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Pre-Existing Immunity to CRISPR Found in 96% of People in Study (xconomy.com)
310 points by sethbannon 3 months ago | hide | past | web | favorite | 93 comments

This will likely not be an impediment to treatments based on CRISPR. The study has been available in preprint form for ~6 months on biorxiv [0]. At least some of the companies researching CRISPR were aware of this issue at the time the paper was released. It has since been mitigated, as specified at the bottom of the article. From Gaetan Burgio's tweets:

"Published now in @NatureMedicine on #CRISPR & Immunity to SpCas9. 6 months has past since the preprint was online & it is a long time in the CRISPR field. Since then additional work showed how to circumvented this by modifying Cas9 protein or using Cas9 orthologs. So No panic !" [1]

[0] https://www.biorxiv.org/content/early/2018/04/04/295139

[1] https://twitter.com/GaetanBurgio/status/1057206850213441542

It's really amazing that humanity is at the stage where we're intentionally evading our own immunity to bacterial components so we can repurpose the components to help ourselves.

I know right. I also just came from an article that had to use an electron microscope to photograph the accelerometer in our phones. I never realised how small things have gotten.

"iPhones are allergic to helium"


What if it’s actually just time travelers coming back to code the immunity into us to protect us from the unintended consequences of gene hacking?

(This is a joke, in case that needs clarifying)

It's already like hacking some alien computer in a short amount of time :)

There's got to be a great scifi story in there somewhere.

This is the plot of the Trunks storyline in Dragon Ball Z.

but it's a bit sad that it can't intentionally help it to handle cancer.


By the way, "cancer" is a class of diseases, not a single disease to treat, and many of them currently have CRISPR-derived treatments being actively developed.

Looking forward to the days that even the worst kinds of cancerous tissues would be a drug or two away from complete destruction. I hope that at one point, when someone asks about what would happen if a single maintainer of a project gets cancer tomorrow or gets hit by a bus, the answer would be, "well she/he can take a pill, and, what is this 'bus' thing you oldies keep joking about anyway?" :)

Cancer is my worst fear and has also killed so many of my family and loved ones. It's a slow painful death where you get progressively weaker. I really do hope there is some light at the end of the tunnel there.

I'm no expert. Do you believe it's just a question of time ?

Well, the experts do at least.

I think this is obvious to anyone familiar with bacteria and immunity. The headlines will go for the 'CRISPR is dead" angle, but the work arounds are simple and relatively easy to implement. I think the article is still extremely valuable. It shows that, yes, we target CRISPR just like any other microbiome protein hanging out in a mucus membrane. But it also shows that it's not a threat (or an indicator of a threat).

So to the non-geneticist noobs (like me), is it correct to interpret this finding as suggesting that the promises of CRISPR may be dead in the water?

Does this mean all the hype was nothing more than hype?

Should anyone with investments in CRISPR be seriously looking at dumping their stock?

Should anyone who was holding out on CRISPR to give us super powers / cure disease / etc start drinking copious amounts of alcohol instead?

Despite my tone, I seriously am asking what the implications of this are, because it's not my area of expertise.

CRISPR holds way more promise than silly fantasies of human genetic enhancement. The most exciting and practical uses for it apply to challenging everyday problems: food, energy, invasive species, biodiversity.

Besides, the ethical problems with experimenting on human beings are extremely intractable.

> CRISPR holds way more promise than silly fantasies of human genetic enhancement

I really dislike pandering, dismissive statements like this.

What's so inherently wrong with the entire category of genetic "enhancements" (changes for a perceived positive benefit)? You can't respond to this by just pointing out some proposed enhancements or motivations that are silly. I'm asking why you object to the very idea of any enhancements.

What about changes to make the following at some point in the future (these are just to give the general idea of positive changes, I'm not saying CRISPR could necessarily be used for them). These are things that in principle could be addressed by genetic "enhancements".

- stop people from getting diseases like celiac disease

- lessen our evolutionary desire for fatty and sugary foods (that no longer makes sense in the modern world, and which causes great harm)

- address some of the more egregious cognitive biases that cause so many problems in the world

> address some of the more egregious cognitive biases that cause so many problems in the world

I'm not sure how to interpret this - are you saying we should use CRISPR to make people think a certain way? If so this seems like a pretty horrific suggestion.

Humans are, for example, very poor at making risk assessments. Evolution has "programmed" our brains to focus too much on certain things and not enough on others. These heuristics might have made sense in ancestral environments bit are quite harmful in today's world. Evolution has already "made us think a certain way". Why would it be so horrific to, for example, lessen certain of those tendancies, if they are harmful?

In order to consolidate the consensus needed to genetically alter specific 'cognitive biases' that are 'harmful' to 'humans' in 'today's world', you'll probably first need to establish a global totalitarian dictatorship ('take over the world'). That adds an extra technical challenge beyond CRISPR itself, but you can always shoot for the moon and land among the stars.

Why do you think it'd require a global totalitarian dictatorship??

(Also, why do you put 'cognitive biases' in quotes, as if it's a notion of suspect legitimacy?)

One reason to maintain skepticism about the “cognitive biases” concept is that the phrase implies a value judgment— “cognitive heuristics” would be a more value-neutral framing.

It's a well-established, respectable area of research. https://en.wikipedia.org/wiki/Cognitive_bias

You think simply because it implies a value judgement that you can be skeptical of it?

How are you going to enforce your eugenics program when a sizeable chunk of the population resists it?

Who said anything about a program enforced on people??

Also, you're assuming it would necessarily be something people resist. Remember that this could be quite a fair way into the future. By that time our understanding of things like the human brain and how it works (and of all its limitations), and of how to change details of our bodies and brains, may be very good and well-accepted, such that it's not a big deal.

And, regarding "How are you going to enforce your eugenics program" (emphasis added), grow up.

Forcing all humans to think one specific 'rational' way, eliminating all 'cognitive biases' to the contrary is definitely something people resist. Not everyone shares your world-view, value system, etc.

And "eugenics" is 'a set of beliefs and practices that aims at improving the genetic quality of a human population' [1], which is exactly what you're talking about here. There's a reason the term has fallen out of favor since WWII.

[1] https://en.m.wikipedia.org/wiki/Eugenics

Who said anything about forcing people!?! I literally said "Who said anything about a program enforced on people??" in my previous comment, and yet you seemingly are going out of your way to misrepresent what I'm saying.

Who said anything about "Forcing all humans to think one specific 'rational' way, eliminating all 'cognitive biases'", either! Show me anything I wrote that even suggests this.

> And "eugenics" is 'a set of beliefs and practices that aims at improving the genetic quality of a human population' [1], which is exactly what you're talking about here.

Show me where I said it wasn't "eugenics". (but there's a big difference between forcing people into it and it being voluntary. There's also a big difference between various alternatives for what the genetic changes are, and I've been very clear about what sorts of things I'm talking about).

I'm amazed at the disconnect in this subthread between what I have actually said and what people are claiming I said!

Changing how people fundamentally think and reason about things is a big deal. Probably the biggest deal out of your suggestions from a societal perspective. Such transformative things will be met with pushback, and if such a program is deemed beneficial by the powers-that-be it will be pushed upon the populace through means anywhere from marketing campaigns to outright genocide.

To suggest otherwise is to ignore history.

And since you suggested it and are actively defending it in this thread, yes it is yours in the context of this thread. Own it.

I'll ask you the same question I asked the other person

Humans are, for example, very poor at making risk assessments. Evolution has "programmed" our brains to focus too much on certain things and not enough on others. These heuristics might have made sense in ancestral environments bit are quite harmful in today's world. Evolution has already "made us think a certain way". Why would it be so horrific to, for example, lessen certain of those tendencies, if they are harmful?

The examples I gave are hardly of "Changing how people fundamentally think and reason".

> Such transformative things will be met with pushback

It certainly could be. There's also what I said in my last comment, about why that's not necessarily so. Which you have ignored.

> if such a program is deemed beneficial by the powers-that-be it will be pushed upon the populace through means anywhere from marketing campaigns to outright genocide.

That is such a ridiculous argument to make in response to what I have said.

That is to assume that 1) the governments feel so strongly about it and 2) feel that they need to go to extreme lengths to make their will accepted. There is no reason to think that either of those conditions would be true in the case of DNA modifications like I have talked about. You certainly haven't attempted to argue for it.

Your argument could be used against any suggestion. "If such a program of combatting global warming through enforced tax on carbon is deemed beneficial by the powers-that-be it will be pushed upon the populace through means anywhere from marketing campaigns to outright genocide." See how ridiculous that sounds?

> And since you suggested it and are actively defending it in this thread, yes it is yours in the context of this thread.

Grow up. You said "How are you going to enforce your eugenics program". Show me where I said anything that even implied some sort of 'program' that is 'enforced' upon people, or that I had some sort of plan to do so? Don't try to make it out as if you were saying something else.

> lessen our evolutionary desire for fatty and sugary foods (that no longer makes sense in the modern world, and which causes great harm)

What about making them harmless instead? Surviving on donuts (plus perhaps supplements) and staying perfectly healthy... Think about it! :D

Sure, that kind of thing might be an option too.

> I really dislike pandering, dismissive statements like this.

And I (as a scientist) really dislike having to frame everything I do as being relevant to human medicine for laymen to appreciate it.

Some things are extremely valuable even if they can't be used to treat cancer and congenital disease.

I can appreciate that.

My only counterpoint is that I and many other "laymen" (as apparently we're referred to?) can't be expected to appreciate your work if you can't explain it.

It's not like genetics is the only field that struggles with this. I'm primarily a web developer and still remember the 10+ years of trying to explain to people why "The Web" was an important technology that would radically impact all of our lives. I still remember the bubble. I still remember being told this was a dead field. Where are those people now?

I remember how dismissive people were about mobile apps, too.

The same challenge applies to AI, blockchain, virtual/augmented reality, etc.

As a non-scientist, I struggle to explain to people why it's important that we increase our funding and support for all of the sciences. It's hard to appreciate how seemingly "useless" discoveries combine with other "useless" discoveries to give us the amazing advances in technology and medicine that we have today.

BUT, we have to try.

And when some "layman" dares to ask about the meaning of such-and-such a discovery, maybe take a deep breath, recognize we don't all have you incredible knowledge about this topic, and appreciate that someone is expressing interest in what you do, in the only terms they have available to them.

All of which was a long-winded way of saying: All I know about CRISPR is what I read in relatively mainstream publications. Help me out. Or don't. Your call, really.

I re-read the thread and you're right, you were a bit unfairly "attacked" for asking a reasonable question. I focused on what you said without taking context into proper consideration, sorry for that. I was not responding to your original question, but more so to ... something in my head I guess.

Of course, absolutely, explaining what we do is hugely important. Actually I think that bringing new knowledge to the rest of humanity is the second most important thing after actually generating said knowledge.

> can't be expected to appreciate your work if you can't explain it.

The frustration is that people only seem capable of appreciating science when it has direct and tangible benefits for humans. (and that's why i posted the previous post, not cause you dared ask a reasonable question)

"Why do you do this?" "What can we use this for in humans?"

In addition to what you've said about the frustration, there's the following.

Basic research is vitally important, and has contributed so much to society. Yet by its very nature you can't predict if how any specific piece of basic research will provide benefit.

It's a fundamental misunderstanding of basic research and scientific and technological development to expect to be able to know, and thus say, what the benefits might be.

Rather than expecting to be able to predict the benefits, we have to have a more 'statistical' set of expectations. That, on aggregate, and over time, basic research will provide substantial benefits.

And it's not just the general public who don't appreciate this. I find that many people working in applied research don't appreciate it either.

Completely agree :-)

(And no apology needed... I shouldn't take things so personally.)

How is a CRISPR trial on a terminal patient any different than another experimental medical trial on that same terminal patient?

Because you don't modify the genetics of terminal, living adults, you want to modify the genetics of single-cell healthy zygotes (who will, you hope, later develop into healthy adults).

Sure you do. A lot of the promise of CRISPR therapies were for modifying cells in an adult or child. Using CRISPR/cas9 to “fix” a genetic issue in someone who was already born. For example for adding back a good copy of the gene that causes cistic fibrosis or sickle cell anemia. There were also potential cancer therapies based on the technique.

In these cases, the presence of cas9 antibodies is a severe limit to many of the techniques that these companies were working towards.

I agree. My father has terminal cancer and has been practically banging down doors to try to get onto medical trials for new experimental treatments. If other people in his position want to do the same thing then who are we to judge?

No. Working around this takes some effort but is straightforward and uses well-known, existing techniques. There's a lab I know of that considered trying to modify the protein so it could evade the immune system, but they decided against it since they figured the group that published this paper would have too much of a head start and there's no way they'd be able to compete. I'd give it a year or so, and that's assuming none of the other Cas9 or Cas12a variants are already usable.

It sounds like they can work around this with immunosuppressants. Which may be for the best... you wouldn't want random bacteria to be able to edit your genome at any time, would you?

Well CRISPR works in flies as some of the fly stocks have been switched from using RNAi to CRISPR for their gene edits.

Fly immune systems obviously are quite different. But the technique still holds a lot of promise. Like any cutting edge technology there are potential problems in developing it into useful therapies, and there is a chance something better will come along and displace it.

It is very difficult to edit all the dna of living organism as each cell has a copy. Easier to do as an organism develops.

This is how you get Brundlefly :O

Do you think humans would stop at the first hurdle they encounter in their endeavours? How about the 99th hurdle? CRISPR is a naturally occurring gene editing tool. We have only recently started engineering solutions using it. Once this tool meets the full might of human ingenuity and our constant resolve to improve things, it can overcome great biological challenges. Eliminating disease carrying pests, curing genetic defects in children, shortened crop cycles, tastier strawberries these are some amazing possibilities that CRISPR holds. It might take some time but we will get there. So no the game is not over. It won't be over as long as we have a few humans on the case.

What the layman thinks of genetic engineering magic is going to have to happen in the germline. That means it's not going to help you or me or anyone else already alive.

This is true for most genetic engineering applications but not all. Somatic gene therapy has been successfully performed in a few cases. There will almost certainly be more applications in the future, and it’s reasonable to expect that they will be able to handle some prevalent diseases (such as all types of diabetes).

The only approved genetic therapies (Luxturna, Strimvelis, Glybera, others) are all for children or adults. To say you can only use it for germ line modification is just plain wrong.

True but that’s purely for legal/ethical reasons, not (directly) scientific ones. Most scientific uses of CRISPR (and other gene editing techniques) by far happen in the germ line. Germ line research (and, thus, applications) are lacking in humans not because it would be scientifically hard, nor because it won’t eventually happen, but because of hard ethical problems with such research.

And the comment that I replied to implies that it is talking about certain applications of genetic engineering which have to happen in the germ line. So I disagree that what it says is “plain wrong”, it’s just incomplete.

I’d say it’s less for ethical reasons (though that’s true) and more because the technology for modifying germ lines is nowhere near as advanced as inserting DNA into non-germ line cells.

We have no idea what the impact would be for modifying germ line cells in a developing human being.

I hope not. CRISPR has a lot of potential to change our lives. I thought they're actually a little closer to finding solutions to treatments of incurable diseases and giving us life longevity. Now I'm not so sure.

Anything as powerful as CRISPR will most likely be misused and have a very high error rate/unexpected consequences initially anyway:


CRISPR is definitely going to go through the "hype cycle" - as in the hype will die out long before we can prove it can be safely used in humans, and these achievements will likely happen in the background over several decades time span.


The difference between CRISPR and many other overhyped technologies is that CRISPR has already proven its mettle. It’s being used productively daily in labs across the world and has lowered the cost of performing many experiments, or even made new experiments possible in the first place.

You’re right that there’s a certain amount of hype surrounding CRISPR, especially when it comes to potential medical application (whether this works remains to be seen, although I and most people in the field remain optimistic). But until something even better comes along I don’t think interest in CRISPR will die down soon.

This is very interesting, is it maybe that CRISPR resembles attacks we faced from viruses and the likes during our evolution as a species, that we have such high rates of immunity to it?

The enzyme commonly used for gene editing is from a bacteria that is a common human pathogen. Bits of these bacteria (including their Cas9 protein) are recognized as foreign. Unfortunately, when gene-edited cells are expressing the Cas9 protein, bits of every protein in the cell, including Cas9, naturally get processed and presented on the surface of the cell. There are immune cells (T cells) that monitor for non-self protein bits on the surface of cells, and when non-self is detected, they kill that cell they perceive as infected.

There's a bit more nuance than this, but this makes it significantly more difficult to pull off gene editing in a human.

Could this be a potential cancer therapy?

In a way, sure. A major roll of the immune system (especially T cells) is to monitor for unusual cells. Some pre-cancerous cells display unusual markers that are recognized and killed by T cells. Those that evade T cell recognition go on to be a problem.

The major problem is still how do you target cancer cells? If you can find something that makes them unique, say a cell surface receptor, or an unusual metabolic process, there are lots of ways to target them for removal. It's just hard to uniquely identify cancer cells. Right now, most chemotherapy drugs target the phenotype of "fast replication" which really isn't too selective.

> It's just hard to uniquely identify cancer cells.

How about performing whole-genome sequencing on a tumor, and then targeting the differences with the patient's natural genome?

That is a potential approach. However, the things that cause cancer are typically dysregulation of self proteins. These are usually things that stop and start cell growth and replication. In these cases, it is not totally clear in these cases what can cause recognition (perhaps overabundance causes higher presentation on the outside of cells and maybe enhanced recognition by some T cells can cause killing--I am speculating as I'm a couple years out of date on the literature).

Other cancers there may be a mutation in one of these genes that makes it more or less effective and lead to cell cycle deregulation. Those are good targets for T cell killing.

In any case, it is probably a more effective approach in cases where we understand potential epitope targets to directly expand T cells that can do the killing rather than having some intermediary in the mix.

Tumor cells encode the same genes as non-tumor cells.

The difference is more likely to be in the expression level or epigenetic (de)repression of a particular gene than the presence or absence of that gene. Organisms don't tend to keep around genes that only serve to form tumors.

A slightly better approach would be to use RNA-sequencing to look for mRNA signatures in tumor vs normal cells.

Wouldn't work reliably due to cases of genetic chimerism, though that could possibly be tested for. Though, in several cases I've read about, there was no consistent place to get samples to test for mismatched DNA.

That sounds way more complicated (expensive) than using a minimalist signature to identify cancerous cells.

With desktop gene sequencers becoming a near commodity product I’m not so sure.

There are a companies that currently focus on this area specifically by leveraging the ever dropping costs and capabilities of gene sequencing by developing targeted immunotherapy solutions that can target the specific genetic makeup of a tumor from a biopsy.

This is all based on the assumption that our understanding of in vivo processes is as good as our understanding of in silico processes. It isn't. Not even close.

But that's also true for mainstream/existing therapies.

My thoughts exactly! Here's how it might work :

Get a construct into the cell that is only transcribed if specific pathways are overly active, effectively testing that cells "cancer status". This is the hard part.....

Then have it translate something pathogenic-looking that gets presented on the surface.

So now the question is, how do you design some kind of promoter sequence that looks for, say, tp53 mutations or something similar?

I like your silver-lining take on this. It wouldn't be bad low-hanging fruit to look at if someone hasn't already done that study.

Per the article > "Michael Schmueck-Henneresse of Charité University Medicine Berlin, who led today’s study, said that he was initially surprised by the 96% finding. “But it made sense because the Streptococcus pyogenes bacterium is one of the most common causes for bacterial infections in humans and we have all been through multiple infections and potentially even been colonized by it,” "

> we have all been through multiple infections

Does that mean it could be used when young, before the immune system is primed?

Actual article: https://www.nature.com/articles/s41591-018-0204-6

This is perhaps not surprising, but still very disheartening news

I could be wrong, but this seems like a blessing in disguise. Maybe I'm just totally ignorant about CRISPR but from what I have read, it seems like this is totally wild-west/uncharted territory. This seems like one of those technologies that could have massive unintended consequences. Perhaps this is a _good_ thing rather than a bad thing.

When you see a hammer lying around, do you think of the things that could be built or the things that could be destroyed?

I think "who left that hammer there?"

Depends on how old I am/mature I'm feeling. Presently? Build. 6 years old? Bottle and rock smash time.

Personally, I make a mad dash to it before one of the kiddos decides to smash something with it!

Hammers don't have unexpected, wide reaching consequences generations down the line, by which time it's too late to do anything about it.

Hammers don't also fundamentally change the course of evolution.

It's like comparing a slingshot with a nuclear missile

Does that mean if we introduce modified enzyme to circumvent this immunity - bacteries could steal it and become much more dangerous?

It depends on how we make the enzyme. If it's made without involving life in any way, it's hard to imagine how bacteria would "learn" to make it after finding it. At most, opportunistic bacteria could better parasite people already loaded with enzymes from CRISPR treatment.

If we modify harmless bacteria to build the enzyme for us, then sure, the modification could well end up on harmful bacteria.

Immunity is the standard problem for most vectors for gene therapy. Viral vectors have neutralizing antibodies, liposomes get eaten by macrophages, and so forth. Minimizing this issue to the degree needed for a therapy to work is the subject of a great deal of effort over past decades, and ongoing today. It isn't a solved problem, but there are many incremental approaches that, when combined, can let therapies work well enough given good engineering and good fortune.

CRISPR Cas9 is present in somewhat varying forms across many (all?) bacteria. I don’t have the quote to hand but I know CRISPR from bacteria that rarely or never come into contact with humans (think extremeophiles like deep sea thermal vent bacteria) doesn’t provoke an immune response, as it’s slightly different in form and novel to the human immune system. This is not a huge setback for CRISPR research.

Also you could argue that the title is misleading, as stating that CRISPR evokes an immune response is inaccurate; CRISPR from a bacterium that frequently comes into contact with most humans evokes it, and not all CRISPRs are the same.

Could we not just use immunosuppressants to give the crispr editing enough time to spread? Once the genes are edited, purging the CRISPR delivery mechanisms from the system should be fine, correct?

This is discussed in the article. Maybe read before commenting?

I see this as more of a reminder of the strength of our immune system than a failure of any particular technology. As a recent post on HN said, fall in love with the problem, not the solution. Whether or not CRISPR works, there’s an enormous community of people who devote their lives to treating genetic disease, which is the underlying problem. At the same time, I’m glad my body has the ability to stop some random bacteria from editing my genome with minimal effort.

"Exploring protein orthogonality in immune space: a case study with AAV and Cas9 orthologs" https://www.biorxiv.org/content/early/2018/01/10/245985

What about the arguably superior and patent free Cpf1 ? https://en.m.wikipedia.org/wiki/CRISPR/Cpf1

Cpf1 is patented, it's just that there's no dispute over who owns it.

Sorry for the delay, SOURCE please

Well, if CRISPR fails it was worth a try anyway. What other potential breakthroughs you got?

Maybe you could deliver the CRISPR payload through some sort of pathogen-like mechanism such as a virus

What could possibly go wrong?

That’s in fact what is being done.

Maybe we're living in a time loop, where the global gene manipulation catastrophe (aka Zombie Apocalypse) has already happened, and we, as the descendants of the survivors, are immune to it.

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