Anonymous. Foreign Affairs. Volume 97, Issue 3, May/June 2018.
At the age of 12, Jennifer Doudna read James Watson’s The Double Helix and got hooked on science in general and genetics in particular. Four decades later, she is a molecular biology professor at the University of California, Berkeley, an investigator with the Howard Hughes Medical Institute, and a researcher at the Lawrence Berkeley National Laboratory. One of the discoverers of CRISPR, a powerful new technology for gene editing, Doudna tells the story of the current genetics revolution in her gripping new memoir, A Crack in Creation (written with Samuel Sternberg). She spoke with Foreign Affairs’ editor, Gideon Rose, in her office in Berkeley in February.
You’ve described CRISPR as a Swiss Army knife and said that it may cause a fundamental break in human history. How can a Swiss Army knife cause a break in human history?
Because it’s a disruptive technology. Crispr is an efficient, effective tool for editing genomes-changing the code of life, the DNA in cells.
Humans have been modifying the genetics of various plants and animals for ages, so why is this new?
What makes this different is that the tool is precise and programmable. We can now change a single letter in the three billion base pairs of the human genome, for example. Ever since the discovery of the structure of DNA in the 1950s, scientists have been dreaming about being able to rewrite that code. What if you could correct mutations that cause disease or introduce new and beneficial traits into a species? Now we have a tool that can do that. And it’s getting cheaper and more accessible all the time.
Instead of breeding creatures by trial and error over many generations to get the traits you want-and not even knowing what the actual code is for the DNA responsible for those traits-now you can simply splice in a trait for a bigger nose, disease resistance, better nutrition, whatever. You can do it precisely in one generation and get exactly what you want. This is changing the way modern biology is being practiced, in everything from medicine to agriculture.
How quickly is this all happening?
This technology is only a few years old, and there are already several clinical trials moving forward to test CRISPR-based gene editing in patients with cancer and other diseases. Agricultural products altered using CRISPR are already coming to market. Animals have already been altered using CRISPR-heavily muscled pigs, micro pigs, hornless cattle. Several CRISPR-related companies have been founded and already have market caps in the billions of dollars.
The description in your book of how the field of gene editing evolved, with different researchers building on each other’s work and propelling knowledge forward, makes it seem like the scientific community is a model of the Enlightenment in action.
In the early days, it wasn’t even a field. There were a few people working on bacterial immune systems. We used to have these meetings here at Berkeley, and there’d be 40 people there, and that would be essentially everybody in the world working on anything to do with CRISPR. Jillian Banfield organized the meetings. A lot of important work done in the early days of CRISPR came from women scientists. Emmanuelle Charpentier, of course, was my collaborator. It was really an incredible time. I’ve never experienced anything else quite like it in my scientific career. There wasn’t this competitive sort of culture that we see now. Everybody knew each other, and absolutely none of us expected the field would go where it did.
It seems to be a story of several different failed technologies, research on each of which paved the way for the later ones that ultimately turned out to be successful.
Yes, but I wouldn’t call them failed technologies. They were successful technologies. They just had flaws, aspects that made them difficult to implement widely. Those earlier methods for gene editing worked very well when they worked, but they were accessible only to the rich and patient.
So CRISPR is part of the democratization of gene editing?
Absolutely. And that’s one of the beautiful things about it. Somebody can be working in a lab in India, and they can decide that they want to use gene editing to do something. And for the cost of reagents, they can get the CRISPR editing materials and start doing experiments. They don’t have to get a huge amount of money together. They don’t have to have a huge amount of special expertise. They can just do it.
Why is germline editing a special problem?
One kind of important near-term clinical work is called “somatic cell editing.” This involves making changes to cells in a person that are already fully differentiated. Those changes can’t be passed on to future generations.
Germline editing is different, because that means making changes so early in an organism’s development that the changes become part of the DNA of the entire organism and can be transmitted to future generations. With that kind of editing, you could remove the traits that cause genetic diseases and get rid of them forever.
There’s a lot of sci-fi-type appeal to that, but it is doubtful whether it will become a reality anytime soon. Still, that’s the sort of question we will have to grapple with. Gene-editing technology is moving very quickly toward a time when it will be technically feasible to edit embryos or even germ cells, like sperm or eggs. Then it’s no longer a question of can we do this; it’s should we do this.
Are we talking years, decades, or generations?
I think we’re talking years.
Is using CRISPR to fix a gene that is damaged in an otherwise healthy creature conceptually the same as taking an otherwise healthy creature and editing its genome to improve performance?
I have a hard time answering that question. And the reason is that for the most part, I would wager that it’s very hard to come up with an absolute definition of traits that way. Let me give you a real-world example. There’s a gene that’s been identified as important for cholesterol levels in people, and a few people have a natural mutation in this particular gene that gives them very low cholesterol- so effectively, they never suffer from heart disease or cardiovascular disorders. Imagine you had a way to introduce that genetic change into the entire human population, so that you could make people immune to heart disease. Should we do it? Is that fixing a health problem or providing an enhancement?
Have you interacted with people who have actually benefited directly from the use of CRISPR technology, or soon will?
Absolutely. It’s profound to think about being able to alter DNA so as to help someone suffering from a genetic disease. I can’t tell you how many people have e-mailed or visited me to discuss genetic disease in their family. I remember one gentleman who came to talk to me in my office here at Berkeley. He had met one of my postdocs on a plane and during the course of the flight had come to realize the potential of the new gene-editing technology. He told us he had watched his father and grandfather die of Huntington’s disease, and two of his sisters had the trait and were approaching the age when symptoms would start appearing. He wanted to know how the technology worked and how he could help advance it. That’s a common experience for me right now-people who come forward saying, “I want to be involved.” It’s very exciting.
There are several players in this with various interests-scientists, politicians and government officials, investors and private companies, the public at large. Who or what is coordinating everything so that the field moves forward constructively?
We need help with that. When new scientific ideas come along and turn into exciting and disruptive technologies, it’s often the case that those technologies race forward ahead of the capacity of regulatory agencies and governments to control them. Artificial intelligence is a great example. Gene editing is in a similar category. The science and technology is advancing so rapidly that there are already well over a thousand scientific publications on it, in every field imaginable. Perhaps the most excitement stems from the possibility that it may be a very effective way of curing genetic diseases. All of that is moving forward, globally, for the most part without coordination.
There are some exceptions. Francis Collins, the director of the U.S. National Institutes of Health, recently announced a $190 million call for proposals that would bring together teams from different medical disciplines to figure out how to advance the technology responsibly. But that’s not really happening in other areas, such as agriculture.
There has been a huge amount of controversy in recent decades over genetically modified organisms. Is CRISPR going to follow the path of GMOs?
Boy, let’s hope not. The controversy around genetically modifying food resulted from a poorly managed effort to explain to people what it meant and how it affected agriculture and the environment. With CRISPR, there’s an active effort to spur discussions about what this technology involves, what potential it has, and what constitutes responsible use.
People have been breeding plants for millennia. The way it’s currently done is that mutations in DNA are introduced randomly by chemical treatments or radiation, usually with seeds, and then the seeds grow into plants, and you select for desirable traits. Who knows what mutations are happening where? Wouldn’t it be better to have a tool for precise DNA alteration, one that could manipulate a single gene without changing anything else? Of course it would. So the question is, How do you explain that? I think you have to make an effort to engage the public and try to explain why this technology is valuable and what it can let us do that we couldn’t do before.
You’ve said that a lot is riding on how regulators and the public define the term “genetically modified” in coming years. What do you mean by that?
In the United States, regulatory agencies define genetic modification based on whether the modified organism includes any foreign DNA. In Europe, it’s defined by the use of gene-editing technology to achieve the result. So right now, the same organism can be considered genetically modified in Europe but not in the United States.
What do you think the definition should be based on, the technique by which the organism was modified or the substance of the modification?
The substance of the modification. Something that has been edited to fix one problem on a gene should not be considered the same as something containing foreign genetic material. To be clear, CRISPR can be used to do both kinds of editing. But in terms of regulation, people should focus less on how the editing is being done and more on what changes are being introduced.
Are the development and exploitation of CRISPR taking place more rapidly in darker shadows of the world, beyond the reach of regulators and the media?
I suspect so, but I don’t really know. I think we may be moving toward that in particular areas.
Members of your lab team have been approached by people trying to make CRISPR babies.
Definitely. Does that mean somebody out there is actually making CRISPR babies? Probably not yet. But you could certainly envision that kind of work going on in parts of the world where there’s less oversight and less regulation.
So who needs to do what, now, to make sure that the positive benefits of this flow and the negative consequences are contained?
It’s got to be a combination of things. The National Institutes of Health’s effort to bring scientists and clinicians together with regulatory agencies here in the United States is a very important step forward. There are international efforts to bring stakeholders together to grapple with issues such as the differing definitions of genetically modified organisms, for example, right now-it’s critical to come up with a unified guideline.
We’re not in a complete wasteland with respect to regulation. In the United States, there’s actually a very good set of guidelines for dealing with embryo research and any kind of clinical use of technologies, and CRISPR work falls largely under that. What we don’t have, though, is any kind of coordination regarding what happens with in vitro fertilization. That was something I was very surprised to learn about when I got into all of this. It turns out that IVF clinics are largely regulated at the state level, without much coordination. So people can go to IVF clinics in one part of the country and have access to different kinds of services than they can get in other parts of the country.
The advances that are happening right now in science and technology are being driven by people’s fundamental interests. Sometimes that’s commercial, but the most fundamental advances are really driven by curiosity and passion. So the question is, How do you take a curiosity-driven research culture and map onto it some kind of framework for making authoritative choices about what kinds of work can proceed? Earlier in my scientific career, that question would never have occurred to me. I never would have imagined that I would see value in having guidelines for what should and shouldn’t be done in science.
What is the appropriate level of regulation? Local, national, regional, global?
There has to be some combination. There might be things that are so critical that we want to have national-level or even international-level guidelines around them-but other uses that are less significant, more discretionary, and can be regulated more locally. So it depends on what you’re talking about.
Should the United States spend more on scientific research?
Undoubtedly. People should appreciate that two kinds of science produce real value. One is targeted science: aiming to cure cancer or solve a known practical problem. But there’s also incredible value in doing curiosity-driven research. We need to continue to invest strongly in the second type of work as well as the first-because the ideas and technologies stemming from it have reshaped the American economy over the last half century. You could double the budget of the National Institutes of Health and still find good things to spend the money on. There are many, many worthy projects going unfunded.
China is investing heavily in all this. CRISPR is huge in China. It’s one of several technologies, including DNA sequencing, that are very rapidly being adopted there for a broad range of applications. Now there’s a technology not only for reading and writing DNA but also for rewriting it and manipulating the sequence precisely. China’s already a huge player, both academically and commercially. If the United States doesn’t do something similar, we will definitely be behind.
Of all the crazy things that we hear about CRISPR, one of the craziest is that something like Jurassic Park might become a reality. Is that actually true?
I think it would be very hard. Bringing back the woolly mammoth and things like that are interesting ideas but mostly a fantasy. The technical challenges to doing that are very large. But it’s important to recognize that we do now have the power to control evolution.
It’s one thing to say we can make better corn that’s less resistant to disease. It’s another to say we can produce pigmen, like Kramer worried about on Seinfeld. The corn is happening now. How far off are the pigmen?
Probably pretty far off. Genes play together in ways that we don’t understand right now. We can’t just say, “I’d like humans to have the ability to fly, so let’s put genes for wings into the human genome.” It will be quite a while before we have pigmen or any other weird chimeras.
After you’ve genetically engineered them, which would you rather fightone horse-sized duck or a hundred duck-sized horses?
I think the horse-sized duck would be easier to deal with.
When you were sitting there as a kid on the beach in Hawaii, reading the beat-up copy of The Double Helix your dad gave you, did you ever dream of writing a sequel?
Never! It was the farthest thing from my mind.
I want to come back to the regulation issue. Who now is managing the balance between risk and reward in this area? Are there any structures setting out authoritative guidelines?
No. Not really.
So the risks are being weighed by each individual actor?
Which means that we’re entirely dependent on the outcome of those individual researchers’ choices?
Which is not really a proper way to collectively think about the deployment and management of a new technology that could affect human evolution.