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The fight against infectious diseases often focuses on epidemics and pandemics, which demand urgent resources and command attention from the health authorities and media. However, the vast majority of deaths caused by infectious diseases occur in endemic zones, particularly in developing countries, placing a disproportionate burden on underfunded health systems and often requiring international interventions. The provision of vaccines and other biologics is hampered not only by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, but also by challenges caused by distribution and storage, particularly in regions without a complete cold chain. In this review article, we consider the potential of molecular farming to address the challenges of endemic and re-emerging diseases, focusing on edible plants for the development of oral drugs. Key recent developments in this field include successful clinical trials based on orally delivered dried leaves ofArtemisia annuaagainst malarial parasite strains resistant to artemisinin combination therapy, the ability to produce clinical-grade protein drugs in leaves to treat infectious diseases and the long-term storage of protein drugs in dried leaves at ambient temperatures. Recent FDA approval of the first orally delivered protein drug encapsulated in plant cells to treat peanut allergy has opened the door for the development of affordable oral drugs that can be manufactured and distributed in remote areas without cold storage infrastructure and that eliminate the need for expensive purification steps and sterile delivery by injection.

The fight against infectious diseases often focuses on epidemics and pandemics, which demand urgent resources and command attention from the health authorities and media. However, the vast majority of deaths caused by infectious diseases occur in endemic zones, particularly in developing countries, placing a disproportionate burden on underfunded health systems and often requiring international interventions. The provision of vaccines and other biologics is hampered not only by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, but also by challenges caused by distribution and storage, particularly in regions without a complete cold chain. In this review article, we consider the potential of molecular farming to address the challenges of endemic and re-emerging diseases, focusing on edible plants for the development of oral drugs. Key recent developments in this field include successful clinical trials based on orally delivered dried leaves of Artemisia annua against malarial parasite strains resistant to artemisinin combination therapy, the ability to produce clinical-grade protein drugs in leaves to treat infectious diseases and the long-term storage of protein drugs in dried leaves at ambient temperatures. Recent FDA approval of the first orally delivered protein drug encapsulated in plant cells to treat peanut allergy has opened the door for the development of affordable oral drugs that can be manufactured and distributed in remote areas without cold storage infrastructure and that eliminate the need for expensive purification steps and sterile delivery by injection. The authors would like to thank the Spanish Ministry of Economy, Industry and Competitiveness (project AGL2017-85377-R), the Spanish Ministry of Science, Innovation and Universities (projects RTI2018-097613-B-I00 and PGC2018-097655-B-I00), the EU Horizon 2020 project Pharma-Factory (774078) and the Gener- alitat de Catalunya (Grups Consolidats2017-SGR828); Ag encia de Gesti o d’Ajuts Universitaris i de Recerca (AGAUR), Departament d’Empresa i Coneixement de la Generalitat de Catalunya (PAND EMIES 2020); Project LISBOA-01-0145-FEDER-007660 (Microbiologia Molecular, Estrutural e Celular funded by FEDER funds through COMPETE2020)—Programa Operacional Compet- itividade e Internacionalizacß~ao (POCI) and by the FCT (Portugal) through the R&D Unit, UIDB/04551/2020 (GREEN-IT—Biore- sources for Sustainability); UKIERI and the Hotung Foundation for sustained support of the Bharathiar University / St. George’s Univ. of London collaboration and the Molecular Immunology Unit at St. George’s Univ. of London. The Max Planck Society, the EU Horizon 2020 project Newcotiana (760331-2) and a grant from the European Research Council (ERC-ADG-2014; grant agreement 669982) to RB. KMOC, RMT and STH acknowledge support from the InnCoCells project funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement 101000373. PSS, KAM, RF and SN are partially supported by a CRAFT award (COVID-19 Research Accelerator Funding Track) by the University of California Davis. KAM and SN were partially supported by NASA Space Technology Research (award number NNX17AJ31G) and by the Translational Research Institute through NASA (grant number NNX16AO69A); EMBRAPA (Brazilian Agricultural Corporation), INCT BioSyn (National Institute of Science and Technology in Synthetic Biology), CNPq, CAPES, Brazilian Ministry of Health, FAPDFnd Universidade Cat olica de Bras ılia (UCB), Bras ılia, Brazil; BBSRC Grant BB/L020955/1, the JIC Strategic Programme Grant ‘Molecules from Nature –Enhanced Research Capacity’ (BBS/E/ J/000PR9794), the John Innes Foundation and the Department of Health and Social Care using UK Aid funding managed by the BBSRC; and The Austrian Science Fund FWF (project W1224). TTW Veni Grant 16740 from the Netherlands Organization for Scientific Research. Research in the Daniell laboratory was supported by NIH grants R01 GM 63879, R01 107904, R01 HL 109442, R01 133191 and grants from Bayer, Novo Nordisk and Shire/Takeda. The National Heart Lung and Blood Institute, National Institutes of Health, Department of Health and Human Services, through the Science Moving TowArds Research Trans- lation and Therapy (SMARTT) programme contracts # HHSN268201600014C, HHSN268201600011C supported IND enabling regulatory, toxicology and pharmacokinetic studies. Any opinions, findings and conclusions or recommendations expressed in this material are those of the author (s) and do not necessarily reflect the views of the University of California, Davis, National Aeronautics and Space Administration (NASA) or the Translational Research Institute for Space Health (TRISH). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Views expressed in this article are those of the authors and do not necessarily reflect those of the employing institutions or the UK Department of Health and Social Care

Infectious diseases, also known as transmissible or communicable diseases, are caused by pathogens or parasites that spread in communities by direct contact with infected individuals or contaminated materials, through droplets and aerosols, or via vectors such as insects. Such diseases cause 17% of all human deaths and their management and control places an immense burden on healthcare systems worldwide. Traditional approaches for the prevention and control of infectious diseases include vaccination programmes, hygiene measures and drugs that suppress the pathogen, treat the disease symptoms or attenuate aggressive reactions of the host immune system. The provision of vaccines and biologic drugs such as antibodies is hampered by the high cost and limited scalability of traditional manufacturing platforms based on microbial and animal cells, particularly in developing countries where infectious diseases are prevalent and poorly controlled. Molecular farming, which uses plants for protein expression, is a promising strategy to address the drawbacks of current manufacturing platforms. In this review article, we consider the potential of molecular farming to address healthcare demands for the most prevalent and important epidemic and pandemic diseases, focussing on recent outbreaks of high-mortality coronavirus infections and diseases that disproportionately affect the developing world. The authors would like to thank the Spanish Ministry of Economy, Industry and Competitiveness (project AGL2017-85377-R), the Spanish Ministry of Science, Innovation and Universities (projects RTI2018-097613-B-I00 and PGC2018-097655-B-I00), the EU Horizon 2020 project Pharma-Factory (774078) and the Gener- alitat de Catalunya (Grups Consolidats 2017-SGR828), Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), Departa- ment d’Empresa i Coneixement de la Generalitat de Catalunya (PAND EMIES 2020). Project LISBOA-01-0145-FEDER-007660 (Microbiologia Molecular, Estrutural e Celular funded by FEDER funds through COMPETE2020 –Programa Operacional Compet- itividade e Internacionalizacß~ao (POCI) and by the FCT (Portugal) through the R&D Unit, UIDB/04551/2020 (GREEN-IT –Biore- sources for Sustainability). UKIERI and the Hotung Foundation for sustained support of the Bharathiar University / St. George’s Univ. of London collaboration and the Molecular Immunology Unit at St. George’s Univ of London. The Max Planck Society, the EU Horizon 2020 project Newcotiana, 760331-2) and a grant from the European Research Council (ERC-ADG-2014; grant agree- ment 669982) to RB. KMOC, RMT and STH acknowledge support from the InnCoCells project funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement 101000373. PSS, KAM, RF, and SN are partially supported by a CRAFT award (COVID-19 Research Accelerator Funding Track) by the University of California Davis. KAM and SN were partially supported by NASA Space Technology Research (award number NNX17AJ31G) and by the Translational Research Institute through NASA (grant number NNX16AO69A). EMBRAPA (Brazilian Agricultural Corporation), INCT BioSyn (National Institute of Science and Technology in Synthetic Biology), CNPq, CAPES, Brazilian Ministry of Health, FAPDF and Universidade Cat olica de Bras ılia (UCB), Bras ılia, Brazil. BBSRC Grant BB/L020955/1, the JIC Strategic Programme Grant ‘Molecules from Nature –Enhanced Research Capacity’ (BBS/E/ J/000PR9794), the John Innes Foundation and the Department of Health and Social Care using UK Aid funding managed by the BBSRC. The Austrian Science Fund FWF (project W1224). TTW Veni Grant 16740 from the Netherlands Organization for Scientific Research. Research in the Daniell laboratory was supported by NIH grants R01 GM 63879, R01 107904, R01 HL 109442, R01 133191 and grants from Bayer, Novo Nordisk and Shire/Takeda. The National Heart Lung and Blood Institute, National Institutes of Health, Department of Healthand Human Services, through the Science Moving TowArds Research Trans- lation and Therapy (SMARTT) program contracts # HHSN268201600014C, HHSN268201600011C supported IND enabling regulatory, toxicology and pharmacokinetic studies. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author (s) and do not necessarily reflect the views of the University of California, Davis, National Aeronautics and Space Administration (NASA) or the Translational Research Institute for Space Health (TRISH). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Views expressed in this article are those of the authors and do not necessarily reflect those of the employing institutions or the UK Department of Health and Social Care.

RESUMO A transformação genética, que compreende a introdução de genes exógenos de forma controlada no genoma de uma célula vegetal e posterior regeneração da planta transgênica, tem contribuído com os programas de melhoramento genético de plantas pela obtenção de genótipos com novas características de interesse. O melhoramento de espécies florestais é limitado por características intrínsecas a tais espécies, como a altura dos indivíduos e o ciclo longo de vida. A transformação genética constitui, portanto, uma alternativa para a obtenção de espécies florestais com características desejáveis em um menor espaço de tempo. Plantas transgênicas com resistência a determinadas pragas, com melhor qualidade de madeira, maior produção de biomassa, tolerância a herbicidas, entre outras características de interesse, já foram obtidas para diferentes espécies florestais de importância econômica como álamo, eucalipto e pinheiros em geral. Este trabalho mostra a importância da transformação genética, associada a outras técnicas biotecnológicas no melhoramento de espécies florestais, as técnicas de transformação mais utilizadas e as características que já foram introduzidas nessas espécies pela transformação.

RESUMO A transformação genética, que compreende a introdução de genes exógenos de forma controlada no genoma de uma célula vegetal e posterior regeneração da planta transgênica, tem contribuído com os programas de melhoramento genético de plantas pela obtenção de genótipos com novas características de interesse. O melhoramento de espécies florestais é limitado por características intrínsecas a tais espécies, como a altura dos indivíduos e o ciclo longo de vida. A transformação genética constitui, portanto, uma alternativa para a obtenção de espécies florestais com características desejáveis em um menor espaço de tempo. Plantas transgênicas com resistência a determinadas pragas, com melhor qualidade de madeira, maior produção de biomassa, tolerância a herbicidas, entre outras características de interesse, já foram obtidas para diferentes espécies florestais de importância econômica como álamo, eucalipto e pinheiros em geral. Este trabalho mostra a importância da transformação genética, associada a outras técnicas biotecnológicas no melhoramento de espécies florestais, as técnicas de transformação mais utilizadas e as características que já foram introduzidas nessas espécies pela transformação. ABSTRACT Breeding of forest species is limited by intrinsic characteristics such as individual’s height and long life cycle. Plant genetic transformation, the integration of known foreign genes into the plant genome, represents a less time consuming alternative for the recovery of forest species with desirable traits. This technology has contributed to plant breeding programs by facilitating the recovery of genotypes containing novel exciting traits of agricultural importance. Many of them including resistance to insect pests, improvement of wood quality and biomass production, and tolerance to herbicides have been introduced in forest species such as poplar, eucalyptus and pine trees using this technology. This review highlights current transformation methods, and illustrates the importance of finally defining the most important traits that have already been introduced into these valuable species.