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Drugs from Fungi, Or Fungi As Drugs?

This is an interesting article, but a lay reader would probably not realize how many important things are left out of it. It’s about a mushroom grower (Tradd Cotter) who’s been studying ways to protect his desired fungi against other pathogens, and who has an idea about extending this work to human therapies. He’s co-culturing fungi that produce a lot of secondary metabolites with the things that are invading his cultures, and using extracts from these co-cultures to keep the undesired fungi at bay. That makes a lot of sense – fungi certainly can produce a lot of interesting and unusual molecules, and if you challenge them, they’ll get to work.

Extending this to human disease, though, is going to be a steep climb. Cotter’s picturing the use of the metabolite-producing fungi themselves as medicinal agents:

It’s not pharmaceuticals he has in mind; he’s not planning to mass produce many different types of secondary metabolites. Rather, he believes it’s his unique style of co-culturing itself––the process of culturing two different microbes together to produce a defense entirely specific to the attacker––that may be able to create custom antibiotics that, at least in theory, could be inherently less susceptible to resistance.

His goal, in other words, is to grow mushrooms that are themselves medicine, because they could create whatever metabolites a sick person needs.

And here’s where the regulatory environment should come into the story, but doesn’t. The FDA approves specific therapies and compounds, not platforms that generate who-knows-what. And that’s not just because they’re hypercautious sticks in the mud, either. These “custom antibiotics” could very easily be toxic to humans – the fungi are under no constraints to produce something that we can tolerate. It’s hard to tell from the article, but there may be a bit of the “all-natural” fallacy working here, either with Cotter himself or the reporter writing the story. To be fair, these issues do come up later in the piece:

But Cotter’s dramatic departure from traditional pharmaceuticals sits uneasy with some scientists I spoke to about his idea. For starters, it strikes many as dangerous. In medicine, science painstakingly searches for and isolates helpful metabolites, because metabolites can be toxic, too. Cotter’s process would have to find a way to identify metabolites that are harmful to people and somehow remove or neutralize them first. “Maybe you found a fungus that produces a metabolite that kills strep. Well fungi don’t just make one metabolite,” says Nancy Keller, a University of Wisconsin microbiologist. “The fungus is likely making many other metabolites, and although one might be useful, other metabolites might be injurious.” At worst, the magic Cotter’s hoping for may just be pseudoscience.

Here’s the tricky part: you can’t just give fungi (or a fungal extract) to patients without knowing something about the active ingredients. Well, if you were in the herbal supplement business, I guess you could, because that is deliberately set up to be a load of crap, but if you’re trying to treat sick people with actual medicine, you need to make sure that you’re not going to make them sicker than when you started. Thus the requirement for safety, and that’s going to be a hard one to meet based on the way Cotter is picturing things.

Another problem is that these antibiotics may not be all that “custom”. Fungi can produce an awful lot of secondary metabolites, to be sure, but any given strain or species probably has a limited repertoire – evolutionarily tried-and-tested substances that have helped their ancestors. The mold that makes penicillin, for example, doesn’t have another two dozen diverse antibiotics up its sleeve: it has penicillin, because that’s what’s worked enough in the past to keep its line going. (It’s true, though, that the idea of cryptic metabolites, compounds that are produced only under rare conditions, has been a popular one in recent years, with Warp Drive Bio being perhaps the best-known example). But for the most part, if Cotter has a particular fungus that seems to be doing a good job fighting off bacteria (or other fungi), it may well be generating the same stuff every time to get the job done. The article seems to assume that the fungi are generating unique, specific things in response to each challenge, but there’s no reason to assume that, and plenty of reasons to assume the opposite.

These systems are still worth looking into, though. Penicillin was pretty damned valuable, and its derivatives still are. The classic antibiotics, of course, came from tapping into just these sorts of fights between microorganisms. Unfortunately, we seem to have long since scooped up the easier-to-find agents via this approach – if Cotter’s fungi have some new compounds to offer, they’d be welcome indeed. But I get the impression that (at least so far) none of the active substances have been identified, so we don’t know if they’re molecules that we’ve known about for decades or not. And I don’t thing that they’ve yet even been into an animal model of infectious disease, even, so these are very, very early days. He’s signed up with some researchers at Clemson to take a look at these things, which is a good first step.

There are a lot of steps to come, however, which brings up another problem with reporting on things like this. That Atlantic article is something that readers may well find interesting, but it’s covering something that’s extremely preliminary. Oak trees do indeed come from acorns, but it’s also true that most acorns never produce an oak tree. I’ve long wondered about general readers getting jaded and cynical from reading about all sorts of “breakthroughs” that never amount to anything. This particular article isn’t that overhyped, not by the standards of medical reporting, anyway, but plenty of them are. Readers, for the most part, probably don’t realize just how big the gap is between the latest article (look! what a neat acorn!) and the oak forest that they’re waiting to see.

16 comments on “Drugs from Fungi, Or Fungi As Drugs?”

  1. bhip says:

    On the next Dr. OZ show!! “All-natural “(Insert disease/condition here)-Be-Gone”- deliberately set up to be a load of crap!!! The Donald says it’s going to be “Yuge”!!!

    1. fajensen says:

      “The Donald ™” as El Presidente, Oprah as Sidekick? Whats not to like?

  2. Mark Thorson says:

    Sure, any one fungus will have a limited repertoire, so the right way to approach this with a whole bunch of fungi and bacteria. That’s what Kombucha is. So co-culture Kombucha with the pathogen you want to defeat. That oughta work. You first.

  3. Mark Thorson says:

    Now that I’ve read the article, this does sound a little scary. This sounds like the sort of work that should be done in a BSL-2 or better laboratory. Also, the possibility of breeding an even more resistant superbug by exposure to these fungal secondary metabolites should be considered. Could the bacteria ride on fungal spores into the air? Probably not, but unless we are certain of that, it must be a BSL-3 or BSL-4 lab.

    1. Mol biologist says:

      Let’s count your coquetry as fear and anxiety are provoked by danger. “Science – it is the habit of thinking”.
      There is a good example of strange interaction which unfortunately was not developed completely but got a lot of attention from NASA. http://www.sciencealert.com/spider-on-drugs
      The question remains open HOW spider did create spiders spun bizarre webs after be exposed to chemicals. What is an algorithm or decoding or how he knows it is different?
      My guess that Tradd Cotter become annoyed by “ Low Probability of Success”. And here it is one (bacteria) is producing chemical another one (fungi) is catching it and translating to his own ‘web design’. The question remains open what is an algorithm? «Aliis si licet, tibi non licet.» or “suum cuique”

  4. passionlessDrone says:

    I’m totally suffering from a condition where I haven’t hallucinated in like a year or more. I think his plan could help.

  5. J Severs says:

    It seems to me that people who like the idea of fungi growing metabolites would also reject the idea as GMO food.

  6. sort_of_knowledgable says:

    From the article
    “Part of this process has been licensed out to Clemson University, where they are better equipped to manage drug-resistant bacteria.”

    So hopefully Clemson is taking the proper precautions. Also the I hope that mammalian cells are part of the culture to screen against all purpose toxins.

  7. sort_of_knowledgable says:

    Aspergillus oryzae has been used for the fermentation of many oriental food products for centuries and is virtually identical genetically to Aspergillus flavus a major food contaminant producing aflatoxin.

    While the long period of domestication has rendered Aspergillus oryzae unlikely to produce aflatoxin in food culture conditions, one wonders if some of Cotter’s fungi with a shorter history of cultivation and challenged by pathogenic organisms might be provoked into producing similar toxins.

  8. Handles says:

    Any fungus that happens to produce ciclosporin or mycophenolic acid is going to be particularly unhelpful against infection.

    1. Pennpenn says:

      Could be useful for other reasons, though.

  9. JAB says:

    Coculture of microbes is a very common approach these days in a lot of microbial labs, so he’s fine on that score. Also, the antibiotic repertoire of actinomycetes, at least (not sure about fungi) IS pretty large. People who have looked find a couple dozen biosynthetic modules in the genomes of each bug, with multiple different structural types in a single organism.

    But as Derek says, using the producing organism in a human just isn’t gonna fly for all of the reasons that he and others have said.

  10. SPQR says:

    It´s a nice concept, but I don´t understand how it would lead to therapeutics that are less vulnerable to resistance. The pathogen will acquire resistance to the fungal antibiotic and the fungus will then evolve a new antibiotic (theoretically), as soon as you isolate the extract from the culture system there is no more adaptabilty.

    Resistance is the final frontier against cancer, parasites or microorganisms. If you could put adaptabilty into a drug it would be pretty cool.

    1. Mol Biologist says:

      There is an example a chess player/vs computer. A human brain can intuitively determine optimal outcomes and how to achieve them or by another words all the time to identify the important from the unimportant, and to separate, but a computer must be systematic in its analysis.
      At the beginning you definitely may rely on yeast as the computer. Once systematic analysis is over and yeast colony survived by acquisition of the resistance. What is next step? Do not lose your logic by fear. Bacteria cannot acquire resistance again because systematic analysis is forbidden and no more co-culturing.
      For my view next step is to separate how acquisition can be aligned with human biology? Yeast has more similarity with human than bacteria.
      Do not mix the resistance with co-culturing. You have to separate it again and understand the meaning of the resistance is different for bacteria vs yeast so they must be treated differently too.

  11. Morten G says:

    Hmm, he’s doing BioAg so why not improve his BioAg business rather than shift it into pharma? No glory in feeding the starving masses any more?

  12. MFernflower says:

    This story reminds me of what Sandor Katz (http://www.wildfermentation.com/) does – He ferments a ton of different foodstuffs with a grab-bag of various fungi and bacteria and then tries the resulting culture broth ON HIMSELF! I cannot tell if we are dealing with a modern day Jonas Salk or if this is the embodiment of the naturalistic fallacy gone horribly wrong.

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