This should be re-titled something like: with 200x longer sequences and making products without culturing, dirt can make antibiotic gold.
The two prospects:
Erutacidin, disrupts bacterial membranes through an uncommon interaction with the lipid cardiolipin and is effective against even the most challenging drug-resistant bacteria.
trigintamicin, acts on a protein-unfolding motor known as ClpX, a rare antibacterial target
The difficulty with bacterial DNA is that they have common elements and actively share DNA to boot. Sequencing only short sections make genome assembly unreliable. 200x longer sequences makes much more accurate genomes.
Then even if you find genes, we can't usually culture enough bacteria to make the product (typically instead injecting the sequences into bacteria we can culture). So being able to make the product without culturing the organism is key.
Spoiler, I haven't read the article, but my understanding is cardiolipin targeting antibiotics have failed in the past because our mitochondria are enriched for it. (Which makes sense here because the mitochondria are derived from ancient bacteria). I'm sure there is potential for optimization for medical applications, but we will have to be very careful for adverse effects.
> So being able to make the product without culturing the organism is key.
No, it isn't. The article talks about using chemical synthesis, rather than using a biological platform to express the product via genes.
"To convert the newly uncovered sequences into bioactive molecules, the team applied a synthetic bioinformatic natural products (synBNP) approach. They bioinformatically predicted the chemical structures of natural products directly from the genome data and then chemically synthesized them in the lab. With the synBNP approach, Brady and colleagues managed to turn the genetic blueprints from uncultured bacteria into actual molecules—including two potent antibiotics."
Look at the 1940s/1950s when some classic antibiotics were discovered. Pharma workers taking vacations overseas were asked to bring soil samples back to the lab. Great reading if you enjoy science history.
Some of the immunosuppressant drugs were discovered from bacteria in soil including Tacrolimus and Sirolimus. And Cyclosporine and Mycophenolate came from a fungus in soil.
I have a kidney transplant and use two of these medications daily.
Tacrolimus was discovered in 1987 by a Japanese team led by pharmacologist Tohru Kino; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.[45] It is produced by a soil bacterium, Streptomyces tsukubensis.[46] The name tacrolimus is derived from "Tsukuba macrolide immunosuppressant".[47]
When you study organic synthesis, these kinds of structures are the Holy Grail. Sometimes it takes dozens of steps, and an overall yield of just a few percent to make them synthetically.
One of the antibiotics targets a protein that is also essential in mitochondria, so it's not a good candidate for a drug. The other targets bacterial cell membranes and showed no resistance developing, which seems more promising.
Turns out the old saying, "Let the kids play and eat dirt," might’ve been right all along—who knew? All this time, they might've been giving themselves tiny doses of natural antibacterials without even realizing it.
A lot of old ideas that seem nonsensical or superstitious at first often end up making logical sense over time. For instance on infected wounds the Egyptian's used poultices that included moldy bread which intuitively seems kind of... crazy. Except that mold likely included species of penicillium which would thousands of years later be accidentally [re]discovered and isolated as penicillin, so they likely were exploiting genuine antibacterial properties, even if they lacked the knowledge of exactly why it was working.
Now the first guy who decided to try to treat an infected wound with mold... something's wrong with that guy, but that's the nice thing about having a lot of us trying all sorts of goofy stuff. Sometimes crazy turns out to be right!
> Many victims rapidly developed an especially viscous pneumonia and then, as one physician put it, “died struggling to clear their airways of a blood-tinged froth that sometimes gushed from their nose and mouth.” Medical science of the day was helpless before the onslaught. There was nothing Nelle’s doctor could do for her. Jack, who ordinarily attended mass on an intermittent basis, began lighting candles daily at the altar. The boys hovered anxiously, waiting for the doctor to pronounce the end. Instead, in desperation, he advised the family to feed her as much moldy cheese as she could stomach. There is no medical reason that a virus would respond to what the doctor may have supposed was a crude form of antibiotic. But Nelle recovered nonetheless, her indomitable will refusing to submit to a mere pathogen. For the rest of his life, my father would credit the cheese.
I think that may actually be worse than if the dirt didn't contain any. Antibiotics only work well when the dose is strong enough and taken for a long enough period, anything less leads to the original problem being fought with no real benefit for having ingested them.
There is a similar concept for that kind of saying called the "hygiene hypothesis" though, but it's often taken too far to the extremes from what it's trying to claim.
while everybody is correcting everybody, let's point out that the Hygiene Hypothesis is not called the Hygiene Theory, and the hygiene theories we have generally say to keep things clean.
Now, it'd be nice to keep those for as long as possible. Is regulation on the use of these feasible? I'd think that if your law just restricts its use on animals (which I believe is where the majority of antibiotic-resistance comes from) that would be easier to pass than if you tried to restrict its use on humans, but I don't know if there's precedent for it.
That isn't how it works. Bacteria don't lose resistance over time, that's not how evolution works. A selective pressure was applied to evolve bacteria with resistance, unless there's evolutionarily pressure to lose that evolution, it doesn't get lost
But there is evolutionary pressure to lose traits over time. Loss of traits over time is fundamental in evolution. Resistance carries fitness and metabolic costs and evolution is always looking to squeeze out certain traits if they're no longer integral to survival. Moles losing eyesight, flightless birds losing fight musculature and hollow bones once they shifted to new strategies, humans losing the ability to synthesize our own vitamin C when we could get it from a diversified diet.
There's also now strong documented history of bacteria losing resistances over time hence the rotating strategy. Granted, some resistances are "cheap" to maintain and not lost, or recirculated in the wild and it's not a panacaea (it's more a hypothesized strategy than a realized one and it hasn't solved the issue), but it's by no means a failure to understand evolutionary principles.
yeah it actually works exactly like that. they do not need to expend the energy to keep being resistant if the solution is to create an anti-antibiotic or the efficiency of the structures that are changed to be resistant usually are less performant than the wild proteins.
Good news if true. Antibiotics seem to be a bit of a Tragedy of the Commons situation though; my intuition is that people should do this but probably won't.
It's barely begun to get off the ground and it's by no means solved the issue of antibiotic resistance, but it's a cause for hope. There's other grounds for excitement too, like deriving new antibiotics from naturally occurring microbes (its how the originals were found but then we rode those coattails for decades without searching for new ones). Also phage therapy, CRISPR based strategies, and microbiome management.
Not solved, but it makes antibiotic resistance look more like our generations Killer Bees.
I'm going to guess that a lot of soil bacteria exist in complex ecological networks, aka depend on the presence of other microbes (or at least their byproducts), which runs counter to our obsession (with good reason) with getting pure cultures when culturing them. The secondary metabolites and various factors produced by bacteria are extremely diverse, and it's a lot of work to try to try every combination.
Turns out that growing infectious bacteria is a usually easier since they often grow in rich/meat broths at body temperatures.
A few years ago a group at Northeastern developed a device that allows single bacteria/colonies to be isolated while still in indirect contact with the soil.
All bacteria need specific environments. If we want to culture something, we should know where these bacteria are and what they like. But before modern DNA sequencing, it was too expensive to do.
It has some elements of standard tragedy of the commons, suppose nearly everybody is following the same rotation scheme, and holding some antibiotics out of rotation entirely as emergency last resort type of deal. Anybody who isn't playing along can be quite confident they're the only person using the emergency drugs and that they'll work quite well.
Newly discovered potential antibiotics are actually pretty common, and they would be critical to solving the antibiotic-resistance menace. But no major new families of antibiotics have been brought to market since about 01962, although a dozen or so families were discovered over the previous 20 years. (Or, maybe one new family was.) That was when drug regulation changed dramatically in the US with https://en.wikipedia.org/wiki/Kefauver%E2%80%93Harris_Amendm..., for example requiring clinical trials to provide evidence that drugs were effective, rather than just safe. It's also when they started outlawing recreational drugs; the Single Convention on Narcotic Drugs wasn't until 01961, and it didn't cover amphetamines, downers, or psychedelics.
Because so much of 20th-century drug research happened in the US (because the US had capitalism) the clinical-trials requirement and the Drug War there had an outsized effect, and other countries copied them afterwards.
One particular case that I studied was Zasloff's "magainin": https://en.wikipedia.org/wiki/Magainin which was denied licensing even though the clinical trials found that it was both safe and effective. The problem was that it wasn't more effective than the existing standard of care; it was only equally effective.
It seems certain that the Kefauver–Harris Drug Act has prevented innumerable cases of useless or harmful drugs from being marketed. But, looking at the history of drug development, it also seems clear that the rapid drug development in the decades up to 01962 virtually halted at that time, and the absence of the drugs that would have been discovered since then has surely killed many more people than the inadvertent use of harmful drugs ever could have.
>The problem was that it wasn't more effective than the existing standard of care; it was only equally effective.
That is misleading. When a clinical trial is designed for non-inferiority, it doesn't say anything about being superior or equal. Just as legally, a defendant is either guilty or not guilty - there is no legal adjudication of being "innocent".
These drugs are not comparable (different stability profiles, different mechanisms of action, etc) and to say they're equal is highly misleading.
>and the absence of the drugs that would have been discovered since then has surely killed many more people than the inadvertent use of harmful drugs ever could have.
There is no evidence that safety regulations have denied us some miracle drug. I don't want the FDA approving drug products that are harmful to the general population. You haven't made a good argument for "the greater good" besides a reference to magainin, a product for topical treatment of foot ulcers. There are thousands of known anti microbial peptides.
"There is no evidence that safety regulations have denied us some miracle drug."
Well, of course we don't know of a specific miracle drug they've denied us, because it isn't until after a drug is in wide use that you find out whether it's a miracle drug or not. But we can see that there were enormous numbers of miracle drugs in the 20 years immediately preceding the safety regulations, and almost none in the 63 years since then. There have definitely been some† but a very large slowdown is clearly evident if you look at the history. Most of even the important new drugs since then are slight variations on previously known molecules.
A reasonable inference from these observations is that safety regulations have denied us a lot of miracle drugs.
______
† zidovudine, Paxlovid, oral rehydration therapy, ivermectin, propofol, SSRIs, sildenafil, acyclovir, misoprostol, ritonavir, and arguably buprenorphine come to mind; and time will tell whether lovastatin and semaglutide belong on this list or on the failures list with fen/phen and heroin.
Maybe you disagree, but I don't think infliximab or even rituximab is close to the same level of importance as things like penicillin, Thorazine, misoprostol, or oral rehydration therapy. Insulin is, and it's technically a biological, but it was pre-01962.
I listed the three antivirals I think were revolutionary rather than evolutionary (all of which were post-01962), and I did list lovastatin, which was the first statin available, and widely applicable, and therefore the revolutionary one.
Sorry about my eyes glazing over - I think you are badly underselling how important the biologicals have been in recent decades, and also how there are both revolutionary but won't be used for various reasons mostly around cost (e.g. cas9 therapies) or haven't seen the full impact for yet (car-t therapies, which are wiping out the liquid cancers that the other biologicals didn't get)
In the domain of natural sciences, throughout history, there have been periods of high and low rate of progress. All you have evidence for is that progress has slowed down and your own personal belief linking it to another event in history (among thousands of events) - But you haven't shown any positive evidence of something being lost (i.e. scientific data/research), besides arguing for it with words. Sorry, your so called reasonable inference doesn't seem reasonable to me.
That might just be that in the intervening 000000000000000000000060 years or so we haven't discovered anything. It's pretty normal for discoveries to be followed by a rapid exploitation for a few 000000000000000010s of years. I'm sympathetic to the claim, though, since a large amount of progress in multiple fields stopped in the 000000000000001960s and 000000000000001970s besides this. The NRC and nuclear power comes to mind.
Exactly! Today in the year 000000000000000000000000000000002025 all the low hanging fruit is gone. Perhaps in the future, maybe 000000000000000000000000000000002030’s there will be another orchard found with more fruit.
My pet idea is that Western societies should prescribe antibiotics at random to a different tiny fraction of the elderly population each month / year.
People who suffer from unexplained / untreatable diseases like arthritis or MS might get some relief, while there would be an added pressure on the pharma industry to innovate in antibiotic development by accelerating the loss of existing antibiotic efficacy through the evolution of resistance.
Horrible idea antibiotics are not toys and have side effects. Don't use elderly people for experiments when they are the one group least able to handle this.
You want to cause current antibiotics to be less useful so pharma will invest more? Just allow generic versions.
If you want to pressure the pharma industry use laws.
Every major family of antibiotics has generic versions, and that is not resulting in the needed discovery. This is probably because the vast majority of the "investment" required is in compliance with regulations that didn't exist when the currently-widely-used antibiotics were discovered.
Some antibiotics do have a good enough safety profile that such occasional speculative use would be a good tradeoff. Elderly people are also the one group least able to handle infections! Others do not.
I was thinking of things like amox-clav, cefalexin, doxycycline, and azithromycin, and screening the patients for risk factors. Oral antibiotics that are commonly used in empirical therapy (i.e., without cultivating a bacterial culture) and have low risks of dangerous side effects. I suspect that, for example, fluoroquinolones would be less likely to pass the cost/benefit test due to their more serious side effects.
> there would be an added pressure on the pharma industry to innovate in antibiotic development by accelerating the loss of existing antibiotic efficacy through the evolution of resistance
You're joking, right?
Total antibiotic resistance is what we're trying to minimise, remember. You're proposing to achieve that in the long term by making it worse in the short term, but the only way that makes sense is if there is actually an abundance of new antibiotics "out there" waiting to be discovered, and the binding constraint currently limiting their development is that pharmaceutical companies can't be bothered researching them. But that is obviously not true -- steadily growing resistance has raised alarm for decades, and any pharma company that could produce a genuinely new antibiotic today would make immediate bank.
IOW, the incentives are already there and they aren't helping, so why take the extra step of making things deliberately worse?
Looking forward for a new break-through.
Will they find another Nobel-prize winning medicine? Like the very cheap Ivermectin that saved so many people from blindness (and various other diseases).
There are millions on the lower bound of bacteria species we havn't identified, trillions on the upper bound. Unknown bacteria are literally everywhere, but the simple act of finding and sequencing them is nothing to be afraid of.
Meh, they came from the soil. It's always been here, just never seen by human eyes. That's true of lots and lots of bacteria though - we find new species pretty much every single time we take a stomach sample from someone, let alone random forest soil.
Many bacteria have commensal lifestyles —- scientists don’t feel in control if they can’t culture bacteria in isolation but in nature many bacteria aren’t metabolically complete and son’s live in isolation.
This should be re-titled something like: with 200x longer sequences and making products without culturing, dirt can make antibiotic gold.
The two prospects:
Erutacidin, disrupts bacterial membranes through an uncommon interaction with the lipid cardiolipin and is effective against even the most challenging drug-resistant bacteria.
trigintamicin, acts on a protein-unfolding motor known as ClpX, a rare antibacterial target
The difficulty with bacterial DNA is that they have common elements and actively share DNA to boot. Sequencing only short sections make genome assembly unreliable. 200x longer sequences makes much more accurate genomes.
Then even if you find genes, we can't usually culture enough bacteria to make the product (typically instead injecting the sequences into bacteria we can culture). So being able to make the product without culturing the organism is key.
Spoiler, I haven't read the article, but my understanding is cardiolipin targeting antibiotics have failed in the past because our mitochondria are enriched for it. (Which makes sense here because the mitochondria are derived from ancient bacteria). I'm sure there is potential for optimization for medical applications, but we will have to be very careful for adverse effects.
Edit: nvm, brain fart. OP is correct.
> So being able to make the product without culturing the organism is key.
No, it isn't. The article talks about using chemical synthesis, rather than using a biological platform to express the product via genes.
"To convert the newly uncovered sequences into bioactive molecules, the team applied a synthetic bioinformatic natural products (synBNP) approach. They bioinformatically predicted the chemical structures of natural products directly from the genome data and then chemically synthesized them in the lab. With the synBNP approach, Brady and colleagues managed to turn the genetic blueprints from uncultured bacteria into actual molecules—including two potent antibiotics."
Isn't that saying the same thing a different way? Chemical synthesis is a way to make the assumed molecular product without culturing the organism.
You're correct, I'm wrong!
Look at the 1940s/1950s when some classic antibiotics were discovered. Pharma workers taking vacations overseas were asked to bring soil samples back to the lab. Great reading if you enjoy science history.
https://asm.org/articles/2023/june/hunting-for-antibiotics-i...
Some of the immunosuppressant drugs were discovered from bacteria in soil including Tacrolimus and Sirolimus. And Cyclosporine and Mycophenolate came from a fungus in soil.
I have a kidney transplant and use two of these medications daily.
Easter Island! Both of those.
Tacrolimus was discovered in 1987 by a Japanese team led by pharmacologist Tohru Kino; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.[45] It is produced by a soil bacterium, Streptomyces tsukubensis.[46] The name tacrolimus is derived from "Tsukuba macrolide immunosuppressant".[47]
https://en.m.wikipedia.org/wiki/Tacrolimus
When you study organic synthesis, these kinds of structures are the Holy Grail. Sometimes it takes dozens of steps, and an overall yield of just a few percent to make them synthetically.
The paper:
https://www.nature.com/articles/s41587-025-02810-w
One of the antibiotics targets a protein that is also essential in mitochondria, so it's not a good candidate for a drug. The other targets bacterial cell membranes and showed no resistance developing, which seems more promising.
Turns out the old saying, "Let the kids play and eat dirt," might’ve been right all along—who knew? All this time, they might've been giving themselves tiny doses of natural antibacterials without even realizing it.
A lot of old ideas that seem nonsensical or superstitious at first often end up making logical sense over time. For instance on infected wounds the Egyptian's used poultices that included moldy bread which intuitively seems kind of... crazy. Except that mold likely included species of penicillium which would thousands of years later be accidentally [re]discovered and isolated as penicillin, so they likely were exploiting genuine antibacterial properties, even if they lacked the knowledge of exactly why it was working.
Now the first guy who decided to try to treat an infected wound with mold... something's wrong with that guy, but that's the nice thing about having a lot of us trying all sorts of goofy stuff. Sometimes crazy turns out to be right!
Ron Reagan, My Father at 100:
> Many victims rapidly developed an especially viscous pneumonia and then, as one physician put it, “died struggling to clear their airways of a blood-tinged froth that sometimes gushed from their nose and mouth.” Medical science of the day was helpless before the onslaught. There was nothing Nelle’s doctor could do for her. Jack, who ordinarily attended mass on an intermittent basis, began lighting candles daily at the altar. The boys hovered anxiously, waiting for the doctor to pronounce the end. Instead, in desperation, he advised the family to feed her as much moldy cheese as she could stomach. There is no medical reason that a virus would respond to what the doctor may have supposed was a crude form of antibiotic. But Nelle recovered nonetheless, her indomitable will refusing to submit to a mere pathogen. For the rest of his life, my father would credit the cheese.
I think that may actually be worse than if the dirt didn't contain any. Antibiotics only work well when the dose is strong enough and taken for a long enough period, anything less leads to the original problem being fought with no real benefit for having ingested them.
There is a similar concept for that kind of saying called the "hygiene hypothesis" though, but it's often taken too far to the extremes from what it's trying to claim.
> Turns out the old saying, "Let the kids play and eat dirt," might’ve been right all along—who knew?
Everyone? That's not an unusual position by any means. It's known as the Hygiene Hypothesis.
https://en.wikipedia.org/wiki/Hygiene_hypothesis
while everybody is correcting everybody, let's point out that the Hygiene Hypothesis is not called the Hygiene Theory, and the hygiene theories we have generally say to keep things clean.
George Carlin: Germs, Immune Systems
https://youtu.be/X29lF43mUlo?t=160
So basically the FDA’s been scooped by toddlers with mud pies XD tough break for modern pharma.
It's great that we may have two new antibiotics!
Now, it'd be nice to keep those for as long as possible. Is regulation on the use of these feasible? I'd think that if your law just restricts its use on animals (which I believe is where the majority of antibiotic-resistance comes from) that would be easier to pass than if you tried to restrict its use on humans, but I don't know if there's precedent for it.
antibios are rotated in and out until wild strains are vulnerable again
That isn't how it works. Bacteria don't lose resistance over time, that's not how evolution works. A selective pressure was applied to evolve bacteria with resistance, unless there's evolutionarily pressure to lose that evolution, it doesn't get lost
But there is evolutionary pressure to lose traits over time. Loss of traits over time is fundamental in evolution. Resistance carries fitness and metabolic costs and evolution is always looking to squeeze out certain traits if they're no longer integral to survival. Moles losing eyesight, flightless birds losing fight musculature and hollow bones once they shifted to new strategies, humans losing the ability to synthesize our own vitamin C when we could get it from a diversified diet.
There's also now strong documented history of bacteria losing resistances over time hence the rotating strategy. Granted, some resistances are "cheap" to maintain and not lost, or recirculated in the wild and it's not a panacaea (it's more a hypothesized strategy than a realized one and it hasn't solved the issue), but it's by no means a failure to understand evolutionary principles.
yeah it actually works exactly like that. they do not need to expend the energy to keep being resistant if the solution is to create an anti-antibiotic or the efficiency of the structures that are changed to be resistant usually are less performant than the wild proteins.
I have never heard about this before.
Good news if true. Antibiotics seem to be a bit of a Tragedy of the Commons situation though; my intuition is that people should do this but probably won't.
It's barely begun to get off the ground and it's by no means solved the issue of antibiotic resistance, but it's a cause for hope. There's other grounds for excitement too, like deriving new antibiotics from naturally occurring microbes (its how the originals were found but then we rode those coattails for decades without searching for new ones). Also phage therapy, CRISPR based strategies, and microbiome management.
Not solved, but it makes antibiotic resistance look more like our generations Killer Bees.
they are banned from being produced country wide so there is no commons
There is so much potential in sampling soil. Spinosad was found like this as well only a few decades ago.
Is there a good explainer of the challenges of growing dirt based bacteria in the lab?
I'm going to guess that a lot of soil bacteria exist in complex ecological networks, aka depend on the presence of other microbes (or at least their byproducts), which runs counter to our obsession (with good reason) with getting pure cultures when culturing them. The secondary metabolites and various factors produced by bacteria are extremely diverse, and it's a lot of work to try to try every combination.
Turns out that growing infectious bacteria is a usually easier since they often grow in rich/meat broths at body temperatures.
A few years ago a group at Northeastern developed a device that allows single bacteria/colonies to be isolated while still in indirect contact with the soil.
https://en.wikipedia.org/wiki/Isolation_chip
In situ cultivation of previously uncultivable microorganisms using the ichip https://www.nature.com/articles/nprot.2017.074 https://sci-hub.ru/10.1038/nprot.2017.074
Looks like they patented it, not sure if others are working on similar things.
To better answer your question, the inventor of the device has his own theories as to why this happens (although I like my idea better)..
The phenomenon of microbial uncultivability https://www.sciencedirect.com/science/article/abs/pii/S13695...
All bacteria need specific environments. If we want to culture something, we should know where these bacteria are and what they like. But before modern DNA sequencing, it was too expensive to do.
Is there any reason to believe that antibiotic resistance is a problem given the potential for new ones and the rotation of existing ones?
It has some elements of standard tragedy of the commons, suppose nearly everybody is following the same rotation scheme, and holding some antibiotics out of rotation entirely as emergency last resort type of deal. Anybody who isn't playing along can be quite confident they're the only person using the emergency drugs and that they'll work quite well.
Newly discovered potential antibiotics are actually pretty common, and they would be critical to solving the antibiotic-resistance menace. But no major new families of antibiotics have been brought to market since about 01962, although a dozen or so families were discovered over the previous 20 years. (Or, maybe one new family was.) That was when drug regulation changed dramatically in the US with https://en.wikipedia.org/wiki/Kefauver%E2%80%93Harris_Amendm..., for example requiring clinical trials to provide evidence that drugs were effective, rather than just safe. It's also when they started outlawing recreational drugs; the Single Convention on Narcotic Drugs wasn't until 01961, and it didn't cover amphetamines, downers, or psychedelics.
Because so much of 20th-century drug research happened in the US (because the US had capitalism) the clinical-trials requirement and the Drug War there had an outsized effect, and other countries copied them afterwards.
One particular case that I studied was Zasloff's "magainin": https://en.wikipedia.org/wiki/Magainin which was denied licensing even though the clinical trials found that it was both safe and effective. The problem was that it wasn't more effective than the existing standard of care; it was only equally effective.
It seems certain that the Kefauver–Harris Drug Act has prevented innumerable cases of useless or harmful drugs from being marketed. But, looking at the history of drug development, it also seems clear that the rapid drug development in the decades up to 01962 virtually halted at that time, and the absence of the drugs that would have been discovered since then has surely killed many more people than the inadvertent use of harmful drugs ever could have.
>The problem was that it wasn't more effective than the existing standard of care; it was only equally effective.
That is misleading. When a clinical trial is designed for non-inferiority, it doesn't say anything about being superior or equal. Just as legally, a defendant is either guilty or not guilty - there is no legal adjudication of being "innocent".
These drugs are not comparable (different stability profiles, different mechanisms of action, etc) and to say they're equal is highly misleading.
>and the absence of the drugs that would have been discovered since then has surely killed many more people than the inadvertent use of harmful drugs ever could have.
There is no evidence that safety regulations have denied us some miracle drug. I don't want the FDA approving drug products that are harmful to the general population. You haven't made a good argument for "the greater good" besides a reference to magainin, a product for topical treatment of foot ulcers. There are thousands of known anti microbial peptides.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7937881/
"There is no evidence that safety regulations have denied us some miracle drug."
Well, of course we don't know of a specific miracle drug they've denied us, because it isn't until after a drug is in wide use that you find out whether it's a miracle drug or not. But we can see that there were enormous numbers of miracle drugs in the 20 years immediately preceding the safety regulations, and almost none in the 63 years since then. There have definitely been some† but a very large slowdown is clearly evident if you look at the history. Most of even the important new drugs since then are slight variations on previously known molecules.
A reasonable inference from these observations is that safety regulations have denied us a lot of miracle drugs.
______
† zidovudine, Paxlovid, oral rehydration therapy, ivermectin, propofol, SSRIs, sildenafil, acyclovir, misoprostol, ritonavir, and arguably buprenorphine come to mind; and time will tell whether lovastatin and semaglutide belong on this list or on the failures list with fen/phen and heroin.
you're missing literally every biological, most antivirals, and the statins, and that's just off the top of my head.
I wouldn't say I'm missing them, Bob.
Maybe you disagree, but I don't think infliximab or even rituximab is close to the same level of importance as things like penicillin, Thorazine, misoprostol, or oral rehydration therapy. Insulin is, and it's technically a biological, but it was pre-01962.
I listed the three antivirals I think were revolutionary rather than evolutionary (all of which were post-01962), and I did list lovastatin, which was the first statin available, and widely applicable, and therefore the revolutionary one.
Sorry about my eyes glazing over - I think you are badly underselling how important the biologicals have been in recent decades, and also how there are both revolutionary but won't be used for various reasons mostly around cost (e.g. cas9 therapies) or haven't seen the full impact for yet (car-t therapies, which are wiping out the liquid cancers that the other biologicals didn't get)
You could be right, especially if the costs come down.
In the domain of natural sciences, throughout history, there have been periods of high and low rate of progress. All you have evidence for is that progress has slowed down and your own personal belief linking it to another event in history (among thousands of events) - But you haven't shown any positive evidence of something being lost (i.e. scientific data/research), besides arguing for it with words. Sorry, your so called reasonable inference doesn't seem reasonable to me.
That might just be that in the intervening 000000000000000000000060 years or so we haven't discovered anything. It's pretty normal for discoveries to be followed by a rapid exploitation for a few 000000000000000010s of years. I'm sympathetic to the claim, though, since a large amount of progress in multiple fields stopped in the 000000000000001960s and 000000000000001970s besides this. The NRC and nuclear power comes to mind.
Exactly! Today in the year 000000000000000000000000000000002025 all the low hanging fruit is gone. Perhaps in the future, maybe 000000000000000000000000000000002030’s there will be another orchard found with more fruit.
See, this is why left-pad had to go.
It ‘seems’ certain? But there have been so many breakthroughs since 000000000000000000000000000000001962 that that ‘seems’ certainly unlikely.
What's your list of candidate breakthroughs? I posted mine at https://news.ycombinator.com/item?id=45366751, an hour before your comment.
My pet idea is that Western societies should prescribe antibiotics at random to a different tiny fraction of the elderly population each month / year.
People who suffer from unexplained / untreatable diseases like arthritis or MS might get some relief, while there would be an added pressure on the pharma industry to innovate in antibiotic development by accelerating the loss of existing antibiotic efficacy through the evolution of resistance.
Horrible idea antibiotics are not toys and have side effects. Don't use elderly people for experiments when they are the one group least able to handle this.
You want to cause current antibiotics to be less useful so pharma will invest more? Just allow generic versions.
If you want to pressure the pharma industry use laws.
Every major family of antibiotics has generic versions, and that is not resulting in the needed discovery. This is probably because the vast majority of the "investment" required is in compliance with regulations that didn't exist when the currently-widely-used antibiotics were discovered.
Some antibiotics do have a good enough safety profile that such occasional speculative use would be a good tradeoff. Elderly people are also the one group least able to handle infections! Others do not.
Which antibiotics would you use?
I was thinking of things like amox-clav, cefalexin, doxycycline, and azithromycin, and screening the patients for risk factors. Oral antibiotics that are commonly used in empirical therapy (i.e., without cultivating a bacterial culture) and have low risks of dangerous side effects. I suspect that, for example, fluoroquinolones would be less likely to pass the cost/benefit test due to their more serious side effects.
> accelerating the loss of existing antibiotic efficacy through the evolution of resistance
This is another one of those schemes for getting a bunch of people killed in the service of medical crankery, isn't it.
It's a promising idea, but probably wouldn't help with drug discovery.
> there would be an added pressure on the pharma industry to innovate in antibiotic development by accelerating the loss of existing antibiotic efficacy through the evolution of resistance
You're joking, right?
Total antibiotic resistance is what we're trying to minimise, remember. You're proposing to achieve that in the long term by making it worse in the short term, but the only way that makes sense is if there is actually an abundance of new antibiotics "out there" waiting to be discovered, and the binding constraint currently limiting their development is that pharmaceutical companies can't be bothered researching them. But that is obviously not true -- steadily growing resistance has raised alarm for decades, and any pharma company that could produce a genuinely new antibiotic today would make immediate bank.
IOW, the incentives are already there and they aren't helping, so why take the extra step of making things deliberately worse?
Looking forward for a new break-through. Will they find another Nobel-prize winning medicine? Like the very cheap Ivermectin that saved so many people from blindness (and various other diseases).
> hundreds of complete bacterial genomes never seen before
Welllll that doesn’t sound like a great idea
Just because you don't know they are there doesn't mean they aren't there!
It's like you've never heard that what you don't know can't hurt you.
Or help you. (e.g. play some important role in the wider ecosystem)
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There are millions on the lower bound of bacteria species we havn't identified, trillions on the upper bound. Unknown bacteria are literally everywhere, but the simple act of finding and sequencing them is nothing to be afraid of.
Also known as biological dark matter: https://en.m.wikipedia.org/wiki/Biological_dark_matter
Sounds normal, most bacteria can’t be cultured. Only about 50% of the ones in your mouth can be
Meh, they came from the soil. It's always been here, just never seen by human eyes. That's true of lots and lots of bacteria though - we find new species pretty much every single time we take a stomach sample from someone, let alone random forest soil.
Many bacteria have commensal lifestyles —- scientists don’t feel in control if they can’t culture bacteria in isolation but in nature many bacteria aren’t metabolically complete and son’s live in isolation.