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The curious DNA circles that make treating cancer so hard
- jcims 5y agoI, like so many others, had a sudden motivation to develop my understanding of cancer. Once you’ve read your hundredth paper and followed as many clinical trials, it takes on another form. Near sentience, its the ultimate survivalist. It’s too bad it has such a devastating outcome on loved ones, we’d all admire it otherwise.
- DrAwdeOccarim 5y agoSadly, I agree 100%. Time and again I see labs/papers/companies trying to "target" cancer cells for specific killing. What we are all awaking up to now in the field is the only way to reliably achieve durable responses you need to a) have a functional immune system, b) somehow convince it to kill cancer cells via surface antigen recognition/MHC all without getting checkpointed. It's a super fucking hard problem and I makes me so angry; but I agree there is a bit of awe in how clever/sneaky/insidious it is.
- space_fountain 5y agoI’m not a biologist, but how I imagine it is that cancer is just evolution + entropy. We can obviously get a lot better at controlling it, but it will always be there because there’s always a way for one cell to go rouge and gobble up resources and make tons of copies to the detriment of the whole. Biology already puts tons of roadblocks in the way to this, and we can surely add more, but at the end of the day it’s such a huge incentive so things will go find the easier faster way to chemical equilibrium
- kiba 5y agoWe probably won't kill cancer through one miracle cure, but probably through death by a thousand cuts. That and we probably need to repair the immune system. The incident of cancer increases with age, after all.
- toomuchtodo 5y agoHow do you improve the immune system to convey the improvements we’ve made with mRNA to it?
- jcims 5y agoWe haven't really made any improvements to the immune system with mRNA, we're just giving it some training film to be ready when the fight comes. An immune system that has a hair trigger to new antigens would likely cause more problems than it solves. Some kind of ability to have contagious antibodies might be an actual improvement but the fact that we don't see that in nature tells me it has downsides that are difficult to see.
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- KMag 5y ago> Some kind of ability to have contagious antibodies might be an actual improvement but the fact that we don't see that in nature tells me it has downsides that are difficult to see. My biology education is a bit weak, but off the top of my head, autoimmunity being contagious sounds like a likely side-effect of contagious antibodies.
- tiborsaas 5y agoWe could sample the actual cancer in the patient and custom print an mRNA cure to that specific person for maximum accuracy. The Pfizer/BioNTech vaccine was created in hours after Covid was sequenced. So this might not be a too far fetched idea.
- DrAwdeOccarim 5y agoEasier said than done, but yes most mRNA companies are trying the non-personalized and personalized cancer vaccine idea. The issue is the immune system is held back, like a big bouncer holding you back in a fight. Checkpoint inhibitors remove that bouncer, but now you're drunk and throwing fists all over the place, hitting both your friends, the bouncer, and the hooligans at the same time...
- tsimionescu 5y agoThe interesting thing going against your fear is that there are organisms like blue whales that do not die of cancer, or at least for them it is an exceedingly rare disease. The reasons for this are not yet understood, and they may not be entirely applicable to humans (e.g. the sheer size of a blue whale may play an important role, since cancer would take much, much longer to grow to any noticeable proportion of the whale than in a human-sized organism), but at least it proves it's not completely impossible to have life without cancer.
- pfdietz 5y agoElephants have 20 copies of the TP53 tumor suppressor gene. https://www.nature.com/articles/nature.2015.18534 https://www.nature.com/articles/nature.2015.18534
- wetpaws 5y agoEvery time I read about it I'm baffled we are not doing the same for humans with gene editing.
- pfdietz 5y agoI'm sure there are many side effects that could only be found and fixed on a mountain of dead babies. For example, if I understand correctly, this makes elephants very susceptible to radiation sickness, as their cells are on a hair trigger to destroy themselves at any sign of genetic damage.
- space_fountain 5y agoI can't actually find a good source for blue whales not dying of cancer. I do see lots of sources claiming the rates are way lower than in humans, and that is indeed interesting. It's evidence that we could do better at suppressing cancer, but I'm very convinced that cells that can evolve eventually deciding to go rouge isn't something that be precisely stopped. Just made less likely
- agumonkey 5y agoI can envision a moment where non invasive intervention and monitoring can be precise enough to stop being a threat. Other than that yeah, I think it's a naturally emergent biological phenomenon that cannot be removed.
- vorejdajo 5y agoSurvivalist? You do realize once the loved one dies,the cells have to die too. A bit counter-inituitive..
- tasty_freeze 5y agoIt is a tragedy of the commons scenario. The individual actors have no conscience or plan, of course, but it all amounts to the same: some cells can morph into freeloaders and those that morph into the most aggressive replicators "win" in the short term.
- djmips 5y agoUnless perhaps if the cancer is transmissible.
- deleted 5y ago[deleted]
- jcims 5y agoYes, quite. Sometimes it's too successful and outstrips its resource. Sounds familiar. If you have a word you prefer I invite you to use it in the future.
- inawarminister 5y agoSome cells survive the death of their organism. Like the HeLa line of cells. There's an interesting and tragic story behinds it too...
- dogma1138 5y agoThat’s because cancer only happens when it manages to survive or bypass every process in the human body that would normally prevent it. It’s the pinnacle of (natural) selection bias.
- nunb 5y agoI am curious if you have read, and of what you think of Jason Fung's book Cancer Code. Is it a fair overview of the papers you have read? What level of understanding does he achieve?
- refurb 5y agoThere is no sentience. It’s a trillion monkeys banging at a trillion typewriters. If anything treating cancer is more akin to antibiotic resistance. One therapy usually just selects for the cancer that is resistant, so you relapse. And cancer cells have notoriously fragile genomes. I remember reading a paper that sequence 1,000 breast cancer samples. There were about 800 different mutations that led to the cancer. Very little similarity between patients.
- djmips 5y agoIt's a wonder we don't all have cancer. Our large functioning multi cellular bodies are a marvel.
- refurb 5y agoEvidence suggest humans “get” cancer way more frequently than we’d expect. Cells are programmed to “self-destruct” if things go wrong and our immune system is primed to destroy cells that express certain proteins associated with uncontrolled growth. It’s really the edge cases that get through.
- jcims 5y ago> There is no sentience. It’s a trillion monkeys banging at a trillion typewriters. I get it but the human genome has ~4^3,200,000,000 possible combinations. Even single genes have 4^1000 possible combinations...that's a number with 600 zeroes in it. That's a trillion^50. It's just odd that the mutations always seem to zero in on the right spot pretty damn quickly.
- agumonkey 5y agoI also had that moment where you're somehow in awe about all the reinforcing intricacies that allow cancer to persist. It's an odd form of anti-life.
- DrAwdeOccarim 5y agoReally fascinating! I wonder if these cells all have defects in innate immune sensing of cytosolic DNA. Like, do cGAS/MAPK/etc. require linear for recognition like RIG-I does for dsRNA or are they all mutated/shutdown in these cells. Would be interesting to see the innate immune transcriptome with and without ecDNA.
- panabee 5y agoone of the best accelerants for science would be empowering non-researchers like you to hire researchers to conduct experiments like this -- or ideally conduct experiments yourself. equipment, material, and people costs are prohibitively high for now. hopefully one day.
- ncmncm 5y agoIdeas are cheap. Every biologist has way more ideas for what to investigate than they could ever get grants to look into. Grant committees, likewise, see applications for way more research programs than they have money to fund. (This is like startup ideas, founders, and VCs.) But grant committees are controlled by the older members of each sub-field. They are biased toward what seemed important to them when they were young, but also against what experience has taught them tend to be dead ends. They want questions explored that have gone wanting for decades. Young researchers will eventually graduate to grant committees, and fund what they wish had been looked into decades before. We can see systematic failure in, e.g., Alzheimer syndrome research, still funding suppression of amyloid plaques and tau tangles decades after every such avenue was found to fizzle. But we don't know a better way to organize evaluating grant applications. We would not know how to evaluate any change proposed. And, we don't know how to change committees over if we found a better one. Each sub-field has its own dynamic, independent of all the others. Probably some have evolved a method that works well for their sub-field, for now, but would certainly be wrong for the next sub-field over, and will be wrong in its own in ten years. They are all playing catch-up all the time. The only thing that keeps it working at all is that they are run by smart people who have had to solve many different hard problems, and those people retire on a regular schedule.
- amelius 5y agoCan't we develop some protein that locks onto these circles and then triggers cell death?
- andrewflnr 5y agoI expect the tricky part, or at least a tricky part, is distinguishing an ecDNA circle from healthy chromosomal DNA. More speculatively, bacterial DNA looks kind of similar, and you don't want to indiscriminately kill your gut bacteria.
- chasil 5y agoThe mitochondria also have circular DNA, exclusively. I wonder how similar these forms are.
- monkeycantype 5y agoor more likely find an organism that already has.
- thaumasiotes 5y agoWouldn't that protein need to penetrate the cell wall? You'd need something more like a virus.
- amelius 5y agoI guess the delivery mechanism is the next step in the development of such an agent.
- bsder 5y agoThe issue is that a single protein might not be specific enough ie. you will kill lots of wrong things if you are too aggressive. Some people have been working on combining two (or more) factors in order to only activate when in the right spot: https://www.science.org/content/blog-post/two-steps-activation https://www.science.org/content/blog-post/two-steps-activati... My guess is that this is how the body actually works. At the chemical level, the human body has many highly individually specific things (like enzymes and receptors). However, at the system level, it's probably easier to take two slightly specific things and combine them to make something that is specific enough but not too brittle.
- panabee 5y agoKey Points: * Scientists discovered a relationship between cancer and extrachromosomal DNA (ecDNA) in 1965, but considered ecDNAs rare and not worth investigating. * Researchers subsequently learned that ecDNAs are common and central to the behavior of some of the most aggressive forms of cancer, enabling remarkably elevated levels of oncogene transcription, creating new gene regulatory interactions, and providing a powerful mechanism for rapid change that can drive very high oncogene copy numbers or allow cancer cells to resist treatment. * Like Ptolemy’s flawed map that placed Earth at the center of the solar system, cancer researchers today may be analyzing genes and diseases with flawed maps. Related Articles: * https://www.the-scientist.com/features/cancer-may-be-driven-by-dna-outside-of-chromosomes-68590 https://www.the-scientist.com/features/cancer-may-be-driven-... * https://chemh.stanford.edu/news/shining-light-extrachromosomal-dna https://chemh.stanford.edu/news/shining-light-extrachromosom...
- jcims 5y agoWould be interesting to see if the mechanisms underlying cancer's genetic agility could ultimately be put to use to search for solutions to other problems.
- panabee 5y agoexactly. cancer is a scourge that must be eradicated, but on the way, we may discover the solution to other health issues.
- clipjokingly 5y agoAre cancer cells immortal? It would be very poetic that the key to cancer would also unlock amortality.
- akiselev 5y agoThey're immortal in the sense that they no longer listen to tumor suppression genes that trigger apoptosis (programmed cell death). Based on our current understanding of senescence, that doesn't really help with the main causes of aging.
- andrea81 5y agoWhich type of cancer?
- ncmncm 5y agoThey particularly mention certain brain and colon cancers. But that is just an artifact of specialization in the researchers. It is likely that some of the cancers that affect any body part exhibit the same phenomenon.
- gxt 5y agoIs there ongoing research looking at adapting cancer fighting mechanisms of large mamals like elephants and whales? I read somewhere they had the lowest occurrence of cancers of all mamals.