Molecular scissors fix disease-causing flaw in human embryos | Science News for Students

Molecular scissors fix disease-causing flaw in human embryos

Scientists learned to use this gene-editing tool better to repair a gene that causes heart failure
Sep 4, 2017 — 7:00 am EST
human embryos

Researchers edited a gene that causes heart failure in newly fertilized eggs (left). Four-celled (center) and five-day-old embryos (right) look normal.


Researchers used “molecular scissors” to mend a faulty gene in human embryos. These tests are the first of their kind in the United States. Scientists used an enzyme known as CRISPR/Cas9 as their scissors. It snipped out the faulty gene, which can lead to heart failure. With this tool, they fixed the problem in nearly three out of every four treated embryos (about 72 percent).

Such tinkering with an embryo’s DNA is known as germline editing. And it is controversial. Many people worry that it could be used to create so-called designer babies. Parents of these still-fictional designer babies might try to choose their child’s eye and hair color. Or they might have doctors change certain genes to make their child into a super-smart athlete.

In fact, the new study suggests such designer babies might be very hard to make. They would require injecting bits of new DNA to supply the desired traits. And in the latest tests, treated embryos rejected pieces of DNA that the researchers had added (in this case, to help fix the faulty gene).

The new work “is not announcing the dawn of the designer baby era,” says R. Alta Charo. She is a lawyer at the University of Wisconsin Law School in Madison. She also is a bioethicist, someone who studies the wisdom, morality or social value of certain decisions or policies. The researchers have not attempted to add any new genes or change traits, she notes. Here they sought only to repair one version of a disease-causing gene.

This research offers lessons in how to more accurately wield the CRISPR/Cas9 scissors. They reduced the share of embryos that were only partly edited.

That’s important if researchers want to use these gene scissors to cure genetic diseases, says Shoukhrat Mitalipov. He is a co-author of the new study. A reproductive biologist, he works at Oregon Health & Science University in Portland. If even one cell in an early embryo is unedited, he explains, “that’s going to screw up the whole process.” His team did its work in Korea, China and two U.S. states (Oregon and California).

They described their new achievements on August 2 in Nature.

Snip . . . then repair!

Mutations are changes that occur in a gene. Some mutations lead to disease. Others seem to cause no harm. In the new work, researchers wanted to fix a mutation in the gene known as MYBPC3.

Nearly every cell of the body has two copies of each gene. People who inherit just one mutant copy of MYBPC3 can develop a life-threatening heart problem. It’s called hypertrophic cardiomyopathy (HY-per-TROW-fik KAR-dee-oh-my-AH-puh-thee). It can cause sudden death from heart failure. The heart problem affects about one in every 500 people worldwide. Mutations in the MYBPC3 gene are to blame for about 40 percent of cases. Doctors can treat symptoms of the condition, but there is no cure.

In the new study, researchers used sperm from a man who carries a flaw in the MYBPC3 gene. They injected that sperm into eggs from women with healthy copies of the gene.

The researchers also injected the gene editor into the egg. The editor has several pieces. One is the scissors, a DNA-cutting enzyme called Cas9. They also need a piece of RNA that directs the enzyme to the exact place in the gene where a cut should be made. The researchers injected another piece of DNA into the egg, too. The researchers had designed that hunk of DNA to serve as directions for repairing the breach that would be made by Cas9. But the cells ignored it. Embryos instead used the mother’s healthy copy of the gene to mend the cut.

That result surprised the researchers. Gene editing in other types of cells usually requires an added piece of DNA as a pattern to guide a repair, Mitalipov says. If all embryos reject added DNA repair patterns, researchers may struggle to fix mutations in embryos. It would be hardest when neither parent has a healthy copy of the gene. The finding also means that embryos may reject attempts to add new traits. That might mean designer babies would be hard to achieve.

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Gene editing
Gene editing of human embryos proved more accurate when researchers inject the gene-editing tool as eggs are being fertilized. If they wait even one day, some cells retained their faulty genes. Those patchwork — or mosaic — embryos might still allow disease to develop. The researchers fixed the patchwork problem by injecting sperm and molecular scissors (CRISPR/Cas9) into egg cells at the same time. All cells in embryos made this way were healthy.
H. Ma et al/Nature 2017

Careful timing

Timing is important in these experiments. At first, the researchers added the scissors one day after fertilizing the eggs. Those experiments often produced patchwork embryos — ones having some unedited cells. Thirteen out of 54 treated embryos had some unrepaired cells. Affected eggs that were fertilized had probably copied the DNA before researchers had added Cas9, Mitalipov now suspects.

When researchers injected the cutting enzyme and sperm at the same time, this didn’t occur. And none of the resulting embryos showed any signs that Cas9 had snipped a cut in the wrong place. (One concern about gene editing is that “off-target” cutting could create errors in other parts of a cell’s DNA.) When an egg was treated at fertilization, this way, only one patchwork embryo occurred. It had repaired the MYBPC3 mutation in all of its cells. Some cells had used the mother’s DNA for repair. Other cells used the DNA template supplied by the researchers.

The new study is a step toward using gene editing to prevent genetic diseases, says Janet Rossant. She is a developmental biologist in Canada at the Hospital for Sick Children and the University of Toronto. Still, she warns, researchers have a lot more work to do before they can do gene editing in people. Doctors will need to be sure the technique will work well and every time, she says.

Researchers have edited human embryos before. But they were merely probing the earliest stages of human development. They also wanted to learn things about basic human biology. Mitalipov and his colleagues instead wanted to probe the use of gene editing in medicine. They want to improve the technique so that it would be safe and reliable enough to use in people. Such studies might one day involve editing embryos in the lab, then implanting these into a women to establish a pregnancy.

In the United States, such human trials are not allowed. The Food and Drug Administration will not allow research meant to introduce changes in embryos that could be passed down to someone’s future children and grandchildren.

Power Words

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bioethics      A code of conduct for research in biology and medicine. To be ethical, people should treat others fairly, avoid cheating or dishonesty in any form and avoid taking or using more than their fair share of resources (which means, to avoid greed). Bioethics applies this idea to research. It focuses on how to avoid putting others at risk without first alerting people to the potential dangers — and having them choose to accept such risks without coercion. A person who works in this field is known as a bioethicist.

biology     The study of living things. The scientists who study them are known as biologists.

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. Depending on their size, animals are made of anywhere from thousands to trillions of cells. Most organisms, such as yeasts, molds, bacteria and some algae, are composed of only one cell.

colleague     Someone who works with another; a co-worker or team member.

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.

developmental     (in biology) An adjective that refers to the changes an organism undergoes from conception through adulthood. Those changes often involve chemistry, size and sometimes even shape.

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.

egg    The unfertilized reproductive cell made by females.

embryo     The early stages of a developing vertebrate, or animal with a backbone, consisting only one or a few cells. As an adjective, the term would be embryonic — and could be used to refer to the early stages or life of a system or technology.

fertilize     (in biology) The merging of a male and a female reproductive cell (egg and sperm) to set in create a new, independent organism.

Food and Drug Administration (or FDA)    A part of the U.S. Department of Health and Human Services, FDA is charged with overseeing the safety of many products. For instance, it is responsible for making sure drugs are properly labeled, safe and effective; that cosmetics and food supplements are safe and properly labeled; and that tobacco products are regulated.

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.

gene editing     The deliberate introduction of changes to genes by researchers.

genetic     Having to do with chromosomes, DNA and the genes contained within DNA.

germline     The egg cells and sperm cells that organisms use pass along their genes to the next generation. Egg and sperm cells are called germ cells. Germ cells also include cells that will become eggs or sperm and fertilized eggs or embryos made from combining eggs and sperm. (All other cells of the body are known as somatic cells.)

heart failure     A weakening of the heart that leads to its inability to pump enough blood to meet the needs of its tissues. It does not mean the heart has stopped. But if left untreated, heart failure can lead to death.

hypertrophic cardiomyopathy     A condition in which heart muscle cells enlarge and cause the walls of the heart’s ventricles to thicken. This can reduce the flow of blood flow out of the heart. Sometimes the condition will disrupt the heart’s electrical signals. Symptoms may include chest pain, shortness of breath, high blood pressure, irregular heartbeats and fainting. Some people have no symptoms until they have a heart attack (while undergoing vigorous exercise).

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.

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.

sperm     The reproductive cell produced by a male animal (or, in plants, produced by male organs). When one joins with an egg, the sperm cell initiates fertilization. This is the first step in creating a new organism.

trait     A characteristic feature of something. (in genetics) A quality or characteristic that can be inherited.


Journal:​ H. Ma et al. Correction of a pathogenic gene mutation in human embryos. Nature. Published online August 2, 2017. doi:10.1038/nature23305.