Oct 13 2015

The Nobel and Chinese Medicine

The 2015 Nobel Prize for Physiology or Medicine went to three scientists who discovered treatments for parasites. Tu Youyou shared half the prize for her discovery of artemisinin, an effective drug against malaria.

Youyou is a Chinese researcher and, as has been widely reported, she relied on traditional Chinese texts to search for candidate herbs to test for activity against malaria. This has sparked a public debate about what lessons we can derive from this fact. Promoters of traditional Chinese medicine (TCM) argue that is shows the value of TCM. Amazingly (revealing their intellectual dishonesty) Naturopaths crowed that this was a vindication of naturopathic medicine.

Scott Gavura over at Science-Based Medicine gives a great analysis of what Youyou’s work really means. Meanwhile the New York Times struggles to give a “false balance” approach to the issue. There are a few interesting points worth highlighting.

The story itself is uncontroversial. Youyou set out specifically to find a drug that would be effective against malaria, which remains a serious medical problem for much of the world. Existing drugs, quinine and chloroquine, were developing resistance, and a replacement was needed. Her starting point was TCM texts, looking for any natural product that was used to treat fever. She came up with 2000 candidates.

After narrowing down the list, she finally settled on Artemisia annua as a promising candidate. Tea made from the plant was used to treat fever. Initial attempts at extracting an active ingredient, however, failed. She now recounts that she went back to TCM texts, one of which indicated that the tea was steeped in cold water. This led to the hypothesis that perhaps boiling was inactivating the active ingredient. She then tried ether extraction, which worked. The resulting chemical showed activity in mice with malaria.

The story is not over, however. The drug, which she called artemisinin, had low bioavailability and a short half-life. This means that the drug would essentially not work as a treatment in humans. It would never get to a therapeutic level at tolerable doses. A Swiss pharmaceutical company, Novartis, bought patents on artemether (an artemisinin derivative) and lumefantrine, another drug with activity against malaria. The combination proved clinically effective.

Pharmaceutical chemists are further developing the drug, removing unnecessary components of the chemical structure to maintain efficacy while reducing side effects.

What, then, are the real lessons we can derive from this story?

The first is that traditional Chinese herbalism (part of TCM) generally doesn’t work. That’s right – the opposite of what TCM proponents are claiming. Artemisia annua, as a tea or herb, has too low bioavailability to be an effective treatment for malaria. The TCM herbal treatment does not work. It took modern pharmacology to develop an effective treatment from the plant.

This is not an isolated example, but a problem that plagues all of herbalism. Herbs as treatments are drugs. They are consumed not for their nutritional value but for their pharmacological activity. The plant kingdom is a massive chemical factory, with evolution resulting in many millions of possible chemicals. Plants evolve chemicals to protect themselves from pests, and so many of these chemicals are horrible toxins.

The only difference between a toxin and a drug, however, is dose. A drug is a toxin that has a dose range in which it has one or more effects that can be safely exploited as a medical intervention. Most cultures found the low-hanging fruit in their environment – plants that have obvious and immediate effects, such as pain relief, moving the bowels, sedation, and especially hallucinogenics. They also found poisons that rapidly made people sick or dead.

More subtle effects, however, are very difficult to find with trial and error alone. Without scientific controls, we will tend to come to the conclusion (through subjective validation and confirmation bias) that anything works for anything. This is why TCM has 2000 herbs to treat fever. Most fevers will go away on their own, so anything you take with seem to work.

Using plants directly has other problems. Plants have dozens or even hundreds of chemicals. The concentration of these chemicals will vary by part of the plant, from plant to plant, from season to season, and with the methods of collection and preparation. As this episode demonstrates, boiling herbs to make tea may inactivate a potential active ingredient.

Perhaps the biggest problem, however, is pharmacokinetics. In order for a drug to be useful as a medical treatment it has to have a host of properties at the same time. Lack of any one is a potential deal-killer. First, it has to have one or more active ingredients that have an effect which can be exploited. Those chemicals need to have their useful effect at a dose that does not produce too many unwanted effects.

The active substances need to have adequate bioavailability, meaning that they get absorbed in adequate amounts. This one factor is probably the thing that renders most herbal treatments useless. Part of this is also water or fat solubility. If the substance is not water soluble or fat soluble, there is no way for it to get absorbed, or get into the blood or into the tissue. Once the drugs get into the system they have to get to the target tissue in adequate concentrations and hang out for long enough. If they are rapidly removed by a first pass through the liver, then they will never get to their target. Or they may be removed by the kidneys, or highly protein bound in the blood, or degraded by enzymes.

Then, of course, the herbal drug cannot have any short or long term toxicity. Many drugs fail in their early stages of development because, despite everything else being great, they cause kidney or liver damage. This is true of many herbs, in fact, including those that are used as part of TCM.

When drugs are developed they typically have to be altered in various ways in order to create a derivative that has all the right properties. The probability of a chemical having all the necessary characteristics simultaneously, as it exists in the plant, is vanishingly small. As a result most herbs are dirty drugs that are pharmacologically useless as they exist unaltered in nature. Their common saving grace, however, is that low bioavailability reduces the toxicity of most (not all) herbs that are in use. Trial and error at least weeded out those herbs that are immediately toxic.

The story of artemisinin demonstrates all of this. It took modern pharmacology to develop a useful drug from the TCM herb, out of 2000 candidates. Further, TCM practitioners did not have the knowledge of what they were treating. They treated fever, because they had no germ theory of disease, and did not even recognize the notion of a physiological disease. They did not understand malaria.

All of this makes me think that finding Artemisia in the first place was mostly luck. One in 2000 is not a great hit rate, and is more consistent with mostly luck. Further, as the New York Times reports, in the 40 years since her discovery, Youyou had used the same methods to try to discover other useful drugs, and has discovered – nothing. How many TCM herbal drug candidates did she screen in her career to find artemisinin? If you spent 40 plus years screening tens of thousands of plant chemicals for useful drugs, without any guidance from any traditional herbalism, I wonder on average how many discoveries you would make.

The career of Tu Youyou, if anything, documents the resounding failure of traditional herbalism. It is mostly useless, with a few lucky hits thrown in.

Modern pharmacology, by comparison, is systematic, based on fundamental knowledge of chemistry, pharmacology, physiology, and an understanding of the mechanisms of diseases. When I prescribe a drug I know exactly how many mg of active ingredient the patient is getting, its half-life, how it is eliminated from the body, its tissue penetration, its effects and side effects, its drug-drug interactions, and any potential toxicity. When you prescribe an herb to a patient, you have no idea about any of these things.

Conclusion

The New York Times article indicates that the Tu Youyou Nobel prize award has renewed debate about TCM. That’s good – if we have a real and informed debate. Ironically, while Western CAM practitioners are flirting with TCM and touting its benefits, China is trying to rid itself of this pseudoscience and embrace Western scientific medicine – because it works.

TCM pracitioners are not happy with the Youyou award. As the NYT reports:

“Are we truly respecting this cultural heritage?” Dr. Liu said. “When we think Chinese medicine needs to be modernized and the path it shall go down must be like Tu Youyou’s path, I think it is a disrespect.”

I wouldn’t use the word “disrespect” – that implies that our prescientific past deserves some respect. Liu is correct in that Youyou’s Nobel was a victory for modern science, and shows the inadequacies of TCM. TCM is based on pre-scientific notions, including yin and yang, and the five elements. It is the Eastern equivalent of the four humors, and the medical equivalent of astrology.

I don’t think that pride in Western culture should make us look seriously at Galenic medicine. Likewise, pride in Chinese culture should not be a motivation to cling to harmful prescientific medical traditions.

21 responses so far

21 Responses to “The Nobel and Chinese Medicine”

  1. edwardBeon 13 Oct 2015 at 9:58 am

    Very nice summary of the problems with herbalist thinking. I’m going to point my true believer friends to this article, and then sit back and watch them clutching at straws to try to justify not giving up their beliefs or in some cases, their income from peddling supplements.

  2. Ivan Groznyon 13 Oct 2015 at 10:39 am

    Mr Novela at his best. Thanks for the article. Finally somebody not being afraid to transgress against PC BS by defending modern science against “cultural heritage” and “natural medicine” nonsense, even if this “heritage” belongs to “oppressed” peoples.

  3. steve12on 13 Oct 2015 at 11:44 am

    Ivan:

    “…not being afraid to transgress against PC BS by defending modern science against “cultural heritage” and “natural medicine” nonsense, even if this “heritage” belongs to “oppressed” peoples…

    I agree with the scare quotes – there are no oppressed people, just people with insufficient bootstrap grip. Apparently the subtext is that cultural heritage doesn’t exist either?

    I love the people who’ve adopted the bifurcation-error politics of our time so deeply that they can see or conceive of little else. You should have a great time with Egnor when he swings by.

  4. Lane Simonianon 13 Oct 2015 at 11:56 am

    If nothing else this Nobel Prize is a reminder that deriving synthetic medicines from natural products should still be at the forefront of many research efforts. Unfortunately, many pharamaceutical companies have largely abandoned this approach in recent years.

    And using some natural products to treat certain disease is not Sisyphus pushing the rock up the mountain. Yes, bioavailability is often a major problem–especially since some compounds enter the bloodstream well but not fatty tissue or vice versa. But inhalation or a combination of compounds can partially overcome these problems.

    A number of other speculated problems are less serious. Plants are a mix of compounds used to defend themselves against various pests. But the same compounds can potentially protect humans against viruses, bacteria, and fungi as well as being antioxidants (or in some cases because they are antioxidants). The method of delivery is the key in many cases. Essential oils, for example, taken internally can damage the kidneys and the liver, but through aromatherapy rarely do any damage. So much effort put into delivering compounds intranasally where this is already possible with compounds in essential oils.

    The mix of compounds can either be a problem or a benefit. Panax ginseng for example contains a variety of compounds that are antioxidants. Some of these may be more powerful than others but the combination is what likely makes Panax ginseng a potentially effective treatment for Alzheimer’s disease.

    I would have to look more closely at how Tu Youyou did her research but I doubt it was just blind luck. It is very likely that more than one out of those 2000 compounds had anti-malarial effects and also highly likely that she knew the chemical composition of artemisinin beforehand.

    Again, I am not anti-“western medicine”. However, to ignore the results from clinical trials using “eastern medicine” is counterproductive especially given the number of diseases that have been poorly treated or not treated at all by drugs so far.

  5. arnieon 13 Oct 2015 at 12:37 pm

    Steve12:” there are no oppressed people, just people with insufficient bootstrap grip”

    Interesting, even provocative, assertion. Could you please explain the difference between the two as you see it since you seem to think those who are often called “oppressed” simply lack good bootstrap grip. e.g., were the African-American people held in slavery in the US for so long not being oppressed by the slave owners and traders? If not, what were the slave owners and traders doing to them — nothing, or simply denying them good bootstrap grip training? Is this all, perhaps, semantic even?

  6. DrNickon 13 Oct 2015 at 1:31 pm

    Lane Simonian:

    The problem, as Dr. Novella touched on in the article, is that the low hanging fruit, the “natural” products with clear evidence of efficacy, like willow bark for pain, have already been picked. I agree that attention should still be paid to testing these remedies, but when they’ve repeatedly been shown to be no more effective than placebo there’s really no point continuing to investigate.

    There’s also the problem of scarce resources – every dollar invested in researching “natural” remedies is a dollar taken away from deriving synthetic medicines, which have proven to provide a much greater return on that investment.

    I’m sure there are some effective herbal/TCM/”natural” remedies out there that have not yet been incorporated into evidence based medicine, but is it worth our time to hunt for those needles in the haystack?

    Also, you refer to the “results from clinical trials using “eastern medicine”” – I assume you mean trials that show strong evidence of efficacy beyond placebo? Would you care to share some of those with us, because I’m not aware of any well-designed blinded placebo-controlled trials showing anything of the sort.

  7. lagaya1on 13 Oct 2015 at 1:54 pm

    arnie-
    I think steve12 was being sarcastic… in response to Ivan.

  8. steve12on 13 Oct 2015 at 2:46 pm

    Arnie:

    lagaya is right – I’m being sarcastic.

    Ivan’s use of scare quotes around oppressed is absurd.

  9. arnieon 13 Oct 2015 at 3:54 pm

    Steve:
    Well, that was my first take, given the source you were responding to. And that first interp fit more with you normally. But after reading it several times, I began to doubt my first take but didn’t want to assume anything, so decided to push a little for clarification without being too critical. Thanks for clarifying. Makes a lot more sense.

  10. steve12on 13 Oct 2015 at 3:57 pm

    Arnie:

    No worries – I became confused reading it back to myself!

  11. Lane Simonianon 13 Oct 2015 at 4:58 pm

    DrNick, some of the low hanging fruit has been picked but perhaps as Tu Youyou’s work shows certainly not all of it has been. I will cite the research using panax ginseng to treat Alzheimer’s disease. These trials could certainly have been designed better. However, if you have something that appears to show efficacy in the treatment of Alzheimer’s disease is it a waste of resources to design better larger-scale trials especially considering every drug designed to lower amyloid or tau tangles has failed to date? Mechanism does not prove results but the old but still viable hypothesis that Alzheimer’s disease is caused primarily by peroxynitrite still is scientifically viable. especially since all the risk factors, all the symptoms of Alzheimer’s disease, all the putative protection measures, and all the successful trials have involved the production, inhibition, or removal of peroxynitrite.

    Widespread Peroxynitrite-Mediated Damage in Alzheimer’s Disease
    Mark A. Smith1, Peggy L. Richey Harris1, Lawrence M. Sayre2, Joseph S. Beckman3, and George Perry1
    The Journal of Neuroscience, 15 April 1997, 17(8): 2653-2657;

    J Med Food. 2009 Feb;12(1):124-30. doi: 10.1089/jmf.2007.0646.
    Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.
    Kang KS1, Tanaka T, Cho EJ, Yokozawa T.

    Nutr Neurosci. 2012 Nov;15(6):278-82. doi: 10.1179/1476830512Y.0000000027.
    Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer’s disease.
    Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M.

    J Ginseng Res. 2011 Nov; 35(4): 457–461.
    Improvement of Cognitive Deficit in Alzheimer’s Disease Patients by Long Term Treatment with Korean Red Ginseng
    Jae-Hyeok Heo,1 Soon-Tae Lee,2,3 Min Jung Oh,2,3 Hyun-Jung Park,2,3 Ji-Young Shim,2,3 Kon Chu,2,3 and Manho Kim2,3,*

    In addition to aromatherapy with rosemary, lemon, lavender, and orange essential oils via aromatherapy, here is the only other trial that has indicated potential efficacy in the treatment of Alzheimer’s disease.

    Herbal medicine Davaie Loban in mild to moderate Alzheimer’s disease: A 12-week randomized double-blind placebo-controlled clinical trial

    Haleh Tajadini, Rostam Saifadini, Rasool Choopanicorrespondenceemail, Mitra Mehrabani, Mohammad Kamalinejad, Ali Akbar Haghdoost
    Received: September 9, 2014; Received in revised form: June 9, 2015; Accepted: June 9, 2015; Published Online: August 27, 2015

    Even if the explanation were wrong, very old observational studies regarding certain herbs for improvement of memory may have been well-founded. The key today is to match the scientific actions of these herbs with the observed results.

  12. DrNickon 13 Oct 2015 at 5:48 pm

    Lane Simonian:

    Interesting, and like I said, I’m sure there are plenty of these kinds of remedies out there, but I guess our point of disagreement is over what percentage of the low handing fruit is still left to pick.

    The fact that Youyou had to winnow down a list of 2000 TCM remedies for fever to find one drug that could be turned into an effective medicine to treat malaria suggests to me that it’s pretty low.

    I’m really not qualified to parse those studies or comment on the overall state of the evidence for the efficacy of panax ginseng as a treatment for Alzheimer’s disease – perhaps Dr. Novella could weigh in with his thoughts on that.

  13. BillyJoe7on 14 Oct 2015 at 5:57 am

    Lane: “some of the low hanging fruit has been picked but perhaps as Tu Youyou’s work shows certainly not all of it has been”

    DrNick: “The fact that Youyou had to winnow down a list of 2000 TCM remedies for fever to find one drug that could be turned into an effective medicine to treat malaria suggests to me that it’s a pretty low [percentage of fruit still left to pick]”

    And…

    New York Times: “in the 40 years since her discovery, Youyou had used the same methods to try to discover other useful drugs, and has discovered – nothing”

  14. Average Joeon 14 Oct 2015 at 7:05 am

    There is some lacking info on how drug discovery is performed.
    To start, a hit rate of 1 in 2000 is very high. Considering the hit rate coming out of combinatorial chemistry (pure synthetic chemistry) is less than 1 in 1,000,000.
    There is a correlation between the drug industry abandoning natural product drug discovery for combinatory chemistry in the early 1990s and the drop in company drug pipelines and new drugs to market. (Of course other explanations are possible). As an aside, all the big drug makes abandoned anti bacterial drug discovery. With the rise of MRSA and the like, it will take a real crisis for big drug companies to reinvest again (ie profitable).

    For every chemist that discovers a drug that makes it to market, there are thousands of chemists that never do. A chemist to discover a second one in their career is very rare indeed.

    Over 55% of drugs approved in the US over the last 30 years are either natural products (NP), modified from a NP or have a structural core based on a NP. That number is >75% for anti infective agents.

    I’m not saying natural remedies are the the same thing as natural products drug discovery. Far far from it. I just wanted to point out the importance of NPs in drug discovery.

  15. Lane Simonianon 14 Oct 2015 at 10:35 am

    To add to the very lucid point made by Average Joe, over 240,000 compounds had been previously studied for the treatment of malaria–none of which had worked (source BBC News).

    The use of Artemisia annuna (sweet wormwood) did not initially work either because heating killed its active components (including artemisinin). For Tu Youyou’s story in her own words see:

    http://www.nature.com/nm/journal/v17/n10/full/nm.2471.html

  16. Steven Novellaon 14 Oct 2015 at 4:37 pm

    Average Joe – I understand what you are saying, but that is all consistent with my main points above.
    We need to consider, using your numbers, not only the 2,000 candidate agents, but also the 40 years of subsequent research she did and the 1,000 other chemists who were also looking for drugs but failed. It is a post-hoc fallacy to only consider the one successful program leading to a successful drug.

    I agree that using anecdotal evidence to get a leg up on the statistics is a reasonable approach. However, we can’t say from this one example if it was actually helpful, or if we are looking back at the one person who hit the chemical lottery and then declaring that whatever they did worked. This is a classic lottery fallacy. You could also pick someone who won big on the stock exchange and declare that whatever methods they used “worked.”

    It is more telling, in my opinion, that her success did not predict later success.

    Also – all of this still leads to a situation in which herbalists are using mixtures of plant-derived chemicals all of which have a chance of one in tens of thousands of having a useful active ingredient, and then even then it probably lacks bioavailability.

  17. Banzai Otison 14 Oct 2015 at 7:08 pm

    @Lane, regarding your Davaie Loban citation:

    Everybody knows that Dr. Choopanicorrespondenceemail is a notorious quack and shill for the Big Loban. 😉

  18. Lane Simonianon 14 Oct 2015 at 8:20 pm

    No matter how you look at it one in 2,000 is still better than 0 in over 240,000. That is not to say an effective medicine for malaria not originally derived from a natural product might have eventually been discovered. But how many tens of thousands of compounds would it have taken?

    As an environmental historian, I like what Tu Youyou did: she found an obscure historical reference and that provided the clue that led to the breakthrough.

    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.

    To infer that her discovery was just blind luck or hitting the lottery is not applicable here. As the old quote from Louis Pasteur goes: chance favors only the prepared mind.

    One should not let ones prejudice against so-called “alternative medicine” get in the way. First identify the chemical composition of the plant, then examine its impact on disease-driving mechanisms, then determine the best way to increase the ability of the compound or compounds to reach and alter the target. I don’t care how the latter is done just as long as it makes the natural product more effective and no less safe.

  19. Average Joeon 15 Oct 2015 at 7:20 am

    My retort to the post hoc and lottery fallacy is that I made an educated opinion as a NP chemist and pharma shill. Argument from authority but it’s my career. You’ll have to excuse me for not mentioning two other NPs discovered based on anecdotes that come to mind (confidential agreement with my employer). I don’t believe in TCM, supplements, herbalism, etc. But I do believe that a strategy that starts with a natural source (plant, bacteria, fungi) has a leg up on pure combinatorial chemistry. Having any additional information to guide the selection for screening is helpful. I would argue that Youyou’s efforts may have succeeded if she had today’s technology used for drug discovery. Historically, most NP discovered required that the amounts in the extracts be substantial enough to give a signal. Now days, the amount of chemical need for screening is several orders smaller.
    For instance, in the absence of prior anecdotes, the screening campaign for an anti cancer drug led to the discovery of Taxol which is wickedly potent. No, that doesn’t support herbalism or TCM or naturopathy as we both agree on.

    The argument goes that NPs are a privileged class of molecules (often beyond rule of 5) that have been selected for by Nature to have bioactivity. Drug companies abandoned NP drug discovery because it’s very resource intensive (slow, costly, difficult). New approaches are being attempted using genome sequencing, genetic engineering, new and innovative screening technologies, molecular modeling, and as so forth.

  20. Bill Openthalton 15 Oct 2015 at 7:30 am

    Lane Simonian —

    No matter how you look at it one in 2,000 is still better than 0 in over 240,000.

    It would be if these odds were recurrent, but they are merely anecdotal.

    Using information from traditional medicine is useful when the symptoms recorded by traditional healers match the symptoms of a disease, as is the case with malaria (quinine, artemisinin), or fever (aspirin). Trying to find cures by using the concepts of disease and physiology these traditions use, is (of course) bound to fail. The fact that traditional healers discovered, through trial-and-error, that certain substances are effective against certain symptoms does not mean that their views on physiology and disease are correct.

    Traditions are valuable because in those halcyon days, healers could test their ideas on people far more easily than doctors and pharmacists today, and low success rates did not stop them from recording a procedure or a substance as a cure. The overall value of this pre-scientific lore is nothing more than an interesting collection of anecdotes; sometimes, you find a nugget in a ton of gravel.

  21. Johnnyon 15 Oct 2015 at 12:26 pm

    Does it even make sense to talk about “Western science”? Sure, modern science historically arose in Europe in the 1600s. But you can find proto-science in many historical cultures across the world (though usually mired in superstition, mythology, and mysticism). It could well have arosen in another culture eventually.

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