faster cheaper DNA synthesis could enable DNA-based data storage.
Can HGP-Write Be Done?
Synthesizing the human genome will be hard, but the proposers think it is feasible. After all, viruses, minimized bacterial genomes, and an entire modified yeast chromosome have already been synthesized, and the Sc2.0 project is currently working on a yeast genome. On the other hand, human genomes include more complex epigenetic information, which is as important for a functional genome as spaces areforreadingthisblogpost. The proposal suggests beginning with smaller pilot projects, one of which might be getting epigenetics and chromatin to work on a synthetic mini-chromosome.
Interestingly, the bacterial genome leaders, including J. Craig Venter and Daniel Gibson, are not authors on the HGP-Write proposal, which was lead authored by Jef Boeke, George Church, Andrew Hessel, and Nancy Kelley. This is more than vaguely reminiscent of the HGP-Read dynamic, which was in a direct race with Craig Venter’s group to publish the first complete sequence.
In addition, some major players are not in favor of the project at all, including Drew Endy, who thinks the project is too ethically fraught, somewhat arrogant, and highly likely to generate public backlash, like when the poliovirus was synthesized in 2002. Instead of human genomes, why not drive technology development with a more innocuous goal, like plasmids on demand? “Taking a step back,” he asks, “just because something becomes possible, how should we approach determining if it is ethical to pursue?”
Will HGP-Write happen? Probably. Eventually. Will it happen as a broadly-backed, public consortium à la HGP-Read? Possibly, but NIH director Francis Collins is not making encouraging noises.
Keep your eyes on Epigenie for developments, and in the meantime, you can check out the writing this HGP has already accomplished in Science, June 2016.