From the paper, it sounds like the particle they constructed is about 120nm in diameter. So a bit larger than the viruses previously used. Which are also nanoparticles, so I guess it's more that this delivery system isn't based on a virus.

I guess, one thing I don't quite understand: are the viruses used in CRISPR really viruses (can they self-replicate using the cells they alter?) Or are they just nanomachines based on viruses?

The viruses used to deliver CRISPR in the past are not able to replicate. They're so small that you have to remove all of the viral DNA in order to even fit your CRISPR-coding genes inside.

Why is there a gene for high cholesterol? In what kind of environment was high cholesterol beneficial?

6. After any surgery, your cholesterol soars. It also increases when you battle infections, are under a lot of stress, or have had a heart attack. Reason being, your body relies on cholesterol as a healing agent – to help create new cells whenever they’re needed. Exposure to environmental agents and toxins can also affect your cholesterol levels.

7. Toxic chemicals, free radicals, pathogens, trans-fats and other damaging agents you’re exposed to end up in your blood stream, where they damage the endothelium – the razor-thin lining of your blood vessels. When endothelial cells need to be repaired, your liver sends LDL to the site, and when the healing process concludes, HDL carries the spent LDL particles back to the liver to be removed from your body.

https://heartmdinstitute.com/heart-health/facts-about-choles...

hdl/ldl - high/low density lipoprotein

Cells need to be able to control how much cholesterol they have (cholesterol, notably, makes up about 25% of the cell membrane). They can either synthesize it themselves, or import it from the blood.

The system for importing cholesterol can't run continuously or else it might cram the cell full of cholesterol, so there needs to be a way of turning it off (or at least slowing it down) when levels are satisfactory. PCSK9, the gene that they targeted, does just that.

So it's not a "gene for high cholesterol" per se - but if you delete it, cells will import more cholesterol, thus lowering the levels in the blood. I really don't know much about this system, but I imagine you'd have to combine this modification with a low-cholesterol diet or else it might have an adverse effect on the modified cells.

Great post. Just adding for additional color that PCSK9 inhibitors like evolocumab are a relatively new/hot thing in pharma right now, for treating high cholesterol.

Coming out with the ability to absolutely wreck a competitor’s blockbuster drug with a gene edit is probably not entirely an innocent coincidence.

Not all genes have to have a function, or even a beneficial one. DNA could be riddled with legacy (inactive) code. As long as there's not enough evolutionary pressure -its negative value doesn't pass a threshold- the code would be retained.

Consider an extremely high-dimensional feature space [not just genes, but transcripts/isoforms (differently diced-up versions of RNAs with different functions), hosts of active-but-not-transcribed-into-proteins RNAs, and dynamic regulation through interactions] which updates a reinforcement learning algorithm one epoch per generation (~20-30 years), and you'll see why it's far from optimized.

I wonder what other dormant code exists that if toggled would trigger dramatic changes

It can just be a mutation that doesn't prevent reproduction. The relatively low occurrence (1 in 500) points towards that.

what's the role of cholesterol in the human body?

It's a component of cellular membranes (so it is found everywhere) and many hormones.

This article doesn't touch on how they also used mRNA coding for Cas9 instead of the protein itself.