One of the things I learned from writing the ThinkPad book is that the technological revolution we’ve been living through isn’t close to being finished. In some ways, in fact, it is accelerating. Consider just this handful of technologies: 3D printing, drones, the Internet of Things, Artificial Intelligence and Virtual Reality, facial recognition, advanced robotics, autonomous driving, nanoscience, and genetic editing. The point we make in the ThinkPad book is that technology gets ahead of a society’s ability to understand what is happening and to create a response. Governments, the media, and all the institutions of a society have to be involved in debating and formulating a coherent policy or set of policies.
This issue was driven home to me in this excellent article on genetic editing. I wanted as many people as possible to see it even though it hides behind a reg wall:
The Gene Editors Are Only Getting Started
Would you eradicate malaria-carrying insects? Change your baby’s DNA? Scientists soon may have the power to do both.
Berkeley, Calif.
Rewriting the code of life has never been so easy. In 2012 scientists demonstrated a new DNA-editing technique called Crispr. Five years later it is being used to cure mice with HIV and hemophilia. Geneticists are engineering pigs to make them suitable as human organ donors. Bill Gates is spending $75 million to endow a few Anopheles mosquitoes, which spread malaria, with a sort of genetic time bomb that could wipe out the species. A team at Harvard plans to edit 1.5 million letters of elephant DNA to resurrect the woolly mammoth.
“I frankly have been flabbergasted at the pace of the field,” says Jennifer Doudna, a Crispr pioneer who runs a lab at the University of California, Berkeley. “We’re barely five years out, and it’s already in early clinical trials for cancer. It’s unbelievable.”
Crispr is much more precise, as Ms. Doudna explains in her new book, “A Crack in Creation.” It works like this: An enzyme called Cas9 can be programmed to latch onto any 20-letter sequence of DNA. Once there, the enzyme cuts the double helix, splitting the DNA strand in two. Scientists supply a snippet of genetic material they want to insert, making sure its ends match up with the cut strands. When the cell’s repair mechanism kicks in to fix the cut, it pastes in the new DNA.
It’s so exact that Crispr blurs the meaning of “genetically modified organism.” The activists yelling about “frankenfish” are generally upset about transgenic plants and animals—those with DNA inserted from other species. But what about using Crispr to alter only a few letters of an organism’s own genome, the kind of mutation that could happen naturally?
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Last year a professor at Penn State created blemish-resistant mushrooms by knocking out a gene that causes them to turn brown when handled. “It attracted attention,” Ms. Doudna says, “because the U.S. Department of Agriculture ruled that that type of plant product would not be regulated as a genetically modified organism.”
Ms. Doudna welcomes this kind of streamlining as the Food and Drug Administration considers its own approach to Crispr crops. “It’s crazy. It takes years and years and years to bring a plant to market,” she says. “I’m all for safety of course and that has to come first. But I think it has to be done with knowledge of the science that makes sense.”
Medical labs are also putting Crispr to work, since it is potentially meticulous enough for routine use on people. The human genome is 3.2 billion letters, and in the wrong place a single typo—a dozen or so misplaced atoms—can create misery. For patients with disorders like cystic fibrosis, the obstacles to fixing the genetic glitch with Crispr seem mostly practical.
First, there’s delivery: A human body contains some 50 trillion cells. How do you get Crispr to the affected ones, and what percentage need to be edited successfully to matter? Ms. Doudna says injecting Crispr-laden viruses into animal tissues has resulted in rates of editing on the order of 70%—enough to have a therapeutic benefit: “In muscular dystrophy, for example, it looks like you only need to have somewhere between 10% to 20%.”
Second, there’s the risk: Although Crispr aims at a 20-letter DNA sequence, occasionally it can hit a partial match and make an unintended edit. “For any drug that we’re developing for treatment, you’re going to have some kind of risk factors,” Ms. Doudna says. “In this case it might be changes to DNA, and you have to decide what’s the right level that you would tolerate.” There are ways to minimize the mistakes, and some studies show so few off-target edits “that it’s difficult to distinguish them from just errors in DNA sequencing.”
What seems to merit the risk today? “Sickle-cell disease,” Ms. Doudna says: “Well-known mutation. Single gene is involved. No treatments right now for people. They have these horrible crises where they’re in terrible pain.” Moreover, the faulty red blood cells can be drawn from a vein and isolated. “The actual DNA editing can be done outside the body,” she says, “validated first, and then the cells implanted and allowed to repopulate the blood supply.” The approach may work for cancer, too: A Crispr clinical trial awaiting FDA approval would pull white blood cells, give them tumor-killing superpowers, and then put them back into action.
It would be technically simpler, rather than working in fully grown patients, to fix genetic disorders early, in human eggs, sperm or embryos. But this raises thorny moral questions, since edits made to these cells would pass down to future generations, who can’t consent to having their genes tweaked. In debates about this, the word “eugenics” comes up.
At first, Ms. Doudna was reflexively opposed. “I’m not a religious person,” she says, “but it’s more, just—I don’t know—sort of an intrinsic reaction, that it feels like a realm where maybe we shouldn’t be messing around.” Her position softened, somewhat to her own surprise, as she heard from hundreds of people facing horrific genetic diseases. “They’re reaching out because they’re desperate,” she says. “A lot of them are asking me the questions you’re asking about: How soon? How long will it be? Is there hope for my child?”
Ms. Doudna recalls an email from a 26-year-old woman who’d found out she carried a mutation in the gene BRCA1 that is associated with a 60% risk of breast cancer by age 70: “She said, ‘Should I have a mastectomy?’ ”—this was right after Angelina Jolie, worried about a similar mutation, did the same—“ ‘Or do you think that gene-editing is going to come along in time for me? Or if not for me, at least so that I can get rid of this mutation in my eggs?’ ”
There was a man who watched his father die of Huntington’s disease and had three sisters diagnosed. There was a woman whose daughter had given birth to a child with Fragile X syndrome, which causes intellectual disability, but deeply wanted to conceive again. “She was very emotional,” Ms. Doudna recounts. “She said, ‘If there were a way to use this, and if I could use it in embryos or germ cells, I would have absolutely no hesitation about doing it.’ ”
A few bioethicists have even argued that research on editing human embryos is a “moral imperative,” since roughly 6% of all babies have “serious birth defects.” As for the risk of “off target” edits, merely smoking cigarettes can create mutations in a man’s sperm. One academic joked that if old-fashioned sex were up for regulatory review, the FDA would never sign off.
Not everyone has the same reaction. A reporter interviewing Ms. Doudna once revealed she had a son with Down syndrome. “She said, ‘I just want you to know that he’s perfect just the way he is.’ It was very touching,” Ms. Doudna recalls, her voice flickering with emotion. Even if Crispr could have fixed that genetic defect, the woman said she wouldn’t change it. Some people in the deaf community feel the same way, and Ms. Doudna respects that. “Everyone’s feeling about DNA and about their inheritance and their children is going to be different,” she says. “It has to be a choice. People can decide what they want to do.”
Ms. Doudna remains opposed to nontherapeutic editing, often characterized as “designer babies,” and she says regulators won’t allow it, at least in the U.S. But other countries are less stringent. Is news of the first Crispr baby simply going to break one day? “It would be naive to think that that won’t happen at some point,” she says. Pressure to push forward will come not only from desperate people but also clinics abroad that may drum up business by saying: “We’ll do things here that will be advantageous for your children that are not allowed elsewhere.”
That’s why Ms. Doudna sees the ethical debate as vital. “It’s very hard to enforce any kind of global regulations on anything, but certainly on science,” she says. “So I think the next best thing is to try to encourage a global consensus that is strong enough that people feel some pressure to conform to it.”
The plan to eradicate the Anopheles mosquito presents a similar problem of collective decision-making. One iteration would involve a version of the insect edited to carry DNA that creates sterile females. That trait could then be forced into the wild population using a “gene drive.” Recall the basic rules of heredity—think back to that Punnett square from high school. Normally, an edited male in the wild would pass on the sterility gene to only half its offspring. Over many generations, the edited DNA would be diluted into oblivion.
That’s where the gene drive comes in. Scientists using Crispr in the lab have given the mosquito DNA that causes its cells to create Crispr.The result is a recursive, self-propagating gene that slices its reproductive competition. The edited mosquito passes on the sterility gene to nearly 100% of its offspring—which in turn do the same. Theoretically, releasing a single gene-drive insect, or letting one escape out an air-conditioning vent, could spread the edited DNA to the entire species.
Theoretically. “Although we understand that these gene drives can work in a laboratory setting efficiently in fruit flies and things like that, how well would they really work environmentally?” Ms. Doudna asks. “Evolution is a very strong force. If you put a species in a wild setting where they have to compete with other species, if they have a disadvantage reproductively, even if it’s a small disadvantage, they’re going to lose out.”
Ms. Doudna still needs to be convinced, too, of the wisdom of letting loose a gene drive. She cites her native Hawaii. “Species were introduced to that environment that ended up having large unintended consequences,” she says. Seeing that made her “very respectful of nature and very cautious about human beings’ thinking they have the knowledge to predict what will happen.”
A final Crispr worry is that it makes DNA editing so easy anybody can do it. Simple hobby kits sell online for $150, and a community biotech lab in Brooklyn offers a class for $400. Jennifer Lopez is reportedly working on a TV drama called “C.R.I.S.P.R.” that, according to the Hollywood Reporter, “explores the next generation of terror: DNA hacking.”
Ms. Doudna provides a bit of assurance. “Genetics is complicated. You have to have quite a bit of knowledge, I think, to be able to do anything that’s truly dangerous,” she says. “There’s been a little bit of hype, in my opinion, about DIY kits and are we going to have rogue scientists—or even nonscientists—randomly doing crazy stuff. I think that’s not too likely.”
Still, a couple of years ago Ms. Doudna had a dream in which a colleague asked her to explain gene-editing to someone very important. Turns out it was Hitler, except with the face of a pig. This, she says now, was her awakening to Crispr’s potential. “Try to imagine: We’re biochemists here, we’re futzing around with bacteria, just fartin’ around the lab, and students are doing experiments,” she says. “Then suddenly you have this discovery that you realize can be harnessed in a very different way.”
A few moments later she adds: “It was just this growing realization that this is no joke. This is a really seriously powerful technology.”
Mr. Peterson is the Journal’s deputy editorial features editor.
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Last year a professor at Penn State created blemish-resistant mushrooms by knocking out a gene that causes them to turn brown when handled. “It attracted attention,” Ms. Doudna says, “because the U.S. Department of Agriculture ruled that that type of plant product would not be regulated as a genetically modified organism.”
Ms. Doudna welcomes this kind of streamlining as the Food and Drug Administration considers its own approach to Crispr crops. “It’s crazy. It takes years and years and years to bring a plant to market,” she says. “I’m all for safety of course and that has to come first. But I think it has to be done with knowledge of the science that makes sense.”
Medical labs are also putting Crispr to work, since it is potentially meticulous enough for routine use on people. The human genome is 3.2 billion letters, and in the wrong place a single typo—a dozen or so misplaced atoms—can create misery. For patients with disorders like cystic fibrosis, the obstacles to fixing the genetic glitch with Crispr seem mostly practical.
First, there’s delivery: A human body contains some 50 trillion cells. How do you get Crispr to the affected ones, and what percentage need to be edited successfully to matter? Ms. Doudna says injecting Crispr-laden viruses into animal tissues has resulted in rates of editing on the order of 70%—enough to have a therapeutic benefit: “In muscular dystrophy, for example, it looks like you only need to have somewhere between 10% to 20%.”
Second, there’s the risk: Although Crispr aims at a 20-letter DNA sequence, occasionally it can hit a partial match and make an unintended edit. “For any drug that we’re developing for treatment, you’re going to have some kind of risk factors,” Ms. Doudna says. “In this case it might be changes to DNA, and you have to decide what’s the right level that you would tolerate.” There are ways to minimize the mistakes, and some studies show so few off-target edits “that it’s difficult to distinguish them from just errors in DNA sequencing.”
What seems to merit the risk today? “Sickle-cell disease,” Ms. Doudna says: “Well-known mutation. Single gene is involved. No treatments right now for people. They have these horrible crises where they’re in terrible pain.” Moreover, the faulty red blood cells can be drawn from a vein and isolated. “The actual DNA editing can be done outside the body,” she says, “validated first, and then the cells implanted and allowed to repopulate the blood supply.” The approach may work for cancer, too: A Crispr clinical trial awaiting FDA approval would pull white blood cells, give them tumor-killing superpowers, and then put them back into action.
It would be technically simpler, rather than working in fully grown patients, to fix genetic disorders early, in human eggs, sperm or embryos. But this raises thorny moral questions, since edits made to these cells would pass down to future generations, who can’t consent to having their genes tweaked. In debates about this, the word “eugenics” comes up.
At first, Ms. Doudna was reflexively opposed. “I’m not a religious person,” she says, “but it’s more, just—I don’t know—sort of an intrinsic reaction, that it feels like a realm where maybe we shouldn’t be messing around.” Her position softened, somewhat to her own surprise, as she heard from hundreds of people facing horrific genetic diseases. “They’re reaching out because they’re desperate,” she says. “A lot of them are asking me the questions you’re asking about: How soon? How long will it be? Is there hope for my child?”
Ms. Doudna recalls an email from a 26-year-old woman who’d found out she carried a mutation in the gene BRCA1 that is associated with a 60% risk of breast cancer by age 70: “She said, ‘Should I have a mastectomy?’ ”—this was right after Angelina Jolie, worried about a similar mutation, did the same—“ ‘Or do you think that gene-editing is going to come along in time for me? Or if not for me, at least so that I can get rid of this mutation in my eggs?’ ”
There was a man who watched his father die of Huntington’s disease and had three sisters diagnosed. There was a woman whose daughter had given birth to a child with Fragile X syndrome, which causes intellectual disability, but deeply wanted to conceive again. “She was very emotional,” Ms. Doudna recounts. “She said, ‘If there were a way to use this, and if I could use it in embryos or germ cells, I would have absolutely no hesitation about doing it.’ ”
A few bioethicists have even argued that research on editing human embryos is a “moral imperative,” since roughly 6% of all babies have “serious birth defects.” As for the risk of “off target” edits, merely smoking cigarettes can create mutations in a man’s sperm. One academic joked that if old-fashioned sex were up for regulatory review, the FDA would never sign off.
Not everyone has the same reaction. A reporter interviewing Ms. Doudna once revealed she had a son with Down syndrome. “She said, ‘I just want you to know that he’s perfect just the way he is.’ It was very touching,” Ms. Doudna recalls, her voice flickering with emotion. Even if Crispr could have fixed that genetic defect, the woman said she wouldn’t change it. Some people in the deaf community feel the same way, and Ms. Doudna respects that. “Everyone’s feeling about DNA and about their inheritance and their children is going to be different,” she says. “It has to be a choice. People can decide what they want to do.”
Ms. Doudna remains opposed to nontherapeutic editing, often characterized as “designer babies,” and she says regulators won’t allow it, at least in the U.S. But other countries are less stringent. Is news of the first Crispr baby simply going to break one day? “It would be naive to think that that won’t happen at some point,” she says. Pressure to push forward will come not only from desperate people but also clinics abroad that may drum up business by saying: “We’ll do things here that will be advantageous for your children that are not allowed elsewhere.”
That’s why Ms. Doudna sees the ethical debate as vital. “It’s very hard to enforce any kind of global regulations on anything, but certainly on science,” she says. “So I think the next best thing is to try to encourage a global consensus that is strong enough that people feel some pressure to conform to it.”
The plan to eradicate the Anopheles mosquito presents a similar problem of collective decision-making. One iteration would involve a version of the insect edited to carry DNA that creates sterile females. That trait could then be forced into the wild population using a “gene drive.” Recall the basic rules of heredity—think back to that Punnett square from high school. Normally, an edited male in the wild would pass on the sterility gene to only half its offspring. Over many generations, the edited DNA would be diluted into oblivion.
That’s where the gene drive comes in. Scientists using Crispr in the lab have given the mosquito DNA that causes its cells to create Crispr.The result is a recursive, self-propagating gene that slices its reproductive competition. The edited mosquito passes on the sterility gene to nearly 100% of its offspring—which in turn do the same. Theoretically, releasing a single gene-drive insect, or letting one escape out an air-conditioning vent, could spread the edited DNA to the entire species.
Theoretically. “Although we understand that these gene drives can work in a laboratory setting efficiently in fruit flies and things like that, how well would they really work environmentally?” Ms. Doudna asks. “Evolution is a very strong force. If you put a species in a wild setting where they have to compete with other species, if they have a disadvantage reproductively, even if it’s a small disadvantage, they’re going to lose out.”
Ms. Doudna still needs to be convinced, too, of the wisdom of letting loose a gene drive. She cites her native Hawaii. “Species were introduced to that environment that ended up having large unintended consequences,” she says. Seeing that made her “very respectful of nature and very cautious about human beings’ thinking they have the knowledge to predict what will happen.”
A final Crispr worry is that it makes DNA editing so easy anybody can do it. Simple hobby kits sell online for $150, and a community biotech lab in Brooklyn offers a class for $400. Jennifer Lopez is reportedly working on a TV drama called “C.R.I.S.P.R.” that, according to the Hollywood Reporter, “explores the next generation of terror: DNA hacking.”
Ms. Doudna provides a bit of assurance. “Genetics is complicated. You have to have quite a bit of knowledge, I think, to be able to do anything that’s truly dangerous,” she says. “There’s been a little bit of hype, in my opinion, about DIY kits and are we going to have rogue scientists—or even nonscientists—randomly doing crazy stuff. I think that’s not too likely.”
Still, a couple of years ago Ms. Doudna had a dream in which a colleague asked her to explain gene-editing to someone very important. Turns out it was Hitler, except with the face of a pig. This, she says now, was her awakening to Crispr’s potential. “Try to imagine: We’re biochemists here, we’re futzing around with bacteria, just fartin’ around the lab, and students are doing experiments,” she says. “Then suddenly you have this discovery that you realize can be harnessed in a very different way.”
A few moments later she adds: “It was just this growing realization that this is no joke. This is a really seriously powerful technology.”
Mr. Peterson is the Journal’s deputy editorial features editor.
Appeared in the July 8, 2017, print edition.
