Gut bacteria from amphibians and reptiles achieve tumor elimination in mice (opens in new tab)

The immune system is pretty good too, which means any given improvement to the replication system is, all else being equal, probably going to prevent mutations the T cells would already handle. If you need to do the research to figure out what's getting past the immune system anyways, and improving the immune system is lower hanging fruit, it's the logical place to start.

But there is much more to it. This is a nice paper for an overview: Hallmarks of Cancer (tng) [0]. It (among others) adds the very important and for years underestimated role of the immune system to the original 2000 paper.

[0] https://www.cell.com/fulltext/S0092-8674(11)00127-9

OTOH our L2 isn't that good, mammals in general (with some notable exceptions such as bats, whales and naked mole rats) are prone to cancer in their older age. There probably is a lot of relatively low-hanging fruit there.

If you think about it - individual cells aren't very precious and if some of them gets FUBARed by something (a virus, radiation or chemical insult), it is better to whack it and reuse the proteins to build a new one, if possible, instead of wasting time and resources on reconstruction of a total wreck.

Which also means that some research into replenishment of stem cells is necessary - and this is, IMHO, the really underfunded part of the whole thing. We lose a lot of stem cells as we age. Maybe we don't have to.

Most cell types have systems to safely manage replication. Broadly, there are gas pedals (oncogenes) and brakes (tumor suppressors). A classic oncogene is something like RAS, which activates a signaling cascacde and stimulates progression through the cell cycle. A canonical tumor suppressor is something like TP53, the most frequently mutated gene in cancer, which senses various cellular stresses and induces apoptosis or senescence.

Most cancer genomes are more complicated than individual point mutations (SNPs), insertions, or deletions. There are copy number alterations, where you have > or < 2 copies of a genomic region or chromosome, large scale genomic rearrangements, metabolism changes, and extrachromosomal DNA. There is a series on the hallmarks of cancer which is a useful overview [1].

All of the mechanisms that intrinsically regulate cell growth would fall under your "L1 defense". Unfortunately, the idea of reversing somatic point mutations is likely to be a challenging approach to treating cancer given the current state of technology.

First, for the reasons above, cancer is often multifactorial and it would be difficult to identify a single driver that would effectively cure the disease if corrected. Second, we don't have currently delivery or in vivo base editing technology that is sensitive or specific enough to cure cancer by this means. There are gene therapies like zolgensma[2] which act to introduce a working episomal (not replacing the damaged version in the genome) copy of the gene responsible for SMA. There are also in vivo cell therapies like CAR T which attempt to introduce a transgene that encodes for an anti-cancer effector on T cells. These sorts of approaches may give some insight into the current state of art in this field.

Edit: also I should note that the genes involved in DNA repair (PARP, BRACA1/2, MSH2, MLH1, etc) are frequently mutated in cancers and therapeutically relevant. There are drugs that target them, sometimes rather successfully (e.g. PARP inhibitors). But the mechanisms of action for these therapies are more complicated than outright correcting the somatic mutations.

1. https://aacrjournals.org/cancerdiscovery/article/12/1/31/675... 2. https://en.wikipedia.org/wiki/Onasemnogene_abeparvovec

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.

You are right. There is a very good explanation in this comic https://phdcomics.com/comics.php?f=1162

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.

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/

Also not a doctor or microbiologist, but just wanted to share my layman’s guess on why fixing enzymes will not completely solve the issue: there’s 2 strands of DNA and to fix the broken (mutated) strand you need to have one correct template strand intact so you know what it should be fixed into. It could be the nucleotides swapped places between strands or are deleted completely or otherwise both mutated, which would mean any repair will not revert the sequence to what it used to be.

The other comments so far are probably more informed.

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".

If we had the tools to easily do that we’d practically be gods.

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 wonder if anyone has tried to engineer a mouse that lives forever by applying all these life enhancing mouse therapies at once.

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.

As they say, "the fame of a mathematician is measured by the number of poor papers", because pioneering works are often awkward, treading completely unknown ground. Maybe the same applies to biology sometimes?

I agree with your overall point though; it's a little annoying that every few weeks we hear about a new experiment that seems to indicate that we'll have a radically new and effective form of treatment for cancer only for it to never materialize.

* 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.

As an engineer I think all drugs tested and efficacies studied are on statistically not so significant data points. Given the permutations and combinations far exceed the clinical trials available and hence everything post clinical trial is also just an extended trial.

Wonder How to fix this? I am assuming heLa cells etc are also not the right test setup to have better test results.

> Many tumor types are not PD-l1 positive. > Doxy is an ancient SOC chemo. This is a nothing burger.

Meh the research didn’t say those were state of the art, but that they were “common” treatments. In other words a baseline for a presumably cheap and well studied animal surrogate.

> CAR-T is ahead of the game, and will be the ultimate winner here as it grows to scale.

Last I read up on it last year CAR-T treatments struggled with solid mass tumors.

Many cancers don’t have unique proteins for CAR-T to target (similar to the pd-l1 issue).

Then CAR-T struggles getting the modified T cells into the solid mass tumors en masse. Interestingly this approach actually makes use of the tumor environment rather than be hindered by it.

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)?

Crocodile blood antibiotics hope

Scientists are catching crocodiles and sampling their blood in the hope of finding powerful new drugs to fight human infections.

Even horrific fighting wounds on the animal heal quickly

Murine studies are a dime a dozen and therefore it’s the default assumption when reading research papers. When human trials commence the fact that it’s in humans is a big part of the research and therefore paper titles.

[0] https://xkcd.com/1217/