Cong Chen,Tao Chen,Zhiwen Wang*,Xueming Zhao

Frontier Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education),SynBio Research Platform,Collaborative Innovation Center of Chemical Science and Engineering (Tianjin),School of Chemical Engineering and Technology,Tianjin University,Tianjin 300072,China

ABSTRACT In recent years,metabolic engineering has made great progress in both academic research and industrial applications.However,we have not found any articles that specifically analyze the current state of metabolic engineering in China in comparison with other countries.Here,we review the current development and future trends of global metabolic engineering,conduct an in-depth benchmarking analysis of the development situation of China’s metabolic engineering,and identify current problems as well as future trends.We searched publications in the Scopus database from 2015 to September 2020 in the field of metabolic engineering,and analyzed the output in general,including publication trends,research distribution,popular journals,hot topics and vital institutions,but also analyzed the share of citations,field-weighted citation impact,and production in collaboration with strategic countries in science and technology.This study aims to serve as a reference for later studies,offering a comprehensive view of China’s contribution to metabolic engineering,and as a tool for the elaboration of national public policy in science and technology.

Keywords:Metabolic engineering Output Citation impact Collaboration China Science metric

1.Introduction

Metabolic engineering is broadly defined as‘the development of methods and concepts for the analysis of metabolic networks,typically with the objective of finding targets for engineering of cell factories [1].The improvement of cellular properties may involve a range of different strategies,such as modification of the substrate range,production of new chemicals,improvement of yield and productivity,as well as improvement of cellular robustness,for example by increasing the tolerance towards toxic compounds and different stress factors[1,2].Since its formal recognition three decades ago [3],metabolic engineering has evolved into a more systematic and high-throughput discipline,sometimes termed’systems metabolic engineering’ [4].By integrating systems biology,synthetic biology,and evolutionary engineering,metabolic engineering has demonstrated its capacity to develop microbial strains for the production of a variety of chemicals [5,6],drugs[7],biofuels [8],nutraceuticals [9]and biomaterials [10]from renewable raw materials.

Metabolic engineering,with its applications aiming to solve a broad range of challenges such as environmental issues,sustainable energy,food safety,advanced materials and medicine,has been selected as one of the key enabling technologies to retain competitiveness and capitalize on new markets by different countries,including developed countries and China.The Department of Agriculture in the United States released a report in 2016 stating that by 2025,bio-based chemicals will account for 22% of the global chemical market,with an annual market value exceeding 500 billion USD [11].In recent years,China has proposed “The 13th five-year plan for the development of biological industry”,the“Development plan of biological industry”and other national development strategies involving metabolic engineering and synthetic biology [11].In addition,there are a number of ongoing metabolic engineering and synthetic biology research projects funded by the National Natural Science Foundation of China and the Ministry of Science and Technology,including general projects in the national fund and key projects.Due to the rapid development of biological science and technology,increasing multi-disciplinary research,high government funding and active participation of enterprises,metabolic engineering research has made great progress in both academic science and industrial applications.However,no study to date conducted an in-depth benchmarking analysis of the current status of metabolic engineering in China in comparison with other countries.It is of great significance to analyze the development situation and trends of global metabolic engineering,and conduct an in-depth benchmarking analysis of the development situation of China’s metabolic engineering,indicating current problems and future trends.

In this study,we investigate the global research performance in the field of metabolic engineering from 2015 to September 2020,and the development situation of China’s metabolic engineering was further analyzed by in-depth benchmarking.We collected data on the global and Chinese scholarly output in Scopus from 2015 to September 2020.The analysis is based on a multidisciplinary corpus of publications selected using the relevant keywords “metabolic engineering”.We focus on the number of publications,the citation impact,collaborations and their influence on production and impact for China and selected countries among those most active in the field.

2.Methods and Data

2.1.Data collection and analysis tools

Scopus (http://www.scopus.com) is the abstract and citation database launched by Elsevier in 2004,covering over 78 million documents published in more than 22,000 journals,book series and conference proceedings by approximately 5000 publishers.Citations date back to the 1970s and are updated daily.Beyond providing comprehensive coverage of scientific data and literature,Scopus goes further,delivering high-quality data available.Scopus uses a rich underlying metadata architecture for all indexed content to connect people,published ideas and institutions.In addition,Scopus is the database of choice for research assessment and evaluation purposes at leading ranking organizations,including Times Higher Education (THE),QS World University Rankings,MacLean’s and US News and World Report.Therefore,Scopus was used to retrieve and collect data in this study.Elsevier has provided the SciVal tool,which can be used to analyze the scientific research performance from an interdisciplinary perspective based on a co-citation clustering principle and visual data analysis.The search query and additional filters are used in SciVal to create a publication set to which all subsequent analyses are applied.

For this paper,we searched the Scopus database for research achievements related to metabolic engineering in China,mainly including academic papers,monographs,patents and other academic outputs.The retrieval date was 23 September 2020,the selected text was “paper title,abstract,keywords”,the keyword was “metabolic engineering”,and the time scope was limited to documents collected and preserved from 2015 to 2020 (5 years).The data set obtained after searching using the described conditions was named “metabolic engineering-world”,after which the top 12 countries with the highest scholarly output were sequentially limited and the data set was renamed as “metabolic engineering-country”.The retrieval date was 23 September 2020,the selected text was “paper title,abstract,keywords”,the keyword was “synthetic biology”,and the time scope was limited to documents collected and preserved from 2015 to 2020 (5 years).The data set obtained after searching using these conditions was named“synthetic biology-world”.Next,all data sets were exported to the document analysis tool SciVal to analyze the retrieved data.Finally,each analysis result of SciVal was exported into an excel file,and Excel 2007 software (Microsoft Corp.,USA) was used for statistical analysis.

2.2.Field-weighted citation impact analysis

Field-Weighted Citation Impact (FWCI) for a set of N publications is defined as:

whereciis the number of citations received by publicationi,andeiis the expected number of citations received by all similar publications in the publication year plus following 3 years.

When a similar publication is allocated to more than 1 discipline,the harmonic mean is used to calculateei.For a publicationithat is part of 2 disciplines:

whereeAandeBare the fractional counts of publications and citations,so thatiwill be counted as 0.5 publications in each ofeAandeB,and the citations it has received will also be shared between A and B [12].

The FWCI in SciVal indicates how the number of citations received by an entity’s publications compares with the average number of citations received by all other similar publications in the dataset.A FWCI of 1.00 indicates that the entity’s publications have been cited exactly as would be expected based on the global average for similar publications.Therefore,the FWCI of“world”,i.e.the entire Scopus database,is 1.00.A FWCI of more or less than 1.00 indicates that the entity’s publications have been cited more or less than would be expected based on the global average for similar publications,respectively.

2.3.Compound annual growth rate

The Compound Annual Growth Rate (CAGR) is defined as the year-on-year constant growth rate over a specified period of time.Starting with the first value in any series and applying this rate for each of the time intervals yields the amount in the final value of the series:

whereV(t0)is the starting value,V(tn)is the finishing value,andtn-t0is the number of years [13].

After all the data sets related to metabolic engineering were analyzed using SciVal,the annual scholarly output for last five years was exported into an excel file using the Benchmarking function of SciVal.Finally,the resulting excel output was used to calculate the CAGR value.

3.Results and Discussion

3.1.Output of publications related to metabolic engineering from 2015 to 2020

3.1.1.Article publication trend and distribution of metabolic engineering research in China and worldwide

Fig.1.Breakdown and Field-Weighted Citation Impact (FWCI) of metabolic engineering by top 10 subject area in the world,from 2015 to 2020.FWCI normalizes the differences in citations due to the subject field,publication year and document type.The world is indexed to an FWCI value of 1.00,which is represented by a gray line.An FWCI of more than 1.00 indicates that the entity’s publications have been cited more often than expected based on the global average for similar publications.

In the period from 2015 to September 2020,the overall production of publications in metabolic engineering reached a total of 12,008,which was compiled into a dataset.The volume increased from 1817 in 2015 to 2287 in 2019 (Fig.1),corresponding to an annual growth rate of 5.98%.Around 15.8%of publications in metabolic engineering between 2015 and 2019 belong to the world’s top 10%most cited publications.At the same time,around 43.5%of publications in metabolic engineering belong to the world’s top 10% journals according to CiteScore,whose data are derived directly from the overview of SciVal.The CiteScore is based on the number of citations in different documents (articles,reviews,conference papers,book chapters,and data papers) by a journal over four years,divided by the number of the same document types indexed in Scopus and published in those same four years.

The SciVal was used to analyze the distribution of subject areas represented in the dataset,based on the classification of the journals in which the papers in this dataset have been published.Fig.1 shows that the subject area in the field of metabolic engineering mainly focuses on “Biochemistry,Genetics and Molecular Biology(29.5%)”,“Immunology and Microbiology(16.7%)”,“Chemical Engineering (14.4%)”,“Engineering (7.9%)”and “Agriculture and Biological Sciences (6.2%)”.The average FWCI of these subject areas was above 1.00,indicating that the influence of metabolic engineering subject areas is higher than the worldwide average.

With the development of synthetic biology,synthetic systems have been widely applied to metabolic engineering [14].Increasingly,researchers engaged in metabolic engineering are moving their research fields from traditional metabolic engineering to synthetic biology,leading to a gradual increase in the total amount of publications in synthetic biology,which is higher than that of metabolic engineering between 2015 and 2019 (Fig.2).Fig.3(a)shows the top 10 countries or regions according to scholarly output in the field.China is the largest contributor,followed by the United States,while Germany,South Korea,United Kingdom,India,Japan,Denmark,France,and Spain are much closer to each other and well below the production of the first two.After excluding the top-ranked countries China and the United States,the top 10 countries or regions for metabolic engineering research are Germany,South Korea,United Kingdom,India,Japan,Denmark,France,Spain,Canada and Sweden.China’s output of publications in metabolic engineering has increased year by year,and it surpassed the United States in 2018,ranking first in the world as shown in Fig.3(b).Remarkably,although the total number of publications by the United States in the past five years is comparable to that of China,the annual number of publications from the United States has gradually decreased.In addition,the number of publications from Canada and the United Kingdom decreased from 2018 to 2019,while the output of the other countries was mostly unchanged in Fig.3(c).

Fig.2.Number of publications,World and China,Metabolic Engineering (ME) and Synthetic Biology (SynBio),from 2015 to 2019.

In contrast with the rest of the world,China’s scholarly output in metabolic engineering has been increasing year by year,and was consistently higher than its output in synthetic biology(Fig.2).In addition,China is the country with the largest number of publications in the field of metabolic engineering in the past five years,accounting for 27.27% of the world’s publications between 2015 and September 2020 in Fig.3(a).At the same time,China’s scholarly output in the field of synthetic biology only accounted for 14.55%,indicating that metabolic engineering has attracted the interest of more researchers in China.

The CAGR of metabolic engineering was close to 6% year-overyear for the past five years as shown in Fig.3(d).Notably,India showed the highest CAGR in publications among the top 10 most prolific countries or regions,at 18.31% in Fig.3(d).It is followed by China (15.51%),United Kingdom (13.23%) and Denmark(9.29%),with CAGR values that are still much higher than the overall worldwide publication growth in metabolic engineering.The United States and Spain had the lowest CAGR among the top 10 countries or regions at -2.22% and -1.65%,respectively.Thus,growth is driven mainly by China,India,United Kingdom and Denmark,while the United States and some European countries struggle to keep up with the global pace.

Fig.3.Number of articles and Compound Annual Growth Rate(CAGR)for the top contributing countries or regions in metabolic engineering.(a)Number of publications top 10 countries or regions from 2015 to 2020.(b) During 2015 to 2019,overall number of publications for the top 10 countries or regions.(c) During 2015 to 2019,overall number of publications for the top 10 countries or regions,excepting China and the United States.(d) During 2015 to 2019,CAGR for the top 10 countries or regions.

3.1.2.Top 20 most popular journals on metabolic engineering in China and the world

To evaluate the quality of the recent publications on metabolic engineering,the top 20 most popular journals were selected for more in-depth analysis.Table 1 shows the 20 most popular journals by scholarly output in metabolic engineering between 2015 and September 2020,which were categorized into quartiles (Q1-Q4).Among these,5 journals (such as Metabolic Engineering) are in Q1,8 journals (such as ACS Synthetic Biology) are in Q2,and 6 journals (such as Biotechnology Journal) are in Q3.The most popular journal is “Metabolic Engineering”,which is consistent with the most popular journals in Q1,and the corresponding number of publications is 737.The following 4 journals“Applied Microbiology and Biotechnology”,“Microbial Cell Factories”,“ACS Synthetic Biology”,and “Biotechnology and Bioengineering”are Q2,and the corresponding number of publications exceeds 300.

Table 2 shows the 20 most popular journals on metabolic engineering by scholarly output in China between 2015 and September 2020.Among these,6 journals(such as Metabolic Engineering)are in Q1,7 journals(such as Microbial Cell Factories)are in Q2,6 journals (such as Journal of Biotechnology) are in Q3 and 2 journals(such as Chinese Journal of Biotechnology) are among the Chinese core journals.The most popular journal is also “Metabolic Engineering”,which was consistent with its rank as the most popular journal from this field in the world.Chinese publications in“Metabolic Engineering”accounted for 28.9%of the worldwide scholarlyoutput in the journal.The following 4 journals were “Applied Microbiology and Biotechnology”,“Microbial Cell Factories”,“Chinese Journal of Tissue Engineering Research”and “ACS Synthetic Biology”,indicating that the journal “Chinese Journal of Tissue Engineering Research”is more popular in China than in the wider world.Another Chinese journal,“ Chinese Journal of Biotechnology”,is also popular in China.Except for these Chinese journals,the top five most popular journals in China are consistent with the top ranking in the world (Tables 1 and 2).

Table 1 The 20 most popular journals by scholarly output in metabolic engineering between 2015 and September 2020

Table 2 The 20 most popular journals by scholarly output among metabolic engineering in China between 2015 and September 2020

3.1.3.Top 15 topics on metabolic engineering in China and the world

Scopus publications are clustered into topics based on a direct citation analysis.Where there is a weak citation link,there is a break and a new topic is formed.Table 3 shows the 15 most popular topics by scholarly output in China and the world on metabolic engineering between 2015 and September 2020.

Globally,the most popular topic in metabolic engineering was“Metabolic Engineering;Isobutanol;Mevalonic Acid”,which was also the most popular topic in China.The next 4 popular topics worldwide were “Metabolic Engineering;Systems Biology;Document Markup Languages”,“Corynebacterium Glutamicum;Metabolic Engineering;Batch Fermentation”,“Muconic Acid;Metabolic Engineering;Shikimate Kinase”and “Synechocystis;

Synechococcu Sp.PCC 7942;Cyanobacteria”.Notably,the second most popular topic of metabolic engineering in the world is only the 12th topic in China (Table 3),and the number of publications in China only accounts for 10% of this topic in the world.The top three most popular topics in China are among the top four topics in the world.The fourth popular topic in China,“Actinobacillus Succinogenes;Succinic Acid;Sulfite Liquor”,is the 12th topic in the world.This comparison indicated that China lags behind the development of the world at the intersection of systems biology and computer science,while the research on succinic acid is at the world’s leading level.

3.1.4.Top 10 institutions according to metabolic engineering output in China and the world

Table 4 shows the top 10 most productive institutions in the world in terms of scholarly output in metabolic engineeringbetween 2015 and September 2020.According to the FWCI,which reflects the quality of the papers,the research output can be roughly divided into 3 levels.The first level of quality(FWCI>2.50)includes 3 institutions,the Technical University of Denmark,University of California at Berkeley and Korea Advanced Institute of Science and Technology.The second level of quality (2.00

Table 3 Top 15 popular topics according to metabolic engineering in China and the world between 2015 and September 2020

Table 4 Top 10 institutions by number of publications in metabolic engineering from 2015 to September 2020

Table 5 shows the top 10 most productive Chinese institutions according to scholarly output in metabolic engineering between 2015 and September 2020.The Chinese Academy of Sciences is also one of the top 10 institutions in China,with the highest scholarly output.Except for Tsinghua University,the FWCI of the other nine institutions of China’s top 10 institutions was below 2.0.In China,Tianjin University ranks third among the top 10 institutions with the largest amount of publications and the FWCI in the five years from 2015 to September 2020.

3.2.Metabolic engineering citation impact from 2015 to 2020

3.2.1.Share of citations among the top 10 countries or regions

The citation frequency of articles is one of the indexes used to assess the value and influence of publications.As shown in Fig.4(a),the United States had the highest share of global citations in the study period,followed by China.However,the global citation share of the United States in metabolic engineering decreased year by year between 2015 and 2020,while the global citation share of China showed the opposite trend.Judging by the number of publications and share of citations of the top 2 countries,we found that China surpassed the United States in the number of publications in 2018,and the citation share of China was close to that of the United States in 2019 as shown in Figs.3(b) and 4(a).This trend was consistent with the increase in the number of Chinese publications year by year in Fig.3(b).A similar pattern can be observed between the share of publications and the share of citations in other countries or regions,in addiiton to the United States and China.In 2019,Fig.4(b) shows that Germany and South Korea showed a significant increase in their relative citation sharse,which was consistent with their share of output.

Table 5 Top 10 institutions by number of publications among metabolic engineering in China from 2015 to September 2020

3.2.2.Field-weighted citation impact in the top 10 countries or regions and the world

The FWCI reflects the impact of scientific research papers after subject standardization.It is based on the ratio of the number of citations of the target paper to the average number of citations for the same subject,year,and type of paper.This index is currently internationally recognized as the best method to quantitatively evaluate the quality of scientific research papers.An FWCI ≥1.00 indicates that the quality of the article has reached or exceeded the world average.The average FWCI of publications in metabolic engineering in the period 2015 to 2020 was 1.36(Table 6).While the global value has decreased from 2015 to 2019,metabolic engineering remains a popular research field with 36% higher citations than the global average of 1.00.

Table 7 shows the trend of FWCI for the top 10 contributing countries or regions and the whole world.By renormalizing the FWCI from Table 7 to the worldwide average value,it becomes easier to compare countries among themselves and with the global average.Fig.5 shows that Denmark has the highest FWCI,which was higher than the world level during the whole period from 2015 to 2019,in sharp contrast with other countries.In addition,the United States,Germany,South Korea,United Kingdom and France were also above the world average from 2015 to 2019,while Japan was significantly lower than the worldwide level(Fig.5).These results indicated that in such a competitive research area,China is keeping pace with the worldwide average citation impact,but has been surpassed by India in 2019,and scores below European countries such as Denmark,Germany,France and the UK(Fig.5).

Fig.4.Share of citations for the top countries or regions in metabolic engineering from 2015 to 2019.(a) Overall share of citations for the top 10 countries or regions.(b)Overall share of citations for the top 10 countries or regions,excepting the United States and China.

Table 6 Total citation count,average number of citations per publication and average FWCI for top 10 contributing countries or regions and the world in metabolic engineering from 2015 to September 2020

Table 7 The FWCI for top 10 contributing countries or regions in metabolic engineering from 2015 to 2019

Additionally,we found that when the FWCI of metabolic engineering was high,the FWCI of synthetic biology was lower,and vice versa (Fig.6).Synthetic biology aims to reconstruct the components of different biological systems and provides corresponding information,while metabolic engineering attempts to apply this information to the optimization of biosynthetic pathways for target compounds [15].Therefore,metabolic engineering and synthetic biology are complementary as well as collaborative fields,which may cause their citation impact to show opposite trends.

Fig.5.Rebased Field-Weighted Citation Impact (FWCI) for the top 10 countries or regions in metabolic engineering from 2015 to 2019.

Fig.6.Field-Weighted Citation Impact (FWCI) in metabolic engineering and synthetic biology from 2015 to 2019.

3.3.Collaboration among the top 10 countries or regions in metabolic engineering from 2015 to 2019

Convenient transportation and the development of internetbased communication have made cross-border research cooperation easier and more efficient.More importantly,many of the problems facing the world today are global and require a global response[16].There are four ways to cooperate,including international collaboration,national collaboration,institutional collaboration and single authorship.International collaboration is defined as multi-authored research whereby the authors are affiliated with institutions in at least two different countries.National collaboration is defined as multi-authored research where the authors are affiliated with more than one institution but within the same country.Institutional collaboration is defined as multi-authored research where all authors are affiliated with the same institution.Single authorship is defined as single-authored research outputs.

By analyzing the cooperation model of the worldwide research community and top 10 output countries or regions,we found that national cooperation accounted for the highest proportion in the field of metabolic engineering,exceeding 36% from 2015 to 2019 and reaching 39.9% in 2019,while institutional collaboration decreased from 2015 to 2019 (Fig.7).In European countries such as Germany,the United Kingdom,Denmark,France and Spain,at least 50% of the country’s cooperation is international in scope(Fig.7).Among these European countries,Denmark has the highest proportion of international cooperation and also the highest FWCI,while its share of citations increases every year.National cooperation is the main type of collaboration in Asian countries such as China,South Korea and Japan,accounting for about 40%–50% of each country’s cooperation (Fig.7).Among these Asian countries,South Korea has a higher share of international collaboration than China,and also has a higher FWCI.This indicates that the higher the proportion of international cooperation,the stronger the citation impact.

In China,cooperation is dominated by domestic cooperation,accounting for 53.9%in 2019,while international cooperation only accounted for 24.3% (Fig.7).Therefore,if China wants to improve its citation impact,it may be more helpful to strengthen the international cooperation.

4.Conclusions and Perspective

Fig.7.Distribution of articles by collaboration type and world or country in metabolic engineering from 2015 to 2019.The red column is international collaboration,green column is national collaboration,blue column is institutional collaboration,and yellow column is single authorship.

In this study,the current development and trends of global metabolic engineering research during 2015 to September 2020 was analyzed,with a special focus on the situation in China,which was further compared by in-depth benchmarking.From 2015 to 2020,a total of 12,008 publications on metabolic engineering was recorded in the Scopus database.With an annual growth rate of 5.98%,the overall research productivity increased from 1817 publications in 2015 to 2287 in 2019.Moreover,we identified the journal that contributed the highest number of publications,namely “Metabolic Engineering”,and identified the most popular topic as“Metabolic Engineering;Isobutanol;Mevalonic Acid”.Furthermore,the institution with the most publications in the world was the Chinese Academy of Sciences.The FWCI of the publications in the world was 1.36 in the period 2015 to 2020,which was 36%higher than the world average of 1.00.In such a competitive research area,China is keeping up with the pace of the worldwide average citation impact,but has been surpassed by India (2019),and scores below European countries such as Denmark,Germany,France and the UK.The average annual growth rate of publication output in metabolic engineering was close to 6% for the past 5 years.Growth is driven mainly by China,India,United Kingdom and Denmark,while the United States and some European countries are struggling to keep up with the global pace.Additionally,collaboration with other countries has increased the citation impact number of Denmark,indicating increasing awareness of the importance of international scientific collaboration is pressing,especially for developing countries.

Although the scholarly output and CAGR are at a high level on metabolic engineering in China,FWCI is only keep up with the pace of the worldwide average level.In order to develop high level research on metabolic engineering in China,the government should strengthen the strategic deployment and financial input of fundamental research in biological science and technology.A good scientific research environment is created to encourage the vast number of scientific researchers to carry out from zero to hero innovative research.The quality evaluation of fundamental research should be emphasized by reforming the evaluation mechanism.For example,rather than the number of papers,workshop lay emphasis on the quality of papers in the evolution of graduate student training and academic performance.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The research was financially supported by the National Natural Science Foundation of China (NSFC-21776209,NSFC-21621004,NSFC-21776208) and Natural Science Foundation of Tianjin (No.19JCYBJC21100).