Now I can't wait for the conspiracy theory types to say this proves reptilian people theories. Lizard people just giving to help us accept them type of stuff, and maybe prove how the ape descendants need the lizard people.
It looks like they screened 45 strains of bacteria to find 9 that passed their safety tests, and then only one of those had a 100-percent response. The sample size is also small: 5/5 sounds a lot less impressive than 100%. I'd expect the true response rate to be substantially lower ("winner's curse").
The bar for an acceptable side effect profile in an FDA-approved drug would also be a lot higher than "five genetically near-identical mice did not show evidence of pathology in a single study."
I'm not saying this work is bad (skimming, it seems fine for what it is, though haven't read in detail), but it's quite preliminary if we're talking about developing a medical treatment that could eventually be deployed in humans. There's a reason it ended up in a mid-tier microbiome journal.
I have been working with my dad on his cancer treatment since last year. My interest in the topic has only peaked ever since.
(Disclaimer- I am an engineer and not a microbiologist/doctor)
Mutations and wrong copying of genome happens all the time in the body and some enzyme has the job of correcting the mutated genes so it doesn’t get into the system. Level 2 defence is T cells killing it as identified as foreign body.
Thing that baffles me is that I see most work happening to eliminate tumor. To me it sounds a tough problem given the permutation and combination of mutation— roughly few trillions.
But I was curious if there is working happening on L1 defence — fixing the enzyme that fixes the wrong copy paste mechanism. Or making the enzyme get more efficient and powerful. Is that line of thought even valid?
I know this is a bit off topic, but have you ever thought about why steroids and other forms of doping are not a free lunch? Why can't we just inject an external chemical to boost our strength for free without any side effects?
If steroids worked, everyone would be constantly injecting them. It would be like drinking coffee.
And that is the reason why steroid injections are harmful. If there is a free lunch, the human body will simply produce the optimal amount of steroids on its own until the Pareto frontier is reached and a tradeoff needs to be made.
Where does the body get the materials to form the steroids? From your diet. So the primary intervention is always a healthy diet and an active lifestyle. You know, the boring things that parents drill into their children.
It's valid but "medicine" that has only upsides and no downsides isn't medicine, it's diet.
> But I was curious if there is working happening on L1 defence — fixing the enzyme that fixes the wrong copy paste mechanism. Or making the enzyme get more efficient and powerful. Is that line of thought even valid?
Mutations in general are not the defining quality of cancer. It's mutations in these very L1 safeguards. There are several such safeguards and a cell needs several mutations in those to become malignant. Eg. https://en.wikipedia.org/wiki/P53
Correcting genes only works in certain conditions (e.g. limited single strand breaks), in a narrow time frame during cell division, safeguards rather trigger cell suicide, or if that fails they mark the cell for destruction by immune cells. A cell can't fix DNA which made it through cell division once, because it got nothing to proof-read against.
After the safeguards are gone, everything goes and genetic diversity increases quickly within each tumor. This diversity is what's making cancer treatment hard. At some point there won't be a shared vulnerability in all malignant cells. The repair mechanisms are working in favor of the cancer now. For example, with radiation therapy you preferably want to induce DNA double strand breaks, because cancer cells can't repair those. Otherwise you need to increase the radical burden enough to overwhelm repair, but migrating radicals may damage distant cells, too.
I presume you could hypothetically inject mRNA of a working safeguard gene (eg. P53) into all cells (at some point cancer cells can't be selected exclusively, since they lost identifying marks and present as stem cells), so the functional enzyme or transcription factor is forced to be built inside. I am sure people are trying this right now. However, the inner workings of cells on a molecular level are insanely complex and our understanding is only scratching the surface. As with P53, you have a transcription factor, which means it's modifying gene expressions elsewhere. It's only a small part of a complex regulatory cascade. I doubt there is a safeguard target, which can easily be injected without considering the precise timing and environment within that safeguard cascade in the cell. Of course, the rest of the safeguard system needs to be present in the cell to begin with. Mind you, you don't want to cause cell suicide in healthy cells, so you want to restore the function of whole selective complex.
Then there is the question of delivery. Can you deliver eg. the mRNA to every cell without raising suspicion of the immune system? With the COVID vaccine, the enabling breakthrough was the delivery vehicle, not as much the mRNA part. Can you even reach the cancer cells at all? Cancer cells are frequently cloaked, shadowed or cut of by senescent, or necrotic cells, or acquired unique ways of metabolic adaptations. A bit similar to bacterial persistence, like M. tuberculosis, which can evade bodily and chemical defenses for decades.
The take-away: Life is complex beyond comprehension! Despite simplifications taught in schools and reductionist zeitgeist, we actually know very, very little about what's going on in genetics and molecular biology, most medical knowledge is empiric guessing instead of explanatory understanding.
I don't know the specifics of efforts to "repair" DNA replication repair (if you get my drift), but I suspect there is some effort in that area.
There definitely are efforts to correct enzymes involved in tumor-suppression (p53 is probably the best known tumor suppressor protein). e.g., here's a study on a small molecule designed to correct mutated p53 https://pmc.ncbi.nlm.nih.gov/articles/PMC8099409/
> fixing the enzyme that fixes the wrong copy paste mechanism
The DNA fidelity issues contribute to only some cancers. Many are caused by mutations due to environmental damage and some are caused by viruses. The point is, there's a huge variety of reasons for developing cancer. So you cover more cases by developing treatments that are more "universal".
While I can't speak to whether there are enzymes for the proper copy/paste I do have a set of random cancer related bits I've picked up over the years.
There are some basic, well-known nutritional interventions that are generally important/critical for DNA repair processes. The 2 main ones are Vitamin D and Magnesium. Ensuring adequate amount of these tend to be helpful (most folks aren't getting enough sun and greens).
Other than that, a steady and adequate source of the substrates seems to be important: ie protein (nitrogen), and phosphates.
One of the interesting bits about some cancer cells is that while they simply haven't gone through apoptosis, physical sheer stress incurred from physical activity (exercise) can cause cancer cells that travel beyond the tumor point (before it becomes metastatic) to finally self destruct.
It seems important to me that the best strategy for cancer is the compounding of many different strategies that optimize the body's innate defenses to run optimally.
It does seem that ketogenic diets may have adjuvant properties, but there is yet to be a clinical trial that demonstrates it, so it's basically stuck in paper and R&D stages as to whether being in a ketogenic state can be one of the last areas that may help cancer patients extend lifetime from say 1 year to 2 years.
Sorry, as someone in this field, this is bullshit. It is in mice.
Several things trigger my bullshit meter. Quote:
"This dramatically surpasses the therapeutic efficacy of current standard treatments, including immune checkpoint inhibitors (anti-PD-L1 antibody) and liposomal doxorubicin (chemotherapy agents)"
PD-L1 monoclonal antibodies are only effective against cancers that are, you guessed it, PD-L1 positive. At high percentages, ranging from 1 to 50%. Are these authors even familiar with the state of the art when it comes to cancer medications? Mouse tumors do not equate to people tumors. Many tumor types are not PD-l1 positive.
Doxy is an ancient SOC chemo.
This is a nothing burger.
Give me phase II/III clinical trials, and then let me know what their PFS/OS was after 5 years. and what the medians were at 3- and 5-years. Also, ORR and CR and needed.
CAR-T is ahead of the game, and will be the ultimate winner here as it grows to scale.
> Sorry, as someone in this field, this is bullshit. It is in mice.
Nice to hear an expert opinion. Let's hope your comment goes back to black. I have a lot of question!
> This is a nothing burger.
Is it enough for a bread-mayo-bread sandwich? Lettuce?
IIUC the bacteria makes the cancer disappear for two weeks, until they end the study and kill the mice. (IIUC this is timeline is usual for very early studies.) They tried other bacterias and one of them made the cancer disappear for a few days, so I'm worried about the long time efficiency of this method.
Is injecting the bacterias a second time as efficient as the first time, or the inmune system kills the bacteria before they hurt the cancer?
What happen in case of metastasis? Each one must be injected with the bacterias or they will jump and make all of them disappear?
Does the bacteria infect other organs and kill you? Is there a good antibiotic in case the bacteria cause problems?
They used cancers that were 200mm3 (i.e. like a sphere of 7mm = 1/4 inch). What happens in bigger cancers? Does bigger cancer have better irrigation and make it more difficult for the bacteria to survive? What happens to tiny hidden metastasis (that probably still have good enough irrigation)?
I have never once seen a promising cancer treatment I've heard of on the news help people. You hear about the breakthrough treatments all the time, but when people get cancer, all you ever hear about is people getting chemotherapy and radiation. Same old scary shit.
Well, I guess Leukemia has been somewhat cured I heard, so that's pretty huge. When I was a kid it was a death sentence IIRC.
* Many breakthroughs from the first research stages never make it into medical application.
* Many breakthroughs are touted as some kind of "novel treatment", but when they get into the hands of the doctor, they talk about it as chemotherapy, because it kills cancer cells. So you might not even notice that you're getting something novel.
* Many breakthroughs take decades until they actually land in mainstream treatment.
* Many breakthroughs are specific to some kinds of cancer.
That said, in most developed countries, survival rates/times for cancer have been steadily improving for decades.
It's a bit like with solar cell and battery tech breakthroughs: you hear about them all the time, but it takes 20 to 30 years until they make it to production. But both have been improving steadily for an impressively long time.
This segment about the mechanism is simple and very profound. I wonder if any cancer researchers here could comment on its universality across various types of cancers:
"Tumor-Specific Accumulation Mechanism
E. americana selectively accumulates in tumor tissues with zero colonization in normal organs. This remarkable tumor specificity arises from multiple synergistic mechanisms:
Hypoxic Environment: The characteristic hypoxia of tumor tissues promotes anaerobic bacterial proliferation
Immunosuppressive Environment: CD47 protein expressed by cancer cells creates local immunosuppression, forming a permissive niche for bacterial survival
Abnormal Vascular Structure: Tumor vessels are leaky, facilitating bacterial extravasation
Metabolic Abnormalities: Tumor-specific metabolites support selective bacterial growth
Excellent Safety Profile
Comprehensive safety evaluation revealed that E. americana demonstrates:
Interesting article, but in the full paper their key figure (Fig 2) shows their treatment group of n=3 mice completely responded to the bacterial treatment, but their methods say they treated n=5 mice? Could be an honest mistake but that’s a little concerning for data manipulation.
Also agree that using a PD-L1 mab feels like it’s for show especially considering the cancer model they’re using (Colon-26) was shown to be substantially less responsive to PD-L1 inhibitors…
Who knows how much knowledge we eradicated due to not bothering with climate change and just letting species go extinct.
Thankfully these were still here for this discovery.
So maybe I am too much a layperson here, but even without any direct therapetutic effects, it is pretty remarkable to have an easily scalable mechanism to get self-replicating agents into tumors, but nowhere else, is it not?
28 comments
[ 4.2 ms ] story [ 49.1 ms ] threadThis sounds like world changing news. Can anyone with domain expertise explain the catch, if any?
The bar for an acceptable side effect profile in an FDA-approved drug would also be a lot higher than "five genetically near-identical mice did not show evidence of pathology in a single study."
I'm not saying this work is bad (skimming, it seems fine for what it is, though haven't read in detail), but it's quite preliminary if we're talking about developing a medical treatment that could eventually be deployed in humans. There's a reason it ended up in a mid-tier microbiome journal.
(Disclaimer- I am an engineer and not a microbiologist/doctor)
Mutations and wrong copying of genome happens all the time in the body and some enzyme has the job of correcting the mutated genes so it doesn’t get into the system. Level 2 defence is T cells killing it as identified as foreign body.
Thing that baffles me is that I see most work happening to eliminate tumor. To me it sounds a tough problem given the permutation and combination of mutation— roughly few trillions.
But I was curious if there is working happening on L1 defence — fixing the enzyme that fixes the wrong copy paste mechanism. Or making the enzyme get more efficient and powerful. Is that line of thought even valid?
If we had the tools to easily do that we’d practically be gods.
If steroids worked, everyone would be constantly injecting them. It would be like drinking coffee.
And that is the reason why steroid injections are harmful. If there is a free lunch, the human body will simply produce the optimal amount of steroids on its own until the Pareto frontier is reached and a tradeoff needs to be made.
Where does the body get the materials to form the steroids? From your diet. So the primary intervention is always a healthy diet and an active lifestyle. You know, the boring things that parents drill into their children.
It's valid but "medicine" that has only upsides and no downsides isn't medicine, it's diet.
You are right. There is a very good explanation in this comic https://phdcomics.com/comics.php?f=1162
Mutations in general are not the defining quality of cancer. It's mutations in these very L1 safeguards. There are several such safeguards and a cell needs several mutations in those to become malignant. Eg. https://en.wikipedia.org/wiki/P53
Correcting genes only works in certain conditions (e.g. limited single strand breaks), in a narrow time frame during cell division, safeguards rather trigger cell suicide, or if that fails they mark the cell for destruction by immune cells. A cell can't fix DNA which made it through cell division once, because it got nothing to proof-read against.
After the safeguards are gone, everything goes and genetic diversity increases quickly within each tumor. This diversity is what's making cancer treatment hard. At some point there won't be a shared vulnerability in all malignant cells. The repair mechanisms are working in favor of the cancer now. For example, with radiation therapy you preferably want to induce DNA double strand breaks, because cancer cells can't repair those. Otherwise you need to increase the radical burden enough to overwhelm repair, but migrating radicals may damage distant cells, too.
I presume you could hypothetically inject mRNA of a working safeguard gene (eg. P53) into all cells (at some point cancer cells can't be selected exclusively, since they lost identifying marks and present as stem cells), so the functional enzyme or transcription factor is forced to be built inside. I am sure people are trying this right now. However, the inner workings of cells on a molecular level are insanely complex and our understanding is only scratching the surface. As with P53, you have a transcription factor, which means it's modifying gene expressions elsewhere. It's only a small part of a complex regulatory cascade. I doubt there is a safeguard target, which can easily be injected without considering the precise timing and environment within that safeguard cascade in the cell. Of course, the rest of the safeguard system needs to be present in the cell to begin with. Mind you, you don't want to cause cell suicide in healthy cells, so you want to restore the function of whole selective complex.
Then there is the question of delivery. Can you deliver eg. the mRNA to every cell without raising suspicion of the immune system? With the COVID vaccine, the enabling breakthrough was the delivery vehicle, not as much the mRNA part. Can you even reach the cancer cells at all? Cancer cells are frequently cloaked, shadowed or cut of by senescent, or necrotic cells, or acquired unique ways of metabolic adaptations. A bit similar to bacterial persistence, like M. tuberculosis, which can evade bodily and chemical defenses for decades.
The take-away: Life is complex beyond comprehension! Despite simplifications taught in schools and reductionist zeitgeist, we actually know very, very little about what's going on in genetics and molecular biology, most medical knowledge is empiric guessing instead of explanatory understanding.
There definitely are efforts to correct enzymes involved in tumor-suppression (p53 is probably the best known tumor suppressor protein). e.g., here's a study on a small molecule designed to correct mutated p53 https://pmc.ncbi.nlm.nih.gov/articles/PMC8099409/
The DNA fidelity issues contribute to only some cancers. Many are caused by mutations due to environmental damage and some are caused by viruses. The point is, there's a huge variety of reasons for developing cancer. So you cover more cases by developing treatments that are more "universal".
There are some basic, well-known nutritional interventions that are generally important/critical for DNA repair processes. The 2 main ones are Vitamin D and Magnesium. Ensuring adequate amount of these tend to be helpful (most folks aren't getting enough sun and greens).
Other than that, a steady and adequate source of the substrates seems to be important: ie protein (nitrogen), and phosphates.
One of the interesting bits about some cancer cells is that while they simply haven't gone through apoptosis, physical sheer stress incurred from physical activity (exercise) can cause cancer cells that travel beyond the tumor point (before it becomes metastatic) to finally self destruct.
It seems important to me that the best strategy for cancer is the compounding of many different strategies that optimize the body's innate defenses to run optimally.
It does seem that ketogenic diets may have adjuvant properties, but there is yet to be a clinical trial that demonstrates it, so it's basically stuck in paper and R&D stages as to whether being in a ketogenic state can be one of the last areas that may help cancer patients extend lifetime from say 1 year to 2 years.
Several things trigger my bullshit meter. Quote:
"This dramatically surpasses the therapeutic efficacy of current standard treatments, including immune checkpoint inhibitors (anti-PD-L1 antibody) and liposomal doxorubicin (chemotherapy agents)"
PD-L1 monoclonal antibodies are only effective against cancers that are, you guessed it, PD-L1 positive. At high percentages, ranging from 1 to 50%. Are these authors even familiar with the state of the art when it comes to cancer medications? Mouse tumors do not equate to people tumors. Many tumor types are not PD-l1 positive.
Doxy is an ancient SOC chemo.
This is a nothing burger.
Give me phase II/III clinical trials, and then let me know what their PFS/OS was after 5 years. and what the medians were at 3- and 5-years. Also, ORR and CR and needed.
CAR-T is ahead of the game, and will be the ultimate winner here as it grows to scale.
Nice to hear an expert opinion. Let's hope your comment goes back to black. I have a lot of question!
> This is a nothing burger.
Is it enough for a bread-mayo-bread sandwich? Lettuce?
IIUC the bacteria makes the cancer disappear for two weeks, until they end the study and kill the mice. (IIUC this is timeline is usual for very early studies.) They tried other bacterias and one of them made the cancer disappear for a few days, so I'm worried about the long time efficiency of this method.
Is injecting the bacterias a second time as efficient as the first time, or the inmune system kills the bacteria before they hurt the cancer?
What happen in case of metastasis? Each one must be injected with the bacterias or they will jump and make all of them disappear?
Does the bacteria infect other organs and kill you? Is there a good antibiotic in case the bacteria cause problems?
They used cancers that were 200mm3 (i.e. like a sphere of 7mm = 1/4 inch). What happens in bigger cancers? Does bigger cancer have better irrigation and make it more difficult for the bacteria to survive? What happens to tiny hidden metastasis (that probably still have good enough irrigation)?
Well, I guess Leukemia has been somewhat cured I heard, so that's pretty huge. When I was a kid it was a death sentence IIRC.
* Many breakthroughs from the first research stages never make it into medical application.
* Many breakthroughs are touted as some kind of "novel treatment", but when they get into the hands of the doctor, they talk about it as chemotherapy, because it kills cancer cells. So you might not even notice that you're getting something novel.
* Many breakthroughs take decades until they actually land in mainstream treatment.
* Many breakthroughs are specific to some kinds of cancer.
That said, in most developed countries, survival rates/times for cancer have been steadily improving for decades.
It's a bit like with solar cell and battery tech breakthroughs: you hear about them all the time, but it takes 20 to 30 years until they make it to production. But both have been improving steadily for an impressively long time.
These are not your parents cancer treatments.
"Tumor-Specific Accumulation Mechanism
E. americana selectively accumulates in tumor tissues with zero colonization in normal organs. This remarkable tumor specificity arises from multiple synergistic mechanisms:
Hypoxic Environment: The characteristic hypoxia of tumor tissues promotes anaerobic bacterial proliferation
Immunosuppressive Environment: CD47 protein expressed by cancer cells creates local immunosuppression, forming a permissive niche for bacterial survival
Abnormal Vascular Structure: Tumor vessels are leaky, facilitating bacterial extravasation
Metabolic Abnormalities: Tumor-specific metabolites support selective bacterial growth
Excellent Safety Profile
Comprehensive safety evaluation revealed that E. americana demonstrates:
Rapid blood clearance (half-life ~1.2 hours, completely undetectable at 24 hours)
Zero bacterial colonization in normal organs including liver, spleen, lung, kidney, and heart
Only transient mild inflammatory responses, normalizing within 72 hours
No chronic toxicity during 60-day extended observation"
Also agree that using a PD-L1 mab feels like it’s for show especially considering the cancer model they’re using (Colon-26) was shown to be substantially less responsive to PD-L1 inhibitors…
Not the world’s best paper imo