Kevin M. Esvelt

Biosafety level (BSL) classifications of biological agents have succeeded at minimizing occupational risk inside laboratories, but largely neglect the potential for onward transmission. As a result, many non- transmissible pathogens that could kill at most one individual per person exposed require greater containment than 1918 influenza, a virus that killed 50-100 million and might cause a new pandemic today. Laboratory workers are consenting professionals; the public is not. We recommend complementing BSLs with explicit thresholds for expected societal harm. Here we formalize Societal Safety Levels (SSLs) based on expected public fatalities per year, which we quantify from (i) estimated probability of laboratory release, (ii) likelihood of societal transmission, and (iii) consequence. SSLs would apply specifically to laboratory research with replication-competent potential pandemic pathogens, and would not restrict field surveillance, sequencing, or countermeasure development using non-replicating systems or pandemic-incapable agents. We find that applying the 0.1 expected deaths per facility-year standard common across multiple major-hazard industries to potential pandemic pathogen research would require marked safety improvements. Complementing BSLs with SSLs would establish enforceable accident- safety thresholds for pandemic-capable pathogens, bringing high-risk biological research into alignment with the quantitative safety standards that help other hazardous industries operate with public acceptance.

Heritable immunization is a promising approach to controlling infectious diseases by embedding immunity directly into the genomes of wild species that spread human pathogens. Here, we report the genetic engineering of Mus musculus to genomically encode a single-chain antibody against Borrelia burgdorferi , the causative agent of Lyme disease. After optimization of the antibody format, engineered mice stably produce a LA-2 scFv-albumin fusion protein targeting the Borrelia outer surface protein A (OspA) across multiple generations, demonstrating robust heritability and stability of gene expression. Following sequential challenges with infected and uninfected ticks, heterozygous mice exhibit strong resistance to infection, effectively interrupting the Borrelia burgdorferi disease transmission cycle. Having recently established protocols to genetically engineer the white-footed mouse Peromyscus leucopus , a key reservoir of Lyme disease, these findings demonstrate the feasibility of heritable immunization as a potential strategy for mitigating Lyme disease transmission in the environment. Engineered reservoir immunity may offer a promising approach to controlling vector-borne and zoonotic disease.

Printing custom DNA sequences is essential to scientific and biomedical research, but the technology can be used to manufacture plagues as well as cures. Just as ink printers recognize and reject attempts to counterfeit money, DNA synthesizers and assemblers should deny unauthorized requests to make viral DNA that could be misused. There are three complications. First, we do not need to quickly update printers to deal with newly discovered currencies, whereas we regularly learn of new potential pandemic viruses and other biological threats. Second, convincing counterfeit bills cannot be printed in small pieces and taped together, while preventing the distributed synthesis and subsequent re-assembly of controlled sequences will require tracking which DNA fragments have been ordered across all providers and benchtop devices while protecting legitimate customer privacy. Finally, counterfeiting can at worst undermine faith in currency, whereas unauthorized DNA synthesis could be used to deliberately cause pandemics. Here we describe SecureDNA, a free, privacy-preserving and fully automated system capable of verifiably screening all DNA synthesis orders of 30+ nucleotides against an up-to-date database of controlled sequences, and its operational performance and specificity when applied to 67 million nucleotides of DNA synthesized by providers in the USA, Europe and China.

Emerging infectious diseases often circulate undetected until they cause clinical illness, leaving surveillance systems reactive rather than anticipatory. The U.S. blood supply, with millions of whole-blood and plasma donations annually, offers an underutilized national resource for proactive pathogen surveillance. We propose integrating metagenomic sequencing (MGS) into existing blood collection and testing workflows to detect known and novel viruses in residual samples within days of collection. Unlike current blood screening, which targets a limited set of predefined pathogens, MGS captures a broad range of viral threats, including blood- and vector-borne agents that produce asymptomatic viremia and may be missed by syndromic surveillance. Modeling suggests that an annual investment of $5.5 million could detect a novel HIV-like pathogen before it infects 0.01% of the U.S. population. Building on established donor monitoring, testing, and privacy infrastructure, blood supply sequencing represents a deployment-ready opportunity to strengthen national and global biosecurity.

Artificial intelligence now shapes the design of biological matter. Protein language models (pLMs), trained on millions of natural sequences, can predict, generate, and optimize functional proteins with minimal human input. When embedded in experimental pipelines, these systems enable closed-loop biological design at unprecedented speed. The same convergence that accelerates vaccine and therapeutic discovery, however, also creates new dual-use risks. We first map recent progress in using pLMs for fitness optimization across proteins, then critically assess how these approaches have been applied to viral evolution and how they intersect with laboratory workflows, including active learning and automation. Building on this analysis, we outline a capability-oriented framework for integrated AI–biology systems, identify evaluation challenges specific to biological outputs, and propose research directions for training- and inference-time safeguards.

U.S. select agent regulations ignore easily assembled DNA fragments, making synthesis screening ineffective regardless of accuracy. We acquired unregulated DNA collectively sufficient for a skilled individual to generate 1918 influenza from dozens of providers, demonstrating that fragments must be regulated as select agents.

CRISPR-based gene drives represent a powerful new technology for limiting disease transmission and controlling invasive populations. These systems rely on homology-directed repair (HDR) to ″drive″ a genetic element through a population. However, mammals tend to favor non-homologous end joining (NHEJ), which generates mutations that halt further drive propagation. Here, we describe the experimental characterization of a gene drive system targeting the haploinsufficient spermatogenesis gene KLHL10 in the laboratory mouse. Using a newly designed ″coding sequence cassette″ we introduce downstream guide RNAs within the gene, ensuring that sperm undergoing NHEJ are selectively removed from the population. As a proof of principle, we demonstrate that targeting KLHL10 with constitutively expressed LbCas12a results in strong selection against frameshift-containing sperm, validating the core purification mechanism required for this drive strategy. Unexpectedly, we also observed that female offspring lacked most frameshift mutations, suggesting a previously unrecognized role for KLHL10 in oogenesis or early embryonic development.