Genome editing for curing sickle-cell anemia, HIV, and cystic fibrosis and other diseases and then to create designer babies

Technology review reports on genome surgery

CRISPR is a new technology that could allow researchers to perform microsurgery on genes, precisely and easily changing a DNA sequence at exact locations on a chromosome. CRISPR changed everything. It replaces the DNA-targeting proteins with a short bit of RNA that homes in on desired genes. Unlike the complex proteins, RNA—which has nearly the same simple structure as DNA—can be made routinely in the lab; a technician can quickly synthesize the roughly 20-letter-long sequences the method requires. The system makes it easy for medical researchers to modify a genome by replacing, deleting, or adding DNA.

CRISPR stands for “clustered regularly interspaced short palindromic repeats”—clusters of brief DNA sequences that read similarly forward and backward, which are found in many types of bacteria. Scientists first observed the puzzling DNA segments in the 1980s but didn’t understand for almost two decades that they are part of a bacterial defense system. When a virus attacks, bacteria can incorporate sequences of viral DNA into their own genetic material, sandwiching them between the repetitive segments. The next time the bacteria encounter that virus, they use the DNA in these clusters to make RNAs that recognize the matching viral sequences. A protein attached to one of these RNAs then cuts up the viral DNA.

It will be several years before CRISPR can be developed into human therapeutics, but a growing number of academic researchers have seen some preliminary success with experiments involving sickle-cell anemia, HIV, and cystic fibrosis.

MIT researcher Feng Zhang can re-create, in both lab mice and cultured human cells, genetic variants found in people with autism and schizophrenia. “You can put a human mutation into the corresponding gene in a lab animal and then see: does that animal become less social or have a learning deficit?” he says. Then, he adds, you can study differences in the behavior and physiology of lab-cultured neurons grown from stem cells that have been modified with the same mutation. “With single-gene mutations, we will start to see aspects of the biological function that are involved in autism,” he says.

Because a CRISPR system can easily be designed to target any specific gene, the technology is allowing researchers to do experiments that probe a large number of them. In December, teams led by Zhang and MIT researcher Eric Lander created libraries of CRISPRs, each of which targets a different human gene. These vast collections, which account for nearly all the human genes, have been made available to other researchers. The libraries promise to speed genome-wide studies on the genetics of cancer and many other human diseases.

Zhang is also using CRISPR to make multiple genetic changes at once. That becomes particularly important with complex diseases like autism and schizophrenia, which for the most part are not caused by the type of single DNA change behind sickle-cell anemia. Different patients are affected by different collections of mutations. Solving a puzzle of such immense complexity will require large, systematic studies on the effects of various genes and the way they interact. CRISPR makes such studies possible, says Zhang, and will be important in finding treatments for a variety of complex diseases. “We will understand more about pathways and disease mechanisms,” he says. “This knowledge will inform all kinds of drug development.”

Late last year, Doudna, Zhang, Church, and two other pioneers of genome editing founded a startup that will develop novel treatments for human genetic diseases. In November the company, Editas MedicineChurch also predicts that if genome editing is used to cure childhood diseases, some scientists will be tempted to use it to engineer embryos during in vitro fertilization. Researchers have already shown that genome editing can rewrite DNA sequences in rat and mouse embryos, and in late January, researchers in China reported that they had created genetically modified monkeys using CRISPR. With such techniques, a person’s genome might be edited before birth—or, if changes were made to the eggs or sperm-­producing cells of a prospective parent, even before conception., announced that it had raised $43 million in venture capital and said it plans to use genome-editing technologies against a broad range of illnesses.

“Making a change or a deletion is out of range for most of those simple viral methods,” Church says. And deleting a bit of DNA, rather than adding a gene, may indeed be the key to treating many illnesses. Take Huntington’s disease. The fatal brain condition arises from a buildup of a toxic protein in neurons. Adding a healthy copy of the gene to the cell would not affect that protein’s poisonous activity: the original dysfunctional version must be rewritten. With the new genome-editing tools, says Church, rewriting the defective DNA may be possible: “You aren’t limited to adding back something that is missing.” And, he adds, “when you start realizing that the most common versions of genes are not necessarily the ideal versions, then you realize this is a much bigger field.” Perhaps scientists could rewrite normal genes so that humans can better fight infectious diseases. They might even be able to shake up the molecular pathways involved in aging.

For now, though, the technology is still evolving: while researchers like Bao, Church, and Zhang ultimately hope to cure some of our most intractable diseases, much of their time is still spent simply fine-tuning the tool and exploring its possibilities. But even in these early days, CRISPR has already transformed how these researchers think about manipulating the genome. They are ham-fisted no longer.

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