CRISPR article | Marie Claire

21 Sep 2016 - 10:45

In 2012, when Kate McMahon and her husband Tim brought their daughter, Olivia, home from the hospital, they knew there was something different about her. She was loving and sweet, but often unengaged, in her own world. It was hard for her to learn the simplest of skills. ‘I knew Olivia’s development wasn’t quite right,’ Kate says. ‘Until she was one year old, we assumed
maybe there was something missing but that everything would eventually fall into place.’ 
It was only when Olivia had to go to hospital because of a lower respiratory tract infection around her first birthday that her doctors began to suspect something else was going on, and referred Tim and Kate to a geneticist. After a few years, Olivia was diagnosed with Kleefstra syndrome – a rare condition caused by the deletion of part or all of a gene. In her case, it was a genetic spelling mistake that occurred by chance. The symptoms vary, but can include developmental delays, low muscle tone and intellectual disability.
Olivia, now three, is almost walking and knows a handful of words – something only about 50% of people with Kleefstra will
ever achieve. ‘In some ways, Olivia is like most three-year-olds; she loves Peppa Pig and she’s always grabbing my hand in the
middle of the lounge so we can dance to Taylor Swift,’ Kate says. ‘But there are a lot of challenges. She gets sensorially overwhelmed and finds it difficult dealing with textures. Some of her behaviour is obsessive-compulsive, and out of routine she can easily go into meltdown. Our future is uncertain.’ 
There is no cure for Olivia’s Kleefstra syndrome, but researchers are looking into fixing the genetic mistake that causes the condition – and that’s how Kate and Tim heard about a revolutionary new tool known as the CRISPR /Cas System. By using CRISPR (clustered regularly interspaced short palindromic repeats), scientists can edit DNA, effectively changing the human genome to delete disease.
While it was only discovered four years ago, it’s already shaping up to be one of the most breathtaking discoveries of all
time. Not only would it be able to cure Olivia’s Kleefstra, but it could eradicate thousands of other diseases, including cancer, autism and HIV. But the power of CRISPR to change DNA has many in the scientific community running scared, struggling
to grapple with the moral and ethical implications of tinkering with what makes us human. Twenty years after the birth of
Dolly the sheep, the first genetically engineered animal, are we getting close to a Gattaca-like future?
Ever since we first realised we could manipulate genes in the 1970s, scientists have desperately been trying to edit out the genetic signatures of diseases. While they’ve made some progress, it turned out to be a lot harder than anyone predicted. But CRISPR is different. The first paper describing its use was published in August 2012 by Jennifer Doudna, professor of molecular and cell biology and chemistry at the University of California, Berkeley, and French researcher Emmanuelle Charpentier.
Basically, when scientists wanted to cut DNA in the past, they’d have to build new custom-made scissors each time. But the
CRISPR system is a universal set of scissors that can precisely cut DNA wherever scientists tell it to. By 2013, scientists had started using the technology to edit genes in mice. Work began in the laboratory on ways to use CRISPR to get rid of cancer-associated genes, such as BRCA1 – the breast cancer gene carried by Angelina Jolie – and treat genetic conditions,
such as anaemia or cystic fibrosis. The positive results continued to roll in; over the next few years, scientists used it to delete HIV out of infected cells, and cured Duchenne muscular dystrophy in mice.
‘Pretty much every lab in the world is using CRISPR to do things they’ve been wanting to do for years,’ says professor Merlin Crossley, dean of the faculty of science at the University of New South Wales in Australia, who’s working with CRISPR to treat blood diseases such as sickle cell anaemia. ‘Projects that would have taken 10 years and cost a million dollars are now taking one year and costing much less. The rate of scientific advance is very rapid,’ he says. In South Africa, researchers have already started using this technology, says professor Nicci Illing from the University of Cape Town’s department of molecular and cell biology. ‘CRISPR has the potential to revolutionise research and was cited as the breakthrough of 2015 in the leading research magazine Science. There is also a lot of excitement for the applied angle of gene editing where it can be used to tackle human disease.’
At the start of 2014, researchers showed they could use CRISPR to genetically engineer primates. It was around then that Jennifer started to lose sleep about the potential consequences of the technology she had unleashed on the world. While CRISPR was shaping up to be a life-saving tool, with thousands of researchers in multiple countries experimenting with it, its potential to be misused started to come into focus. What if one country started to edit humans for things other than disease, like eye colour or even IQ? Who would judge where and when the line would be crossed? In March last year, concerned about this possibility, a group of scientists, led by Edward Lanphier, authored an article for Nature journal, warning the industry about pushing the system too far. ‘In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations,’ they wrote. ‘This makes it dangerous and ethically unacceptable.’
Then, a month later, a team in China, who were working on curing a deadly blood disorder, announced that they’d used CRISPR to edit a human embryo for the first time in history. The lid came off Pandora’s box. ‘Genome-engineered humans are not with us yet, but this is no longer science fiction,’ Jennifer said in a TED talk later that year. ‘And this puts in front of all of
us a huge responsibility, to consider carefully both the unintended consequences as well as the intended impacts of a scientific breakthrough.’ It might sound like some sort of Star Trek-esque technology, but most scientists agree that some form of CRISPR therapy for humans will be available in hospitals within the next 10 years.
That’s what Kate and Tim McMahon heard in a conference on treatments for Kleefstra last year. Scientists have already shown that reactivating the faulty gene can reverse the symptoms of certain syndromes in organisms like fruit flies, and they’re now looking into whether CRISPR could do the same thing in mammals. If that works, it would mean Olivia’s condition could be erased from her body. 
However, the families who would benefit the most from this tool are keenly aware of the conundrum that CRISPR presents. ‘It’s difficult to weigh up the potential benefits so many people could gain, considering some risk takers may be pushing the boundaries of ethics a bit far,’ Kate says. Mother-of-two Emily Shepherd believes the benefits of CRISPR are worth the potential risks. Her six-year-old son, Louis, has Usher syndrome, a genetic mutation that causes deafness. He also suffers from retinitis pigmentosa, which will gradually make him blind. Vision loss is something that scientists are beginning to treat in mice using CRISPR. ‘Every day Louis’s vision gets worse, and we’re watching it disappear. Until you have a child who has this, you can’t fully understand or comprehend the nature of it,’ she says. ‘Louis has this dream when he grows up that he wants to be a train driver. I don’t have the heart to tell him that maybe it’s not the best career path for someone with vision loss. I need to know that scientists are working on CRISPR – and that maybe this won’t be his reality forever.’
Emily knows the ethical concerns are real, but she trusts the scientific community to regulate itself, and in the meantime: ‘You just want a healthy baby, and if the technology is there, then it’s there to be used. Until you watch your child struggle with day-to-day life, I don’t think you can have an opinion on it.’
To be fair, pretty much everyone using CRISPR at the moment wants to cure diseases and improve lives. And they want to do it in adult cells, which isn’t really any more controversial than current genetic editing technologies. But what happens when people with less honourable intentions use CRISPR, and don’t stop at treating adults and children? There’s no getting around the fact that each time researchers get better at using CRISPR, it takes them closer to being able to impact the make-up of future generations. Bestcase scenario, scientists could theoretically design babies resistant to disease and obesity; worst-case scenario, it means they could pick and mould the next generation of humans. (However, here and in around 40 other countries, it’s illegal to bring genetically edited embryos to term.) The problem is that editing embryos doesn’t just change things for one individual, it creates genetic changes that will be passed down to future generations. And we still have no idea if changing certain genes could have side effects down the line. 
‘While many researchers do not have qualms about using CRISPR technology to correct mutated genes in human somatic cells, there is real concern that it might be used to edit the human germ line [the sex cells that pass genes on to descendants],’ Nicci says. ‘The pros and cons and ethics of the application of CRISPR genome editing technology needs to be carefully debated by society.’ 
Ultimately, the question that no one has been able to answer is will the technology do more harm than good?
‘I lie in bed almost every night and ask myself that question,’ Jennifer told The New Yorker magazine last year. ‘When I’m
90, will I look back and be glad about what we have accomplished with this technology? Or will I wish I’d never discovered how it works?’ Some leading geneticists have discussed their concern over the speed at which CRISPR research is progressing. One of the leading scientists on the 21st century, John Craig Venter, wrote a piece for Time magazine in February on why we need to be careful with CRISPR. ‘We should proceed with extreme caution in this brave new world,’ he said. In response to these concerns, at the end of last year, the national science academies of the US, UK and China brought together almost 500 scientists from around the world to debate whether CRISPR should be banned on use in humans. They decided research on CRISPR should continue – the potential benefits are too great to throw it away – but argued that they need to draw a line between use in regular cells and using it in embryos. Then at the start of this year, a committee in the UK gave London’s Francis Crick Institute the go-ahead to use CRISPR on embryos to find out how to reduce miscarriages and improve IVF outcomes.
For Kate, the answers still aren’t clear. ‘I don’t want to change the person Olivia is. ‘But I would love for her to do the things others take for granted, like driving a car, or getting a job, or even walking down to the park. Whatever decision we make [about using CRISPR], it’ll have to be one that respects the person she is, but also gives her the best opportunity possible to fulfil her dreams. I’m just grateful that the research is continuing. I know it won’t be easy, but we’d like the chance to help make that choice one day.’

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