Accessibility to standard of care remains a challenge to patients in low- and middle-income countries (LMIC), hampering efforts to alleviate the burden of cancer and to improve overall health outcomes. In response to this pressing global health care issue, we propose here a new strategy to create affordable, easily accessible, and effective therapeutic solutions to address this inequity in cancer treatment: the use of science-based biodiversity medicine as an alternative to modern drug therapy, in which we will leverage and combine high-throughput omics technologies with artificial intelligence, to study local biodiversity, their potential anticancer properties, and short- and long-term clinical response and outcomes.
INTRODUCTION
Urbanization is one of the major threats to biodiversity. Many nations are not immune to biodiversity loss, including Singapore. Since the founding of modern Singapore till today, the decline in species diversity in the country is highly noticeable, with significant loss of its primary, swamp, and mangrove forests, resulting in a plant extinction rate of about 34% (1). To date, an estimated 50,000 to 80,000 flowering plant species are utilized globally for medicinal purposes, as reported by the International Union for Conservation of Nature and the World Wildlife Fund (2, 3). These plants have a long history as traditional medicines in Asia and Africa, dating back to early civilization. In addition, developed nations have also recognized and used them for their perceived health benefits and minimal toxicity. These plants are currently consumed in different ways, ranging from direct ingestion of plant matter to brewing them into tea or consuming freeze-dried extracts in capsules.
For cancer treatment, four classes of established anticancer drugs have been derived from plants: taxanes (e.g., docetaxel and paclitaxel), camptothecin (e.g., irinotecan), epipodophyllotoxins (e.g., etoposide and teniposide), and alkaloids (e.g., vincristine, vinblastine, and vindesine) (4, 5). Taxol, for example, a well-known drug extracted from the bark of the Pacific yew tree (Taxus brevifolia), is currently used to treat various cancers such as breast, lung, and ovarian cancer. Consequently, an increasing number of previously unidentified phytocompounds from medicinal plants have been explored for their anticancer potential (6), but because of limitations in conventional isolation techniques and subsequent molecular–structural characterization, the process to identify new compounds with proven anticancer properties has been tedious with different challenges. We believe, however, that new available technologies can be exploited to reignite interest and transform the field with renewed vigor. In view of the fact that Singapore is central to the very rich biodiversity of Southeast Asia, we established in 2021 the SingHealth Duke-NUS Institute of Biodiversity Medicine (BD-MED) to translate biodiversity studies to impact health and medicine. We focus on local and regional plant biodiversity, and in one of the programs we target bile duct cancer or cholangiocarcinoma (CCA), a cancer known to be plagued by disparities in treatment accessibility and outcomes. In our approach, we leverage and combine high-throughput omics technologies with artificial intelligence (AI), in studying local plant biodiversity and their potential anticancer properties as well as short- and long-term clinical response and outcomes. We hope to impact how people perceive, approach, and use biodiversity medicine in combating diseases including cancer, fostering a future in which effective health care solutions are within reach for all, irrespective of socioeconomic constraints or geographic location.
BIODIVERSITY MEDICINE FUELED BY THE LATEST TECHNOLOGIES TO DISCOVER NOVEL MEDICINAL AND NUTRITIONAL BENEFITS
Unveiling bioactive compounds from biodiversity sources is a crucial step for drug discovery and development. We accelerate the process through high-throughput genome assembly coupled with chemogenomic profiling. By harnessing the increasingly portable and cost-effective third-generation long-read sequencing technology combined with short-read sequencing, we can decode plant genomes with high speed, precision, and manageable costs. Chromosomal conformation capture (3C) technologies, such as Hi-C and Omni-C, are instrumental in understanding the spatial relationship among DNA elements in the nucleus, resulting in the linkage and creation of genomic scaffolds from long-read sequences. The integration of omics technologies with computational algorithms results in the ability to generate polished genome assemblies at chromosomal scale resolution. Transcriptomic and metabolomic studies from different organs can be performed to generate detailed chemogenomic profiles and to identify the main active metabolites arising from the plant genome. These profiles serve as foundation for identifying the potential functional applications of each plant and plant organ, including their toxicities and efficacies against diseases. Plant extract sensitivity screening on well-characterized human and animal cancer models with subsequent transcriptional profiling of these models allows understanding of the mechanisms of actions resulting from each plant extract treatment. These efforts will establish a valuable resource database to facilitate our cause.
Recently we performed genome assembly and chemogenomic profiling to find therapeutic bioactive compounds within Singapore's and Brunei's national flowers, Papilionanthe Miss Joaquim “Agnes” and Dillenia Suffruticosa, respectively. This led to the discovery of an antiaging compound in the former, for example (7), and the root extract of the latter that demonstrates anticancer properties (8). Beyond treatment, one can envisage harnessing a similar approach to study the nutritional value of plant biodiversity for patients with cancer, including those suffering from cachexia. Previously, we conducted similar studies to explore the nutritional content of the durian, an iconic local fruit also known as the King of Fruits, that led to further studies on its potential nutritional benefits and applications (9). This approach allows us to delve into the nutritional profiles of various fruits, plant-based food, and their derivates, offering valuable insights into their nutritional roles in supporting the health and well-being of patients with cancer.
COMBINING AI TO INCREASE PACE AND EFFICIENCY
With the incredible advances of AI technologies, it is only natural to deploy them in due course to enhance the pace of discovery from data generated through omics technology (Fig. 1). One can identify potential biosynthetic gene clusters and predict protein biosynthesis outcomes. The translation of amino acids into predicted 3D protein structures has been accelerated by AI tools, such as AlphaFold or Rosetta, offering the potential for in silico molecular docking and design to train AI methodologies in predicting potential reactions with cellular moieties. In addition, molecular networking can be used to visualize and analyze the intricate MS/MS data acquired in metabolomics experiments for annotating novel metabolites useful for cancer therapies. To identify candidate molecules, the annotated metabolites will be validated using high-throughput mass spectrometry and other AI-related analyses (e.g., deep learning and machine learning). By synthesizing these plant-derived molecules, we can also assess their efficacy through in vitro and in vivo studies and evaluate their toxicology and safety profiles, pharmacokinetics, pharmacodynamics, and dosage.
AI may be artfully used to facilitate and eventualize “Grow Your Medicine,” benefiting patients from LMICs.
AI may be artfully used to facilitate and eventualize “Grow Your Medicine,” benefiting patients from LMICs.
The above approach will seemingly take similar route of conventional drug development, which could significantly inflate costs, rendering them inaccessible to financially challenged patients. Our goal to synthesize plant-derived therapeutic molecules will be to validate their scientific and efficacy value and biosafety profile. One can then possibly turn to the use of the original plants studied in the “Grow Your Medicine” approach, although the challenge would surround the dosage and route of taking them. Again, with further studies and fine-tuning of this approach, we aspire to revolutionize the scientific application of biodiversity medicine and, if proven successful, be extended to other diseases.
DIFFERENCES IN CHOLANGIOCARCINOMA BIOLOGY AND CANCER INEQUITIES
Cholangiocarcinoma (CCA) is prevalent in low- and middle-income countries (LMIC), such as Northeast Thailand, Laos, Myanmar, and Cambodia, primarily due to the dietary habit of consuming uncooked local fresh water fish that harbor liver flukes known as Opisthorchis viverrini (10). The vast majority of the patients of low socioeconomic status are usually diagnosed at an advanced stage, with accessible and affordable treatment options lacking, resulting in a notably high mortality rate. Our previous studies revealed underlying differences in driver mutations, methylation patterns, and enhancer activities between liver fluke and non–liver fluke-associated CCA (11, 12). The former are mainly characterized by TP53 and SMAD4 mutations, and unlike the non-liver fluke CCA cases found in the Western countries, there is a lack of therapeutic targets such as FGFR fusions and IDH mutations. The lack of targetable alterations, coupled with financial constraints and remoteness of the patients’ residence from major cities lead to inaccessibility to modern therapies, including standard-of-care chemotherapy (i.e., gemcitabine), as well as newly approved treatments such as targeted therapy and checkpoint immunotherapy. Furthermore, pharmaceutical companies show little interest and are reluctant to conduct research and clinical trials in this low-income demographic.
“GROW YOUR MEDICINE” TO BRIDGE CANCER INEQUITIES
This simple idea is based on the rich biodiversity found in tropical and semitropical countries with undiscovered plant species and their medicinal potential. Although many of them have been utilized for generations, their underlying scientific basis and modes of action remain elusive and never explored in a scientifically rigorous manner. The latest technologies described above offer unprecedented opportunities to revolutionize our approach in harnessing our biodiversity in a more sustainable way. To begin with, the ease of cultivation in a tropical climate enhances the appeal of leveraging on local plant biodiversity whereby the local patients can grow their own medicinal plants. If they are provided with accurate information on how to utilize them in the most appropriate manner, they may have the viable alternative for the modern therapy they cannot afford. In a recent study, seven herbal plants, Vitex trifolia, Clinacanthus nutans, Clausena lansium, Leea indica, Strobilanthes crispus, Pereskia bleo, and Vernonia amygdalina, all traditionally used in folk medicine in Asia, exhibited varying degrees of growth inhibition across different cancer cell lines (13). Similarly, extracts from plants including Astragalus hamosus and Imperata cylindrica have demonstrated significant in vitro inhibition of cancer cell proliferation in other studies (14, 15). To tackle liver fluke–associated CCA, we hope to identify the best anticancer plant for the patients. The patients can grow the studied plant and based on the outcomes of our studies, they would know the choice of plant organs that are to be used, form of utilization, their dosage, side effects, contraindication, etc. We appreciate the above studies are no small feat and will take time, but we strongly feel that it is timely to embark on such a journey that may eventually revolutionize the use of biodiversity medicine.
CONCLUSIONS
As the global burden of cancer and other diseases continues to escalate, particularly in LMICs, there is an increasing demand for therapeutic alternatives that are not only effective but also affordable. Although the utilization of plants as biodiversity medicine may seem like a new revelation for some people, it is essential to recognize that plants have played a central role in medical treatments for centuries. Our approach seeks to synergize the latest technologies with ancient knowledge of herbal plants and has the potential to revolutionize modern medicine. By integrating cutting-edge know-how with traditional wisdom, we aim to foster a future in which effective health care solutions are within reach for all, irrespective of socioeconomic constraints or geographic location.
Authors’ Disclosures
No disclosures were reported.
Acknowledgments
The authors would like to thank the Verdant Foundation for their support.