Molecules from nature: Reconciling biodiversity conservation and global healthcare imperatives for sustainable use of medicinal plants and fungi

Melanie-Jayne R. Howes1,2 | Cassandra L. Quave3 | Jérôme Collemare4 | Evangelos C. Tatsis5,6 | Danielle Twilley7 | Ermias Lulekal8 | Andrew Farlow9,10 | Liping Li11 | María-Elena Cazar12 | Danna J. Leaman13 | Thomas A. K. Prescott1 | William Milliken1 | Cathie Martin14 | Marco Nuno De Canha7 | Namrita Lall7,15,16 | Haining Qin17 | Barnaby E. Walker18 | Carlos Vásquez-Londoño19 | Bob Allkin20 | Malin Rivers21 | Monique S. J. Simmonds22 | Elizabeth Bell1,20 | Alex Battison1 | Juri Felix1 | Felix Forest23 | Christine Leon24 | China Williams25 | Eimear Nic Lughadha18


| INTRODUC TI ON
Non-communicable diseases, including heart disease, stroke, cancer, diabetes, and chronic lung disease, are responsible for almost 70% of deaths globally (World Health Organization [WHO], 2016). In addition, deaths due to dementias have more than doubled between 2000 and 2016, making it the 5th leading cause of deaths worldwide in 2016 (WHO, 2019a). There are global programmes that aim to address these and other health challenges such as the WHO's Sustainable Development Goals (SDGs). SDG 3, to ensure healthy lives and promote well-being for all at all ages, aligns with the WHO's 13th General Programme of Work to achieve universal health coverage (UHC), address health emergencies, and promote healthier populations (WHO, 2019b). Despite some progress for SDG3 targets for particular communicable diseases, including global declines in HIV and tuberculosis (TB) incidence, TB is still a leading cause of ill health and death. Drug-resistant TB remains a threat, and progress in malaria control appears to have slowed (WHO, 2018a). TB and other potentially life-threatening bacterial infections occur against a backdrop of emerging antibiotic resistance (Woolhouse et al., 2016), which is an escalating threat to global health and food security. For these, and other diseases, drugs derived from plants and fungi are fundamental in our armory against global health challenges (Dauncey & Howes, 2020).
Today, plants and fungi are embedded in global healthcare systems as sources of pharmaceuticals (Newman & Cragg, 2020a) or as traditional/complementary medicines, and are often associated with cultural and social significance (WHO, 2019d). It is therefore unsurprising that global demand for natural product medicines threatens the survival of certain species and is a driver of biodiversity loss.
Furthermore, many medicinal species are used by people in the region of origin, who have been their primary custodians and often hold unparalleled local knowledge. Scientists, governments, and other stakeholders must establish functional and equitable agreements to ensure that with respect to therapeutics from nature, there is compliance with the Nagoya Protocol and associated Access and Benefit Sharing legislation and consideration of the value and origins of any specimens collected .
It is not the intention of this review to discuss the efficacy and safety of natural products as medicines, or their impact on public health. Rather, we consider how the interactions between people, plants, and fungi have revealed new understanding of the role and preservation of natural resources for medicines, health, and well-being. We also discuss recent advances in natural product medicines discovery, and the role of plants and fungi in human health and well-being, particularly in the context of strategies to harmonize the therapeutic use of biodiversity with its proactive conservation through nature-based solutions.

| Global health challenges
Plants and fungi are the source of some of our most important drugs, including those so chemically complex (e.g. the anticancer drugs vincristine and vinblastine from the Madagascar periwinkle [Catharanthus roseus (L.) G.Don] (Howes, 2018)) that they may never have been discovered without natural product research. It has been suggested that prospecting nature to find new drugs is unnecessary because the number of different biological functions would not equate to the millions of chemically distinct natural molecules, and because ligands for specific molecular targets are likely to be found in many different species (Tulp & Bohlin, 2002). However, the remarkable chemical diversity of plants and fungi, and their impressive capability to synthesize highly complex novel compounds with 'drug-likeness' properties (Harvey, Edrada-Ebel, & Quinn, 2015;Jia, Li, Hao, & Yang, 2020;Koehn & Carter, 2005), provide substantial evidence that new drugs may still be discovered amongst the estimated 350,000 known vascular plant species, and estimated 2.2-3.8 million fungal species, many of which remain chemically unexplored (Dauncey & Howes, 2020;Harvey et al., 2015;2017;Hawksworth & Lücking, 2017). Indeed, there has been some criticism from industry and academia of the focus on high-throughput screening of synthetic compounds for drug discovery, whilst natural products are regarded as yielding higher 'hit rates' (Amirkia & Heinrich, 2015).
Of 185 small molecule drugs approved for cancer , 65% were natural product derived or inspired (Newman & Cragg, 2020a).
Chronic obstructive pulmonary disease (COPD) is a leading cause of death globally (WHO, 2016); smoking and air pollution are contributing factors (WHO, 2020b). Pharmaceuticals derived from plant alkaloids are used to support smoking cessation, including nicotine originally from tobacco (Nicotiana tabacum L.) and varenicline, designed from the laburnum (Laburnum anagyroides Medik.) alkaloid, cytisine (Dauncey & Howes, 2020;Niaura, Jones, & Kirkpatrick, 2006). The Solanaceae alkaloid atropine was the basis for antimuscarinic drugs (e.g. tiotropium) for COPD (Moulton & Fryer, 2011). A 'green infrastructure' (urban vegetation) is predicted to improve urban air quality (Hewitt, Ashworth, & MacKenzie, 2020), with potential impact on human health, however, forests and certain plantations (e.g. oil palm [Elaeis guineensis Jacq.]) are the largest global emitters of biogenic volatile organic compounds (bVOCs), including monoterpenes and their precursor isoprenes, which can influence ground-level ozone formation. More research is needed to understand the complex interactions among bVOCs, ecosystems, and climatic factors, and the long-term effects on human health and well-being.
Two drugs specifically developed for dementia symptoms are derived from plant alkaloids: galantamine, originally discovered in snowdrop (Galanthus woronowii Losinsk.) bulbs, and rivastigmine, developed from physostigmine, an alkaloid from calabar beans (Physostigma venenosum Balf.) . Since 2002, every drug developed for Alzheimer's disease, the most common form of dementia, has failed in clinical trials (Crow, 2018), and those showing promise are unlikely to be sufficiently cost-effective for widespread clinical implementation in the foreseeable future. Despite some promising natural product drug candidates (Howes, 2013;Williams, Sorribas, & Howes, 2011), the urgent need remains to discover new strategies to prevent or delay dementia, including greater consideration of therapeutic and nutraceutical interventions. Certain plant oils may alleviate behavioral and psychological symptoms of dementia (e.g. agitation) and may also influence cognition, and benefit quality-of-life Burns et al., 2011;Elliott et al., 2007;Huang et al., 2008;Okello & Howes, 2018;Press-Sandler, Freud, Volkov, Peleg, & Press, 2016). Emerging data suggest that particular dietary components or nutraceuticals may reduce or prevent cognitive decline (Howes, Perry, Vásquez-Londoño, & Perry, 2020), emphasizing the necessity for future research on how plants and fungi as medicines, nutraceuticals, or dietary components may benefit humanity by promoting healthy aging.
For diabetes, recent advances include the development of sodium-dependent glucose transporter (SGLT)-1/2 inhibitor drugs (e.g. sotagliflozin approved in the EU in 2019), based on the dihydrochalcone phloretin 2ʹ-O-glucoside (Newman & Cragg, 2020a), which occurs in plants such as apples (Malus domestica (Suckow) Borkh.) (Simmonds & Howes, 2016). Other current strategies for prevention or management of diabetes and cardiovascular disease are underpinned by healthy diets (WHO, 2020c) to help prevent obesity and reduce disease risk (WHO, 2017(WHO, , 2018b. Dietary approaches to address malnutrition, obesity and other health challenges must be aligned with strategies for food security (Ulian et al., 2020), and with research to understand the impact of climate change on the nutritional and medicinal value of plants and fungi, and the potential consequences for long-term human health (Borrell et al., 2020). The benefits of plants to human health may be even more extensive than simply providing medicines and a healthy diet; recent evidence links green spaces to positive effects on human health, including obesity reduction, improved mental health, mood and other indicators of well-being (Buck, 2016;Burton, 2014;Whear et al., 2014). With respect to public health, trees, and urban nature may promote health and social well-being by removing air pollution, reducing stress, encouraging physical activity, and promoting social ties and community (Turner-Skoff & Cavender, 2019).
Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a major concern to human health and was subject to 1,253 patents between 1976 and 2010 (Oldham, Hall, & Forero, 2013). Some plant constituents (e.g. sophoradiol) are active against drug-resistant strains of M. tuberculosis and show additive effects with anti-TB pharmaceuticals (Lu et al., 2020). A promising area of research is BOX 1 Drug discovery from Taxus spp.
Paclitaxel, originally from Pacific yew (Taxus brevifolia Nutt.) bark, was developed as an anticancer drug in the 1970s; thousands of trees were needed to obtain sufficient quantities for clinical use (Cragg & Pezzuto, 2016;Oberlies & Kroll, 2020). This contributed to a decline of around 30% in the populations within the last three generations, and the species is now Near Threatened (Thomas, 2013).
Similarly, Asian yews T. chinensis (Pilg.) Rehder and T. mairei (Lemée & H.Lév.) S.Y.Hu have undergone significant population reductions as a result of their exploitation following paclitaxel discovery and are now Endangered and Vulnerable respectively (Thomas, Li, & Christian, 2020;Yang, Christian, & Li, 2013). In northwest India and western Nepal, exploitation led to a decline of up to 90% of Taxus populations, notably T. contorta Griff., which is also now Endangered (Thomas, 2011).
Knowledge embedded in taxonomy and chemistry enabled a more sustainable solution -precursor chemicals in the leaves and twigs of the common yew (T. baccata L.) were discovered, and could be used not only for semi-synthesis of paclitaxel, but also for the analogues docetaxel and cabazitaxel (Cragg & Pezzuto, 2016;Howes, 2018). Today, international policies (Williams et al., 2020) aim to protect biodiversity from such exploitation, but may also discourage research to discover new medicines that benefit humanity.
Paclitaxel can be produced by plant cell cultures (Expósito et al., 2009) and in the future, paclitaxel yield could be further improved by synthetic biology applications. Although efforts to improve paclitaxel yields by heterologously expressing the biosynthetic pathway (Li et al., 2019) in other organisms are currently incomplete (all of the required genes are currently undetermined), such discoveries could provide new insights, strategies, and techniques to understand how paclitaxel is produced, paving the way to provide more sustainable sources of natural product medicines.

Taxus baccata L.
Photo credit: Dr Aljos Farjon the use of plants to produce vaccine antigens for TB; the secretory antigenic target (ESAT-6) in M. tuberculosis has been expressed in Brassica cretica Lam. via Agrobacterium-mediated transformation, inducing an immune response in vivo (Saba et al., 2020). This suggests that plants could be used as sources of low-cost agriculturally produced vaccines, while fungal leads for TB also show promise.

| Fungi as sources of pharmaceuticals
Since the serendipitous discovery of penicillin from Penicillium rubens Biourge, fungi have provided humans with important bioactive compounds, including the immunosuppressant ciclosporin, that allowed successful organ transplantation and the antihypercholesterolaemic statins (Hyde et al., 2019); and inspired drugs for Parkinson's disease (e.g. bromocriptine) (Dauncey & Howes, 2020), and for multiple sclerosis, such as fingolimod and its analogues (Newman & Cragg, 2020a). Since the twentieth century, prospecting fungal biodiversity has mostly been restricted to easy-to-grow soil moulds in high-throughput screens, which are not adapted to mimic the diverse conditions that trigger bioactive compound production (Keller, 2019). Genome analyses have identified an outstanding number of uncharacterized biosynthetic pathways in fungi (Kjaerbølling et al., 2018;Nielsen et al., 2017), a largely untapped resource for drug discovery. Prospection of fungal biodiversity offers key advantages over plants: collecting fungi is not detrimental to ecosystems as only a minuscule portion of mycelium is sampled. It even facilitates preserving biodiversity because sampled fungal strains, if cultured in

BOX 2 Medicinal Species in Latin America
In Latin America there is high plant biodiversity, such as in the Amazon rainforest, the Andean Mountains, and the Central American tropical and subtropical forests (Galvez-Ranilla, Kwon, Apostolidis, & Shetty, 2010). The use of medicinal plants generally increases with the species richness of the local flora (De la Torre, Cerón, Balslev, & Borchsenius, 2012), yet it is estimated that fewer than 25,000 plant species have been scientifically evaluated (Calixto, 2005). There are numerous threats to the long tradition of plant and fungal uses as medicines, foods, and in healing rituals (Bussmann & Sharon, 2006; Figure 1; Table S2); in 2019, the world witnessed destruction to the Amazon basin by fires (Borunda, 2020). Facing this situation, Latin American medicinal plant research needs to ensure impact in demonstrating the richness and potential of this natural resource to scientific and social sectors, whilst providing additional incentives to protect biodiversity.

BOX 3 Medicinal Species in South Africa
South Africa ranks amongst the top countries worldwide in terms of frequency of medicinal plant use, with approximately 27 million individuals relying on traditional healthcare (Chen et al., 2016). A major concern is the overharvesting and unsustainable use of wild medicinal plants, resulting in biodiversity loss; e.g. Encephalartos woodii Sander is extinct in the wild (Mander, 1998;Van Wyk, Oudshoorn, & Gericke, 2013;Williams, Victor, & Crouch, 2013). The variation seen in numbers of species traded as medicinal plants between 1998 (700) and 2013 (350) may be due to reduced availability of plant species (Van Wyk & Prinsloo, 2018). Trade of bulbs, bark, and roots is particularly destructive, especially since plants are not replaced (Mander, 1998;Van Wyk et al., 2013); approximately 86% of harvested plant parts result in death of the plant (Mander, Ntuli, Diederichs, & Mavundla, 2007). Several South African medicinal plants are traded at traditional markets, and many are listed on the South African Red Data List as species of concern (Table S3).
South African government regulations and acts aim to control the overharvesting and biopiracy of indigenous biological resources.
Examples include the National Environmental Management: Biodiversity Act 10 (2004) Conservation risks associated with exploitation of certain medicinal species are well-documented (Figure 1), so the relatively low mean extinction risk to medicinal plants may seem surprising to the general reader. However, this low mean extinction risk is consistent with observations over two decades that 'weedy' and/ or introduced species are over-represented in traditional medicinal floras, and that availability is a key factor in explaining this (Stepp & Moerman, 2001;Hart et al., 2017). Low mean extinction risk for medicinal plants is also consistent with the fact that weeds are over-represented among plants that are the sources of modern drugs (Stepp, 2004), and a more recent report notes that the likelihood of development of an alkaloid into a medicinal product is considerably influenced by the abundance of the source species (Amirkia & Heinrich, 2014). This latter finding also supports the view that access and supply constraints represent a key obstacle to the development of natural products by the pharmaceutical industry (Harvey, 2008).
Availability as a key factor in determining which plants are recognized to be useful as medicines goes beyond the consideration of weedy or introduced plants and is supported by our finding that, overall, medicinal plants tend to have larger native ranges than species not reported as medicinal (W = 1.13 × 10 9 , p < .001) (Notes S2).
Since native range size is the strongest predictor of extinction risk in plants (Darrah,  List criteria may nonetheless be of conservation concern, and attract research and timely conservation intervention. Indeed, one in five of the Chinese medicinal plants considered highest priority for conservation are not assessed to be threatened following IUCN Red List criteria (Huang, Zhang, & Qin, 2020; Notes S3; Figure S1).

Tamarindus indica L.
Photo credit: Dr Gwilym P. Lewis the use of these names bedevils regulation, research, and attempts to count or analyse trends statistically (Allkin et al., 2017). Harmonization of medicinal plant (Allkin et al., 2017;MPNS, 2020) and fungal terminologies will be fundamental to track past research, and to predict which plants and fungi will be important medicinally.

BOX 5 Plant-based malaria therapeutics
Identification of new plant-based malaria therapeutics may be facilitated by phylogenetic approaches. These identify 'hot zones', such as Cinchoneae (Rubiaceae) and Rauvolfioideae (Apocynaceae), based on existing knowledge, thus focusing on potential active compounds. Some of these genera in the antimalarial 'hot zones', do not occur in malaria regions [e.g. Skytanthus (Apocynaceae)] (Flora do Brasil, 2020), so are not known by local people as potential malaria remedies (De Albuquerque et al., 2004;Silva et al., 2011).
This makes it difficult to predict the impact of species loss on medicines, and therefore, health. As a result, many species will likely be lost before we know their potential medicinal value (Zhu et al., 2011).
The number of plants that have medicinal uses is under-estimated, due to the lack of ethnobotanical publications for some regions (Souza & Hawkins, 2017). Over 60 species used for malaria in Latin America are not cited at all in the published scientific literature, their use being documented only on herbarium specimen labels (William Milliken, unpublished data). Of the species used for malaria in Latin America, 32% are assessed on the IUCN Red List and 48% on ThreatSearch; of these, 6% and 7%, respectively, are threatened, principally due to agriculture and logging.
Protecting locally threatened medicinal plants and fungi in areas where they are used may be more important than focusing on globally threatened species. This means considering plant habitats and their protection, rather than individual species. The Important Plant Areas criteria developed at Kew has incorporated culturally important species into site-based conservation prioritization (Darbyshire et al., 2017). Similarly, in malaria therapeutics, better collaboration between modern and traditional systems is also required (Willcox, 2011).
Meanwhile, for malaria prophylaxis, the saponin QS-21 from the soap bark tree (Quillaja saponaria Molina) is being developed as a vaccine adjuvant (Didierlaurent et al., 2017). forrestii is assessed as Endangered within China (MEP & CAS, 2013;Qin et al., 2017). Nonetheless, its cultivation on a large scale is a factor that deems it an appropriate substitute .

Cinchona pubescens Vahl bark
Phylogenetic analysis at the level of individuals and subpopulations within a single species may help pinpoint the factors determining chemical diversity within species, and thus accelerate discovery of medicines. In Cinchona calisaya Wedd., the most productive source of the antimalarial quinine, chemical diversity between individuals has been demonstrated to be primarily driven by phylogeny (Maldonado et al., 2017).

| Future approaches for natural products as therapeutics
Advances in high-throughput screening, combinatorial chemistry, and molecular biology, and shifts in therapeutic strategies underpinned by the development of biological agents, combined with necessary legislation to protect biodiversity, have together contributed to a decline in natural product drug discovery in recent decades (Harvey et al., 2015;Howes, 2018 (Tilburt & Kaptchuk, 2008), although more studies are needed to further evaluate their observed effects, due to methodological issues with the clinical trials in which Chinese herbal medicines were evaluated for efficacy in SARS (Leung, 2007;Liu, Manheimer, Shi, & Gluud, 2004).
In this context, the role of traditional medicines in global health challenges merits greater scrutiny, including their chemistry, pharmacology, authentication, safety, and efficacy, with the latter evaluated in controlled clinical trials, to the level of standards comparable to those for pharmaceutical drugs.
The 'waste' or untapped potential of plants and fungi currently used in non-medical industries, could also yield rewards through provision of other molecules for medicines manufacture, and thus could contribute to SDG12 for sustainable management and efficient use of natural resources. A notable example is sisal (Agave sisalana Perrine): its leaves are a source of fiber used in the textile industry, yet the remaining waste is a source of steroidal compounds (e.g. hecogenin) which provides the starting material for producing around 5% of global steroids for the pharmaceutical industry (Dauncey & Howes, 2020), making use of this natural resource more efficient.

| Discovering molecules from nature
Limitations in analytical chemistry and computing technologies required for dereplication of complex plant and fungal extracts (to eliminate compounds previously studied) have been barriers for drug discovery. Recent advances are resulting in striking changes. Community-wide contributions to data annotation (Wang et al., 2016) enable rapid identification and discovery of natural products. Dereplication through molecular networking has emerged as such a means for rapid compound identification in complex mixtures through visualization of tandem mass spectra (MS/MS) data; the largest repository and data analysis tool for this approach is the Global Natural Products Social Molecular Networking (GNPS) (Quinn et al., 2017;Wang et al., 2016). Advances in mass spectrometry (MS) imaging, such as matrix assisted laser desorption ionization (MALDI-MS), desorption electrospray ionization (DESI-MSI), and laser ablation electrospray ionization (LAESI-MS) have expanded capabilities for in situ analyses of samples (Jarmusch & Cooks, 2014).
Advances in nuclear magnetic resonance (NMR) spectroscopy include the Metabolomics and Dereplication by Two-dimensional Experiments (MADByTE) tool, which leverages heteronuclear single quantum coherence (HSQC) spectroscopy and total correlated spectroscopy (TOCSY) data to construct spin systems of a compound, and uses these features to generate association networks for analyses (Egan & Linington, 2019). In addition to applications of these new analytical techniques in drug discovery initiatives, exploration of plant metabolite diversity has also proven useful to phylogenetic and evolutionary studies within genera and across larger groups of angiosperms (Ernst et al., 2019;Henz Ryen & Backlund, 2019). Beyond advances in mass spectrometry and nuclear magnetic resonance, emerging technologies that unite the strengths of X-ray crystallography with electron microscopy are enabling crystal structures of tiny quantities of certain natural products in mixtures to be determined. A recent application of electron cryo-microscopy and microcrystal electron diffraction demonstrated the utility of this technique in structural determination of heterogeneous mixtures of natural products (Jones et al., 2018). Leveraging this and other advancing chemical technologies offers great potential to obtain rapid analytical data from small (<1 mg) samples.
Never before have plant and fungal natural products been more accessible for scientific study. Government funded science agencies are availing their resources to scientific partners for investigation; e.g., the USA's National Cancer Institute (NCI) Program for Natural Product Discovery Prefractionated Library includes over 150,000 fractions of natural products available to scientists (Thornburg et al., 2018). This library integrates biodiversity breadth and chemical diversity, with the full collection covered by existing ethical bioprospecting agreements. Combined with better access to taxonomically diverse collections of plants and fungi (Paton et al., 2020), large chemical repositories of natural products, and robust ethical guidance for cultural data and plant genetic resources, these recent advances in analytical chemistry could support finding new chemical blueprints for drug development across many fields of medicine.

| Advances in the biosynthetic pathways of medicinal molecules
The elucidation of biosynthetic pathways, combined with engineered fungal/plant/bacterial cell factories, offer new strategies to produce bioactive compounds while preserving biodiversity. Linking biosynthetic genes to bioactive molecules is now possible, due to an increasing number of available genomes and transcriptomes, and the use of heterologous hosts (e.g. Aspergillus oryzae (Ahlb.) Cohn and yeast: Saccharomyces cerevisiae Meyen ex E.C. Hansen) (Harvey et al., 2018;Skellam, 2019). Such a strategy is commonly used in fundamental research and is promising for large-scale industrial production (Hyde et al., 2019;Steiniger et al., 2017).
Genomic and biotechnological advances make fungal fermentation-based processes ideal to produce bioactive compounds from fungi and plants (Pyne, Narcross, & Martin, 2019). Yeast cell factories enable production of medicinally valuable plant alkaloids (Galanie et al., 2015;Srinivasan & Smolke, 2019), steroids (Rieck et al., 2019), and coumarins (Zhao et al., 2019). A successful example of this approach is the heterologous expression of the precursor artemisinic acid in yeast, with yields appropriate for industrial-scale production; it can be converted to the antimalarial artemisinin using a chemical source of singlet oxygen (Paddon et al., 2013). Similarly in yeast, biosynthesis of the opium alkaloid cough suppressant noscapine was reconstructed using over 30 genes from plants, bacteria, mammals and fungi .
Combining biosynthetic genes from different pathways in the same fungal host has also successfully produced new compounds with different or enhanced activities (Srinivasan & Smolke, 2019;Steiniger et al., 2017). Global demand for the herbal medicine rhodiola (Rhodiola rosea L.) and its compound salidroside, has resulted in this species and some varieties being threatened (BGCI, 2020). Elucidation of the salidroside biosynthetic pathway enabled its heterologous production in yeast and tobacco plants, offering future sustainable salidroside production (Torrens-Spence, Pluskal, Li, Carballo, & Weng, 2018).
These examples illustrate the power of synthetic approaches to reconstruct biosynthetic pathways of bioactive compounds, with potential to reduce exploitation of natural resources. While engineered yeast has been used to produce bioactive compounds, the use of filamentous fungi such as Aspergillus species may be more promising as these fungi are already good secondary metabolite producers and they can accommodate genes from different organisms in order to produce compounds of interest (Frandsen et al., 2018). Mosses are also being developed as 'cell factories' for the production of plant compounds, with the obvious advantage of being more closely related to vascular plants (Reski, Parsons, & Decker, 2015).
Plant biosynthetic pathways for specialized metabolites are usually long and highly branched; their regulation is controlled by multiple regulatory elements, which are often poorly understood.
Himalayan mayapple (Podophyllum hexandrum Royle) contains higher levels of podophyllotoxin than the American mayapple (P. peltatum L.) so is the preferred source of this lignan for semi-synthesis of anticancer drugs (e.g. etoposide) (Howes, 2018). However, trade in P. Producing new bioactive compounds in fungal 'cell factories' still requires significant efforts to become more widespread and economically viable. One key challenge is to develop tools to allow accurate prediction of biosynthetic pathways and enzyme specificities. A more cost-effective approach could also be to integrate this knowledge into semi-synthesis strategies that combine precursors produced by fermentation with chemical modifications (Sandargo et al., 2019).

| CON CLUS ION
The future of therapeutics from nature is evolving as new challenges to human health and to biodiversity arise. Scientific evaluation of plants and fungi for their medicinal or other uses can demonstrate their value, providing additional incentives to protect global natural capital. In 2019, 1,955 and 1,886 new species of plants and fungi, respectively, were reported (Cheek, 2020); some may yield compounds useful to humanity (Cheek et al., 2018). Despite these discoveries, and the success of natural product drug discovery to provide essential pharmaceuticals, the full potential of the world's biodiversity remains heavily underexplored in the search for new medicines, and in the formation of strategies for our health and well-being. Advances in science and technology provide future opportunities to discover new molecules from nature, a plethora of metabolic pathways for their synthesis, and more sustainable ways to source them, underpinning potential solutions for global health challenges. These strategies, using biodiversity for inspiration, provide hope for increasing yields and safeguarding supplies of valuable medicines in the future.

ACK N OWLED G M ENTS
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