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Natural Products: Always Coming Back

I get asked fairly often about natural products in drug discovery – it’s a topic that appeals to reporters and the general public, since the idea of pulling some sort of cure out of the rain forest or a deep-sea coral is interesting and dramatic. (Of course, some of the natural product cures have come from rotting pieces of fruit from a corner store, which isn’t quite as good a scene in a movie. For every rapamycin, isolated near an Easter Island statue, you have a rosaramicin, isolated from the soil in a Texas golf course.

The question I want to put to people today is: how bad is the diminishing-returns problem in this field? I think that we’ve clearly picked a lot of the proverbial low-hanging fruit. By now we’ve raided the traditional pharmacopeias from cultures all around the world, largely using up the rough-and-ready human activity data that have been accumulated over the last few thousand years. Past that, huge natural product collections have been screened in all sorts of directions, by all sorts of techniques, for decades now. Biological space is huge, and chemical space is huge, but in the intersection of “testing for activities we care about with compounds we can obtain from nature”, I’d say that a fair amount of coverage has occurred.

Now, that coverage is certainly not enough to say that we should give it up, and just not screen natural product collections. That would be foolish; there are still plenty of things to try. But what I’m wondering is how far down the “long tail” of the distribution are we by now? Have we discovered a majority of the really interesting natural products, or perhaps just a majority of the ones that can be fairly readily discovered? I don’t know about the former, but I’m willing to believe that latter.

Over the years, in reaction to beliefs like this, people have turned to less-explored regions and ecosystems, searching for things that have a better chance of not having shown up before. Extreme environments, less-sampled marine organisms, remote jungles – all of these have had (and are having) their days. (I should also mention that we humans create some pretty extreme environments ourselves that are worth sampling!) I would like to see some good drug leads and tool compounds come from Antarctic valleys and deep-sea sampling, but I don’t believe that just moving to odder environments will balance out the amount of searching we’ve done so far. We’re still in the position of doing more and more work, to make larger and large screening collections, to find fewer and fewer hits.

There are several possible ways out of this situation, but none of them are particularly easy. You have to think that there are many interesting compounds that just have never been isolated or tested in sufficient quantities, either because we do’t have enough of them in any collection and/or because they’re just found in such small amounts to begin with. So analytical chemistry’s relentless march could pull some of these back out into the light, but it’ll be work, for sure. There’s also the “cryptic natural product” idea that came up around here again just recently – inducing the formation of rare active substances that only get produced under specific threats or stress conditions. I like that one, and it has the advantage of probably selecting for things that have fairly high biological activities (as opposed to random metabolites), but it’s still a young field, with a lot of work to be done in it. Similarly, there’s the (old) idea of co-culturing microorganisms in order to pit them against each other. That has the advantage of perhaps producing some new active compounds as well as leading to screens against organisms that otherwise can’t be cultured at all – never forget, most bacteria and fungi don’t grow under standard in vitro conditions at all.

Every few years, it seems that you can find articles about the rebirth of natural products research (here are some from the recent crop of them). I wouldn’t mind that at all, if it’s true, but I can’t help but think that I’ve heard it before. So what do you think? Are natural products always poised to make a comeback, or will they really do it?

46 comments on “Natural Products: Always Coming Back”

  1. Given how many zillions of kg of African, Chinese, Indian and other continental herbal remedies (‘erhem) have been triaged to purified substances and 1000s of papers over the last few decades, the yield of (solidly evidence supported) bioactive NPs seems low. JFTR only 242 have currently passed the curation selection threshold in the IUPHAR/BPS Guide to Pharmacology (http://www.guidetopharmacology.org/about.jsp)

  2. Wavefunction says:

    “By now we’ve raided the traditional pharmacopeias from cultures all around the world”

    I would debate that. I think there’s tons of stuff from traditional Chinese or Indian medicine that is either unexplored or sloppily explored.

    1. GutDecipher says:

      Second this. Part of the slowdown in drug discovery from natural products is related to the overall slog that drug development and approval inherently is in this day and age. Lots of promising compounds can’t or won’t be subjected to clinical trials because of concerns distinct from efficacy, such as IP or access to quantity. It’s frustrating, but I just don’t really apply with the thesis of this article and looking at the trends, even with the rise of biologics, natural products still carve out a strong niche in new drug approvals year-over-year. source: http://pubs.acs.org/doi/full/10.1021/acs.jnatprod.5b01055

      1. GutDecipher says:

        Argh. Can’t edit comments. “apply with the thesis of this article” should be “agree with the thesis of this post”

    2. Derek Freyberg says:

      I wonder about that.
      Traditional Chinese Medicine has hundreds of what I’ll call “basic ingredients”, but many more medicines, only because the basic ingredients are very often combined in different ways to treat different conditions. And, while it is probably worthwhile to see what’s in cinchona bark that makes it antipyretic, I don’t think you have to extract every medicine, just each basic ingredient.
      Perhaps I’m being too reductionist about this, but I don’t think so.

  3. littlegreenpills says:

    Any organism worked on before the 1990’s should be considered unexplored. In most of those cases only the major components were explored due to limits in isolation and structure elucidation. Also, much of the literature from that time has no bioactivity data. In my opinion, there is still a lot of profitable work remaining because of those advances in technology. We just cannot go about it in the same way we have in the past. Minor components must be examined, and samples need to be stored so that they can be screened over and over as new assays are developed.

    1. Isidore says:

      Looking at just one method, mass spectrometry, the sensitivity achievable today is orders of magnitude better than 15-20 years ago. And coupled with the much improved chromatography it should be possible to identify and characterize really minor components.

  4. Dan Udwary says:

    There’s a near-infinite supply of compound variability in nature, and they’re all bioactive (though maybe not in humans, of course). Certain soil bacteria typically have 20-30 clusters, but may only express a few at high levels in normal culture conditions, so you have a strong signal swamping out the low ones. Looking purely from a genomics perspective, there are literally millions of compounds left to be found even in existing “well-explored” culture collections. You can throw a stone at GenBank and find clusters for which nobody has a clue of the products. Entire new compound classes we’ve never seen in an NMR. Once DNA synthesis technology can adequately and cost-effectively tackle large-scale, accurate syntheses of functional biosynthetic gene clusters (some of which are in the hundreds of kb in size and highly repetitive, so it’s not an easy problem), then there will be another natural products revolution.

    1. Dan Udwary says:

      Put another way, it’s not that we picked the low-hanging fruit. We picked the fruit off the ground, saw that a lot of it is rotten, and industry decided that fruit isn’t productive enough. We’ve barely reached up to get stuff out of the trees, let alone figured out the best time to pick, or bought a ladder, or started breeding more productive fruit trees, etc etc.

    2. DrOcto says:

      I’m not sure that I agree with the postulate that if an organism makes something then it must be bioactive in some way (if that was what you were suggesting?). Take terpenoids as an example, which seem to me to be a plants version of compound library screen. Test everything, and see what sticks.

    3. eub says:

      This seems very likely to me. From a biodiversity point of view, we know nothing about what all lives in a single spoonful of dirt. The vast, vast majority of bacterial species in there are unknown to science. Easily 99% unknown, probably a lot more, it’s hard to guess.

      Then multiply that by how well known each ‘known’ species is. In 99% of them, all we have is a new 16S signature, and we know nothing about the creature, certainly not an inventory of its products.

      Some estimates: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC539005/

      Now, that said, the big question is whether all these new species and new natural compounds have new activity. Multiple species will make the same compound and multiple compounds will have similar activity. I don’t know an estimate of those overlap factors, and would love to see one.

      I have a gut guess there may be a lot of overlap. It’s things like tetanus bacteria, who as far as we know have no interest in poisoning animals, but for their own purposes produce this compound that happens to be extremely good at that poisoning. Not even just the protease activity itself, also comes with another chain that gets the toxin endocytosed into neurons.

  5. CMCguy says:

    Like majority of drug discovery I think exploring Natural products requires favorable Serendipity as have to have a timely mating of the hunt for new molecules or mixtures that can be screened with an assay that is hoped has meaningful value. Limits of isolated or even base material quantities available can be generally restrictive then not all bio-assays can efficiently be adapted for HTS to reliable search. Even though I think NIH and NCI does continue that have such active programs in the end natural product drugs seems more of a niche field, partly because being “old ways” does not have same glamor as the wonders of gene therapy or whatever the current popular paradigm is.

  6. Annoned says:

    I provided analytical support for medical chemists for close to 25 years. The most unique structures and I have heard the most active compounds were natural products and their derivatives. I was surprised and sad when the natural products departments and groups were shut down where I worked and at other companies. Maybe some places will restart them. It consistently seemed that there were always new and novel compounds to be found the wider you look for samples and the closer you examine what you have.

  7. Dave Newman says:

    The comments above, particularly by Dan U and those on MS technologies are absolutely correct. If one now adds to these, the truly massive numbers of endophytes / epiphytes and not yet cultivatable microbes, the opportunities are limited only by imagination. The modification of bioactive compounds to improve their “drugability” (you can choose what you wish for that definition) and then their use as leads to modified structures with “certain improvements” have consistently beaten “de novo combinatorial chemistry” as sources of drugs. There are perhaps three maybe four de novo combichem drugs marketed world wide, so as a discovery tool, forget de novo combichem. On the other hand, candidate drug development via combichem is unmatched, but you still need that pesky NP-based bioactive starting structure!!!

  8. Crouton says:

    Our ability to search the deep-sea for natural products, be they from sponges, bacteria or other forms of sea life, is very much restricted to areas that have access to the equipment needed, typically a submersible vessel. Invariably, “deep sea-derived organisms” were isolated from those places in the world that have deep sea exploration programs, such as areas around New Caledonia and parts of the South China Sea, and few others. Suffice it to say, the deep sea has barely been explored and I definitely wouldn’t say this field has “had it’s day”. It will have it’s day when a cost-effective and efficient method to undertake widespread deep sea exploration is feasible.

    1. Crouton says:

      *Its

    2. Scott says:

      The problem with compounds from the sea is finding them. 71% of Earth is covered by water, and we’ve honestly only explored the part that is less than 200ft deep. You need highly expensive specialized equipment to go deeper than that and do anything while you’re down there.

      I couldn’t tell you how many times I heard ‘Quartermaster, sounding’ followed by a reply of some absurd number of fathoms of water (multiple thousands of fathoms, so 12-24,000 feet) beneath the keel out somewhere in the middle of the Pacific. Titanic and Bismark are in similar depths of water in the Atlantic, and there are all sorts of interesting critters living on those wrecks.

      Personally, I think the pharmaceuticals business would have a lot more luck raiding traditional medicines, though sorting out placebo effect would be a pain in the butt.

  9. Cameron Pye says:

    Shameless self promotion re analysis on Natural Product structural novelty trends:

    Retrospective analysis of natural products provides insights for future discovery trends.

    http://www.pnas.org/content/114/22/5601.abstract

  10. Old Timer says:

    I was talking to Danishefsky a few years ago, and he mentioned that one of the big problems with modern natural products research is the dearth of truly new structures. If one examines the vast number of natural product families, it becomes obvious that the last 20 years has produced more members (same basic skeletal arrangement) than families. Consequently, I think this does have an impact on the size of libraries vs. hits from those libraries (thus, the “low-lying fruit” argument). Along these same lines, a postdoc in the Clardy lab shocked me by saying he finds several new natural products EVERY DAY… they’re just not new families, so he basically tosses them.

    1. Will the real SAB members step forward says:

      Yeah but Danishefsky was on the SAB of the fraud Cellceutix , under Krishna Menon, which now changed their name to “innovation”

      Or was he??

  11. Barry says:

    PCR has shown us the DNA of many many more soil (and marine, and probably sewer-sludge…)organisms that we have ever been able to culture ’til now. Some of them just don’t like out culture conditions. This means that all the ground that we though we had plowed so well has to be revisited. Some of those cryptic organisms have secondary metabolites we’ve never seen yet.

  12. Calvin says:

    I have a couple of thoughts. Much as I was scarred by natural product total synthesis, I am still fond of natural products medicinally. I do think we have not really quite explore as broadly as we think we have.

    I think there are some areas where small molecules and natural products just have overwhelming advantages, like antibiotics. Bacteria have been playing chemical warfare with each other for millions of years so we should still look carefully in that space. I’m not convinced that natural products are appropriate in every therapeutic area but there are a few.

    A few comments have been made that there’s not much diversity out there when it comes to skeletons. Firstly, I’m not sure how you can prove that that’s true so I’m still hopeful that there’s novelty out there. Secondly, even if there is indeed some limit on the number of skeletons I have seen a number of examples where modification of the structure makes quite a difference. I know of at least one natural product that has gram positive activity, and only gram positive activity, only for it to turn out that with some relatively minor modifications to find that it becomes broad spectrum (gram positive and negative). So even the existing templates have opportunities if we get lucky/work hard enough.

    So, yeah, I think there’s a place for natural products and more modern techniques give us different options in terms of finding them and making them. I’m only glad that it is not me that is going to have to synthesize them.

  13. greasypocket says:

    I think natural products went out of vogue with the advent of combinatorial libraries, which by definition, are many orders of magnitude easier to make and to larger scales. Where I work (small biotech in USA where organic synthesis is outsourced to China), the head of medicinal chemistry winces at the presence of even a single chiral center in a hit series (!). Thus, for a lot of smaller biotech and academic labs, I think the low-hanging fruit argument doesn’t have much weight. If all you are doing is crawling around on the floor looking for the most chemically tractable hits from combinatorial libraries, that’s all you’re going to get out (i.e. natural products are a no-go from the outset).

    For larger pharma, I’d like to see a resurgence of the use of natural products and expeditions to source new ones. I think we’ve still only scraped the surface of what nature can provide. It would be especially interesting to have dedicated natural products teams which test these by HTS is 3D phenotypic assays.

    1. CMCguy says:

      GYP I saw NP interest fading well before combichem, likely due to Biologic’s focus, however perhaps to achieve “resurgence of the use of natural products and expeditions to source new ones” we will first need to come up with the instrument in old Sean Connery Movie “Medicine Man” that gave the full structure of a complex molecule with desire therapeutic use (from the Flowers or Ants?) instantly after simple injection. Of course if we can do that guess should just aim for Dr. McCoy’s equipment to make exactly what you need anytime you need it.

      1. greasypocket says:

        Wow. You must be really helpful around the lab. Do you have a good Scottish accent as well?

  14. Steve says:

    I know someone who started a company trying to isolate the active ingredients from Chinese medicines and failed. What she claimed was that there is not a single component that makes most Chinese medicines work (assuming they do); rather it was synergies of multiple components acting in concert. Part of the problem with natural product research might be that we are trying to apply Western medical concepts of a single high affinity compound to biology that works in subtler ways. Sort of like banging on a piano playing one key instead of playing a Mozart concerto.

    1. Wavefunction says:

      I think that with the advent of synergistic combination therapies, especially in AIDS and cancer, that idea might start to get some traction in the West.

      1. anon says:

        The explanation I’ve heard for why that is not done more frequently is that it is harder to get things approved by the FDA.

        1. steve says:

          The point is that it’s a synergy of a large number compounds with small effects, not similar to a combination product where two different compounds each with independent activity are combined.

  15. Natural Chemist says:

    It’s nice to wishy-washy (e.g., “we just need to go deeper in the ocean”) but I think the notion that there are vast swaths of novel structure types just waiting to be found is flawed.

  16. Shalon Wood says:

    Wasn’t there recently (as in the last two or three years) a new antibiotic type discovered in bacteria which couldn’t be effectively cultured outside its native soil?

    I’m not a biologist or a chemist, but I _am_ knowledgable enough to know that a completely new type of antibiotic would be a Very Good Thing (and, IIRC, there were claims that it would be hard for bacteria to evolve resistance to it because of the way it worked, although that may have just been, you know, bad journalism).

    I also seem to recall that they thought there were far more bacteria which fell in the “can’t be effectively cultured outside it’s native soil’ vastly outnumbered bacteria which could be easily cultured.

    If so, well, the two together could be promising. Or, of course, it could be Bad Science Journalism striking again….

  17. Halla Bhol says:

    Cancer drug discovery research is largely bullshit! After spending some time in the field, I can honestly say a lot of the leads and front-runner compounds have “beautiful data” in vitro and in vivo but fail miserably in humans. The science really needs to re-evaluate itself in progressing forward. Especially immuno-oncology based studies where effects of compounds are studied on immune cells in isolation.

    1. steve says:

      Nonsense. Immuno-oncology drugs like Yervoy, Opdivo, etc. have obtained cures in patients that have failed all previous treatments. That’s why they were approved for first-line in melanoma. You’re letting your prejudice get in front of the facts.

      1. steve is a motherfucker says:

        Absolute bullocks! Yervoy and Opdivo only work such a small subset of patients that normally would respond to any other small molecule treatments other than standard regimen. Get your facts straight! They’re both failing miserably in the clinic with reports of cytokine storms.

  18. GladToMoveToProcess says:

    Not quite “natural” products, but there’s another approach along the lines of the cryptic NPs and co-culturing that could be explored more, namely rather random, brute-force mutating the bacteria, fungi, and possibly higher plants. Some interesting things came out long ago by UV-irradiation, spritzing cultures with mutagens, and the like. A lot of this was done in attempts to figure out the biosynthesis, but it could be exploited as a drug discovery tool.

  19. exGlaxoid says:

    Given that we have made about 100 million new molecules (in CAS/Scifinder) and there are supposedly 10 ^ 60 small molecules under mw 500-600 possible, I don’t think we need to only depend on natural products for drugs. They do obviously have allure as being “biologically active”, but that does not mean that they are medically useful. We could test any number of compounds from nature or man-made libraries of compounds, but the key is that we don’t often know what we are looking for in the tests, since many diseases don’t have a simple assay that can be run in a 96 (or higher) well plate.

    I would rather see a program that looks at testing more “random” natural or man-made compounds/mixtures in phenotypical assays, be them cellular, artificial organs, animals, or even lawyers and politicians looking for signs of activity. That was the way many existing drugs were found, and seemed to work well. For examples, see Benadryl, Penicillin, and aspirin. All came from testing compounds in simple models, animals and then rapidly in humans. That is the weak part of the system today, that testing compounds in humans has become very difficult compared to just 50 years ago. With the advent of microdosing, LC-MS, and many other techniques, we can use very low dosed to test for safety, PD, PK, metabolism, etc, so it should be easier than ever to test a number of compounds quickly to find the best compounds sooner.

    The other issue is not finding drugs, but the very few are ever developed. I saw more than a dozen promising drugs for cancer, arthritis, and diabetes dropped, not due to safety, efficacy, or scientific issues, but due to commercial, patent, or legal considerations. Several companies dropped PR based drugs for endometreosis and uterine cysts due to RU-486 type political issues. I saw prostate cancer drugs (AR modulators) dropped due to fears of liability issues that were not based on any science I know. And several anesthesia drugs were dropped due to low sales forecasts, even though they looked very promising,, but insurance companies don’t want to move from generics which are dirt cheap to pay for better drugs.

    So the search for new drugs is tough, but not just the science, also the financial, legal, and political hurdles.

  20. Istvan says:

    Well said!
    However, both academia and industry should do natural products research for the simple reason: curiosity. They are out there! And the reward could financially and healthwise be enormous.

  21. Joy Craig says:

    Even if every NP ever made has “been tested already”, isn’t there ever-expanding room for discovery as biological insight lets us develop better assays?
    Wishful thinking, maybe, but results are only as good as the assays they come from.

  22. Putmebackinfrontofthehood says:

    Maybe the problem is that pharma doesn’t want to pay chemists to do the difficult work of making the analogs of natural products required to turn them into drugs.

  23. greasypocket says:

    Definitely part of the problem. US Pharma a lot of the time just doesn’t want to pay US chemists to make the analogs; they’d rather out-source these jobs to Chinese companies thinking it will boost their bottom line. It is wrong on so many levels and needs to stop.

  24. The Pharma Rapture says:

    Guys I’m gonna be completely honest, I think there’s a bubble brewing in this biotech/pharma industry especially around the Boston area and I would give it another 7-8 years for it to pop drastically. There’s gonna be such massive layoffs and serious hit to the economy coming. If I were you, I’d work my butt of getting rid of any debts and liabilities (by which I mean housing cuz you’ll end up paying higher property tax to support welfare bums). You don’t have to believe me but don’t say you weren’t warned.

    1. Putmebackinfrontofthehood says:

      Yup, the current biologics craze will wane.

      But chemistry will come back, to the US.

      What else will the rich throw their money at?

      You can’t trust the Chinese and Indians to work on your secrets

      No other industry holds the potential of generating billions from a little white pill

  25. Derek Lowe is my bitch says:

    I read something about that the other day

  26. JG4 says:

    Here’s a nice example of stress-induced chemical defense in plants

    https://www.schneier.com/blog/archives/2017/07/tomato-plant_se.html

  27. simpl says:

    There is plenty left in Mother Nature’s apron-pockets. I can only see two periods where synthetic products beat out natural ones; the late 19th century, where existing organic products, often dyes, were tested for medical effects, and the mid 20th C, raising the idea of pharmacophores, or me-too, where new synthesis brought mostly incremental improvements.
    However, consider just the main branch of Biotech, antibodies. There are potentially multiple antibodies for any invasive substance, from different persons or animals, or from a single donor over time. Over two decades, the issues around antibodies triggering other antibodies have been addressed. Production techniques have concentrated on choosing product that reduce these reactive antibodies, by making them more like the recipient’s ones (humanised), and by choosing the single source (monoclonal) with the best response. Chemists don’t know yet how to humanise by e.g. removing glycan side chains, nor can they tinker with improvements at any molecular level. Their biggest contribution has been to improve the useful duration, by attaching polyethylene glycol, and the still-experimental ideas of antibody targeting, by attaching an active chemical to an antibody. The chemist’s hour may come, but currently it is a time for discovering new medical uses.

  28. Joe Chemler says:

    (My statements do not represent the views of my employer)

    NP cannot be patented anymore without structural modifications.
    Dereplication is a very costly endeavor.
    Poor PK and PD; NPs were not evolved to be taken as a oral drug. IV formulation is a tough sell or nonstarter.
    Unless the US government subsidies NP antibiotic research, Big Pharma will not be a major player in new antibiotic research. For a host of reasons including rapid occurrence of resistance and poor ROI (antibiotics are expected to be cheap).
    NP drug discovery takes much longer than medicinal chemistry. By the time a single compound is found, tested in vitro, scaled up for in vivo, a handful of medchem programs making hundreds scaffolds and variants could have come and passed. Timelines are now extremely accelerated to maximize profits.

    There are niches that small molecules cannot address such as hard to drug targets that NPs are more suitable as a starting point.
    NPs can serve as chemical probes to inspire medchem efforts.

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