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engineering CRISPR to be more discriminating in how it recognizes the target DNA. For example, scientists have successfully expanded the sequence of DNA that CRISPR
Finally, the dosage of CRISPR affects the likelihood of the genome being riddled with unintended mutations. In general, the more Cas9 and guide RNA a cell gets and the longer those molecules hang around, the more likely it is that CRISPR will find slightly related but mismatched sequences and introduce off-target edits. The trick is to deliver just enough CRISPR into cells so that the right DNA target sequence gets edited, but no more than that.
published scientific literature reveals a growing list of diseases for which potential genetic cures have been developed with CRISPR: achondroplasia (dwarfism), chronic granulomatous disease, Alzheimer’s disease, congenital hearing loss, amyotrophic lateral sclerosis (ALS), high cholesterol, diabetes, Tay-Sachs, skin disorders, fragile X syndrome, and even infertility. In virtually
CRISPR—save for the advancements on one front. I think we should refrain from using CRISPR technology to permanently alter the genomes of future generations of human beings, at least until we’ve given much
Christina assured him that her company planned to introduce only prophylactic genetic modifications in human embryos; if he wanted to be involved, he needn’t worry about making any mutations that weren’t necessary to ensure the health of the unborn child.
later, he’d perceived a Promethean glint in her eyes and suspected she had in mind other, bolder genetic enhancements in addition to the well-intentioned genetic changes she’d described.
Thus, unlike CRISPR, the technology of somatic cell nuclear transfer was effectively self-limiting due to the extensive expertise it required.
Once the technique of in vitro fertilization transformed the act of conception into a rather simple laboratory procedure, it became feasible to subject early-stage human embryos to DNA sequence analysis just like any other biological sample.
That distinction goes to mitochondrial replacement therapy, colloquially known as three-parent IVF. Paradoxically, any babies born from this procedure contain DNA from not two, but three parents: one father and two mothers. This
support. Asilomar II was not without its critics, though. The conference was invitation-only, and with
absolutely agree that society as a whole—rather than scientists individually or even as a group—should decide how any given technology is used. But there’s a wrinkle here, which
Luckily, I didn’t need to go at it alone. I’d recently co-founded an institute in the Bay Area called the Innovative Genomics Institute (IGI) with the goal of advancing gene-editing technologies,
In one example, the embryo had at least four different edited DNA sequences, only one of which was the correct one. Rather than editing the beta-globin gene at the one-cell stage and thus repairing the sole master copy of the embryo’s genome, CRISPR had acted too slowly and begun working only after the fertilized egg had split into multiple daughter cells.
In this case, at least, Huang had taken care to ensure that no CRISPR babies could be born as a result of his experiments by using triploid human embryos. So named because they contain three sets of twenty-three chromosomes (sixty-nine in total) instead of the normal two (forty-six in total), triploid embryos are nonviable, and in IVF procedures, it’s easy for doctors to identify triploid embryos
Worldwide Threat Assessment—the annual report presented by the U.S. intelligence community to the Senate Armed Services Committee—described genome editing as one of the six weapons of mass destruction and proliferation that nation-states might try to develop, at great risk to America.
How accurate must CRISPR be in order to be safely used in the human germline? It seems obvious that we should reject any procedure that might trigger DNA editing at unintended sites, as sometimes occurs with CRISPR and other gene-editing technologies. But the truth is that our entire lives are spent at risk of such random genetic changes, and the threat from them is arguably far greater than any that CRISPR would pose.
Every person experiences roughly one million mutations throughout the body per second, and in a rapidly proliferating organ like the intestinal epithelium, nearly every single letter of the genome will have been mutated at least once in at least one cell by the time an individual turns sixty. This mutational process begins from the earliest moment of fertilization, and as the single-cell zygote goes on to divide into two cells, then four, then eight cells of the growing embryo, the new mutations it has acquired
never before existed in either family’s germline. As a result, each one of us begins life with fifty to a hundred random mutations that arose de novo (“anew”) in our parents’ germ cells.
“Genetic editing would be a droplet in the maelstrom of naturally churning genomes.” If CRISPR could eliminate a disease-causing mutation in
One such tool is PGD, which could make it possible to detect rare, undesirable mutations after CRISPR has edited the genome but before the growing embryo is placed in the mother’s womb. Another option that might become possible in the future is to avoid off-target mutations entirely by editing primordial egg and sperm cells instead of fertilized embryos. Although the technology is still in its infancy, research in mice has demonstrated that eggs and sperm can be grown in the laboratory from stem cells and used to establish pregnancies. By eliminating disease-causing mutations with CRISPR and
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but also whether the effects of accurate edits will be the ones we intend. We already know that some of the gene edits scientists are considering for clinical use have secondary effects. For instance, editing an embryo’s CCR5 gene might make the resulting human resistant to HIV but more susceptible to the West Nile virus.
Researchers now suspect that people who carry one copy of the mutated gene that causes cystic fibrosis (which requires two copies) have an increased defense against tuberculosis, an infectious disease that accounted for 20 percent of all European deaths between 1600 and 1900.
“The notion that we need complete knowledge of the whole human genome to conduct clinical trials of heritable gene editing seems at odds with medical reality.”
that turned out to be suboptimal. Similarly, the argument that germline editing is somehow unnatural doesn’t carry much weight with me anymore. When it comes to human affairs, and especially the world of medicine, the line between natural and unnatural blurs to the point of disappearing. We
I’ve now had numerous opportunities to meet with people who have experienced genetic disease themselves or in their families, and their stories are deeply moving.
Not everyone shares these views. It’s not uncommon to hear people talk about our genomes as if they were part of a precious evolutionary inheritance, something to be cherished and conserved.
The first has to do with whether anyone will be able to control how germline editing is employed once doctors start using it to save people’s lives.
The second has to do with questions of social justice—of how CRISPR would affect society.
Many kinds of enhancements that come to mind—things like high intelligence, prodigious musical ability, mathematical prowess, tall stature, athletic skill, or stunning beauty—don’t have clear-cut genetic causes. That’s not to say they aren’t heritable, just that the complexity of these traits may place them beyond the reach of a tool like CRISPR.
For example, mutations in the EPOR gene, which responds to the hormone erythropoietin (the famous doping drug used by Lance Armstrong and countless other athletes), confer exceptional levels of endurance; mutations in a gene called LRP5 endow individuals with extra-strong bones; mutations in the MSTN gene (the same myostatin gene that’s been edited to create supermuscular pigs and dogs) are known to result in leaner muscles and greater muscle mass; mutations in a gene called ABCC11 are associated with lower levels of armpit odor production (and, oddly, the type of earwax an individual
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of these liminal examples of germline editing involves the gene PCSK9, which produces a protein that regulates a person’s level of low-density lipoprotein cholesterol (the “bad” cholesterol), making the gene one of the most promising pharmaceutical
Editing CCR5 with CRISPR could confer lifelong resistance to HIV; editing the APOE gene could lower an individual’s risk of developing Alzheimer’s disease; altered DNA sequences in IFIH1 and SLC30A8 could lower a person’s risk of developing type 1 and type 2 diabetes; and changes to the GHR gene could reduce an individual’s risk of cancer. In all these cases, the primary objective would be to save an individual from disease, but
Germline editing may inadvertently transcribe our societies’ financial inequality into our genetic code—but it may also create a different kind of injustice. As disability-rights advocates have pointed out, using gene editing to “fix” things like deafness or obesity could create a less inclusive society,
Part of what makes our species unique, and our society so strong, is its diversity. While
That’s because eugenic, as it was originally defined, means “well-born” and so could apply to any action intended to lead to the birth of a healthy child. Our current, looser interpretation of the term
As Charles Sabine, a victim of Huntington’s disease, put it, “Anyone who has to actually face the reality of one of these diseases is not going to have a remote compunction about thinking that there is any moral issue at all.” Who are we to tell him otherwise?
funding for germline editing. There’s also a risk that overly restrictive policies in some countries will encourage what might be called CRISPR tourism in others.
Once a game-changing technology is unleashed on the world, it is impossible to contain it. Blindly rushing ahead with new technologies creates problems of its own. For example, the race for
One of the defining characteristics of our species is its drive to discover, to
Aldous Huxley famously imagined a future of genetic castes in his chilling novel Brave New World, and rarely does the topic of germline gene editing come up in the media nowadays without the book being directly or indirectly referenced. But Huxley’s dystopia is set in the year 2540. It seems unlikely
These twin poles of science—competition and collaboration—have defined my career and shaped me as a person.
have also come to appreciate the importance of stepping out of my comfort zone and discussing science with people beyond my circle of specialists.
cutting and DNA-copying enzymes from gut- and heat-loving bacteria. Rapid DNA sequencing required experiments on the remarkable properties of bacteria from hot springs. And my colleagues and I would never have created a powerful gene-editing tool if we hadn’t tackled the much more fundamental question of how bacteria fight off viral infections. The story
reminder that breakthroughs can come from unexpected places and that it’s important to let a desire to understand nature dictate the path forward. But it’s also a reminder that scientists and laypeople alike bear a tremendous responsibility for the scientific process and its outputs.
