Data Mining a Medieval Medical Text Reveals Patterns in Ingredient Choice That Reflect Biological Activity against Infectious Agents

Abstract

The pharmacopeia used by physicians and laypeople in medieval Europe has largely been dismissed as placebo or superstition. While we now recognize that some of the materia medica used by medieval physicians could have had useful biological properties, research in this area is limited by the labor-intensive process of searching and interpreting historical medical texts. Here, we demonstrate the potential power of turning medieval medical texts into contextualized electronic databases amenable to exploration by the use of an algorithm. We used established methodologies from network science to reveal patterns in ingredient selection and usage in a key text, the 15th-century Lylye of Medicynes, focusing on remedies to treat symptoms of microbial infection. In providing a worked example of data-driven textual analysis, we demonstrate the potential of this approach to encourage interdisciplinary collaboration and to shine a new light on the ethnopharmacology of historical medical texts. IMPORTANCE We used established methodologies from network science to identify patterns in medicinal ingredient combinations in a key medieval text, the 15thcentury Lylye of Medicynes, focusing on recipes for topical treatments for symptoms of microbial infection. We conducted experiments screening the antimicrobial activity of selected ingredients. These experiments revealed interesting examples of ingredients that potentiated or interfered with each other's activity and that would be useful bases for future, more detailed experiments. Our results highlight (i) the potential to use methodologies from network science to analyze medieval data sets and detect patterns of ingredient combination, (ii) the potential of interdisciplinary collaboration to reveal different aspects of the ethnopharmacology of historical medical texts, and (iii) the potential development of novel therapeutics inspired by premodern remedies in a time of increased need for new antibiotics.

Criteria for the selection, evaluation and application of traditional knowledge in contemporary health practice, education, research and policy: A systematic review

“…Step 2—Intervention selection: The most common method used to inform selection of interventions involved positioning the traditional evidence alongside scientific evidence, contemporary texts and/or expert opinion to draw comparisons, validate evidence or develop a ‘totality of evidence’ (Adams et al, 2007, 2011; Adams, Schneider, et al, 2012; Arabshahi et al, 2015; Bae et al, 2019; Buentzel et al, 2020; Chen et al, 2015; Choi et al, 2015; De Vos, 2010; Fatali, Emami, et al, 2020; Fatali, Sadeghpour, et al, 2020; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; Leach et al, 2018; May et al, 2016; Pae et al, 2016; Park et al, 2018; Petran et al, 2020; Sahranavard et al, 2014; Steel & Adams, 2011b; Thomas, 2011; Watkins et al, 2012; Xia et al, 2020; Yang et al, 2019; Zhang et al, 2014). It was also common for selection processes to place importance on TK with greater predominance in traditional sources, such as interventions appearing frequently within or across sources, and those with consistency of use over time as proxy measures for safety and potential efficacy (Alizadeh et al, 2017; Bae et al, 2019; Birch & Sherman, 1999; Buentzel et al, 2020; Chen et al, 2015, 2020; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; May et al, 2014; Sahranavard et al, 2014; Steel & Adams, 2011c; Thomas, 2011; Xia et al, 2020; Zhang et al, 2014). The perceived authority, authenticity and influential impact of the source on its tradition were also given importance during selection of TK in research and practice (; Adams et al, 2011; Adams, Schneider, et al, 2012; Alizadeh et al, 2017; Bae et al,…”

“…It was also common for selection processes to place importance on TK with greater predominance in traditional sources, such as interventions appearing frequently within or across sources, and those with consistency of use over time as proxy measures for safety and potential efficacy (Alizadeh et al, 2017; Bae et al, 2019; Birch & Sherman, 1999; Buentzel et al, 2020; Chen et al, 2015, 2020; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; May et al, 2014; Sahranavard et al, 2014; Steel & Adams, 2011c; Thomas, 2011; Xia et al, 2020; Zhang et al, 2014). The perceived authority, authenticity and influential impact of the source on its tradition were also given importance during selection of TK in research and practice (; Adams et al, 2011; Adams, Schneider, et al, 2012; Alizadeh et al, 2017; Bae et al, 2019; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Jaric et al, 2014; May et al, 2012; Petran et al, 2020; Reid et al, 2018; Yang et al, 2019).…”

“…Step 3—Intervention exploration: During intervention exploration, TK theory and practice were examined from both traditional and contemporary views, without equating the two perspectives, in order to avoid reductionism or misapplication of TK while also incorporating the benefits of scientific research (Adams et al, 2009; Canaway et al, 2018; Connelly et al, 2020; Flatt, 2016; Gerontakos et al, 2021; Harrison et al, 2015; May et al, 2014; Steel & Adams, 2011c). TK was explored for pragmatic adaptations to meet the needs of individual patients and the requirements of contemporary environments (Adams, 2017; Brien et al, 2012; Brosnan, 2016), while also ensuring core characteristics were preserved to maintain the integrity of the tradition (Flatt, 2016; Harrison et al, 2015; Zargaran et al, 2016).…”

“…While this level of attention to fidelity was limited, other studies sought compromise between the traditional basis of TK and its alignment with contemporary science by triangulating TK with scientific research (Adams et al, 2009; Buentzel et al, 2020; Flatt, 2016; Gerontakos et al, 2021; Guo‐Jing et al, 2020; Harrison et al, 2015; Lumlerdkij et al, 2018; Yao et al, 2021; Zhang et al, 2014) and/or seeking opinions from TK experts regarding scientific findings (Brien et al, 2012; Chen et al, 2015; Fatali, Emami, et al, 2020; Guo‐Jing et al, 2020; Kasiri‐Martino & Bright, 2016; Wang et al, 2017; Yao et al, 2018, 2021). The pre‐clinical studies included in the review all addressed bacterial infections using recipes described in traditional texts (e.g., Bald's Leechbook) (Connelly et al, 2020; Harrison et al, 2015; Kadam et al, 2020; Watkins et al, 2012). These studies clearly aligned with traditional practice through fidelity to the original recipe described by the premodern doctors and scientists, adapting the recipes only as necessary to the context of contemporary scientific research.…”

Criteria for the selection, evaluation and application of traditional knowledge in contemporary health practice, education, research and policy: A systematic review

“…Step 2—Intervention selection: The most common method used to inform selection of interventions involved positioning the traditional evidence alongside scientific evidence, contemporary texts and/or expert opinion to draw comparisons, validate evidence or develop a ‘totality of evidence’ (Adams et al, 2007, 2011; Adams, Schneider, et al, 2012; Arabshahi et al, 2015; Bae et al, 2019; Buentzel et al, 2020; Chen et al, 2015; Choi et al, 2015; De Vos, 2010; Fatali, Emami, et al, 2020; Fatali, Sadeghpour, et al, 2020; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; Leach et al, 2018; May et al, 2016; Pae et al, 2016; Park et al, 2018; Petran et al, 2020; Sahranavard et al, 2014; Steel & Adams, 2011b; Thomas, 2011; Watkins et al, 2012; Xia et al, 2020; Yang et al, 2019; Zhang et al, 2014). It was also common for selection processes to place importance on TK with greater predominance in traditional sources, such as interventions appearing frequently within or across sources, and those with consistency of use over time as proxy measures for safety and potential efficacy (Alizadeh et al, 2017; Bae et al, 2019; Birch & Sherman, 1999; Buentzel et al, 2020; Chen et al, 2015, 2020; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; May et al, 2014; Sahranavard et al, 2014; Steel & Adams, 2011c; Thomas, 2011; Xia et al, 2020; Zhang et al, 2014). The perceived authority, authenticity and influential impact of the source on its tradition were also given importance during selection of TK in research and practice (; Adams et al, 2011; Adams, Schneider, et al, 2012; Alizadeh et al, 2017; Bae et al,…”

“…It was also common for selection processes to place importance on TK with greater predominance in traditional sources, such as interventions appearing frequently within or across sources, and those with consistency of use over time as proxy measures for safety and potential efficacy (Alizadeh et al, 2017; Bae et al, 2019; Birch & Sherman, 1999; Buentzel et al, 2020; Chen et al, 2015, 2020; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; May et al, 2014; Sahranavard et al, 2014; Steel & Adams, 2011c; Thomas, 2011; Xia et al, 2020; Zhang et al, 2014). The perceived authority, authenticity and influential impact of the source on its tradition were also given importance during selection of TK in research and practice (; Adams et al, 2011; Adams, Schneider, et al, 2012; Alizadeh et al, 2017; Bae et al, 2019; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Jaric et al, 2014; May et al, 2012; Petran et al, 2020; Reid et al, 2018; Yang et al, 2019).…”

“…Step 3—Intervention exploration: During intervention exploration, TK theory and practice were examined from both traditional and contemporary views, without equating the two perspectives, in order to avoid reductionism or misapplication of TK while also incorporating the benefits of scientific research (Adams et al, 2009; Canaway et al, 2018; Connelly et al, 2020; Flatt, 2016; Gerontakos et al, 2021; Harrison et al, 2015; May et al, 2014; Steel & Adams, 2011c). TK was explored for pragmatic adaptations to meet the needs of individual patients and the requirements of contemporary environments (Adams, 2017; Brien et al, 2012; Brosnan, 2016), while also ensuring core characteristics were preserved to maintain the integrity of the tradition (Flatt, 2016; Harrison et al, 2015; Zargaran et al, 2016).…”

“…While this level of attention to fidelity was limited, other studies sought compromise between the traditional basis of TK and its alignment with contemporary science by triangulating TK with scientific research (Adams et al, 2009; Buentzel et al, 2020; Flatt, 2016; Gerontakos et al, 2021; Guo‐Jing et al, 2020; Harrison et al, 2015; Lumlerdkij et al, 2018; Yao et al, 2021; Zhang et al, 2014) and/or seeking opinions from TK experts regarding scientific findings (Brien et al, 2012; Chen et al, 2015; Fatali, Emami, et al, 2020; Guo‐Jing et al, 2020; Kasiri‐Martino & Bright, 2016; Wang et al, 2017; Yao et al, 2018, 2021). The pre‐clinical studies included in the review all addressed bacterial infections using recipes described in traditional texts (e.g., Bald's Leechbook) (Connelly et al, 2020; Harrison et al, 2015; Kadam et al, 2020; Watkins et al, 2012). These studies clearly aligned with traditional practice through fidelity to the original recipe described by the premodern doctors and scientists, adapting the recipes only as necessary to the context of contemporary scientific research.…”

Phase 1 safety trial of a natural product cocktail with antibacterial activity in human volunteers

“…Natural products provide a potential pool of candidate compounds for development into clinically-useful antibacterial agents 11,30 . Historical medical texts can act as a database of NPs which have traditionally been used to treat infection, with a rich set of contextual data on how plants and other natural materials were prepared, combined and assigned to treat symptoms of conditions that we know to be microbial infections 22,23,31 .…”

Criteria for the selection, evaluation and application of traditional knowledge in contemporary health practice, education, research and policy: A systematic review

“…Step 2—Intervention selection: The most common method used to inform selection of interventions involved positioning the traditional evidence alongside scientific evidence, contemporary texts and/or expert opinion to draw comparisons, validate evidence or develop a ‘totality of evidence’ (Adams et al, 2007, 2011; Adams, Schneider, et al, 2012; Arabshahi et al, 2015; Bae et al, 2019; Buentzel et al, 2020; Chen et al, 2015; Choi et al, 2015; De Vos, 2010; Fatali, Emami, et al, 2020; Fatali, Sadeghpour, et al, 2020; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; Leach et al, 2018; May et al, 2016; Pae et al, 2016; Park et al, 2018; Petran et al, 2020; Sahranavard et al, 2014; Steel & Adams, 2011b; Thomas, 2011; Watkins et al, 2012; Xia et al, 2020; Yang et al, 2019; Zhang et al, 2014). It was also common for selection processes to place importance on TK with greater predominance in traditional sources, such as interventions appearing frequently within or across sources, and those with consistency of use over time as proxy measures for safety and potential efficacy (Alizadeh et al, 2017; Bae et al, 2019; Birch & Sherman, 1999; Buentzel et al, 2020; Chen et al, 2015, 2020; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; May et al, 2014; Sahranavard et al, 2014; Steel & Adams, 2011c; Thomas, 2011; Xia et al, 2020; Zhang et al, 2014). The perceived authority, authenticity and influential impact of the source on its tradition were also given importance during selection of TK in research and practice (; Adams et al, 2011; Adams, Schneider, et al, 2012; Alizadeh et al, 2017; Bae et al,…”

“…It was also common for selection processes to place importance on TK with greater predominance in traditional sources, such as interventions appearing frequently within or across sources, and those with consistency of use over time as proxy measures for safety and potential efficacy (Alizadeh et al, 2017; Bae et al, 2019; Birch & Sherman, 1999; Buentzel et al, 2020; Chen et al, 2015, 2020; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; May et al, 2014; Sahranavard et al, 2014; Steel & Adams, 2011c; Thomas, 2011; Xia et al, 2020; Zhang et al, 2014). The perceived authority, authenticity and influential impact of the source on its tradition were also given importance during selection of TK in research and practice (; Adams et al, 2011; Adams, Schneider, et al, 2012; Alizadeh et al, 2017; Bae et al, 2019; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Jaric et al, 2014; May et al, 2012; Petran et al, 2020; Reid et al, 2018; Yang et al, 2019).…”

“…Step 3—Intervention exploration: During intervention exploration, TK theory and practice were examined from both traditional and contemporary views, without equating the two perspectives, in order to avoid reductionism or misapplication of TK while also incorporating the benefits of scientific research (Adams et al, 2009; Canaway et al, 2018; Connelly et al, 2020; Flatt, 2016; Gerontakos et al, 2021; Harrison et al, 2015; May et al, 2014; Steel & Adams, 2011c). TK was explored for pragmatic adaptations to meet the needs of individual patients and the requirements of contemporary environments (Adams, 2017; Brien et al, 2012; Brosnan, 2016), while also ensuring core characteristics were preserved to maintain the integrity of the tradition (Flatt, 2016; Harrison et al, 2015; Zargaran et al, 2016).…”

“…While this level of attention to fidelity was limited, other studies sought compromise between the traditional basis of TK and its alignment with contemporary science by triangulating TK with scientific research (Adams et al, 2009; Buentzel et al, 2020; Flatt, 2016; Gerontakos et al, 2021; Guo‐Jing et al, 2020; Harrison et al, 2015; Lumlerdkij et al, 2018; Yao et al, 2021; Zhang et al, 2014) and/or seeking opinions from TK experts regarding scientific findings (Brien et al, 2012; Chen et al, 2015; Fatali, Emami, et al, 2020; Guo‐Jing et al, 2020; Kasiri‐Martino & Bright, 2016; Wang et al, 2017; Yao et al, 2018, 2021). The pre‐clinical studies included in the review all addressed bacterial infections using recipes described in traditional texts (e.g., Bald's Leechbook) (Connelly et al, 2020; Harrison et al, 2015; Kadam et al, 2020; Watkins et al, 2012). These studies clearly aligned with traditional practice through fidelity to the original recipe described by the premodern doctors and scientists, adapting the recipes only as necessary to the context of contemporary scientific research.…”

Phase 1 safety trial of a natural product cocktail with antibacterial activity in human volunteers

“…Natural products provide a potential pool of candidate compounds for development into clinically-useful antibacterial agents 11,30 . Historical medical texts can act as a database of NPs which have traditionally been used to treat infection, with a rich set of contextual data on how plants and other natural materials were prepared, combined and assigned to treat symptoms of conditions that we know to be microbial infections 22,23,31 .…”

Criteria for the selection, evaluation and application of traditional knowledge in contemporary health practice, education, research and policy: A systematic review

“…Step 2—Intervention selection: The most common method used to inform selection of interventions involved positioning the traditional evidence alongside scientific evidence, contemporary texts and/or expert opinion to draw comparisons, validate evidence or develop a ‘totality of evidence’ (Adams et al, 2007, 2011; Adams, Schneider, et al, 2012; Arabshahi et al, 2015; Bae et al, 2019; Buentzel et al, 2020; Chen et al, 2015; Choi et al, 2015; De Vos, 2010; Fatali, Emami, et al, 2020; Fatali, Sadeghpour, et al, 2020; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; Leach et al, 2018; May et al, 2016; Pae et al, 2016; Park et al, 2018; Petran et al, 2020; Sahranavard et al, 2014; Steel & Adams, 2011b; Thomas, 2011; Watkins et al, 2012; Xia et al, 2020; Yang et al, 2019; Zhang et al, 2014). It was also common for selection processes to place importance on TK with greater predominance in traditional sources, such as interventions appearing frequently within or across sources, and those with consistency of use over time as proxy measures for safety and potential efficacy (Alizadeh et al, 2017; Bae et al, 2019; Birch & Sherman, 1999; Buentzel et al, 2020; Chen et al, 2015, 2020; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; May et al, 2014; Sahranavard et al, 2014; Steel & Adams, 2011c; Thomas, 2011; Xia et al, 2020; Zhang et al, 2014). The perceived authority, authenticity and influential impact of the source on its tradition were also given importance during selection of TK in research and practice (; Adams et al, 2011; Adams, Schneider, et al, 2012; Alizadeh et al, 2017; Bae et al,…”

“…It was also common for selection processes to place importance on TK with greater predominance in traditional sources, such as interventions appearing frequently within or across sources, and those with consistency of use over time as proxy measures for safety and potential efficacy (Alizadeh et al, 2017; Bae et al, 2019; Birch & Sherman, 1999; Buentzel et al, 2020; Chen et al, 2015, 2020; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Guo‐Jing et al, 2020; Han et al, 2017; Lardos et al, 2011; May et al, 2014; Sahranavard et al, 2014; Steel & Adams, 2011c; Thomas, 2011; Xia et al, 2020; Zhang et al, 2014). The perceived authority, authenticity and influential impact of the source on its tradition were also given importance during selection of TK in research and practice (; Adams et al, 2011; Adams, Schneider, et al, 2012; Alizadeh et al, 2017; Bae et al, 2019; Connelly et al, 2020; De Vos, 2010; Flatt, 2016; Jaric et al, 2014; May et al, 2012; Petran et al, 2020; Reid et al, 2018; Yang et al, 2019).…”

“…Step 3—Intervention exploration: During intervention exploration, TK theory and practice were examined from both traditional and contemporary views, without equating the two perspectives, in order to avoid reductionism or misapplication of TK while also incorporating the benefits of scientific research (Adams et al, 2009; Canaway et al, 2018; Connelly et al, 2020; Flatt, 2016; Gerontakos et al, 2021; Harrison et al, 2015; May et al, 2014; Steel & Adams, 2011c). TK was explored for pragmatic adaptations to meet the needs of individual patients and the requirements of contemporary environments (Adams, 2017; Brien et al, 2012; Brosnan, 2016), while also ensuring core characteristics were preserved to maintain the integrity of the tradition (Flatt, 2016; Harrison et al, 2015; Zargaran et al, 2016).…”

“…While this level of attention to fidelity was limited, other studies sought compromise between the traditional basis of TK and its alignment with contemporary science by triangulating TK with scientific research (Adams et al, 2009; Buentzel et al, 2020; Flatt, 2016; Gerontakos et al, 2021; Guo‐Jing et al, 2020; Harrison et al, 2015; Lumlerdkij et al, 2018; Yao et al, 2021; Zhang et al, 2014) and/or seeking opinions from TK experts regarding scientific findings (Brien et al, 2012; Chen et al, 2015; Fatali, Emami, et al, 2020; Guo‐Jing et al, 2020; Kasiri‐Martino & Bright, 2016; Wang et al, 2017; Yao et al, 2018, 2021). The pre‐clinical studies included in the review all addressed bacterial infections using recipes described in traditional texts (e.g., Bald's Leechbook) (Connelly et al, 2020; Harrison et al, 2015; Kadam et al, 2020; Watkins et al, 2012). These studies clearly aligned with traditional practice through fidelity to the original recipe described by the premodern doctors and scientists, adapting the recipes only as necessary to the context of contemporary scientific research.…”

Phase 1 safety trial of a natural product cocktail with antibacterial activity in human volunteers

“…Natural products provide a potential pool of candidate compounds for development into clinically-useful antibacterial agents 11,30 . Historical medical texts can act as a database of NPs which have traditionally been used to treat infection, with a rich set of contextual data on how plants and other natural materials were prepared, combined and assigned to treat symptoms of conditions that we know to be microbial infections 22,23,31 .…”