Cells edited using CRISPR–Cas9 injected into a person for the first time

http://www.nature.com/news/crispr-gene-editing-tested-in-a-person-for-the-first-time-1.20988

by snake117 • 10 years ago

201 52 10 years ago

banhfun• 10 years ago

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

mfoy_• 10 years ago

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• 10 years ago

With CRISPR, it's even better right; live gene editing. You can be a rakunk, rather than just own one!

jostmey• 10 years ago

On a side note I read that book too & loved it.

yread• 10 years ago

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?

psychometry• 10 years ago

The effectiveness of drugs like pembro varies with cancer type and other factors. Here's a recent study where patients exhibited only a 56% response rate: http://www.nejm.org/doi/full/10.1056/NEJMoa1603702

The field is extremely promising and it's worth exploring fully, especially considering that even good responders can suffer relapses due to subclonal evolution.

Gatsky2• 10 years ago

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

ejstronge3• 10 years ago

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.

refurb• 10 years ago

Agree with the other comment that CRISPR is unlikely to cost less.

Also, there is toxicity associated with gene modification. Take a look at the patient deaths with CAR-T therapy.

dghughes• 10 years ago

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?

teaearlgraycold• 10 years ago

The "gene drive" - the quine of the genetic world.

leggomylibro3• 10 years ago

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?

xorxornop3• 10 years ago

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

Symmetry3• 10 years ago

GATTACA just relied on gene analysis (including among a number of blastocycts) but no gene editing. Though I was very annoyed at that movie for implying that people who get diseases just have insufficient willpower.

avisser• 10 years ago

We want to give your child the best possible start. Believe me, we have enough imperfection built in already. Your child doesn't need any more additional burdens. Keep in mind, this child is still you. Simply, the best, of you. You could conceive naturally a thousand times and never get such a result.

I always thought the editing was implied even if it wasn't explicitly called out.

Jerome was different in that he was not edited.

leggomylibro3• 10 years ago

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• 10 years ago

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.

leggomylibro3• 10 years ago

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 :)

ihodes3• 10 years ago

Startups working on this (with credible founders, i.e. inventors of CRISPR) include Editas Medicine, Caribous Biosciences, and CRISPRx. Look out for Doudna, Qi, Charpentier, Elledge, and Church. Also see J. Listgarten for computation approaches to improving CRISPR/CAS9.

This isn't ready for in vivo use yet due to off-target effects (CAS9 is a very permissive protein that often binds to the wrong part of the DNA).

In the US, Carl June's group at U Penn is working on editing adoptive, engineered CAR T cells for cancer therapy, going into clinical trials. They're probably bummed to have been scooped (first to do an adoptive CRISPR engineered T cell transfer), though their work is certainly more clinically relevant than Lu's.

guelo• 10 years ago

The headline seems fine to me. Your complaint seems to be that you think "CRISPR gene-editing" should only refer to editing of cells while they are still inside a live body. But I don't see why that specific type of therapy should claim full ownership of the term "CRISPR gene-editing". Grammatically, any therapy that uses CRISPR modified genes would qualify.

andygates• 10 years ago

Watch the low-quality comments for an illustration of how to misread that headline as "We edited a human! I want wings and a giant pulsating brain!" /s

xorxornop3• 10 years ago

The term you're looking for is in vivo.

This study was in vitro (and then in vivo!)

I would agree, though, that most people would have thought "in vivo" from the title alone, since the prospect of and actual practicality of doing it in vivo is what really differentiates CRISPR from the tech that came before it.

dekhn3• 10 years ago

ANy time a person says about human medical processes "more sense to just..." it means you don't understand the complexity of the problem.

We've already seen previous methods of attempting to "knock out" or "Repair" genes with gene therapy; it's an entirely non-trivial problem for a large number of different reasons.

nonbel6• 10 years ago

"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.

ejstronge3• 10 years ago

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&...

nonbel6• 10 years ago

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.

ihodes3• 10 years ago

It's certainly the former; CRISPR is used to mess with a gene, not kill a population of cells. This isn't what the trial is looking to validate.

nonbel6• 10 years ago

"CRISPR is used to mess with a gene, not kill a population of cells."

Look it up, in every paper where they report on that aspect, the vast majority of the cells die. Also, they detect small numbers of mutants in the control (non-"modified") cells.

qoobaa• 10 years ago

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?

xorxornop3• 10 years ago

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)

Symmetry3• 10 years ago

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?

xupybd• 10 years ago

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

kleigenfreude• 10 years ago

https://en.wikipedia.org/wiki/CRISPR -> Cures Disease

Eventually...

https://en.wikipedia.org/wiki/CRISPR -> https://en.wikipedia.org/wiki/Gattaca

And...

https://en.wikipedia.org/wiki/CRISPR -> 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.

cowardlydragon• 10 years ago

A biotech arms race with the US?

That's laughable after this election.

lwhalen• 10 years ago

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.

dharma12• 10 years ago

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

Ralfp• 10 years ago

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.

dharma12• 10 years ago

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....

Cells edited using CRISPR–Cas9 injected into a person for the first time

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