The Future of CRISPR, As Kevin Davies Sees It

“If you're a geneticist or a clinician, it doesn't get much better than that - Kevin Davies”

-But is there some sort of unrealised goal that scientists are focused on, like sequencing the human genome once was? While I'm sure it doesn't exist, is there anything approximating a finish line?

I think the most gratifying part of the story is that while writing and closing the book, we started to hear about patients like Victoria Gray, the sickle cell patient from Mississippi, who is the first American patient to be treated in the CRISPR Therapeutics gene-editing trial, and by all accounts after a year is doing incredibly well. Nobody wants to use the c-word »cure« yet, but all the results looked great.

Now, we've also got to extend that trial to dozens, if not hundreds of additional patients. And, I think, keep our hopes and expectations firmly grounded and not get ahead of ourselves. But that's amazingly exciting.

-I'm glad you mentioned the Holy Grail aspect of it before, because that's one of the things I planned on asking about. In your book, you wrote that CRISPR is the closest thing scientists have to »the coveted chalice of salvation.« That's particularly evocative, but it also suggests you think that there's yet-untapped potential for the technology. Where do you feel that potential lies? For instance, are there unexplored or nascent applications for CRISPR from a medical standpoint? Are there things people have tried but not quite sorted out?

Yeah. We're just starting to see a new wave of CRISPR gene-editing companies. Everyone's familiar with the big ones: CRISPR Therapeutics, Editas, having been joined by Beam Therapeutics. So you have these publicly traded CRISPR or CRISPR-derived companies. And now there's a whole wave of new companies that I didn't talk about much in the book, because I mean, some of them are just coming out of stealth mode now.

-Oh yeah.

And so all of these groups are finding new tools, new tools in the toolbox, or new strategies, and it's very exciting. And I think, whether it ends up that CRISPR-Cas9 becomes the predominant gene-editing method, or if it's base editing or prime editing or something that hasn't even been published yet, it's hard not to get excited by the thought that we're going to be able to perform, as David Lewis says, chemistry on the genome.

Base editing can, to a large degree, already do this. That doesn't mean it's going to be successful in the clinic. A lot of things still have to be figured out. But once you can do that, then the main question - and this is the consensus of the experts in the field, not me - is delivery. We've got the tools to do the chemistry and we can probably do it safely and precisely and transiently. But how do we get the components to the right cells, without triggering immune complications or other unwanted side effects?

So that's perhaps where there needs to be more attention paid. But I think once that is solved, then there's a catalogue called Mendelian Inheritance In Man that lists 6- or 7,000 known genetic disorders. So, what's to stop us now just poring through that book of genetic diseases and starting to check off more and more of them? Because once you can figure out how to target one liver disease, then there's hundreds more that, potentially with tweaks on that procedure, could become amenable.

-Right, and from following the space, it sounds like a lot of the challenge is in going from basic to applied science, if I can overly simplify it. For instance, there are possible treatments for neurodevelopmental disorders but it's difficult to penetrate more than five percent or some equally-dismal number of neurons. Is that really the main challenge? Actually, getting the sophisticated tools where they need to go?

I think it's a good example of how the ingenuity of the scientific community is going to now get this amazing toolbox. I think that for CRISPR gene editing - the world is its oyster, and there's so many applications that people are going to find for it.

-But to that point, getting this amazing tool where it needs to go is the obstacle. Is that the main issue across the board?

Yeah, I think so. We did an episode of our program, GEN Live. Neville Sanjana, neuroscientist at NYU Langone Health, said «delivery, delivery, delivery.» So that I think is the big challenge for therapeutic purposes.

“10 years from now, who's going to stop someone else from taking matters into their own hands and setting up an offshore clinic? - Kevin Davies”

The worry is that when the dust settles on the [He Jiankui] debacle, when it's five or 10 years from now, who's going to stop someone else from taking matters into their own hands and setting up an offshore clinic somewhere and saying, »You know, I don't care what the rest of the setting what the experts say, I don't care what the Western society says. I know what my community wants, and I know what's best for my clients and my patients, and you're not going to stop me.« So I think my biggest concern is that we may not have seen the last of these efforts to just go it alone.

-I would love to zoom out from this one particular issue. Certainly He Jiankui's experiments are the most prominent ethical conundrum for the CRISPR community, but one of the things I was really curious about getting your perspective on is the broader concerns of bioethicists. You've said in the past that you've felt perhaps that bioethics gets overlooked in the CRISPR field. What are some of these issues that you feel have gone unaddressed?

It struck me as bizarre that at the American Society of Human Genetics in 2019, I think it was - I was appalled, because here's the first big international gathering of geneticists, since the [He Jiankui] saga. And it didn't get a single mention in the presidential address. I thought that was absolutely extraordinary.

-Was the attitude more »business as usual«?

I think there was one or two satellite, specialised discussions, you know, over in a back room somewhere. But I was just struck that here, for the first time, somebody has tried to interfere with the natural order of DNA sequences in human embryos and play God - whether you like that term or not - and that didn't merit some sort of condemnation from the President.

Of course, the final ethical question is what about the children? What about the three gene-edited children who were born, two in November 2018, one six months later? We know next to nothing about them and I think a lot of people would like to help them. We know the editing of the first two was so slipshod, people would really love to volunteer their time to give these kids the medical checkups and healthcare that they need. They may well be getting it; I have no idea.

-But that's the question.

That is the big question, yeah.

-And wouldn't you want to know what the genetic changes were? Not that these children should be subjected to study or anything, but the fact that so little information is available makes the whole case so much more nebulous.

Yeah. I'm not so interested in whether they are immune to HIV but I think the first thing is to ensure that nothing untoward happened to them, no off-target effects or the way that their CCR5 gene was screwed up hasn’t done some sort of harm. We sure hope not.

-Of course, of course. So we actually talked about everything I planned to ask you. But before I let you go, is there anything you want to add, whether it's about the book or the field in general?

It's the right question to ask at the end!

You know, the first quarter of the book is really devoted to the heroes of CRISPR. The heroes sung and unsung — and it's just a privilege to reflect and try to share some of these people's stories and the role that basic research played in getting this technology off the ground. So that's one message.

The role of serendipity always fascinates me. There's so many lucky breaks and twists of fate; publishing delays that have perhaps changed how history views the winners and the losers. It makes this an interesting story.

Dan Robitzski is a science journalist and former neuroscientist based in Los Angeles.