242 hESC Lines and Their Use in International Research Table 3. Number of hESC research papers published 1998–2008 Number of hESC research papers % of Total hESC research papers Country Australia Belgium Canada China (including Taiwan) Czech Republic Denmark Estonia Finland France Germany Hungary India Iran Israel Italy Japan Korea Netherlands Romania Russia Singapore Spain Sweden Switzerland Turkey United Kingdom United States Total 36 10 30 43 4 6 1 8 9 17 1 11 7 71 7 31 61 13 1 4 55 13 42 4 4 94 406 989 3.6 1.0 3.0 4.3 0.4 0.6 0.1 0.8 0.9 1.7 0.1 1.1 0.7 7.2 0.7 3.1 6.2 1.3 0.1 0.4 5.6 1.3 4.2 0.4 0.4 9.5 41.1 100 Search of the PubMed database and paper selection were performed according to the method described in the supporting information. Assignment of papers to a country was according to the address of the corresponding author. Note that 56 hESC research papers that were published online ahead of print in 2008 but were printed in 2009 are not included. A detailed paper list is provided as supporting information. publicly known hESC lines (6.5%) harbored genetic altera- tions linked to an inheritable human disease [2]. Thus, there has been a considerable increase in this fraction of hESC lines over the past 4 years. When compared to recently pub- lished ﬁgures [9], the number of reported ‘‘diseased’’ hESC lines even doubled. This highlights the outstanding interest in this type of hESC lines, because they might be a valuable tool for studying the pathomechanisms of genetically inher- itable diseases [10, 11]. Second, although xeno-free deriva- tion of hESC lines was considered to be a crucial prerequi- site for later clinical use [12], only a few hESC lines were produced without any exposure to animal-derived com- pounds or in accordance with standards of good manufactur- ing practice. However, many cell lines were derived on human feeder cells, without performing immune surgery or under conditions free of animal-derived serum. A detailed list of the hESC lines reported here is provided as support- ing information. In addition, there is a multitude of hESC sublines, some of which have been applied frequently, such as the sublines H9.2 of H9 (WiCell Research Institute, Inc., Madison, WI, http://www.wicell.org), ENVY of HES-3 (ESI, ES Cell International Pte Ltd, Singapore, http:// www.escellinternational.com), or SA002.5 of Sahlgrenska 002 (Cellartis AB, G o¨teburg, Sweden, http://www.cellartis.- com), which were not considered separately in the present analysis. Figure 1. Share of published hESC research from selected countries in the total number of research papers published 2003–2008 world- wide in English language journals. Number and Impact of Publications Regarding Experimental Work Involving hESC Next, we analyzed the number and impact of scientiﬁc papers published by the end of 2008 and describing results of hESC derivation and experimental work involving hESCs. We per- formed a broad search of the PubMed database for papers describing hESC work according to the method described ear- lier (for details, see also supporting information methods), which resulted in nearly 6,000 initial hits. These results were manually evaluated to exclude those papers in which hESCs were not experimentally used (e.g., comments, reviews, news, editorials, work on mouse ES cells, papers on ethical or polit- ical aspects of hESC research, etc.). We further excluded articles that summarized previously described methods and protocols, as well as papers in which only hESC-derived materials (e.g., DNA, RNA, or protein extracts) were used. Work involving stem cell lines derived from parthenogenetic embryos was also excluded from the analysis. Finally, we identiﬁed a total of 989 hESC research papers from 27 coun- tries published between 1998 and 2008 in English-language peer-reviewed journals (a complete list of papers is provided in the supporting information). As shown in Table 3, most of these 989 research papers originated from groups in the United States (41.1%), followed by the United Kingdom (9.5%), Israel (7.2%), Korea (6.2%), and Singapore (5.6%). The leading position of US research in the hESC ﬁeld has remained nearly unchanged as approximately 40% of publica- tions in this ﬁeld were from groups based in the United States over the last 6 years, although the total extent of this research increased dramatically worldwide (Fig. 1). Because the number of papers does not necessarily reﬂect the impact of research, we also determined the Institute for Science Information citation impact factor for journals that published those 989 papers. The weighted overall average 5- year impact factor (2004–2008) for journals that had pub- lished experimental hESC work was 7.422, indicating the out- standing interest in hESC research. However, hESC work from US-based groups was published in journals with a higher average impact factor (9.123). The same is true for work published by Canadian groups (10.769), while work from Chinese, Korean, and Swedish groups were published in less inﬂuential journals (average 5-year impact factors of 4.041, 4.425, and 4.768, respectively). Because the impact factor of a journal does not necessarily reﬂect the impact or quality of individual papers published in this journal [13], we also deter- mined citation frequencies for said 989 papers (supporting in- formation). According to these data, hESC papers published between 2000 and 2007 were cited on average 14.9 times by studies published in 2008. However, studies from US and