FEATURE ARTICLE

POINT OF VIEW Bioengineering horizon scan 2020

Abstract Horizon scanning is intended to identify the opportunities and threats associated with technological, regulatory and social change. In 2017 some of the present authors conducted a horizon scan for bioengineering (Wintle et al., 2017). Here we report the results of a new horizon scan that is based on inputs from a larger and more international group of 38 participants. The final list of 20 issues includes topics spanning from the political (the regulation of genomic data, increased philanthropic funding and malicious uses of neurochemicals) to the environmental (crops for changing climates and agricultural gene drives). The early identification of such issues is relevant to researchers, policy-makers and the wider public.

LUKEKEMP*,LAURAADAM,CHRISTIANRBOEHM,RAINERBREITLING, ROCCOCASAGRANDE,MALCOLMDANDO,APPOLINAIREDJIKENG, NICHOLASGEVANS,RICHARDHAMMOND,KELLYHILLS,LAURENAHOLT, TODDKUIKEN,ALEMKAMARKOTIC´ ,PIERSMILLETT,JOHNATHANANAPIER, CASSIDYNELSON,SEA´ NSO´ HE´ IGEARTAIGH,ANNEOSBOURN, MEGANJPALMER,NICOLAJPATRON,EDWARDPERELLO, WIBOOLPIYAWATTANAMETHA,VANESSARESTREPO-SCHILD,CLARISSARIOS- ROJAS,CATHERINERHODES,ANNAROESSING,DEBORAHSCOTT, PHILIPSHAPIRA,CHRISTOPHERSIMUNTALA,ROBERTDJSMITH, LALITHASSUNDARAM,ERIKOTAKANO,GWYNUTTMARK,BONNIECWINTLE, NADIABZAHRAANDWILLIAMJSUTHERLAND*

Introduction (Hanea et al., 2017), with some minor adjust- Bioengineering is expected to have profound ments (see Methods). We tasked our experts impacts on society in the near future as applica- with identifying ‘novel, plausible and high- tions increase across multiple areas, while costs impact’ issues in biological engineering, and *For correspondence: ltk27@cam. and barriers to access fall. The speed of this they produced a long list of 83 issues. Partici- ac.uk (LK); [email protected]. change and the breadth of the applications pants then scored the issues anonymously (with ac.uk (WJS) make the task of forecasting the impacts of bio- a score out of 1,000, reflecting likelihood, Competing interest: See engineering both urgent and difficult (Gus- impact and novelty), arriving at a short list of 41 page 15 ton, 2014). In 2017 we published the results of a issues to be discussed at a workshop. This was Funding: See page 15 ’horizon scan’ that looked at emerging issues in coupled with a ‘yes/no’ question to determine bioengineering (Wintle et al., 2017). Here we whether the issues were novel, based on Reviewing editor: Helena Pe´rez report the results of an updated horizon scan whether the experts had heard of the issue pre- Valle, eLife, United Kingdom based on a wider range of inputs (38 partici- viously. After deliberation, participants re-scored Copyright Kemp et al. This pants from six continents and 13 countries, com- these issues. The issues identified in the latest article is distributed under the pared with 27 participants from the UK and US horizon scan differ substantially from those iden- terms of the Creative Commons in the 2017 exercise) and a broader definition of tified in 2017. This change likely stems from an Attribution License, which permits unrestricted use and bioengineering. increase in the diversity of the participants, redistribution provided that the We followed the same structured ‘investigate, improvements in the methods used, a broader original author and source are discuss, estimate and aggregate’ (IDEA) proto- definition of bioengineering, and changes in the credited. col for identifying and prioritising issues research landscape since 2017.

Kemp et al. eLife 2020;9:e54489. DOI: https://doi.org/10.7554/eLife.54489 1 of 20 Feature Article Point of View Bioengineering horizon scan 2020

Since it was undertaken, there have been the basis for research roadmaps developments in a number of the issues identi- (Kennicutt et al., 2015). fied in the 2017 bioengineering horizon scan. In this article we provide a high-level sum- Human germline genome editing came to prom- mary of the top 20 issues identified in the bioen- inence in late 2019 when researcher He Jiankui gineering horizon scan 2020 (while announced the birth of two girls with CRISPR/ acknowledging that the number of topics cov- Cas9-edited genomes (Cyranoski, 2019). Mili- ered means that there will be some sacrifice of tary funding of bioengineering projects also depth for breadth). We take a broader view of remained substantial: for example, projects bioengineering than we did in 2017, defining it funded by DARPA included programs to explore as the application of ideas, principles and techni- the use bioelectronics for tissue repair and ques to the engineering of biological systems. regeneration (BETR) and to develop mosquito- This means that we now cover more aspects of repellent skin (ReVector). There have also been bioengineering, as well as issues that contribute to or result from bioengineering advances (such breakthroughs in the use of enhanced photosyn- as funding). To avoid giving a false sense of fore- thesis for agricultural productivity: a 2018 study casting precision or overemphasising minor dif- reported that metabolic engineering strategies ferences in scoring, the issues are not ranked, increased photosynthetic efficiency by 17%, and are instead grouped into issues that are which resulted in an increase of about 20% in expected to be most relevant within five years, biomass in field conditions (South et al., 2019). within 5–10 years, and on timescales of longer This technology is now being deployed in sev- than 10 years (Table 1). Our intent is to spur fur- eral crops. The use of ‘platform technologies to ther research into these issues and further dis- address emerging disease pandemics’, another cussion of their implications by researchers, topic identified in 2017, has taken on particular policy-makers and the wider public. significance as a result of the COVID-19 pan- demic. Many of the vaccine candidates for COVID-19 currently undergoing clinical and pre- The issues most relevant within clinical evaluation have been developed from five years platforms for non-coronavirus candidates such as influenza, SARs and Ebola (WHO, 2020). Access to biotechnology through Horizon scanning aims to build societal pre- outsourcing paredness by systematically identifying upcom- Traditionally, the biotechnology sector has had ing opportunities and threats from high barriers to entry, with organizations need- technological, regulatory and social change ing to build extensive physical and knowledge- based assets. New ’cloud labs’ and services labs (Sutherland and Woodroof, 2009). Horizon are circumventing this model by using technolo- scanning with the Delphi technique has a long gies such as robotics, automation and the inter- history. It has been used to identify emerging net to offer widely-accessible standardised critical issues in areas as diverse as conservation services with limited need for physical material biology (Sutherland et al., 2006; transfer (Jessop-Fabre and Sonnenschein, Sutherland et al., 2017), invasive species in the 2019). This facilitates both broader access and UK (Ricciardi et al., 2017), poverty reduction faster development of new products through the (Pretty et al., 2010) and biosecurity sharing of capital and knowledge across projects (Boddie et al., 2015). Periodic horizon scanning (Lentzos and Invernizzi, 2019). It is also helping is also undertaken in some areas: in global con- to empower non-traditional researchers by low- servation, for example, these scans have identi- ering the threshold for participating in cutting- fied issues such as micro-plastics, gene editing edge research. for invasive species, and cultivated meat approx- This distributed approach poses a biosecurity imately six years before they captured public gap as research activities are separated from attention (Sutherland et al., 2017). Horizon- intent: the cloud lab may not seek additional scanning activities related to the Antarctic and details on an experiment’s context, including Southern Ocean (Kennicutt et al., 2014) have why it is being performed. There is also a lack of also directed funding and policy appropriate biosecurity guidelines and gover- (Kennicutt et al., 2019), and helped to provide nance models to handle this (Palmer et al.,

Kemp et al. eLife 2020;9:e54489. DOI: https://doi.org/10.7554/eLife.54489 2 of 20 Feature Article Point of View Bioengineering horizon scan 2020

Table 1. Overview of the bioengineering horizon scan 2020. Summary of the 20 issues identified through the scan; issues are grouped according to likely timeline for realisation. <5 Years 5–10 Years >10 Years Access to biotechnology through Agricultural gene drives Bio-based production of materials outsourcing Crops for changing climates Neuronal probes Live plant dispensers of chemical expanding new sensory signals capabilities Function-based design in protein Distributed pharmaceutical Malicious use of advanced engineering development and neurochemistry manufacturing Philanthropy shapes bioscience Genetically engineered Enhancing carbon sequestration research agendas phage therapy State and international regulation Human genomics Porcine bioengineered of DNA database use converging with replacement organs computing technologies Microbiome engineering in The governance of cognitive agriculture enhancement Phytoremediation of contaminated soils Production of edible vaccines in plants The rise of personalised medicine such as cell therapies

2015; Dunlap and Pauwels, 2019). As outsourc- 2019). Technical progress is still required for ing through cloud labs becomes increasingly success in the field. However, deployment may prevalent in the next five years, these challenges be hindered by a comparative lack of funding may require the development of new guidelines for plant science, as well as lengthy and expen- and business and incentive models for responsi- sive regulatory regimes in most jurisdictions. ble innovation and biosecurity. New models for public-private co-operation will be needed to advance the translation of basic Crops for changing climates research through to the field, including business Climate change is predicted to result in more models that are not based on simple economic frequent droughts and intensive precipitation returns. The effects of novel traits on biodiversity events. This will increase soil salinity, elevate and ecosystems will require further scrutiny average temperatures, and shift the range, before being deployed in a warmer world. abundance and genotypic diversity of pollina- tors, pests and pathogens. All of these factors Function-based design in protein are expected to impact crop yields. In response, engineering efforts are intensifying to adapt food production Despite a growing understanding of the relation- using agro-ecological strategies (Altieri et al., ship between protein structure and function, 2015), as well as the provision of well-adapted efficient design of new proteins with a desired crop varieties by genetic engineering and new action has remained a laborious process. For breeding technologies (Dhankher and Foyer, example, chimeric antigen receptor (CAR) thy- 2018): Drought-tolerant genetically modified mus lymphocyte (T cell) therapies which combine (GM) plant varieties have reached the market functional protein moieties to activate T cells and more are in development (Nuccio et al., against malignant tumours have only recently 2018); the capabilities of plant immune recep- been approved for human use after decades of tors have been broadened by protein engineer- iteration (Feins et al., 2019). The convergence ing (De la Concepcion et al., 2019); and the of ongoing developments, including substantial identification of conserved submergence-acti- improvements in predicting protein structure vated genes has revealed novel genetic targets from amino acid sequences using machine learn- for enhancing flood tolerance (Reynoso et al., ing (AlQuraishi, 2019; Yang et al., 2019a),

Kemp et al. eLife 2020;9:e54489. DOI: https://doi.org/10.7554/eLife.54489 3 of 20 Feature Article Point of View Bioengineering horizon scan 2020 could overcome previous technical and compu- State and international regulation of tational challenges. This indicates a potential deoxyribonucleic acid (DNA) database use revolution in function-based protein design, Personal genomic sequencing continues to drop leading to various useful industrial compounds in price and increase in accessibility. The inher- (such as the development of catalysts for any ent inability to truly anonymise such data, cou- desired organic reaction) and medical applica- pled with the wealth of information it provides tions (such as the ability to selectively destroy, on both individuals and families, distinguishes it suppress or stimulate any malfunctioning tissue, from conventional data types such as finger- which is the key to treating many refractory dis- prints (identifiable but uninformative) or shop- eases). However, as this field grows so will the ping habits (Finnegan and Hall, 2017). The risk of deliberate misuse. Protein engineering drop in price and the use of technologies such could be used to produce agents that have a as cloud storage have allowed wider use of DNA higher lethality or specificity than existing agents databases by different actors. While the vulnera- (including new agents based on novel mecha- bility of cloud infrastructure is a concern, there is nisms of action). Protein engineering might also greater potential for misuse by states and law enforcement in the name of security. This has simplify the production of toxins currently been seen in efforts to target Muslim Uighurs in derived from natural sources. China via blood samples (Wee, 2019), and in a Philanthropy shapes bioscience research consumer genetics database allowing the Fed- agendas eral Bureau of Investigation in the US to com- pare genetic data from crime scenes to a Over the past decade, philanthropic funding database of over two million profiles without (including venture philanthropy) of research and customer consent (Haag, 2019). The potential innovation has been increasing (Coutts, 2019; to accrue and analyse vast amounts of genomic Depecker et al., 2018). This has largely been information raises concerns over privacy, espe- driven by the increasing concentration of wealth, cially mass surveillance (Solove, 2011); the and erosion of public health and scientific potential expansion of state surveillance powers research initiatives within key countries. These necessitates dialogue and policy intervention investments can provide particular research domestically and internationally. groups or areas with substantial funding over prolonged periods of time, and they can also support areas of research that are not usually Issues most relevant in 5–10 years funded by governments. Philanthropic invest- ments can also promote innovation, such as Agricultural gene drives allowing for more exotic approaches not usually Gene drives were initially proposed for the con- funded by governments. However, these invest- trol of insect vectors for human diseases (Gantz et al., 2015; Neve, 2018), but recent ments might also influence the development of work suggest that they could provide major eco- biotechnologies in a way that has less of a public nomic benefits to the agricultural sector (Col- mandate than government-funded research. lins, 2018; Neve, 2018). However, while there is Philanthropic investments also operate without potential for gene drives to eliminate or sup- the traditional mechanisms for accountability, press pest species, their widespread uptake and transparency or oversight often required by fed- use could lead to problems in their application eral or state law (Reich, 2018). Some areas of and governance (Evans and Palmer, 2018). One medical research are already considerably concern is that commercial interests will seek to underfunded compared to health needs maintain sales of agrochemicals by configuring (Rafols and Yegros, 2018), and philanthropic gene drives to reduce chemical resistance in tar- investments may exacerbate this discrepancy in get pest insects and weeds as opposed to caus- the near-term future. Significant investment into ing sterility in those species. A second concern is a small range of actors could also undermine that unilateral deployment of gene drives may diversity, particularly at the international level cause rapid and unintended ecosystem pertur- (Lentzos, 2019). A possible response would be bations without proper oversight or recall. There partnerships between public and private invest- have also been questions around their control ors, though such partnerships might not fully and the lack of public consultation (or participa- address concerns about accountability, transpar- tion) regarding their release, as well as legal ency or oversight. implications if populations are eliminated within,

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or new gene configurations are carried to, native research and development (Munos, 2010; locations (Montenegro de Wit, 2019). Efforts Gassmann et al., 2018; Open Source Pharma, are already underway to counter, control and 2020). That itself may shape regulatory frame- even reverse the undesired effects of genome works, and may provide new open or distributed editing, including DARPA’s Safe Genes program models for drug manufacturing. However, in the (Wegrzyn, 2019). Policy-makers will need to be absence of appropriate norms or regulations vigilant to more problematic applications as (Blum, 2010), it may also lead to the agricultural gene drives become more prevalent. manufacturing, at scale, of drugs that are not vetted for safety, or administered under appro- Neuronal probes expanding new sensory priate clinical guidance (Coleman and Zilinskas, capabilities 2010). New research into creating probes that mimic neurons could enable novel medicinal and Genetically engineered phage therapy enhancement applications such as the creation The World Health Organization (WHO) recently of new sensory capabilities. Traditionally, neuro- reported a worrying lack of new antibiotics to nal probes have both structural and mechanical address the dangerous trends of rising resis- dissimilarities from their neuron targets, leading tance to existing antibiotics (WHO, 2015), and to neuro-inflammatory responses. However, it is antimicrobial resistance has been identified as a now possible to fabricate neuron-like electronic potential global catastrophic risk. Phage therapy probes (with widths similar to those of neurons) has recently seen a renaissance as a potential and unobtrusively fuse them with live neurons alternative to antibiotic treatment. In particular, (Yang et al., 2019b). Potentially, the technology the ability to rapidly engineer phage sequences could be used to add new sensory capabilities and phage cocktails opens up the prospect of by implanting neuronal probe arrays as a visual personalised treatments for tackling genetically- cortical prosthesis system. However, such biomi- diverse infections and overcoming problems of metic sensory probes could introduce unin- antimicrobial resistance (Schmidt, 2019). The tended vulnerabilities, from a risk of malicious technical advances observed in the medical attack via the internet to possible mass monitor- application of phage therapy will also have an ing of implanted civilians by law enforcement impact on other uses of phages as delivery sys- (Yetisen, 2018). tems in biotechnology. Efforts have also been significantly buoyed by the development of eas- Distributed pharmaceutical development ier methods for engineering phages to combat and manufacturing the inevitable evolution of phage resistance in Outsourcing and increasingly lower barriers to bacteria (Pires et al., 2016). However, barriers access in bioengineering are allowing for greater to widespread commercial use persist, including localisation and geographical distribution of the high costs, instability of the medication, the manufacturing and development of pharmaceut- need to type the infection (instead of giving a icals. Bioengineering offers the capacity to cre- broad-spectrum pill) and immunogenicity. This ate pharmaceutical compounds or their makes it more likely for phage therapy to be precursors by genetically modifying organisms used as a last resort once other treatments have to produce them. The prospect of non-tradi- failed. tional pharmaceutical manufacture has gained some traction, but with few tangible results. Bar- Human genomics converging with riers to distributed pharmaceutical manufactur- computing technologies ing becoming broadly adopted include the scale Human genomics is increasingly incorporating of production required for individual or commu- technologies such as blockchain, cloud comput- nity use; meeting appropriate safety standards ing and machine learning. Firms such as Amazon for manufacturing and administration; and inter- and Google offer cloud computing-based stor- facing with drug approval pathways. Efforts in age and data analytics services for the petabytes non-traditional pharma, such as The Open Insulin of genetic data stored online, while companies Project (Gallegos et al., 2018), are rising in pro- such as Encrypgen and Nebula use blockchain in file and will likely continue, whether individual systems that reward individuals for sharing their projects are successful or not. This is supported genetic data. Artificial intelligence and machine by the Open Pharma movement which seeks to learning are enabling deep analysis of thousands empower innovation through open-access of molecules with potential to become future

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drugs (Japsen, 2016), as well as human genomic their introduction to and implications for the data (iCarbonX, 2018). Most recently, deep environment. Certain plant species have natural learning used molecular structure to predict the mechanisms that enable both uptake and toler- efficacy of antibiotic candidates (Stokes et al., ance of natural and anthropogenic inorganic pol- 2020). Some uses of these technologies could lutants. Identifying, expressing and potentially help address current privacy concerns. This engineering these traits is receiving increased includes the use of blockchain as well as ’secret research interest. Preliminary work on transgenic sharing’ techniques in which sensitive informa- plants in the lab by overexpression of metal tion is divided across multiple servers ligands, transporters and specific enzymes has (Cho et al., 2018). However, as they are applied led to successful phytoextractions of pollutants to human genomic data in increasingly powerful including explosives and heavy metals. However, and connected ways, additional ethical issues few experiments have been conducted in the will arise. Enlivened and global discussion on field on contaminated soils (Fasani et al., 2018), how best to handle societal implications will where toxicity of various pollutants and the become necessary (Yakubu et al., 2018). impact of various environmental factors on the plant-microbiome interaction has limited the Microbiome engineering in agriculture success of phytoremediation to date. Realising Progress on microbiome engineering and geno- biotechnological phytoremediation will depend mic sequencing could allow for beneficial new on a number of factors: a more robust systemic understanding of plant-microbiome interactions applications in agriculture, but also risks. Micro- with pollutants (Basu et al., 2018); the surviv- biome engineering and the development of syn- ability of these engineered organisms in the thetic microbiomes offer wide-ranging uses for environment; understanding and controlling mammalian health as well as plant and animal environmental impacts; and robust societal dis- productivity, soil health and disease manage- cussion and carefully designed regulatory ment. A bottom-up approach to microbiome regimes. engineering aims to predictably alter micro- biome properties and design functions for agri- Production of edible vaccines in plants cultural and therapeutic applications. Plants offer a scalable low-cost platform for Microbiome engineering strategies could pro- recombinant vaccine production (Merlin et al., vide alternatives to the use of antibiotics for live- 2017). The introduction of the oral polio vaccine stock management (Broaders et al., 2013). in the 1960s led to huge interest in developing These approaches offer the potential for innova- vaccines that can be delivered without the need tive, sustainable pathways for plant disease sup- for injection. Given that plants are widely con- pression by engineering the microbiomes sumed, they offer an attractive means of vaccine indigenous to agricultural soils (Foo et al., delivery. Plant-expressed antibodies can protect 2017). Advances in genome sequencing, meta- against tooth decay. Similarly, expression of nor- genomics and synthetic biology have already ovirus-like particles in transgenic potatoes could provided a theoretical framework for construct- raise antibodies against the virus when the mate- ing synthetic microbiomes with novel functionali- rial is consumed (Tacket et al., 2000). Plant-pro- ties. New methods, such as in situ mammalian duced vaccines have also been developed for gut microbiome engineering, could help to over- some animal diseases (Marsian et al., 2019). come existing limitations and offer new capabili- Oral delivery with minimal processing has the ties for the future (Ronda et al., 2019). These potential to reduce requirements for extensive new methods and advances can support better frameworks for production, purification, sterilisa- design of microbiome modulation strategies in tion, packaging and distribution. A major chal- mammalian health and agricultural productivity. lenge is the need for improvement of the Yet, the engineering of agricultural microbiomes chemical and physical stability of vaccines during on a large scale could also create vulnerabilities transit through the gut in order to ensure effi- towards malicious intervention. cacy (Berardi et al., 2018). Also, commercialisa- tion may be difficult under current regulatory Phytoremediation of contaminated soils regimes (Merlin et al., 2017). Moreover, if pro- Research in phytoremediation is leading to the duction is scaled up beyond contained green- creation of engineered plants that could help houses, this will require the deliberate recuperate contaminated soils, but further field environmental (field) release of plants engi- trials are needed along with discussions about neered to contain vaccines.

Kemp et al. eLife 2020;9:e54489. DOI: https://doi.org/10.7554/eLife.54489 6 of 20 Feature Article Point of View Bioengineering horizon scan 2020 The rise of personalised medicine such as existing methods, attention is still required in cell therapies addressing specific impacts on feedstocks, There is an accelerating trend towards the devel- energy, water and other environmental and soci- opment and approval of personalised therapeu- etal factors (Matthews et al., 2019). This is tics. These are medical treatments that are accompanied by technical barriers in product tailored towards individuals, accounting for their processing. While some bio-based materials are likely response based on genomic and epige- already on the market, significant private invest- netic data. In the US in 2018, 42% of all new ment and supportive public policy frameworks drug approvals by the Food and Drugs Adminis- (including but not limited to carbon pricing, as tration concerned these treatments well as more speculative nitrogen pricing) will be (PMC, 2019). However, significant challenges required over the next decade and beyond to stand in the way of developing and deploying accelerate the widespread worldwide transition personalised medicine and cell therapies. These to these materials (HM Government, 2018). includes issues of delivery logistics and cost. The key factor to clinical adoption of personalised Live plant dispensers of chemical signals medicine is the value recognition by all health- Plants emit volatile signals that can activate care stakeholders. Most personalised medicines defence responses in other nearby plants. The are genetically guided interventions that address concept of using GM plants to deliver these sig- relatively small subsets of patients with rare nals has made practical progress in recent years. genetic mutations. The treatment approaches These genetically modified plants are intended are sometimes costlier due to their increased to be helpers that protect surrounding conven- sophistication and lower demand. Once these tional crops that are cultivated for consumption. barriers are overcome there will be some poten- Field trials have evaluated the potential of trans- tial problems that will need to be mitigated via genic wheat to repel different pests and virus policy. One is ensuring equitable access. Reim- vectors (Bruce et al., 2015). Despite excellent bursement from third-party payers such as results in the lab, in planta synthesis of the alarm health insurance companies is also likely to pheromone failed to reduce aphid numbers. become an issue for targeted treatments Other studies have demonstrated the feasibility (Bilkey et al., 2019; Genetics Home Reference, of making insect sex pheromones to trap male 2019). Public health policy must adapt to this insects (Ding et al., 2014). Further finessing of new frontier of healthcare while addressing its the pheromone blend may be enabled by syn- potentially detrimental effects on equality of thetic biology. This could open up the possibility healthcare access and treatment. of using plants as chemical-producing green fac- tories, or field-based disruptors and dispersers of insect pests. Unlike current GM solutions for The issues most relevant in 10 protection from insect herbivory, the use of years or more pheromones is a non-lethal and less-persistent Bio-based production of materials intervention, and chemically-manufactured pher- Biological engineering and production methods omones have been in use for many years. Ques- facilitate the transformation of renewable plant tions remain as to whether the broader adoption feedstocks and microorganisms into substitutes of pheromones will simply displace pests to for a wide range of existing and new materials, unprotected crops. including plastics and other materials that are produced from fossil fuels Malicious use of advanced neurochemistry (European Commission, 2017). These develop- Agents that could attack the central nervous sys- ments are being driven by increasing govern- tem were investigated during the Cold War but ment, private and civil society efforts to lack of knowledge only permitted the develop- decarbonise economies. New opportunities may ment of sedating agents. Concerns over such be created for small, bio-based production facili- agents and manipulations continues ties and clean bio-refineries to be located close (Ward, 2019), but could be empowered through to the markets for these materials, potentially advances in neuroscience and other fields. A replacing much of the petrochemical sector, and driving force in these advances is significant gov- there are potential roles for rural areas in grow- ernment interest and investments, including an ing bio-based feedstocks. While bio-based pro- investment of almost $1bn by the US govern- duction promises to be more sustainable than ment in the Brain Initiative (NIH, 2019).

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Resulting drugs and nootropics offer health ben- endogenous retroviruses, which otherwise pose efits, but could also be maliciously used a risk of cross-species transmission (Niu et al., (Nixdorff et al., 2018). Governments could use 2017). Such advances hold promise as one tech- neuro-chemicals to make a populace more sub- nological way to address the global shortage of servient. Advanced applications in undeclared transplant organs. Over 6,500 patients died biological warfare could include fostering emo- while on waiting lists in the USA alone in 2017 tional resentment in a targeted population. (UNOS, 2019). Several challenges remain, These drugs could be appealing to governments including engineering sufficient immune compat- around the world as a tool for counter-insur- ibility in the organs for successful human trans- gency or non-lethal law enforcement. The use of plantation, and determining the expected these new chemicals for law enforcement and in lifespan of the porcine organs in humans. There non-traditional conflicts may greatly erode the are differing views over the acceptability of por- norms against chemical agent use on the battle- cine xenotransplantation within major religions, field, threatening the Chemical Weapons Con- such as Islam and Judaism (Nuffield Council on vention in the long term. Bioethics, 1996). Before commercial develop- ment, consideration must be given to questions Enhancing carbon sequestration surrounding the ethics of using animals for trans- Metabolic engineering manipulates cells to pro- plantation, cost and access, and using a techni- duce target molecules by optimising endoge- cal solution for an essentially social problem that nous metabolic pathways or by reconstructing could be addressed through other approaches, these pathways in alternative species. ’Next such as opt-out organ donation schemes. level’ metabolic engineering aims to design met- abolic networks de novo, thus bypassing the The governance of cognitive enhancement bottlenecks and inefficiencies of evolution Cognitive enhancement is already a widely (Erb, 2019). Thus far, experimental success is embraced idea throughout society – caffeine is lacking. However, recent research in photosyn- the most widely consumed drug on earth. Novel thesis may be promising, and examples include methods of cognitive enhancement such as noo- engineering a new molecule to perform a tropics, wakefulness enhancers, or the potential designed synthetic photorespiration bypass to directly modulate brain function through (Trudeau et al., 2018) and developing an opti- implants or biotechnology are emerging. Uptake mised carbon dioxide fixation pathway using of these is being driven by both a productivity- enzymes from bacteria, archaea, plants and focused culture, commercial opportunities and humans (Schwander et al., 2016). Other meth- increased understanding of neurochemistry. ods have included laboratory evolution of a bac- Although some cognitive enhancers require pre- terium able to use CO2 for growth (Gleizer et al., 2019). These approaches hold scriptions, others only have to meet basic safety potential for more efficient carbon sequestration guidelines and are available to purchase online. and biomass production, as well as for advanc- While numerous trials have supported the safety ing the development of photovoltaics (the pro- of most nootropics and wakefulness enhancers, duction of electricity from light) and light- there are few long-term longitudinal studies sustained biomanufacturing. Yet, such develop- (Fond et al., 2015). A large section of those ments remain speculative. There are still signifi- who have embraced cognitive enhancement – cant technical challenges to overcome, and a the ’do-it-yourself’ experimenters – may also be long path to widespread commercial deploy- ignored by the research community. Lax regula- ment. Moreover, the field will need to engage tion around safety standards for these products with its socio-political, ethical and environmental and tools has led to calls to tighten regulatory dimensions. loopholes, and for academic researchers to part- ner with and include communities in research on Porcine bioengineered replacement organs cognitive enhancers (Wexler, 2017). Regulatory Pigs represent a promising candidate species for frameworks are necessary to both minimise risks production of human-compatible replacement and gather long-term safety data from end- organs for xenotransplantation. A recent users, as well as to provide health and safety advance in porcine genome editing using guidance for international trade of cognitive CRISPR/Cas9 addresses one of the key scientific enhancing drugs and devices (Maslen et al., challenges: successful inactivation of porcine 2015).

Kemp et al. eLife 2020;9:e54489. DOI: https://doi.org/10.7554/eLife.54489 8 of 20 Feature Article Point of View Bioengineering horizon scan 2020 Discussion deployment of GMOs and are now prominent in discussions around gene drives (Evans et al., Emergent themes 2019). Such concerns also factored into many of Seven underlying themes emerged from the the issues we have identified, most notably edi- workshop discussion: 1) political economy and ble vaccines and live plant dispensers. Further funding; 2) ethical and regulatory frameworks; 3) development of bioengineered products will climate change; 4) transitioning from lab to field; require appropriate regulation. Additionally, the 5) inequalities; 6) technological convergence; necessary social, environmental and human and 7) misuse of technology. None of these health risk assessments need to take place to were judged precise enough to qualify as hori- transition bioengineering from the lab into the zon-scanning items, although some sub-compo- wider world. nents were. These themes represent underlying A fifth theme is the potential for bioengineer- commonalities and drivers across issues. ing to exacerbate existing inequalities in wealth First, participants expressed concern about and health. This factored into several issues the political economy of bioengineering (that is, including the rise of personalised medicine, how political and economic institutions influence replacement organs, and the regulation of cog- bioengineering, including the role of regulation nitive enhancement. In contrast, distributed and politics) and, related to this, about funding. pharmaceutical development and manufacturing These concerns centred around a view that was an emerging area fuelled in part by the research funded by the military, industry or phi- desire to deliver more equitable, cheap and lanthropy was less accountable than civilian gov- accessible medicine. Ensuring that the benefits ernment-funded research and could create real of bioengineering are spread fairly and widely or perceived conflicts of interest (see, for exam- will be a defining feature of future debates. ple, Licurse et al., 2010). Enhancements also come with risks, especially at Second, a recurring theme across several the earliest stages. Many of these are expected issues was the need for ethics and better regula- to be borne by unwilling or uninformed recipi- tory frameworks to manage the problems ents (as in the case of the CRISPR twins) before expected to emerge from technologies on the being marketed to the wealthy. These problems horizon. This was true for most issues of inequality also highlight the need for horizon- highlighted in the scan, ranging from carbon scanning efforts to make efforts to include rep- sequestration to bioengineered replacement resentatives from more oppressed and marginal- organs. This underscores the need for greater ised groups. engagement between ethicists, social scientists, The sixth theme is that the convergence of policy-makers and the cutting-edge of different technologies will be crucial in the future bioengineering. development of bioengineering. Many of the Third, climate change is likely to be a critical issues in this horizon scan are driven by progress driver of bioengineering in the future. Our list in adjacent fields. Both neuronal probes and includes an application to both adaptation malicious uses of neurochemistry will be enabled (crops for changing climates) and negative emis- by progress in neuroscience, and the overlap of sions (sequestration). Others, such as live plant human genomics with computing technologies dispensers, could be boosted in relevance as a brings both opportunities and threats. As auto- way to enhance agricultural productivity in the mation and measurement, neuroscience, chemis- face of detrimental climate impacts. Progress in try and artificial intelligence continue, they will climate policies will shape the development and shape both what is possible and what is pursued demand of bioengineering technologies. Cli- in bioengineering. This poses a challenge for mate change impacts will also create new prob- regulators, who may need to think about policy lems that could be addressed through that cuts across bioengineering into other areas, bioengineering and policy. This includes changes such as cybersecurity. It also highlights a need in the range of vector-borne diseases, such as for continued horizon scanning and foresight the expansion of tropical infectious diseases. exercises to engage a broad range of technolog- A fourth theme is that of transitioning from ical expertise so that key points of intersection lab to field. The deliberate release of a new bio- and convergence are not overlooked. engineering product into the environment Last, our scan highlights ongoing concerns entails risks in both practice and perception. around the misuse of technology by state or Concerns over the unintended consequences of non-state actors. Examples included various bio- environmental release have hindered the weapons and the misuse of DNA databases.

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Table 2. Overview of the bioengineering horizon scan 2017. Summary of the 20 issues identified in 2017; issues are grouped according to likely timeline for realisation. <5Years 5–10 Years >10 Years Artificial photosynthesis and Regenerative medicine: 3D New makers disrupt carbon capture for producing printing body parts and pharmaceutical makers biofuels tissue engineering Enhanced photosynthesis for Microbiome-based Platform technologies to address agricultural productivity therapies emerging disease pandemics New approaches to synthetic Producing vaccines and Challenges to Taxonomy-Based gene drives human therapeutics in description and management of plants biological risk Human genome editing Manufacturing illegal drugs Shifting ownership models in using engineered biotechnology organisms Accelerating defense agency Reassigning codons as Securing the critical infrastructure research in biological engineering genetic firewalls needed to deliver the bioeconomy Rise of automated tools for biological design, test and optimisation Biology as information science: impacts on global governance Intersection of information security and bio- automation Effects of the Nagoya Protocol on biological engineering Corporate espionage and biocrime

The 2017 scan noted themes of equality, bio- and political economy in the 2020 exercise. This informatics and regulation, all of which feature reflects the significant deviation in issues prominently in the 2020 scan (see Table 2 for a between the two studies. summary of the previous scan). The 2017 exer- Some issues from 2017 also appear in the cise discussed the intersection between biotech- 2020 exercise in a slightly altered form: concerns nology and information and digital technologies. about the military use of bioengineering are now Technological convergence also features in the more specific (for example, ‘Malicious use of present scan, but with a broader scope encom- advanced neurochemistry’), and there are new passing neuroscience (adding new sensory capa- concerns about the misuse of DNA databases. bilities) and neurochemistry (malicious uses of Both scans also focussed on different meth- advanced neurochemistry) as well as other fields. ods for the production of replacement organs. Both scans featured a strong emphasis on the The 2017 exercise identified 3D printing cells on potential for bioengineering to amplify or allevi- organ-shaped scaffolds, while the 2020 exercise ate inequalities. In the 2017 scan this included examined the potential for porcine genome the potential for human genomics to create new editing to allow for xenotransplantation. Finally, ’sociogenetic’ classes, while differences in both scans assessed the issue of pharmaceutical healthcare and access to cognitive enhancement manufacturing becoming increasingly distrib- were the flagship issues in this 2020 scan. The uted. The 2017 exercise focused on start-up thematic convergence between the two scans entrepreneurs and biohacking communities, demonstrates that many of the underlying trends whereas the 2020 exercise took a broader look in bioengineering include important structural at the possibility of decentralisation. issues involving ethics and regulation. These will The differences between the scans are likely likely influence the field for years to come. There due to three reasons. First, we used a wider defi- were also several differences in themes, includ- nition of bioengineering which encompassed ing the greater importance of climate change issues such as biomechanical implants. Two of

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the issues identified in this scan would not have under future triennial iterations, and by clearly been covered by the 2017 definition: neuronal describing the methods used, have made the probes expanding new sensory capabilities and process open for uptake by others. the governance of cognitive enhancement. Sec- Future pathways for forecasting bioengineer- ond, half of the participants (19/38) were not ing issues are manifold. Further updates of this involved in the 2017 scan; the new participants scan could be paired with systematic reviews of were also more geographically diverse (see their accuracy and efficacy, as well as deeper Methods), and included a higher proportion of dives into the issues that have been identified. social scientists. Third, there have been signifi- Extensions of the horizon-scanning process cant changes in research and the world at large. could include: focusing on specific areas of bio- For example, all the research underpinning the engineering, such as catastrophic risks; incorpo- issue of neuronal probes has occurred in the last rating decision-support tools such as fault-trees; three years. Similarly, recent research in climate examining the development of bioengineering change has highlighted the continued increase issues in tandem with overlapping technological in emissions and warming (Friedlingstein et al., areas such as artificial intelligence; and produc- 2019), and that tipping points are more proba- ing a policy-focused scan which involves greater ble than previously expected (Steffen et al., engagement with regulators. 2018; Lenton et al., 2019).

Limitations and ways forward Methods While useful, horizon scanning has its limits. Cri- Our study made use of the Investigate Discuss tiques have suggested that the Delphi technique Estimate Aggregate (IDEA) protocol. In this pro- (of which the IDEA protocol is a relatively recent cess, participants were asked to investigate and evolution) can give unjustified confidence in submit candidate issues, privately and anony- results that are essentially the subjective judge- mously score the gathered issues, and discuss ments of experts (Sackman, 1975). However, in their thinking with others. They then provided a the absence of data, expert elicitation is war- second score which was mathematically aggre- ranted, and structured approaches such as Del- gated (Hanea et al., 2018a). The element of dis- phi and the IDEA protocol have been found to cussion is powerful, as the sharing of information improve group judgement and outperform other between participants has been shown to forecasting methods, such as prediction markets improve the accuracy of Delphi-style forecasts (Hanea et al., 2017). While it is difficult to evalu- (Hanea et al., 2018b). The IDEA protocol has ate the efficacy of the Delphi technique due to also performed well relative to prediction mar- inconsistencies in its application (de Loe¨ et al., kets in early studies (Hanea et al., 2017). 2016), those that do exist are promising. A Despite being a relatively recent evolution of the review of a long-term Delphi in predicting devel- Delphi technique, the IDEA protocol has already opments in the health sector found that results been successfully applied to a range of areas were accurate in 14/18 identified issues including natural resource management (Parente and Anderson-Parente, 2011). The (Hemming et al., 2018) and assessing pollinator method continues to show significant utility in abundance in response to environmental pres- both accurately sighting emerging develop- sures (Barons et al., 2018). Aside from seeking ments and exploring the implications of poten- a shared understanding of terms and reducing tial issues on the horizon. linguistic ambiguity, consensus is not sought We acknowledge that the issues identified in during discussion and scores are kept anony- this horizon scan are ultimately representative of mous during both rounds. This is done to avoid the participants involved. While the 2020 scan is undesirable group dynamics and peer pressure an improvement on previous efforts in terms of distorting individual judgements. Our use of the diversity, the majority of respondents were still IDEA protocol can be split into three phases: i) from a developed economy background. The recruitment and issue gathering; ii) initial scor- scan did capture a large cross-section of aca- ing; and iii) workshop preparation, deliberation demic sub-fields in bioengineering, but under- and re-scoring. represented industry, communities and policy- makers. Moreover, we achieved a rough gender Phase one: recruitment and issue gathering balance with 21 male participants (55%) and 17 Our study drew on a group of 38 participants female participants (45%). We intend to make from six continents. Participants came from the process increasingly global and diverse countries including the UK, US, Canada,

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Australia, Germany, Croatia, Thailand, France, participant’s issues scores. Z-scores are created Chile, Peru, Switzerland, Malaysia, Zambia and by subtracting the mean and dividing by the Pakistan. Recruitment was done via a panel of standard deviation for each issue against the six initial experts (EP, PM, SO´ hE´ , CR-R, CR, LS participant’s set. This ensures that variations in and BW). The panel aimed to ensure a balance the range of participants’ scoring is accounted across areas such as plant sciences, medicine, for. We then ranked the average z-scores across bioindustry and biosecurity. They also sought to the issues and selected the highest ranked 41 have a mix of approximately half new partici- (approximately cutting the long list in half). pants and half participants from the 2017 exer- We discussed two potential reforms on the cise scan. Selected bioengineering scholars and previous scoring approach: breaking scoring practitioners were asked to submit two to five down across the three criteria, and including issues each. Our initial request was for issues uncertainty estimates. We decided against both that were ‘novel, plausible and high-impact’. We potential reforms. Experts are poor at estimating asked participants to provide issues that were at their own uncertainty and this could incentivise a specific level of granularity. As with the previ- overconfidence. We decided that greater disag- ous scan we asked participants not to focus on a gregation in voting was likely to impose a general topic, such as ’gain of function’ research, greater burden on participants while providing nor on multiple topics simultaneously. Instead little additional benefit. Moreover, keeping the they were guided to focus on one area within a protocol similar to the 2017 scan was desirable general topic and its implications, such as an for comparison. emerging regulatory change for GMOs. After One amendment was made to the previous duplicates were merged, a long list of 83 issues horizon-scanning methodology: the introduction was generated from the initial submissions. This of ’devil’s advocates’ into the process. included 10 merged issues. Goodwin and Wright, 2010 have noted that most forecasting methods are inadequate for Phase two: scoring identifying high-impact, low-probability events Participants were asked to vote on the ’suitabil- (some times called ’black swan events’). How- ity’ of these issues. This involved assigning a ever, the Delphi technique can be better suited score of 0–1,000 to each of the issues. Partici- to the task if it includes devil’s advocates who pants were asked to ensure that each score was can advocate for less likely but significant issues. unique (no identical scores within a given score- We empowered two individuals during the first sheet). The suitability scores reflected a combi- phase of the process to propose more specula- nation of plausibility, novelty and impact. Nov- tive and transformative issues. Two different par- elty was also captured by respondents noting ticipants were then asked during the third phase whether they had heard of the issue previously (workshop deliberation) to provide more critical (through a ’yes/no’ response). We then calcu- inputs and actively push against the prevailing, lated the percentage of participants who had dominant view during discussions. In each case heard of each issue. These novelty scores were their designation was not revealed to the group. published alongside all issues in the short list. The devil’s advocates appear to have been a This was conducted by sending the participants useful addition and were disproportionately suc- both the long list of issues, along with a tem- cessful in suggesting issues. Six of the nine plate score-sheet and instructions. At this stage issues they proposed in the first round made it participants were reminded that "our aim is to through to the short list, and four of the six identify plausible, novel bioengineering-related issues they proposed in the second round made issues with important future implications for soci- it through to the final list of 20; with 38 partici- ety that are not too broad or already well pants, we would expect approximately only one known’. They were given approximately three issue for every second participant to make it weeks to complete their scoring. All anonymised through to the final list. 68% of participants had score-sheets are provided in Supplementary file heard of the issues proposed by the devil’s 1; this file also includes the z-scores of the top advocates, making these issues moderately 20 issues identified in the 2017 scan. Participants more novel than the rest. Overall, an average of were also able to provide comments on the dif- 70% of participants had heard of each issue. The ferent issues on the voting sheet. These critiques level of novelty of the issues suggested by dev- led to a further eight issues being merged into il’s advocates is partly skewed by two more well- four. Comments were kept to stimulate future known issues which both scored 82.35%. When discussion. We calculated the z-scores for each both of these issues were excluded, the devil’s

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Table 3. A comparative analysis of the groups involved with phases one and two, and phase three (the workshop). Characteristics Phases one and two Phase three (workshop) Sample Size 38 25 Gender 21 male participants (55%) and 17 female participants (45%) 13 females (52%) and 12 males (48%). Balance Geographical 13 countries (UK, US, Canada, Australia, Germany, Croatia, Thailand, 10 countries (UK, US, Canada, Australia, Germany, Croatia, Coverage France, Chile, Peru, Switzerland, Malaysia, Zambia and Pakistan) Thailand, France, Chile, Switzerland and Pakistan) Disciplinary 15 participants from humanities and social sciences (39%) and 23 from 9 participants from humanities and social sciences (36%) and Distribution natural sciences (61%) 16 from natural sciences (64%)

advocates suggestions were significantly more z-scores of the top and bottom 20 issues, but a novel at an average of 61%. much smaller spread of scores within the top 20. Participants were then given time to discuss the Phase three: workshop preparation, final list and whether any amendments were deliberation and re-scoring needed. The group was content with the spread The 41 issues with the highest scores were kept of the final list and that it accurately reflected as a part of a shortlist. These were sent back to the deliberations and hence decided that no participants on the 13th of September 2019. alterations were needed. Participants were assigned ’cynic’ roles for each A comparison of the rankings of the top 20 issue. This involved doing deeper background issues after the first and second round of scoring research into the topic. Each issue had at least can be found in Supplementary file 2. There two cynics, ensuring that at least three partici- was a noticeable difference between the two pants (the cynics and proposer) had an in-depth rankings. For example, 11 out of the final top 20 knowledge of the area. The workshop was held (55%) issues had been ranked outside of the top in Cambridge on the 9th of October 2019 with 20 during the first round of scoring. Indeed, four 25 participants; 13 could not attend due to other of the top five issues (80%) were outside the top obligations. This resulted in a group with 20 after the first round of scoring. This suggests approximately the same characteristics as the that deliberation was effective in shifting partici- group that was involved in he first two phases. pants’ perspectives and scores. The novelty The characteristics of both groups are compared scores are also summarised in in Table 3. Overall, the gender balance was Supplementary file 2. The final list of issues had maintained (although the slight skew was a slightly higher degree of novelty, but this was reversed towards female participants), the disci- minor. The short list of issues resulted in an aver- plinary split between social and physical scien- age score of 70.52% and a median of 73.53%. tists was approximately the same, and the By contrast the final list had an average of geographical coverage became less balanced 68.97% and a median of 67.75%. due to the loss of participants from Peru, Zambia and Malaysia. Acknowledgements These discussions were overseen by an expe- First and foremost we thank Clare Arnstein for rienced facilitator (WJS, with LK and AR acting her indispensable work in helping to organise as scribes) and followed a deliberate structure. the horizon-scanning process and workshop. We Each issue was discussed for approximately ten thank Andrew Balmer, George Church, Nick minutes before being voted on anonymously. Matthews, Robert Meckin, Penny Polson, Fate- During discussions, proposers of the issue were meh Salehi and Andrew Watkins for their asked not to speak until at least three other involvement in submitting issues. This project respondents had contributed. This was done to was made possible through the support of a avoid biasing the conversation and allowing the grant from Templeton World Charity Founda- cynics time to provide an orientating, more neu- tion. The opinions expressed in this publication tral intervention. The standardised z-scores for are those of the authors and do not necessarily each issue were calculated and ranked at the reflect the views of Templeton World Charity end of the workshop, resulting in a top 20 list. Foundation. The decision to keep the list to 20 was made by consensus by the workshop group and was influ- Luke Kemp is in the Centre for the Study of Existential enced by a significant difference between the Risk (CSER) and the Biosecurity Research Initiative at St

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Catharine’s College, University of Cambridge, https://orcid.org/0000-0003-2195-5810 Cambridge, United Kingdom Megan J Palmer is in the Center for International [email protected] Security and Cooperation (CSIAC) and the Department https://orcid.org/0000-0002-7447-4335 of Bioengineering, Stanford University, Stanford, Laura Adam is in Ebiosec, Inc, Seattle, United States United States https://orcid.org/0000-0002-4822-2695 https://orcid.org/0000-0001-8310-2325 Christian R Boehm is in the Centre for the Study of Nicola J Patron is in the Earlham Institute, Norwich, Existential Risk (CSER), University of Cambridge, United Kingdom United Kingdom https://orcid.org/0000-0002-8389-1851 https://orcid.org/0000-0002-6633-7998 Edward Perello is at Arkurity Ltd., London, United Rainer Breitling is in the Manchester Institute of Kingdom Biotechnology, Faculty of Science and Bioengineering, Wibool Piyawattanametha is in the Biomedical University of Manchester, United Kingdom Engineering Department, Faculty of Engineering, King https://orcid.org/0000-0001-7173-0922 Mongkut’s Institute of Technology Ladkrabang, Rocco Casagrande is in Gryphon Scientific, Takoma Bangkok, Thailand, and in the Institute of Quantitative Park, United States Health Sciences and Engineering, Michigan State Malcolm Dando is in the Division of Peace Studies and University, East Lansing, United States International Development, University of Bradford, https://orcid.org/0000-0002-2228-8485 Bradford, United Kingdom Vanessa Restrepo-Schild is in the Chemistry Research Appolinaire Djikeng is in the Centre for Tropical Laboratory, University of Oxford, Oxford, United Livestock Genetics and Health, Royal (Dick) School of Kingdom Veterinary Studies, University of Edinburgh, https://orcid.org/0000-0002-3486-454X Edinburgh, United Kingdom Clarissa Rios-Rojas is in the Centre for the Study of https://orcid.org/0000-0002-0955-171X Existential Risk (CSER), University of Cambridge, Nicholas G Evans is in the Department of Philosophy, Cambridge, UK, and at Ekpa’Palek: Empowering Latin- University of Massachusetts Lowell, and at Rogue American Young Professionals, Huacho, Peru Bioethics, Lowell, United States https://orcid.org/0000-0001-6544-4663 https://orcid.org/0000-0002-3330-0224 Catherine Rhodes is in the Centre for the Study of Richard Hammond is at Cambridge Consultants, Existential Risk (CSER) and the Biosecurity Research Cambridge, United Kingdom Initiative at St Catharine’s College, University of Kelly Hills is in Rogue Bioethics, Lowell, United States Cambridge, Cambridge, United Kingdom Lauren A Holt is in the Centre for the Study of https://orcid.org/0000-0002-7747-2597 Existential Risk (CSER) and the Biosecurity Research Anna Roessing is in the Department of Politics, Initiative at St Catharine’s College, University of Languages and International Studies, University of Cambridge, Cambridge, United Kingdom Bath, Bath, United Kingdom Todd Kuiken is at the Genetic Engineering and https://orcid.org/0000-0002-2888-3963 Society Center, North Carolina State University, Deborah Scott is in Science, Technology & Innovation Raleigh, United States Studies at the School of Social and Political Sciences, https://orcid.org/0000-0001-7851-6232 University of Edinburgh, Edinburgh, United Kindom Alemka Markotic´ is in the Medical School, University https://orcid.org/0000-0002-5962-2002 of Rijeka, the University Hospital for Infectious Philip Shapira is in the Manchester Institute of Diseases, and the Catholic University of Croatia, Innovation Research, Alliance Manchester Business Croatia School and SYNBIOCHEM, University of Manchester, Piers Millett is in the Future of Humanity Institute, Manchester, United Kingdom, and the School of Public University of Oxford, Oxford, UK, and in the iGem Policy, Georgia Institute of Technology, Atlanta, Foundation, Boston, United States United States Johnathan A Napier is at Rothamsted Research, https://orcid.org/0000-0003-2488-5985 Harpenden, United Kingdom Christopher Simuntala is in the National Biosafety https://orcid.org/0000-0003-3580-3607 Authority, Lusaka, Zambia Cassidy Nelson is in the Future of Humanity Institute, Robert DJ Smith is in Science, Technology & University of Oxford, Oxford, United Kingdom Innovation Studies, School of Social and Political https://orcid.org/0000-0003-0934-8313 Science, University of Edinburgh, Edinburgh, United Sea´ n S O´ hE´ igeartaigh is in the Centre for the Study of Kindom Existential Risk (CSER) and the Biosecurity Research https://orcid.org/0000-0002-5814-6032 Initiative at St Catharine’s College, University of Lalitha S Sundaram is in the Centre for the Study of Cambridge, Cambridge, United Kingdom Existential Risk (CSER) and the Biosecurity Research Anne Osbourn is in the John Innes Research Centre, Initiative at St Catharine’s College, University of Norwich, United Kingdom Cambridge, Cambridge, United Kingdom

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https://orcid.org/0000-0002-9595-9753 Biology. Todd Kuiken: Holds a grant from the Open Philanthropy Foundation to study DIYbio, including Eriko Takano is in the Manchester Institute of gene drives; member of the IUCN task force on syn- Biotechnology, Faculty of Science and Bioengineering, thetic biology and gene drives; co-chair of the human University of Manchester, United Kingdom https://orcid.org/0000-0002-6791-3256 practices committee of iGEM; member of the bio- safety/security advisory board for MIT Broad Foundry; Gwyn Uttmark is in the Department of Chemistry, has been affiliated with the Genetic Biocontrol of Inva- Stanford University, Stanford, United States sive Rodents consortium at NC State but has never https://orcid.org/0000-0001-8758-5256 received any salary or other compensation. Piers Mil- Bonnie C Wintle is in the School of BioSciences, lett: Co-founder of Biosecure Ltd. Johnathan A Napier: University of Melbourne, Melbourne, Australia Listed as an inventor on multiple patents; most rele- Nadia B Zahra is in the Department of Biotechnology, vant patent is US 2019/0323022 A1 and family. Acted Qarshi University, Lahore, Pakistan as a consultant to BASF (2014-2019). Anne Osbourn: William J Sutherland is in the Biosecurity Research Director of the Industrial Biotechnology Alliance, Nor- Initiative at St Catharine’s College and the Department wich Research Park; trustee with the New Phytologist of Zoology, Cambridge University, Cambridge, United Trust. Megan J Palmer: Recipient of a grant and a gift kingdom from the Open Philanthropy Foundation to study bio- [email protected] security at Stanford university; volunteer director of the human practices committee of the international Author contributions: Luke Kemp, Conceptualization, Genetically Engineered Machine (iGEM) Foundation; Data curation, Formal analysis, Investigation, Method- member of the board of directors of Revive & Restore. ology, Writing - original draft, Writing - review and Edward Perello: Holds shares in Celixir Ltd and Arkur- editing; Laura Adam, Christian R Boehm, Rainer Brei- ity Ltd; has received payment from Deep Science Ven- tling, Rocco Casagrande, Malcolm Dando, Appolinaire tures Ltd, the Nuclear Threat Initiative, Revive & Djikeng, Nicholas G Evans, Richard Hammond, Kelly Restore, Celixir Ltd, Arkurity Ltd, CSIRO, International Hills, Lauren A Holt, Todd Kuiken, Alemka Markotic´, Union for the Conservation of Nature and Biosecure. Johnathan A Napier, Cassidy Nelson, Anne Osbourn, Deborah Scott, Robert DJ Smith: Involved in a consul- Megan J Palmer, Nicola J Patron, Wibool Piyawattana- tancy for the ERA-CoBioTech programme (an ERA-Net metha, Vanessa Restrepo-Schild, Anna Roessing, Deb- network funded by Horizon 2020). The other authors orah Scott, Philip Shapira, Robert DJ Smith, Lalitha S declare that no competing interests exist. Sundaram, Eriko Takano, Bonnie C Wintle, Nadia B Received 16 December 2019 Zahra, Investigation, Writing - original draft, Writing - Accepted 14 May 2020 review and editing; Piers Millett, Edward Perello, Clar- Published 29 May 2020 issa Rios-Rojas, Investigation, Methodology, Writing - original draft, Writing - review and editing; Sea´n S O´ hE´ igeartaigh, Funding acquisition, Investigation, Ethics: Human subjects: Contributors were informed Methodology, Writing - original draft, Writing - review and agreed with the intent to publish at the outset, and editing; Catherine Rhodes, Supervision, Funding and were aware that they could withdraw at any time. acquisition, Investigation, Methodology, Writing - orig- Initial contact via email with all contributors outlined inal draft, Project administration, Writing - review and the conditions of the exercise, details about the previ- editing; Christopher Simuntala, Gwyn Uttmark, Investi- ous scan, the expectations of their involvement (such gation, Writing - review and editing; William J Suther- as the time required) and the intent to publish the land, Conceptualization, Formal analysis, Supervision, results of the exercise with them acting as co-authors. Funding acquisition, Investigation, Methodology, Writ- Participants were all above the age of 18 and agreed ing - original draft, Project administration, Writing - to these terms via email. The decision to publish with review and editing eLife was reached by consensus by contributors. We followed the Key Principles of Ethical Research from Competing interests: Nicholas G Evans: Has received the Humanities and Social Sciences Research Ethics funding in the past five years from the following organ- Committee of the University of Cambridge. Board izations to conduct research and speak on issues approval was not deemed necessary as the study did related to this article: Greenwall Foundation; Max not involve minor, vulnerable groups, manipulation, or Planck Institute for Evolutionary Biology; Davis Founda- any research beyond the UK. All contributors were tion; National Science Foundation. Has participated in reimbursed for their costs in participating in the hori- the International Genetically Engineered Machine zon-scanning workshop. (iGem) competition as a judge and a member of the Safety Committee several times over the past five Funding years. Kelly Hills: Has participated in the International Grant reference Genetically Engineered Machine (iGem) competition as Funder number Author a judge and a member of the Safety Committee sev- Templeton TWCF0128 Luke Kemp World Charity eral times over the past five years; has accepted travel Foundation funding from the Max Planck Institute for Evolutionary

Kemp et al. eLife 2020;9:e54489. DOI: https://doi.org/10.7554/eLife.54489 15 of 20 Feature Article Point of View Bioengineering horizon scan 2020

Biotechnology BB/M017702/1 Rainer Breitling and Biological Philip Shapira Database and Sciences Re- Eriko Takano Author(s) Year Dataset Identifier search Council URL Kemp L, Adam 2020 https://osf.io/ Open Science Engineering and EP/S01778X/1 Philip Shapira L, Boehm CR, ej8p2/ Framework, Physical Rainer Breitling Breitling R, ej8p2 Sciences Re- Eriko Takano Casagrande R, search Council Dando M, Dji- European Re- ERC 616510 Deborah Scott keng A, Evans search Council Robert D.J. Smith NG, Hammond R, Hills K, Holt Biotechnology BB/R021554/1 Nicola J Patron LA, Kuiken T, and Biological Markotic´ A, Sciences Re- Millett P, Na- search Council pier JA, Nel- son C, Biotechnology BB/P010490/1 Nicola J Patron O´ hE´ igeartaigh and Biological SS, Osbourn A, Sciences Re- Palmer M, Pa- search Council tron NJ, Perel- Biotechnology BB/S020853/1 Nicola J Patron lo E, and Biological Piyawattana- Sciences Re- metha W, Re- search Council strepo-Schild V, Rios-Rojas C, Rhodes C, The funders had no role in study design, data collection Roessing A, and interpretation, or the decision to submit the work Scott D, Sha- for publication. pira P, Simun- tala C, Smith RD, Sundaram LS, Takano E, Decision letter and Author response Uttmark G, Wintle B, Zahra Decision letter https://doi.org/10.7554/eLife.54489.sa1 NB, Sutherland Author response https://doi.org/10.7554/eLife.54489. WJ sa2

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