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Humans 2.0: The New Yorker on CRISPR


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I like the comparison of CRISPR to the Model T.

At least since 1953, when James Watson and Francis Crick characterized the helical structure of DNA, the central project of biology has been the effort to understand how the shifting arrangement of four compounds—adenine, guanine, cytosine, and thymine—determines the ways in which humans differ from each other and from everything else alive. CRISPR is not the first system to help scientists pursue that goal, but it is the first that anyone with basic skills and a few hundred dollars’ worth of equipment can use.

“CRISPR is the Model T of genetics,” Hank Greely told me when I visited him recently, at Stanford Law School, where he is a professor and the director of the Center for Law and the Biosciences. “The Model T wasn’t the first car, but it changed the way we drive, work, and live. CRISPR has made a difficult process cheap and reliable. It’s incredibly precise. But an important part of the history of molecular biology is the history of editing genes.”

Scientists took the first serious step toward controlling our genes in the early nineteen-seventies, when they learned to cut chains of DNA by using proteins called restriction enzymes. Suddenly, genes from organisms that would never have been able to mate in nature could be combined in the laboratory. But those initial tools were more hatchet than scalpel, and, because they could recognize only short stretches within the vast universe of the human genome, the editing was rarely precise. (Imagine searching through all of Shakespeare for Hamlet’s soliloquy on suicide, relying solely on the phrase “to be.” You’d find the passage, but only after landing on several hundred unrelated citations.)

When the first draft of the Human Genome Project was published, in 2001, the results were expected to transform our understanding of life. In fundamental ways, they have; the map has helped researchers locate thousands of genes associated with particular illnesses, including hundreds that cause specific types of cancer. To understand the role that those genes play in the evolution of a disease, however, and repair them, scientists need to turn genes on and off systematically and in many combinations. Until recently, though, altering even a single gene took months or years of work.

The Cas9 Mouse is amazing: An editable animal.

Despite our growing knowledge of the way that cancer develops in human cells, mutations can’t be studied effectively in a petri dish, and, since the late nineteen-eighties, genetically modified mice have served as the standard proxy. What cures (or kills) a mouse won’t necessarily have the same effect on a human, but the mouse genome is surprisingly similar to our own, and the animals are cheap and easy to maintain. Like humans, and many other mammals, mice develop complex diseases that affect the immune system and the brain. They get cancer, atherosclerosis, hypertension, and diabetes, among other chronic illnesses. Mice also reproduce every three weeks, which allows researchers to follow several generations at once. Typically, technicians would remove a stem cell from the mouse, then edit it in a lab to produce a particular gene or to prevent the gene from working properly. After putting the stem cell back into the developing embryo of the mouse, and waiting for it to multiply, they can study the gene’s effect on the animal’s development. The process works well, but it generally allows for the study of only one characteristic in one gene at a time.

The vivarium at the Broad houses an entirely different kind of mouse, one that carries the protein Cas9 (which stands for CRISPR-associated nuclease) in every cell. Cas9, the part of the CRISPR system that acts like a genetic scalpel, is an enzyme. When scientists originally began editing DNA with CRISPR, they had to inject both the Cas9 enzyme and the probe required to guide it. A year ago, Randall Platt, another member of Zhang’s team, realized that it would be possible to cut the CRISPR system in two. He implanted the surgical enzyme into a mouse embryo, which made it a part of the animal’s permanent genome. Every time a cell divided, the Cas9 enzyme would go with it. In other words, he and his colleagues created a mouse that was easy to edit. Last year, they published a study explaining their methodology, and since then Platt has shared the technique with more than a thousand laboratories around the world.

The “Cas9 mouse” has become the first essential tool in the emerging CRISPR arsenal. With the enzyme that acts as molecular scissors already present in every cell, scientists no longer have to fit it onto an RNA guide. They can dispatch many probes at once and simply make mutations in the genes they want to study

What CRISPR is:

CRISPR has two components. The first is essentially a cellular scalpel that cuts DNA. The other consists of RNA, the molecule most often used to transmit biological information throughout the genome. It serves as a guide, leading the scalpel on a search past thousands of genes until it finds and fixes itself to the precise string of nucleotides it needs to cut. It has been clear at least since Louis Pasteur did some of his earliest experiments into the germ theory of disease, in the nineteenth century, that the immune systems of humans and other vertebrates are capable of adapting to new threats. But few scientists had considered the possibility that single bacterial cells could defend themselves in the same way. The day after Zhang heard about CRISPR, he flew to Florida for a genetics conference. Rather than attend the meetings, however, he stayed in his hotel room and kept Googling. “I just sat there reading every paper on CRISPR I could find,” he said. “The more I read, the harder it was to contain my excitement.”

It didn’t take Zhang or other scientists long to realize that, if nature could turn these molecules into the genetic equivalent of a global positioning system, so could we. Researchers soon learned how to create synthetic versions of the RNA guides and program them to deliver their cargo to virtually any cell. Once the enzyme locks onto the matching DNA sequence, it can cut and paste nucleotides with the precision we have come to expect from the search-and-replace function of a word processor. “This was a finding of mind-boggling importance,” Zhang told me. “And it set off a cascade of experiments that have transformed genetic research.”

With CRISPR, scientists can change, delete, and replace genes in any animal, including us. Working mostly with mice, researchers have already deployed the tool to correct the genetic errors responsible for sickle-cell anemia, muscular dystrophy, and the fundamental defect associated with cystic fibrosis. One group has replaced a mutation that causes cataracts; another has destroyed receptors that H.I.V. uses to infiltrate our immune system.

The potential impact of CRISPR on the biosphere is equally profound. Last year, by deleting all three copies of a single wheat gene, a team led by the Chinese geneticist Gao Caixia created a strain that is fully resistant to powdery mildew, one of the world’s most pervasive blights. In September, Japanese scientists used the technique to prolong the life of tomatoes by turning off genes that control how quickly they ripen. Agricultural researchers hope that such an approach to enhancing crops will prove far less controversial than using genetically modified organisms, a process that requires technicians to introduce foreign DNA into the genes of many of the foods we eat.

The technology has also made it possible to study complicated illnesses in an entirely new way. A few well-known disorders, such as Huntington’s disease and sickle-cell anemia, are caused by defects in a single gene. But most devastating illnesses, among them diabetes, autism, Alzheimer’s, and cancer, are almost always the result of a constantly shifting dynamic that can include hundreds of genes. The best way to understand those connections has been to test them in animal models, a process of trial and error that can take years. CRISPR promises to make that process easier, more accurate, and exponentially faster.

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