Are we on the cusp of creating superhumans?

A Chinese cancer patient has become the first person to have their DNA edited using a revolutionary approach. Australian Doctor investigates whether it means genetic engineering will finally deliver on its promise.

On 28 October, Professor Lu You, an oncologist at West China Hospital in Chengdu, made history. He became the first doctor to treat a patient with a new gene-tinkering technique called CRISPR.

Immune cells were removed from the lung cancer patient, and their DNA edited to make them better at attacking the disease. The souped-up immune cells were then injected back into the patient.

The world's medical community is holding its breath to find out whether the approach works, and whether it is safe. Researchers behind the Chinese trial plan to test the technique in 10 lung cancer patients and monitor them for six months for any adverse effects.

A similar trial has been given the green light to start in the US early next year, as the two superpowers battle to stay at the forefront of gene-editing technology. A total of 18 cancer patients will have their immune cells genetically engineered using CRISPR.

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Quick and easy
The concept of gene-editing is not new. Genetic modification of animals began in mice in 1974, and has led to glow-in-the-dark rabbits, meatier pigs and fast-growing salmon. In 2015, gene-editing saved a person's life for the first time, when a technique known as TALEN was used to create beefed-up immune cells that cured a one-year-old girl of leukaemia.

But TALEN and other approaches for editing human DNA have been eye-wateringly expensive, complicated and time-consuming. CRISPR (the acronym stands for Clustered Regularly Interspaced Short Palindromic Repeats, and pronounced ‘crisper') alters DNA using a natural process found in bacteria (see box).

It can be carried out by anyone with a lab and a basic knowledge of molecular biology. Since being invented three years ago, the technique has proven to be cheap, easy, fast, precise and can even be performed on live cells.

As a result, it is claimed there is an unprecedented opportunity to wipe out disease: the potential to better equip the immune system to fight illness, or erase sections of DNA that cause disease in the first place. Engineering animals and insects could also prevent the spread of zoonotic diseases like bird flu and malaria.

In the laboratory setting, scientists have already shown that CRISPR can be used to snip HIV and herpes DNA out of infected cells. They have also corrected genetic mutations in cells that cause sickle cell anaemia and Huntington's disease. In adult mice, they have edited liver cell DNA to cure tyrosinaemia, and in mosquitoes, they have introduced genes to reduce malaria transmission.

Rewriting the human genome
Altering DNA in immune, blood, liver and other non-reproductive cells is seen as relatively uncontroversial, because the edited genes will not be passed to the next generation. But playing with DNA in human reproductive cells and embryos is another story, when any modifications will be inherited by future generations and change the human gene pool.

In April 2015, Chinese scientists reported the first attempt to edit human embryos using CRISPR. The editing technique was used to modify the gene responsible for the blood disorder beta-thalassaemia. To allay fears about creating mutant humans, the researchers used non-viable embryos from IVF clinics so that they could not result in live births.

Then in April this year, another Chinese group reported using CRISPR to introduce an HIV resistance mutation into non-viable human embryos.

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In both studies, only a fraction of the treated embryos were successfully modified, showing that the technology still has a long way to go. The technique would need to be 100% successful to be used clinically.

However, the early research has already made many people jittery. A group of international experts meeting at a summit in Washington last December called for a worldwide moratorium on making inheritable changes to the human genome.

The summit, which was co-hosted by the US National Academy of Sciences and the Chinese Academy of Sciences, released a consensus statement saying that the moratorium should only be lifted if relevant safety and efficacy issues were resolved, and there was a "broad societal consensus about the appropriateness of the proposed application".

Supersized humans
On the one hand, embryo modification has the potential to eradicate genetic diseases. CRISPR has already been used to stop Duchenne muscular dystrophy from being passed down in mice, by editing sperm and egg cells that carry the gene. Theoretically, the same could be achieved for all 6000 genetic disorders that affect humans.

But equally, physical and mental traits could be enhanced by tinkering with embryo DNA, opening the door to eugenics. The technology could potentially be used to select for desirable traits like eye, skin or hair colour, height, or even intelligence.

And beyond that, some argue that gene-editing could one day be used to create supersized athletes or soldiers. Chinese researchers have already shown that dogs can be bred with twice the normal muscle mass by using CRISPR to slice out the gene for myostatin — a protein that inhibits excessive muscular growth. Applying the same technique to human embryos could potentially lead to the creation of bigger, faster people.

This is not simply a new ethical headache for those wanting to drive out cheats from professional sports. Once introduced to the human population, genetic modifications would be hard to reverse and impossible to contain within a single country.

Professor Paul Thomas, professor of biochemistry and director of the SA Genome Editing Facility at the University of Adelaide, uses CRISPR to edit genomes in mice.

"I don't think we should be in the business of modifying genes in an embryo with the intention of creating certain traits that we're interested in," he says. "That's ethically a no-go zone. I think just about everyone you speak to would agree with that point of view. That's not an area which I think will ever be or should be approved."

He points out that we can already screen embryos for genetic disorders and terminate the pregnancy if necessary.

"I'm much more in favour of that kind of approach than trying to correct mutations within the embryo using CRISPR.

"There's still a risk with CRISPR that you're going to make off-target mutations — modifications that aren't at the intended location within the genome. That's a significant concern around CRISPR. That's another reason why you would want to be very, very careful if you were considering doing any germ-line modifications because you might create mutations in genes that you're not intending to target."

He says this is also a concern for the Chinese trial using CRISPR to edit immune cells.

"You need to be very confident that you're creating the mutations that you want to create and not creating mutations elsewhere in the genome that could have negative consequences."

Asked if he believes the international scientific community is committed to using CRISPR ethically, he says: "There's been a lot a discussion in all the major journals, and there's a very conscious effort to use CRISPR responsibly. I think all reasonable scientists would agree that we need to proceed very carefully ... The technology has enormous potential, but we do need to proceed very carefully with appropriate regulation."

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Road blocks
The obvious problem with CRISPR is that although it has made it easy to cut and paste DNA, predicting how these edits will manifest is not as simple. We still don't know every single function of every single gene, meaning that any modifications could have unintended effects.

Another issue is that the effects of genetic modifications could vary under different circumstances, due to the interactions between genes and the environment.

A Canadian team investigating CRISPR's potential to treat HIV has already come across unforeseen road blocks. DNA editing successfully cut the virus from some infected cells. But in others, the virus became even more deadly, perhaps because the editing process introduced mutations. The researchers believe they will be able to iron out this problem, but it highlights the unpredictability of genetic manipulation.

One thing is for certain though — now that we've boarded the CRISPR train, it will be impossible to get off.

The Chinese cancer trial will be the first of many in non-reproductive cells, and the temptation to apply CRISPR to reproductive cells may become too great to ignore.

It is hoped the international scientific community co-operates to ensure that CRISPR is used in a responsible manner. As the ultimate gene-edited fictional being Spider-Man is warned: "With great power comes great responsibility."

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