Bioengineering horizon scan 2020 - POINT OF VIEW - Office of Research and ...

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                                    POINT OF VIEW

                                    Bioengineering horizon scan
                                    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.

                                    LUKE KEMP*, LAURA ADAM, CHRISTIAN R BOEHM, RAINER BREITLING,
                                    NICHOLAS G EVANS, RICHARD HAMMOND, KELLY HILLS, LAUREN A HOLT,
                                    CASSIDY NELSON, SEÁN S ÓHÉIGEARTAIGH, ANNE OSBOURN,
                                    MEGAN J PALMER, NICOLA J PATRON, EDWARD PERELLO,
                                    ROJAS, CATHERINE RHODES, ANNA ROESSING, DEBORAH SCOTT,
                                    NADIA B ZAHRA AND WILLIAM J SUTHERLAND*

                                    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- (LK);   change and the breadth of the applications             pants then scored the issues anonymously (with (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 Pérez
                                    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                                                              these issues. The issues identified in the latest
                                    pants from six continents and 13 countries, com-
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.

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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.,

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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.
10 Years
Access to biotechnology through                            Agricultural gene drives                           Bio-based production of materials
Crops for changing climates                                Neuronal probes                                    Live plant dispensers of chemical
                                                           expanding new sensory                              signals
Function-based design in protein                           Distributed pharmaceutical                         Malicious use of advanced
engineering                                                development and                                    neurochemistry
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

                                     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),

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                                   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
                                                                                          consumer genetics database allowing the Fed-
                                   Philanthropy shapes bioscience research
                                                                                          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
                                   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.

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                                   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).

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                                   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.
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
Accelerating defense agency                                 Reassigning codons as                             Securing the critical infrastructure
research in biological engineering                          genetic firewalls                                 needed to deliver the
                                                            Rise of automated tools for
                                                            biological design, test and
                                                            Biology as information
                                                            science: impacts on global
                                                            Intersection of information
                                                            security and bio-
                                                            Effects of the Nagoya
                                                            Protocol on biological
                                                            Corporate espionage and

                                         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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Feature Article                                                                      Point of View Bioengineering horizon scan 2020

                                   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 Loë 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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Feature Article                                                                    Point of View Bioengineering horizon scan 2020

                                   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, SÓhÉ, 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

Kemp et al. eLife 2020;9:e54489. DOI:                                                            12 of 20
Feature Article                                                                         Point of View Bioengineering horizon scan 2020

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%).
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

Kemp et al. eLife 2020;9:e54489. DOI:                                                                    13 of 20
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