
Cells edited using CRISPR–Cas9 injected into a person for the first time - snake117
http://www.nature.com/news/crispr-gene-editing-tested-in-a-person-for-the-first-time-1.20988
======
leggomylibro
So this title is a bit misleading; something like, "cells edited with CRISPR
injected into a person for the first time" would be better. While CRISPR is
promising for topological treatments, that's not what happened here.

The team took white blood cells out of a patient's body, used CRISPR to knock
out a gene which suppresses immune response, then injected those same cells
back into the patient, hoping that they would attack the cancer without that
inhibiting gene.

If this _were_ a live CRISPR treatment in a human, it would probably make more
sense to just knock out the activated oncogene(s) in the patient's cancer
cells and/or repair the deactivated tumor suppressant gene(s).

~~~
dave_sullivan
> it would probably make more sense to just knock out the activated
> oncogene(s) in the patient's cancer

I've been wondering about that for the past couple of years, since I heard of
CRISPR basically. Who is working on this aspect most seriously right now? Is
there any interesting published progress? I understand it will take a while to
make real progress, but mostly I'm just curious as an outsider to the
industry.

~~~
leggomylibro
I don't think anyone is; it's still too far out there. I'm sure that there's
plenty of research building towards it, but I couldn't name any names. I'm
also an outsider to the industry, but CRISPR is actually a simple protocol
that doesn't require much advanced equipment, and I've been looking into using
it for some home science projects.

The problem as I understand it is that right now, CRISPR requires some manual
steps in the lab to make it work well. You can design the protein and guide
RNA and spacers until you're blue in the face, but if you can't find a
specific enough cutting site on the genome, or one that is close enough to
your target, or something like that, you'll wind up with a lack of specificity
in that cut, which can lead to unwanted mutations. And since the CRISPR system
was originally a sort of bacterial immune system, it's really geared towards
'knocking out' specific genes by (I think, but I'm really shaky on this part)
introducing a bunch of extra mutations when the cut it makes in the DNA gets
repaired. But there are two kinds of repair mechanisms, and apparently there's
a way to encourage the more accurate one, although this is really an area I
need to read more about.

Anyways, the technique has also been used to introduce entirely new genes, but
I think that involves using modified CRISPR proteins called 'nickase's to make
single-stranded cuts in the DNA, rather than double-stranded ones. You
introduce plasmid DNA with your genes to match up with the cleavage sites, and
ideally it gets taken up.

Whatever the approach, you still aren't going to get 100% expression or
transfection, and stable transfection either requires invasive techniques like
biolistics (shooting DNA through membranes on accelerated nanoparticles) or
delivery by viruses, which has a lot of potential, comparatively minimal side
effects, and can even be targeted somewhat to certain types of cells. But I
think the FDA is nervous about, especially in humans.

Again though, I'm a layman here too, so someone please correct me where I'm
wrong :)

~~~
tropo
Project idea: The death cap mushroom is really tasty according to people who
are now dead. Disable the poison.

~~~
dekhn
you would do that chemically, after collecting the mushroom/while cooking it,
because that's easy.

~~~
tropo
not for the death cap

The poison is a bicyclic polypeptide that shuts down ribosomes in your liver.
Destroying or removing the poison is as difficult as destroying or removing
all the protein. (like dealing with mad cow prions) It's just not going to
happen unless you like your mushrooms charred pure black all the way through.
Well, that or dusty white ash.

Just half a mushroom will kill an adult human. This isn't something to take
chances with.

~~~
dekhn
Right, my protocol would have been: fully homogenize the mushroom, treat it
with an antibody known to disable all the toxins, then cook and eat. I wasn't
really proposing anybody does this.

------
banhfun
Here's a Kurzgesagt video about CRISPR for anyone that's curious:
[https://www.youtube.com/watch?v=jAhjPd4uNFY](https://www.youtube.com/watch?v=jAhjPd4uNFY)

------
mfoy_
I was reading Oryx and Crake and I was thinking "There's no way this could
happen... right?" then Trump said he basically wants to get rid of the FDA and
EPA and now there's talk of a biomedical duel in human gene-editing?

Oh boy.

I can't wait to get a rakunk, myself.

~~~
jakewins
With CRISPR, it's even better right; live gene editing. You can _be_ a rakunk,
rather than just _own_ one!

------
nonbel
>"The researchers removed immune cells from the recipient’s blood and then
disabled a gene in them using CRISPR–Cas9, which combines a DNA-cutting enzyme
with a molecular guide that can be programmed to tell the enzyme precisely
where to cut. The disabled gene codes for the protein PD-1, which normally
puts the brakes on a cell’s immune response: cancers take advantage of that
function to proliferate.

Lu’s team then cultured the edited cells, increasing their number, and
injected them back into the patient, who has metastatic non-small-cell lung
cancer. The hope is that, without PD-1, the edited cells will attack and
defeat the cancer."

Or maybe it was this:

>"The researchers removed immune cells from the recipient’s blood and then
_selectively killed most cells containing a certain sequence_ using
CRISPR–Cas9, which combines a DNA-cutting enzyme with a molecular guide that
can be programmed to tell the enzyme precisely where to cut. The _targeted_
gene codes for the protein PD-1, which normally puts the brakes on a cell’s
immune response: cancers take advantage of that function to proliferate.

Lu’s team then cultured the _surviving_ cells, increasing their number, and
injected them back into the patient, who has metastatic non-small-cell lung
cancer. The hope is that, without PD-1, the _selected-for cell population_
will attack and defeat the cancer."

Since there is no paper (only press release) we can't say much more about
which explanation is most plausible in this case.

~~~
ejstronge
Luckily the article linked to the clinical trials.gov record for this trial
[1] which suggests that the first approach (editing vs selection) is being
used.

1\.
[https://clinicaltrials.gov/ct2/show/NCT02793856?term=crispr&...](https://clinicaltrials.gov/ct2/show/NCT02793856?term=crispr&rank=4)

~~~
nonbel
That seems to be the favorite interpretation. We need to see what data they
present that favors it (ie % survival of the treated cells, number of initial
cells, % mutants at that location detected in control cells). Also, this is
kind of weird, because they say it is non-randomized:

    
    
      Study Design: 	
      Allocation: Non-Randomized
      Endpoint Classification: Safety Study
      Intervention Model: Parallel Assignment
      Masking: Open Label
      Primary Purpose: Treatment
    

But later it says:

    
    
      Progression free survival - PFS [ Time Frame: From date of randomization until 
      the date of first documented progression or date of death from any cause, whichever
      came first, assessed up to average 10 months ] [ Designated as safety issue: No ]
    
      Overall Survival - OS [ Time Frame: The time from randomization to death from any
      cause, assessed up to 2 years ] [ Designated as safety issue: No ]
    

So is the treatment randomized or not? The info on that site may not be
reliable... maybe it makes sense somehow though.

~~~
ejstronge
I would be surprised if this safety trial were randomized with respect to the
CRISPR manipulation. I agree with your assessment of needing more data to
believe that the gene editing manipulation was successful.

I suspect the randomization relates to the allocation to the experimental arms
as described on the reporting page:

    
    
        This is a dose-escalation study of ex-vivo knocked-out, 
        expanded, and selected PD-1 knockout-T cells from 
        autologous origin. Patients are assigned to 1 of 3  
        treatment groups to determine the maximal tolerant dose

~~~
nonbel
Nice catch, why do you think a safety trial should not use randomized
allocation of the treatment (but it does make sense for dose) though?

------
qoobaa
This makes me feel that i.e. looking for bone marrow donors may become
obsolete in some cases, _if_ we know the gene sequence responsible for the
disease. Instead of looking for donors, it may actually be possible to repair
bone marrow cells and inject them back, fixing the problem. Am I missing
something here?

~~~
xorxornop
Nope, not missing anything. It should also be possible to use it it to
reprogram mature cells (such as skin cells) into homeopoetic stem cells _in-
mass_ , and simply introduce them into the appropriate site (eg bone marrow,
for your example)

~~~
Symmetry
Wait, I thought that CRISPR was a matter of gene editing but that stem versus
other types of cells was a matter of gene activation? Wouldn't that require
different techniques?

------
lwhalen
Good! I can't wait for the day I can get a shot to knock out my debilitating
'seasonal' allergies permanently, at the gene level, instead of having to rely
on potions and powders of steroids, anti-inflammatories, and other fun
chemicals.

------
yread
> The hope is that, without PD-1, the edited cells will attack and defeat the
> cancer.

It seems that we already have good drugs which inhibit interaction between
PD-1 and PD-L1 is there really enough benefit from this?

~~~
Gatsky
Those drugs cost $100K+ per year, and have toxicity.

~~~
ejstronge
I can't imagine that personalized gene editing therapy will ever be cheaper
than the current checkpoint blockade agents.

It will be interesting to see if there are differences in side effect profiles
in the PD-1 knockout T-cells vs our current biologicals, however.

~~~
Gatsky
I took the original comment to be asking why bother taking out PD-1 from the
T-cells. The answer is that it obviates the need for checkpoint inhibitors,
which you would otherwise need to administer together with the CAR T-cells for
best efficacy. Maybe they meant something different.

Checkpoint blockade alone is a great development, but having treated patients
with these drugs, I can tell you it is far from a cure for 80% of people.

------
dghughes
I think the best (or worst?) part is that CRISPR can be used with a 'gene
drive' it keeps the changes active on on-going it's not a one shot thing.

GATTACA?

~~~
leggomylibro
Can't CRISPR achieve stable transfection through pathways like AAV, though? If
that's the case, can't the cell lines carry on the changes without any need
for on-going therapy?

~~~
xorxornop
Yup. You'd target sex cells instead, but that's only a slight modification.

------
dharma1
I have a feeling this won't stop at medical use cases

~~~
Ralfp
Most of technology is neither good or evil, and has usages in both civilian
and military space. That is how the things are with technological progress.
Machine learning may be used to find corelation between gene mutations and
cancer, but it may also be used to put missile into unsuspecting enemy.

Roman road system allowed for flow of goods and people within empire on scale
never before seen in acient world, but also for their legions to strike
empire's enemies.

~~~
dharma1
That's true. But I'm not talking just about military use.

I'm talking about germline gene editing, beyond gene therapy.

It will have consequences that span multiple generations, and are self-
replicating. It will completely change the fabric of society. We are going to
be changing what we are as life forms, without really understanding life in
the first place.

[http://www.nature.com/news/don-t-edit-the-human-germ-
line-1....](http://www.nature.com/news/don-t-edit-the-human-germ-line-1.17111)

------
xupybd
Isn't this the back story to I am legend?

------
cowardlydragon
A biotech arms race with the US?

That's laughable after this election.

------
kleigenfreude
[https://en.wikipedia.org/wiki/CRISPR](https://en.wikipedia.org/wiki/CRISPR)
-> Cures Disease

Eventually...

[https://en.wikipedia.org/wiki/CRISPR](https://en.wikipedia.org/wiki/CRISPR)
->
[https://en.wikipedia.org/wiki/Gattaca](https://en.wikipedia.org/wiki/Gattaca)

And...

[https://en.wikipedia.org/wiki/CRISPR](https://en.wikipedia.org/wiki/CRISPR)
->
[https://en.wikipedia.org/wiki/Gremlins_2:_The_New_Batch](https://en.wikipedia.org/wiki/Gremlins_2:_The_New_Batch)

I hope we cure a lot of diseases before we get into the bad side of genmods.

