The 2015 Nobel Prize in Physiology or Medicine for the discoverer of Artemisinin: A triumph of natural product pharmacology, not traditional Chinese medicine

Earlier this week, the Nobel Prize in Physiology or Medicine was awarded to Youyou Tu for her discovery of the anti-malaria compound Artemisinin, as well as to William C. Campbell and Satoshi Ōmura for their discovery of a novel therapy for roundworm. Artemisinin, as some of you might know, is a compound derived from traditional Chinese medicine, which is why, to my irritation, it didn’t take long for headlines like How traditional Chinese medicine finally won its Nobel Prize, What the 2015 Nobel Prizes mean for traditional Chinese medicine, and A Medical Breakthrough Made Possible By Ancient Chinese Remedies Just Won A Nobel Prize. In each of these there is, to a varying degree, an underlying implication (in one case not even an implication) that somehow the awarding of the Nobel Prize this year to Tu is a vindication of not just Artemisinin, but of the entire system of traditional Chinese medicine. I will argue that it is nothing of the sort, but rather a vindication of the modern science of pharmacology, specifically pharmacognosy, the branch of pharmacology that concerns itself with finding medicines in natural products.

In one glaring example of the crowing of how this Nobel Prize somehow “vindicates” TCM and shows how it is becoming accepted by “Western” scientists, Sam P.K. Collins writes at ThinkProgress about how “Western” doctors “didn’t catch on” to Artemisinin until the 1980s (Youyou Tu had worked on it in the late 1960s and 1970s) and the World Health Organization didn’t recommend it for malaria until 24 years later, going on to claim:

Despite its more than 4,000-year history, detractors say traditional Chinese medicine stems from a superstition-based culture that predates modern medicine. They also say the medicine’s reliance on anecdotal evidence goes against what the reliability of scientifically controlled experiments that have proven the efficacy of conventional medicines and therapies.

However, Chinese medical practitioners have pushed back against that view, arguing that opening up to traditional medicine could help advance conventional treatments — especially as developments of new medications are hampered by a lengthy research process and growing drug resistance has rendered some drugs useless.

Note the argument from antiquity, the implication that, because TCM has been around thousands of years, there must be something to it. There is a false dichotomy there, as well. TCM is indeed based on prescientific views of how the human body works and how diseases develop that is very much like the idea of the four humors in what I like to call “traditional European medicine” promulgated by Hippocrates and his followers. After all, in TCM there are the “five elements” thought to be associated with disorders of various organs and the activity of what are known as the Six Pernicious Influences: Heat, Cold, Wind, Dampness, Dryness and Summer Heat. These are thought to cause “imbalance” in the body and thus disease. Indeed, the very basis of TCM is far more philosophical than scientific, the idea being to restore “balance” to the body, perhaps in much the way that the Chosen One would restore balance to the Force, often with much the same effect.

To Collins, the awarding of the Nobel Prize to Tu is both a vindication of TCM and an indication that the tide is turning in terms of acceptance of TCM by “Western” science. Citing a keynote address by Dr. George Y.C. Wong at a TCM conference in 2012 (an address full of tropes about TCM, so much so that it might be worht addressing in a separate blog post) about how, “unlike Western medicine, ancient Chinese treatments take into account patients’ individual characteristics and the connection between the body and mind,” Collins declares:

Three years later, that’s becoming more of a possibility. As more Americans grow distrustful of doctors, traditional Chinese medicine and other non-Western practices have grown in appeal. One survey conducted earlier this year showed that young cancer patients eager to ease the symptoms and side effects of chemotherapy have turned to traditional treatment. In response, hospitals across the country have started to integrate their health care with Eastern-based treatments and therapies — including acupuncture, massage therapy, and herbal medicine. And some medical schools now include these practices in their curricula, creating a field known as “complementary medicine,” which allows doctors to infuse conventional and alternative medical practices to their patients’ liking.

Globally, the medical community may be changing its tune. Tu counted among three recipients of the Nobel Prize in medicine, all of whom used natural-based remedies against parasites. William Campbell, an Irish-born researcher who lives in New Jersey, and Satoshi Omura, who is from Japan, both won for their discovery of avermectin, which was developed into ivermectin, a treatment for river blindness. These drugs have replaced their quinine-based counterparts which have proven ineffective in years past.

This is, of course, an old tune, one we’ve been hearing for a long time, how TCM is really valid, how it is being proven scientifically and embraced by the masses outside of China. Of course, forgotten in such descriptions is how, in China itself, TCM is increasingly being abandoned for scientific medicine and how TCM as we now know it is actually a creation of Mao Zedong, who, lacking sufficient resources after World War II and into the 1950s and 1960s to provide “Western”-style scientific medicine to all of his people, enlisted “barefoot doctors” practicing TCM and advocated the “integration” of TCM with “Western medicine” in a prescient foreshadowing of how alternative medicine evolved into “complementary and alternative medicine” (CAM) and then into “integrative medicine.” Mao himself did not use TCM and did not believe it worked, finding the Five Element concept implausible and stating bluntly, “Even though I believe we should promote Chinese medicine, I personally do not believe in it. I don’t take Chinese medicine.”

My citing this history should in no way be viewed as viewed as an attempt to denigrate Tu’s accomplishment. Rather, I point it out because there is a long history of TCM advocates latching on to one discovery that appears to show that there is medical value in something in TCM and trying to argue that it means that we should take seriously the rest of the prescientific edifice of TCM, the pseudoscientific baggage that comes along with the occasional pearl. Indeed, this sort of argument was on full display earlier this year when Science shamefully published a multi-part supplement that was basically an advertisement for TCM research. In fact, Tu deserves all the honors she has received over the last few years, first with the Lasker Award in 2011 and now with the Nobel Prize in 2015.

While the concepts behind TCM are prescientific and superstition-ridden, the one area of TCM, as is the case with other kinds of folk medicine, is the natural products used by folk medicine healers to treat various conditions. Indeed, in the case of TCM and other traditions, such as Ayurveda, I tend to like to separate the herbal medicine component from everything else, because it is there, regardless of the philosophy that spawned the treatments, that actual useful medicines might be found. The tools that find such medicines includes pharmacognosy, and that’s what happened here. A little history is in order.

In the US and most developed countries, malaria is not much of a problem because the mosquitos that carry it thrive in tropical and subtropical climates, such as Sub-Saharan Africa, Asia, and Latin America. There the disease is associated with poverty and reaps a horrible toll every year. Indeed, the WHO estimates that there were close to 200 million cases of malaria worldwide in 2013, resultin in 584,000 to 855,000 deaths, the vast majority in Africa. Because the disease affects those living in tropical regions so heavily, it is often forgotten in developed nations just how many people suffer and die every year from the disease.

In the 1950s, attempts to eradicate malaria failed because of the emergence of a chloroquine-resistant strains of Plasmodium falciparum, the parasite that causes malaria. At the time chloroquine was the main drug used to treat malaria, and this resistance led to a resurgence of malaria in tropical regions, including North Vietnam and parts of China. There was a vital need for new anti-malarials, which led the Chinese government in 1967 to set up a national project against malaria under the leadership of what was called Project 523. Youyou Tu herself told the tale in a fascinating article published in Nature Medicine in 2011 after she had won the Lasker Prize. Tu had the necessary qualifications to head this project, having graduated from the Beijing Medical University School of Pharmacy in 1955 and been involved in the research of Chinese hebal medicine in the China Academy of Chinese Medical Sciences (previously known as the Academy of Traditional Chinese Medicine). From 1959 to 1962, she had participated in a training course in Chinese medicine especially designed for professionals with backgrounds in “Western” medicine, which led her to see the potential in TCM herbal remedies.

She described the process thusly:

During the first stage of our work, we investigated more than 2,000 Chinese herb preparations and identified 640 hits that had possible antimalarial activities. More than 380 extracts obtained from ~200 Chinese herbs were evaluated against a mouse model of malaria. However, progress was not smooth, and no significant results emerged easily.

The turning point came when an Artemisia annua L. extract showed a promising degree of inhibition against parasite growth. However, this observation was not reproducible in subsequent experiments and appeared to be contradictory to what was recorded in the literature.

One notes that, to identify these 2,000 TCM herbal preparations, Tu scoured TCM texts. Here’s where the insight from a TCM text came in:

Seeking an explanation, we carried out an intensive review of the literature. The only reference relevant to use of qinghao (the Chinese name of Artemisia annua L.) for alleviating malaria symptoms appeared in Ge Hong’s A Handbook of Prescriptions for Emergencies: “A handful of qinghao immersed with 2 liters of water, wring out the juice and drink it all” (Fig. 1). This sentence gave me the idea that the heating involved in the conventional extraction step we had used might have destroyed the active components, and that extraction at a lower temperature might be necessary to preserve antimalarial activity. Indeed, we obtained much better activity after switching to a lower-temperature procedure.

When I read this passage, I note two things. First, qinghao was not used in TCM to treat malaria, only to lower fever; indeed, its whole plant extract does not result in a sufficiently high concentration of the active ingredient to treat malaria. Basically, Youyou Tu and her team scoured TCM texts to identify anything used to treat fever. Second, I wasn’t exactly sure how that particular passage led to the insight that heating the extract was degrading the active component of Artemisinin. After all, all that was in that text was a lack of a mention of heating the extract, and noticing an absence of a step is a different thing than noting the presence of a step in preparing an extract, after all. When I see a recollection like this, I tend to suspect that the person relating the memory was already thinking along those lines anyway and that the text jarred something in Tu’s brain to cause the proverbial lightbulb to go off. There’s nothing wrong with that, but she could just as easily have been wrong about this. Fortunately, she was not. This new method of preparation led to Tu’s being able to separate the extract into its acidic and neutral portions. On October 4, 1971, Tu isolated a nontoxic neutral extract that was 100% effective against parasitemia in mice infected with Plasmodium berghei and in monkeys infected with Plasmodium cynomolgi. Next, because it was during the Cultural Revolution and there were “no practical ways to perform clinical trials of new drugs,” Tu and her colleagues volunteered to be the first to take the extract. After determining that it was safe for human consumption, they began testing it in patients infected with both Plasmodium vivax and P. falciparum. The results were encouraging. In patients treated with the extract, fever rapidly declined, as did the number of parasites detected in the blood, which did not happen in patients receiving chloroquine.

But Tu was still not done, and this is the message frequently forgotten by advocates who latch on to this Nobel Prize as a vindication of TCM. Pharmacognosy led to the discovery of Artemisinin, but it took medicinal chemistry to turn this compound into a usable, useful drug. Sources rich in the molecule had to be identified, methods of isolating it on a large scale developed, and a stable formulation produced. As Tu put it, her team now had to go from molecule to drug:

In keeping with Goldstein’s view, the discovery of artemisinin was the first step in our advancement—the revelation. We then went on to experience the second step—creation—by turning the natural molecule into a drug.

We had found that, in the genus Artemisia, only the species A. annua and its fresh leaves in the alabastrum stage contain abundant artemisinin. My team, however, used an Artemisia local to Beijing that contained relatively small amounts of the compound. For pharmaceutical production, we urgently required an Artemisia rich in artemisinin. The collaborators in the nationwide Project 523 found an A. annua L. native to the Sichuan province that met this requirement.

The first formulation we tested in patients was tablets, which yielded unsatisfactory results. We found out in subsequent work that this was due to the poor disintegration of an inappropriately formulated tablet produced in an old compressing machine. We shifted to a new preparation—a capsule of pure artemisinin—that had satisfactory clinical efficacy. The road leading toward the creation of a new antimalarial drug opened again.

As Kausik Datta notes, Tu was also using medicinal chemistry to modify Artemisinin to improve it:

In the true tradition of proficient medicinal chemists, Tu wasn’t satisfied with existing qinghaosu [the Chinese name for Artemisinin]; as early as in 1973, she had already chemically modified Artemisinin to dihydroartemisinin. Overcoming the initial concerns about its chemical stability, she found that this substance was stable, possessed ten-fold higher anti-malarial potential than Artemisinin, reduced the risk of recurrence, and provided the opportunity to develop newer Artemisinin derivatives through chemical modifications.

Several of the articles touting Tu’s Nobel Prize implied that the reason Artemisinin wasn’t accepted right away in the “West” was prejudice against TCM. It turns out that Tu’s results were not published internationally until 1979. As Tu put it in her Nature Medicine article, the chemical structure of Artemisinin was determined in 1975 and published in 1977, but “the prevailing environment in China at the time restrained the publication of any papers concerning qinghaosu, with the exception of several published in Chinese.” After publication in 1979, Tu presented her group’s work in 1981 at the Scientific Working Group on the Chemotherapy of Malaria in Beijing, sponsored by the United Nations Development Programme, the World Bank and the World Health Organization (WHO). She noted that the “efficacy of artemisinin and its derivatives in treating several thousand patients infected with malaria in China attracted worldwide attention in the 1980s”21.

Indeed, WHO representatives at the conference were very impressed with what they heard. They immediately approached the Chinese government for samples of the plant and details of the extraction process, so that they could replicate the findings reported. This is, of course, what scientists do when they hear of a highly promising new treatment like this. However, at the time, the Chinese government was reluctant to share these details, and, as Maude et al put it in a description of the history of Artemisinin, “further collaboration did not occur at that time.” It’s likely that Cold War politics and the insular nature of the Chinese government was a bigger factor in the delay in acceptance of Tu’s findings by the rest of the world than distrust of the source of the drug. After all, scientists have been screening various natural products and extracts for pharmacological activity against diseases such as cancer for many decades, and many of our most useful drugs were derived or modified from natural compounds.

Tu’s accomplishment is remarkable and definitely deserving of the Nobel Prize, as it is a triumph or modern pharmacognosy and medicinal chemistry. Unfortunately, even the Nobel press release about Tu’s award seems to imply that this discovery was due to TCM. Yes, there may well be more pearls like Artemisinin in the thousands of herbal remedies used in TCM, but they will only be identified and validated by rigorous science of the sort applied by Tu nearly five decades ago. What is also forgotten is what a small proportion of these compounds will actually pass this test of rigorous science. Remember, Tu screened over 2,000 compounds, only a third of which showed any promise and only one of which became a useful drug. TCM herbalists tend to forget this and skip the steps that Tu went through over several years of hard work. They also tend to forget that the validation as a safe and effective medicine of an active compound derived from a TCM herbal preparation does not validate the mystical ideas that underlie TCM and are the basis for all of its non-herbal practices. Science works. Mysticism does not.