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CRISPR eliminates HIV-1 infection in live animals

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Re: CRISPR eliminates HIV-1 infection in live animals

#241
post #225

Earlier quoted context omitted.

I fully support basic science pursuing crazy ideas. I think this is a very interesting piece of basic science, it's just at an incredibly speculative stage that's unsuitable for clinical investment. Efficient delivery of novel proteins into a cell by genetic methods, nanoparticles, or direct transduction is -the- challenge for a lot of novel ideas. Massive effort is ongoing to find breakthroughs here. The proteins in…

Seems XKCD was on point this week: https://www.xkcd.com/1831/

To be fair, a lot of breakthroughs happen by people outside the field in question applying new ways of thinking to that field.

Sure, these people can be kind of annoying, but I think we lose more than we gain by discouraging cross-pollination between fields of science.

Re: CRISPR eliminates HIV-1 infection in live animals

#242
post #217

Earlier quoted context omitted.

It's not. An egg moments After fertilization experiencing suffering requires quite a bit of inagination, while we all can agree a child can suffer. Where we draw the line between that is obviously somewhat up for debate (and no one in their right mind is saying we should kill born babies for pleasure).

You seem to be using subjective experiences and the ability to experience them as base for your moral system. Is it the case? Why?

I dont believe for a second that let's say you did something you knew to be evil, such as kill a child for convenience, and were hypothetically asked about this in an after life: "why did you do it, you knew it was evil," that you'd be able to say honestly that you didn't actually know that.

As far as I am aware anything is possible, but suffering and happiness seem to be real.

Re: CRISPR eliminates HIV-1 infection in live animals

#243
post #240

Earlier quoted context omitted.

I find it difficult to adhere to the meaning of guidelines like this, because I don't know exactly what they intend. For example, I would say what I did in a face-to-face conversation, and I don't think I'm being gratuitously negative.

This case is well covered by the guideline that says: > Please avoid introducing classic flamewar topics unless you have something genuinely new to say about them.

I haven't obviously broken that rule. Is it even a classic flame war topic? I've seen more flame wars about vim vs. emacs than I have about this issue, at least how I framed it.

Re: CRISPR eliminates HIV-1 infection in live animals

#244
post #239

Earlier quoted context omitted.

I find it difficult to adhere to the meaning of guidelines like this, because I don't know exactly what they intend. For example, I would say what I did in a face-to-face conversation, and I don't think I'm being gratuitously negative.

What your comment (and followup) shows is that you think some other people's behaviour makes them deserve HIV. That's an utterly intolerable position, and especially so in this community. Nobody deserves HIV.

Why is it intolerable? I think many who have HIV now deserved it because of their licentious behavior.

Re: CRISPR eliminates HIV-1 infection in live animals

#245
post #241
post #225

Earlier quoted context omitted.

Seems XKCD was on point this week: https://www.xkcd.com/1831/

To be fair, a lot of breakthroughs happen by people outside the field in question applying new ways of thinking to that field. Sure, these people can be kind of annoying, but I think we lose more than we gain by discouraging cross-pollination between fields of science.

Definitely; I was thinking that earlier while reading this post. On the one hand, you have newcomers who might have an answer no one thought would work, but on the other hand experience nets wisdom that often is more accurate than the newcomer's logic.

It is a tough call to make between what's happened and what's possible.

Re: CRISPR eliminates HIV-1 infection in live animals

#246
post #132

Earlier quoted context omitted.

You can spend hundreds of millions of dollars before you even get to the point where you can ask the FDA if you can start human trials. Even having spent all that time and money, you still won't have any guarantee that your drug will prove to be safe, effective, or better than any existing drugs.

> You can spend hundreds of millions of dollars before you even get to the point where you can ask the FDA if you can start human trials. What's a rough breakdown of costs? Salaries certainly don't seem to be the dominant factor. Is it lab equipment & facilities?

I'm not a chemist, but here's how I understand it to work.

It's all trial and error. You start with some model about how your target disease works. Perhaps, for the sake of argument, your model is that disease Q is caused by a deficit of protein N. Protein N is broken down by enzyme F, so obviously if you found a drug that suppressed enzyme F, you could cure disease Q. Now all you have to do is try every chemical you know how to make to see if it reacts with enzyme F.

Of course, you have to be a little more picky than that. Elemental Flourine would probably react with the enzyme, but might react with other important parts of the patient's anatomy as well; probably there would be side effects. So you screen millions of compounds against your enzyme, and against thousands of other molecules commonly found in the human body that you _don't_ want it to interact with, looking for the one that interacts with as few of them as possible. These days this part is somewhat automated. Machines can squirt thousands of chemicals into thousands of test cells every second, and automatically check them for chemical reactions. There are apparently whole companies that do nothing but this, on a contract basis. They maintain a library of compounds to test against, you ship them a big bottle of your enzyme F in solution, and they run all the tests for you. That takes a big logistical problem off your plate, which is nice. Since this is all they do, they can really specialize and increase their efficiency.

Now you've spent a couple of years on the project and identified a few dozen likely candidates. The next step is to optimize them to improve their effect. You're basically trying to guess what part of the molecule is most important (hopefully backing that guess up with some data), then changing the less important looking parts of the molecule to see what happens. Think of all the different combinations of side groups you could add to it, or remove from it, or swap out with other groups, etc, and try them all. Lots of synthesizing small batches of chemicals nobody else has ever synthesized before, determining their structures to make sure you synthesized what you set out to synthesize, lots of assays to see what kind of reactions they get up to, lots of failures.

After a few years of that and you might have something you can start testing in a real biological system. For this step you use cell cultures, rather than going immediately to the full complexity of an animal model. Your drug isn't much good if the liver immediately thinks it's a poison and dismantles it, or if it kills the cultured liver cells, etc.

If none of that goes wrong, then maybe you do tests in an animal model (provided you can find some animals that are susceptible to disease Q, or something close enough), and then later do human testing. Hopefully your disease model was correct; not all of them are. Look at all the alzheimers drugs that have failed, for instance. It seems that none of our hypotheses for how alzheimers works are correct.

Also, don't forget that at some point you also have to work out how to synthesize your drug efficiently, safely, inexpensively, and in large batches.

Labs are presumably a big part of the costs, but a lot of the cost of a lab is the people, not just the equipment.

I think changing the way the FDA works is a hopeless cause, because the real costs are at the beginning of the process. Fund basic research instead, so that we can find new types of chemicals to build, new ways of building them, new natural products, etc. Maybe someone will even crack the simulation problem (the problem is that accurate chemical simulations take months and years to run, and simulations that are faster than physical tests are inaccurate).

Re: CRISPR eliminates HIV-1 infection in live animals

#247
post #239

Earlier quoted context omitted.

I find it difficult to adhere to the meaning of guidelines like this, because I don't know exactly what they intend. For example, I would say what I did in a face-to-face conversation, and I don't think I'm being gratuitously negative.

What your comment (and followup) shows is that you think some other people's behaviour makes them deserve HIV. That's an utterly intolerable position, and especially so in this community. Nobody deserves HIV.

What about the degenerate subculture of "bug chasers"? Aren't they literally asking for it?

Re: CRISPR eliminates HIV-1 infection in live animals

#248

Earlier quoted context omitted.

This is fascinating. How in the world does the body "raise antibodies" that are effective against arbitrary proteins it hasn't seen before? How does this get "remembered" and how does the memory get communicated through the body? If there's an ELI5 (or, ELI-college-101) I'd be interested to read it.

Very over-simplified: You have a random library of many billions of cells each making a single unique antibody that was created via random combinatorial genetic shuffling early on. The ones that accidentally bind to your own natural proteins are filtered out by killing them before they leave the bone marrow, so the circulating cells remaining form a library that could only bind -foreign- proteins. When one of these f…

Also google "somatic hypermutation". That multiplication process for B cells is inexact, and introduces mutations into the DNA (and therefore structure) of its children. There's a process which indicates whether any of these new antibodies binds better than the original one, which becomes a new candidate for multiplying.

There's fairly recent technology to sequence these antibodies en masse, which gives you a whole load (~10^6) of these antibody DNA sequences. It's a fascinating and frustrating exercise to try and reconstruct the mutation history and families of related cells from this data.

Re: CRISPR eliminates HIV-1 infection in live animals

#249
post #230
post #222

Earlier quoted context omitted.

A disease is a good fit if you can just inject the therapy into a localized region (say, the eye, or an organ) and the treatment works for a reasonably long period of time (months+). Typically another requirement is that the target is a defective gene where the phenotype can be repaired through addition of a "corrected" form of the gene, without the defective gene needing to be removed. This is the case in X-linked r…

We learned early on that one of the difficulties in eliminating HIV is that it hides in the nervous system and can reemerge at any time. This article show promise in that it can reduce HIV viral load during active shedding. I think it is less likely that it could ever eliminate HIV entirely (i.e. cure)

which is why press releases like this aren't really accurate and create false expectations

Re: CRISPR eliminates HIV-1 infection in live animals

#250
post #32

Back in 2011, there was an announcement from MIT about a new approach to a broad-spectrum antiviral that appeared to work.[1] This goes way beyond an AIDS-specific cure. But it was at MIT Lincoln Labs, which doesn't usually do bio. So the researcher moved to Draper Labs, but didn't get much funding. Then that funding ran out. Now the guy behind this is trying to get funding on Indiegogo.[3] The problem seems to be th…

Given billionaires running their own space programs it makes me wonder why there aren't more billionaires running biologic research companies. Between life extension and immunity to (or protection from) really pathological conditions it seems like their interests would be aligned with folks like this.

Both Google and Apple have biomedical venture efforts. Google founders are 40 and feel mortal.
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