Monday, the Nobel Prize of Physiology or Medicine was awarded to three scientists that have efficiently discovered the therapeutical effects of artemisinin in the treatment of malaria. Some outlets lauded the recognition of Traditional Chinese Medicine, others went up to claim it is a sign that alternative medicine such as homeopathy, naturopathy or acupuncture should be accepted as mainstream medicine. However, this is where they all got it wrong. Indeed it was a big success for the whole discipline of pharmacy as it shows how different disciplines of pharmacy with the help of multidisciplinary approaches including all STEM is a celebration of 150 years of pharmaceutical research.
You may ask: “Under which statement can I can make such claims?”. Here are my statements and for which I will use this review article from Miller and Su (Cell 2011) that detail the discovery of artemisinin by Dr. Youyou Tu and led to her Lasker DeBakey award in 2011 (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3414217/), one of the highest distinction in biomedical research years before hipsters and quacks discovered her.
If you read the review, you will learn that finding a cure against Plasmodium falcifarum (the parasitic agent of malaria) was driven by an effort of war. Malaria had already a treatment available, its name was chloroquine. It was a synthetic compound developed by Bayer in 1934 and was successfully used to treat WW2 soldiers during the Pacific operation. However as evolution goes, the widespread use of chloroquine resulted in a positive selection of chloroquine-resistant parasites, leading us back to square one when the Vietnam War started.
Again, medicinal chemistry, at the foundation of Western Medicine, came to the rescue of US soldiers and South Vietnamese Army by the introduction of mefloquine, whereas the North Vietnam Army had nowhere to go since any US product was banned from import. China therefore used its Traditional Chinese Medicine “database” to find a possible candidate for an alternative drug to fight chloroquine-resistant parasites. This is where Dr. Tu story starts, in a secret research lab done to identify a possible drug candidate.
This is the birth of each new drug hitting the market: it is either a seed planted amongst millions of other synthetic compounds produced by medicinal chemistry (chemical library) or isolated from plants or animals based on some traditional medicine.
Traditional medicine and traditional chinese medicine: healing patients with empirical approach and a lot of mysticism
If you want to understand the driving force of pharmaceutical research, you have to understand the motivation: finding a remedy and a cure for alleviating or curing a disease condition.
This was certainly already anchored in our ancestors that were capable to develop cognitive functions and identify natural products that were either capable to kill you or that did not kill you. This lead in the Ancient Greece is the development of “pharmakon” (poison) that is at the base of the word “pharmacy”. In its very essence, the practice of pharmacy is related to the identification of poisons or living organisms displaying the expression of poisons and toxins.
In a very elegant try and error approach, these ancestors may have tried to see if those compounds that were not killing you may help relieve some conditions. This is where all things start and can be still found in modern shamanism. These shaman or “medicine-men” have learnt about certain plants were harboring some biological properties. Because the healing procedures involved also the concept of supernatural phenomenons, it blended these plants which magical invocations in the goal of healing the ill and the sick.
All civilization have their own medicinal plants and shamanism methods, however the Traditional Chinese Medicine has the one that have built the most extensive and documented “database” concerning the nature of the plant used, its preparation and its therapeutical applications. However most of the time, this process is empirical and remains as is fairly inefficient.
However, if you consider as a scientific standpoint, by applying the scientific rationale and thinking to these empirical observations, you may extract some precious gems out of this raw ore. This is the job of a particular branch of pharmacy called “ethnopharmacology”. Its function is to interview shamans, medicine-men, sorcerers, healers and learn from them which natural products they use to treat particular illnesses. By doing this job, the ethnopharmacologist can identify plants using botanical taxonomy methods. This is where Dr. Tu project started, Project 523, a top-secret project that involved over 500 scientists to screen for a plant extract capable to kill the parasite. Now here is some catch about Traditional Chinese Medicine. Why does it matter? It is matter because as Traditional Chinese Medicine may have some hidden gems that can lead us to a novel anticancer drugs, it also contains an amount of quackery. Does anybody heard about using elephant tusk as a remedy against epilepsy or bone tumor? It sound fallacious right? It is because it never showed any therapeutical effects yet it is driving an important share of elephant poaching and contributing to its exinction (http://www.kcet.org/living/food/the-nosh/commentary-1/chinese-market-for-ivory-elephant-tusks.html). Same applies to tiger penises and testicles, or shark fins. All these animals are under danger of extinction, as their products are used for application with no demonstrated clinical efficacy.
Traditional Chinese Medicine by its impressive collection of natural products and documentation built on thousands years of knowledge may represent a formidable source for tomorrow’s drug. However, blindly believing that Traditional Chinese Medicine holds cures without bringing the modern scientific approach and privileging the approach taken using pseudoscientific fallacies (such as naturopathy and homeopathy) not only constitute a modern form of “snake oil” quackery but also will significantly discredit the the therapeutical potential hidden in chemical compounds hidden in Traditional Chinese Medicine.
Finding a positive hit: using low-technology bibliographical research and hi-tech high-throughput screenings (HTS).
As I have previously mentioned, a new drug maybe hiding somewhere among millions of other synthetic compounds or natural substances, just waiting to be discover and germinate. In the case of medicinal chemistry, we have a robust and systemic approach allowing us to have access to 100’000 chemicals, all with their distinctive chemical structure. This is what scientists refer as “chemical library”. On the other hand, natural products have to be firstly isolated, characterized and classified based on the chemical structure. This is the function of another branch of pharmacy named “pharmacognosy”. This discipline is combining the knowledge of botany and chemistry to isolate pure chemicals from plants secondary metabolism. Plants have two types of metabolisms: the primary metabolism aimed to ensure the proper function of the plant by producing molecules it needs, whereas the secondary metabolism is characterized by the biosynthesis of chemicals that have no functional role for the plant except ensuring some accessory function such as repelling predators and other competitive plants or attracting some animals to improve the spread of seeds and pollen to remote sites. The list can be huge but some examples of plant-derived chemicals we ingest everyday: theophylline and catechines (tea leaves), caffeine (coffee), theobromine (cocoa), tannins (whiskey and cognac), anthocyanins (wine, beet), carotenoids (tomatoes, carrots), flavonoids (fruits and vegetables)….We are ingesting milligrams of these chemicals everyday and most of them are important to keep us healthy. Yet, we don’t know which ones and how much we need of these to remain healthy.
Some can also be dreadful poisons to us: cyanid (peaches core), nicotine (Nicotania tobaccum), digoxin (Digitalis purpura), paclitaxel (Taxus brevifolia). These compounds can kill you. But by controlling the amount of these compounds, you may have an active substance capable to treat a condition. This postulate was done in the 16th century by Paracelsus that established the basis of modern pharmacology “every substance is poison, no substance is no poison. The dose and only the dose makes the substance a poison”.
This is where we have a convergence between natural products and synthetic products. If you have the right chemical, with the right dose, you may have a possible new drug candidate for treating a certain disease.
When you work with natural product, you have to know with plant will have the desired effect, because you have to isolate the chemical carrying this activity. The only way to achieve such goal with natural products is to go through a bibliographical approach. Dr. Tu went over 2000 recipes, narrowed it down 600 to identify those with an indication for malaria and ended up with 380 herbal extracts.
Here is an important point, Dr. Tu initially reported an efficacy of 68%, but later studies only reported 12% to 40% efficacy. This raises important issues when working in sciences. Ability to reproduce data in different hands, in different laboratories, in different settings. If you want to trust some studies, you need to show evidence that such studies were replicated by different groups and different locations. In terms of medicinal chemistry, the systematic and rational approach makes such reproducibility rate much higher, leading to variation in reported efficacy small or negligible. In terms of natural compounds, you have to deal with different conditions, in particular with isolation.
In order to achieve a proper isolation, you have to determine is your chemical is hydrophilic (water-soluble) or lipophilic (fat-soluble) to ensure you have a proper extraction, you have to consider how to extract it from the plant, using either mechanical extraction and/or thermal extraction. Using the modern scientific methodology she went back to a textbook dated from the Jin Dynasty (283-343 BCE) and applied the original protocol based on hydrophilic extraction under warm condition, followed by an extraction of an acidic component that was displaying the toxic effect that hindered the usage of this drug.
This is an important point to note. Dr. Tu never used the Artemisia raw plant extract to treat patients with malaria. It was only after optimal isolation (by extraction using organic solvent instead of a tea infusion as described in the original document) and extraction of the neutral fraction that Dr. Tu isolated the artemisinin. Dr. Tu isolated and characterized artemisinin chemical structure (a sesquipene lactone) using modern-days technologies (X-ray diffraction) and pharmacological approaches.
It is important to note that such discovery process is important but also long (it took her 5 years to isolate and demonstrate reproducible results) and exhaustive (2000 initial leads). In pharmaceutics R&D, a common number estimates out of 10’000 chemical compounds from a chemical library, only ONE will end up FDA-approved to treat a condition.
Refining the pharmacological activity: the importance of medicinal chemistry and pharmacology in drug R&D
Once you have a lead, you are still way far from an FDA approval. You have to determine the pharmacological activity and the toxicity. This is determined by understanding how pharmacology works.
Every biological processes function around one duet: the ligand (from latin ligare, to bind) and receptor. A real-life analogy would be the key/keylock mechanism. What matters for a pharmacologist is to find the best key that will fit the key lock, this is what we call the affinity. This results in having in the highest pharmacological activity with the lowest dose. You rarely achieve such things with a raw chemical from synthesis or from natural extract. You have to tweak using modern chemistry it to achieve the best fit.
Artemisinin as a purified showed promising results but it only showed its full potency once it was combined with mefloquine, a synthetic derivative of chloroquine, a chemical compound firstly isolated from a chemical library. This success story show that a complementary approach taking the best from both natural products and from modern synthetic chemistry can drive the discovery of novel therapeutics. Neither natural nor synthetic chemistry alone can provide the pace needed in modern days pharmaceutics.
Pathogens and drug resistance: a cautionary tale
If we have to learn lessons from History and Biology, we have to remember what drives Life: evolution. We are the products of billions of years of evolution, from LUCA (latest unicellular common ancestor) to human beings. Evolution driving force is through the essence of living organism: inside our genomes. Mutations are random and randomly produce a phenotype within individual within a population). Such mutation may lead to deleterious outcome (death), may remains silent or may provide an advantage (giving those harboring such mutations an advantage versus competitors).
Once you have a selection pressure (in example an antibiotic treatment), you will induce the elimination of those incapable to deal with such pressure. However, by the randomness of mutation, you may select some lucky few having a mutation in the right place, having an alteration in the key lock such as the key is not matching it anymore. You have now a resistance trait. This is what happened to chloroquine-resistant parasites. It also happened to mefloquine in Southeast Asia. Since Dr. Tu initial discovery of artemisinin, there are some reports of artemisinin-resistant parasites in the region spanning between the Thai-Cambiodian border and other parts of Thailand. Artemisinin needs another anti-malarial drug due to its short half-life (the drug gets eliminated from the body faster that he can act on the parasite) and these other combination drugs are the ones currently being challenged by most cases of drug-resistance in Asia and Africa. Finding a new therapeutic is needed and requires time and an timeless effort as evolution keeps up running against.
To conclude this post, this Nobel prize is a victory for reminding us that identification of novel therapies lies on chemical compounds contained in medicinal plants and other living micro-organisms. Pharmaceutical research solely based on compounds obtained by de novo synthesis cannot fully fuel the innovation. Medicinal chemistry has done very well but still have to deal with huge technical and cost challenge for synthetizing certain class of compounds.
Evolution has lead some living organisms formidable “natural chemical plants” that may have tomorrow’s blockbusters medicine hidden in them. Hard-wiring such biological process with modern genetic engineering help the synthesis of compounds that otherwise would be a hell to produce. For instance, genetically-modified yeasts producing morphine is an amazing example of how future pharmaceutical research may help us optimize and coax millions years of evolution into few years. But using small molecules is already maybe something so “20th century”.
Certainly in 50 years, the Nobel Prize will go to the discover on a team that will have found a way to produce biologicals such as antibodies, growth factors and human hormones in a bioreactor in industrial sizes and therefore cut the cost of the final drug products. Recent success in immunotherapy (targeting cancer by boosting up the immune system).
Modern success in medicine were only achieved when the practice of medicine and pharmacy transitioned from an empirical and esoteric approach prior the mid-19th century into the scientific, skeptical and rational-based approach we know today.
Those who decide to ignore such approach, by lacking the scientific knowledge or voluntary maintaining such esoteric practices through a pseudoscientific approach, as modern “snake oil salesmen” (naturopathy, homeopathy) are not only perpetuating a practice that has failed to achieve the milestones obtained with modern pharmacy but also are dangerously discrediting the discovery of novel molecules from traditional medicine, as many of these perpetrators are following the same textbook than their ancestor: a short-term pecuniary profit in complete opposition of Hippocrates and Pharmacists oaths.