Imagine a world in which terrible hereditary diseases such as cystic fibrosis and hemophilia could be edited out of an unborn baby’s genetic code with the ease of cutting and pasting a sentence in your word processor. Or using that same technology to create drought-resistant wheat.
While it sounds like science fiction, this kind of genetic engineering is now becoming easier, thanks to a process called CRISPR, an acronym for “clustered regularly interspaced short palindromic repeats.” Less than a decade old, the use of CRISPR gene editing technology has taken the scientific world by storm and is being hailed by many experts as the greatest medical advance since vaccines and antibiotics.
“CRISPR is a huge development because it’s such a powerful tool,”said Kristian Laursen, a Danish researcher in pharmacology at New York City’s Weill Cornell Medical College. “It allows you to target specific places in the genome and is much easier to use than the cumbersome systems of the past.”
CRISPR is a discovery rather than an invention. It’s based on the revelation that many single-celled bacteria have immune systems that contain repeating bits of DNA. Between these identical repetitions are short segments of “spacer DNA,” which match virus DNA from previous exposures, ensuring that the bacterium can recognize and ward off further attacks. Whenever a previously exposed bacterium encounters the virus, the sequence acts like tiny scissors to chop it up.
CRISPR RESEARCH IN HUMANS
Using this knowledge, Jennifer Doudna, a professor of biochemistry and molecular biology at the University of California, Berkeley, and Emmanuelle Charpentier, a microbiologist and director of the Regulation in Infection Biology department at the Max Planck Institute for Infection Biology in Berlin, realized that by adding an enzyme they dubbed Cas9 (CRISPR associated protein 9) and some guidance proteins, they could direct those tiny scissors to a desired location in any genome and snip out a single bit of a gene.
In the space of just a few years, use of CRISPR to edit plants, animal and even human genomes has taken off. One remarkable experiment involves using CRISPR to take samples of frozen DNA from a woolly mammoth, which has been extinct for 4,000 years, and use an elephant as a surrogate mother to bring the species back to life, a scenario reminiscent of the film Jurassic Park.
And now scientists are making the first forays into using CRISPR on humans. In July 2016, Chinese scientists in Chengdu announced that they plan to use CRISPR technology to treat lung cancer in human patients by knocking out a gene in immune system T cells. Four groups of other scientists in China have already edited the human genome, albeit in embryos that could not survive to birth.
Meanwhile, the Recombinant DNA Advisory Committee (RAC) of the US National Institutes of Health (NIH) announced in June 2016 that it had approved the use of CRISPR/Cas9 gene technology to edit two genes in immune system T cells to make them target cancers that include myeloma, melanoma and sarcoma.
INHERITING ALTERED GENES
But some scientists have mixed feelings about experimenting in humans. “While the application of new gene editing technologies in this field has great potential to improve human health, it is not without concerns,” said Carrie D. Wolinetz, associate director for science policy at the NIH, in a 2016 post to the NIH blog “Under the Poliscope: Bringing Science Policy into Focus.”
One major concern about such experiments in living humans is that any changes in the genome will be passed down to future generations, and those tiny alterations may cause profound but unknown mutations decades from now.
Another immediate concern is that because CRISPR is so simple (synthetic biologist Josiah Zayner is just one of many already marketing DIY bacterial kits online for home use), terrorists or rogue governments could use the technology to create “Frankenstein” diseases as a weapon. In fact, James R. Clapper, the director of US National Intelligence, included genome editing in his list of “weapons of mass destruction and proliferation” when he made his annual “Worldwide Threat Assessment” to the US Congress in February 2016.
CRISPR RESEARCH WITH CROPS
For the time being, scientists believe that the most practical and commercial use of CRISPR technology will be in agriculture. Seed companies are already scrambling to improve crops such as rice and wheat with CRISPR to make them more resistant to pests and drought.
Caixia Gao, a researcher at the Institute of Genetics and Developmental Biology at the Chinese Academy of Sciences who is now working in Denmark, noted that scientists previously used a process called mutagenesis – dousing plants with chemicals or exposing them to radiation – to force genetic mutations, but the mutations could change thousands of parts of genes. Forced mutation therefore involved a long and laborious process, until the precisely desired mutation was achieved.
Another controversial method has been the creation of transgenic plants and animals, in which a gene from one type of plant or animal is inserted into another. This has prompted a smoldering debate about the safety of genetically modified organisms (GMOs), which have been dubbed “Frankenfoods” by critics.
Examples are soybeans that have received a gene from a bacterium to make them resistant to pesticides, so farmers can spray fields to kill weeds without harming the GMO crops. Canadian scientists have even created a transgenic Atlantic salmon that grows in half the time of a natural fish by inserting a growth hormone gene from a Chinook salmon.
Unlike GMOs, Gao said, scientists can now simply use CRISPR to target not only a specific gene, but one part of a specific gene, known as a base pair, eliminating the need to transplant genes from another species. She said she has used gene editing to knock out a wheat gene that makes the plant susceptible to disease, creating a strain that stays disease free.
“In the future, CRISPR will be a common and useful tool to modify plants and agricultural animals and breed new varieties,” Gao predicts.
US APPROVES FIRST CRISPR-ALTERED FOOD
The commercial benefits are already becoming apparent. Yinong Yang, a professor in the department of Plant Pathology and Environmental Microbiology at Penn State University in University Park, Pennsylvania, for example, used CRISPR to create a mushroom that doesn’t turn brown when exposed to air.
The US Department of Agriculture ruled that it did not have to regulate the mushroom, which is not a plant but a type of fungus, making it the first organism created with CRISPR technology to gain US government approval.
“Technically, agriculture might be the one big use of CRISPR because you don’t have the problem of off-target mutations,” Yang said. “You can simply go back and remove any unintended mutations.”
Yang has set up a company that has applied for patents on CRISPR-edited rice as well as his mushrooms. He said that altering just a few base pairs – there are 3,000 in a gene – reduce rice’s need for water and fertilizer.
One problem with CRISPR is that snipping out parts of genes is proving much easier than pasting something new into the space created.
“The efficient replacement of genes in plants is still very difficult,” Yang said. But many positive changes can take place without replacing the snipped gene. In humans, some scientists have estimated that changing the genes in only 10% of cells might be sufficient to cure a disease.
THE WAY FORWARD
Going forward, scientists like Laursen believe CRISPR will have a dramatic impact on treating disease – not only hereditary conditions, but problems such as bacteria that have become resistant to antibiotics through overuse.
CRISPR could be used to create a virus that attacks the bacteria and overcomes their immune defenses. It might also be used to knock out a human gene that makes people vulnerable to the HIV virus.
From extending the shelf life of fruit to the human lifespan, CRISPR holds the promise of changing the fundamental genetic makeup of virtually all plants and animals, including humans. CRISPR-derived techniques and variations continue to evolve, and alternative genome-editing systems and new enzymes are coming into play. Whether these changes prove to be beneficial or create new problems is a challenge that scientists and regulators will be watching closely.
CRISPR was awarded the 2020 Nobel Prize in Chemistry; read more here.
Learn more about how the CRISPR process works.