
Pre-Existing Immunity to CRISPR Found in 96% of People in Study - sethbannon
https://www.xconomy.com/boston/2018/10/29/pre-existing-immunity-to-crispr-found-in-96-of-people-in-study/
======
nickles
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](https://www.biorxiv.org/content/early/2018/04/04/295139)

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

~~~
meowface
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.

~~~
naravara
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)

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

~~~
justfor1comment
This is the plot of the Trunks storyline in Dragon Ball Z.

------
nickelcitymario
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.

~~~
chongli
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.

~~~
jamesrcole
> _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

~~~
SmellyGeekBoy
> 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.

~~~
jamesrcole
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?

~~~
wgjordan
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.

~~~
jamesrcole
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?)

~~~
abundant
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.

~~~
jamesrcole
It's a well-established, respectable area of research.
[https://en.wikipedia.org/wiki/Cognitive_bias](https://en.wikipedia.org/wiki/Cognitive_bias)

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

------
grenoire
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?

~~~
virusduck
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.

~~~
TheSpiceIsLife
Could this be a potential cancer therapy?

~~~
virusduck
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.

~~~
amelius
> 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?

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

~~~
dogma1138
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.

~~~
User23
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.

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

------
virusduck
Actual article:
[https://www.nature.com/articles/s41591-018-0204-6](https://www.nature.com/articles/s41591-018-0204-6)

This is perhaps not surprising, but still very disheartening news

~~~
nvahalik
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.

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

~~~
codeulike
I think "who left that hammer there?"

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

~~~
emiliobumachar
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.

------
reasonattlm
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.

------
jf-
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.

------
jjcm
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?

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

------
plaidfuji
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.

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

------
The_rationalist
What about the arguably superior and patent free Cpf1 ?
[https://en.m.wikipedia.org/wiki/CRISPR/Cpf1](https://en.m.wikipedia.org/wiki/CRISPR/Cpf1)

~~~
88e282102ae2e5b
Cpf1 is patented, it's just that there's no dispute over who owns it.

~~~
The_rationalist
Sorry for the delay, SOURCE please

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

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

~~~
gowld
What could possibly go wrong?

------
Uhrheber
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.

