key: cord-0753057-pmqxlvmu
authors: Weng, Jing-Ke
title: Plant Solutions for the COVID-19 Pandemic and Beyond: Historical Reflections and Future Perspectives
date: 2020-05-20
journal: Mol Plant
DOI: 10.1016/j.molp.2020.05.014
sha: 054d0aa615b2c118d420f7e13bd5be6e3753a198
doc_id: 753057
cord_uid: pmqxlvmu

nan

As I write this commentary in late April 2020, the world is scrambling to cope with the COVID-19 pandemic. COVID-19, short for Coronavirus disease 2019, is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

COVID-19 was first reported in December 2019 in Wuhan, China, and has since spread to 187 countries and territories, infecting more than 3 million people. More than two hundred-thousand people have died of the disease. Normal lives of billions of people around the world are disrupted. The global economic loss is incalculable. From where I am (Massachusetts, USA), universities have closed down since mid-March. Most researchers were sent to work from home, which means in-person lab research has to be abruptly halted. COVID-19 pandemic ruthlessly deprives us from some of the very basic activities that we take for granted living in a modern society, such as going to work, eating out with friends, and attending social gatherings. As painful as it gets, COVID-19 also serves as a wakening call that reminds us how fragile our society still is when challenged by a pandemic, and much is to be learned about infectious diseases since we still lack effective ways to eradicate them.

Here, I reflect on the COVID-19 pandemic from the perspective of plant science.

First, plants have served as the main source of medicine for humans since the beginning of our species. Some of the earliest modern medicines are indeed plant natural products for treating infectious diseases. Plants have a lot to offer for treating COVID-19 and other infectious diseases, but it will require interdisciplinary research efforts to fully realize this potential. Second, the countermeasures that were quickly deployed against COVID-19 this time, including disease detection and potential treatments, are resulted from previous science and technology development in broad disciplines. This strongly advocates for not just maintaining but significantly increasing societal funding into basic sciences, including plant science, in order to better prepare us for future pandemics and other societal challenges alike. Last but not least, the global COVID-19 crisis exposed several weaknesses of human nature, and in many ways echoes other looming crises, such as climate change and food insecurity. Plant science could contribute to the solutions of these problems, but such effort needs to be integrated into a global grand strategy yet to be established.

Infectious diseases have afflicted humans since the hunter-gatherer days. When the agricultural revolution occurred around 10,000 years ago, the rise of densely populated communities greatly increased the chance of epidemics. Diseases such as malaria, tuberculosis, leprosy, influenza and smallpox became known during that time. Through trial and error followed by extensive empirical exercises, indigenous people around the world have independently discovered a plethora of medicinal plants for treating various infectious diseases. For instance, in central Africa, Ageratum conyzoides (billygoat weed) was used to clear parasitic worm infection (Wabo Poné et al., 2011) . A wide variety of medicinal plants were used for treating malaria, with Artemisia annua (sweet wormwood) native to China and Cinchona officinalis (Cinchona tree) native to South America being the most well known (Mohammadi et al., 2020) ( Figure 1A ). In traditional Chinese medicine (TCM), elaborate multi-ingredient herbal remedies also emerged, most of which were indeed developed for treating infectious diseases, the primary cause of ailments in ancient times. As a prominent example, Treatise on Cold Pathogenic and Miscellaneous Diseases, regarded as a crown jewel among ancient TCM texts, was written by Zhang Zhongjing (AD 150-219) during the late Eastern Han dynasty when continuous wars and multi-year pandemics caused great human suffering and death ( Figure 1B ). Using a dialectic approach, Zhang Zhongjing systematically documented 113 herbal formulae and 397 therapeutic strategies for treating illnesses that were meticulously categorized by their differential disease manifestations and responses to alternative initial investigative treatments. The Treatise has since served as a cornerstone for TCM over the following two millennia.

The age of exploration led by the Europeans starting in the 15th century inevitably spread many infectious diseases globally. Without previous exposure, as many as 90 percent of the indigenous people inhabiting North and South Americas perished due to smallpox, measles and bubonic plague among other infectious diseases brought by the Europeans. Upon arrival at new continents, colonists encountered many indigeneous medicinal plants, which they then introduced back to Europe and other parts of the old world through trade. For instance, the miraculous antimalarial property of Cinchona tree bark was rediscovered by Spanish settlers in Peru in the mid-17th century. In the following years, Cinchona tree bark quickly became a highly prized medicine, and was traded globally. Driven by curiosity and the need to deter species adulteration in medicinal plant trade, the field of plant systematics flourished. This culminated in the publication of Species Plantarum by Carl Linnaeus in 1753, which established the foundation of plant taxonomy as we know it today. In addition, the growing interest in medicinal botany prompted the origins of botanical gardens in several European countries, so that plants brought back by the colonists from all over the world could be cultivated and studied. Long-distance maritime voyages also caused health problems, such as scurvy, a common disease among sailors in British Navy in the 18th century, manifested by deteriorating connective tissue. To find a cure for scurvy, James Lind, a naval physician, ran the first reported, controlled clinical trial in the history of medicine on the ship HMS Salisbury in 1747, and found citrus fruit to be an effective cure for scurvy. The rapid advances in medicinal botany and medical sciences for diseases during this period in turn protected the health of colonists when they continued to explore distant territories, contributing to the establishment of many colonial empires by the 19th century.

The mysteries behind many medicinal plants were ultimately resolved in the past two centuries when modern science took off. Quinine was isolated from Cinchona tree bark by French chemists Pierre-Joseph Pelletier and Joseph-Bienaimé Caventou in 1820 with its chemical structure fully resolved a century later (Hoffmann, 2018) ( Figure   1A ). Quinine and its synthetic analogs became some of the earliest modern medicines for treating various diseases. Vitamin C, or chemically named as L-ascorbic acid in honor of its activity against scurvy, was discovered collectively by Hungarian biochemist Albert Szent-Györgyi and British chemist Norman Haworth in the 1920-1930s. Inspired by an antimalarial remedy documented in the ancient TCM text Prescriptions for Emergencies authored authored by Ge Hong (AD 284-346), Chinese phytochemist Tu Youyou identified artemisinin from sweet wormwood in the 1970s, which led to the development of a new antimalarial medicine that saved millions of lives. Using modern chemical biology approach, the action mechanism of artemisinin was recently elucidated, which entails activation of the signature endoperoxide bridge of artemisinin by heme iron enriched in Plasmodium falciparum parasite to form highly reactive radicals that in turn bind to numerous target proteins (Wang et al., 2015) . Medicinal plants not only have guarded human health against infectious diseases over millennia, but also played an important role in the modernization and globalization of human society in the recent centuries. As our scientific knowledge about plants grows, there is no doubt that we will continue to discover new plant-derived medicines.

TREATMENT Similar to several other pandemics in recent decades, COVID-19 emerged as a new disease, and currently there is no effective medicine to stop SARS-CoV-2. Since a new drug discovery program can easily take more than 10 years with a high probability of failure, finding cures for COVID-19 to meet urgent need through this route seems were also put in use for treating COVID-19 patients with many concomitant clinical observations currently ongoing. This topic was recently reviewed by (Zhang et al., 2020) and will not be discussed in detail here.

The chemical composition of LCDD is complex; the control of herbal remedy quality consistency is challenging; and its action mechanism of treating COVID-19 is unknown.

Atractylodes macrocephala show antiviral activities against H1N1 and H3N2 influenza viruses in cell-based assays, whereas Atractylodes root extract attenuated influenza A virus (IAV)-induced pulmonary injury in mice (Cheng et al., 2016) . Ephedrine and pseudoephedrine, the principal bioactive compounds of Ephedra sinica, are clinically approved decongestants and bronchodilators (Abourashed et al., 2003) . Scutellaria baicalensis produces baicalein and several related flavonoids, which are antiinflammatory agents acting upon the NF-κB pathway (Hsieh et al., 2007) . In a recent preprint, baicalein was found to be a potent inhibitor of the main protease of SARS-CoV-2, 3C-like protease, which could suppress the replication of SARS-CoV-2 in Vero cells (Liu et al.) . The cyclopeptide Astin C from Aster tataricus was recently found to specifically inhibit the innate immune cytosolic DNA sensor STING, and thus modulates the STING-mediated immune response (Li et al., 2018) . Licorice, Dioscorea polystachya, Wolfiporia extensa and Polyporus umbellatus are rich sources of triterpenes, many of which harbor antiviral activities and/or act as steroidal hormone mimetics to modulate mammalian immune system (Ríos, 2010; Khwaza et al., 2018) . Hence there is no mechanism for herbal remedies like LCDD to quickly enter clinics for treating COVID-19 as an investigational therapy or complementary medicine in the US for example. Second, although the US Food and Drug Administration (FDA) has a route for botanical drugs to obtain approval through clinical trials, due to practical challenges such as patent protection, drug sourcing and market acceptance, few sponsors have taken herbal remedies through FDA-guided clinical trials. Third, herbal remedies in their current form with largely unknown chemical composition and action mechanism, fall below the high standard set by modern medicines. This results in low patient and physician acceptance, even though the safety and effectiveness of a given herbal remedy could be established clinically.

To solve this dilemma in the short run, countries wanting to test herbal remedies as potential therapies for COVID-19 need to reform their existing regulatory policies to facilitate and incentivize sponsors to run their own clinical trials. However, to fully unleash the medicinal power of plants to treat human diseases globally, significant amount of interdisciplinary research is needed to study the genetics, chemistry and biochemistry of diverse medicinal plants, develop capabilities of producing bioactive plant natural products and their analogs at will through metabolic engineering, and elucidate their action mechanisms and potential synergistic effects when used in combination (Li and Weng, 2017) . Future generation of TCM-inspired modern medicines should contain single or combined bioactive plant natural products with known composition and action mechanisms, and show equivalent or superior safety and efficacy when compared to traditional herbal remedies. Moreover, to preserve and research the world biodiversity of medicinal plants, agencies such as the World Health Organization could play a role to help establish a framework, under which all regions of the world could gain access to funding and expertise to study their own medicinal plants and exchange the learnt knowledge with the rest of the world.

When science is weak, people have little clue why epidemics occur and how to cope with them. Many resort to religion; however, the consequences could be deadly. When smallpox was brought to South America by Spanish conquistadors in the 16th century, the Aztec rulers ordered hundreds of humans to be sacrificed at a time to feed the angry god, which they believed was the cause of the epidemic. Millions died of the disease soon afterwards. Aggregation of people in churches and temples to pray during an epidemic also exacerbates disease spread, which still happens today. The advance of modern science for the first time enabled humans to understand the ground truth of infectious diseases and delivered miraculous cures closest to what was once promised by religion.

Scientifically, we were in a better position than ever before when COVID-19 hit.

Scientists were able to quickly identify the disease-causing virus, sequence its genome, and develop various methods of disease diagnosis. Within months, a multitude of prevention and treatment strategies were devised, many of which were put in practice. This is a strong testament for the paramount importance of science to the future wellbeing of humans. Without prior research investment in areas such as virology, genomics, immunology, chemistry and CRISPR technology, we would not have the tools nor the scientist workforce to battle against COVID-19. Without pharmaceutical industry's previous effort to find cures for other diseases, we would not have the list of investigational drugs and vaccines to quickly enter clinical trials targeting COVID-19.

Unfortunately, the pre-COVID-19 world did not seem to value science enough, despite its purported importance. In the US, for example, the total federal budget for major science funding agencies, including the National Institutes of Health (NIH), the National Science Foundation (NSF) and the Department of Energy (DOE), has been miniscule compared to its annual defense budget in past decades. For the fourth straight year, the Trump administration has proposed deep cuts in federal research spending (Mervis, 2020) . Had we invested more in science, for instance in the underfunded area of infectious diseases, we probably would have a few more tools in hand to fight against COVID-19, hence reducing its toll on society. Research projects to study medicinal plants with antiviral properties, for which funding was difficult to obtain under pre-COVID-19 climate, might have yielded potential cures for COVID-19. Even for the seemingly distantly related field of plant engineering, clever heterologous expression systems in plants might well be adapted to produce vaccines or therapeutic antibodies.

We now painfully learned that a global public health crisis like COVID-19 in the 21st century can cost society even greater than a regional war. Our inability to eradicate COVID-19 is due to our ignorance about the disease and lack of technological capabilities to dismantle it, both of which can be solved by science. In a post-COVID-19 world, societal funding into science should be significantly increased to better prepare us for future societal challenges like COVID-19. It is important that diverse scientific disciplines should be funded, as it is impossible to predict what the next challenge will be and what scientific solutions will be needed to address it. Given the significant contributions that plant science has made to societal advancement in human history, increasing funding into plant science will be critical and totally worth it.

The COVID-19 pandemic exposes several weaknesses of human nature. The unwillingness to take inconvenient near-term preventative measures to avert predictable long-term crises have hurt some countries during this pandemic. Moreover, when disasters hit, the tribalism nature of humans gets amplified, which hampers our species' unique strength of collaborating with each other. This is the exact opposite of what we need right now to defeat the virus. Although COVID-19 is already bad enough, I can't help thinking about other looming crises of similar nature. For example, we are currently on a trajectory towards continued atmospheric CO 2 concentration rise, global climate change, sea level rise, and ultimately, environmental and socioeconomic catastrophes.

Unlike COVID-19, which will fade away in the coming months to years, the curve of atmospheric CO 2 concentration rise cannot be easily flattened and the consequences will stay with us for much longer term (National Academies of Sciences, 2019). The COVID-19 pandemic also sounded the alarm for food insecurity. Temporary interruptions to the global food supply chain due geopolitical reasons or a pandemic like COVID-19 put food security at instant risk. In the long run, overpopulation, diminishing arable land, and climate change-caused plant productivity loss have been forecasting significant global food supply shortfalls as compared to demand in the future.

As a society, we must learn from where we succeeded and failed in dealing with the COVID-19 pandemic, and take these lessons to heart when addressing other global challenges facing mankind. Again, plant science is well poised to make important contributions to these challenges. Plants are primary sequesters of atmospheric CO 2 on Earth, using only sunlight as the energy input. For instance, engineering plants to accumulate inert carbon-trapping polymers such as suberin and sporopollenin can help rebalance the global carbon cycle. Developing crops with enhanced productivity, disease resistance, and abilities to withstand harsh environmental conditions will be critical to ensure future sustainability of humans on Earth. However, we need comprehensive collaborations at a global scale to integrate plant biotechnologies with other technologies and policies to create grand actionable mitigation strategies. As scientists around the world work collectively to defeat COVID-19, sharing their results with unprecedented transparency and speed, I see hope that united as one human race, we will overcome challenges lying ahead. 

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