We now have a precise way to correct, replace or even delete faulty DNA. Ian Sample explains the science, the risks and what the future may hold

Ian Sample Science editor @iansample

2018

Gene editing has the potential to treat or prevent thousands of forms of human disease. Illustration: Guardian design team

So what is gene editing?
Scientists liken it to the find and replace feature used to correct misspellings in documents written on a computer. Instead of fixing words, gene editing rewrites DNA, the biological code that makes up the instruction manuals of living organisms. With gene editing, researchers can disable target genes, correct harmful mutations, and change the activity of specific genes in plants and animals, including humans.

What’s the point?
Much of the excitement around gene editing is fuelled by its potential to treat or prevent human diseases. There are thousands of genetic disorders that can be passed on from one generation to the next; many are serious and debilitating. They are not rare: one in 25 children is born with a genetic disease. Among the most common are cystic fibrosis, sickle cell anemia and muscular dystrophy. Gene editing holds the promise of treating these disorders by rewriting the corrupt DNA in patients’ cells. But it can do far more than mend faulty genes. Gene editing has already been used to modify people’s immune cells to fight cancer or be resistant to HIV infection. It could also be used to fix defective genes in human embryos and so prevent babies from inheriting serious diseases. This is controversial because the genetic changes would affect their sperm or egg cells, meaning the genetic edits and any bad side effects could be passed on to future generations.

What else is it good for?
The agricultural industry has leaped on gene editing for a host of reasons. The procedure is faster, cheaper and more precise than conventional genetic modification, but it also has the benefit of allowing producers to improve crops without adding genes from other organisms – something that has fuelled the backlash against GM crops in some regions. With gene editing, researchers have made seedless tomatoes, gluten-free wheat, and mushrooms that don’t turn brown when old. Other branches of medicine have also seized on its potential. Companies working on next-generation antibiotics have developed otherwise harmless viruses that find and attack specific strains of bacteria that cause dangerous infections. Meanwhile, researchers are using gene editing to make pig organs safe to transplant into humans. Gene editing has transformed fundamental research too, allowing scientists to understand precisely how specific genes operate.

So how does it work?
There are many ways to edit genes, but the breakthrough behind the greatest achievements in recent years is a molecular tool called Crispr-Cas9. It uses a guide molecule (the Crispr bit) to find a specific region in an organism’s genetic code – a mutated gene, for example – which is then cut by an enzyme (Cas9). When the cell tries to fix the damage, it often makes a hash of it, and effectively disables the gene. This in itself is useful for turning off harmful genes. But other kinds of repairs are possible. For example, to mend a faulty gene, scientists can cut the mutated DNA and replace it with a healthy strand that is injected alongside the Crispr-Cas9 molecules. Different enzymes can be used instead of Cas9, such as Cpf1, which may help edit DNA more effectively.

An illustrated example of Crispr in action

Remind me what genes are again?
Genes are the biological templates the body uses to make the structural proteins and enzymes needed to build and maintain tissues and organs. They are made up of strands of genetic code, denoted by the letters G, C, T and A. Humans have about 20,000 genes bundled into 23 pairs of chromosomes all coiled up in the nucleus of nearly every cell in the body. Only about 1.5% of our genetic code, or genome, is made up of genes. Another 10% regulates them, ensuring that genes turn on and off in the right cells at the right time, for example. The rest of our DNA is apparently useless. “The majority of our genome does nothing,” says Gerton Lunter, a geneticist at the University of Oxford. “It’s simply evolutionary detritus.”

What are all those Gs, Cs, Ts and As?
The letters of the genetic code refer to the molecules guanine (G), cytosine (C), thymine (T) and adenine (A). In DNA, these molecules pair up: G with C and T with A. These “base pairs” become the rungs of the familiar DNA double helix. It takes a lot of them to make a gene. The gene damaged in cystic fibrosis contains about 300,000 base pairs, while the one that is mutated in muscular dystrophy has about 2.5m base pairs, making it the largest gene in the human body. Each of us inherits about 60 new mutations from our parents, the majority coming from our father.

But how do you get to the right cells?
This is the big challenge. Most drugs are small molecules that can be ferried around the body in the bloodstream and delivered to organs and tissues on the way. The gene editing molecules are huge by comparison and have trouble getting into cells. But it can be done. One way is to pack the gene editing molecules into harmless viruses that infect particular types of cell. Millions of these are then injected into the bloodstream or directly into affected tissues. Once in the body, the viruses invade the target cells and release the gene editing molecules to do their work. In 2017, scientists in Texas used this approach to treat Duchenne muscular dystrophy in mice. The next step is a clinical trial in humans. Viruses are not the only way to do this, though. Researchers have used fatty nanoparticles to carry Crispr-Cas9 molecules to the liver, and tiny zaps of electricity to open pores in embryos through which gene editing molecules can enter.

Does it have to be done in the body?
No. In some of the first gene editing trials, scientists collected cells from patients’ blood, made the necessary genetic edits, and then infused the modified cells back into the patients. It’s an approach that looks promising as a treatment for people with HIV. When the virus enters the body, it infects and kills immune cells. But to infect the cells in the first place, HIV must first latch on to specific proteins on the surface of the immune cells. Scientists have collected immune cells from patients’ blood and used gene editing to cut out the DNA that the cells need in order to make these surface proteins. Without the proteins, the HIV virus can no longer gain entry to the cells. A similar approach can be used to fight certain types of cancer: immune cells are collected from patients’ blood and edited so they produce surface proteins that bind to cancer cells and kill them. Having edited the cells to make them cancer-killers, scientists grow masses of them in the lab and infuse them back into the patient. The beauty of modifying cells outside the body is that they can be checked before they are put back to ensure the editing process has not gone awry.

What can go wrong?
Modern gene editing is quite precise but it is not perfect. The procedure can be a bit hit and miss, reaching some cells but not others. Even when Crispr gets where it is needed, the edits can differ from cell to cell, for example mending two copies of a mutated gene in one cell, but only one copy in another. For some genetic diseases, this may not matter, but it may if a single mutated gene causes the disorder. Another common problem happens when edits are made at the wrong place in the genome. There can be hundreds of these “off-target” edits that can be dangerous if they disrupt healthy genes or crucial regulatory DNA.

Will it lead to designer babies?
The overwhelming effort in medicine is aimed at mending faulty genes in children and adults. But a handful of studies have shown it should be possible to fix dangerous mutations in embryos too. In 2017, scientists convened by the US National Academy of Sciences and the National Academy of Medicine cautiously endorsed gene editing in human embryos to prevent the most serious diseases, but only once shown to be safe. Any edits made in embryos will affect all of the cells in the person and will be passed on to their children, so it is crucial to avoid harmful mistakes and side effects. Engineering human embryos also raises the uneasy prospect of designer babies, where embryos are altered for social rather than medical reasons; to make a person taller or more intelligent, for example. Traits like these can involve thousands of genes, most of them unknown. So for the time being, designer babies are a distant prospect.

How long before it’s ready for patients?
The race is on to get gene editing therapies into the clinic. A dozen or so Crispr-Cas9 trials are underway or planned, most led by Chinese researchers to combat various forms of cancer. One of the first launched in 2016 when doctors in Sichuan province gave edited immune cells to a patient with advanced lung cancer. More US and European trials are expected in the next few years.

What next?

Base editing
A gentler form a gene editing that doesn’t cut DNA into pieces, but instead uses chemical reactions to change the letters of the genetic code. It looks good so far. In 2017, researchers in China used base editing to mend mutations that cause a serious blood disorder called beta thalassemia in human embryos.

Gene drives
Engineered gene drives have the power to push particular genes through an entire population of organisms. For example, they could be used to make mosquitoes infertile and so reduce the burden of disease they spread. But the technology is highly controversial because it could have massive unintended ecological consequences.

Epigenome editing
Sometimes you don’t want to completely remove or replace a gene, but simply dampen down or ramp up its activity. Scientists are now working on Crispr tools to do this, giving them more control than ever before.

Further reading

A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution by Jennifer Doudna and Samuel H. Sternberg

The Gene: An Intimate History by Siddhartha Mukherjee

The Epigenetics Revolution: How Modern Biology is Rewriting our Understanding of Genetics, Disease and Inheritance by Nessa Carey

Modern Prometheus: Editing the Human Genome with Crispr-Cas9 by Jim Kozubek