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Genome Editing

The ability to create primates with intentional mutations could provide powerful new ways to study complex and genetically baffling brain disorders.

Breakthrough

The use of a genome-tool to create two monkeys with specific genetic mutations.

Why It Matters

The ability to modify targeted genes in primates is a valuable tool in the study of human diseases.

Key Players

  • Yunnan Key Laboratory
  • Jennifer Doudna, UC Berkeley
  • Feng Zhang, MIT
  • George Church, Harvard

The Experiment

By Christina Larson

Until recently, Kunming, capital of China’s southwestern Yunnan province, was known mostly for its palm trees, its blue skies, its laid-back vibe, and a steady stream of foreign backpackers bound for nearby mountains and scenic gorges. But Kunming’s reputation as a provincial backwater is rapidly changing. On a plot of land on the outskirts of the city—wilderness 10 years ago, and today home to a genomic research facility—scientists have performed a provocative experiment. They have created a pair of macaque monkeys with precise genetic mutations.

Last November, the female monkey twins, Mingming and Lingling, were born here on the sprawling research campus of Kunming Biomedical International and its affiliated Yunnan Key Laboratory of Primate Biomedical Research. The macaques had been conceived via in vitro fertilization. Then scientists used a new method of DNA engineering known as CRISPR to modify the fertilized eggs by editing three different genes, and they were implanted into a surrogate macaque mother. The twins’ healthy birth marked the first time that CRISPR has been used to make targeted genetic modifications in primates—potentially heralding a new era of biomedicine in which complex diseases can be modeled and studied in monkeys.

CRISPR, which was developed by researchers at the University of California, Berkeley, Harvard, MIT, and elsewhere over the last several years, is already transforming how scientists think about genetic engineering, because it allows them to make changes to the genome precisely and relatively easily (see “Genome Surgery,” March/April). The goal of the experiment at Kunming is to confirm that the technology can create primates with multiple mutations, explains Weizhi Ji, one of the architects of the experiment.

Ji began his career at the government-affiliated Kunming Institute of Zoology in 1982, focusing on primate reproduction. China was “a very poor country” back then, he recalls. “We did not have enough funding for research. We just did very simple work, such as studying how to improve primate nutrition.” China’s science ambitions have since changed dramatically. The campus in Kunming boasts extensive housing for monkeys: 75 covered homes, sheltering more than 4,000 primates—many of them energetically swinging on hanging ladders and scampering up and down wire mesh walls. Sixty trained animal keepers in blue scrubs tend to them full time.


The lab where the experiment was performed includes microinjection systems, which are microscopes pointed at a petri dish and two precision needles, controlled by levers and dials. These are used both for injecting sperm into eggs and for the gene editing, which uses “guide” RNAs that direct a DNA-cutting enzyme to genes. When I visited, a young lab technician was intently focused on twisting dials to line up sperm with an egg. Injecting each sperm takes only a few seconds. About nine hours later, when an embryo is still in the one-cell stage, a technician will use the same machine to inject it with the CRISPR molecular components; again, the procedure takes just a few seconds.

During my visit in late February, the twin macaques were still only a few months old and lived in incubators, monitored closely by lab staff. Indeed, Ji and his coworkers plan to continue to closely watch the monkeys to detect any consequences of the pioneering genetic modifications.

The Impact

By Amanda Schaffer

The new genome-editing tool called CRISPR, which researchers in China used to genetically modify monkeys, is a precise and relatively easy way to alter DNA at specific locations on chromosomes. In early 2013, U.S. scientists showed it could be used to genetically engineer any type of animal cells, including human ones, in a petri dish. But the Chinese researchers were the first to demonstrate that this approach can be used in primates to create offspring with specific genetic alterations.

“The idea that we can modify primates easily with this technology is powerful,” says Jennifer Doudna, a professor of molecular and cell biology at the University of California, Berkeley, and a developer of CRISPR. The creation of primates with intentional gene alterations could lead to powerful new ways to study complex human diseases. It also poses new ethical dilemmas. From a technical perspective, the Chinese primate research suggests that scientists could probably alter fertilized human eggs with CRISPR; if monkeys are any guide, such eggs could grow to be genetically modified babies. But “whether that would be a good idea is a much harder question,” says Doudna.

The prospect of designer babies remains remote and far from the minds of most researchers developing CRISPR. Far more imminent are the potential opportunities to create animals with mutations linked to human disorders. Experimenting with primates is expensive and can raise concerns about animal welfare, says Doudna. But the demonstration that CRISPR works in monkeys has gotten “a lot of people thinking about cases where primate models may be important.”

At the top of that list is the study of brain disorders. Robert Desimone, director of MIT’s McGovern Institute for Brain Research, says that there is “quite a bit of interest” in using CRISPR to generate monkey models of diseases like autism, schizophrenia, Alzheimer’s disease, and bipolar disorder. These disorders are difficult to study in mice and other rodents; not only do the affected behaviors differ substantially between these animals and humans, but the neural circuits involved in the disorders can be different. Many experimental psychiatric drugs that appeared to work well in mice have not proved successful in human trials. As a result of such failures, many pharmaceutical companies have scaled back or abandoned their efforts to develop treatments.

Primate models could be especially helpful to researchers trying to make sense of the growing number of mutations that genetic studies have linked to brain disorders. The significance of a specific genetic variant is often unclear; it could be a cause of a disorder, or it could just be indirectly associated with the disease. CRISPR could help researchers tease out the mutations that actually cause the disorders: they would be able to systematically introduce the suspected genetic variants into monkeys and observe the results. CRISPR is also useful because it allows scientists to create animals with different combinations of mutations, in order to assess which onesor which combinations of themmatter most in causing disease. This complex level of manipulation is nearly impossible with other methods.

Guoping Feng, a professor of neuroscience at MIT, and Feng Zhang, a colleague at the Broad Institute and McGovern Brain Institute who showed that CRISPR could be used to modify the genomes of human cells, are working with Chinese researchers to create macaques with a version of autism. They plan to mutate a gene called SHANK3 in fertilized eggs, producing monkeys that can be used to study the basic science of the disorder and test possible drug treatments. (Only a small percentage of people with autism have the SHANK3 mutation, but it is one of the few genetic variants that lead to a high probability of the disorder.)

The Chinese researchers responsible for the birth of the genetically engineered monkeys are still focusing on developing the technology, says Weizhi Ji, who helped lead the effort at the Yunnan Key Laboratory of Primate Biomedical Research in Kunming. However, his group hopes to create monkeys with Parkinson’s, among other brain disorders. The aim would be to look for early signs of the disease and study the mechanisms that allow it to progress.

The most dramatic possibility raised by the primate work, of course, would be using CRISPR to change the genetic makeup of human embryos during in vitro fertilization. But while such manipulation should be technically possible, most scientists do not seem eager to pursue it.

Indeed, the safety concerns would be daunting. When you think about “messing with a single cell that is potentially going to become a living baby,” even small errors or side effects could turn out to have enormous consequences, says Hank Greely, director of the Center for Law and the Biosciences at Stanford. And why even bother? For most diseases with simple genetic causes, it wouldn’t be worthwhile to use CRISPR; it would make more sense for couples to “choose a different embryo that doesn’t have the disease,” he says. This is already possible as part of in vitro fertilization, using a procedure called preimplantation genetic diagnosis.

It’s possible to speculate that parents might wish to alter multiple genes in order to reduce children’s risk, say, of heart disease or diabetes, which have complex genetic components. But for at least the next five to 10 years, that, says Greely, “just strikes me as borderline crazy, borderline implausible.” Many, if not most, of the traits that future parents might hope to alter in their kids may also be too complex or poorly understood to make reasonable targets for intervention. Scientists don’t understand the genetic basis, for instance, of intelligence or other higher-order brain functions—and that is unlikely to change for a long time.

Ji says creating humans with CRISPR-edited genomes is “very possible,” but he concurs that “considering the safety issue, there would still be a long way to go.” In the meantime, his team hopes to use genetically modified monkeys to “establish very efficient animal models for human diseases, to improve human health in the future.”

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Credits: Photo courtesy of Yunnan Key Laboratory of Primate Biomedical Research, illustrations by John Macneill; Source: Cell

Tagged: Biomedicine, EmTech2014, DNA, genetics, TR10 2014, genome editing, CRISPR

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