HEADS UP: Altering genes, human and otherwise, made easy

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By Tuesday, Dec 8 Environment
The CRISPR-Cas9 system causes a precise double strand break in DNA, which leads to a gene being turned off. Researchers have scaled up to turn off genes accurately and efficiently at a genomic of just one or a few genes at a time. Composite image by Lauren Solomon, Broad Communications.

An international array of scientists — prominent among them Jennifer Doudna of Berkeley and Feng Zhang of Harvard and M.I.T. — have come up with a new molecular technology called CRISPR-Cas9, which can edit genes swiftly and with relative ease. Its applications are so vast and ubiquitous that the science blogs and the business pundits are calling it “the CRISPR Craze.” Millions of investor dollars are lining up behind one application or another. Biofuels. Bug-resistant plants. Personalized chemotherapy. And ordinary folks who have never even said “Hi” to molecular biology must decide whether this will lead to a more perfect world or a nightmare of unintended consequences.

The picture shows an edited Brassica plant on the right, which is shorter and has an altered pod structure. The Brassica wild type plant is on the left. In Brassica the edited gene affected the ease with which the seedpods shattered. Photo: The John Innes Centre

The picture shows an edited Brassica plant on the right, which is shorter and has an altered pod structure. The Brassica wild type plant is on the left. In Brassica the edited gene affected the ease with which the seedpods shattered. Photo: The John Innes Centre

CRISPR is an acronym for “clustered regularly interspersed short palindromic repeats,” which describes the structure of the molecular keyboard on the genome where one might find spots to play a new or revised tune. Cas9 is a protein that has two RNA fingers to strike the keyboard — one to find the notes to be affected, the other to cut them out and reunite the severed ends of the DNA, completing the revision to create a smoothly working genome playing a desirable new melody. In addition, you can take out multiple genes at one time. No previous gene editing technology has come near to being this facile and swift.

The CRISPR-Cas9 technique of gene editing foresees a time when genetic diseases, like sickle cell and Tay-Sachs and cystic fibrosis, can be found in the DNA of potential parents and edited out to protect future generations. I think about women I know who carry the BRCA gene for breast cancer, the one that killed Angelina Jolie’s mother and caused the actress to choose prophylactic mastectomies to avoid the same fate. I think about a friend whose siblings have been felled one after the other by inherited heart disease. Imagine how great it would be if the children could have been saved by gene editing in the afflicted parent.

Dr. Gideon Blumenthal, team leader for lung cancer at the FDA and an attending physician at NIH, feels that “specifically in oncology there’s a lot of promise for CRISPR- Cas9. Right now it’s being used in pre-clinical trials, where human tumors are modeled and treated in mice to see how genes interact within a tumor and to explore which gene mutations respond best to which chemical interventions.” Human applications may be some years off. But without a doubt, says Blumenthal, the time for finding precise, personalized delivery of chemotherapy, targeted therapy and immunotherapy has been shortened,

CRISPR-Cas9 had also opened the way for attacks on the pestilences of nature in the wild. Imagine re-tuning the genome of the malaria mosquito so no females can be born and the disease-bearing breed just dies out, taking malaria with it. Imagine destroying the genes in Asian milfoil that make it grow into thickets that proliferate and clog the waters of our local lakes. Already scientists are seeking applications to prevent Lyme disease. (Being an inveterate worrier, I now imagine some lab targeting the wrong gene in error, then releasing the mistake into a wild population where it will run amuck around the defenseless world. Shades of The Andromeda Strain! ) Professor Ben Carone, who teaches Molecular Biology at Williams, points to the scary way such a mutation could spread. “Now that we have a system where you can pinpoint the region of the DNA whose genes are responsible for a given trait, you can just snip it out, and because of something called ‘gene drive’ those changes may become stable in a population, even potentially taking over non-genetically modified organisms.”

Many scientists favor a complete ban on genetic interventions in wild populations until Federal regulations are in place. This worrier enthusiastically agrees. Below is a video explaining the potential of the CRISPR-Cas9 process:



Professor Doudna declares that the new gene editing technology is so simple and straightforward that a bright grad student with a good teacher can learn to use CRISPR-Cas9 in a matter of weeks. This is corroborated by Prof. Carone. “With proper instructing,” he says, ” I can train my kids to get their CRISPR gene editing skills up and running.” (Of course I immediately think of the hit TV series Breaking Bad in which the teacher is anything but proper, the student is a stoner and the purpose is not to cure disease but to make millions cooking meth.) “It’s not a bad analogy,” says Professor Carone. “This is one of those instances that makes us ask ourselves what our true intentions really are. Right now the technology is moving so fast that the regulatory agencies are rushing to catch up. Leading scientists are trying to decide what the guidelines should be. Self-regulation will precede political regulation.”

Scientists in China recently used CRISPR-Cas9 to modify human embryos, attempting to repair the gene responsible for a rare blood disease. The embryos were non-viable and the experiment would never have produced a human being. The scientists spelled out all the problems they encountered and concluded that the technology was no way ready for any kind of application. But their work raised the specter of eugenics and memories of horrific Nazi efforts to breed a “master race.” Could this technology be used not just to cure disease but also to create cosmetic preferences, like long eyelashes and big muscles? The general reaction was terror.

“The danger is hypothetical in this country,” said Professor Carone. “We long ago outlawed human genetic engineering.” But the Chinese experiment showed it could be done. And once it can be done, there is every reason to believe that someday somebody is going to do it.

CRISPR-Cas9 is most likely to be used in agriculture — in plant genetic engineering. Notes Professor Carone: “One of the major advantages of using CRISPR is its ability to work in new model organisms. Previously, we were restricted to a few agriculture crops because very few plant genomes were sequenced and the method to perform genetic modifications had to be fine tuned for each species. Now with the advent of cheap DNA sequencing combined with CRISPR genome editing, almost any organism has the potential to have its genome edited.”

The greatest impact may show up in wheat. Up to now, wheat – 20 percent of the world’s calories — has been guarded against genetic modification by its complicated, quirky, hard-to-mediate genome. In the United States, half the cotton, three quarters of the corn, 60 percent of the soybeans and almost all the sugar beets have been genetically modified by the great chemical poison companies like Monsanto, Dow, Syngenta, BASF and Bayer. But they are still working to develop wheat that can, for example, withstand the anticipated droughts of climate change and resist the herbicides those same corporations use to control weeds. Now along comes CRISPR, which may immeasurably simplify the task.

The John Innes Center in England has conducted experiments with a type of broccoli (and also with barley) showing that CRISPR-Cas9 could make genomic changes that would remain permanently in the plant and show up harvest after harvest. Even more importantly, the transgenes that were used to pinpoint the editing location could be removed after the edit, making the whole transaction invisible. According to Britain’s Prof. Wendy Harwood “the final plants…have no additional DNA inserted so they are essentially the same as plants with naturally occurring changes to genes or plants that have been bred using conventional methods.”

Some folks worry that this CRISPR-bred invisibility will leave us everyday eaters unable to tell what genomic shenanigans went on before the food got to our plates. Some folks think it could be the best thing that ever happened to broccoli.

Each application, if you will, each new tune that CRISPR-Cas9 plays, may eventually be owned by those who invent and perfect it. But right now, the technology itself belongs to no one and everyone. Just like the Internet. Just like the keyboard on the piano. And the possibilities, for better or worse, are boundless.

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