Questions to consider about gene synthesis technology

Microbiological research is increasingly troubled by ethical questions regarding its potential misuse. In the near future, a criminal, terrorist, or state seeking to build a bioweapon might choose to obtain a pathogen by synthesizing it in vitro and changing its properties, instead of isolating it from nature or stealing it from maximum-containment facilities. Numerous logistical and technological obstacles complicate the construction and release of a bioweapon, but the first step–obtaining a suitable agent through clandestine synthesis–is becoming a realistic scenario that needs to be addressed by scientists and the arms control community.

In the past, in-vitro synthesis of biological agents was restricted to viruses with small infectious genomes that not only had to be sequenced fully but also had to be physically available as templates. In 2002, researchers at SUNY Stony Brook first demonstrated that a template genome was not necessary to create a poliovirus from scratch. Over a two-year time period, this group assembled the genome using short overlapping oligonucleotides designed according to the published poliovirus genome sequence and ordered through a commercial supplier. Similar experiments in 2003 yielded an encephalomyocarditis virus.

The newest technology on the market, fittingly named gene synthesis, combines microfluidic chip technology, one-step polymerase chain reaction assembly, and a novel assembly technique to accurately create large nucleotide building blocks that can later be joined. By using these new techniques in combination with standard molecular biology, it will be feasible to synthesize genomes the size of all known viruses and bacteria in vitro.

Limiting access to the sequence information on which the design of genomes is based could control what is synthesized, but would the costs be worth the benefits? Addressing the following questions would help to understand this larger issue:

• Is gene synthesis an “easy” technology that, with the proper access to machinery and reagents, could truly be used by nonprofessionals (e.g. criminals and terrorists) to create microbial genomes in the nearest future? Or does the technology require a level of sophistication and financial support that will only be available to professionals?
• Would limited access to pathogen sequences impede scientists’ ability to develop countermeasures against these agents?
• Who would decide to withhold or withdraw sequence information, and according to which criteria would decision makers allow individuals or organizations to access otherwise unavailable sequences?
• How much would we actually gain by withholding sequence information? Aren’t technologically advanced aggressors, such as nation states, able to obtain natural organisms and then sequence their genomes? Wouldn’t technologically advanced aggressors, such as nation states, prefer to obtain their own sequences? If technologically advanced aggressors can obtain natural organisms, what need would they have for sequence databases, and what implications would this have for any effort to control sequence information?
• Should access to sequences from eradicated pathogens or artificial microbes be limited? If the public-health concern is considered grave enough to retain eradicated viruses or to resurrect them, shouldn’t information about them be publicly available?
• If a nation chose to withdraw existing, publicly available sequences, is it possible to ensure that other nations not grow suspicious of its motives? Is it even feasible to withdraw previously available information from the public?
• What is the overlap between “bioweapons agents” and “public health agents”? Couldn’t an aggressor turn those agents into weapons that we consider non-bioweapons agents and for which sequence information would remain publicly available?