Helen Beilinson • 2019 Issue
From The Editors:
To advance medicine, we face the challenges of developing newly efficacious and selective drugs that cure illnesses with a success rate higher than its predecessor. Despite the need for novel solutions, however, many of today’s illnesses have plagued human for centuries. So how did our ancestors deal with illnesses before the advent of modern medicine? In “Traditional Medicine”, Beilinson advocates for the re-consideration of the significance and value that traditional medicine has for the pharmaceutical industry. Presented with many of the same problems, our ancestors developed medicinal practices using natural products, so why not use this wisdom to advance today’s medicine?
It’s an odd sensation, having honey in your nose. You lay still, waiting, staring at the ceiling while the viscous sweetness makes its way down your nasal cavity. It isn’t painful, but the obscure feeling is a tad discomforting. Endure this, and ten minutes later, the runny nose you’ve been battling for days has vanished.
Growing up, I dreaded getting sick because a runny nose meant enduring several minutes of freshly-strained honey making its way to the back of my throat. As an adult, however, I find myself going back to this supine position every time I have a stuffy nose. Whether it is truly an ancient Russian medicinal treatment or a family remedy, I cannot say, but it is the best cure for a runny nose I have ever encountered. And, much to the content of my mother, whenever I find myself staring at the ceiling, I remember her advice to never forget the treatments of the days of yore, because if they worked for centuries, why wouldn’t they work today?
Outside of my family’s runny nose prescription, honey is a product that has had a long history in medicine. In addition to being a popular food amongst humans for millennia (the earliest evidence of humans collecting honey is dated to be 8000 years old), honey has been used extensively in medicine in ancient Egypt, China, India, Greece, and a variety of Middle Eastern countries as a potent antibiotic, wound healer, and preservative (1). In the last few decades, the power of honey as a medical anecdote has been substantiated. In regards to honey’s potent bactericidal activity, it has been shown that honey protects against nearly sixty species of infectious bacteria, including those that are antibiotic resistant. Typical antimicrobials target specific bacterial proteins to destroy their cellular barriers or to inhibit necessary metabolic pathways. To prevent the antibiotics from annihilating complete, bacterial populations, bacteria evolve modifications in their genome to render the antibiotics ineffective. Remarkably, in studies aimed to determine whether bacteria can develop resistance to honey, none have been found (2).
Honey is not the only natural product that has regained contemporary medical glory. The medical use of turmeric, a golden plant related to ginger, is dated back nearly 4000 years (3). It was historically used in South Asia and the Caribbean to treat a variety of conditions including but not limited to pain, fatigue, breathing problems, food poisoning, a wide-range of infections, and inflammation. Basic and clinical research has shown that turmeric is highly active in relieving pain, slowing the progression of cancer, promoting wound healing, minimizing inflammation, and aiding in cardiovascular performance (3). In addition to turmeric, ancient Egyptian doctors gave poppy seeds to patients as a means of pain relief (4). Poppy seeds contain small quantities of both morphine and codeine (5). Today, both of these compounds are still actively used as pain-relieving drugs. Another notable historical antidote is the fecal microbiome transplant. Although this treatment has gained clinical popularity in the last decade, its initial use was in the 4th century BC in ancient China. In the past, it was used as a means to combat diarrhea, intestinal infections, and other bowel syndromes (6). Today, it is used predominantly as a means to combat intestinal infections caused by Clostridium difficile, an opportunistic bacterium that predominantly infects hospitalized immunosuppressed patients (7).
Historically, natural products, or products synthesized by living organisms, have been used for curing many diseases and illnesses. The earliest evidence of the usage of natural products for medicinal purposes dates back to 2600 BC Mesopotamia. On clay tablets in cuneiform, the Mesopotamians described oils from a Mediterranean cypress and members of the Commiphora genus, such as myrrh and frankincense, to treat colds and inflammation (8). The Ebers Papyrus, dating to 1550 BC, is an Egyptian pharmaceutical record documenting over 700 plant-based drugs. From China, the Materia Medica from 1100 BC has 52 prescriptions, the Shennong Herbal from 100 BC has 365 drugs, and the Tang Herbal from 659 AD has 850 drugs. Many Greek physicians and philosophers, including Dioscorides and Theophrastus, recorded the use of hundreds of herbs, specifying how to collect and store them.
Despite centuries of traditional medicine success, contemporary drug discovery predominantly focuses on developing novel, synthetic, highly-specific medications and using high-throughput screens to identify active compounds in specific disease settings.
The use of natural products in human medicine is not particularly surprising, given that the medicinal use of natural products is not unique to humans. Self-medication is often seen in animals through innate responses, instead of learned ones (9). To prevent microbial growth in wood ant colonies, worker ants incorporate conifer tree resin—a potent antibiotic—into their nests (10). Monarch butterflies prevent the spread of parasitic infections to their offspring by laying their eggs on milkweed, which is a potent anti-parasitic (11). Primates have been observed ingesting plant materials that have little or no nutritional value, but have high anti-parasitic properties (12).
Despite centuries of traditional medicine success, contemporary drug discovery predominantly focuses on developing novel, synthetic, highly-specific medications and using high-throughput screens to identify active compounds in specific disease settings (13). It is undeniable that looking forward is critical to the advancement of medicine, but explorations of natural products for specific ailments can inform our current understanding of disease state and provide us with new alternatives to synthetic drugs.
So how did we get to synthetic drugs if natural products have been the backbone of healing for thousands of years? Historically, herbs or plants with medically-active compounds were prescribed to patients without extensive processing, only grinded or boiled. However, starting in the 19th century, the advancement of biochemical techniques allowed for the isolation and characterization of active compounds from natural products (8). The identification and isolation of the active ingredients in these natural sources facilitated their large-scale synthesis and administration to patients in a dose-dependent manner. Today, nearly half of all available drugs are derived from natural products, either from direct isolation from nature or by synthesis of the active compound in a lab (14). The success of natural products for medicinal purposes is plentiful: from morphine (derived from opium) to the anti-malarial drug quinine (derived from the chinchona plant) to the most prominent antibiotic available— penicillin (derived from a fungus) (15-17).
One of the best-known success stories of a natural product being used as a biomedical aid is the discovery of the most widely used breast cancer drug, paclitaxel. In the 1960s, the National Cancer Institute commissioned the United States Department of Agriculture to collect samples from plant species around the world and test them for anticancer activity. The bark from a single Pacific yew tree in the state of Washington, collected by botanist Arthur S. Barclay, was processed into an extract and showed a high efficacy in killing tumor cells (18). The effect of the isolated ingredient was so robust that, in 1967, the active compound was isolated and is now the first-line of therapy for patients with ovarian, breast, non-small cell lung, and pancreatic cancers (8).
The field of cardiology has also been impacted by historically-used natural products. Extracts from foxglove plants were first shown to be effective in treating heart conditions in 1785 by William Withering, after being told a long-kept secret by “an old woman in Shropshire who had sometimes made cures” (19). In 1930, after further investigation into the extract’s active components, digoxin was developed. Approved in 1998 for the treatment of heart failure, digoxin proved to be a highly effective drug in controlling heart rate and increasing cardiac contractility and was subsequently approved in 1998 for the treatment of heart failure (20). Today, digoxin is on the World Health Organization’s List of Essential Medicines, considered to be the most effective and safe medicine used in our health system (World Health Organization, 2017) (21).
Despite the remarkable success stories of natural products, the effort to identify novel, medically-active substances in natural products has decreased over the last decade (22). Pharmaceutical companies have reduced their research investment and financial support for natural product discovery. The argument for this decision is two-fold: (a) natural product discovery and development is slow in comparison to the high-throughput screening of synthetic compounds because extracts must be tested before the active compounds can be isolated, and (b) it is thought that the most active biological compounds, and those that would most benefit society, have already been discovered, reducing the need to continue the search for more products (14, 23).
As a result, the pharmaceutical industry has gravitated towards the chemical synthesis of novel products or the modification and redevelopment of existing synthetic drugs (24-25). Drug products need to interact with their chemical targets precisely to optimize the reaction, be it inhibitory or activating. Computer visualization and biochemical techniques are used to design compounds that interact with their targets with optimal efficacy. However, the structural and chemical complexity of medically-beneficial natural products exceeds that of synthetically-made compounds. Currently, nearly 40% of chemical scaffolds found in natural products cannot be duplicated synthetically in labs (23). To find naturally-synthesized compounds that interact with targets, large-scale, high-throughput screenings should be done with vast libraries of collected samples to test their reactivity in particular disease settings.
Although natural product discovery is a time investment, as one would have to screen many samples for activity in the context of many disorders, the success of discovery is highly promising. The synthesis of natural molecules in living organisms comes at a high metabolic and genetic cost, such that, all molecules in an organism are under high evolutionary pressure to be bioactive or to be eliminated altogether. Evolution serves as a natural means to edit molecules to most optimally pair with their targets. Drug development focuses on identifying molecules that most optimally interact with specific targets in a disease in order to either activate, inactivate, or otherwise modulate the target. By identifying natural molecules that have been optimized under evolutionary pressure to interact with these targets, we can isolate natural products that are already active and typically require minimal additional modifications. Only 10% of the world’s biodiversity has been evaluated for potential medicinal purposes (8). The remaining 90% of products, some of which have been historically used by our ancestors for various human ailments, have not reached the benches of scientists. In addition, many currently available naturally-occurring products have been tested only within the context of particular diseases, but may be found to be useful for other disease states. For example, the collections of terrestrial plant samples, owned by the US National Cancer Institute, have been screened predominantly in anticancer screens, but their use can be tested in other disease-specific screens (26).
A continued effort to isolate and screen for naturally-occurring products is critical, as they are a crucial source of novel pharmacologically-active compounds (8). However, a streamlined and targeted approach to maximize the time and money provided in drug discovery is missing. By generating a list of natural products that have been successfully used for medicinal purposes in the past, we can narrow the focus of ongoing research to selectively explore the active substances of these natural products. Once one or more extracts are shown to be effective, they can be further investigated for target specificity, potency, and adverse side effects. This targeted approach allows for the investigation and confirmation of previously used medications. We learn what drugs to take for specific ailments from our family and doctors—why not look further into our history to get advice from our ancestors?
A continued effort to isolate and screen for naturally-occurring products is critical, as they are a crucial source of novel pharmacologically-active compounds.
As a scientist, I have been trained to think innovatively to find solutions to old problems. However, many of the ailments that require novel drugs, such as infections, wound healing, and bowel disorders have been problematic for humans since prehistoric times. In fact, some argue that even our extinct species relative, Neanderthals, may have had precise medicinal practice (27). The medicinal practices of the past did not depend on the synthesis of novel drugs with new biochemical structures by scientists, instead our prehistoric ancestors depended on the master craftsman of molecules—nature.
By assessing the specific disease contexts in which specific plants and herbs were used historically, one establishes a base ground for compounds to test for medical activity with modern experiments. Seeking insight from the past is important in evolving medicine. However, natural product drug discovery should not be separated from synthetic chemistry—their marriage is important. If historians of medicine were to collaborate with biologists and synthetic chemists, the targeted testing of specific natural products in specific disease settings could accelerate drug discovery. Through this collaboration, we can identify medicinal practices that can reveal new bioactive molecules proven to be potent in specific disease contexts. This method provides a means to identify natural products for a variety of ailments, in parallel with the current means of drug development. As different as the world we live in is to that of our ancestors, we are still afflicted with many of the same ailments. If my great-great-grand-whoever was able to cure runny noses with honey better than any over-the-counter medication, who knows what other home remedies hold in store for other medical nuisances.
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Helen Beilinson is a doctoral student in the Department of Immunobiology at Yale University.
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