May 23, 2024

After a lifelong battle with sickle cell anemia filled with hospital stays and unpredictable pain, 34-year-old Victoria Gray became the first patient to receive an experimental CRISPR treatment targeting the gene responsible for sickle cell. This treatment was conducted in 2019. During the week of March 6-8, Gray spoke at the International Summit ­ on Human Genome Editing and she did it symptom-free — thanks to successful gene editing.

CRISPR gene editing is an emerging technique that holds potential for genetic conditions such as sickle cell anemia.

“CRISPR has a very unique feature that allows you to direct an enzyme to a particular area in the genome,” said Dr. Daniel Szeto, professor of biology and biochemistry. “You are able to incorporate another stretch of sequence to replace the one that you cleave.”

This process essentially allows you to cut out incorrect segments of DNA and replace them with the correct sequence. Since sickle cell anemia is a genetic condition, CRISPR has the potential to “fix” the mutation.

“Sickle cell anemia is a single point mutation,” Szeto said. “It is a well-characterized mutation. They know exactly where the mutation is within the genome of hemoglobin. They are able to attract the enzyme to the area first, creating a cut and then bringing in a particular sequence that is correcting the mutation.”

Gray said in an interview with NPR that her experimental CRISPR treatment began with the removal of some of her bone marrow cells. Researchers genetically modified these cells with CRISPR. The modified cells were designed to produce fetal hemoglobin to compensate for the defective ones that caused sickle cell anemia. Gray then received infusions of billions of her genetically modified cells and began to see her symptoms subside.

“The life that I once felt like I was only existing in, I am now thriving in,” Gray said in her speech to the International Summit on Human Genome Editing. “I stand here before you today as proof that miracles still happen — and that God and science can coexist.”

Since Gray received the treatment, 31 other sickle cell patients were given the same treatment. All 31 patients are now symptom-free, according to the American Society of Hematology. These results are encouraging. However, CRISPR is far from a perfected science. Detailed research is required before CRISPR can be offered as a solution to chronic disease.

“Guide RNAs are a very small stretch of sequence, but remember that your genome has a billion bases,” Szeto said. “So you may have off-targets that create unnecessary or unwanted cleavage.”

Guide RNAs are small fragments of RNA that enable the CRISPR associated enzyme to cleave the desired DNA segment. The problem remains that in the billions of bases in our genome, more than one region may be recognized by the enzyme, resulting in unintended cleavage.

“The drawback is really the search to understand how we can generate specificity in terms of the enzyme targeting a specific region of the genome,” Szeto said.

Over time, research has uncovered a lot about sickle cell anemia. Even so, we are just beginning to see the results.

“There’s a difference between animal models and the application in human trials,” Szeto said.

“When you apply CRISPR to human clinical studies, you have to create a system that tests the specificity. You test many, many different overlapping sequences within the region you are targeting to see which gives you the highest specificity before you actually take it into a clinical trial.”

This is where CRISPR sees perhaps its greatest disadvantage.

“In theory it is a very good advancement in medicine, but who can afford that?” Szeto said.

Looking beyond the practical concerns of CRISPR, other ethics-based questions arise.

“There are ethical concerns with CRISPR because we are dealing with human genes that can then be passed down to other generations,” said Valeria Molina, senior biomedical science major.

CRISPR has encountered much controversy over its potential in reproduction. Its ability to alter genes could enable CRISPR to “design babies” based on desired characteristics. This would allow parents to change hair color, eye color or any other trait of their children.

“That used to be a fantasy, but with the precision of CRISPR people are beginning to worry that this could one day happen,” Szeto said.

Trait selection is just the tip of the iceberg of the ethical dilemmas presented by CRISPR.

“You could create an army of superhuman soldiers so that their mentality is no longer afraid of dying,” Szeto said. “Their mission is just to kill. Suddenly, you don’t have to send your brother or your father or someone you know to the battlefield, just somebody out of the lab.”

Despite ethical concerns, CRISPR provides hope to those struggling with chronic genetic disorders.

“When you are weighing the risk, if you have an incurable disease, you are going to die from it,” Szeto said. “Then even a 10-15% chance is still better than nothing.”

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