The human body is a mosaic of different genomes | Hacker News Reader

The human body is a mosaic of different genomes

nature.com

114 pointspseudolus12 comments

We all have tiny little cancers right now. Our bodies are constantly producing mutations that disable growth regulation, promote proliferation, change cell adhesion, etc.

It's just that our body is programmed to defeat these irregularities and disease states. The immune system is a major component, as it can recognize cell surface epitopes of a variety of types - mutated ones, or even suicide signals. Cells that detect that they have entered a disease state will often enter apoptosis or tell their neighbors about it.

We get cancer when cells accumulate so many mutations that they not only grow unchecked, but they also evade the body's natural forms of detection and clearance. And then they eventually hill climb into a state where they leave their original tissue and move about the body uncontrolled.

You evolved to defeat cancer. It's just a numbers game until one of your precancerous cells accumulates enough mutation to escape capture.

I recall reading a study describing cancerous/mutated cells very similarly. I don’t recall exactly but the study was in regards to diet (maybe specifically vitamins/minerals or antioxidants) that promoted detection (again I don’t recall but maybe by the immune system).

As I remeber the diet not only was supposed to improve detection but response and I think the improved response included the body releasing other cells (again I don’t remember but think fat cells, although that doesn’t sound right) to surround/isolate/starve the cancer cells, so in a best case the cancer cells would die and if they wouldn’t die then they would not be permitted to grow/replicate/freely travel.

Does this ring a bell to you vis-a-vis any diet?

Nothing has been proven, but it's hypothesized that chronic inflammation (and the foods that can cause it) are bad and can lead to the development of cancer.

Here's a review article on the current understanding: https://translational-medicine.biomedcentral.com/articles/10...

I wonder if saying "chronic inflammation can lead to the development of cancer" is like saying "being dumb can lead to not being smart". Chronic inflammation is obviously immune system dysfunction, and cancer is also immune system dysfunction. Perhaps the same process could be described with either term at some point in time, but is that an explanation of anything?

In retrospect this shouldn’t surprise anyone, but it still feels like a radical departure from the more or less cute stories we are taught in intro Bio.

Biology is fractally weird and emphatically deals in probability distributions not binary classes. You can and should always expect an “except...” clause at the end of any declarative statement about a biological system. If it’s not there explicitly, it’s implicit.

Confusing the map (“individuals have unique DNA”) for the terrain (“...except for here and here and maybe over there, especially if you look really hard”) is always a risk.

Being able to know which map to use for which terrain (i.e., do we need to care about mosaics for this problem or not) is, more or less, the reason we do research.

Are mutations in DNA arising from truly random events? When I say random, I mean outside of the knowability of Laplace's demon?

I know quantum mechanics contains true randomness, in the creation of DNA copies does this randomness contribute?

They are definitely not random. Sequence context matters a lot - e.g. in humans CG mutates about 10x more often than other dinucleotides. Other contexts also contribute - genes that are expressed more are more mutable, and so on.

As the other comment says, most of the mutation have chemical and thermodinamical causes, that can be seen by a Laplace's demon. (There are some quantum effects here, so add "almost" somewhere in the previous sentence.)

Also, it is important that the mutations are random, but nut uniformly random. Some base replacements are mor common than other, some DNA patterns are more prone to get bad copies, ...

But if you put a radioactive source that produce x-ray or gamma rays, the emission is a truly quantum random phenom and even a Laplace's demon can't predict them. I'm not sure if the Laplace's demon can "see" the photons while they are traveling, it's difficult to discuss about the properties of fictional entities. But for not very high energy x-rays, the wavelength is bigger than the distance between atoms and the Laplace's demon can't predict in which atom it will hit, but they have less energy are less prone to cause mutations.

>In retrospect this shouldn’t surprise anyone

It doesn't, because it's not news. The article mentions

>Previous studies have found high levels of mosaicism in the skin[2], oesophagus[3] and blood[4].

Then novelty is the scale of the experiment, not the insight.

Also worth noting: this is further evidence that cancer, like many other diseases, is in part an immune disease.

When central tolerance is too lax, tumor cells can more easily survive a trip through the bloodstream to seed metastasis (the eventual cause of nearly all cancer deaths, aside from treatment sequelae and thrombosis).

By contrast, if central tolerance is overly tight, then you see autoimmune diseases (severe aplastic anemia is a classic example) where the immune system wipes out the competition from healthy progenitors, and mutant clones better able to survive the onslaught seed cancers. This is one reason why both immunosuppressive therapies and immunostimulatory agents can both increase cancer risk.

It’s also worth noting just how different the mutational profiles of pediatric tumors are versus adults. To grossly oversimplify, peds tumors tend to carry mutations (typically gene fusions, amplifications, or deletions) that confer a developmental-stage-specific advantage in proliferation, such that no normal progenitor could ever hope to keep up. By contrast, the most frequently observed point mutations in adult cancer (to TP53, in particular, although DNMT3A in leukemia is another example) confer stress resistance to the mutant clones. They are nearly absent from tumors seen in children. Even Li-Fraumeni syndrome, where people carry deleterious TP53 variants inherited from their parents, does not begin to show a huge risk differential until adolescence. So there are evolutionary, developmental, and immune differences that shape the genesis, selection, and growth of different tumors in different age groups, and tend to indicate different treatment.

The standard chemo regimens for pediatric ALL (acute lymphoblastic leukemia, the most common cancer in kids) would kill many adults, and despite over 90% cure rates in kids, far less than half of adults with the “same” disease will survive it. (In quotes, because as with every other tumor that spans the full range of age groups, the drivers in adults are different from those in kids for almost all instances).

Similarly, immune checkpoint inhibitors can generate miraculous responses in adults tumors, though these are seldom seen in pediatric patients. With the benefit of hindsight, it’s more obvious why this is so (the random accumulation of mutations over decades in adult tumors is more likely to generate immune-recognized non-self proteins), but it took a long, long time to get here. (Look up “Cooley’s Toxins” if you think immunotherapy is new :-/)

I still find the fields fascinating, despite having enough ghosts on my conscience to stock a mausoleum. Cancer is part of our evolutionary heritage; the best we can do in adults is usually try to control its spread and cut out enough of it for the immune system to mop up the rest. Kids are different, but that’s another story for another time. It’s a great period in history to be working on understanding these things and they interact.

> Also worth noting: this is further evidence that cancer, like many other diseases, is in part an immune disease.

I think about that sometimes but from the lens that perhaps there is an additional state that cancerous cells are preventing from occurring.

"We cured cancer, but then the worst appeared"

Dubious — cellular senescence (whether proliferation- or oncogene-induced) is the usual failsafe for avoiding proliferation of damaged cells. It relies heavily upon TP53, RB1, and CDKN2A, all of which are routinely deleted in tumors. When anti-aging researchers refer to senolytic drugs, usually they’re referring to drugs that clear senescent cells.

Oddly, the drugs tend to clear out tumor cells in many cases, as senescence bypass is a critical step in carcinogenesis.

Not oddly, the inflammatory paracrine (secreted) profile of senescent cells tends to engage the immune system in clearing them out. Immunosenescence gets in the way of this and also of clearing precancerous cells, hence it is a risk factor for both age-related frailty and cancer.

Reply on news.ycombinator.com