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3 Potency Assays: The ‘Bugaboo’ of Stem Cell Therapy . . . . . . . . 29
Sílvia Torrents, Marta Grau-Vorster, and Joaquim Vives
3.1 Potency – What a Cell Can Do . . . . . . . . . . . . . . . . . . . . . . . . 29
3.2 Relevance of Potency Assays . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3.3 Regulatory Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.3.1 EMA Regulatory Requirements . . . . . . . . . . . . . . . . . . 32
3.3.2 FDA Regulatory Requirements . . . . . . . . . . . . . . . . . . 32
3.3.3 Japanese FDA Regulatory Requirements. . . . . . . . . . . 32
3.4 Development of Potency Assays . . . . . . . . . . . . . . . . . . . . . . . 33
3.4.1 Use of Surrogate Markers . . . . . . . . . . . . . . . . . . . . . . 33
3.4.2 Autologous and Allogeneic Products . . . . . . . . . . . . . . 34
3.4.3 Standardisation of Assays . . . . . . . . . . . . . . . . . . . . . . 35
3.4.4 Further Considerations . . . . . . . . . . . . . . . . . . . . . . . . . 36
3.5 The Quality Target Product Prole . . . . . . . . . . . . . . . . . . . . . 36
3.6 Final Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
4 Identifying Biomarkers for Osteogenic Potency
Assay Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Jorge S. Burns and Moustapha Kassem
4.1 Skeletal Stem Cell for Conservative Bone Healing . . . . . . . . . 39
4.2 The Challenge of hBM-MSC Donor-Specic
Heterogeneity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4.3 Telomerised MSC; Scalable Clonal Populations
with Consistent Bone- Forming Potential . . . . . . . . . . . . . . . . . 42
4.4 Comparative Analysis of Gene Expression, microRNA,
Morphological Phenotypes and Cell Membrane
or Secreted Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
4.5 Compelling Pathways for Functional Attributes
in Osteogenic Potency Assays . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.6 Lessons Learned for Bone Repair ATMP Development . . . . . 50
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Contents
5 Potency Assay Considerations for Cartilage Repair,
Osteoarthritis and Use of Extracellular Vesicles . . . . . . . . . . . . . 59
Lucienne A. Vonk
5.1 Articular Cartilage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
5.2 Cell-Based Treatment of Cartilage Defects . . . . . . . . . . . . . . . 59
5.2.1 Potency Assays Used for Autologous Chondrocyte
Implantation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
5.2.2 Mechanism of Action (MoA) of MSC-Based
Cartilage Defect Repair . . . . . . . . . . . . . . . . . . . . . . . . 61
5.2.3 MoA: Differentiation Versus Paracrine Signalling . . . 61
5.2.4 Cell Fate of MSCs Used to Treat Cartilage Defects . . 62
5.3 Considerations and Suggestions for Potency Assays
for MSC- Based Cartilage Defect Repair . . . . . . . . . . . . . . . . . 64
5.3.1 Potency Assays for Differentiation . . . . . . . . . . . . . . . 66
Contents
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5.4 Treatment of Osteoarthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
5.4.1 MSC-Based Treatment of Osteoarthritis . . . . . . . . . . . 67
5.4.2 Tracking MSC After Intra- Articular Injection
in Osteoarthritic Joint . . . . . . . . . . . . . . . . . . . . . . . . . . 67
5.5 Considerations and Suggestions for Potency Assays
for MSC- Based Treatment of Osteoarthritis . . . . . . . . . . . . . . 67
5.5.1 Effects on Macrophage Polarisation . . . . . . . . . . . . . . 68
5.5.2 Effects on NK Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
5.5.3 Effects on T Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
5.5.4 Effects on B Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
5.5.5 Effects on Cartilage Formation . . . . . . . . . . . . . . . . . . 70
5.5.6 Possible Surrogate Potency Markers . . . . . . . . . . . . . . 70
5.6 Extracellular Vesicles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
5.6.1 Functional Assays for EVs . . . . . . . . . . . . . . . . . . . . . . 72
5.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6 Advanced Technologies for Potency Assay Measurement . . . . . . 81
Raghavan Chinnadurai
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
6.2 Variability of MSC Therapeutics . . . . . . . . . . . . . . . . . . . . . . . 81
6.3 General Considerations for MSC Release Criteria . . . . . . . . . 82
6.4 Key Aspects of Potency Assays . . . . . . . . . . . . . . . . . . . . . . . . 83
6.5 Potency Assay Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.5.1 Immunological Assays . . . . . . . . . . . . . . . . . . . . . . . . . 84
6.5.2 Genomic Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
6.5.3 Secretome Assays. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
6.5.4 Phosphorylation Assays . . . . . . . . . . . . . . . . . . . . . . . . 87
6.5.5 Morphological Proling Assays . . . . . . . . . . . . . . . . . . 88
6.5.6 Biomaterial-Based Assays . . . . . . . . . . . . . . . . . . . . . . 89
6.5.7 Angiogenic Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
6.5.8 Metabolic Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
6.6 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
7 Innovative Quantification of Critical Quality Attributes . . . . . . 97
Sotirios Papamatthaiou and Despina Moschou
7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
7.2 Lab-on-PCB . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
7.2.1 PCB Technology Overview . . . . . . . . . . . . . . . . . . . . . 98
7.2.2 Early Prototypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99
7.2.3 Materials and Processes for Microuidic
Integration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
7.2.4 Advanced Quantication Diagnostic Device
Examples . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
7.2.5 Recent Developments in Lab- on- PCB Commercially
Relevant Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
7.3 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
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8 Release Assays and Potency Assays for CAR T-Cell
Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Juliana Dias, Amaia Cadiñanos-Garai, and Claire Roddie
8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
8.2 Regulations and Requirements for Quality Control Testing
and Batch Release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
8.3 Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
8.3.1 Sterility Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
8.3.2 Mycoplasma Detection . . . . . . . . . . . . . . . . . . . . . . . . 121
8.3.3 Replication Competent Lentivirus (RCL)
or Retrovirus (RCR) . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
8.3.4 Vector Copy Number (VCN) per Transduced Cell . . . 122
8.3.5 Identity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
8.3.6 Purity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
8.3.7 Quantity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
8.4 Potency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
8.4.1 Potency Assessment for CAR T-Cell Therapies . . . . . 125
8.5 Regulatory Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
8.6 Methods for Potency Assessment of CAR T-Cell Products . . . 126
8.6.1 Target-Directed Cytotoxic Activity . . . . . . . . . . . . . . . 127
8.6.2 Direct Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
8.6.3 Indirect Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129
8.6.4 Immunophenotyping . . . . . . . . . . . . . . . . . . . . . . . . . . 130
8.6.5 Target-Induced Proliferation . . . . . . . . . . . . . . . . . . . . 130
8.6.6 Polyfunctionality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
8.7 Challenges and Potential Improvements for CAR
T-Cell Potency Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
8.8 Future Challenges and Directions for CAR T-Cell Product
Release Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Contents
9 Illustrative Potency Assay Examples from Approved
Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Sílvia Torrents, Marta Grau-Vorster, and Joaquim Vives
9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
9.2 Regulatory Framework. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
9.3 CAR-T: Super T Cells to Fight Cancer . . . . . . . . . . . . . . . . . . 142
9.3.1 Description and Indication . . . . . . . . . . . . . . . . . . . . . . 142
9.3.2 Characterization of Tisagenlecleucel Product
KYMRIAH® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
9.4 Holoclar®: A Tissue Engineering Product to Regenerate
Cornea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
9.4.1 Description and Indication . . . . . . . . . . . . . . . . . . . . . . 143
9.4.2 Characterization of Limbal Epithelial Stem Cell
Product Holocar® . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Contents
9.5 Remestemcel-L: MSC for the Management of GvHD . . . . . . 143
9.5.1 Description and Indication . . . . . . . . . . . . . . . . . . . . . . 143
9.5.2 Characterization of Remestemcel-L Product
PROCHYMAL® (or RYONCIL™) . . . . . . . . . . . . . . . 144
9.6 Addressing Potency in Other Selected ATMP . . . . . . . . . . . . . 144
9.6.1 Approved ATMP . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
9.6.2 ATMP Under Clinical Investigation. . . . . . . . . . . . . . . 145
9.7 The Case of Pluripotent Stem Cells . . . . . . . . . . . . . . . . . . . . . 146
9.8 Final Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
10 From the Integrity of Potency Assays to Safe Clinical
Intervention: Legal Perspectives
. . . . . . . . . . . . . . . . . . . . . . . . . . 151
Waltter Roslin and Juli Mansnérus
10.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
10.2 The Evolving Regulatory Concept of Potency. . . . . . . . . . . . 152
10.3 The Emergence of the Regulatory Landscape
for Stem Cell- Based ATMPs and Their Potency Assays . . . . 152
10.4 Overview of the Current EU Regulatory Framework
for Stem Cell-Based Therapies . . . . . . . . . . . . . . . . . . . . . . . 153
10.4.1 ATMP Regulation Covering the Market Access,
Supervision and Pharmacovigilance of Advanced
Therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
10.4.2 Allogeneic or Autologous: Does the Origin
of the Source Materials Affect the Process? . . . . . . . 157
10.4.3 EU Clinical Trials Regulation Streamlining
the Application Procedure . . . . . . . . . . . . . . . . . . . . . 157
10.4.4 “Soft Law” Encountering “Hard Science”:
Flexibilities Are Needed to Deal with Rapid
Scientic Advancements in an Ethically
Sensitive Field . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
10.4.5 EU “Soft Law” Levelling the Playing Field
for Potency Assay Developers . . . . . . . . . . . . . . . . . . 160
10.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163
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11 The Evolving Landscape of Potency Assays . . . . . . . . . . . . . . . . . 165
Jorge S. Burns
11.1 Getting Potency Assays Just Right . . . . . . . . . . . . . . . . . . . . 165
11.2 Finessing the Potency of ATMP . . . . . . . . . . . . . . . . . . . . . . . 165
11.3 Potency Assays for Acellular Products . . . . . . . . . . . . . . . . . 167
11.4 Cryopreservation and Scale-Up: Balancing Complexity
and Product Quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168
11.5 Highlighting COGS in the Wheel of CAR T-Cell
Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
11.6 Potency Assays for Induced MSC . . . . . . . . . . . . . . . . . . . . . 173
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11.7 Enhancing Potency Assays: Cell Priming,
Nanotechnology and 3D Culture . . . . . . . . . . . . . . . . . . . . . . 174
11.8 Regulations, Guidelines and Evolving
Institutional Roles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181
Glossary of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
Contents
Contributors
Jorge S. Burns Department of Environmental and Prevention Sciences,
University of Ferrara, Ferrara, Italy
AmaiaCadiñanos-Garai USC/CHLA Cell Therapy Program, Keck School
of Medicine of USC, University of Southern California (USC), Los Angeles,
CA, USA
Raghavan Chinnadurai Department of Biomedical Sciences, Mercer
University School of Medicine, Savannah, GA, USA
Juliana Dias UCL Cancer Institute, University College London, London,
UK
Royal Free Hospital London, NHS Foundation Trust, London, UK
MartaGrau-Vorster Banc de Sang i Teixits, Edici Dr. Frederic Duran i
Jordà, Barcelona, Spain
Transfusion Medicine Group, Vall d’Hebron Research Institute, Universitat
Autònoma de Barcelona, Barcelona, Spain
MoustaphaKassem University Hospital of Odense, University of Southern
Denmark, Odense, Denmark
Danish Stem Cell Center, University of Copenhagen, Copenhagen, Denmark
College of Medicine, King Saud University, Riyadh, Saudi Arabia
JuliMansnérus University of Helsinki, Helsinki, Finland
EvaMargreiter Innovacell AG, Innsbruck, Austria
RainerMarksteiner Innovacell AG, Innsbruck, Austria
Despina Moschou Centre for Biosensors, Bioelectronics and Biodevices
(ToC3Bio) and Department of Electronic & Electrical Engineering, University
of Bath, Bath, UK
Sotirios Papamatthaiou Centre for Biosensors, Bioelectronics and
Biodevices (ToC3Bio) and Department of Electronic & Electrical Engineering,
University of Bath, Bath, UK
ClaireRoddie UCL Cancer Institute, University College London, London,
UK
Department of Haematology, UCL Hospital, London, UK
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xviii
WaltterRoslin University of Helsinki, Helsinki, Finland
MarcoThurner Innovacell AG, Innsbruck, Austria
Finnegan, Henderson, Farabow, Garrett & Dunner LLP, Munich, Germany
RaffaelaTorggler Innovacell AG, Innsbruck, Austria
SílviaTorrents Banc de Sang i Teixits, Edici Dr. Frederic Duran i Jordà,
Barcelona, Spain
Transfusion Medicine Group, Vall d’Hebron Research Institute, Universitat
Autònoma de Barcelona, Barcelona, Spain
JoaquimVives Banc de Sang i Teixits, Edici Dr. Frederic Duran i Jordà,
Barcelona, Spain
Musculoskeletal Tissue Engineering Group, Vall d’Hebron Research Institute
(VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona,
Spain
LucienneA.Vonk Department of Orthopaedics, University Medical Center
Utrecht, Utrecht, The Netherlands
Contributors
About the Editor
JorgeS.Burns received his degree in Cellular Pathology at the University
of Bristol and PhD at the University of Wales College of Medicine in 1992,
authoring the rst UK manuscript to describe the use of retroviral vectors in
epithelial cells. At the Ludwig Institute for Cancer Research, University
College London Branch, a postdoctoral fellowship in Breast Cancer research
provided technology insights leading to an appointment at renowned proteome research facilities at the University of Southern Denmark in Odense.
Subsequent industrial experience was obtained with management of a cell
culture facility supporting mass spectrometry for immune therapy target discovery at MDS Proteomics A/S.Joining the academic research team led by
Prof. Moustapha Kassem at Odense University Hospital brought focus on
human bone marrow-derived stromal cells and their osteogenic differentiation potential, plus participation in the Innovation Consortium 3-D scaffolds.
Preclinical stem cell characterisation studies progressed to translational
regenerative medicine at the University of Modena in Italy, upon joining the
EU Framework 7 Reborne consortium, whereby bone therapy clinical trials
required exploration of novel osteogenic potency assays. To pursue development of potency assay biosensors, Prof. Burns obtained an award for project
number 154/25.11.2016, P_37_221/2015, “A novel GRaphene Biosensor
Testing Osteogenic Potency; capturing best stem cell performance for regenerative medicine” (GRABTOP), from the Ministry of Research and Innovation
in Romania, Operational Program Competitiveness Axis 1 Section E, conanced from European Regional Development Fund “Investments for your
future”. The multidisciplinary laboratory inaugurated at the Faculty of
Medical Engineering, University Politehnica of Bucharest, tested the applicability of the nanomaterial graphene and its diverse functionalised forms.
Current research interests revolve around improved methods of invivo mimicry at the Department of Environmental and Prevention Sciences at the
University of Ferrara.
xix
The Art ofStem Cell-Based
Therapy
JorgeS.Burns
Yet an experiment, were you to try it, could free you from your cavil–and the source of
your arts’ course springs from experiment.
Dante Alighieri, The Divine Comedy, Paradiso, Canto II, lines 94-96, c. 1304-1321.
English translation by Allen Mandelbaum.
1
1.1 The Dawn ofaNew Era
Centuries before Robert Hooke’s description of
cells as observation XVIII in Micrographia,
1655, the importance of experiment had already
been highlighted in one of the most important
poems of the Middle Ages. Just as Dante’s use of
a Florentine vernacular and around 90 neologisms marked a radical shift from writing poetry
in Latin, so too cellular therapy has represented a
paradigm shift in medicine whereby advanced
therapy medicinal products (ATMP) can revolutionise the medical treatment of numerous traumatic pathologies of unmet medical need,
literally making La Vita Nuova, the new life.
However, potency assays achieve far more
than freedom from one’s cavil or petty objections, they represent crucial experiments at the
hub of the comprehensive complexity surrounding cell therapy [23]. Moreover, numerous factors beyond biological and scientic
considerations underly the increasing signicance and importance that potency assays currently accrue. Many of the issues surrounding
J. S. Burns (*)
Department of Environmental and Prevention
Sciences, University of Ferrara, Ferrara, Italy
e-mail: js.burns@unife.it
Potency assays today have been encountered in
historical situations where medicine progressed
in the face of risk, when therapeutic approaches
were adopted without there necessarily being a
full understanding of the mechanisms responsible for a benecial effect. A brief account of the
ancient therapeutic procedure of variolation can
highlight the many facets involved in the development and establishment of new therapeutic
approaches and the emerging critical role of
potency assays.
1.2 Lessons fromaPast Disease
The word variola was introduced as a term for
Smallpox by Bishop Marious of Avenches in AD
570, derived from the Latin word varius meaning
‘stained’ or from varus, denoting ‘mark on the
skin’. Small pockes was terminology used in
England at the end of the fteenth century (pocke
meaning sack) and would distinguish the devastating disease from syphilis, then referred to as
the great pockes. As early as 430BCE it had been
appreciated that Smallpox survivors were protected from a recurrence of the disease and could
nurse the aficted. The origins of the most successful approach to combat Smallpox, termed
inoculation (from Latin inoculare, ‘to graft’)
© Springer Nature Switzerland AG 2023
J. S. Burns (ed.), Potency Assays for Advanced Stem Cell Therapy Medicinal Products, Advances
in Experimental Medicine and Biology 1420,
https://doi.org/10.1007/978-3-031-30040-0_1
1
2
Fig. 1.1 Variolation for smallpox originated in the Far East and later spread to Europe and Africa. This Japanese
memorial relief by Fumio Saita in front of the Asakura Ishikai Hospital depicts a patient receiving a smallpox variolation in 1790 from the physician Ogata Shunsaku (1748–1810). His inspiration came from reading the 60th volume of
the ‘Imperially Commissioned Golden Mirror of the Orthodox Lineage of Medicine’ a compilation of medical writings
of the Han dynasty (202BCE–220 CE) published in China in 1742. Ogata went on to publish the booklet Shutō hitsujun
ben (種痘必順弁), pox essentials, describing how variolation ensured gentle smallpox in 1793. Original photograph by
Wolfgang Michel-Zaitsu ‘Between East and West-Variolation in Early Modern Japan’: Proceedings of the International
Symposium on the History of Indigenous Knowledge (ISHIK 2022), Kaifeng, China
J. S. Burns
were ancient, practiced in Africa, India, China
and Japan long before its introduction to Europe
in the eighteenth century (Fig. 1.1). Perhaps as
early as the tenth century CE, the Chinese knew
that by opening pustules of a Smallpox patient
and drying the matter with a little cotton subsequently transferred to a recipient’s nostrils, it was
possible to transmit a relatively mild form of the
disease that was prophylactically protective,
helping avoid death in an epidemic. By the fteenth century, the documented methods, in
effect, a form of cell-based therapy, indicated
careful ritualisation; ‘nasal insufation’ involved
use of silver blowpipes, right nostril for boys, left
for girls. Those with relatively mild Smallpox
symptoms, (possibly because they were infected
with variola minor as opposed to variola major),
were favoured donors of the scabs that were then
left to dry for some time and ground to a powder
or exposed to hot steam and various herbs or a
grain of musk. Although unknown at the time, it
is now appreciated that such procedures would
damage virus particles, helping attenuate the
infectious dose that was riskily being administered via the same route as natural Smallpox
infections. In contrast to the Asian and African
inhaled variolation procedures, Europeans and
Americans inoculated via a puncture to the skin,
a route avoiding a potential swift spread of the
disease in the lungs, promoting a slower viral
progress that would favour a more effective
immune system defense. The geographical EastWest discrepancy in inoculation routes largely
reects the pivotal role played by Lady Mary
Wortley Montague, born to an aristocratic family
in 1689, in bringing the procedure of variolation
to the West from Turkey [18]. Her motivation was
high; in 1713, her only and younger brother died
of Smallpox aged just 20. Two years later she
contracted the disease herself and against expectation survived, although she was left badly
scarred. When her husband was appointed British
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