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CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

innovativegenomics.org

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Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#111

Post by andy_ppp »

spligak wrote: post #103
Gethsemane wrote: post #63

Earlier quoted context omitted.

Have you written about your experience anywhere? It would be interesting to see how you approached the research sector as a layperson. Are there any plans to move to in vivo? Best of luck with your research!

I haven't written about it publicly, but I can elaborate here. I don't mind answering further questions about it even if you believe they'd make me uncomfortable - they won't. I've come to terms with what's happening to my body and that I may not benefit from my efforts. Background: ~3 years ago I was diagnosed with a very rare MPLW515L-driven blood cancer known as a myeloproliferative neoplasm. My hematopoietic stem…

"When have you most successfully hacked a non-computer system to your advantage?" Amazing resourcefulness, you should consider applying to YC if you haven't! And I hope you manage to find a solution to your problem it sounds very promising.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#112

Post by CamperBob2 »

andy_ppp wrote: post #111
spligak wrote: post #103

Earlier quoted context omitted.

I haven't written about it publicly, but I can elaborate here. I don't mind answering further questions about it even if you believe they'd make me uncomfortable - they won't. I've come to terms with what's happening to my body and that I may not benefit from my efforts. Background: ~3 years ago I was diagnosed with a very rare MPLW515L-driven blood cancer known as a myeloproliferative neoplasm. My hematopoietic stem…

"When have you most successfully hacked a non-computer system to your advantage?" Amazing resourcefulness, you should consider applying to YC if you haven't! And I hope you manage to find a solution to your problem it sounds very promising.

And by the way, when Anthropic (sic) tells you that it's too dangerous to allow GPT-2/GPT-3/GPT-4/GPT-5/Sonnet/Opus/Mythos/Fable to discuss human biology, and some of us object vociferously to their premise, this is what we're talking about.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#113

Post by [deleted] »

toponijo wrote: post #102
jyounker wrote: post #94

Earlier quoted context omitted.

Cancer treatments are really scary things. There are all sorts of impacts that we have no idea about when using drugs that fundamentally attack pieces of our own body. My partner of many years had one of the nastiest cancers around, one with no targeted treatments. She went through an experimental combination of existing drugs. Some of the side effects included: * Her heart stopping during a drug infusion. This happe…

The point of going slowly is that we make sure something works, even if it has these bad side affects. Do we try experimental drugs with worse effects so that we can find effective ones faster? There are brave souls out there who will participate in clinical trials or experimental exceptions

[deleted]

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#114

Post by spligak »

shevy-java wrote: post #68
spligak wrote: post #50

Earlier quoted context omitted.

You're correct about CRISPR Cas9. The off-target affects are difficult to manage. The paper describes Cas12a2. This is a different mechanism with discovery origins in - of all things - agriculture. It does not attempt in any way to reprogram cells. It uses a guide protein to locate a specific mutation with exacting precision and, when it activates, unleashes total destruction of the cell. The implications of Cas12a2…

So how does Cas12a2 mitigate off-target effects? If it were to work, gene therapy as-is would be possible. Which it is not, not even for those overpriced therapies. I have no doubt that sooner or later it will happen, as the problem space is finite, not infinite, but I simply don't see the correlation here. > The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound…

> So how does Cas12a2 mitigate off-target effects?

Others in this thread may be able to give a better analogy, but I'll try:

Cas9 is like open heart surgery on millions of cells all at once. We know the specific outcome we want - a surgical replacement of a sliver of a sequence - but just like open heart surgery, it's an inexact operation. Cas9 tolerates mismatches which categorically allows off-target matching. It also operates on DNA, so any off-target effects reprogram the cell's primary source code.

We want the Cas9 "patient" cell to survive.

In contrast, Cas12a2 is key-locked self-destruction switch. It targets single-stranded RNA transcripts with a specific guide protein. So the specificity is two-fold: the guide protein doesn't tolerate mismatches, and its operating on a _downstream byproduct_ of the DNA. When the key (guide protein) matches, it unleashes total destruction within the cell.

We want the Cas12a2 "patient" cell to die.

> If it were to work, gene therapy would be an accurate - and affordable - technique. Which it is not right now.

Correct on the first point. If it were to work, gene therapy could be more common. I do not know how to make it affordable, yet. In the models I've built to commercialize this I estimate a Cas12a2 treatment would cost approximately as much as a bone marrow transplant.

> How does "answering questions" offset the technology being inferior right now?

In fairness, asking and seeking answers to questions is all I have right now. There is no cure to my disease so the upside - no matter how futile you may perceive it to be - to me, is infinite.

If I can solve it I may get a few more years with my daughter. If I can't, I can show her how to live fighting for an answer that may never come.

You're not wrong, you and I just have different perspectives on the upside.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#115

Post by cyberax »

MontyCarloHall wrote: post #83
cyberax wrote: post #75

Earlier quoted context omitted.

There are some ideas about making it triggerable. So first you load the cells with a protein that is ready to start shredding but is inactive. Then you trigger it with a second compound.

This would shorten the timeframe for cells to mutate and acquire resistance mechanisms, but would not address the issue of cells with preexisting (epi)genetic resistance mechanisms that would then be promptly selected for.

Yes, and if you shorten the timeframe enough, there's a chance that it can clear all the cancerous cells. You also ideally would use multiple variations of the therapy to further reduce the chance of a pre-existing escape mutation.

That's how we deal with HIV. No single HIV therapy (so far) is effective enough to suppress the virus all by itself, but a combination of them provides a barrier that is too high for mutations to jump.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#116

Post by reenorap »

spligak wrote: post #103
Gethsemane wrote: post #63

Earlier quoted context omitted.

Have you written about your experience anywhere? It would be interesting to see how you approached the research sector as a layperson. Are there any plans to move to in vivo? Best of luck with your research!

I haven't written about it publicly, but I can elaborate here. I don't mind answering further questions about it even if you believe they'd make me uncomfortable - they won't. I've come to terms with what's happening to my body and that I may not benefit from my efforts. Background: ~3 years ago I was diagnosed with a very rare MPLW515L-driven blood cancer known as a myeloproliferative neoplasm. My hematopoietic stem…

My aunt had the same disease you mention and was on medications since the 90s. She lead a healthy life with no real side effects from her medication and she passed away last year in her 80s. To be perfectly honest, she did die of the disease, because her medication stopped working and her bone marrow was all scarred. But up until a year before she passed away she was very active and healthy. Once the medication stopped working, she went steadily downhill until she passed away.

Hopefully you get great progress on your research but I just wanted to reassure you that the name sounds scary but the current treatment appears to work well and hopefully gives you enough runway to find your cure.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#117

Post by spligak »

cyberax wrote: post #78
shevy-java wrote: post #69

Earlier quoted context omitted.

Lipid nanoparticles are quite old as-is. How do you target cells specifically? > If you get really good at delivery, you can destroy A LOT of cells very quickly. You can destroy cells quickly. Ok. So the question is: how do you detect specifically only cancer cells via lipid nanoparticles? That was already a problem years ago with Herceptin. The rationale that is always used is that "we need to do something" for cert…

> So the question is: how do you detect specifically only cancer cells via lipid nanoparticles? You don't. Healthy cells will also get these nanoparticles, but without the triggering DNA sequence, the mRNA payload will remain inert and eventually will be degraded.

> Healthy cells will also get these nanoparticles, but without the triggering DNA sequence, the mRNA payload will remain inert and eventually will be degraded.

This is my understanding as well.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#118

Post by inglor_cz »

cyberax wrote: post #75
MontyCarloHall wrote: post #70

The idea of using CRISPR/Cas to detect tumor-specific mutations that aren't necessarily oncogenic and then kill the cell is not a new one [0, 1, 2]. However, previous studies used Cas9, which just damages the DNA at the target site; this uses Cas12a2, which is far more destructive because it shreds the chromatin in the cell once activated by detecting the target sequence. As with any cancer treatment, it's likely the…

There are some ideas about making it triggerable. So first you load the cells with a protein that is ready to start shredding but is inactive. Then you trigger it with a second compound.

This will also cause problems because too many cells die at once. See the comments in other threads; killing the entire cancer at once is very hard on the body.

Re: CRISPR tech selectively shreds cancer cells, including "undruggable" cancers

#119

Post by darkwizard42 »

spligak wrote: post #103
Gethsemane wrote: post #63

Earlier quoted context omitted.

Have you written about your experience anywhere? It would be interesting to see how you approached the research sector as a layperson. Are there any plans to move to in vivo? Best of luck with your research!

I haven't written about it publicly, but I can elaborate here. I don't mind answering further questions about it even if you believe they'd make me uncomfortable - they won't. I've come to terms with what's happening to my body and that I may not benefit from my efforts. Background: ~3 years ago I was diagnosed with a very rare MPLW515L-driven blood cancer known as a myeloproliferative neoplasm. My hematopoietic stem…

Incredible story, just pure resourcefulness and grit in following this through. I know it sucks to have this disease, but kudos for how you approached this.
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