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THE bouts of terrible pain began further back than Victoria Gray can remember. Her grandmother would try to ease the discomfort with hot towels and medication, but it was fruitless. 鈥淚 was born having to endure pain,鈥� she says. 鈥淚t was a life that I felt wasn鈥檛 worth living.鈥�

Gray has an inherited condition known as sickle cell disease, which causes red blood cells to form an abnormal 鈥渟ickle鈥� shape that can block capillaries, causing pain and sometimes organ damage. As Gray aged, her pain got worse. On one occasion, she temporarily lost the use of her arms and legs. By her 30s, Gray required in-home care. So, when she was offered the chance to become the first person to receive an experimental CRISPR gene-editing treatment, she took it.

Today, four years after this took place, she no longer has episodes of pain and works full time. 鈥淣ow my life is full of optimism,鈥� she says.

The treatment involved will probably be given the green light by regulators in the US, UK and Europe soon, which will make it the first CRISPR therapy to be approved. It won鈥檛 be the last.

There is now no doubt that this technology 鈥� used to edit genes 鈥� can treat and potentially even cure a huge range of conditions. The only question is, just how far can it go? Will it be an expensive therapy used only occasionally? Or will it become so widely used that many of us will be getting a CRISPR jab to, say, lower our cholesterol levels and enable us to live longer, healthier lives?

CRISPR gene editing exploded onto the scene in 2012. It came about thanks to the discovery that many bacteria produce so-called CRISPR-Cas proteins that can cut DNA at specific sites. The DNA-cutting part wasn鈥檛 new 鈥� biologists had already found proteins that can do this, but each protein could only bind to and cut DNA at one specific sequence. To target a different sequence, biologists had to alter the shape of the DNA-binding part of the protein, a difficult and expensive process taking many months.

The revolutionary thing about CRISPR-Cas proteins is that the target sequence is determined by a piece of 鈥済uide RNA鈥� that links up with the Cas protein and binds to any matching DNA sequence 鈥� and RNAs are cheap and easy to make.

Within months, hundreds of labs worldwide were trying CRISPR gene editing in all kinds of organisms. Many studies involve using CRISPR for research: detecting viruses, say, or recording cells鈥� activities. But it is no longer restricted to labs. In some countries, people are already eating CRISPR-edited plants and animals 鈥� and in 2018, it was announced that three genetically modified children had been born in China. Their genes were edited using CRISPR technology at the embryonic stage by scientist He Jiankui in an effort to prevent them contracting HIV from their fathers (see 鈥淓diting eggs and sperm鈥�). Jiankui was jailed for his actions.

Most remarkably, more than are under way or have already been completed. This is a phenomenal achievement as new medical technologies typically take several decades to develop to the point where they are ready to try on people.

鈥淭hese gene-editing therapies are really exciting in the near term and I think are going to change people鈥檚 lives for the better in a lot of important ways,鈥� says bioethicist at Stanford University in California.

Around half of these trials involve treating cancer. The idea here is generally to take immune cells from a person with cancer, edit them to be better at attacking the cancer and replace them in the body.

Most of the other CRISPR trials involve treating inherited conditions, such as sickle cell disease. This is caused by mutations in both copies 鈥� one inherited from each parent 鈥� of the gene for adult haemoglobin, the protein that carries oxygen in the blood. But a few people with mutations in both gene copies don鈥檛 get ill because they keep producing fetal haemoglobin as children and into adulthood, instead of stopping after birth as usual. This gave researchers the idea for a therapy: use CRISPR to reactivate fetal haemoglobin production.

This is how doctors treated Victoria Gray. First they extracted blood stem cells that produce red blood cells from her body. They then used CRISPR technology with a Cas enzyme called Cas9 to destroy the genetic 鈥渙ff switch鈥� for fetal haemoglobin. Next, chemotherapy was used to kill the unmodified blood stem cells in Gray鈥檚 bone marrow, to make room for the edited ones. Finally, the gene-edited cells were put back in her body.

Another 35 people have since received the same treatment. Of the 17 people treated long enough ago to assess the results, 16 have been free from episodes of pain for at least a year.

The procedure, developed by Vertex Pharmaceuticals in Boston, Massachusetts, can also be used to treat people with beta thalassaemia, a blood disorder that is also caused by haemoglobin mutations. So far, and out of the 27 with long follow-ups, 24 have gone at least a year without needing blood transfusions and the other three need fewer transfusions.

If, as expected, this CRISPR therapy becomes the first to be approved sometime this year, it will be a momentous milestone. But there is a major issue with the standard CRISPR-Cas9 method that could limit its future use: it is more accurately described as targeted gene destruction than gene editing.

That is because the Cas9 protein cuts DNA at the site determined by the guide RNA. The cell鈥檚 repair systems then kick into action to stick the two severed ends back together. They may repair it perfectly, says at Harvard University, but then the Cas9 cuts the DNA again and again until a faulty repair is made, introducing mutations that disable a gene.

It is the equivalent of correcting a mistake in a text by scratching out an entire word. In a few instances, that can work well 鈥� say, if there is a stray 鈥渘ot鈥� in a sentence that shouldn鈥檛 be there. But, for most misspellings, it isn鈥檛 enough. Similarly, treating most genetic diseases requires correcting genes rather than destroying them. 鈥淭he vast majority require precise genome correction,鈥� says Liu. There are also safety issues with completely severing DNA. If several cuts are made, the wrong ends can get joined up, limiting the number of changes that can be made at the same time.

The good news is that several solutions have already been developed. One of the most promising, called CRISPR base editing, is a way to turn one of the four DNA letters 鈥� A, G, T and C 鈥� directly into another without any cuts.

Liu created the first base editor by swapping the cutting part of the CRISPR-Cas9 protein for an enzyme that chemically alters an individual letter instead. While more base editors are still being developed and improved, the first few have produced many therapies that are already in the pipeline 鈥� and that may have already saved at least one life.

Life-saving solution

Last year, a teenage girl called Alyssa had run out of options after all the usual treatments for her leukaemia had failed. So her doctors instead tried an experimental approach that involves engineering immune cells to attack the cancer.

These modified immune cells, called CAR T-cells, are created by using a virus to add a gene to T-cells that makes them target a specific cell type. They are highly effective at treating many forms of leukaemia.

The trouble was that Alyssa had T-cell leukaemia, and if you make CAR T-cells target T-cells, the therapeutic cells kill each other. So, in addition to adding the targeting gene, at the Great Ormond Street Institute of Child Health in London also used base editing to stop the CAR T-cells recognising each other as T-cells.

In fact, Qasim made four additional changes altogether via base editing to improve the cells. Soon after receiving the base-edited CAR T-cells, no cancerous cells could be detected in Alyssa鈥檚 body, though it is too soon to know if this is a complete cure.

While base editing is looking like an even more powerful and safer gene-editing tool than standard CRISPR, it is limited to altering single DNA letters. Enter prime editing, created by Liu鈥檚 colleague , now scientific co-founder of biotech company Prime Medicine.

Prime editors are Cas9 proteins modified in several ways. Instead of cutting right through DNA, they just 鈥渘ick鈥� one of the two strands that make the classic double helix shape. The Cas9 protein鈥檚 guide RNA is given an extra bit of RNA, which is what the cell uses as a template when repairing the damage. This allows short stretches of around 40 DNA letters to be added or deleted.

Liu says that is enough to treat 95 per cent of genetic diseases. But biologists haven鈥檛 stopped there. Last year, researchers reported that they had managed to add to specific sites using a modified form of prime editing.

All this means we now have a rapidly growing set of CRISPR tools for true gene editing, not just targeted gene destruction. But there remains another major issue: cost.

A cost barrier

Vertex won鈥檛 announce the pricing for its sickle cell treatment until after approval. Other gene therapies cost millions to make and buy, but they are usually for very rare diseases. Sickle cell affects millions worldwide, so Vertex may be able to charge much less and still make a profit, but it will still be very expensive due to its complex nature. 鈥淭here are a couple of people in my family that are still suffering from this disease,鈥� says Gray. 鈥淭hat鈥檚 our biggest worry, that once it becomes mainstream, they won鈥檛 be able to afford it.鈥�

One way to reduce costs is to take cells from a single donor and gene edit them so they can be used to treat many different patients. Such off-the-shelf cells are already being used for cancer treatments, including the one Alyssa received.

The immune systems of people getting treatments for leukaemia are so weakened that rejection of the donor cells as foreign isn鈥檛 an issue, but the donor CAR T-cells can see the body they are transplanted into as foreign. Gene editing can prevent this by disabling the key receptor protein T-cells use to spot foreign cells.

If the treatment is successful and people鈥檚 immune systems are restored, the donor CAR T-cells get killed off. By this time, they have done their work, so this isn鈥檛 an issue. But at least one company is editing out proteins on the donor cells that mark them out as foreign to the recipient, meaning they could persist indefinitely in the body without rejection. The aim is to use this approach to treat diseases such as type 1 diabetes in addition to cancer.

While all off-the-shelf cells could greatly reduce costs compared with extracting and modifying each individual鈥檚 cells, any cell-based therapy is still going to be expensive because of the issues involved in growing and maintaining cells outside the body while ensuring their purity and safety.

To get treatments to all the people who need them around the world, what is really needed is a single shot that can be given to people without complex treatments and long hospital stays, says at the Bill & Melinda Gates Foundation in Seattle. 鈥淭his is a big challenge.鈥�

Editing cells in the body

But it could be done by editing cells inside people鈥檚 bodies instead of outside them. What鈥檚 more, this approach would solve a major drawback with treatments like the one Gray got: the chemotherapy that makes room for the edited blood stem cells usually renders people infertile.

To edit cells in the body, the CRISPR machinery has to be delivered to those cells. This is usually done by packaging a type of RNA called mRNA, which codes for Cas proteins, alongside guide RNAs in tiny fatty nanoparticles or in viruses, then injecting them into the blood.

When the mRNAs get into a cell, the cell will make the Cas protein, which then hooks up with the guide RNAs and edits the genome of the cell. After a few days, the added mRNAs and the Cas proteins will break down, so the gene-editing machinery doesn鈥檛 persist in the body, which reduces the risk of unwanted changes to the wrong bits of DNA.

The first trial of in-body CRISPR-Cas9 gene editing, for treating a hereditary form of heart disease called ATTR amyloidosis, began in 2021 and suggest it is safe and effective.

Even so, because numerous studies show that standard CRISPR can cause unwanted mutations 鈥� and thus potentially cancer 鈥� it is questionable whether the balance of benefits versus risk justifies its use for less serious conditions for now. Regulators will want to see much more evidence of safety.

Base editing, on the other hand, is safer than standard CRISPR because it doesn鈥檛 cut DNA. In July last year, the first trial of within-body base editing got under way in New Zealand, with the aim of permanently reducing cholesterol levels 鈥� no more need for popping pills, with their attendant side effects. In animal tests, .

Cutting cholesterol

The people in the trial have dangerously high cholesterol levels due to an inherited condition called familial hypercholesterolemia. But if the treatment is a success, Verve Therapeutics, the company behind this, aims to expand it to people with heart disease due to clogged arteries, and eventually to anyone merely at risk of getting this kind of heart disease.

In other words, Verve is hoping that, in the not-too-distant future, its one-time shot will start to replace the cholesterol-lowering drugs currently taken daily by more than 200 million people around the world.

Even if Verve鈥檚 bold strategy succeeds, there is yet another challenge to overcome: delivery. To lower cholesterol, Verve is gene editing liver cells, which are the easiest cells in the body to target. That is because when lipid nanoparticles are injected into the blood, most of them get taken up by the liver.

The issue is that only a few conditions can be treated by targeting livers. For most purposes, we will need to target other tissues, such as brain or muscle cells, which is much harder. Researchers are exploring lots of different ways to achieve this, and while the matter certainly hasn鈥檛 been solved, many teams around the world are reporting promising results. For instance, in April, researchers reported that they had managed to by injecting them with a virus that delivered prime-editing machinery to blood stem cells inside their bodies.

Such a one-shot treatment would be a lot less costly and complex than the one Gray received, and would also avoid its big downside 鈥� the need for fertility-destroying chemotherapy.

鈥淭here鈥檚 tremendous and exciting progress, but we still have a way to go,鈥� says at Stanford University. It isn鈥檛 just about solving the biological problems, he says 鈥� rolling out CRISPR cures en masse would also require everything from training people to building infrastructure to industrialising the manufacture of the required components to having regulations that ensure safety without being too onerous.

The true finish line is delivering one-time cures to all the people in the world who need them, says Porteus. That process is now getting started for sickle cell disease, and could begin soon for many other conditions. 鈥淚鈥檓 part of something that could be amazing for all mankind,鈥� says Gray.

Michael Le Page is a senior reporter聽at 快猫短视频