As far as I know a few labs in this space are operating under the basic question, "why haven't viruses killed everything by now?"

So this category of research is more or less the answer.

> Do mammals have a CRISPR analog?

Not exactly. There are things like https://en.wikipedia.org/wiki/Ribonuclease_L that nuke cells and are stimulated by interferons. This might be why interferon injections are common chronic therapeutics for diseases in this space.

The closest thing we have is probably whatever adaptability B or T cells can muster on their own? I'm sure someone lurking in the comments has a better answer.

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 on undruggable conditions that exhibit known driver mutation profiles is profound.

Source: I have personally funded novel research based on Cas12a2 for an undruggable condition I have. I have personally seen my condition "cured" in vitro using this technology and it left all of my WT cells unharmed. Some of the researchers I've funded are co-authors in the paper linked. I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.

Yes! That's the next step. There wasn't a mouse model for my variant so they're building that, too. But in vivo testing should be underway this calendar year.

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 cells (HSCs) acquired this mutation and they produce busted downstream products.

Most notably, one of those downstream products are hyper-lobulated megakaryocytes that spew inflammatory cytokines into my bone marrow and destroy the bone marrow niche over time. The destruction happens specifically because the inflammation mobilizes stromal cells and they erroneously produce scar tissue (fibrosis) all along the walls of the good, spongy marrow. There are other sources of damage but this is the one path most aligned to abbreviated survival and transformation into AML.

In effect, my bone marrow is rusting and very slowly failing. The failure could speed up with the acquisition of additional mutations or any other systemic inflammatory condition.

Anyway, 3 years ago my first retail hematologist told me "it's rare, you're fine, take aspirin and go home."

I couldn't accept that - this seemed bad. I decided that if I wanted to know the truth I needed to physically stand in front of the foremost expert in the world on the topic and ask them "what is the state-of-the-art?"

I came to this conclusion after about a year of reading all the most well-cited academic papers about AML, Myelofibrosis, and Essential Thrombocythemia. In particular, anything that mentioned MPL. There are virtually no papers mentioning MPL.

To put that in perspective: 500,000 patients in the US deal with the broad disease category. 5% of those are MPL, and 40% of those are the -K variant. So 10,000 people - which means anything targeting it would be well into orphan drug designation territory. I'd need to find a pretty niche researcher.

So, I laddered up the academic food chain using a little cash (donations), emails, airline tickets, and conference admission. ~2 years after my diagnosis I found myself in a closed-door session called the MPN Roundtable in Chicago with 100 of the foremost experts in the world. No cameras, no transcripts, just some of the greatest minds in the field earnestly debating the path forward to a cure.

I listen carefully to them, ask dumb questions, connect dots across research. I rehomed my care to an academic research hospital specializing in MPN research, and started funding research on the condition it includes my specific MPL mutation. Researchers happily oblige.

Cas12a2 was the keynote topic at this year's meeting and there was _very little_ dissent.

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.

Even a charitable read is condescending. This person just wrote they are in the innermost research circles. I think they are beyond the "scary name" - needs reassurance phase.

How much overall has this costed you? Do you think that a middle-class person could afford to do what you did?

> So, I laddered up the academic food chain using a little cash (donations), emails, airline tickets, and conference admission. ~2 years after my diagnosis I found myself in a closed-door session called the MPN Roundtable in Chicago with 100 of the foremost experts in the world. No cameras, no transcripts, just some of the greatest minds in the field earnestly debating the path forward to a cure.

Why don't they allow recordings at the MPN Roundtable? It could be useful for others to learn from.

For this project, seed capital low six figures. I am collaborating with family and friends, non-profits, and using doubling mechanisms available to me to at work to fund the very early speculative bench research. This is where we are and its sustainable today.

Once we have the basic tech worth scaling up - to raise the first round of capital, I estimate $1-2m with a wider friends & family and angel investor round. This will be early de-risking research and delivery mechanism testing.

Beyond that I can see a path to a ~$20m round to further de-risk any assets that come out of these speculative efforts, but I haven't gotten this far.

In rare disease therapeutics the challenge isn't raw capital, it's finding the _right_ capital that understands how assets like these get de-risked and can tolerate the shape of the upside. Anything CRISPR-based is usually not a chronic therapeutic, so that disqualifies most of big pharma. Acute, curative technology like this requires informed capital.

> Do you think that a middle-class person could afford to do what you did?

Yes.

In the rare disease field even a small amount of capital attracts enough attention to have meaningful conversation with bench researchers. If you're willing to travel to the niche conferences, ask dumb questions, grind out the studying, and approach the speakers after their sessions.

Researchers respect people who do their homework and mobilize to meet them. They want (need) to hear from patients and caregivers - so they tend to listen very carefully.

Fun fact: I've had multiple researchers ask me for samples of my bone marrow. Has only happened in-person :)

> Why don't they allow recordings at the MPN Roundtable? It could be useful for others to learn from.

I don't know, it's been going on for a while. I can speculate: they're discussing pre-publication data, some of which had come out of their labs only hours prior to their presentation. It's completely unfiltered. I think there's real risk of some of the things that are shown being sensationalized or taken out of context.

The audience is trained and practiced in keeping a sober, skeptical lens on everything they see - so it's more about the debate and tear-down of the early data for the betterment of the niche.

There's zero attempt to hide anything, it's just a forum for collegial debate.

As an aside if you end up cryogenically freezing yourself for a future treatment don't forget to actually cure your boneitis when they thaw you out.

> other folks dealing with a tough diagnosis

The toughest part has been the spiritual journey. Loneliness unlike anything I've experienced. I felt forgotten without the opportunity to be known in the first place. I was happy - and emotional - to learn I wasn't alone. It took me 2 years, but I've found my people.

It’s only a matter of time before the next better thing shows up.

The approach I'm reviewing now uses lipid nanoparticles (LNPs) for delivery. It isn't great for targeting my bone marrow condition but its workable. The team hasn't optimized it at all, either. There are also viral delivery mechanisms that I haven't studied yet.

The collateral damage problem is the backpressure on the delivery problem. If you get really good at delivery, you can destroy A LOT of cells very quickly. The human body (usually) responds to these events by releasing a lot of pro-inflammatory cytokines. This can lead to cytokine storms or worse.

As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.

> 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 certain aggressive cancers. It has never been a super-effective technique, despite all the promo of how monoclonal antibodies are so accurate.

> As you "get good" at killing the target cells, the net effect can turn bad. It will probably be a balancing act.

That's already the status quo in the whole cancer field. I don't think that more than sloppy accuracy is acceptable for any gene therapy - and the off-target cleaving of CRISPR has always been the number #1 problem here.

Valid critiques of Cas12a2 must acknowledge the mechanistic differences between Cas9 and Cas12a2. There is no research to suggest Cas12a2 is "sloppy" and significant research that demonstrates it is not "sloppy."

I appreciate the skepticism but I would encourage you to study the actual mechanism discussed in the paper.

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.

This is my understanding as well.

Yes, this is an approach. This starts to exceed my understanding of the problems the teams are facing - but there are concerns about the efficacy of Cas12a2-based approaches fading. Not because the cells adapt, but because your immune system starts acting funny in the presence of the payload.

I don't recall the specifics but there seems to be a window of opportunity for these things.

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.

Enemy #1 in a large data center is power. When he mentioned the entire rack pulls 1,000W for the density suspected in this thread (~500TB to ~1PB), that piqued my interest. Even if you can't push 2-3PB per rack, the top stat you're crunching forever and always is watt-per-gigabyte. Space is important but if it breaks into the top spot you've done something else wrong along the way.

Enemy #27 for cold(ish) storage might be, say, pressure per sq. in. on your floor. I'd be interested to see a weight comparison of a fully-loaded LTO/cartridge rack and this design.

Perhaps not what you were looking for in an answer, but I'm interested to look over the schematics.

The FISA court of 11 judges is appointed by the Chief Justice of the United States. [2] It absolutely is an Article III court. The ACLU has even acquired its rules [3].

The fact this is the top comment without citation is troubling. Please don't encourage these sort of claims without at least a cursory glance at the documents governing these institutions.

[1] http://www.law.cornell.edu/constitution/articleiii [2] http://www.law.cornell.edu/uscode/text/50/1803 [3] http://www.aclu.org/patriot_foia/2003/court_rules.pdf

I don't think membership consisting of judges who would otherwise preside over Article III courts necessarily makes FISC an Article III court, and judges appointed by the Chief Justice actually suggest the opposite.

There's an article at the Yale Law Review that criticizes FISC for not being a regular Article III court.

It is very easy to get caught up in examining the mechanism itself as a way of stamping out the abuse of the mechanism. As much as I dislike what the court represents, I can't fully qualify its dissolution.

In 50 USC § 1803 (b) it specifically states the Supreme Court has jurisdiction over the decisions. The Title itself is designed for expediency and proximity - something its "parent" court isn't designed for.

I don't think the evidence we have is reliable enough to call someone "wildly misinformed" or "intentionally misleading", though.

Perhaps not. However, my original challenge to rayiner's comment has produced far more meaningful and mostly-cited comments. Could it have been less inflammatory? Absolutely. Would it have produced this discussion if it had been? Uncertain.

The original comment did not add any value to the post. I have never read Orrin Kerr's writings and both of you citing him caused me to do so.

Perhaps citing Kerr in the original comment, as he has well regarded opinions on the subject, would have been additive as I assume rayiner intended to be.

After all, if we don't challenge for citation and additional information, what are we doing here?

That said, I don't think Glidden v. Zdanok unarguably supports the idea that FISC is an Article III court (though Kerr doesn't claim it does), just because it is composed of article III judges. Glidden is actually about the opposite question: whether the judges were article III judges based on whether the Court of Claims and the Court of Customs and Patent Appeals were article III courts. And most of the analysis of Glidden focuses on things like the courts' ability to hear justiciable cases and controversies and to exercise the Article III judicial power. Under these criteria, you cannot call the FISC an Article III court because it can't even hear any cases and controversies, nor can it exercise the essence of article III judicial power (the power to render binding, final judgments with regards to matters affecting life, liberty, and property).

So I would personally call the FISC an Article I court staffed by Article III judges sitting by designation. But I worry it would be an idiosyncratic use of the term. In any case, whatever you call it, it is clearly not empowered to exercise even a substantial amount of the Article III power, which is the substance of my point. It can't put you in jail or take your property.

Obama said yesterday,

"On this telephone program, you've got a federal court with independent federal judges overseeing the entire program," the president continued. "And you've got Congress overseeing the program, not just the intelligence committee and not just the judiciary committee, but all of Congress had available to it before the last reauthorization exactly how this program works."

This is slippery and brings to light a problem with FISC. Its judges are independent, but the process is not. The FISA process (necessarily!) begins with the premise that NSA has a Constitutionally unchecked authority to conduct foreign surveillance.

I think this would be fine, were it not for the fact that NSA seems to be transitioning from a role that was principally involved in nation-state intelligence to a role that is inextricably bound up with law enforcement. You can see the problem when Mueller starts talking about what it would take for FBI people to dig deeper into NSA work product. The FBI shouldn't have access to NSA product to begin with.

Any organization will act to grow its responsibilities and thus its resources. The USA has no real enemies anymore, and yet these agencies keep growing. Organizations will grow until they encounter some sort of limit.

Is the problem that those who would previously have overseen these agencies and curbed the over-extension you cite no longer want that oversight role, or that they are no longer capable of that oversight role? Barrack Obama talked on the phone all his life just like all other Americans do. His predecessors were the same. What kind of President would be able to cut the NSA budget?

But we do have an unmistakable and terrifically serious security problem: proliferation. We spent decades in an arms race with a foreign power that built an arsenal that could end the world several times over. When we won, they disintegrated. Meanwhile, the technology to duplicate atomic weapons technology that we had in the 1950s is improving.

There isn't a lot of foreign surveillance I can imagine having a problem with allocating to the problem of nuclear proliferation.

This would be an excellent priority for our intelligence agencies. Do any of the practices revealed recently seem designed to address that priority? An adversary capable of obtaining, maintaining, and deploying nuclear weapons would probably be capable of secure communications even in the face of PRISM, whether here or overseas. The most likely vector would be something like a submarine or a well-shielded shipping container, but if the plan did require agents in this country I doubt those would be discussing their plans on Facebook or over the phone.

The set of skills required to carry out an atomic attack and the set of skills required to evade surveillance by NSA are disjoint and seem unlikely to get more correlated. But that's just speculation on my part.

My only point here was that "terrorism" isn't the only threat that NSA is tasked with dealing with.

https://www.eff.org/deeplinks/2013/06/public-first-secret-co...

"For the foregoing reasons, EFF's motion is granted in part. The Court holds that FISC Rule 62 does not have the effect of sealing copies of the Opinion in the Government's possession and that the Court has not otherwise prohibited the Government's disclosure of such copies in response to the EFF's FOIA request. This Court expresses no opinion on the other issues presented in the FOIA litigation, including whether the Opinion is ultimately subject to disclosure under FOIA. Such questions are appropriately addressed by the District Court in the FOIA litigation."

Treatable mental illness: depression, anxiety, etc. do not fall into this category. They are not terminal.

Proximity to an instrument of death when a person is contemplating suicide (due to treatable mental illness) is a very real issue. If there is no barrier in place, the rate of change from thought to action is astonishing.

It's also important to note intoxication plays a role in this same sort of escalation.

In these cases you're looking for anything which increases access (proximity) or reduces inhibition (chemicals). Eliminating these gives professionals and loved ones time to help.

Years ago when I was working at a small ISP in Columbia, SC I had lunch with Austin Meyer. He came in to upload the latest release of X-Plane to his FTP servers. We went across the street to get some shrimp and grits.

The man oozes genius. Over lunch he was rambling about some technique he discovered to render scenes at a much higher frame-rate. Something to do with culling and inlining a series of functions responsible for a very particular set of expensive transformations.

His almost hysterical, passionate, hyper, consuming personality made it a completely one-sided encounter. It was my pleasure to just sit and listen.

While we were walking out, I noticed the tail of his plaid shirt had come partially untucked. He had also missed 2 belt loops.

We're reading today about a man who legitimately doesn't have the cycles to spare for belt loops, let alone a patent battle. If for no other reason than to stop distracting people like Austin from doing what they do, we desperately need software patent reform.

Anyway. He probably thought I was a dope, but I still recall that lunch as one of my fondest memories while starting out in the industry.

When we built out our message queue offering at SoftLayer (which uses Cloudant/BigCouch as a data store), latency out to the DB cluster simply never ended up being an issue. Properly leveraging DB features, I/O priority tuning, the caching tier behaving properly - all more often these end up being the culprit in performance issues.

What you need to better understand when considering a cloud-based data store is who's running your cluster. When it comes to guys like Adam, Mike and Robert, you're going to be very hard-pressed to find better (and available to you) talent in the CouchDB world. We certainly appreciate having them around.

The catch is you'll probably want to do this in a friendly country or one you're already a citizen of.