Once we figure out all that's going on — and believe me, we know almost a percent of what's going on — once we figure out what's going on, we're really going to be able to have a lot of control over what we do with our health, with what we do with future generations, and how long we're going to live. And hopefully we'll be able to use this to discover more truth, and more beauty.

illperipheral 72 points 7 months ago*

The gif is really cool, but it's hugely simplified (and for good reason -- it'd be pretty hard to visualize what's going on in a cell if it were portrayed realistically due to the chaotic nature of cellular processes).

I'm not sure how anyone can hold on to any belief in (for example) intelligent design after they learn about how eukaryotic transcription and protein translation are regulated, or really after learning details about how any biological system works (not that I'm saying this necessarily applies to you, of course).

It's a huge chaotic mess, quite frankly. A good proportion of transcripts are degraded before they make any protein, and a good proportion of proteins are mistranslated, misfolded, or not needed and are enzymatically broken down before actually doing anything important. A large percentage of eukaryotic genomes are nonsense, and a not-insignificant proportion of the nonsense is even transcribed.

It's just not the way any intelligent entity would design a system. Why not make a 100 % perfect DNA replication and repair mechanism? Why not have it so that the transcription and translation can be completely shut off for transcripts and proteins that aren't necessary? (DNA methylation and chromatin remodeling aside -- even DNA methyltransferases and histone acetylases/deacetylases have nonzero background activity).

Why not have an intracellular transport mechanism that efficiently brings its cargo immediately to where it's needed, and only to where it's needed, instead of taking them in all directions at once and relying on the equilibrium to (eventually) shift toward its destination?

The path that a transport vacuole takes as it's traveling along the cytoskeleton can look like a "drunkard's walk" -- three steps forward, two back, and eventually it'll make it there. Specifically, the microtubules of the cytoskeleton are polar, so enzymes can "tell" which direction it's facing. Two motor proteins, dynein and kinesin, move attached cargo in opposite directions -- kinesin moves toward the (+) end of the microtubule, dynein toward the (-) end.

There are cases such as fast axonal transport where unidirectional movement predominates, but generally cargo such as transport vesicles or organelles can be attached to multiple motor proteins at one time, so the vacuole might move one direction down a microtubule and suddenly go back the opposite direction if the action of the other motor protein starts to predominate. It sort of makes sense in that the organelle can then jump from one microtubule to another and travel in something other than a completely straight line, but it's far from the best way of doing it, and certainly isn't how an intelligent entity would design it.

Don't get me wrong, it's quite marvelous how so many independent positive and negative feedback loops can interact so chaotically and yet it just *works*.

These are just a couple examples -- the workings of any aspect of cell biology preclude an intelligent designer, and that's just one sub-field of the biological sciences. There's a good reason that Dobzhansky wrote,

Nothing in biology makes sense except in the light of evolution.

Every facet of biology points to the fact that the biology and diversity of life is the result of the naturalistic process of evolution. I thought that evolution was a really stupid theory that completely went against common sense until I took my first biology class, and then it just 'clicked'.

Some links: Regulation of transcription in eukaryotes at NCBI

Noncoding RNA and gene expression at Nature

edit: clarification and typo fix

hwillis 47 points 12 hours ago

They are very hard to destroy.

Bacteria are complex cells with tons of exploitable processes, that invade, colonize and eat people before reproducing. They are fragile because they are big bags that have to eat, digest, metabolize and reproduce. Most antibiotics rely on poisoning them in some way.

Viruses are much smaller. They're still bags of stuff, but they don't really do much. There's practically nothing going on inside, and they just kind of sit around waiting for a host. Because of this they are very hard to destroy- they can't be killed with poison or starved like bacteria. Some things can destroy the bag and kill viruses in the same way they kill bacteria, but it doesn't always work against all viruses and you can't use those substances to treat viral infections. Proteins on the surface of the bag are what the immune system targets, and it just eats the viruses and breaks down the structures inside.

Prions are even smaller than viruses. They are totally inert and very hard to destroy/render noninfectious. Heat and formaldehyde aren't even that effective. Pretty much all that works is things that totally destroy organic matter. Your immune system can't do very much about it, and doesn't even really recognize it, because it has no antigens. Prions just float around, not needing to enter cells to reproduce and using some of the most common bodily proteins. This speeds up exponentially and just overwhelms the body, like cancer.

It's lethal because its super hard to kill and it doesn't naturally alert your immune system, although vaccines in mice exist. It's mysterious because the misfolded proteins accumulate in extremely large and complex structures, because its so hard to destroy, and because of its similarity to other diseases like Alzheimers. The way prions kill is also very enigmatic- targeting the brain, causing strange and disturbing symptoms, turning tissue into spongy swiss cheese. Kuru, the laughing sickness or "shiver", shuts down your coordination first, then sets your emotions loose and makes you uncontrollably depressed or laughing, and then you eventually die. Fatal familial insomnia destroys your ability to sleep, causing paranoia, hallucinations, and panic attacks. Eventually you lose the ability to sleep at all, waste away and die in less than a year. Creutzfeldt–Jakob disease can go unnoticed in cows and then passed to humans when eaten. Even more bizzarely:

The disease has also been shown to result from use of human growth hormone obtained from the pituitary glands of persons who died from Creutzfeldt–Jakob disease, though the known incidence of this cause is (as of April 2004) quite small. The risk of infection via cadaveric HGH in the US ceased when the medication was withdrawn in 1985.

It's all the horror of debilitating unstoppable diseases like alzheimer's, parkinsons or genetic diseases, but its infectious. It's at the very top of the list of disease fatality rates. Note that the pink boxes are for untreated diseases- the red or white boxes are what you should look for to compare. The red boxes are genetic diseases or amoeba that literally eat your brain in about two weeks, moving so fast they just can't be stopped. Prions are like rabies, but even rabies has been survived, plus it has a vaccine. It's more like Ebola, which has no vaccine, but it trades the infectiousness for absolute lethality. If you get enough prions, you have up to 7 years before you simply die.

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–()Ntebrx 13 points 9 hours ago

Great answer! I like it in general, but I have a few things to say about it that I think would make it more accurate. I mean this mainly as a sparking point for discussion, not as a criticism - I don't mean to upset or question you.

Prions just float around, not needing to enter cells to reproduce and using some of the most common bodily proteins

Prions are found in cells mainly, not floating around (Kovács et al 2005, which has other good references; Salès et al 2001 looks like it has promising info but is behind a paywall I can't currently overcome). These sources do say that they are also found extracellularly, but apparently restricted to synapses. (I'm not particularly pleased with the quality of these sources - just googled for them, I'm not really a prion expert and so this could use some verification if anyone has the time).

Entry into cells actually is pretty important to the pathogenesis of prion diseases, if not the fundamental part. I think PrPSC does have to enter cells in order to 'reproduce', because it does have to find PrPC and induce it to misfold, and PrPC is a cellular protein found inside cells (Aguzzi, Sigurdson, and Heikenwaelder 2008). The fact that this misfolding happens inside neurons and is somehow toxic to them is what causes the neuronal cell death and subsequent neurodegeneration (more or less). Drisaldi et al 2003 is the first reference I found, they think neurotoxicity is by ER retention (I only skimmed the article though), but that was 13 years ago so there are probably studies out there either confirming or refuting this.

I'm not sure how correct it is to say that prions "use" proteins. They ARE proteins, and only proteins - are they really *using* proteins? Can we really say prion 'reproduction' involves anything other than the one PrPC/SC molecule? On the flip side, I guess it 'uses' the PrPC to make more prion protein - but is it actually considered using the cellular protein when it is in reality just converting the PrPC to a different form? I guess what you're saying is that it replicates using protein that is endogenous/native to the host rather then bringing along any of its own.

I disagree that PrPC really one of the most common bodily proteins. The list of most bodily proteins by common-ness is topped by structural proteins and housekeeping proteins. Maybe PrPC is common in the brain, or found in all neurons? Or common as in 'found throughout the human population?" Or common as in conserved widely among different species? I'm not sure which you mean.

Your immune system can't do very much about it, and doesn't even really recognize it, because it has no antigens

I don't think this is exactly right, at least not the wording. It might be true that the immune system "can't" do much about it; I think it's more likely that the immune system just *doesn't* do much about it, and even more likely that the immune system is definitely doing stuff, but that it just isn't at all beneficial to an affected (infected) person.

To say "it has no antigens" is strange. A prion protein doesn't "have" anything - it's just a protein. This protein might be completely non-antigenic, but I'd be willing to be it is just not very *immunogenic*. (Best I could do on short notice: Souan et al 2001; also, you said there are vaccines in mice, which in itself almost certainly indicates that they contain antigenic regions).

Creutzfeldt–Jakob disease can go unnoticed in cows and then passed to humans when eaten

Also to get very, very technical: CJD cannot go unnoticed in cows. If it goes unnoticed, it is not a disease. This seems like I'm splitting hairs, but saying the above about CJD is like saying "AIDS can go unnoticed in some people and then be passed to others". If AIDS goes unnoticed, it isn't AIDS. AIDS/CJD are defined entirely by being noticed - you don't have the syndrome/disease if you don't have any signs or symptoms - so you can't have AIDS/CJD unnoticed. It would be better to say that infectious prions (PrPSC)/HIV can go unnoticed in cows/people and then passed onto humans/others.

TL:DR I'm a pedant and prions are wack