Organizational change of synthetic biology research: Emerging initiatives advancing a bottom-up approach

Bottom-up Synthetic Biology (buSynBio) is an approach focused on the artificial making of minimal functional biosynthetic systems by recombining existent biochemical modules or manufacturing them from scratch. Over the last decade, this emerging orientation has gained new momentum with the development of new bioengi-neering tools, theories, and technologies. Despite the growing acceptance of buSynBio, few studies have dedicated attention to the analysis of its organizational aspects. This article offers the first systematic investigation of emerging research initiatives in buSynBio and their meaning to bioengineering research. Our analysis is based on a multi-method qualitative study, including expert literature review, bibliometric research and a documentary analysis of online materials such as reports and project descriptions available in official grant data repositories. Our study found that publications of specialized articles on “ bottom-up synthetic biology ” have increased, both in absolute numbers and normalized to total number of publications. We show how that might be enabled by novel mechanisms of organization that reposition material, intellectual and political resources in synthetic biology. Drawing on theoretical analyses within Science and Technology Studies (STS), we examine 14 research initiatives in 5 selected countries (Germany, United Kingdom, United States, Netherlands, and Switzerland). The bottom-up approach is supported by a variety of “ tentative regimes ” of scientific governance in different stages of consolidation, but holding in common the establishment of novel basic research in Chemistry, Biology, Engineering and Physics. The study aims to contribute to social science research in synthetic biology by shedding light on the implications of buSynBio as trend driving the current organizational change of bioengineering research.


Introduction
On March 7, 2022, The New Yorker featured an article titled "A Journey to the Center of Our Cells", which highlighted advances in research that manipulates "the fundamental unit of life".As per the article, multiple teams of "synthetic biologists" are approaching the point to construct living cells from nonliving components.The article boldly claims that if we can design and regulate these cells with precision, we can employ them to accomplish our desired objectives.It further discusses achievements at J. Craig Venter Institute in the United States such as the development of a bio-hybrid component baptized as "JCVI-syn3A" and the first "minimal cell" generated from a gene editing and bioengineering of a bacteria (Somers, 2022).
In light of this renewed interest in synthetic biology, the examination of key developments in the organization of this field is critical (Meng and Ellis, 2020).Synthetic Biology (SynBio) is an international academic endeavor of life sciences research that aims to understand basic operating physical-chemical principles of living organisms through the reconstruction of minimal functional biological systems (Deplazes, 2009;Anderson et al., 2012;Trump et al., 2018).Since the 2000s, the field has gained much attention from social scientists and people from Science and Technology Studies (STS), specifically addressing issues related to governance, regimes of knowledge production, and its institutionalization in democratic societes (Calvert and Martin, 2009;Powell et al., 2007).It has been examined through multiple lenses, focusing on the configuration of its scientific landscape (Oldham et al., 2012), field definitions and disciplinary settings (Scott et al., 2018), philosophical and epistemic considerations (Calvert, 2010;Dupré, 2012), regulation (Tait, 2009;Zhang et al., 2011;Trump, 2017Nov), risk (McLeod et al., 2018), uses and public attitudes towards the field (Marris et al., 2014;Akin et al., 2017), promises and future (Serrano, 2007;Schyfter and Calvert, 2015), its ethical, legal, and social implications (Macnaghten et al., 2016;Balmer et al., 2015), and challenges involving SynBio clinical translation (DeNies et al., 2020).
Since mid-2010s, increasing possibilities of building synthetic celllike systems from scratch have driven innovation in SynBio.Traditionally, starting from a living cell or other functional biological system and then proceeding to take things apart seemed to be the logic way to investigate how things work on the intra-cellular level.That engineering method has become known as the "top-down approach" to synthetic biology research (Szostak et al., 2001).
However, the top-down paradigm in SynBio has faced the emergence of a complementary approach.A 2018 article in Nature titled "Biology from scratch" has explored how scientists are reorganizing their work to "reveal the boundaries of life" and how by "starting from scratch they aim to rebuilt living systems with the precise knowledge of individual components" (p.173) (Powell, 2018).This approach has been named by experts in the field as "Bottom-up synthetic biology" (buSynBio), emerging as a trend of contemporary research in SynBio.It brings together professionals from Physics, Chemistry, Biology, Biotechnology, Materials Sciences, Biomedical Sciences and Computer Sciences to work on the artificial reconstruction of complex biosynthetic systems through design and manipulation of minimal units of life, producing desirable biochemical functions in those systems (Landfester and Sundmacher, 2019;Jia and Schwille, 2019).
Despite widespread appreciation for the potential of buSynBio, there is a scarcity of research on its social and organizational aspects.We aim to fill this gap by exploring major research initiatives in buSynBio and conceptualizing their implications for the future of bioengineering.The paper is organized as follows: First, we provide background on synthetic biology as an emerging discipline and look at how the bottom-up approach is characterized in recent specialized work.It is followed by quick remarks on the history of the field aiming to contextualize the botton-up approach accordingly.We then describe the methods adopted to gather data on emerging initiatives in buSynBio.We further scrutinize selected buSynBio initiatives in five countries (Germany, United Kingdom, United States, Netherlands, and Switzerland).In "Discussion" we engage in a critical analysis of the buSynBio through the lens of STS, emphasizing the idea of "knowledge infrastructures."This concept provides a suitable tool for social and political analysis of SynBio research.We finally conclude with some considerations about the implications of emerging reconfigurations around buSynBio to shape the future of bioengineering and SynBio research.

Background
Issues concerning the scientific organization of life sciences research have received significant attention in areas such as Sociology, History and Philosophy of Science, Public Policy, and Science and Technology Studies (STS).The proper governance of research and development (R&D) activities is critical for facilitating the production and commercialization of expert knowledge and technologies in society (Edwards et al., 2007;Fujimura, 2013;Frickel et al., 2006).Since the mid-2000s, changes in the organization of SynBio research have led humanities and social science scholars to develop methods and theories to understand the unique aspects of scientific governance in that field (Marris and Calvert, 2020;Shapira et al., 2017;Braun et al., 2019).
SynBio is a relatively new field that has produced novel technical and societal challenges for biotechnology research.Professionals working in this field promise breakthrough discoveries with transformational potential for biopharma, healthcare, energy and environment -by applying engineering principles to design and manufacturing specific life-inspired systems and solutions (Endy, 2005;Heinemann and Panke, 2006;da Silva and Blasimme, 2024;Hirschi et al., 2022).Specifically, SynBio "was stipulated to involve abstracting away intricate biological complexity into simpler parts and modules whose behavior can be quantified" (p. 1) (Laohakunakorn et al., 2020).
The mapping of the growing body of published SynBio research has confirmed the high level of heterogeneity of this emerging area, noting at least four distinct approaches towards the synthesis of living systems: DNA-nanotecnologies or biobricks engineering, cell engineering, protocell creation, and metabolic engineering (Raimbault et al., 2016;Garamella et al., 2019;Volk et al., 2023).Each of these approaches is characterized by different methods and concepts regarding the construction of functional biological components, and further entails a range of positions on intellectual property and regulatory regimes (O'Malley et al., 2008).
Understanding SynBio involves looking at different motivations held by research communities in the field.SynBio is essentially not defined by its object of investigation, but by its aims, disciplinary frames and methodologies (See Fig. 1).
Presently, scientists from leading research institutions agree that SynBio is characterized by two methodological approaches: Top-Down and Bottom-up: "Both approaches have developed methods for building and manipulating living systems (…) For example, top-down synthetic biology has equipped existing cells with new functionalities, while the bottom-up approach starts with cellular parts to study their function in isolation".However, the combination of both approaches is seen as critical "to engineering and programming living matter" (Jahnke et al., 2021) (See Fig. 2).

Bottom-up synthetic biology: quick historical and disciplinary considerations
Quick remarks are welcome to situate the buSynBio approach in the origins and historical developments of SynBio.buSynBio did not emerge solely from within the SynBio community but evolved from studies from chemistry, biochemistry, materials science, and more.In this sense, a crucial distinction is needed between SynBio scholars, primarily biologists, and buSynBio scholars, who have more diversified academic origins.
This diversity stems from the historical context wherein buSynBio's foundational research was conducted outside the SynBio framework.The term "bottom-up synthetic biology" was not present prior to 2008, as the part of buSynBio dedicated to constructing synthetic cells of minimal complexity had not yet been associated with the SynBio label.Instead, these studies were initially rooted in fields such as origins of life, biomimetic chemistry, and biophysics.From 2008, scientists were successful in adopting the SynBio label to frame their research aims, advancing many areas in parallel and turning SynBio into a robust promising research agenda internationally.
To this end, we should highlight the pivotal role played by leading scientists and events in the 2000s, such as the 3rd Conference on Synthetic Biology in 2007, organized by ETH Zurich (Synthetic Biology 3.0., 2007).The synthesis of various research strands into what is now recognized as buSynBio started to take shape during this period.The commentary by S. Benner (Benner, 2003) and the book "Emergence of Life" by P. L. Luisi (Luisi, 2006) are seen as notable instances where the connection between earlier research on biomimetic chemistry and the emerging field of SynBio was acknowledged.
It is crucial to examine the international presence of buSynBio as a decentralized community around the world, while acknowledging the focus on Europe and United States.Notable contributions from Japanese scholars, for example, exemplified by studies led by T. Yomo (Kashiwagi et. al., 2006), should be mentioned as relevant to current strategies in the field.
We finally acknowledge that this is just a first overview of buSynBio and much needs to be inquired regarding its historical and organizational roots.Our study, then, aims to foster research about the bottomup approach and be useful as support to contextualize future initiatives that advance SynBio as a promising field of scientific and technological research.
This study focuses on initiatives aiming at fostering buSynBio.According to Hirschi and colleagues (2022), the fundamental principle of the bottom-up approach involves the isolation and examination of individual biological and chemical components.It aims to recreate biological processes starting from their essential molecular constituents or adapt them for novel purposes.(p.16294) (Hirschi et al., 2022).Likewise, Yue and colleagues (2023) provide a definition for buSynBio: "[…] technical advances in biotechnology have greatly accelerated the development of bottom-up synthetic biology.Unlike top-down approaches, bottom-up synthetic biology focuses on the construction of a minimal cell from scratch and the application of these principles to solve challenges" (p.1) (Yue et al., 2023).
Researchers claim that "Cell-like functionality is derived by reconstituting functional modules, made from natural or artificial molecular building blocks."(p.939) (Göpfrich et al., 2018).It suggests that the functioning of biological matter can only be demonstrated if they can be reproduced under controlled conditions.It mirrors a statement done once by the US physicist Richard Feynman: "What I cannot create, I do not understand" (Feynman and Plenty, 1960).Additionally, the bottomup logic is heavily supported within shared frames of scientific convergence and technical progress historically advanced by Physics and Engineering traditions over the last century (Roco, 2020).(See "definition articles" for more references).
Typical approaches in buSynBio are based on the notion of compartmentalization and biomimetic interfaces.As the structure of a cell is considered the fundamental prerequisite for the formation of life,  many experiments in buSynBio start with the creation of artificial cell membranes made up from lipid bilayers facing an aqueous solution.We can gain insights into the fundamental principles of life with such simple systems.Jack Szostakwho is considered among the pioneers of buSynBio -observe competitive behavior between simple artificial lipid vesicles (Chen et al., 2004).The idea of buSynBio is to start with very simple systems for which the complexity is then increased.For example, biomembranes can be functionalized with proteins interacting with the lipid interface.This way, for example, the dynamic behavior of membrane proteins facilitating cell division in bacteria could be reproduced in an in-vitro environment (Loose et al., 2008;Schweizer et al., 2012).
These studies are purely intended in order to better understand cell division in bacterial cells and dynamic protein self-organization in general.However, buSynBio experiments do not necessarily rely on membranes for functionalizing proteins.Scholars are reconstituting various enzymes in a pure in-vitro experiment in order to create a complete synthetic cascade to fixate CO2 (Schwander et al., 2016;Nattermann et al., 2023).These studies are considered as a precursor for possible applications of artificial leaves with high efficiency in order to fight climate change.
Finally, to many scientists, the buSynBio approach assumed multiple synonyms and labelsdescribed as the bottom-up assembly molecular systems (Hirschi et al., 2022), bottom-up construction of complex biomolecular systems (Laohakunakorn et al., 2020), or "Constructive Biology" (de Capitani and Mutschler, 2023).But scholars might disagree in fitting their approaches and methodologies as buSynBio, since the label is in its early days, currently an object of discussion in SynBio community.

Methods
This is a multi-method qualitative study that aims to identify research initiatives and organizations related to buSynBio in Europe and United States.This includes discussions with R&D professionals involved with involved with buSynBio in both geographic locations, along with bibliometric analysis and online documentary research.
First, we performed a search for publications in the last 20 years, which used the term "bottom-up synthetic biology," on the platform "Dimensions.ai"(Digital Science and Research Solutions Inc.).We opted to use only this single term since "bottom-up synthetic biology" has been used in articles, grants, and website descriptions, and because it has been deployed as a term to identity scientific bandwagons and field identity among scientists running interdsiciplinary projects and consortia in the field (Powell et al., 2007;Au and da Silva, 2021).A similar approach has been previously used by the authors to access data on organ-on-a-chip research in Europe (da Silva and Blasimme, 2023 Sep).Our search found a total of n ¼ 1,056 results of publications (articles, editorial piece, book chapters, etc.), 41 grants, and 73 patents from 01.01.2008 (year that the term was first used) to 25.10.2023(day of the last update of the search).
The initial search was conducted in January 2023 aiming exclusively at gathering definitions of buSynBio-related efforts.The inclusion criteria were to select recent papers (published not more than five years ago, i.e., from 2018 to 2022, full year, n ¼ 639 articles) and those holding non-technical/specialized narrative to explain the bottom-up approach.The inclusion of the latter aimed of including publications intended for a more general audience on what buSynBio research is and the objectives of researchers working in the field.
After two meetings in 2022 (one in person and one remote) with senior scientists in buSynBio in Switzerland (Basel) and Germany (Heidelberg), we used the software Rayyan to analyze paper abstracts and to select a list of documents to be included as sources of credible definitions of buSynBio.From that search, we selected 18 documents (named as "definition articles") for an in-depth analysis, annotation, and discussion between the authors of this paper.The team is composed of a STS scholar, a sociologist, three bioethicists and a molecular biophysicist working with synthetic biology.The last team member was scientific coordinator of a key European initiative in SynBio, and provided crucial input for identifying main definition articles.By being a specialist in SynBio, he guided the examination of documents, provided translation of meanings and clarified differences among the buSynBio when compared to the top-down approach (see Fig. 1).
The "definition articles" were useful in improving our understanding about the buSynBio approach in terms of its disciplinary setting, technological platforms its uses, and on what makes the buSynBio approach different from previous approaches in SynBio.
To make this characterization more accurate with the critical aspects driving research projects in buSynBio, we updated the list in October 2023.Specifically, three papers were added to the list, resulting in 21 definition articles.They were included due to their relevance and more specific definition of buSynBio.Details about the selected articles are available in Table 1.
Following the analysis of the "definition artciles", we collected data from the main sample (n = 1,056) about characteristics of publications mentioning the term "bottom-up synthetic biology." We extracted data on the disciplinary affiliations of authors of papers from that sample, as well as information regarding funders, research organizations, research categories, and source titles (journals).After a close examination of data with the assistance of Dimensions.ai, we then selected for analysis only publications with correspondence address from one at least one of the five countries: Germany, United Kingdom, United States, Netherlands, and Switzerland.They were selected by being top-ranked in number of publications on buSynBio in the last five years.Countries as China (ranked in #4) called our attention, as well as Italy (#6), Spain (#7), Japan (#8) and France (#9).Switzerland (#10) have been selected due to our aim to examine European experiences with robust resources applied in SynBio in the last years, as well by important connections and research collaboration with centers in Germany (e.g., Heidelberg University).Countries under consideration were selected from the top 10 because of the EU-US scope of the analysis.
Additionally, experts based in centers of SynBio research in USA, Switzerland and Germany named people from one of the five countries when asked where buSynBio has grown in the last decade.These opinions were solicited during an interview in November 2021 by this paper's first author RGL da Silva with Principal Investigators and a former scientific coordinator of SynBio research consortia from Netherlands and Germany.
Finally, we applied tools of co-authorship network analysis by using the software VOS Viewer Online, currently available as integrated analytical tool in Dimensions.ai.Since bibliometrics is not sufficient as a method to be presented by itself, it is rather applied here to illustrate our exploratory inquiry of buSynBio initiatives.Our findings were contextualized by our multi-method qualitative study, self-guided literature review, and documentary evidence collected virtually.
Finally, we conducted documentary research about grants in official websites of centers and online repositories of funding agencies.

Limitations
The methodology for this study has certain limitations.First, the search for information in grant repositories and the selection of countries were partially oriented by the availability of online data, and the results were further limited by the keyword "bottom-up synthetic biology," the use of which may have led to the exclusion of relevant publications and grants that do not use this specific term.As result, research done in several important organizations in Europe and United States might not appear in the study (e.g., key initiatives from France, Spain, Italy, or different US states).Additionally, due to the cumulative dynamics of knowledge in bioengineering, we bring evidence that do not necessarily exclude interfaces and complementarities with the top-down approach, or previous areas of bioengineering and systems/synthetic biology.Since SynBio has advanced through a combination of methods, tools and technologies, both approaches might co-exist in research.

Results
The publication of specialized articles on "bottom-up synthetic biology" have increased both in absolute numbers and normalized to total number of publications (Fig. 3A).Likewise, we also see an increase when considered the quantitative development of publications with the term "bottom-up synthetic biology" normalized to all publications with the term "synthetic biology" (Fig. 3B).Here we present our bibliometric analysis of publications, institutions cited, and co-authorship networks in buSynBio.Where they publish?

Social and ethical checkpoints for bottom-up synthetic biology, or protocells
The research categories indicate preferable journals where buSynBio work are being published.(See Supplementary Material 1: Top-50 Source Titles (Journals), ranked by number of publications,

Research organizations
Likewise, our dataset shows that the label "bottom-up synthetic biology" has been adopted mainly in publications authored by people based in European universities and research organizations.

Selected countries
Here we provide a quick and descriptive overview of selected research initiatives on buSynBio in five countries.These included cases in Germany composed mainly by research done at Max Planck Society's institutes such as the Max Planck Institute of Biochemistry, the Max Planck Institute for Dynamics of Complex Technical Systems, and the Max Planck Institute for Medical Research, as well as an emerging center at Heidelberg University.In United Kingdom, publications are associated to fundamental and applied research completed at Imperial College London and the University of Bristol as relevant organizations in this manner.Likewise, institutions in the United States were examined, highlighting some based at the Cambridge-Boston ecosystem, such as Massachusetts Institute of Technology MIT and Harvard University's Science and Medical Centers, and centers and departments from the University of California System.Additionally, some Dutch initiatives were taken into consideration, which are organized in international consortia (Gravitational grants) for SynBio research, and include Delft University of Technology, Eindhoven University of Technology and Radboud University in Nijmegen.Finally, we selected several emerging research initiatives in Switzerland, with key initiatives in buSynBio shared between ETH Zürich, University of Basel, and the Swiss Federal Institute of Technology Lausanne (EPFL).

Germany
Two initiatives were selected based on the number of publications, directly associated with the buSynBio approach: the Max Planck Research Network in Synthetic Biology (MaxSynBio) and the "The Flagship Initiative -Engineering Molecular Systems" at Heidelberg University (funded by the German Research Foundation's Excellence Centers Program).
Active from 2014 to 2020, MaxSynBio aimed to be an endeavor to advance the field of SynBio in Europe, and had the buSynBio approach as a key topic for research and technology development.It was an intrainstitutional and multi-centered research consortium of the Max Planck Society.Its leaders define the field as: "Like engineering, synthetic biology involves building new biological systems from units and modules", stating that "scientists working in the field of synthetic biology are exploring ways in which technology can not only alter life, but create it" and that they aim "to produce novel living systems with desirable properties" (Schwille et al., 2018).The consortium was organized in three different clusters: 1) Cluster T: Enabling Technologies; 2) Cluster L: Life-mimicking processes; and 3) Cluster S: Systems Perspectives.Max-SynBio was composed by three facilities: 1) Research on cell-free protein expression in Martinsried: 2) Research on a Microfluidic Systems in Göttingen; and 3) a Protein Facility in Dortmund (MaxSynBio, 2020).
Taking Max Planck's units collectively, MaxSynBio mobilized the higher number of publications that explicitly mention "bottom-up synthetic biology" as a research endeavor.As Table 3 shows, co-authors of publications are associated mainly with three institutions: Max Planck Institute for Biochemistry (#1 in total of publications and #3 in total of citations); Max Planck Institute for Dynamics of Complex Technical Systems (#3 and #15) and Max Planck Institute for Medical Research (#4 and #9).See Fig. 5).
The second German initiative is the Flagship Initiative -Engineering Molecular Systems (FI-EMS), launched in 2019 and funded by the     2021).In 2015, the Institute for Molecular Sciences and Engineering (IMSE) was launched at Imperial College, working as an interdepartmental institution that aims to advance research in molecular sciences and engineering and solve "real-life" problems of society through the system of Grand Challenges.Through collaboration with business sectors on high priority research subjects (e.g., green economy, antimicrobial resistance, water, new materials, and biopharmaceuticals), the center became a relevant hub of research in chemical engineering, biochemistry, synthetic biology, and related disciplines (IMSE, 2021).
The Greater London area's academic landscape has provided important human and technological resources to the field of synthetic biology (Marris and Calvert, 2020) and has also played a significant role in buSynBio research.It is important to note the establishment of a virtual research center call FABRICELL, which was launched in 2017 as a joint initiative between Imperial College, King's College and University College London (UCL).FABRICELL is an explicit research endeavor in buSynBio, engaging over 30 research groups, affiliated partners from universities, and small knowledge-based companies working on "artificial cell design".According to Dunning (2017), researchers in the Center "aim to construct such artificial cells from the bottom up, by hijacking biological machinery (such as DNA, enzymes, proteins, and lipids) and by fusing together living and non-living components."Nonetheless, scientists expect that new cells can "perform designated functions seen in real cells such as environmental sensing and replication" (Dunning, 2017).
Beyond the London metropolitan area, a partnership between Max Planck Society of Germany and the University of Bristol appears relevant to the contemporary institutional building of buSynBio in a European context.The Max Planck-Bristol Centre for Minimal Biology was launched in 2019 with a mandate "to investigate the foundations of life from non-living constituents."The research undertaken by this entity is described as "advancing the bottom-up approach," and researchers claim that they "will construct artificial cytoskeletons and develop nanoscale molecular machines to investigate the building blocks necessary for life" (MaxSynBio, 2020).
The UK initiatives occupy a central place based on the number of publications, scientific collaborations and multidisciplinarity.Their publications have been frequently cited internationally (Fig. 4).When we apply a search for "Country/territory: United Kingdom", researchers from University of Bristol contribute the second highest number of published documents (N = 23) with publications co-authored by researchers based in Germany (Max Planck Institute for Medical Research and Heidelberg University), The Netherlands (Radboud University Nijmegen and Eindhoven University of Technology), and China (Harbin Institute of Technology).The data indicates important outcomes from traditional and newborn academic arrangements in this field, placing centers based in the greater London area as the priority in the destination of robust grants from national funders thus reaffirming the idea of "Golden Triangle" in the last decade's synthetic biology research (Kirk, 2019).
We can highlight three key trends in the academic arrangements of buSynBio in UK.First, buSynBio publications are associated with authors working in traditional research centers in fundamental Chemistry and Chemical Engineering in that country.Second, university-industry partnerships geared towards practical applications of biochemical and engineering research have become a major source of funding to complement science projects as indicated by the type of grants and funding schemes supporting buSynBio research in that national context.Finally, the presence of publications from "newcomers," such as King's College London, University College London, and the University of Bristol, fits as emerging hubs in buSynBio research internationally.

United States
Synthetic biology has been pioneered in the US since the turn of the 21st century.This field has grown in genomics and biotechnology hubs such as the Craig Venter Institute and its partners from the University of California System, centers for biological and biomedical research in traditional science and engineering departments, medical centers within the Harvard University System, Massachusetts Institute of Technology (MIT) and other leading research institutions, and, finally, in early research networks for Synthetic Biology.One example of such a national research network is the Synthetic Biology Research Center (SYNBERC), which was established in 2006 and funded with a ten-year grant from the National Science Foundation (NSF) to support the development of synthetic biology" (SYNBERC Synthetic Biology Research Center/Engineering Biology Research Center, 2021).
Based on our examination of the institutional affiliations of the authors of published research, we can highlight four major research centers associated to buSynBio: 1) the Department of Biological Engineering at the Massachusetts Institute of Technology (MIT-BE) and local partners; 2) departments and institutes within Harvard University System (i. e., Department of Chemistry and Chemical Biology, School of Engineering and Applied Sciences, and Harvard Medical School); 3) the University of California at San Diego's Department of Chemistry and Biochemistry and regional collaborations; and 4) the University of Chicago's Pritzker School of Molecular Engineering in partnership with the Argonne National Laboratory.Selecting and describing those initiatives is a challenge, since most of the scientific work in buSynBio has been sustained by a multi-sectoral network with no clear borders between disciplines, institutions, and goals.
The MIT Department of Biological Engineering (MIT BE) started as an interdisciplinary academic unit in the School of Engineering in 1998.
In 2002, it was renamed to Biological Engineering Division, and in 2007 it became an official department, just two years after accepting undergraduate majors (MIT Libraries, 2021).Its official website states that the department's mission is to generate "new knowledge in the interface of engineering and biology" and that its researchers are "defining and leading the emerging discipline of biological engineering, fusing engineering with modern molecular-to-'omic biology to measure, model, manipulate, and make biological systems for powerful new biological technologies."It also claims that its mandate is "to prepare the next generation of scientists and engineering who will advance bioscience and biotechnology through quantitative, integrative, design-oriented analysis and synthesis of biological mechanisms" (MIT Biological Engineering, 2021).
The Department of Biological Engineering is a key MIT center associated with publications on buSynBio in the US, together with researchers based in the Department of Chemical Engineering, the David H. Koch Center for integrative cancer research, and the Department of Biology.Hence, as shown by the bibliometric and documentary search, the MIT's research endeavors in buSynBio are the result of a system of multiple institutions and academic units, rather than from isolated departmental initiatives.
Furthermore, three Harvard University System's centers in the Boston-Cambridge area deserve attention: 1) the Department of Chemistry and Chemical Biology; 2) the School of Engineering and Applied Sciences; and 3) the Harvard Medical School.Additionally, researchers pursuing buSynBio at Harvard are often associated with the Wyss Institute for Biologically Inspired Engineeringa philanthropic initiative for accelerating innovation and new biomedical applications of bioengineered entities.These institutions are funded with grants from the NSF and the National Institutes of Health (NIH) and produce high-cited articles found in our sample (N = 739), involving researchers from both Harvard and MIT.
Knowledge networks between scientists and engineering academics in the Boston area play an important role in the emerging US landscape of buSynBio due to their sustained access to public and private funding schemes over the last twenty years (Libraries and History, 2021).The search on grant repositories also identified several research groups based in the University of California at San Diego (UCSD), and national laboratories and research institutes on the west coast of the US.Here we highlight two examples from that regional context: the UCSD Department of Chemistry and Biochemistry's funded project in the Molecular Engineering for Cellular Imaging and Reprogramming project (MECIR) and the Scripps Research Institute and its regional collaborators.
During the period of 2008-2020, the Department of Chemistry and Biochemistry of the UCSD received at least 14 grants associated with the Molecular Engineering for Cellular Imaging and Reprogramming, mostly funded by an "Integrated NSF Support Promoting Interdisciplinary Research and Education" (NSF INSPIRE) between 2013 and 2018.Published articles by researchers at the Scripps Research Institute have a significant number of citations (N = 335) (see Table 3, showing the institution #3 in number of citations and #7 in number of publications in the US).Researchers from UCSD have published with partners from the previous centers, and other institutions as Oak Ridge National Laboratory, Lawrence National Laboratory, and J. Craig Venter Institute.
The last selected initiative is the University of Chicago's Pritzker School of Molecular Engineering (PME).Launched in 2011 thanks to an investment from Pritzker Foundation, it focuses on molecular engineering research and development and has collaborated with buSynBiorelated initiatives on nanofabrication of complex biological structures.A key characteristic of the PME is its partnership with the Argonne National Laboratorya national laboratory funded by the US Department of Energy Office of Science (DOE), located in Lemont, IL.An example of this collaboration is the work done in partnership with the Argonne's Center for Nanoscale Materials (CNM), a research facility with "extensive synthesis capabilities and expertise for the creation of novel nano-bio hybrid materials and biological assemblies."(Argonne National Laboratory, 2021).
Considering publications that explicitly cited the key word "bottomup synthetic biology", the United States have registered the wider network of collaborations (N = 166), showing that buSynBio has a nationally-oriented, collaborative academic pattern.
The academic initiatives on buSynBio in the US exhibit at least three relevant trends in the field's organizational configuration.First, wellestablished research centers in sciences and engineering in the Harvard -MIT axis play a continuous crucial role in facilitating buSynBio knowledge production, with emphasis on competences in traditional areas of Chemistry and Biochemistry, Chemical engineering and collaborative work with medical centers in both institutions (e.g., Harvard Medical School and David H. Koch Center for integrative cancer research).Second, our analysis of publications uncovered the importance of philanthropic initiatives for the improvement of the buSynBio knowledge landscape in highly innovative fields, as exemplified by the involvement of Pritzker Foundation in the University of Chicago's case.Finally, scientific collaborations among universities and the Department of Energy's National Science Laboratories are associated with fundamental and applied breakthrough research in the field, highlighting the importance of stable state funding sources for the advancement of SynBio research as whole (Burke Group, 2021).

Netherlands
Dutch research in SynBio is well-known for its breakthrough achievements over the past years (Bhatt et al., 2022).Strong research capabilities in traditional research centers in fundamental Chemistry have supported the implementation and growth of national collaborative initiatives and consortia in synthetic biology and molecular engineering research.Most of them are now explicitly focused on buSynBio.
Here we highlight two of them: 1) the Research Center for Functional Molecular Systems (FMS) initiative, and 2) the Building a Synthetic Cell (BaSyC) program.
FMS is a national research consortium funded by the Ministry of Education, Culture and Sciences of The Netherlands that was established in 2013 as a collaboration of three research centers: Eindhoven University of Technology, the Radboud University Nijmegen, and the University of Groningen.Those organizations are strongly connected by its scientific activities in three respective excellence centers: the Institute for Complex Molecular Systems (ICMS, Eindhoven), the Faculty of Science's Institute for Molecules and Materials (IMM, Nijmegen), and the Faculty of Science and Engineering's Stratingh Institute for Chemistry (SIC, Groningen).According to the platform of the Netherlands Organization for Scientific Research (now), 6 out of the 8 grants found by our search had at least one researcher from FMS as a PI or a project member.It shows how centers like ICMS and IMM were able to reorganize local research competences in fundamental sciences and engineering to collaborate through broader initiatives for synthetic biology research.
Additionally, the Gravitational BaSyC Program is considered one of the main projects on buSynBio internationally.The description of its project goals is itself a definition of the bottom-up approach.BaSyC is described as a research program "aimed at creating an autonomous, selfreproducing synthetic cell with a bottom-up approach, that is, through integration of molecular building blocks".Launched in 2017, the project is composed by 17 team-leaders with strong interdisciplinary backgrounds, and the program involves six Dutch research institutions, i.e., Delft University of Technology, Groningen University, Radboud University Nijmegen, Vrije Universiteit Amsterdam, Wageningen University, and the AMOLF Institute (Building a Synthetic Cell Project (BaSyC), 2021).
The initiative is funded by the Dutch Ministry of Education, Culture and Science, in cooperation with the Netherlands Organization for Scientific Research (NWO).It is configured by the "gravitation grant" style (i.e., structured through the form of a research consortium), which has the advantage to mobilize existent national research networks.The search in grant repositories combined with the analysis of the coauthorship network show that buSynBio has been structured through scientific and technological collaborative efforts in successful national consortia.Our dataset indicates that Delft University of Technology and Eindhoven University of Technology had most publications (16 and 14 respectively) and citations (707 and 466), followed by Radboud University Nijmegen with 9 publications and 494 citations.
Dutch initiatives on buSynBio have translated renowned national science capabilities in chemical and experimental biochemistry to new applied research projects.We have identified three trends on buSynBio research in that national context.First, the adoption of "gravitational grant" model has been effective in promoting meaningful collaborations in science and technology among different types of research organizations (university, industry, public research institutes, etc.).Second, technology institutes have played an important role in moving forward projects towards technological development and biological applications of new materials and artificial components, as exemplified by the above discussion of the two projects involving Chemical Sciences, Materials Sciences, Nanotechnology, and molecular engineering.The third trend is the participation of researchers from the Netherlands in international networks such as German and UK initiates, such as the partnerships of FMS and BaSyC with MaxSynBio and FABRICELL.

Switzerland
New academic arrangements of chemical and molecular engineering research have been implemented in Switzerland over the last decade, which have impacted the growth of buSynBio research in that country.Our search strategy combined with data collected from the Swiss National Science Foundation's (SNSF) grant repository has determined the initiative "National Centre of Competence in Research Molecular Systems Engineering" (NCCR MSE) as instrumental in fostering the study of buSynBio.Structured as a national consortium, NCCR MSE is a multicentered initiative funded by the SNSF since 2014.The consortium converges researchers from traditional elite Swiss universities (e.g., University of Basel and University of Geneva), institutes of technologies (ETH Zürich and the École Polytechnique Federale de Lausanne), and business research hubs (IBM, Roche, Novartis) from the interdisciplinary domains of sciences, engineering, and technologies.According to the grant description and official website information, the project is currently organized in three research streams: "1.Top-down fabrication of molecular factories"; "2.Bioinspired molecular factories" and "3.From cellular systems to health control" (NCCR Molecular Systems Engineering, 2022).Almost one hundred researchers are involved with interdisciplinary research in "systems chemistry, systems biology and synthetic biology for the creation of chemical and biological modules integrated into molecular factories and cellular systems," oriented towards the advancement of new theoretical and methodological approaches to the study of multi-level biological functions (i.e., from the chemical-physical dynamics of molecules to the two-way road bottom-up and top-down approaches of synthetic biology).The consortium aims to develop innovative applications of engineered technologies in biomedical and healthcare technology development (NCCR, 2021).
Three Swiss research institutions have registered relevant academic collaborations in that field: ETH Zürich Department of Biosystems Science and Engineering; University of Basel's Departments of Chemistry and Biomedicine; and the École Polytechnique Federale de Lausanne.Swiss institutions have generated 25 publications and 66 co-authorships that explicitly mentioned the term "bottom-up synthetic biology".
We have identified two key trends in the NCCR MSE's work on buSynBio.First, the Swiss consortium plays a relevant role in articulating competences from sciences, engineering and biomedicine structured through a two-way road SynBio dynamic (integrating both bottom-up and top-down approaches in multiple basic science projects and technology development activities).Second, research and development activities are focused on biomedical applications of advanced molecular technology (e.g., R&D in gene circuits, tissue engineering, new bio-inspired functional nanomaterials, artificial metalloenzymes, etc.) and aim to develop new research competencies and high-level collaborations for applied biomedical engineering technologies in the healthcare sector.

Discussion
Scientific governance (i.e.how we organize research efforts, its policies, agendas, and priorities to receive scarce resources) plays a critical role in science and technology development.According to Irwin (2008) (Irwin et al., 2008), the management of knowledge systems, and the ways scientists anticipate future outcomes of their work, has key implications in the institutional trajectory of scientific fields.Both expert knowledge and technological innovations are possible thank to process that go beyond the resolution of internal challenges faced by people involved with R&D activities.Instead, novel science and technology emerge and solidify through a broader cultural and political processes.Scientific governance assumes a central role in establishing collective interests and viable mechanisms to co-produce expert knowledge.It does so in alignment with a wide array of stakeholder priorities and views of ethics of science and technology, and social feasibility of research, agendas, policies and institutions (p.589).(Clarke and Fujimura, 1994;Pickersgill, 2012).
The funding of scientific activities is essentially a political process in which knowledge and technology producers are constantly negotiating and defining when, how and who will be in charge of optimally allocating scarce resources to advance or interrupt scientific projects (Nelkin, 1992).Decision-making, management, funding repositioning, and institutional adaptations are integral to reshaping science and technology landscapes.These aspects should be examined by robust multimethod strategies and interdisciplinary frameworks (Nowotny, 2003;Morange, 2006;Frickel and Gross, 2005).
The social study of the sciences offer tools to examine how the implementation of novel scientific governance systems and strategies are taking place to repositioning the material, intellectual and political resources of synthetic biology -driving this field to a new disciplinary, technical and organizational configuration (Undone, 2016).As in many studies analysisng organizational change in life sciences research, our work demonstrates that initiatives advancing the buSynBio approach are increasing in relevance and geographical presence, and are organized through provisional and tentative institutional arrangements.Previous research on organizational changes in science and technology has advanced theories and tools to examine the provisional state of knowledge systems and regimes.Kuhlmann et al. (2019) terms this state as "tentative governance regimes," which is also described by Lyall and Tait (2019) as "tentative forms of governance."In this context, notions of provisional governance have driven sociological discussions towards SynBio as a field, and its implications in science policy and society (Marris, 2015).Additionally, there is a growing body of literature dedicated on the techno-epistemic aspects of Synbio research practices and cultures of work (Kastenhofer, 2013;Meloni, 2014).Likewise, much study is now available on why and how some fields take a tentative shape, and under what conditions they negotiate the building of new infrastructures that are politically feasible to produce expert knowledge and technologies in society (Gibbon et al., 2018;Eyal and Medvetz, 2023;Fox et al., 2020;Silva et al., 2021;Au, 2021).
Among various frameworks developed to study governance of science and technology, the notion of "knowledge infrastructures" offers a lens to understand the organization of scientific activities in modern societies (Edwards et al., 2013;Karasti et al., 2016).Heavily sustained by previous developments on "infrastructures" present in Star (1999) and Bowker et al. (1999); "Knowledge Infrastructures" (KIs) are defined as "robust networks of people, artifacts, and institutions that generate, share, and maintain specific knowledge about the human and natural worlds" (Karasti et al., 2016).Furthermore, they are seen as provisional arrangements where stakeholders test different institutional setups to govern emerging research, or revise traditional agendas and institutions.
KIs are useful to conceptualize how cultural systems and processes are shaping buSynBio.The research initiatives we outlined above illustrate a current reconfiguration of SynBio research, a field that has undergone multiple organizational settings over the last two decades.This dynamism is evident in the growing number of publications on SynBio involving input from various disciplines, contributing to the development of fields like molecular systems engineering and biomedical engineering.For example, the case of the University of Chicago's Pritzker School of Molecular Engineering (PME) and its SynBio research collaborations with Argonne National Laboratory highlight the potential of buSynBio to mobilize support in new institutions and foster prosperous environments for future applied buSynBio research in other fields as new materials and precision medicine.
KIs also serve to contextualize specific science and technology within a broader framework of epistemic categories as networks and system.As noted by Karasti and colleagues (2016), the organizational aspects of research are evolving through digitization, and virtualization of scientific communities and networks, and the interconnectedness of underlying systems, structures, and services.This aligns with the evidence presented in our results, where all examined research initiatives incorporated digital platforms to organize research activities in buSynBio.
Regarding the digitization of data and collaboration, the virtual research center FABRICELL demonstrates the significance of digitizing scientific tasks and enabling remote engagement as critical components of their work in SynBio.This joint initiative facilitates meaningful collaboration among scientists and efficient communication, particularly during challenging periods like the COVID-19 pandemic.
The virtualization of research communities and networks is also a crucial aspect of consortium-based buSynBio initiatives, as demonstrated in many cases such as Max Planck Research Network in Synthetic Biology (MaxSynBio) in Germany, the Research Center for Functional Molecular Systems (FMS) and the Building a Synthetic Cell (BaSyC) program in the Netherlands, and the National Centre of Competence in Research -Molecular Systems Engineering in Switzerland.A common characteristic of these initiatives is the implementation of virtual research infrastructures and participation through national and international decentralized efforts within Europe.
In terms of interconnectedness of underlying systems, structures, and services, notable examples can be found in early SynBio research initiatives in the United States in the 2000s, such as SYNBERC and the NSF INSPIRE project.Both laid the groundwork for the subsequent growth of SynBio research, leading to the establishment of centers of excellence on the western and eastern coasts of the country.Networks generate intangible resources that are crucial for the development of science and technology.
It is important to clarify that the term "infrastructures" does not refer to fully coherent systems but rather to ecologies or complex adaptive systems.This adaptive process is ongoing, with individual elements constantly changing and new ones being introduced (da Silva et al., 2024).As a concept, KIs capture the dynamism, instability, and adaptability inherent in systems of expert knowledge production.
The adaptive aspect can be observed in emerging centers in the United Kingdom, Germany, and the USA.These centers build on previous R&D efforts in SynBio within traditional departments, serving as platforms for new research projects that advance buSynBio.For example, Imperial College's Institute of Molecular Sciences and Engineering embodies a multi-disciplinary infrastructure that fosters new science and technology through institutional adaptations within traditional departments.The collaborative landscape among national laboratories, the Scripps Institute, and the University of California at San Diego also exemplifies the adaptability of more established KIs in promoting new research.An analysis based solely on static institutional affiliations and disciplinary departments cannot capture the nuances and hybrid nature of research agendas in biological and biomedical engineering.
Finally, KIs helps to understand the provisional nature of science and technology.Many of the examples in our study involve initiatives designed to be provisional, such as "The Flagship Initiative -Engineering Molecular Systems" at Heidelberg University, transnational initiatives like the Max Planck -Bristol Center for Minimal Biology, and temporary engagements supported by science consortia in Switzerland, the Netherlands, and the United Kingdom (e.g., in the Greater London area).KIs provide a flexible and comprehensive tool for analyzing processes of scientific governance offering insights into the adaptive, ever-evolving nature of scientific institutions and networks.

Conclusions
In this article, we examined emerging research initiatives in the field of buSynBio through the lens of the literature on governance and organizational change of science and technology.Our analysis presents an overview of national initiatives in Europe and United States that have gained prominence and are currently reshaping KIs of SynBio towards the development of theories and technologies based in its bottom-up approach.
Our analysis situates the emergence of the bottom-up approach as a key organizational change of contemporary SynBio research.In applying the concept of KI, we aimed at open new venues to discuss the cultural aspects and social challenges driving SynBio research and innovation, and why it assumed its current organization around the world.Ultimately, our study aimed to advance empirical social research on how expert knowledge becomes socially and politically feasible through the reorganization of practices, institutions and promises of new biotechnologies.
Exploring the organizational complexity of contemporary SynBio research can help develop more accurate ST&I policies, as well as more targeted interdisciplinary public-private initiatives to foster the bottomup approach of synthetic biology as a platform for future innovations in translational bioengineering, responsive bionanomaterials and novel engineered molecular systems and technologies.
by the authors with data from Dimensions.ai.most publications are associated with Biological Sciences (N = 365), with the majority coming from Biochemistry and Cell Biology (N = 295).In addition, there were publications from Chemical Sciences (N = 233)mainly from Macromolecular and Materials Chemistry (N = 69), Engineering (N = 198), and Physical Sciences (N = 63).This is followed by disciplines, which achieved relevant number of citations (C) in the period, i.e., Engineering (N = 62; C = 1,316), Genetics (N = 51; C = 1,151) and Biomedical Engineering (N = 30, C = 925).The timeline evolution in the number of publications in each research category is available in the Fig. 4 below.
Data from Dimensions.ai brought 41 grants associated with publications from 2008 to August 2023, related to 11 funders in the fields of Engineering, Biotechnology and Biological Sciences in Europe and United States.Additionally, we conducted a manual search in funding agencies' platforms for "Engineering and Physical Sciences" and "Biomedical and Bioengineering research" of 8 funders from Europe and United States.These included: German Research Foundation DFG -GEPRIS; German Federal Ministry for Education and Research; Bundesministerium für Bildung und Forschung -Max-Planck-Gesellschaft; U.S. National Science Foundation (NSF); Engineering and Physical Research Council EPRC -UKRI Research Gateway; Dutch Research Council (NWO); Swiss National Science Foundation (SNSF), and European Commission/European Research Council ERC (only Consolidator and Advanced Grants from 2016 to 2020).With this complementary search, the final sample of grants totaled 146 grants from 9 funders.
Our document analysis was discussed in virtual conferences, e-symposiums, project retreats and workshops in buSynBio in Europe and United States from November 2020 to June 2022, and the insight generated was used to improve the methodology, search strategy, and to reduce selection bias.Details of the documentary research are available in the Table2.

Table 2
Details of the document search in official grant repositories (N = 146).
With regards to research organizations, the results indicate two divergent science policy agendas practiced by its funders: (1) in United States, research on buSynBio takes place in departmental-driven initiatives in traditional Chemistry, Biochemistry and Biomedical Engineering research centers, such as Harvard University System's research centers, or in departments of Biological and Biomedical Engineering at Massachusetts Institute of Technology MIT, which indicates a more advanced stage of the spread of SynBio knowledge into bioengineering and biomedical domains; and (2) in Europe, grants from funding agencies directed to improve buSynBio research capabilities in countries like United Kingdom, Germany, Netherlands, and Switzerland are organized through national/supranational research consortia and inter-departmental University initiatives (echoing studies on governance regimes and organizational preferences of scientific research and policies in Europe as analyzed in Cramer and Hallonsten, 2020).(See previous Supplementary Material 3: Top-50 Research Organizations associated with publications on "bottom-up synthetic biology", 2008-2022).

Table 3
Selected research initiatives on bottom-up Synthetic Biology (N = 14).
(continued on next page) R.G.L. daSilva et al.

Table 3
(continued ) Key research organizations by number of citations 2008-2021.other countries), which expanded academic research capabilities to other centers of biochemistry and molecular biology, and chemistry and molecular systems engineering.Finally, the implementation of the Heidelberg University's cluster of excellence indicates a movement of buSynBio knowledge to be applied in biomedical sciences, translational research, and clinical innovation.Bristol Centre for Minimal Biology (based at the University of Bristol UK and the Max Planck Institute for Medical Research in Heidelberg, Germany).According to the documents collected through UK Research and Innovation platform "Gateway to research" of the Engineering and Physical Sciences Research Council of UK (EPSRC), academic competences of tailoring biosynthetic components and minimal biochemical sytems appear as the aim of a grant from 2007 titled "Molecular Systems Engineering: from generic tools to industrial application."This research focused "on the development of methods and tools for the design of better products and processes in applications where molecular interactions play a central role" (UK Research and Innovation Platform, 2021).The grant funded activities and projects under the Research Programme "Molecular Systems Engineering" were implemented from 2007 to 2013 under the auspices of the Department of Chemical Engineering at Imperial College London.RP-MSE is considered by interlocutors as an early-initiative in Europe to advance control of biochemical systems at the molecular level, with applications to buSynBio and other emerging biotechnology domains.RP-MSE leaders and new academic and corporate stakeholders implemented years later a new interdepartmental initiative to improve research and development of innovative applications of molecular engineered technologies in areas such as energy, new materials, and healthcare (Research Programme Molecular Systems Engineering, Excellence Strategy of the German Research Foundation (DFG) -Clusters of Excellence at Heidelberg University.This new initiative appeared as a relevant player in the European context of buSynBio research, being responsible for the implementation of the Institute for Molecular Systems Engineering (IMSE-Heidelberg), where research competences have been organized around different applications of molecular engineering sciences and technologies since 2020.According to data, this center connects Heidelberg university with researchers from other institutions, with the major partner being the Max Planck Institute of Medical Research and its programs on SynBio research.We can distinguish three trends of selected research initiatives on buSynBio in Germany.First, publications originated in research centers that were supported by long-term funding schemes impacted the building of buSynBio initiatives.Max Planck Institute should be highlighted as playing a key role in SynBio research nationwide, and has been active in promoting educational and scientific training with innovative graduate programs.Here we could highlight the Max Planck School Matter to Lifea network and graduate program which has played a critical role in the development of research/teaching initiatives on buSynBio and beyond.Second, knowledge spillovers were fostered by sustained national research networks (indicated by the number of scientific collaborations of researchers based in Germany with peers from Source: information from grant platforms and official websites.***Add European SynCell Initiative (Transnational) after BaSyC.Fig. 5.