Human gene editing has arrived – here's why it matters

• by Penny Sarchet and Michael Le Page

Taking aim at faulty DNA (Image: Power and Syred/Science Photo Library)

It's becoming possible to edit our genes to treat and prevent conditions like HIV and sickle cell disease or, more controversially, create designer babies

GENE editing is here. The first work attempting to edit human embryos grabbed headlines last week. And another study showed how gene editing might prevent children inheriting disease.

It could be decades before it is safe to snip out and replace stretches of DNA to genetically engineer babies – even if it is deemed ethically acceptable. But the approach is already being tested for treating disease in adults and could soon be used to treat a wide range of disorders.

It has been a long time coming. Rudimentary editing methods were first developed some 30 years ago, but only now have techniques been honed to the point that they can be used for treating people. It raises the curtain on a new era of genomic tinkering and genetic medicine.

HIV therapy

In the coming months, four US clinics will recruit people with HIV to a trial of a therapy based on gene editing. HIV wreaks havoc by destroying immune cells called T-cells. It does this by exploiting a receptor, CCR5, on the surface of these cells. Destroy the gene for CCR5 and you can block infection.

Last year, researchers targeted and destroyed this gene in the T-cells of 12 people with HIV using custom-made proteins called zinc finger nucleases. This raised their resistance to the virus. The new trial goes further, knocking out the gene in the stem cells that give rise to T-cells, making it a possible one-shot, lasting treatment. "The goal is a functional cure," says John Zaia, of the City of Hope hospital in Duarte, California.

The trial blazes a path for using the approach to treat other diseases. For example, another trial set to start soon will focus on sickle cell disease, in which the oxygen-carrying haemoglobin molecules in red blood cells are abnormal. The technique would switch on a protein that can be used instead of the haemoglobin.

There could be downsides to this approach though. "Genome editing offers both tremendous promise and significant potential risk," says David Liu of Harvard University. Almost all editing techniques have the potential to modify unintended DNA sequences, he says. "Some of these off-target genome modification events will likely lead to negative biological consequences."

But, if it can be made safe, editing adult stem cells is likely to face fewer ethical hurdles than other applications of gene editing.

Inherited change

Some teams are already exploring the possibility of using gene editing to make heritable changes. Last week, researchers showed that gene editing can weed out mutations in the mitochondria that a female mouse passes on to her offspring.

Mitochondria generate energy in our cells and have their own set of DNA, which differs from that in the cell nucleus. Mutations in mitochondria can cause diseases for which there are no treatments.

Earlier this year, the UK gave the green light to mitochondrial replacement therapy. This involves creating "three-parent babies" with healthy mitochondria donated from a third person preventing such diseases being passed on.

The new approach offers an alternative. It uses a gene-editing technique based on custom-made proteins called TALENs. These proteins can be designed to latch on to the DNA in faulty mitochondria and target them for destruction. Healthy mitochondria remain unharmed.

Most women at risk of passing on faulty mitochondria carry some healthy and some mutated mitochondria, so TALENs could lower the number of mutated mitochondria in their eggs. Harmful effects only kick in once the number of mutated mitochondria crosses a threshold, so this may be enough to prevent disease in their child, and perhaps in future generations too.

Using gene editing in this way isn't without risk, says Robert Lightowlers at Newcastle University, UK. It is unclear whether reducing the number of mitochondria could have a long-term effect, he says. And although the TALENs protein in the study seemed to target only the intended mitochondria, it could be harmful if even a very low amount of it got into the nucleus and altered DNA there.

Juan Carlos Izpisua Belmonte of the Salk Institute for Biological Studies in La Jolla, California, who is part of the team doing the TALENs work, says they plan to begin testing the safety of the technique. "The idea will be to obtain oocytes and discarded embryos from IVF treatments in order to test this technology using human samples."

Taking the research to the next level will be controversial. Last month, a group of scientists called for a moratorium on gene editing research in cells that can form embryos. The plea was made by those working on gene editing with adult cells who are concerned that embryo editing could have unpredictable effects on future generations and stimulate a public outcry.

Uncharted waters

Despite the call for a hiatus, a team in China announced last week that it hadedited DNA in the nucleus of human embryos.

The work involves a technique called CRISPR/Cas9, developed in the last few years. It has the potential to accelerate progress enormously because CRISPR is much faster than conventional gene editing methods (see "How to edit genes").

Despite the hype, there is a long way to go before CRISPR could be used to write genetic disease out of the DNA of future generations. The Chinese study flagged up a number of potential problems. Of the 86 eggs injected, just four were successfully modified. And the resulting embryos were a mosaic of modified and unmodified cells.

This may have been down to the unviable embryos used, which were created when two sperm fertilised the same egg. The team said it used them because ethical concerns preclude the study of gene editing in normal embryos. But that hasn't stopped the work being criticised.

The fuss is because it is the first phase of a more controversial effort to make genomic changes in human embryos intended to be implanted, says George Annas of Boston University. "It is only in the context of this wider project that manipulation of non-viable human embryos moves from curiosity to potentially dangerous – both to the resulting children and their children, and to society at large," says Annas. These concerns over designer babies are less of an issue for mitochondrial gene editing because it is only possible to delete mutant mitochondria, not alter them.

Yuet Kan of the University of California, San Francisco, describes the study as a publicity gimmick. The disease it targeted, beta-thalassaemia, can already be detected by pre-implantation embryonic screening during IVF. "I don't see any need for embryo gene editing," says Kan, who is using CRISPR to treat HIV.

Despite the controversy, at least one group in the US and several more in China are also reportedly working with human embryos. But when it comes to treating disease in the near future, it is the adult methods that hold the most immediate promise. One thing is for sure, the gene-editing genie is well and truly out of the bottle.

How to edit genes

Target a specific sequence

For the TALENs or zinc finger gene editing systems (see main story), this requires designing proteins to bind to the DNA you want to edit.

With CRISPR, only RNA complementary to the target DNA is needed. It takes days to make these, but customised proteins take years.

Cut the target DNA

This is the easy part – enzymes cut your chosen DNA.

Hijack DNA repair systems

Cells repair any strands of cut DNA using the nearest matching DNA as a template. So if you supply the template DNA, you can trick cells into making the changes you want.

Current state of play

Treating disease by modifying genes in adults

Human trials under way

Pros: Could be used to treat all kinds of diseases and disorders

Cons: Could turn cells cancerous if the wrong bit of DNA gets modified

Preventing disease by destroying mutant mitochondria

Testing in human cells about to start

Pros: Could prevent mitochondrial diseases without using a donor

Cons: Effects are heritable, so ethically controversial

Preventing disease by modifying genes in embryos

Testing in human embryos under way

Pros: Could prevent many genetic disorders

Cons: Uncharted ethical and scientific waters; treatments are a long way off

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