Gene Method Makes Mutants More Easily, and Sparks Concerns

Image: Mutant fruit fly

The left half of this fruit fly has been mutated using mutagenic chain reaction, hence the pale color. The right half remains normal. Valentino Gantz / UCSD

Scientists have found a way to create mutant organisms more reliably, using a recently developed gene-editing technique known as CRISPR. And just as in the "X-Men" movies, not everyone is happy about that.

The procedure, known as mutagenic chain reaction, is described in a paper published online Thursday by the journal Science. It uses genetic engineering to put a specific mutation in both copies of a gene associated with a particular trait. That gets around a cellular mechanism that usually keeps recessive mutations from being expressed.

Here's the classic, if overly simplistic, example: Children inherit sets of chromosomes from each of their parents, with each chromosome containing the genes for various traits. A blue-eyed child has to inherit the blue-eyed gene from both the mother and the father. Otherwise, the dominant brown-eyed gene trumps the recessive blue-eyed gene.

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In reality, eye color is determined by more than one gene. But the same principle applies to genetic defects such as muscular dystrophy: Even if you inherit the mutated gene for muscular dystrophy from one parent, the normal gene from the other parent can compensate and keep you from getting the disease.

The downside for genetic engineers is that the mechanism makes it harder to introduce desired mutations. Mutagenic chain reaction, or MCR, makes the job easier. The researchers behind the Science study tweaked the CRISPR genome-editing procedure in fruit flies to make a mutation that's generated on one copy of a chromosome spread automatically to the other copy. Thus, both copies of the gene carry the mutation.

"MCR is remarkably active in all cells of the body, with one result being that such mutations are transmitted to offspring via the germline with 95 percent efficiency," study lead author Valentino Gantz, a graduate student at the University of California at San Diego, said in a news release.

Profound consequences

UCSD Professor Ethan Bier, the paper's co-author, said the technique has "several profound consequences." It could accelerate the pace of genetic research, and facilitate the rapid dispersal of genetically engineered traits.

For example, researchers already have worked out genetic codes to prevent mosquitoes from spreading malaria and other diseases, but it's not easy to breed mosquitoes to incorporate those codes. With MCR, the codes could spread to virtually all the individuals in a mosquito population in as few as 10 generations, "which is less than one season for mosquitoes," Bier said.

Gantz said the same technique could be used to spread genes among cells within an individual using modified viruses, or even hunt down and fix HIV-infected cells or cancer cells.

Serious risks

The researchers acknowledged there could be serious risks as well. Bier said scientists would have to guard against having MCR organisms get loose in the wild. "It is also possible that MCR technology could be intentionally misused, which should be considered as a risk on par with that associated with nefarious uses of select agents," he said.

Bier noted that biologists worked out safety procedures for recombinant DNA technology in 1975 at what is now known as the Asilomar Conference. "Perhaps a similar meeting should be convened to discuss how MCR technology should be regulated at both federal and institutional levels," Bier said.

In a news report accompanying the research paper, Science quoted Harvard geneticist George Church as saying the paper shouldn't have been published because the technique described by Gantz and Bier didn't include adequate safeguards. "It is a step too far," Church said.

Bier rejected the criticism, saying that he and his colleagues thought carefully about the requirements for the research as well as the safeguards. The fruit-fly experiments were conducted under what Gantz and Bier called "triple-contained" safety measures.

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Update for 8:30 p.m. ET March 20: In a perspective piece published online by Science, Church and more than a dozen other prominent geneticists say that researchers should be banned or strongly discouraged from genetically modifying the human germline with CRISPR tools, pending an Asilomar-style forum to define the appropriate and safe applications for the technology.

The geneticists say such experiments with human nuclear DNA would raise concerns "because there are limits to our knowledge of human genetics, gene-environment interactions and the pathways of disease." The group said another form of genetic engineering, involving mitochondrial transfer, raises different issues that are already being addressed by authorities in Britain and the United States.

The perspective article follows up on a meeting on the implications of genome biology that was held in Napa, California, in January.