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Gene Editing with CRISPR-Cas9: Promises and Perils

The ability to alter DNA in precise ways that will reverse serious diseases is now a reality, thanks in part to a remarkable technology called CRISPR-Cas9. Using this approach, it is possible to snip out a piece of a person’s DNA that is mutated to cause disease and even replace it with another piece. The development of the CRISPR-Cas9 gene-editing technique was recognized by the awarding of a Nobel Prize in 2020, and what may sound like science fiction is actually a clinically meaningful possibility.

The excitement that scientists, clinicians, and people suffering from genetic diseases have about CRISPR-Cas9 and its implications for human health are tempered, unfortunately, by at least three factors: first, the approach is incredibly expensive and time consuming; second, it is not now applicable to the many complex illnesses that are caused by mutations in multiple genes; and third, it raises a number of serious ethical issues.

In an excellent op-ed piece published in the New York Times last December, University of California, Berkeley molecular and cell biologist Fyodor Urnov detailed many of the promises, challenges, and perils of recent developments in gene editing. In his article, titled “We can cure disease by editing a person’s DNA. Why aren’t we?” Urnov wrote, “The greatest obstacles are not technical but legal, financial and organizational.”

A Gene Editing Method Adapted from Bacteria

What is CRISPR-Cas9? When bacteria are infected by viruses, they use a molecular mechanism to capture pieces of the viral DNA and make sequences of RNA that bind to the viral DNA and bring along enzymes, like Cas9, that cut up the viral DNA. Scientists adapted this naturally occurring phenomena to create small pieces of RNA that can bind to specific spots in human DNA and guide Cas9 to the spot, enabling the enzyme to cut out a single base pair or small sequence of the DNA. Further technology allows the insertion of new DNA where the deletion has been made and then for the DNA to heal.CRISPR stands for “clustered regularly interspaced short palindromic repeats.”

Urnov described what can now be done to cure people with some genetic diseases. Currently available gene therapies involve “taking a virus, replacing its harmful contents with a disease-treating gene, and injecting it into a person (or exposing the person’s cells to that virus in a dish and putting them back).” Theoretically, this process could be done in a matter of weeks to a few months, but various regulatory demands lengthen the development to years, at a cost that can be as high as $3.5 million for a single dose. Urnov notes that so far 31 people with sickle cell anemia have been cured with the CRISPR-Cas9 gene-editing approach. It was nearly 70 years ago that scientists discovered that sickle cell anemia is caused by a mutation in a single base in a person’s DNA; now at last there is a way to repair that mutation. So why isn’t this approach being used to help everyone with sickle cell anemia and the approximately 7,000 other illnesses that are caused by simple mutations?

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Enormous Cost and Lengthy Development Process

The problem is that many genetic diseases involve rare mutations that affect only a handful of people. That means that the exact RNA sequence needed for the CRISPR-Cas9 system to work must be developed on an individual basis and the process can take years and cost millions of dollars per person. Pharmaceutical companies are unwilling to take on this burden, because even charging that $3.5 million for a single vial of gene-editing medicine is not enough to recoup the costs of developing it, which can run from $8 to $10 million. That has left university laboratories, like Urnov’s Berkeley facility, with the responsibility of developing the medications, something they are also generally unable to afford to do. The government could step in and subsidize development of the drugs but, Urnov cautions, “This approach poses a difficult but essential question: Why should the average taxpayer contribute to building medicines for rare disease? Would the money be better spent on finding treatments for common ailments.” He concludes that public funding should be spent on CRISPR cures because they will not only “help us treat people with uncommon mutations (a global community numbering hundreds of millions of people) but also can provide insights that can be infused in CRISPR clinical innovation for common diseases.”

Furthermore, sickle cell anemia is not a rare disease and patients who have it all share the same mutation. Hence, CRISPR-Cas9-based medications to treat it should be relatively straightforward to make. Hopefully, the cost will not be prohibitive and the hundreds of thousands of people in the world who suffer from sickle cell anemia will not have to wait too much longer to benefit.

Gene Editing Not Available Yet for Complex Diseases

While cost and regulations make it difficult to extend the gene editing technologies we already have to people who can benefit, biology presents the challenge to making them work for millions of other people with heritable diseases. Most illnesses we inherit are not caused by mutations in a single gene but rather involve a complex interplay between mutations in multiple genes and environmental factors. Type 2 diabetes and schizophrenia are two examples. In the case of type 2 diabetes, one has a higher risk of getting the illness if a parent has it and studies have shown a clear genetic basis. Still, environmental factors like how much weight a person gains are also critically important in determining whether a person gets type 2 diabetes. It is highly unlikely that a single mutation is responsible for type 2 diabetes and therefore no immediate gene editing solution is available. Similarly, many studies have shown that schizophrenia is in part a heritable condition and numerous candidate risk genes have been proposed. Once again, however, environmental risk factors like exposure to early life adversity are also important. Right now, there is no obvious way that something like CRISPR-Cas9 gene editing would be a treatment for schizophrenia.

Promising Leads for Treating Cancer

That does not mean that we have seen the end of where CRISPR-Cas9 gene editing may take us in combating disease. For instance, new approaches to using this technique are very promising for ultimately treating some forms of cancer. A team at Harvard Medical School led by Khalid Shah, for example, has figured out how to engineer living tumor cells using CRISPR-Cas9 so that they release a tumor killing agent. Shah’s research group used these repurposed cells in mice to treat a deadly form of brain cancer called glioblastoma. In addition, they were able to engineer the tumor cells so that they express markers that make them recognizable by the immune system, creating the possibility that this could serve as a vaccine to prevent glioblastoma from occurring in the first place. This approach could well work for humans, which would be a major advancement because glioblastoma is almost always fatal. And it might work for other types of cancer as well. Lots of work is still needed before a mouse study like this proves useful in treating human disease, but it will be exciting to see how CRISPR-Cas9 and other gene editing methods progress over the next few years.

Gene Editing Raises Serious Ethical Concerns

That progress will be accompanied by ethical concerns. So far, all of the applications of CRISPR-Cas9 gene editing we have discussed involve somatic cells, that is cells in the body that are not passed on to the next generation. But it is entirely possible to apply the technology to germline cells and alter the DNA of sperm and egg cells. Matthew Cobb, a biologist and historian at the University of Manchester, U.K. and author of the book As Gods: A Moral History of the Genetic Age, points out that back in 2018, us, a Chinese scientist announced that he had used the CRISPR system to genetically modify human embryos leading to the birth of twin girls. “The experiment went horribly wrong,” Cobb stated in the interview. “They [the embryos] didn’t have a genetic illness, they were perfectly normal. He introduced mutations into their DNA, some of which have never been seen before in anybody else on the planet…So it was a very, very bad experiment.”

There is nothing theoretically stopping us from using gene editing techniques to engineer “desired” traits in embryos. The ethics of doing that is questionable. What if we figured out what genetic mutations increase intelligence or physical stamina? Would it be okay to use CRISPR-Cas9 and other gene editing technologies in an attempt to make smarter or stronger humans? The Chinese scientist who did the experiment that Cobb objects to was in fact sentenced to three years in prison for practicing medicine without a license. Scientists have recognized the potential ethical and moral challenges that genetic engineering presents and many countries, including the U.S. and the U.K., now have laws limiting the ways these methods can be applied.

It would be wrong to stop gene editing research because of these concerns; CRISPR-Cas9 and other systems have the potential to do enormous good by providing cures for currently intractable genetic disease, some cancers, and many other human illnesses. In fact, we need to find ways to better finance clinical applications of the CRISPR-Cas9 method for treating genetic diseases that are already available and we need to fund even more research to make these potential cures a reality. At the same time, we should continue to look carefully at gene editing that involves germline cells, ensuring that it is used only to cure or prevent serious disease and not to create “designer babies.”

With CRISPR-Cas9 we have an exciting time in science that needs careful consideration and reflection by experts and the public. We want to go far enough to help people suffering from potentially reversible disease without going so far as to create unethical practices. All of us should watch these developments with both excitement and concern.

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