Gene editing will transform cancer treatment

You may have heard of the gene-editing technique CRISPR-cas9, often simply called CRISPR. Introduced in 2012, CRISPR works like a pair of scissors to cut DNA, inserting or reordering bits of genetic code with remarkable, science-fiction-like results: CRISPR can help create mosquitoes that don’t transmit malaria, or be used to breed unusually muscular beagles, or even create mini pigs. In humans, the technology is being tested to battle cancer — by removing patients’ immune cells, editing them, and reinserting the weaponized cells into the body to hunt cancer.

One of the leading scientists who developed the technique is Jennifer Doudna, a biochemist at the University of California, Berkeley. With the help of Emmanuelle Charpentier, Martin Jinek, and Krzysztof Chylinski, Doudna adapted the system that bacteria use to defeat viruses to create the much-vaunted cell-editing technique. We sat down with Doudna in October to discuss just what CRISPR might mean for the future of science, and disease research. While CRISPR marks a landmark breakthrough, the technology also presents plenty of concerns about genetic modification — some ethical, some practical — and Doudna has made a habit of stepping out from among the ranks of other scientists to discuss those concerns with the public. We talked to Doudna about the possibility of using CRISPR to combat disease, to help preserve threatened species, and how close we are to creating a real-life Jurassic Park.

The Interview

What’s the public perception of CRISPR?

The public perception of CRISPR is [that] it’s in its early stages. People have heard about it. They’ve heard of the acronym often. I’ll get into taxis and I’ll have a taxi driver say, “Oh, you work on CRISPR. Yeah, I’ve read about that.” People are still trying to understand what it’s all about and what it means for them, personally, and for the future.

It’s very hard for people, generally, to appreciate that new technologies always take time to have an impact in a real-world sense. What we’re seeing with the CRISPR technology for gene editing is that the field has moved remarkably quickly in the scientific sense. I mean, it’s only sort of a four-year-old technology and it’s  already altered the way scientists do research. It’s altered the commercial landscape — lots of companies are using this technology now. But it’s really hard for people to appreciate just how long it really takes to do something like create a therapeutic [agent]. A very common discussion that I have with people outside the scientific community is, How long is it going to be until we have a technology from this, or a real therapeutic [agent] from this? An approved treatment, or even a cure? You know, we’re probably still a decade out from that, realistically, because it’ll take time to ensure that it’s safe and effective.

Medical research moves very slowly. We’re only just starting to see the first human trials of CRISPR technology. What do you imagine will be happening in 2021?

The next five years will be extremely interesting in this space. By 2021, we will certainly see more clinical trials. Right now the trials that are approved are all for cancer. They’re doing a particular type of editing that might be impactful in treating cancer — namely being able to program a patient’s own immune cells to target and destroy their cancer cells. That’s an exciting opportunity, but going forward we will see increasing efforts, and I hope clinical trials, to address genetic diseases of the blood, of the eye, of the liver. Then probably farther down the road, diseases that affect other tissue. I’m thinking Duchenne muscular dystrophy is one that people talk about a lot. Cystic fibrosis is another that’s discussed a lot.

You mentioned blood disorders. Perhaps you can give me a sense of how that particular area of research is going to progress in the next five years. What sorts of trials could we see for sickle cell anemia, for instance?

The gene-editing technology that is available today is already sufficient to cure the defect that causes sickle cell anemia in cells that are cultured in the laboratory. That’s been the case already for a couple of years. The challenge is how to take that and deploy it in a way that’s going to be effective in patients. To do that, gene-editing technology really needs to get a very high level of editing in blood cells. We need to be able to do it in blood stem cells, so that they can actually repopulate a patient’s blood system with cells that don’t have the sickle cell trait. The exciting thing right now is that there’s clearly a big effort in this space in many labs. I think that we’ll just continue to see a lot of progress in this area.

It’s always hard to predict exactly how long it’ll take to do something like this, but from talking to my clinical colleagues who really think deeply about this sort of challenge, we’re all hopeful that within the next two to three years we will see advances in the technology that will make it possible to initiate clinical trials. Whether that happens will depend a lot on how things unfold, really, over the next couple of years.

For a disease like cystic fibrosis, for instance, what does the future look like if we decide, “Okay, we’re going to treat this in such a way that genetic mutations we introduce won’t be passed on to children?”

Various labs working on various model systems of cystic fibrosis have had success in the laboratory. They’ve been able to use gene editing in lab-grown tissue samples that reflect the tissue in patients that have cystic fibrosis. We know the technology has this capability. Now we need to, again, bridge the gap between what goes on in the lab and what we’d like to be able to do in the clinic, and be able to do it safely. There’s clearly a lot of work that needs to be done, but it’s an exciting time because you can start to see how the pieces could fall into place to make that possible.

There’s a way of applying CRISPR to embryos that we haven’t fully explored, in part because of some of the ethical issues and in part because we don’t totally know what that’s going to do.

What might altering embryos mean for diseases like cystic fibrosis or muscular dystrophy?

One thing that’s very interesting right now is that there are four countries that have approved human embryo experiments using the CRISPR gene-editing technology.

We’re just talking about using this tool in very early embryos to find out, how effective is it, is it safe, [and] does it have the desired properties for making changes to the human genome that would be, in principle, effective at curing disease? Depending on how those experiments work out, there will be increasing interest, and probably pressure, for certain kinds of applications of gene editing in embryos to go forward. This is why it’s critical that we have an open conversation about this right now, even though we’re not there today with this technology. How do we ensure an ethical path forward?

There are no easy answers, but I do feel there may be reasons that, in the future — assuming that the technology can be shown to be safe and effective in embryos for certain applications — we may come to a time when we say, “It might not be ethical to not use it for those uses in certain cases.” Again, this will really depend on how things unfold with the technology coupled with a responsible discussion about responsible use.

Is there anything that frightens you about this technology, about the power of it?

When I think about what makes me nervous about this technology, it really comes down to how little we really understand the function of genes, especially the interactions between genes in our own genomes. [For] humans, but for other organisms, too. One of the big unknowns is if we were to deploy this technology to make a permanent change in the germline of an embryo, would there be unintended consequences of that change that might not really show up for dozens of years? How do you even think about testing such a thing? I don’t know. Could you do it in animals? Maybe, but at some point you have to actually try it in a person if you’re going in that direction. Just thinking about how to do that, how to do even the research that would be needed to provide the data that would allow us to make an informed decision is a challenging question.

Do you ever worry that there might be folks with the capability of using this kind of technology unethically?

It does concern me, definitely, but frankly not maybe any more that it concerns me that we have nuclear capabilities. We have other technologies that are clearly very powerful as well, and can also be employed by people that might not have the same ethical concerns that we’d like to see in those decisions. Yes, it’s a concern, but I don’t think it’s unique to this technology.

We’ve been talking mostly about humans. When we consider modifying crops or animals, do the challenges change? Are the risks and benefits potentially different?

In terms of the technology, the challenges are similar but the details are different. For example, in plants the excitement is that you can potentially introduce changes to plant DNA much more quickly, and certainly much more accurately than has been possible in the past. That means that instead of having to do something like mutagenize seeds with chemicals and then try to select for those that give rise to plants with the desired trait — which is frankly what’s done currently — we can now, if we have enough information, just introduce the desired change to a gene precisely and not have to make or guess about what other changes might be happening elsewhere in the DNA of that organism. That’s very attractive, but again it comes down to delivery. How do we deliver editing molecules into plants? Very challenging. Plants have a cell wall so it makes it even harder to get into plant cells.

Really what the CRISPR tool does is introduce a break into DNA at a particular place. Then the cell takes over and repairs the break. That’s where the editing actually occurs. In plants it’s not so easy to control that. It’s a challenge in animals, too, but in plants we don’t know very much about how that actually works. Getting a handle on that in the future will be a big effort on the research side.

How long do you imagine it would be before we start to introduce things like modified mosquitoes into the environment?

It’ll happen in the short term. There’s a lot of interest, on the part of foundations especially, that are thinking about, “How do we deploy technologies to avoid the spread of disease?” Diseases like Zika, and dengue, and others that are insect-borne have very huge negative impacts on humans. Thinking creatively about how to use new technologies to help us mitigate these diseases is really critical. Again, it has to be done with an open-eyed approach to the potential risks of deploying these organisms and ensuring that appropriate guidelines and regulatory procedures are followed to try to avoid any unintended environmental consequences.

This can be tested by mixing populations of mosquitoes in a controlled environment and just watching over time what happens. This is just the law of natural selection, right? If an organism has a reproductive disadvantage in a population, then it will tend to be out-competed by its peers over time. Or the other way around, too. If it has a reproductive advantage then it will tend to over-populate an environment over time, other things being equal. That’s already being seen with these modified mosquitoes. As these experiments are conducted in controlled settings, the hope is that scientists will get more sophisticated about the way they’re employing technologies that control properties of mosquitoes that might be beneficial to humans and ensuring that those properties are maintained over the long term in those populations, but without unintended, undesired consequences.

Are there broader applications? Could we potentially modify animals that exist now and sort of back-form a dinosaur, or back-form a mammoth?

There’s a lot of interest in what’s called “de-extinction”: the idea that you could bring back an organism that is no longer walking the Earth by using gene editing to make modifications to a genome of an existing organism; reintroduce genes that have been lost within the extinction process. There are various efforts to do things like bring back the woolly mammoth. It’s not quite a dinosaur, but it would be pretty cool if you could do that. I’ve also talked a bit to Beth Shapiro down at University of California, Santa Cruz. She studies animals like bears, and evolutionary patterns of bears, and also in birds. There are opportunities with those kinds of organisms.

Whether you could really bring back a dinosaur, that’s a much harder challenge. We don’t really know the DNA sequence that would encode a dinosaur. In Jurassic Park, you may remember that the premise of Michael Crichton’s story was that there were insects trapped in resin that contained blood from dinosaurs that had DNA still available for sequencing. Unfortunately, DNA is a chemical that doesn’t last 65 million years. I think being able to do that is not so likely, but maybe it’s possible to piece together information that we have about amphibians, about birds, it might be possible to start walking in that direction. I don’t know how close you could get to a real dinosaur, but certainly we’ll learn a lot about the genetic traits that are encoded in DNA that give rise to some of the traits that we think dinosaurs had.

Would you say you’re an optimist about the future?

I’m an optimist about the future, yes.

The thing I like to point out is that a lot of the technologies that have come to the fore over the last few decades, and the CRISPR gene-editing tool is in this category, too, have come about due to fundamental research. Rather than a focused effort to invent or discover a technology or an idea or an insight, these kinds of things often come about from scientists who are working in a seemingly different area of science, who through circumstances and just paying attention to their data come across insights that lead to either new technologies or new fundamental understanding of nature.

I like to point that out because there’s been a real push in the US and elsewhere in the world for scientists to be more applied in their work, to focus on a particular problem: Let’s cure cancer, let’s have a brain initiative that allows us to understand consciousness or something like that. It’s not that those aren’t valuable as well, but I think we don’t want to get too far away from the idea that we don’t know, really, enough about our natural world to know where the next insights or technologies are coming from. I hope our new administration will support fundamental discovery science that allows scientists and researchers in the US and around the world to positively impact human health.