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    Science Saturday: The gene-editing tool CRISPR, explained

With a new gene-editing tool called CRISPR, scientists have the power to tweak the genomes of plants, animals and even humans. Read on to learn what CRISPR is, how it works and why it could change your life.

What It Is

CRISPR (pronounced “crisper”) stands for Clustered Regularly Interspaced Short Palindromic Repeats – repetitive fragments of DNA that bacteria use to defend themselves against invading viruses. Viruses can infect bacteria, just like they can infect you or me. When we develop a viral infection, our immune system produces antibodies against the virus so we can quickly respond the next time we are threatened.

For many bacteria, CRISPR serves as a kind of immune system. When infected, the bacteria gather pieces of the viral code and tuck them into their own genomes for safekeeping. These sequences serve as a kind of immunological memory, providing the bacteria with a molecular fingerprint of the viruses that infected them. If that same virus shows up again, the bacteria recognizes it and unleashes a DNA-cutting protein called Cas9 to chop up the invader’s genetic code. That’s why many people refer to the technology as CRISPR/Cas9.

How It Works

CRISPR enables researchers to cut and paste DNA sequences. First, scientists compose a string of genetic letters or “guide RNA” that, like those original snippets of viral code, can recognize a specific stretch of DNA among the billions of As, Ts, Gs and Cs in the genome.

Second, they introduce this guide sequence to the target cell, along with an enzyme like Cas9, which recognizes the matching text and cuts it open. Scientists use this mechanism to delete, mutate, insert or repair genomic DNA sequences in cells, animals and humans.

Since the technology was developed in 2012, more than 8,000 scientific papers mentioning CRISPR have been published. Today, research labs in more than 80 countries use it to study the molecular basis of disease and develop new treatments.

See How CRISPR Works: Narrated animation

Why CRISPR Could Change Your Life

The potential applications of CRISPR technology are limitless. In the petri dish and in animal models, researchers have used CRISPR to fix major genetic errors, such as those responsible for muscular dystrophy, cystic fibrosis and fragile X syndrome. They have tapped the technology to engineer pigs to grow organs for people in need of a transplant. Other efforts are underway to eliminate HIV infections, design smarter antimicrobials and control disease-carrying mosquitoes. But don’t expect to have a CRISPR pill for whatever ails you anytime soon.

“With any potentially transformative technology ─ remember the cloning of Dolly the sheep or the completion of the Human Genome Project ─ the hype around that technology at its earliest stages is quite great,” said Richard Sharp, Ph.D., director of the Biomedical Ethics Research Program at Mayo Clinic. “But as we begin to understand how many limitations there are, we pull back and recognize that it may be decades before this technology will impact patient care directly.”

Mayo Clinic bioethicist Richard Sharp, Ph.D.

Dr. Sharp believes the biggest effects of CRISPR technology ─ at least in the short term ─ will come in the area of rare diseases. These diseases can have devastating consequences, ending pregnancies, sickening children and shortening life spans. Many can be traced to a single genetic defect or “typo” in the genome. As a result, these rare, single-gene disorders often are well-understood at the molecular level, making it easier for scientists to predict what will happen when they manipulate that part of the genetic code. Indeed, a Switzerland-based biotech company plans to launch a clinical trial of CRISPR in patients with the rare blood disorders sickle-cell disease and beta-thalassemia later in 2018.

Other clinical trials of the technology are also in the offing, targeting various metabolic, autoimmune and neurodegenerative diseases. One trial will use CRISPR to treat many forms of cancer, including melanoma, sarcoma and multiple myeloma. The proposed approach entails altering two genes in cancer patients’ immune cells so they can more effectively fight tumors.

Though in many ways the field is moving quickly, many of the most promising trials have been stalled for months.

“Most of this work is in the basic research stage, but, even when it moves onto clinical trials, there is still a lot of safety and efficacy data that will need to be collected before it will ever become standard of care,” said Zubin Master, Ph.D., a bioethicist at Mayo Clinic. “This is going to be a lengthy process, which is good because we need to take the time to make sure we are asking the right scientific and ethical questions.”

One example of a basic research effort at Mayo Clinic is the use of CRISPR in lung and pancreatic cancer research. Scientists are examining the different forms of the cancer-linked gene KRAS to get a more detailed understanding of what's necessary to inhibit tumor development. The project, funded through Mayo Clinic's Center for Biomedical Discovery, is examining the different gene mutations using CRISPR/Cas9-mediated genomic editing in mice so they can correlate the changes to tumor formation and progression.

The Questions

It is one thing to wield this power to cure otherwise incurable conditions. But what about using CRISPR to generate cosmetic enhancements by manipulating the genes associated with characteristics such as height, eye color or IQ? Will efforts to improve the genome inevitably lead to a generation of designer babies?

“In ethics, we often worry about so-called slippery slope arguments. That once we do 'X,' it will be a small step to doing 'Y' and 'Z.' And 'Y' and 'Z' are problematic, even if 'X' isn’t. That kind of argument is usually flawed,” says Dr. Sharp. “However, we need to think about where we would draw the line for this technology. That, from a moral point of view, is still unresolved.”

For now, nature has drawn the line.

Before scientists can use CRISPR to manipulate a particular trait, they need a firm understanding of the genetic changes involved, and the biological underpinnings of many desirable traits are still a mystery. Take height, an easily measurable, seemingly simple characteristic. Scientists have found hundreds of genes that contribute to height, and they’re still counting. And genes aren’t the only thing that determines whether someone is short or tall. A person’s environment, particularly his or her access to nutrition, also plays a big part.

That’s not to say that there aren’t any manmade boundaries being put in place. Congress has banned the U.S. Food and Drug Administration from considering any clinical trial that results in genetically modified offspring. Should that ban be allowed to expire, a group of researchers, bioethicists and legal scholars convened by the National Academy of Sciences have developed guidelines for altering DNA in human embryos. The report states that gene editing should only be permitted for “compelling reasons” and “with strict oversight.” It prohibits any edits that might be considered “enhancement.” Based on these guidelines, fixing the faulty dystrophin gene in patients with muscular dystrophy would be OK, while altering that same gene in healthy people to produce an Olympic athlete would be taboo.

So scientists agree that CRISPR has the potential to change human lives forever. Just when and how is an open question.

- Marla Vacek Broadfoot, Ph.D., August 2018