[kinj28]

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?

[jjk166]

Our L1 defense is actually incredibly good. A human will undergo about 10^16 cell divisions over the course of their lifetime. Around 10^3 to 10^6 of those divisions will result in a mutation that gets past the L1 defenses and need to be eliminated by the T cells. It's not generally easy to make dramatic improvements to something with a 99.9999999% success rate.

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.

[top_sigrid]

Thanks for these insights! Do you have any material or sources for a layman to learn more about this and where these numbers come from?

[littlestymaar]

Aren't the elephants and whales orders of magnitude better than us at that though (they have roughly as many cancer as we do, but with respectively x100 and x1000 times as many cells.

Or is it the second layer that works better for them?

[jjk166]

Different species do have different levels of protection, and different lineages tend to employ different methods of protection. For example elephants have numerous duplicates of cancer suppression genes, whereas naked mole rats produce a variant of hyaluronan which prevents tumor formation. When compared to other great apes, Humans seem to be worse at both layers of defense.

It's worth noting though that humans also have much higher levels of exposure to many carcinogens than most animals, and we screen for cancers at a much greater rate for humans, so just because a species has lower cancer rates doesn't necessarily mean their cancer defenses are better.

[vibrio]

also, Elephants have a much higher copy number of a gene called p53/ It codes a protein that acts to force suicide in cells that have damaged DNA (think from UV light, cigarette smoke, age, etc). In cancer this is a common 'early' mutation that allows collection of further mutation and progession towards cancer. In having many more copies of p53, it makes it less likely the p53 function will be eliminated

[cassepipe]

I am not sure how much consensus there is around it but this is so cool I have to repeat it sorry: Whales and elephants do develop cancers but since those cancers also have mutations, well their cancers have cancers and overall the cancers are never able to grow big enough to threaten the whole organism.

Too big to fail basically

[jjk166]

The idea that tumors develop their own tumors, suppressing cancer is known as the Hypertumor Hypothesis and, while it works in computer models, there isn't actually any evidence backing it up.

The hypothesis doesn't really resolve Peto's paradox, the observation that cancer rates don't scale directly with the number of cells in an organism. Not only do large organisms like whales get fewer cancers per cell division, small animals like mice get more cancers per cell division, which can not really be explained by a threshold beyond which hypertumors suppress tumors. The actual evidence suggests organisms just evolve whatever level of cancer resistance they need to have low odds of dying of cancer before something else kills them.

That being said, the main observation underpinning Peto's paradox was actually just due to lack of good data. Over the years much more data has been collected from animal autopsies and it turns out that big animals do get cancer and cancer rates actually do scale with body size, just different species have varying levels of cancer protection, with the levels of protection being similar in closely related species of different sizes.

[comp_bio]

This is a fascinating niche of evolutionary biology that I have worked in for a while. The short answer is that yes, as far as we can tell all organisms evolve increasingly more efficient replication machinery, however at some point the strength of selection is no longer powerful enough to overcome the strength of genetic drift and some degree of error rate persists. As far as we can tell it seems like population size governs where this balance ends up such that small populations have high mutation rates and large populations have reduced mutation rates. Michael Lynch coined the term drift barrier hypothesis to describe this phenomenon. https://pubmed.ncbi.nlm.nih.gov/23077252/

[ajuc]

If the organism is too efficient at preventing mutations - it would evolve slower, right?

[mfld]

Yes, but note the mutation rate of germline cells - that are passed to your offspring and hence influence evolution - is estimated to be two orders of magnitude lower than other (somatic) cells.

[gavinrees]

Not necessarily if it had recombination (as in sexual reproduction), but as far as I understand, yes, you’d probably get fewer novel alleles/coding sequences of DNA generated per organism replication

[teekert]

It starts with mutations (sometimes accelerated by mutagens (smoke, alcohol, etc) or inflammation (viruses, infections, etc) or just chance (things like asbestos up the division rate by constant physical damage and thus up the probability or an error in copying).

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

[allie1]

Would sports also increase the rate of division? Bodybuilding for example you intentionally make micro tears in muscles to get them to repair and grow (lay person, apologies for the mistakes)

[adrian_b]

The problem is that many things that reduce the probability of cancer increase the probability of other diseases.

Therefore there is no good solution for this.

For instance, some studies have demonstrated that certain kinds of malnutrition, i.e. the consumption of inadequate amounts of protein and/or with bad amino-acid profile, inhibited the development of tumors caused by carcinogen agents (in rats and mice). This was not really surprising, because tumors grow faster than the rest of the body so they need to synthesize more proteins. If they are starved, they grow slowly and the immune system has time to react and to eliminate the incipient tumors early enough.

Despite this, starving yourself in the hope to avoid cancer would be a very bad idea. While the probability of cancer is lowered, the probabilities of low resistance to infectious diseases or of muscular weakness leading to falling and breaking some limb, or of cardio-vascular diseases, become higher.

[teekert]

Hmm, I'm a molecular biologist, not an expert at this particularly, what I do know is that damage of muscle fiber may not be necessarily mean new cell growth and thus extra DNA replication. The growth of the muscle cell certainly does.

Exercise is good for the immune system, this helps clear cancer, helps stay away from inflammation (ie auto-immune diseases). Where as a sedentary life style a poor diet will promote this.

But indeed for some things/behaviors, the relation the cancer may be complex.

[inglor_cz]

L2 is being prioritized because our L1 defences are already very good. We are a long-lived species, and our natural ability to fix errors is so good that it is hard to improve upon. Maybe the long-lived tortoises or whales can do it better, maybe. But we have "several nines of reliability" there.

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.

[biotechbio]

While cancer is caused by mutations in the genome, these mutations in turn produce the unifying property of cancer: unchecked cell replication.

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

[itchyouch]

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.

[gus_massa]

> To me it sounds a tough problem given the permutation and combination of mutation— roughly few trillions.

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

[imtringued]

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.

[busyant]

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/

[yes_man]

Cancer sucks and I wish your father the best.

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.

[mechsy]

Cancer sucks, I wish all the best towards a recovery.

You’d also have to ‘fix’ DNA: unless we can re-engineer a bunch of key enzymes and then re-encode the entire genome (or maybe key parts) with forward error correction without breaking everything else, it might work. You might also break evolution to some degree by making random point mutations less likely.

But what I learned so far is that as soon as you’d attempt something like this in bacteria, the fitness advantage from an evolutionary standpoint is negligible compared to the efficiency loss introduced by FEC, so your colony would get outcompeted by other bacteria unless there is a niche your resistant bacteria survive in (high radiation environments?). The efficiency loss induced ‘disadvantages’ would probably be less pronounced in mammals though - If (big if) you manage to not also break anything essential in the wonderful yet surprisingly efficient Rube Goldberg machine that is life.

[kinj28]

What I meant was there are collection of genes responsible for error correction. If there is a failure in duplication then these genes have not done their job.

Thought experiment, again as a layman, was to see if these genes responsible for error correction at the base level can be fixed or bolstered and that will act like a cancer vaccine. But looks like from other comments that this is even more harder!

[f6v]

> 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".

[mr_toad]

> fixing the enzyme that fixes the wrong copy paste mechanism. Or making the enzyme get more efficient and powerful

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

[jijijijij]

> 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.