Area of interest: Biosecurity regulation for gene synthesis providers

What is the gene synthesis industry?

Biologists all over the world need specific DNA sequences for experiments and projects. Those sequences are provided by the rapidly growing gene synthesis industry. Customers send their desired genetic sequences as digital files to gene synthesis companies. Companies “print” the files into actual lengths of DNA (and other genetic material, like RNA), and ship them back to the customers. With actual genetic material, the customers can then insert their sequences into live organisms and biological systems.

Customers might invent their genetic sequences themselves, or might use sequences from the many published genomes available freely online. A couple decades ago, gene synthesis was prohibitively difficult and expensive for most scientists. It has become drastically cheaper over the past 15 years, and this service is now available to many end users.

Cost per Raw Megabase of DNA Sequence.jpg

Image from the National Human Genome Research Institute

Biosecurity relevance

Custom gene synthesis advances biotechnology and synthetic biology in numerous ways, and also raises major biosecurity risks: once a customer has a digital sequence from a pathogen or toxin, they could add this to an existing pathogen to make it more dangerous, or even to create a virus that they did not originally have. In 2016, a small group of Canadian researchers spent about six months and $100,000 dollars to create live horsepox virus (an extinct relative of the smallpox virus) using commercially synthesized genes.

Access to dangerous sequences is not a problem: the genetic sequences for Covid-19, Ebola virus, anthrax, smallpox, and virtually all other known human diseases are freely available online, hosted by the National Institutes of Health. The capabilities to manipulate these genetic sequences and insert them into live pathogens is also here now, and getting easier and cheaper all the time.

Getting these digital sequences synthesized into actual genes is the important step, and is where gene synthesis companies come in.

In short, the concern is that a malicious actor could purchase genes from a dangerous pathogen and use it to modify or even create an organism for use as a biological weapon. Current measures such as the Federal Select Agent Program regulate the sale and trade of complete pathogens and some genetic material, but at the time this program was established, there was no real chance that a pathogen could be assembled piecemeal from commercially ordered sequences. Now, we know that this can be done by a small team on a budget.

Current regulatory status

Gene synthesis providers are not legally required to screen orders shipped within the USA.

Transport and access to dangerous organisms themselves is regulated by the Federal Select Agent Program (FSAP), which is run jointly by the CDC and APHIS. The FSAP also regulates DNA sequences when either (A) they represent the complete genome of a pathogen, or (B) they contain the entire sequence that encodes a toxin. Furthermore, the Australia Group (the biological/chemical weapons export control regime, of which the US is a member state) requires that all exported genome sequences be screened and restricted if they encode any length of DNA (including smaller genes from a pathogen genome) that would likely make a disease more dangerous. This requirement is enforced in US industries by the Department of Commerce.

The US Department of Health and Human Services issues voluntary guidance on how gene synthesis providers screen their orders to determine if they meet the SAP guidelines.
Many large synthesis providers are members of the International Gene Synthesis Consortium (IGSC), an industry group that voluntarily screens every order (whether domestic or international) with the stricter Australia Group requirements. IGSC members also screen their customers to verify that they are legitimate researchers.

The California proposal

Proposed California bill AB-80 would have legally required all commercial gene synthesis providers in the state to screen all orders and customers at least as strictly as current IGSC protocols require. It also required that all entities that used state resources would be required to purchase their genes from providers that screened orders in such a manner.

In their 10/05/2021 veto message, the California governor noted that the proposed State Health Department-based implementation structure was not viable and that a state-based approach did not seem to be the best fit for “an issue of international magnitude”.