Gene Hackers Edit Immune System Cells to Fight Diseases

Researchers at the University of California (San Francisco and Berkeley) and Berkeley Lab have developed a new strategy to precisely modify human immune system cells known as T cells using the genome-editing system known as CRISPR/Cas9.

T cells or T lymphocytes are a type of lymphocyte (in turn, a type of white blood cell) that plays a central role in cell-mediated immunity. A scanning electron micrograph of a human T cell is shown in the image below. T cells, which circulate in the blood, could be easily gathered from patients, edited with CRISPR/Cas9, then returned to the body to fight diseases.

Cut-And-Paste Gene Editing in Human Patients

Human T cellThe CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) /Cas9 technique allows scientists to cut out faulty sections of DNA and replace them with healthy ones. In the two-part process, re-using a trick borrowed form bacterial immune systems, first an RNA “guide” molecule marks the DNA strand that needs to be removed or fixed, then a Cas9 protein attaches to the DNA and cuts out the strand, which in some cases can be replaced by a new one.

The researchers developed a programmable tool to replace specific nucleotide sequences in the genome of mature immune cells. The research paper, published in the Proceedings of the National Academy of Sciences (PNAS) with the title “Generation of knock-in primary human T cells using Cas9 ribonucleoproteins,” is freely available online.

The scientists edited T cells to disable a protein on the cell surface called CXCR4, which can be exploited by HIV when the virus infects T cells and causes AIDS, and shut down PD-1, a protein that has attracted intense interest in the burgeoning field of cancer immunotherapy, as scientists have shown that using drugs to block PD-1 coaxes T cells to attack tumors.

“Genome editing in human T cells has been a notable challenge for the field,” said Alexander Marson of the University of California, San Francisco (UCSF). “So we spent the past year and a half trying to optimize editing in functional T cells. There are a lot of potential therapeutic applications, and we want to make sure we’re driving this as hard as we can.”

The scientists achieved efficient genome editing of T cells, which was difficult to achieve so far, by delivering Cas9 protein pre-assembled with guide RNAs.

“We wanted not only to cut the genome, but to paste in sequences of DNA into the genome of T-cells,” said Marson. “We have now been able to cut as well as paste pieces of the genome into human T-cells – for the first time to our knowledge.”

While recent reports of CRISPR/Cas9 editing of human embryos have stirred up controversy, T cells are created anew in each individual. Therefore, modifications would not be passed on to future generations, which shields the technique from attacks by so-called “bioethicists.” Marson is persuaded that therapeutical T cells editing will find its way to clinical applications:

I think CRISPR-edited T cells will eventually go into patients.

Images from Wikimedia Commons.

Giulio Prisco is a freelance writer specialized in science, technology, business and future studies.