Fly image provided by V. Gantz and E. Bier, UCSD.

Gene drives have spurred controversy of late. In the October issue of Nature Biotechnology, we hear the perspective of several researchers who have been developing gene drive technology, in some cases for decades. Their perspective has been seemingly missing from the extensive reporting that followed publication of a CRISPR-Cas9 mediated gene drive in Drosophila in April 2015, and much of the debate has focused on the potential hazards of the technology. We talked to them and to researchers raising alarm bells about the technology to explore just how likely the doomsday scenarios are.

The connection between CRISPR/Cas9 and gene drives—genetic elements that bias inheritance and upset the rules of Mendelian genetics—was brought into the spotlight in 2014, when George Church’s group at Harvard published a thought piece that laid out the basic design of a RNA-mediated gene drive. In that article, the authors suggested that the release of organisms carrying gene drives could imperil indigenous species in the wild. The group struggled to find a publisher for their article—too speculative, they were told, come back when you have data.

Less than a year later, researchers from University of California, San Diego, published a paper in Science describing the first CRISPR/Cas9 gene drive in flies and demonstrating its ability to spread a mutant gene through a lab strain population in two generations. That sparked the current controversy, and since then some of the same journals that turned down the Harvard paper have published commentaries and perspectives, sounding a warning on gene drives upsetting ecosystems.

But can gene drives do this? That was the question we posed to researchers who have been working in this field. For decades, the grail for many scientists working in this area is to develop systems that eradicate human disease vectors, such as Anopheles gambiae, a malaria vector. Before CRISPR-Cas9, researchers were developing transposons and homing endonucleases, so-called ‘selfish DNA,’ which propagate horizontally through genomes, though not particularly efficiently. And researchers feel the approach shows great promise. As Anthony James of the University of California, Irvine, puts it, “People working with mosquitoes feel that they have a legitimate application of the technology, as opposed to neat little tricks. There was a strong belief that good can be done in the public health arena if this technology was available.”

And it’s not as if these researchers have failed to consider possible ecosystem imbalances. James, for example, has trolled the mosquito genome for what he calls neutral areas, locations where secondary effects are unlikely. “You can sequence the gene from wild populations and find conserved domains,” he says, that way, “when you make the insertion, you don’t have a major impact on fitness.”

To be sure, there are university institutional review boards to oversee such experiments, though Kenneth Oye, from MIT’s Department of Political Science and Engineering Systems and a co-author on one of the perspectives questions whether they are up to the task.  “University review boards are heavily focused on protection of human subjects and pathogens and toxins,” he says. “[Gene drives] just don’t fit.”  This creates another hole that must be filled before gene drive research can advance. Oye wants a systematic review of “the way we are thinking about security and environmental risk associated with advanced biotechnologies.”

That would be effective only if those doing the review are qualified to do so. Todd Kuiken, a principal investigator on the Wilson Center’s Synthetic Biology Program, points out that some of the people making decisions on using gene drives “are not ecologists. In fact a lot of them aren’t even biologists. And so their understanding of the impact of release of one or a handful of organisms outside the lab, I’m not sure they are thinking about that clearly.”

But for those working with gene drives, disaster scenarios border on the fantastical, as they can point to numerous mechanisms that will likely limit spread of a gene drive allele in the wild. Andy Scharenberg, at the Seattle Children’s Research Institute and the University of Washington, Seattle, who has worked on retargeting endonucleases, points out that “organisms expressing a nuclease are likely to take some reproductive fitness hit, for example, and mutations accruing within the nuclease target site following repair of a nuclease-induced break will lead to the development of resistance to a gene drive.”

Clearly this is just the beginning of the discussion. The US National Academy of Sciences has convened a panel to discuss gene drive research in non-humans (while also looking separately at the issue of human germline gene editing). The gene drive panel took testimony in July and will meet again in October. Our feature drills down on some of the issues mentioned here. Click on the link below to download the full PDF, made freely available until release of October issue.

Gene_Drive_Overdrive

Laura DeFrancesco, Features Editor

Setting standards for synthetic biology

Power Button

Standards[1] are traditionally claimed to be one of the pillars of modern engineering and as such they are also vindicated as one of the core tenets of contemporary synthetic biology – which is basically looking at biological systems through the eyes of an engineer. Standardization of physical assembly of DNA-encoded genetic parts was one of the first issues that the early pioneers of synthetic biology at MIT pointed to as being critical for the development of the field. This is still today one of the principles of the iGEM student competition and its associated repository of biological parts. But soon after the issue was raised more than a decade ago, an avalanche of criticism followed, because regardless of how one standardizes physical composition, the result is not a predictable functional outcome, as biological activities delivered by given DNA segments are context-dependent in practically all cases. This raised the question: should we simply give up robust design of biological systems with new-to-nature properties?

A lot has happened since those days. There has been an increased effort to develop orthogonal devices and even complete systems that are intended to work in a fashion minimally dependent and even autonomous of the biological host. These involve not only a suite of genetic patches and expression systems based on phage polymerases, but also recoding and/or expansion of the genetic code. Also, physical assembly of DNA pieces is no longer an issue, due to the ease of chemical synthesis and the onset of many procedures for composing genetic constructs that do not use restriction enzymes.

More importantly, the debate on standards has moved beyond technicalities on DNA composition, now focusing on what else can and should be standardized. For example, how do we measure biological activities? And, along the way, the sector has added benchmarks for synbio practices, including risk assessment methods.

At the same time, the growing awareness that synbio can ultimately become a transformative technology has prompted a (mostly implicit) footrace for who will succeed in establishing the rules and standards that will shape the field of synbio for the future.

There is a general sentiment that the level of knowledge right now is not sufficient to address standards in biological design with the same rigour as electric or civil engineering does. There have indeed been partial advances in metrology and proposition of operating systems in living organisms, but most standards proposed thus far have not made it beyond very limited communities of users. There is still a considerable wander in the wilderness that the synbio community has to go through before reaching the promised land of full-fledged standardized biology!

In the meantime there is a remarkable (and worrisome) difference in the interest of the US and EU agencies on the issue at stake. The American National Institute of Standards and Technology (NIST), belonging to the United States Department of Commerce, has been very proactive in bringing together a great number of US synthetic biologists from academia and industry by means of specialized workshops and follow up networking.

Their agenda includes both getting things done through a solid research program and, of course, establishing early US leadership for whatever development may come later. In contrast, no EU level-related agency or stakeholder on standards has expressed thus far the slightest interest in becoming involved in the synbio standardization process. Every proposition to develop a European Institute of Biological Standards that could team up and compare with US initiatives has been ignored, ridiculed or turned down (with the stand-alone 4-year EC research project ST-FLOW being the only exception).

This means that when the field will be ripe to deliver, Europe will be reactionary, losing an opportunity to partner with our US peers. But do not blame only Brussels bureaucracy. The EU-based synbio community is both mesmerized by the awesome (and quick!) progress made in the US, and engrossed in the difficulties of scientific bottlenecks. By focusing only on scientific bottlenecks we may gain more knowledge, but will altogether lose any chance of being global players in the bioeconomy that will be brought about by synbio.

We Europeans pride ourselves on producing the best local gourmet food, the key ingredients needed for a chef’s inspiration. Yet we often disdain the multi-billion business of franchised, standardized food. Setting standards is not only a decision between quality and quantity, but it is also the basis of a successful bioeconomy and a flourishing society. Science needs freedom to operate, but as European society longs for a knowledge-based bioeconomy, we cannot ignore the risks of simply signing up for heteronomous standards developed by others!

Victor de Lorenzo and Markus Schmidt