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Thanks to decades of genetic engineering, specialized viruses have been completely retooled so that they are still able to deliver DNA to the body—either systemically or to specific organs—but can’t infect their host with anything except the therapeutic payloads that researchers give them.
an innocuous human virus known as adeno-associated virus (AAV). AAV provokes only a mild immune response and is not known to cause any human disease. This viral vector can easily be outfitted with therapeutic genes that encode the Cas9 protein and its guide RNA, and it is highly effective at delivering its genetic material to host cells.
family of AAV vectors that can target cells in many different types of tissues. One strain of AAV might be best suited to deliver CRISPR to cells of the liver, while another might work best in the central nervous system, the lungs, the eyes, or the cardiac and skeletal muscles.
By the end of 2015, no fewer than four independent laboratories delivered CRISPR to fully grown mice suffering from muscular dystrophy and showed that the ravages of the disease could be reversed.
By packaging genetic instructions for CRISPR into AAV vectors, the researchers repaired skeletal and cardiac muscle cells, either by injecting the loaded viruses into the mouse’s muscles or by delivering the viruses to the same tissues through the bloodstream.
After gutting these adenoviruses and removing their pathogenic genes, researchers can insert a greater amount of therapeutic DNA than is allowed by AAV vectors. Lentiviruses, the most prominent example of which is HIV, have also been defused in the laboratory and converted into effective delivery vehicles.
Building on advances in nanotechnology—the science of fabricating submicroscopic structures—researchers are exploring the use of lipid nanoparticles to ferry CRISPR throughout the body.
Resistant to degradation and easy to manufacture, these delivery vehicles also have the benefit of releasing the Cas9 protein and its guide RNA into the patient’s body in a regimented
lipid nanoparticles deliver CRISPR so that it acts quickly before being broken down by the natural recycling factories of the cell.
instead of asking what gene mutations caused the cancer (as Ebert’s team had done), Sabatini’s team wanted to discover gene mutations that disabled the cancer.
In a true tour de force, Sabatini’s team addressed this question for four different blood-based cancer lines and discovered a whole host of new genes that seemed to be essential for them to thrive.
Another strategy involves the manufacture of genetically engineered T cells that are precisely designed to target a patient’s unique cancer. This process—yet another example of ex vivo therapy—is known as adoptive cell transfer, and it’s in this mode of immunotherapy that gene editing enters the picture.
It seems likely that gene editing will go a step further and transform cancer immunotherapy into more of an off-the-shelf treatment, where a single batch of engineered T cells, designed for a specific type of cancer, could be given universally to all patients suffering from that pathology.
Editas Medicine has an exclusive multimillion-dollar license with Juno Therapeutics to develop T cell therapies, and Intellia Therapeutics has partnered with the major health-care firm Novartis to similarly pursue cancer immunotherapy.
CRISPR—at least, the original version of it found in bacteria—is not an entirely error-free method of targeting and cutting DNA.
virtually all medical drugs have some kind of off-target activity, and as long as the intended on-target benefits outweigh those risks, physicians and regulators are generally pretty forgiving. For instance, antibiotics kill off both pathogenic bacterial strains and beneficial strains, and chemotherapy drugs kill off both cancerous cells and healthy cells.
With gene editing, however, any off-target DNA sequence, once edited, is irreversibly changed. Not only will unintended edits to the DNA be permanent, they will also be copied into every cell that descends from the first one.
If CRISPR is programmed to target a twenty-letter sequence in gene X, but gene Y has a similar DNA sequence that differs in only one letter, there is a finite probability that CRISPR will introduce edits in both genes. The less closely the two sequences mirror each other, the lower the likelihood of off-target mutations.
Researchers have already begun to find ways around this potential problem. Multiple laboratories have written computer algorithms that will automatically probe the three-billion-letter human genome to see how many other regions have sequences similar to the one a scientist wants to edit. If the number of potential off-target DNA sequences is too high, the researcher, aided by the algorithm, can simply select a new region to target.
By simply tweaking the natural Cas9 protein in a few different places—swapping out one amino acid for another—researchers, including Keith Joung from Harvard Medical School and Feng Zhang from MIT, have developed higher-fidelity versions of CRISPR that are less prone to off-target gene editing than the version nature evolved on its own. Finally, the dosage of CRISPR affects the likelihood of the genome being riddled with unintended mutations.
The trick is to deliver just enough CRISPR into cells so that the right DNA target sequence gets edited, but no more than that.
the 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.
New studies surface at a rate of more than five per day, on average, and investors have poured well over a billion dollars into the various startup companies that are pursuing CRISPR-based biotechnology tools and medical therapeutics.
The birth of Louise Brown in 1978, the world’s first “test-tube baby,” was a watershed moment for reproductive biology, proving that human procreation could be reduced to simple laboratory procedures: the mixing of purified eggs and sperm in a petri dish, the fostering of a zygote as it grew into a multicellular embryo, and the implantation of that embryo in the female womb.
human phenotypes, from physical traits to cognitive ones.
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. Since each parent passes down only 50 percent of his or her DNA to offspring, the particular constellation of chromosomes and genes that a child inherits is essentially random. But the ability to generate multiple embryos in the laboratory using multiple eggs and sperm changed all that. Instead of implanting random embryos into the mother, IVF doctors
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Emmanuelle and I, and our collaborators, had imagined that CRISPR technology could save lives by helping to cure genetic disease. Yet as I thought about it now, I could scarcely begin to conceive of all of the ways in which our hard work might be perverted. Overwhelmed by how fast everything was moving and by how quickly it seemed it could all go wrong, I began to feel a bit like Dr. Frankenstein. Had I created a monster?
The article, published in the journal Protein and Cell, described experiments in Junjiu Huang’s lab at Sun Yat-sen University in Guangzhou, China. Huang and his colleagues had injected CRISPR into eighty-six human embryos.
Huang’s goal was to precisely edit the beta-globin gene in these eighty-six embryos,
In purely scientific terms, the results of Huang’s experiments were mixed. Upon examining the beta-globin genes of the tested embryos, the researchers found that a mere four of the eighty-six embryos contained the intended mutations, a gene-editing efficiency of just 5 percent.
The American Society of Gene and Cell Therapy, the premier professional organization for DNA-based medicine,
American spy agencies seemed rattled by the experiments too. I was shocked when the next 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. (The others were Russian cruise missiles, Syrian and Iraqi chemical weapons, and the nuclear programs of Iran, China, and North Korea.)
Julian Savulescu, a distinguished philosopher and bioethicist, asserted that there was a moral imperative to aggressively continue pursuing similar lines of experimentation.
Steven Pinker, the acclaimed Harvard scholar, vented his general frustration at the overly cautious reactions to biotechnological advances like CRISPR in an opinion article in the Boston Globe.
the Hinxton Group—a global network of ethicists, scientists, lawyers, and policy experts—extolled
prestigious Francis Crick Institute in London
genetic enhancement)
we have tools to safeguard against these off-target effects—at least, we do where germline editing is concerned. 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 ...
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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. Correcting the two mutated copies of the beta-globin gene in people who suffer from sickle cell disease would rid them of the illness but also deprive them of the mutation’s protection against malaria. These are far from the only gene edits that have both positive and negative effects.
dominant genetic disorders—conditions like Huntington’s disease, the familial form of early-onset Alzheimer’s disease, and Marfan syndrome—in which a single copy of the mutated gene is sufficient to cause disease, regardless of whether it comes from the father or mother.
Although these diseases could still be treated with therapeutic gene editing in somatic cells, germline editing would prevent children from developing the diseases in the first place and thus could prevent suffering.
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.
But plenty of other genetic enhancements do result from simple mutations that could be re-created with 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, ...
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nonmedical enhancements.
therapeutic germline editing or enhancement gene editing?
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.
Since the wealthy would be able to afford the procedure more often, and since any beneficial genetic modifications made to an embryo would be transmitted to all of that person’s offspring, linkages between class and genetics would ineluctably grow from one generation to the next,
