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Published in final edited form as: Drug Discov Today. 2022 May 30;27(10):103297. doi: 10.1016/j.drudis.2022.05.023

A global bibliometric and visualized analysis of bacteria-mediated cancer therapy

Jiawei Wang 1, Mohammed Maniruzzaman 1,*
PMCID: PMC9530009  NIHMSID: NIHMS1819823  PMID: 35654388

Abstract

Bacteriotherapy has proved to be a powerful tool to fight against cancer. Herein, we used VOSviewer, CiteSpace, and Python to perform the first global bibliometric analysis of the literature from 2012 to 2021 on bacteria-mediated cancer therapy. Based on the results, East Asia and North America contributed the most publications to this research area. Additionally, the keyword analysis indicated that immunotherapy and nanoparticle (NP)-based drug delivery systems have long been popular topics in cancer bacteriotherapy, whereas the gut microbiota and probiotics are emerging research hotspots. This study provides crucial insights into the historical development of bacteria-mediated cancer therapy from 2012 to 2021, which will be helpful for scientists to conduct further investigation into this promising field.

Keywords: Cancer, Bacteria, Cancer bacteriotherapy, Immunotherapy, Bibliometric analysis

Introduction

According to the World Health Organization (WHO), cancer has been the leading cause of death worldwide for over 10 years.1 Furthermore, the risk of cancer incidence and mortality is rapidly increasing worldwide; therefore, there is an urgent need to develop effective strategies to reduce cancer burden and prolong the survival of patients. Despite remarkable progress in conventional cancer therapies, several bottlenecks remain to be addressed, such as insufficient tumor penetration and off-target effects.2,3 With the rapid development of biomedical engineering techniques, bacteriotherapy has emerged as a powerful tool to overcome these challenges owing to the excellent tumor selectivity and tumor penetration capabilities of bacteria, 4–6 including many anaerobic and facultatively anaerobic bacteria, such as Escherichia coli (E. coli), Salmonella, Clostridium, Listeria, and Bifidobacterium.7 These bacterial species have been used broadly as tumor-targeting therapeutics for anticancer treatment.8–11 For instance, Murphy et al. developed recombinant E. coli K12 expressing tumor necrosis factor-alpha (TNF-alpha), an anticancer cytokine that can directly kill cancer cells and induce antitumor immunity.8,12 Studies showed that the engineered E. coli K12 specifically accumulated within tumors and significantly reduced tumor burdens. In another study, Lee et al. evaluated the tumor-targeting and gene-delivery ability of recombinant Salmonella carrying an endostatin expression vector.9 Endostatin is an angiogenesis inhibitor that can inhibit tumor vascularization and suppress tumor growth.13 Results showed that the recombinant Salmonella preferentially colonized tumors, reduced tumor microvessel density, and caused tumor regression.

Bacillus Calmette–Guerin (BCG), an attenuated strain of Mycobacterium bovis, was initially developed by Calmette and Guérin in 1921 as a vaccine against tuberculosis (TB).14 In 1976, Morales showed that BCG was effective in preventing the recurrence of non-muscle invasive bladder cancer and it was approved in 1990 by the US Food and Drug Administration (FDA) to treat superficial bladder cancer.15,16 Since then, bacteriotherapy has been successfully applied in cancer clinical trials and achieved desired therapeutic outcomes.17 Lamm et al. conducted a randomized trial to compare the therapeutic efficacy of doxorubicin (DOX)-based chemotherapy with BCG-based immunotherapy in treating transitional-cell carcinoma of the bladder.18 BCG treatment enhanced tumor regression and improved the protection against cancer recurrence compared with chemotherapy. Additionally, the BCG vaccine has been widely used in many countries, including UK, USA, Canada, China, and India, among others.19 To broaden its clinical application further, several patents were invented to enhance its therapeutic efficacy. For instance, Russell et al. invented a method to treat bladder cancer using modified BCG with reduced amounts of cell envelope lipids.20 Compared with conventional BCG therapy, intratumoral injection of delipidated BCG led to an improved safety profile, which decreased the possibility of significant adverse effects and prolonged the survival of patients. In addition to bladder cancer, an invention that used recombinant BCG to treat prostate cancer was created by Geliebter.21 The recombinant BCG induced robust immune responses against prostate-specific antigens, which are effective for the treatment of primary, locally recurrent, and metastatic prostate cancer. In another patent application, an attenuated Salmonella strain, Ty21a, was used for the treatment and prevention of bladder cancer.22 Ty21a preferentially colonized tumors and induced tumor regression. These inventions in cancer bacteriotherapy are under ongoing investigations before they can enter the clinic.

Bibliometrics is an approach widely applied to qualitatively and quantitively analyze high-impact publications on a specific subject. In addition, this approach integrates statistical and mathematical methods with data visualization to identify the knowledge structure, current development, and research frontiers of a particular domain.23–25 Bibliometrics is also an important tool to identify the most influential authors, institutions, countries, and journals within a particular research area.25 Moreover, the bibliometric analysis of existing research can provide an objective measure of landmark literatures and peer recognition of research work by analyzing the highly cited publications in a given field.26 In the current study, Python was used to visualize the descriptive statistical analysis. Python is an open-source programming language with high flexibility and productivity.27 Compared with conventional data visualization tools, Python programming language offers several benefits, including the availability of multiple plotting and graph libraries and the customization of different types of advanced chart, such as geographical maps.28 In addition to versatile visualization, Python allows the batch downloading of scientific literature.29 Furthermore, with a couple of keywords in a particular research domain, required information can be automatically extracted from online databases through web scraping, which can significantly improve the work efficiency of researchers.30.

Driven by advances in the field of biomedical engineering and a deeper understanding of cancer biology and microbiology, research on bacteria-mediated cancer therapy has gained increasing attention, with numerous articles on this topic published over the past decade.7,31,32 Therefore, we conducted a bibliometric analysis of publications on bacteria-mediated cancer therapy over the past decade to provide crucial insights into the current status and future research trends of cancer bacteriotherapy. We also hope that this comprehensive bibliometric analysis will be helpful for researchers to conduct in-depth explorations of this promising research field.

Bibliometric data source

Bibliometric data were retrieved from Web of Science Core Collection database on January 8, 2022, using the following keyword query: (Topic = [‘cancer treatment’ OR ‘cancer-treatment’ OR ‘cancer therapy’ OR ‘cancer-therapy’ OR ‘tumor treatment’ OR ‘tumor-treatment’ OR ‘tumor therapy’ OR ‘tumor-therapy’] AND Topic = [‘bac teria*’ or ‘bacteriotherapy’]). The resulting records contained 1,758 publications, including 1,109 articles, 538 reviews, 37 book chapters, 25 proceedings, 20 early accesses, 20 editorials, six abstracts, two news articles, and one letter. The bibliometric information of selected publications was collected, including keywords, authors, journal, subject category, institution, country, year of publication, number of citations, and reference records. Python programming language was used for the visualization of descriptive statistical analysis. Online literature metrology analysis (https://bibliometric.com/app) was used to analyze the co-authorship between countries/regions. Co-occurrence of keywords, citation, and co-citation analysis were conducted and visualized using VOSviewer (version 1.6.16) and CiteSpace (V.5.8.R3).

Bibliometric landscape of cancer bacteriotherapy

Overview of annual publications

The recent decade has witnessed a noticeable increase in both annual publication numbers and number of citations of articles on bacteria-mediated cancer therapy, peaking at 320 and 11,843, respectively in 2021 (Fig. 1a). The total citations of collected publications from 2012 to 2021 was 37,205, indicating that bacteriotherapy on cancer treatment has attracted significant research interest over the past 10 years and is likely to be a research hotspot in 2022 and beyond.

FIGURE 1.

FIGURE 1

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Descriptive statistical analyses of articles on cancer bacteriotherapy published from 2012 to 2021. (a) Annual publication numbers and citation times of publications. (b) Global geographical distribution of publications. (c) Network visualization map of country/region collaborations. (d) The most-contributing institutions according to number of publications.

The most-productive countries and institutions

According to the total number of publications (2012–2021; Table S1 in the supplemental information online), China contributed the most published papers (436, 24.8%), followed by the USA (375, 21.3%), and India (136, 7.7%). Additionally, publications from the USA were cited 13,860 times, ranking first in all countries, followed by China (9,386 times), and Germany (2,770 times). The H-index is a bibliometric indicator that combines the influence of productivity (representing quantity) and impact (indicating quality), and is used to evaluate the overall research performance of a scholar, journal, institution, or country.33 Among all contributing countries, the USA obtained the highest H-index score (55), with China coming in second (51).

Most articles were published by authors from East Asia and North America (Fig. 1b). In addition, the number of publications from East Asia was 1.53 times higher than that from North America. The international cooperation visualization map suggested that China collaborated most closely with the USA, whereas research collaborations among other countries were scattered (Fig. 1c). In terms of the leading research institutes, the Chinese Academy of Science topped the ranking of the most-productive institutions, with 60 publications cited 2,107 times, whereas 33 publications came from Chonnam National University with a total of 807 citations (Fig. 1d). This was followed by the University of California San Diego, Islamic Azad University, Zhejiang University, and Harvard University, each of which generated more than 20 publications and >130 citations. Geographically, most leading institutions came from China, USA and Iran, further signifying the robustness of bacteria-related cancer research in these countries.

Leading publication sources

The top 10 leading journals published a total of 192 articles on cancer bacteriotherapy from 2012 to 2021 (Fig. 2a). International Journal of Molecular Sciences published the most articles (29), whereas Scientific Reports ranked second, with 23 publications, followed by Frontiers in Immunology (21) and PLOS ONE (20). Nevertheless, the citation ranking was not in accordance with the ranking based on publication numbers (Fig. 2b). As the most-influential journal, Science was cited more than 2,000 times with merely two publications, whereas ACS Nano ranked the second with 1,092 total citations. This was followed by Advanced Materials (955 citations), Chemical Society Reviews (758 citations), and Biomaterials (700 citations). The density visualization of the journal co-citation network is shown in Fig. 2c. The most-cited journals displayed higher density (red color), whereas the less frequently cited journals exhibited lower density (blue color). Accordingly, Science, The Proceedings of the National Academy of Sciences, and Nature were the most-influential publication sources in the field of bacteria-mediated cancer therapy over the analysis period.

FIGURE 2.

FIGURE 2

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The top-ten (a) publishing journals and (b) cited journals in the field of cancer bacteriotherapy; (c) Journal density map based on the co-citation network.

The most-productive authors

The scholars who contributed the most publications and who received the most citations (Table S2 in the supplemental information online) each published five or more articles on cancer bacteriotherapy from 2012 to 2021. The most-productive author was Jung-Joon Min, who published 19 papers with a total of 381 citations. In terms of the total citation ranking, Giorgio Trinchieri took the first place, with 1,575 citations, followed by Yu Chen (611) and Laurence Zitvogel (574).

The most-cited publications

Citation analysis is considered as an important approach to evaluate the impact of a publication. Additionally, the analysis of highly cited articles contributes to the identification of research hotspots. Herein, the 50 top-cited publications were selected based on average annual citations (Table S3 in the supplemental information online). The top-cited article was published by Matson et al., with an average yearly citation of 247.5. According to this publication, microbiota composition had a significant impact on antitumor immune response and immunotherapeutic outcome.34 The second most-influential article was published by Iida et al., which received an average of 113.1 citations per year. This publication revealed that the microbiota had a crucial role in modulating the tumor microenvironment and also controlled the tumor response to immunotherapy and chemotherapy.35 Thus, bacterial effects on immunotherapeutic efficacy are an attractive and popular research topic.

Co-citation analysis of references

Two articles that were both cited as references in another publication have a co-citation relationship.36 The cited articles represented in the co-citation network were classified into eight clusters (Fig. 3a) by CiteSpace. These clusters were named by extracting nominal terms from the keywords using the latent semantic indexing (LSI) algorithm. By studying the references corresponding to each node category as well as publications that cited these articles, the intellectual base of current research on cancer bacteriotherapy was summarized as follows: Cluster 0 (microbiome): studies that investigated the impact of microbiome and its composition on tumor response to cancer therapy; Cluster 1 (Salmonella): studies that used Salmonella to selectively colonize hypoxic tumor regions; Cluster 2 (photothermal therapy): studies that used the hyperthermia produced by photothermal agents to induce cancer cell death; Cluster 3 (combination therapy): studies that combined multiple cancer therapies to treat cancer; Cluster 4 (magnetic hyperthermia): research that used magnetic hyperthermia agents to generate excessive heat to kill cancer cells; Cluster 5 (bacteriotherapy): studies that used bacteria or their products to treat cancer; Cluster 6 (gene therapy): studies that used bacteria as gene vectors for cancer treatment; and Cluster 7 (ribosome-inactivating proteins): studies that investigated the tumor-killing effect of ribosome-inactivating proteins, which - exist in plants and bacteria.

FIGURE 3.

FIGURE 3

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Network visualization of reference co-citation. (a) Clustering analysis of cancer bacteriotherapy co-citation network; (b) the top-ten references with the strongest citation bursts in the co-citation network.

The top-ten citation bursts are shown in Fig. 3b. A citation burst is defined as an article that received a surge in citations within a certain period of time, indicating its prompt recognition and spread in the research field.37 The main topic showing strong burst was bacteria engineering for tumor imaging and anticancer treatment.31,38–42 The highest citation burst strength (27.32) was observed for a paper published by Forbes,31 implying its significant influence on bacteria-related cancer research.

Analysis of keyword co-occurrence

Keywords are an essential part of an article and represent the research topic of a publication. Accordingly, 63 out of 8,785 keywords with a frequency of 30 and above were extracted and analyzed using VOSviewer software. The top-ten keywords over the past 10 years were ‘cancer’, ‘cancer therapy’, ‘bacteria’, ‘nanoparticle (NP)’, ‘cell’, ‘drug delivery’, ‘in vitro’, ‘therapy’, ‘apoptosis’ and ‘immunotherapy’. The network visualization of keyword co-occurrence is shown in Fig. 4. The node size of each term is proportional to its number of occurrences, with larger nodes reflecting the higher occurrence of the keyword. A shorter distance between nodes indicates closer correlation between selected terms. The 63 core keywords were classified into three clusters (Fig. 4a): Cluster 1 (red) was the largest and contained the most items (27) which mainly related to the application of Gram-negative bacteria in cancer therapy. Keywords such as E. coli, Salmonella, tumor/cancer, therapy, antitumor activity, and immune response were included in this section. Cluster 2 (green) focused on the application of NP-based drug delivery systems on anticancer and/or antibacterial treatment as evidenced by the keywords: magnetic/iron-oxide/gold/silver NPs, drug delivery, anticancer, antibacterial, and toxicity/cytotoxicity. Cluster 3 (blue) primarily referred to the application of chemotherapy and probiotics in cancer therapy, especially colorectal cancer treatment. The keyword evolution over time is displayed in Fig. 4b. Keywords marked in blue denote their average year of publication was in an earlier era whereas green indicates that the terms have been used continuously during the time span of this study. Conversely, light-green or yellow-highlighted keywords represent newly emerging research hotspots. In terms of studies on bacteria-mediated cancer therapy (2016–2020), the research trend has shifted from Gram-negative bacteria such as E. coli and Salmonella to gut microbiota and probiotics. In addition, immunotherapy and NP-based drug delivery systems were continuously attractive research fields and have been widely applied in cancer bacteriotherapy over the past 5 years

FIGURE 4.

FIGURE 4

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Network visualization of keyword co-occurrence. (a) Keyword cluster map based on different research fields; (b) A chronological overview of keywords based on the average publication year.

Discussion

Bacteriotherapy, which has gained worldwide research interest over the past decade, has proved to be a powerful tool in the fight against cancer. Additionally, bacteriotherapy has several advantages over conventional cancer therapies, particularly the tumor-targeting ability and enhanced tumor penetration efficiency of bacteria. Analyzing the high-impact publications on cancer bacteriotherapy by bibliometrics can help researchers to identify the knowledge structure, current development, and research hotspots of this domain. Herein, We presented the first bibliometric analysis of articles on bacteria-mediated cancer treatment published from 2012 to 2021, providing crucial insights into the historical development and research frontiers of this field.

The publication records obtained from Web of Science Core Collection database were analyzed from different perspectives by VOSviewer and CiteSpace. VOSviewer is a software tool used to construct and visualize the bibliometric networks of scientific literatures, whereas CiteSpace focuses on analyzing and visualizing the trends and dynamic patterns of a particular research field.43,44 VOSviewer was used to visualize the keyword co-occurrence and journal co-citation network and CiteSpace was used to conduct reference co-citation analysis. Python programing language was combined with these two bibliometric analysis tools to visualize the descriptive statistical analysis.

Based on our results, research attention on cancer bacteriotherapy has been growing over the past decade, leading to a significant increase in both annual publication numbers and total citations of articles on bacteria-mediated cancer therapy. Among all countries, China and the USA made the most contributions to this research domain, publishing a total of 436 and 375 papers, respectively. In terms of international cooperation, China collaborated most closely with the USA, whereas research collaborations among other countries were scattered. Accordingly, East Asia and North America contributed more publications compared with other regions.

In terms of the most productive research institutes, the Chinese Academy of Science ranked the top, followed by Chonnam National University, the University of California San Diego, Islamic Azad University, Zhejiang University, and Harvard University, each of which generated more than 20 publications and accumulative 130+ citations. Moreover, Science was the most influential publication source according to both citation and co-citation analyses. Jung-Joon Min was the most productive author, publishing 19 papers with a total citation of 381, whereas Giorgio Trinchieri ranked first in terms of citation ranking. The top-two most-cited publications both revealed that the microbiota had a significant influence on the tumor response to cancer therapy,34,35 which laid the foundation for the further development of bacteria-related cancer research. With respect to the reference co-citation analysis, the topic showing the strongest burst was bacteria engineering for tumor imaging and anticancer treatment.31,38–42 Forbes (2010)31 had the highest citation burst strength (27.32), indicating the significant influence of this publication on bacteria-related cancer research. This review paper presented an overview of different bacterial cancer therapies and discussed their current progress and limitations, such as intrinsic bacterial toxicity and genetic instability, inadequate production of cytotoxic agents, and insufficient tumor-targeting efficiency.31 It also provided feasible strategies to overcome these challenges to achieve the best therapeutic outcome without causing toxicity, representing a milestone in bacteria-mediated cancer research.

In addition, according to the keywords co-occurrence analysis, the research trend shifted from E. coli and Salmonella to gut microbiota and probiotics from 2016 to 2020. Salmonella and E. coli are both Gram-negative anaerobes with excellent tumor selectivity and tumor penetration capability, which have been widely applied in bacteria-mediated cancer therapy.45–47 In particular, Salmonella can directly kill cancer cells by inducing tumor apoptosis and necrosis as well as eliciting robust antitumor immune responses, whereas E. coli serve as versatile gene delivery vectors, which can be engineered to express a range of anticancer agents, including cytotoxic proteins, cytokines, and prodrug-converting enzymes.8,48–51 However, their potential virulence and infectivity have restricted their use in clinical trials, making beneficial gut microbiota and probiotics promising candidates for future cancer treatment.52 Furthermore, immunotherapy and NP-based drug delivery systems have attracted research attention continuously, and have been widely applied in cancer bacteriotherapy over the past 5 years. NPs have been broadly used as drug carriers to deliver therapeutic agents to tumor sites for cancer treatment.53 Immunotherapy represents a shift in the cancer treatment paradigm from directly killing tumors to harnessing the host immune system to treat cancer.54 The combination of these two strategies, NP-based cancer immunotherapy, has drawn extensive research attention in recent decades, in which nanocarriers are used to co-deliver tumor-associated antigens and immunostimulatory adjuvants to elicit robust antitumor immune responses and suppress tumor progression.55,56 Driven by these advances, bacteriotherapy has been further combined with these two strategies for enhanced anticancer therapeutic efficiency.57 Wei et al. used poly (lactic-co-glycolic acid) (PLGA) polymers to formulate resiquimod (R848)-loaded NPs (PR848) and DOX-loaded NPs (PDOX) for anticancer treatment.57 PR848 were attached to E. coli K12 via electrostatic interaction and intravenously injected into tumor-bearing mice. These NPs exclusively colonized tumor sites and released R848, inducing the expression of proinflammatory cytokines and eliciting a potent antitumor immune response. Following intratumoral injection, PDOX triggered immunogenic cell death, promoted the maturation of cytotoxic T lymphocytes, and effectively caused tumor eradication. With such progress, nanotechnology and immunotherapy will continue to be the important impetus for the development of cancer bacteriotherapy.

Admittedly, the present study has its own limitations, such as the omission of literature from other databases (e.g., PubMed) as well as the potential bias because of self-citation. In the future, we could use different query terms to narrow the records down to a set of publications specific to a subdivision of this field and perform a more precise literature metrology analysis. Nevertheless, this is the first study to conduct a bibliometric analysis of literature on bacteria-related cancer research, and our results could help researchers conduct in-depth exploration of this promising research field.

Concluding remarks

Recent decades have witnessed a dramatic increase in research studies on bacteria-related cancer therapy. The current work presented the first bibliometric analysis of articles on bacteria-mediated cancer treatment, providing crucial insights into the development of this research area from 2012 to 2021. In particular, East Asia and North America dominate the cancer bacteriotherapy field. Furthermore, immunotherapy and NP-based drug delivery systems have attracted long-lasting research interest. Additionally, the application of probiotics in cancer research is likely to be a future research trend. Moreover, through examination of the two most-cited articles, by Matson et al. and Iida et al., it was found that bacteria played a key role in modulating the tumor microenvironment and significantly influence the antitumor immune response to chemotherapy and immunotherapy.

With advances in bacteria-mediated cancer treatment, several bacterial strains with promising preclinical results have been used in clinical trials to test their anticancer therapeutic efficacy and safety. Kawana et al. used human papillomavirus (HPV) 16 E7 protein-expressing Lactobacillus casei to develop an oral vaccine for cancer treatment.58 The anti-HPV vaccine was used to treat patients with HPV16-associated cervical intraepithelial neoplasia grade 3. The Phase I/IIa clinical study reported no adverse events and 70% of patients underwent pathological downgrading after 9 weeks of treatment. In another clinical study, patients with refractory cancer were treated with attenuated Salmonella typhimurium expressing cytosine deaminase via intratumoral injection and 5-fluorocytosine (5-FC) via oral administration.59 Cytosine deaminase can convert 5-FC into 5-fluorouracil (5-FU), a widely used anticancer drug. It was demonstrated that 67% of patients experienced bacterial colonization and 5-FU production within tumors. Furthermore, no significant systemic toxicity was observed. Thus, this clinical study showed that attenuated Salmonella can be used as a delivery platform for cytosine deaminase to enable the intratumoral production of 5-FU at clinically relevant concentrations for anticancer treatment.

Despite current progress in bacteria-mediated cancer therapy, considerable research efforts are still required to broaden its application in clinical practice. First and foremost, recruited patients should be carefully examined for their suitability to participate in live bacteria-based cancer clinical trials. Immunocompromised patients should be excluded to avoid the risk of uncontrollable bacterial infection. Additionally, the initial clinical dose and dose schedule are essential for conducting clinical studies. To optimize the dose regimen for clinical use, it is crucial to develop a suitable pharmacokinetics model to describe the absorption, distribution, metabolism, and excretion (ADME) profile of bacteria after administration. Given that bacteria are live biopharmaceutics, cancer–bacteria interaction, bacteria metabolic rate, and protein expression efficiency should be thoroughly examined when evaluating the pharmacokinetics performance of bacteria following administration. Furthermore, delivery of free bacteria might lead to treatment failure because of immune clearance before they can reach the tumors. Therefore, bacteria should be encapsulated within a protective matrix to preserve their viability and metabolic activity during administration. Additionally, bacteriotherapy can be further combined with conventional cancer therapies, such as radiotherapy, chemotherapy, and photodynamic therapy, to achieve enhanced therapeutic outcomes in clinical trials. As evidenced by our bibliometric analysis, the integration of bacteriotherapy with immunotherapy and NP-based drug delivery systems has attracted long-lasting research attention. By connecting clinical investigations with bibliometric analyses, researchers can gain an in-depth understanding of current bottlenecks, development status, and future directions of cancer bacteriotherapy. Such understanding will be helpful for scientists to conduct further investigations into this promising research field.

Supplementary Material

Supplementary data

Acknowledgements

The authors gratefully acknowledge funding through the Food and Drug Administration, National Institutes of Health (1R01FD007456-01) to M. Maniruzzaman.

Footnotes

Conflicts of Interest

The authors declare the following conflicts of interest. Wang J. and Maniruzzaman M. are co-inventors of related intellectual property (IP). Maniruzzaman. M., an author of this manuscript, holds stock in, serves on a scientific advisory board for, or is a consultant for CoM3D Ltd. (Surrey, UK) and Septum Solutions LLC (Houston, TX, USA). The terms of this arrangement have been reviewed and approved by the University of Texas at Austin in accordance with its policy on objectivity in research.

Appendix A. Supplementary material

Supplementary data to this article can be found online at https://doi.org/10.1016/j.drudis.2022.05.023.

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