# Insights Don't Fear the CRISPR - Comments

1. Apr 28, 2015

### Ygggdrasil

Last edited by a moderator: Apr 28, 2015
2. Apr 28, 2015

### Staff: Mentor

He is talking in the third person now? ;)

If this is an automatic post, I wonder how it got into the right forum.

Great post!

3. Apr 28, 2015

### Staff: Mentor

When you write the blog entry, you select which forum is relevant.

This thread is created so people can comment on the blog.

4. Apr 28, 2015

### Ygggdrasil

Yup, this was an automatic post that'll pop up whenever I post to the Insights blog. Greg has done a great job getting the blog integrated with the forums so that things like this are possible.

5. Apr 28, 2015

### Greg Bernhardt

Comments should also appear in the article, but they are not. There are still some kinks to hammer out.

I was listening to NPR today and there was a segment on CRISPR. It's a big deal!

6. Apr 28, 2015

### Jimster41

Very cool development. Seems like a huge milestone. Cancer, your f days are numbered...

Since the bait was sort of "should we fear our coming ability to control our world at an entirely new level" ... I'll kick it off with, you bet! Not too much in the article convinces one (if fearful) that all the crazy things imagined in the movies couldn't or won't happen. The breakthrough seem to declare with seamless authority, it is now truly, more realistically possible.

Good for us! It's still exactly what we should be trying to do, what we have always done, and what we will always do, or die tryin. What we also have, must and will do, is struggle mightily to bring the good parts of our humanity along with us. To keep making the novel human choice with what we discover we can do. What made Gattaca such a compelling story to me (a favorite) is that is one story of how that might really happen. Moon is another one. Both are nail biter's.

I for one am totally supportive of our efforts to master what we are made of AND our worry about the risks of those efforts.

I would also love to know what the short list of anticipated breakthroughs in our burgeoning ability to control the genetic engine that creates and destroys us. Are we not living in the golden age of this field?

Last edited: Apr 28, 2015
7. Apr 28, 2015

### jerromyjon

I'm sure they are just scratching the surface. Are we still in the information age or what? I think you are right on track for a "eugenics age" going straight to the genes?

8. Apr 28, 2015

### Evanish

You could fix the gene for vitamin c and end scurvy forever. Not that scurvy is much of a problem in the modern age.

9. Apr 28, 2015

### gravenewworld

Cancer's day's numbered? Not quite. CRISPR-Cas9 was just tried in human embryos and it had horrendous off target effects (surprise surprise).

There are also other techniques that exist like TALENs and ZFNs which supposedly have lower off target effects (which come at the cost of lower efficiency), but get far less press. Don't forget, siRNAs got tons of hype when they first came out too and were supposed to revolutionize medicine and our treatments of disease. Well, we're still waiting for the revolution over a decade later, and many pharma companies have completely abandoned siRNAs due to their intractability for now.

Last edited by a moderator: May 7, 2017
10. Apr 28, 2015

### ShayanJ

"Don't Fear the CRISPR?"
We really shouldn't? Let's see!
As anything else in science, this is a tool, as much as applications are concerned, and we know that tools can be used for good or for bad! That depends on the hands holding the tool. Now its said that this tool is not ready yet because of some problems but scientists will solve these problems. The may not make it limitless, but they will push the limits away. And that makes such tools really powerful and experience teaches us that, unfortunately, its more probable for such powerful tools to be in the wrong hands. There are always people who want to get bad things out of such tools and, unfortunately, there are always scientists who are willing to serve those people.
Of course its ridiculous to say CRISPR or its innovators are the ones to be blamed. Its like blaming Einstein for the atomic bomb because without $E=mc^2$, such a weapon couldn't be built!
But then, who should be blame? What can we do?
The situation is like this. We have people who know how to pick a lock. Some of them use this skill to help people who are locked out. Some others use it to break into people's house. You can't blame the innovator of lock picking. The problem is with the ones who hire lock pickers for breaking into people's house and also with the lock pickers who accept to do it. But the present situation is just a bit bigger. The tool is more powerful and so the people who hire its experts are more important people and the bad things that can come out of it has broader scope, wider range and deeper impact.
It seems to me we can do nothing about this situation. I was going to say we need to care about science ethics but it doesn't seem to work. In fact when I think about this world and the way some people think, it seems inevitable to me that there will be some really bad consequences of this.
Don't take me wrong. I too like to see science going forward. But my problem is, there is something as necessary as science that is being overlooked in today's world.
So what do I think? We should fear CRISPR and that's the only thing we can do about it. In fact I should say we should fear all sciences, because without the necessary thing I mentioned, all of it is a tool in the wrong hands and as sciences moves forward, those wrong hands can do more damage to humanity.

11. Apr 28, 2015

### Ygggdrasil

To be fair, the Liang et al paper did not use newer CRISPR methods that can reduce off-target effects by 50-1000 fold. We're not yet at the point where off-target effects are not a concern, but there is clearly room for improvement.

Yes, TALENs and ZFNs will probably still have uses (for example, some of the clinical trials to edit T-cell to be resistant to HIV are being done with ZFNs). A good way forward may to use CRISPR for the initial research (because it's easier to test different targets with CRISPR), and once a good target has been identified and validated, to design TALENs or ZFNs. Of course, there are other problems such as the difficulties in cloning TALENs or the fact that the TALEN genes are quite large and difficult to package into some viral delivery vectors (like adeno-associated viruses).

I'd agree with the comparison to siRNAs, in that it will be difficult to perform gene editing in vivo. For many of the same reasons why siRNA has failed to take off as a therapy, gene editing in live humans may not ever become a worthwhile pursuit. Ex vivo gene editing to engineer immune cells or correct genetic disorders in blood cells, however, certainly seems to be a very feasible goal in the near future.

Last edited by a moderator: May 7, 2017
12. Apr 28, 2015

### Evanish

Most of us alive today wouldn't exist without science. Should we all fear the thing that feeds and cloths us? Maybe, but I think it’s important to put that fear in perspective. A far great horror would be a world without science. It's important to consider the benefits along with the costs. In that light the question we should be asking ourselves in regard to genetic manipulation of humans is will the benefits outweigh the costs.

13. Apr 29, 2015

### ShayanJ

I never said we should abandon science. But we should fear its bad consequences the same as when we fear an airplane crash. We don't abandon airplanes, we just try to prevent crashes and still prepare for them in lots and lots of ways. I'm just saying the "airplane" of science and its "passengers" aren't ready for the possible "crash" and haven't been preventing it either.
I also should mention that we had several of such crashes before. Where science worked as a weapon in the wrong hands. I'm not mentioning any specific event because I don't mean to say there is one or even several countries who should be blamed. Its something related to all of us, as humans.

Last edited: Apr 29, 2015
14. Apr 30, 2015

### Greg Bernhardt

15. May 2, 2015

### Ygggdrasil

Gene editing technologies are currently being used in clinical trials to treat HIV. There are potential applications in cancer, but none that I am aware of that are close to being close to clinical trials. We're probably at least a decade away.

16. May 3, 2015

### Les Tete

This is really annoying. You do something like this, which at first glance appears to flout the policy agreements in place to not edit the human germline. You get people worked up, the researchers put something in like "it caused unintended mutations in the embryos", and it sounds even worse. Of course it caused unintended mutations - the technology is only 2 years old. Clinical trials for HIV are presumably the ex-vivo method of generating the CCR5delta32 cells? Much less risky than in vivo editing.

I just wrote a risk assessment on CRISPR-Cas9 for therapeutic use; the tech is evolving quickly, risks of off-target effects are being mitigated every day by improvements such as tru-gRNAs, dimeric hybrid Cas9-FokI Nucleases, etc. but no way would I consider it safe to use for human therapeutics at the moment. We've only just had the postulation of possible methods for detecting genome wide off-target effects in the last few months - at the first instance we need to be able to detect all off-target effects, then they can be used to develop rules for enhanced target specificity. The initial computer programs (MIT, etc.) most researchers have used thus far to generate gRNAs were pretty much rendered obsolete by the new genome-wide off-target detection methods because of their inability to accurately predict off-target binding sites.

17. May 5, 2015

### entropy1

Would it be possible, in the future, to -compose- DNA strands that are designed on a computer? You'll have to do statistical fenome-genome calculations then, I imagine.

18. May 5, 2015

### Ygggdrasil

It is possible to design DNA sequences and make those physical DNA molecules. For example, scientists at the J. Craig Venter Institute synthesized a complete bacterial genome in 2010 and used that to create a synthetic cell. They currently use similar technologies to synthesize viruses for vaccine production. Instead of having virus samples sent to their lab, they can just get the virus's DNA sequence in an email and synthesize the virus themselves. Similar work has been done to synthesize yeast chromosomes.

Although we are working towards having the technology to build new genomes from scratch, we lack a lot of the knowledge required to build new functions into genomes. It's as if we have a printing press, but no one knows how to read.

19. May 5, 2015

### atyy

Roughly, what is the strategy? Oh, wait, I see you've linked an article http://www.nejm.org/doi/full/10.1056/NEJMoa1300662#t=article in the blog post.

OK, I read the article quickly. It seems they take out some of the immune cells of the patient which are usually infected by HIV, make the immune cells resistant to HIV infection, then put the cells back in the patient. Here they do it just once.

In the full treatment, presumably they will have to do it multiple times, since I assume the body will generate more immune cells that are not resistant, while those that were made resistant will die off over time?

Last edited: May 5, 2015
20. May 6, 2015

### Ygggdrasil

Yes, ex vivo editing of T-cell to make them resistant to HIV is the strategy. The NEMJ paper describes the T-cells persisting to at least 3.5 years after transplantation (the latest time point measured), but it is possible that the resistant cells could die off over time. The treatment could potentially be made permanent by editing bone marrow cells ex vivo then transplanting in the edited bone marrow. A similar procedure was done on a patient in Berlin in 2007 (instead of edited bone marrow, marrow from a donor naturally carrying the CCR5 mutation was used). This patient has not seen the virus return despite remaining off of antiretroviral drugs, and is considered by many to be the only individual ever cured of HIV.