The answer to some genetic diseases may be a powerful “molecular scissors.” Known as CRISPR/Cas9, it has healed genetic diseases in some animals. Soon, doctors may learn how well it works in people. The first human studies to test its promise are just getting underway.
CRISPR/Cas9 cuts through DNA. But it doesn’t randomly chop. This gene editor comes in two parts. The CRISPR part is a short piece of genetic material called a guide RNA. Like seeing-eye dogs, these guides lead Cas9, an enzyme, to where it needs to go. Scientists can use CRISPR/Cas9 to intentionally break some genes or repair others.
In the first group of human trials, scientists are using the technique to fight cancer and blood disorders. Other researchers are set to study how CRISPR/Cas9 works inside the human body. In one upcoming trial, people with an inherited blindness will have the molecular scissors injected into their eyes.
If successful, such tests could lead to CRISPR trials for diseases affecting millions of people.
Out of body experience
In one pioneering trial, researchers at the University of Pennsylvania in Philadelphia are treating two people with recurring cancers. One has multiple myeloma (a disease that starts in the blood’s plasma cells). The other has a sarcoma. Both patients received a type of immune cell that had been programmed with CRISPR to go after cancer cells. (Similar trials are under way in China.)
Another trial is under way for two blood disorders: sickle-cell disease and beta-thalassemia (Bay-tuh Thah-lah-SEE-mee-uh). Both result from defects in the gene for hemoglobin. That’s the oxygen-carrying protein in red blood cells.
People who inherit a sickle-cell mutation or a beta-thalassemia mutation normally get these diseases, says David Altshuler. He’s the chief scientist at Vertex Pharmaceuticals. It’s a drug company based in Boston, Mass., and London, England. Changing a different gene may help people avoid these disorders.
In the womb, one form of hemoglobin helps fetuses grab extra oxygen from their mother’s blood. The body normally stops making this hemoglobin right after birth. But in some people, a harmless gene variant causes fetal hemoglobin to be produced throughout their lives.
People who have mutations that cause beta-thalassemia or sickle cell disease didn’t get either disorder if they also had the lifelong fetal-hemoglobin gene.
Vertex and CRISPR Therapeutics, a company in Cambridge, Mass., are now testing whether CRISPR/Cas9 can engineer changes in the body to mimic the change that keeps fetal hemoglobin turned on for life.
Both the cancer and blood-disorder trials take cells from people’s blood. DNA in those cells is edited with CRISPR/Cas9 in lab dishes. Scientists can test the cells to make sure the DNA has been edited properly. In the case of the blood disorders, CRISPR/Cas9 cuts a piece of DNA that usually helps turn off fetal hemoglobin after birth. Now the fetal-hemoglobin gene can turn on again. Doctors then return these edited cells into the sick people.
One person was given this treatment for beta-thalassemia in February. One got the treatment for sickle-cell disease in July.
Other scientists are trying something much harder: editing DNA in cells that are still inside the body. Researchers will test this in people with an inherited type of blindness.
Some people have a mutant form of the gene known as CEP290. It causes rod cells in the eye’s retina to die, leading to blindness. In July, two companies started recruiting patients for a clinical trial of the gene editor.
One company is Editas Medicine of Cambridge, Mass. Editas is working with the drug maker Allergan. In their trial, CRISPR/Cas9 will make two cuts in the defective gene. This should snip out the troublesome piece of DNA.
The first people to get the test therapy will be adults who are nearly blind, says Charles Albright. He’s the chief scientist at Editas. “We’re going into arguably the most difficult patients to start with,” he says.
Small amounts of the CRISPR editor will be injected under the retina to test the treatment’s safety. Such low doses may not improve vision. But if those doses prove safe, later volunteers will get higher doses. The researchers may also test the therapy in children.
Editing as few as 10 percent of retinal cells might help restore some sight, Albright says. In animal tests, CRISPR edited up to about 60 percent of cells in mice and almost 28 percent in monkeys. The study’s authors reported their accomplishment in the February Nature Medicine.
Even if these first trials don’t work quite as hoped, CRISPR won’t be shelved, Albright says. “This is a technology that’s here to stay.”
“CRISPR is so intriguing,” adds Laurie Zoloth, “and so elegant.” A bioethicist, she works at the University of Chicago Divinity School in Illinois. Science, she says, just has to explore whether this new technology can live up to the hype.
cancer Any of more than 100 different diseases, each characterized by the rapid, uncontrolled growth of abnormal cells. The development and growth of cancers, also known as malignancies, can lead to tumors, pain and death.
Cas9 An enzyme that geneticists are now using to help edit genes. It can cut through DNA, allowing it to fix broken genes, splice in new ones or disable certain genes. Cas9 is shepherded to the place it is supposed to make cuts by CRISPRs, a type of genetic guides. The Cas9 enzyme came from bacteria. When viruses invade a bacterium, this enzyme can chop up the germs DNA, making it harmless.
cell The smallest structural and functional unit of an organism. Typically too small to see with the unaided eye, it consists of a watery fluid surrounded by a membrane or wall. as yeasts, molds, bacteria and some algae, are composed of only one cell.
clinical trial A research trial that involves people.
CRISPR An abbreviation — pronounced crisper — for the term “clustered regularly interspaced short palindromic repeats.” These are pieces of RNA, an information-carrying molecule. They are copied from the genetic material of viruses that infect bacteria. When a bacterium encounters a virus that it was previously exposed to, it produces an RNA copy of the CRISPR that contains that virus’ genetic information. The RNA then guides an enzyme, called Cas9, to cut up the virus and make it harmless. Scientists are now building their own versions of CRISPR RNAs. These lab-made RNAs guide the enzyme to cut specific genes in other organisms. Scientists use them, like a genetic scissors, to edit — or alter — specific genes so that they can then study how the gene works, repair damage to broken genes, insert new genes or disable harmful ones.
disorder (in medicine) A condition where the body does not work appropriately, leading to what might be viewed as an illness. This term can sometimes be used interchangeably with disease.
DNA (short for deoxyribonucleic acid) A long, double-stranded and spiral-shaped molecule inside most living cells that carries genetic instructions. It is built on a backbone of phosphorus, oxygen, and carbon atoms. In all living things, from plants and animals to microbes, these instructions tell cells which molecules to make.
engineer A person who uses science to solve problems. As a verb, to engineer means to design a device, material or process that will solve some problem or unmet need.
gene (adj. genetic) A segment of DNA that codes, or holds instructions, for a cell’s production of a protein. Offspring inherit genes from their parents. Genes influence how an organism looks and behaves.
genetic Having to do with chromosomes, DNA and the genes contained within DNA. The field of science dealing with these biological instructions is known as genetics. People who work in this field are geneticists.
hemoglobin A molecule that binds to oxygen in the blood, carrying it around to tissues.
immune (adj.) Having to do with the immunity. (v.) Able to ward off a particular infection. Alternatively, this term can be used to mean an organism shows no impacts from exposure to a particular poison or process. More generally, the term may signal that something cannot be hurt by a particular drug, disease or chemical.
insight The ability to gain an accurate and deep understanding of a situation just by thinking about it, instead of working out a solution through experimentation.
multiple myeloma This cancer starts in a type of white blood cells known as plasma cells. Part of the immune system, they help guard the body from germs and other harmful substances.
muscle A type of tissue used to produce movement by contracting its cells, known as muscle fibers. Muscle is rich in protein, which is why predatory species seek prey containing lots of this tissue.
mutation (v. mutate) Some change that occurs to a gene in an organism’s DNA. Some mutations occur naturally. Others can be triggered by outside factors, such as pollution, radiation, medicines or something in the diet. A gene with this change is referred to as a mutant.
nerve A long, delicate fiber that transmits signals across the body of an animal. An animal’s backbone contains many nerves, some of which control the movement of its legs or fins, and some of which convey sensations such as hot, cold or pain.
neuron An impulse-conducting cell. Such cells are found in the brain, spinal column and nervous system.
oxygen A gas that makes up about 21 percent of Earth's atmosphere. All animals and many microorganisms need oxygen to fuel their growth (and metabolism).
pharmaceuticals Medicines, especially prescription drugs.
plasma (in medicine) The colorless fluid part of blood.
protein A compound made from one or more long chains of amino acids. Proteins are an essential part of all living organisms. They form the basis of living cells, muscle and tissues; they also do the work inside of cells. Among the better-known, stand-alone proteins are the hemoglobin (in blood) and the antibodies (also in blood) that attempt to fight infections. Medicines frequently work by latching onto proteins.
red blood cell Colored red by hemoglobin, these cells move oxygen from the lungs to all tissues of the body. Red blood cells are too small to be seen by the unaided eye.
retina A layer at the back of the eyeball containing cells that are sensitive to light and that trigger nerve impulses that travel along the optic nerve to the brain, where a visual image is formed.
RNA A molecule that helps “read” the genetic information contained in DNA. A cell’s molecular machinery reads DNA to create RNA, and then reads RNA to create proteins.
sarcoma A family of more than 70 cancers that begin in bones or in connective tissues.
technology The application of scientific knowledge for practical purposes, especially in industry — or the devices, processes and systems that result from those efforts.
therapy (adj. therapeutic) Treatment intended to relieve or heal a disorder.
variant A version of something that may come in different forms. (in genetics) A gene having a slight mutation that may have left its host species somewhat better adapted for its environment.
womb Another name for the uterus, the organ in mammals in which a fetus grows and matures in preparation for birth.
Journal: C.A. Hodges and R. A. Conlon. Delivering on the promise of gene editing for cystic fibrosis. Genes & Diseases. Vol. 6, June 2019, p. 97. doi: 10.1016/j.gendis.2018.11.005.
Journal: M.L. Maeder et al. Development of a gene-editing approach to restore vision loss in Leber congenital amaurosis type 10. Nature Medicine. Vol. 25, February 2019, p. 229. doi: 10.1038/s41591-018-0327-9.