Doctors altered a person’s genes with CRISPR for the first time in the U.S. Here’s what could be next.

Last week, for the first time, doctors in the United States used the gene editing tool CRISPR to attempt to remedy a genetic disease in a living person. Victoria Gray, a 41-year-old woman from Mississippi was born with sickle cell disease, an often painful and debilitating condition caused by a genetic mutation that alters the shape of red blood cells. As of now, only one treatment for the condition exists—a donor transplant that works for just 10 percent of patients—but doctors think editing cells extracted from Gray’s own bone marrow could restore proper red blood cell formation. If successful, it could prove to be the treatment 90 percent of sickle cell patients have been waiting for.

People with sickle cell disease don’t make beta-hemoglobin—the protein that both makes your red blood cells nice and round and helps transport oxygen through your body. Instead, they produce a faulty protein called hemoglobin S that changes the red blood cells’ chemistry and causes them to cave in on themselves and become rigid and sickle-shaped. The hook-like cells are not nearly as efficient at transporting oxygen as their healthy, circular counterparts. Instead, they get stuck in small blood vessels and breakdown prematurely, depriving tissues and organs of much-needed oxygen, leading to pain and extreme fatigue. To try and treat it, doctors removed stem cells from Gray’s bone marrow and used CRISPR to tweak the DNA to turn on a specific protein that would allow for proper red blood cell production.

Gray is the first person in the U.S. to have her cells altered with CRISPR and the second globally. The first patient was treated in Germany, according to an announcement by CRISPR Therapeutics (one of two biotech companies heading up the study) in February, for a similar genetic blood disorder called beta thalassemia. According to a recent press release, the patient (whose identity hasn’t been disclosed) is improving and has not needed blood transfusions—the typical treatment for the disease—in over four months.

CRISPR Therapeutics, a Cambridge, Massachusetts-based company focused on developing gene-based therapies, and Vertex Pharmaceuticals of Boston will eventually enroll around 45 people between ages 18 and 35 in the two companies’ joint study to see if genetically-modifying blood cells with CRISPR could remedy these faulty sickle cells for good.

What is CRISPR?

CRISPR stands for clustered, regularly interspaced short palindromic repeats. They are repeating sequences of DNA that when matched with an enzyme—in this case Cas9—act like DNA-cutting scissors and can chop, remove, and replace various segments of DNA.

Scientists first identified CRISPR as a defense system in bacteria. When viruses try to take over a bacterial cell, the microorganism keeps pieces of the virus’s DNA so that if the bacteria survives the attack, it has a way to recognize the invader the next time around. If the virus returns, the cell would use the stolen DNA to make RNA called “guide RNA”, so named because it literally guides the DNA chopping enzyme, Cas9. The guide RNA finds its match in the invading viral DNA and then Cas9 makes a cut that damages the viral DNA and defends the bacterial cell from viral take over.

Scientists have repurposed the CRISPR-Cas9 system to do all sorts of things. They design guide RNA to match any genes that they might want to remove or change, like a disease-causing mutation in humans or a gene that regulates growth in plants, then attach Cas9. For the sickle cell therapy, they targeted BCL11A in red blood cells. BCL11A has many important roles in the body, but in red blood cells, it represses a protein called fetal hemoglobin. If its disabled, the cells will make fetal hemoglobin—which prevents cells from sickling.

How does CRISPR therapy actually work?

For the treatment, doctor’s removed stems cells from Gray’s bone marrow, Bao says. Then, they used CRISPR-Cas9 to cut and disable the BCL11A gene so that the cell no longer produces the repressor.

Once the edited cells are injected back into the patient’s bone marrow, they should begin to produce fetal hemoglobin. All humans produce fetal hemoglobin when they are babies, but over time fetal hemoglobin falls dramatically and the body replaces it with beta-hemoglobin, normally, or hemoglobin S in patients with sickle cell.

“In 1941 a pediatrician named Jane Watson noticed that babies with sickle cell didn’t have symptoms until 6 months to 1 year of age,” says Vivien Sheehan, a hematologist at Baylor University. She also noticed that babies with sickle cell disease produced fetal hemoglobin for longer, until around two years of age.

Since Watson’s discovery there’s been a lot of research to suggest that increasing fetal hemoglobin is a viable treatment strategy, says Sheehan. It prevents the faulty hemoglobin S from caving in the red blood cell. But it’s taken almost 80 years to find a way to actually execute the strategy.

The treatment, however, is not without its risks. Before the doctors can inject the edited cells back into the patient’s bone marrow they have to damage their other stem cells using radiation and chemotherapy. If they don’t, the unedited stem cells will continue to produce sickled red blood cells faster than the edited cells can produce healthy ones. To give the fetal hemoglobin an advantage and make sure healthy, round blood cells get ahead, they injure the original stem cells that produce sickled cells.

After that, it becomes a waiting game. They wait for fetal hemoglobin to increase and for the amount of sickled blood cells to decrease. For the treatment to be worth it for the patient, Sheehan says, it has to significantly improve the patient’s quality of life. There must be a functional payout, a long term alleviation of the condition.

Is gene editing dangerous?

Gene editing has the potential to treat a number of genetic and other currently incurable diseases, including some cancers. But because it can cut essentially any DNA segment at will it must be used with extreme caution.

A few months ago, Chinese scientist He Jiankui used CRISPR to edit human embryos. He then implanted the embryos into a woman’s uterus and she gave birth to twin girls in November of 2018. His intention was to disable a gene called CCR5 in the embryos so that they would be resistant to the H.I.V. infection carried by their father. But, unlike the sickle cell trials, He’s experiment was a huge ethical misstep and illegal in many countries.

When scientists use CRISPR to edit an embryo they are altering every cell in that person’s eventual body, Sheehan says. So, He turned off the CCR5 protein in the twins heart cells, brain cells, skin cells — everywhere. Scientists have no idea what side effects that could have, especially since the same gene can have different roles in different types of cells.

Gene editing an embryo also makes changes to their sex cells, adds Gang Bao, a bioengineer at Rice University. So, “whatever genetic alterations are made will be passed to new generations—that’s dangerous.”

For the sickle cell treatments, scientists are only editing a single type of somatic cell (any cell that’s not a sex cell), says Bao who studies CRISPR therapies for sickle cell but is not involved in the clinical trial. This means the alterations only affect the individual being treated, and can’t be passed on to other generations. The researchers also edited a specific type of stem cell such that red blood cells would be the only cell types affected. In other words, the experimental treatment is contained to a single type of cell in a single person.

With CRISPR there’s also always the risk of unintended consequences, says Bao. For these clinical trials, CRISPR is intended to make a double strand cut in one gene, but inevitably there will be so-called “off-target effects.” It’s normal when using CRISPR for the enzyme to occasionally cut somewhere that researchers didn’t intend. There are some extremely precise versions of the enzyme, but even then the number of off-target cuts is never zero, he says.

To know if these unintended snippings are harmful or too few to be a problem, researchers will have to watch Gray and other patients for at least 15 years, Sheehan says, possibly longer. It could take that long to understand if fetal hemoglobin is a long-term solution and to see if there are any unintentional effects from using CRISPR.

It’s too early to draw conclusions but researchers are still eager, because for the vast majority of people with sickle cell disease, Sheehan says, “this is the only potential cure.”