PERSPECTIVE published: 14 April 2022 doi: 10.3389/fbioe.2022.868736 The Emergence of Genome Editing —Innovation Network Dynamics of Academic Publications, Patents, and Business Activities Natalie Laibach 1* and Stefanie Bröring 2* 1 Laboratory for Sterol and Terpenoid Metabolism in Plant Development and Stress Responses, Department of Plant Synthetic Biology and Metabolic Engineering, Centre for Research in Agricultural Genomics (CRAG), Barcelona, Spain, 2Chair Entrepreneurship and Innovative Business Models, Center for Entrepreneurship, Innovation and Transformation, Ruhr-University Bochum, Bochum, Germany Transformative societal change can both be triggered and influenced by both macro-level political means and the emergence of technologies. Key enabling technologies and therein biotechnology hold the power to drive those changes forward, evolving from breakthrough academic discoveries into business activities. Due to its increasing empirical relevance, we picked genome editing as an example for an emerging technology and extracted publication, patent, and company data from the years 2000 to 2020. By drawing upon Edited by: social network analysis, we identify major networks and clusters that are dominating the Miguel Rocha, respective time and layer. Based on these networks, we draw vertical connections University of Minho, Portugal between scientific knowledge, patented technologies, and business activities to Reviewed by: Surendra Sarsaiya, visualize the interlevel relationships between actors through technological development. Zunyi Medical University, China Thereby, we identify network dynamics of the emergence of genome editing, the most *Correspondence: important actors and clusters evolving, and its spread into different areas. Natalie Laibach natalie.laibach@cragenomica.es Keywords: genome editing, social network analyses (SNA), innovation, technology and innovation management, Stefanie Bröring sustainability, biotechnology Stefanie.broering@ruhr-uni- bochum.de 1 INTRODUCTION Specialty section: This article was submitted to Amid fossil resource and land scarcity, climate change, and a growing and aging world population, Synthetic Biology, sustainable and resource-efficient strategies are required to enable the prosperity of future a section of the journal generations. To comply with the United Nations’ Sustainable Development Goals (SDGs), which Frontiers in Bioengineering and address among others climate change, health, innovation, and sustainable consumption, societal Biotechnology change and sector-spanning activities are needed that are, mutually, driven by and fostering new Received: 03 February 2022 technological developments (United Nations, 2015; El-Chichakli et al., 2016). If they hold great Accepted: 22 March 2022 potential, niche innovations manifesting in start-ups can become key enabling technologies (KETs) Published: 14 April 2022 (Geels and Schot, 2010; Hausknost et al., 2017; Priefer et al., 2017; Philp, 2018)—and industrial Citation: biotechnology is among them (Dupont-Inglis and Borg, 2018; Małyska and Jacobi, 2018): “Industrial Laibach N and Bröring S (2022) The biotechnology is broadly accepted as one of the EU’s core technological strengths and has been Emergence of Genome recognized as a ‘key enabling technology’ which can help enable a more competitive and sustainable Editing—Innovation Network Dynamics of Academic Publications, bioeconomy” (Dupont-Inglis and Borg, 2018, p. 141). Patents, and Business Activities. Certainly, one of the most critical developments in recent years peaking in the reception of the Front. Bioeng. Biotechnol. 10:868736. Nobel Prize (Cohen, 2020; Strzyz, 2020) is genome editing or CRISPR/Cas9 (clustered regularly doi: 10.3389/fbioe.2022.868736 interspaced short palindromic repeats/CRISPR-associated protein 9)—a tool to induce precise Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 1 April 2022 | Volume 10 | Article 868736 Laibach and Bröring Innovation Network Dynamics of Genome Editing modifications in the genome of any organism. This reveals great 2016), we assume that over time, network clusters surrounding opportunities not only in plant breeding but also for new the most successful technological applications emerge and move medicinal applications. Genome editing such as CRISPR/Cas9 from science to the business layer. By mapping these clusters, we and its fewer famous predecessors such as zinc finger nucleases can provide empirical evidence for the advancement of genome (ZFN) and transcription activator–like effector nucleases editing whereby policymakers and managers can identify the (TALENs) have the potential to (and currently do) improve collaboration partners, emerging/retarding, and area potential diverse biotechnological applications to promote the transition setscrews to intervene. toward a bio-based economy (Barrangou and Doudna, 2016; Laibach et al., 2019). It could alter crops with respect to climate change adaptation (e.g., drought resistance), thus ensuring food 2 TECHNOLOGICAL INNOVATIONS ARE security, reducing the amount of fertilizer and pesticides, which EMBEDDED IN THE CONTEXT OF THEIR will benefit the environment and could empower farmers in developing countries (Lopes, 2015; Huang et al., 2016; Yang ECOSYSTEMS et al., 2017; Goold et al., 2018). Moreover, the plants and microorganisms could be designed to provide optimal 2.1 Innovation Ecosystems and Networks of feedstock for non-food products and applications (Lopes, Emerging Technologies 2015; Nemhauser and Torii, 2016; Flores Bueso and Tangney, Innovation ecosystems generate economic dynamics of different 2017), and medical treatments can be developed (Barrangou and actors (universities, research organizations, and enterprises) and Doudna, 2016) by means of this novel approach. in space, which facilitate technological development, through Given its impact and importance, genome editing is an their human capital, knowledge, and material resource synergy outstanding case from a technology and innovation (Majava et al., 2013; Binz et al., 2014; Markard et al., 2015). management point of view that is disrupting its own Hence, technology transfer through interconnections and technological regime (Martin et al., 2020). Here, genome synergy of scientific institutes, technological projects, and editing can be defined as an emerging technology as it fulfills established firms and technology-based ventures/start-ups are the five criteria radical novelty, relatively fast growth, coherence, considered to be highly important for dynamic technological prominent impact, and uncertainty and ambiguity developed by systems (Bergek et al., 2008, 2015; Tigabu et al., 2015). Firms Rotolo et al. (2015); Rotolo et al., 2015. Patent analysis of specific engaged in innovation ecosystems are also known to obtain a application areas points toward future increase in technological higher total value than without cooperation (Hellström et al., development (Gupta et al., 2020) and already identified some key 2015; Xu et al., 2018). These emerging networks within players connected to the patent licensing of major scientists innovation ecosystems can be used for a better understanding involved, including the recent Nobel laureates (Egelie et al., of such systems and their drivers and studies using social network 2016). However, a systemic change is only possible if new analysis (Xu et al., 2018). This has been used to identify dynamics, potential technologies diffuse from scientific knowledge into key actors, and areas that facilitate the market implementation of the market applications and efficient transfer systems are scientific developments using publication data (Kajikawa et al., established (Geels and Schot, 2010; Vandermeulen et al., 2012; 2007; de Souza et al., 2015), combining patents and publications Graff and Sherkow, 2020). Especially when emerging (Curran et al., 2010; Binz et al., 2014; Goeldner et al., 2015; technologies have the potential to change different areas such Gaviria and Kilic, 2021), and including company information (Xu as agriculture and medicine, the dynamics of the innovation et al., 2018). The key actors and their roles can be identified by networks from science to business can reach a high level of their network values (Stolz and Schlereth, 2021). The cooperation complexity (Golembiewski et al., 2015a). The networks or and diffusion of knowledge between universities and companies ecosystems of involved actors can illustrate the most and across disciplines is enhanced by collaborative research important players in this field and visualize key connections activities and institutionalized infrastructures, thus providing between scientific research and business application. This opportunities for academic entrepreneurship (Etzkowitz, 2012; appears to be very important because although it is possible to Wu et al., 2018). carry out scientific research, technological developments, and their commercialization by oneself (single university, research institute, and company), it is assumed that precisely collaboration 2.2 Social Network Analysis to Identify the and networking at academic and technological levels create the Innovation Ecosystem of Genome Editing needed synergic effect, and thus the partners may mutually One major aim of this study is to investigate the scientific and develop faster, achieve better results, and innovate more technological layers within the genome editing ecosystem effectively (Daugherty et al., 2006; Hewitt-Dundas, 2006). framework so as to entangle the technologies developing As genome editing techniques and its development have been clusters and growth pathways toward its market extensively reviewed, we aimed to shed light on its development commercialization. Therefore, we analyze the publication, from a technology and innovation management perspective. patent, and company database landscapes, which is one widely Drawing on the theoretical background of emerging used approach in scientific publications to investigate and technologies in innovation networks and ecosystems (Markard understand the emerging technologies and products (Dai et al., and Truffer, 2008; Rotolo et al., 2015; Campbell and Carayannis, 2015; Goeldner et al., 2015) and, in particular, novel technologies Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 2 April 2022 | Volume 10 | Article 868736 Laibach and Bröring Innovation Network Dynamics of Genome Editing in the context of bio-economy (Milanez et al., 2014; Berg et al., CrunchBase) and consolidated by periods (2000–2009, 2018). Real market applications of scientific knowledge and 2010–2014, 2015–2017, and 2018–2020). Then, using Microsoft intellectual property are beneficial in terms of revenue Excel, datasets were redistributed in order to sort all authors of generation, general business development, and novel goods each particular entry. Then, the organization of one entry—that is, and service market extension (Siegel et al., 2007). Hence, to affiliations of publication authors, non-persona co-assignees—were identify the important actors and technology lines in genome paired among each other manually (e.g., if the document consists of editing, we conducted a research strategy that first identifies the the authors from MIT, Harvard University, and Broad Institute, major actors and areas in genome editing using social network there are next links: MIT—Harvard University, MIT—Broad analysis and thus quantifies the conjuncture of the industry. Institute, Harvard University—Broad Institute; in case of the Afterward, we linked the three layers of publication, patent, same institution per entry, self-nominating organizations were and company networks and highlighted the corresponding paths. eliminated). For the business layer, company connections were obtained by merger and acquisition activities and co-founders 2.2.1 Data Generation who are listed in different companies. The network as such To obtain the relevant datasets for our analysis, we extracted includes several indicators (degree centrality, closeness centrality, publication data from Web of Science (WoS; https://apps. betweenness centrality, network density, average path length, and webofknowledge.com/), which is one of the most popular and clustering coefficient) which were calculated using the software R comprehensive existing scientific search engines that has already 3.5.3 and the RStudio desktop version 1.1.463. Specifically, we been used for bioeconomic research description and also to applied the packages igraph (Csardi and Nepusz, 2006), ggplot2 describe the rise of genome editing research in recent years (Wickham, 2016), and readr (Wickham et al., 2017). The full script (Mao et al., 2015; Eriksson et al., 2018). This resulted in 9,992 can be found in Supplementary Material S1.1. A pajek file was then publications from which bibliographic information was created to load the data into Gephi (Bastian et al., 2009) so as to extracted. Publication analysis already was applied to describe obtain standardized visualization of the network. The the scientific ecosystems using bibliometrics, which is an Fruchterman–Reingold and expansion algorithm were used, and important instrument for analysis and evaluation of scientific the network parameters of adapted networks were calculated in research output (Van Raan, 2005; Cobo et al., 2015; Martínez Gephi. et al., 2015). To gain insights into technological dynamics in a certain area, patent information is widely used as it is relevant for 2.2.3 Vertical Analysis strategic planning and to evaluate R&D activities (Ernst, 2003; The bridging of the three analyzed layers was conducted by Chen et al., 2013). The patent data for the research were obtained matching organizations that occurred both in publication and from Derwent Innovations Index (DII; www.derwentinnovation. patent or patent or company data. To visualize the most com/)—one of the most comprehensive existing patent important clusters among each layer, we further considered information databases, which was used as a reliable source for the 100 actors with the highest degree of centrality among the conducting similar research studies (Ma and Porter, 2015; Berg years and indicated the organization’s technological area, if et al., 2018) and resulted in 27,583 patent families. The applicable (universities for instance are usually corresponding search strings can be found in Supplementary multidisciplinary). In addition, we included all those Table S1, Supplementary Material. The publications were organizations that have connections throughout the layers. restricted to English articles, and in addition, the timespan from 2000 to 2020 was applied in order to incorporate the beginning of genome editing. Data for the business layer data, 3 GENOME EDITING SPANS DIFFERENT in total 606 hits, were obtained using the Pitchbook (https:// SECTORS AND CONNECTS pitchbook.com//) database. Here, it was necessary to change the search string because of the peculiarities due to which the Boolean INTERDISCIPLINARY ACTORS operators and wildcards cannot be used. Company foundations To explore networks emerging around genome editing, we first and business deals were collected and used for further analysis. obtained publication, patent, and company data for genome editing in the period from 2000 to 2020 and retrieved the 2.2.2 Horizontal Analysis dominant actors and second identified the most dominant areas Social network analysis (SNA) is recognized as a useful tool for the (Figure 1A). Each information is then at last used to conduct SNA description of central actors, hubs, and main movements of certain to delineate network positions and collaborations. The number of fields (Sternitzke et al., 2008; de Souza et al., 2015) and allows for a entries in each dataset rapidly increased over the last 5 years comprehensive visualized understanding of the flows between the (Supplementary Figure S1), reflecting the success of the top-actors of a certain technology field (or other). SNA possesses a CRISPR/Cas9 method from 2012 onward (van Erp et al., 2015; range of analysis and visualization methods, for example, building Barrangou and Doudna, 2016). Before, TALEN and other genome collaboration and citation networks (Perianes-Rodríguez et al., editing approaches were identified and patented, but none of these 2010). All calculations, visualization, and coefficients for social resulted in a comparable boost in patenting and publication networks were generated similarly for scientific, technology, and activities. The major actors in terms of the record numbers of business layers as follows. The necessary organizational data were academic publications and patents are Harvard University with its collected from the corresponding database (WoS, DII, and associated institutes (MIT and Broad Institute), the University of Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 3 April 2022 | Volume 10 | Article 868736 Laibach and Bröring Innovation Network Dynamics of Genome Editing FIGURE 1 | (A) Thematic areas of genome editing by record number during the periods of 2000–2009, 2010–2014, 2015–2017, and 2018–2020. The data shown display the 15 areas with the highest record number per period. Data for academic publications (s), patents (p), and company data (c) were obtained using Web of Science, DII, and Pitchbook (B) Network of institutions active in academic publications, patents, and business from 2018 to 2020. Network generated from publication (s, WoS), patent (p, DII), and company (c, Pitchbook) data from 2018 to 2020, using the institutions with the top 100°, visualized by Gephi. Thematic areas, red; medicine, orange; pharmaceuticals, pink; chemistry, green; agriculture, blue; biotechnology, dark red; venture capital, gray: other. California, the Chinese Academy of Science, and the French analysis. The networks for each layer reflected the development of research institutes CNRS and INSERM (Supplementary Figures genome editing throughout the years until a saturation was S2, S3). The most active companies in terms of patenting are attained after 2015 for patents and academic publications, Monsanto (now Bayer) and PioneerHiBred from the agricultural making the networks nearly impossible to read sector, which also displays the most relevant areas for CRISPR/ (Supplementary Figures S6–S9). However, some companies Cas9 application (Supplementary Figures S2–S4). such as Monsanto that hold many patents but were scarcely We then performed social network analysis to identify the engaged in collaboration largely disappear from the collaborative most relevant clusters and leading organizations in each period of landscapes. Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 4 April 2022 | Volume 10 | Article 868736 Laibach and Bröring Innovation Network Dynamics of Genome Editing FIGURE 2 | Reduced network of institutions active in academic publications, patents, and business from 2018 to 2020. Connections are based on a network generated from publication (Science, WoS), patent (Technology, DII), and company (Business, Pitchbook) data from 2018 to 2020, using the institutions with the highest degrees and betweenness centralities, calculated by Gephi. Thematic areas, red; medicine, orange; pharmaceuticals, pink; chemistry, green; agriculture, blue; biotechnology, dark red; venture capital, gray: other. Abbreviations see Supplementary Table S2. The big clusters are centered around French (i.e., Institute (i.e., Harvard University, MIT) and California (i.e., University Pasteur, CNRS, INSERM), Chinese (i.e., Chines Academy of of California). In the later years, the companies emerged and Science), and two U.S. institutions from Massachusetts formed these innovation ecosystems, many specializing in Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 5 April 2022 | Volume 10 | Article 868736 Laibach and Bröring Innovation Network Dynamics of Genome Editing genome editing, that is, Editas Medicine, CRISPR Therapeutics, the hands of established companies such as Bayer/Monsanto, and Mammoth Biosciences. To find not only the actors with the DowDuPont, or Syngenta The discouraging politics in Europe most ties but also such that are important bridges for technology may repel new company foundations and investments (Huang transfer and collaboration, we calculated the degree of centrality et al., 2016) as is the general ethical discussion around and the betweenness centrality of the networks. While the former bioengineering for food production (Gupta et al., 2020), displays the number of ties, the latter is considered an indicator which could be the reason behind the observed lack of for power within the network (Burt, 2003; Stolz and Schlereth, network density and could be pointing toward 2021). From 2000 to 2009, Sangamo Therapeutics (Sangamo uncertainty—and the still emerging character of this Biosciences) and Iowa State University have the highest values, technology (Rotolo et al., 2015, 2017). In the same vein, reflecting an important tying position in the early genome editing expectations for application in agriculture are remaining high technology development before CRISPR/Cas9 (Supplementary (Maximiano et al., 2021; Hüdig et al., 2022), and in-detail patent Figure S5). While Sangamo Therapeutics can hold its position as analysis prospects a strong increase in product development a very collaborative institution, especially in academic (Gupta et al., 2020). A most surprising result was that although publications, the organization with the most records is gaining CRISPR/Cas9 genuinely belongs to microbiology, this area is network power. largely underrepresented in our analysis, although there are But which networks and actors are currently active in which many opportunities (van Doren et al., 2013; Barrangou and areas and around which areas do the clusters evolve? To show Doudna, 2016). A possible explanation might be the immediate the actual state of institutions involved in genome editing, we monetary benefit from the other areas and the comparably early combined the data from academic publications, patents, and stage of development of the promising field of synthetic biology. business activities in single network analysis in the period from As this technology field is also rising, we may see similar 2018 to 2020 and included, where possible the thematic area. developments in near future (van Doren et al., 2013). This Figure 1B and Figure 2 show the whole network of could be an asset for a sustainable bioeconomy and a fundus for organizations truncated by the degree of centrality. The many new applications to produce high-value chemical major clusters in agricultural sciences involve the U.S. compounds etc. (Lopes, 2015; Flores Bueso and Tangney, Department of Agriculture, the University of Cologne, 2017). Knowledge-intensive fields such as genome editing Benson Hill, and others. Medical clusters are dominated by and biotechnology require a broad and strong boundary U.S. universities and the U.S. Health and Human Services spanning (interdisciplinary) scientific base; hence, companies Department and encompass not only medical but also most will engage in joint R&D efforts with academia (Akbar et al., pharmaceutical companies such as Novartis or Pfizer. The 2012; Golembiewski et al., 2015b; Lokko et al., 2018). The cluster with a majorly pharmaceutical focus involves development of the CRISPR/Cas9 technology clearly CRISPR/Cas9 start-ups with a medical focus and mostly benefited from the engagement of academic institutions and French universities. Moreover, some companies from two individuals in the commercialization of their ideas, as was different areas begin to collaborate. For instance, shown in other areas before (Etzkowitz, 2012; Wu et al., DowAgrosciences, a big agricultural player, is co-assigning 2018)—and is likely to be shaped by these in the future inventions in genome editing with Sangamo Therapeutics (Graff and Sherkow, 2020; Whelan et al., 2020). This is from the medical biotechnology area. The latter is also visible in our analysis of public–private networks throughout involved in business-academic networks, for example, with the layers. The visualization of the technological orientation of the University of California. Another example is Syngenta each connection might be interesting to detect new emerging which is scientifically collaborating with the Memorial Sloan fields of science and hence for future research avenues. Kettering Cancer Center (see also Figure 2). This again Moreover, as the data obtained in the present analysis also highlights the boundary-spanning potential of genome provide information about authorship (inventor, founder) and editing that as a KET triggers cross-sectoral innovation and geographical location, this can be used to extend the three-layer possibly convergence, thus giving rise to new innovative model upon the spatial perspective and additional connections systems. (Markard and Truffer, 2008). Although this research is limited by the use of the datasets, it can highlight successful pathways of emerging technologies with 4 DISCUSSION an innovation ecosystem. From here, scientists, managers, and policymakers can dig deeper and identify reasons for the success The emergence of genome editing, especially after discovering or failure of inventions. Hot spots of technological development, the CRISPR/Cas9 methodology, resulted in very complex key partners, and application areas can be identified. CRISPR/ horizontal networks in academia and patents—that reflect Cas9 as the major genome editing technology is a vertical also the great diversity of technology transfer models in this technology, spanning different area, which are expanding technological system (Graff and Sherkow, 2020). Therapeutics from medicine and healthcare to agriculture. In addition, the and medical solutions are currently the most relevant field for stagnation of successful technology areas into the science or genome editing applications, as our analysis of the patent data technological layer may be caused not only by the feasibility to and the major company clusters show. The second counts plant design prototypes on an industrial scale but also by political or science (agricultural biotechnology); however, that is mostly in societal circumstances. Policy-based regulations or public Frontiers in Bioengineering and Biotechnology | www.frontiersin.org 6 April 2022 | Volume 10 | Article 868736 Laibach and Bröring Innovation Network Dynamics of Genome Editing concerns may form a barrier hampering the market entrance AUTHOR CONTRIBUTIONS and thus the further development of technological clusters. Future research could aim at studying the social legitimacy of NL: conceptualization, data curation, social network analysis, major clusters and elaborate on the business models employed visualization, validation, and writing—original draft. SB: initial by the start-ups centered on CRISPR/Cas9. Overall, our study concept, writing—review and editing, and funding research can help visualize those developments or locked-in acquisition. states and point toward further necessary actions. FUNDING DATA AVAILABILITY STATEMENT This work was supported by the German Federal Ministry of The data analyzed in this study is subject to the following licenses/ Education and Research (Grant number 031B0019). restrictions: The patent and company data were purchased from databases provided by Web of Science (WoS; https://apps. webofknowledge.com/), Derwent Innovations Index (DII; SUPPLEMENTARY MATERIAL www.derwentinnovation.com/), and Pitchbook (https:// pitchbook.com//), which are commercial entities. The requests The Supplementary Material for this article can be found online at: to access these datasets should be directed to NL, natalie.laibach@ https://www.frontiersin.org/articles/10.3389/fbioe.2022.868736/ cragenomica.es. full#supplementary-material Cohen, J. (2020). A Cut above: Pair that Developed CRISPR Earns Historic Award. REFERENCES Science 370 (6514), 271–272. doi:10.1126/science.370.6514.271 Csardi, G., and Nepusz, T. (2006). 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