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The first draft of the human genome was published 15 years ago. And since then, scientists have scoured its three billion-odd letters for clues to cancer’s origins.

To carry out this biological text-analysis, researchers have employed virtually every method of manipulating DNA they can get their hands on, learning a huge amount along the way. They’ve torn out pages, spell-checked lines, written in the margins of cellular history, and stuck bits back in – all in the hope of understanding how genes work and, crucially, how they can go wrong.

But to do this scientists have relied on some imperfect, albeit vital, lab tools, which can be expensive and labour-intensive. And this has meant that entire research groups have often been limited to studying single genes.

Add to this the fact that many cancers’ root cause lies in combinations of multiple faulty genes, and it’s clear there’s a long way to go. While the previous generation of gene editing techniques have helped scientists document many chapters of cancer’s history, it’s fair to say the ink would also sometimes run, or glued pages might slip.

So the precise function of many genes – and, importantly, how they collude with others in cancer – has been left unclear and smudged.

But in the last 12 months, a potential solution to these challenges has emerged. Labs across the world are trading in their weathered toolkits in exchange for something much shinier.

And it’s called CRISPR.

Short for ‘Clustered Regularly Interspaced Short Palindromic Repeats’, the technique promises a cheaper, quicker and more accurate way of studying the inner workings of our genes – a bit like exchanging a stone tablet and chisel for a fast laptop running modern publishing software.

But, as with any new technology, there are important considerations before making the trade – and these are all the more important if the technique becomes something that could be used to permanently change humanity’s DNA.

There are tough ethical questions, some of which have been in the spotlight today as the Human Fertility and Embryology Authority (HFEA) has given a licence to UK researchers at London’s Francis Crick Institute, allowing them to study human development by genetically altering human embryos donated from couples undergoing IVF.

But while our scientists aren’t doing research that involves editing human embryos (and away from the associated debate), they are already putting the technology to work on lab-grown cancer cells and other more conventional research models. And this is showing extraordinary potential to transform research on cancer.

DNAcode

The DNA code. Credit: Flickr/CC BY-NC-ND 2.0

Pre-CRISPR

Until recently, researchers working with cells in the lab, or with animals, had a handful of DNA editing approaches to choose from.

In cancer cells, for example, they might insert short chunks of genetic material into the cells, designed to seek out and switch off genes.

But there were problems. Sometimes these approaches would miss the target, or hit another gene at the same time. This made interpreting the results tricky, and experiments would become more cumbersome and time-consuming as extra checks were put in place to ensure the results were true.

There were also efficiency problems, meaning that the gene might not be fully switched off. Again, this would make monitoring the effects of these changes difficult.

While improvements arose as scientists turned to newer proteins, able to snip away chunks of DNA and replace them with different ones, these techniques were expensive to set up, and very complicated to use. So they never really caught on.

And researchers working with mice could use techniques to insert edited DNA into the animals’ stem cells, using these to develop genetically-engineered animals.

But, once again, there have been problems. While researchers have learned a lot from this technique, it doesn’t always work, and it’s time-consuming to develop.

Here’s where CRISPR comes in.

What is CRISPR anyway?

We have bacteria’s immune systems to thank for CRISPR.

And behind the acronym sit two molecules, which effectively work as a pair of scissors and a microscopic sat nav.

The ‘scissors’ are a protein called Cas9, which can chop up DNA. But precisely where it does so is directed by the ‘sat nav’: a short piece of DNA’s molecular cousin, RNA.

These two components evolved to protect against invading viruses, by helping bacteria spot – and destroy – viruses’ DNA.

But researchers have worked out how to isolate and adapt these primeval tools to let them edit any gene they wish, in any cell they like, with unprecedented precision.

First, the RNA sat nav precisely matches up with a particular stretch of DNA. And it brings the Cas9 molecule along with it, allowing the scissors to cut at that exact point in the DNA sequence.

CRISPR’s power as a research tool comes from being able to engineer bespoke versions of the RNA sat nav, allowing Cas9 to be directed to any gene a researcher wishes.

But it’s what happens next that makes the CRISPR system a cellular version of the ‘find & replace’ tool in a word processor: once Cas9 has cut the DNA, the cell’s built-in repair machinery swings into action.

Researchers can use this response to disrupt the gene that has been cut, essentially switching it off to see what happens.

Or they can do more sophisticated experiments that precisely change the DNA code. Here they can make spelling mistakes in a gene, like certain faults seen in cancer cells, which alter the gene’s function rather than merely scrambling it.

It’s hard to overstate how powerful this precision editing could be for lab scientists. “It’s revolutionised the research we are doing,” says Dr Adrian Saurin, a Cancer Research UK-funded expert in cancer cell biology from the University of Dundee.

And this revolution has seen researchers around the world upgrading their old tools to get a more precise look at cancer.

Can CRISPR help us understand cancer?

Genes carry the recipes for proteins, and Saurin’s team want to understand the particular proteins that control when a cell divides – a process that goes haywire in cancer.

“Traditionally we would have had to make cells artificially produce excess amounts of these proteins, and look and see what happened,” says Saurin.

We can observe biology, without artificially interfering with it, and then make changes just to the DNA and examine the consequences

– Dr Adrian Saurin, University of Dundee

“Now, with CRISPR, we can directly edit the DNA inside cells to see what happens to the proteins. We can really change what these proteins are doing and watch them at a natural level inside the cells.”

The implications of this will be enormous, particularly for studying faulty proteins in cancer. “We can observe biology, without artificially interfering with it, and then make changes just to the DNA and examine the consequences,” Saurin adds.

“That’s the only true way to get cause from effect. It’s going to open up a whole load of new questions that we just weren’t able to address before.”

And researchers around the world are already putting the techniques to good work.

Two independent teams – one in Canada and one in the US – recently used CRISPR to switch off almost every gene in a handful of lab-grown cell lines, one by one. This allowed the teams to test how essential each gene is for the cells’ ability to grow. Their analysis included cancer cells, offering one of the most comprehensive pictures to date of how certain genes may be vital in helping these cells grow uncontrollably.

“Those studies were great,” says Saurin. “They were able to use these tools to find genes that only affect the growth of cancer cells, and not healthy ones, which is really important.”

Another study from last year used CRISPR to test whether switching off different genes in cancer cells increased the cells’ ability to spread to the lungs of mice. Led by Professor Feng Zhang, one of several pioneers of CRISPR research, it was a clear example of how the technology could help unpick the complex process of how cancer spreads.

It’s early days, but we’re beginning to see the potential power of CRISPR as a tool to study cancer in the lab. And researchers will now be able to build on these studies and uncover weaknesses in these cells that may lead to new treatments.

Genome

Precision editing. Credit: Flickr/CC BY-SA 2.0

CRISPR 2.0

Away from cells in a dish, there’s also a lot of interest in putting CRISPR to work in developing newer, more efficient ways of studying how different types of cancer develop in organisms. And that’s something Ian Rosewell, who heads up a team at the Francis Crick Institute working on  developing animal models of cancer, is quick to point out.

“In terms of efficiency, we can achieve a faster result, but working with fewer mice,” he says.

This is a really important part of the work they do, following very strict guidelines on finding ways to replace, reduce and refine the work done with animals in research.

So far the team have used the technique to speed-up and hone the work they were already doing. But Rosewell is particularly excited about research that just simply wasn’t possible before.

“The next generation of experiments suddenly look a lot easier. We have the potential to switch multiple genes on or off, introduce multiple different faults in genes we’re interested in, or even make larger scale changes to big chunks of DNA ,” he says.

This type of research will be vital for accurately recreating the complicated genetic picture found in many cancers.

But, as with any new technology, it’s not perfect… yet. And as Rosewell points out, boosting the system’s efficiency and accuracy is a crucial next step. This means addressing the same shortcomings of previous techniques. Researchers need to be sure that the approach is only targeting the gene they’re interested in.

“There are lots more developments in the pipeline,” says Rosewell, “so this promises to just keep moving.”

And it already is. Researchers have been combing bacterial immune systems for alternatives to Cas9, which may be more accurate. And while high-level legal debates rage on over who ‘owns’ the technique, a team based in the US recently published a study on an upgrade to Cas9 that could make CRISPR even more efficient.

“In 15-20 years of working in the lab I can’t think of anything that has moved so fast,” says Saurin.

“I’ve only just started my own research group, so I have to think very carefully about what I can afford to do.

“The beauty of this technology is that it’s actually relatively cheap. It’s also really easy to do. And that’s exciting for me, because it means that I can compete with some of the biggest labs in the world. The questions we could ask are endless.”

And it’s this simplicity and cost-effectiveness that has left the door open for people to speculate on what this approach might make possible in the future.

What about treating patients?

CRISPR will undoubtedly speed up research. But with so-called ‘biological’ therapies becoming more and more important, what about using it to create new cancer treatments?

Some of the earliest signs that gene editing might find a use in treating people with cancer have come from the high-profile story of Layla – a young girl with leukaemia treated with an experimental immune therapy at London’s Great Ormond Street Hospital in late 2015.

The beauty of this treatment was the fact that the cells were edited in a way to make them invisible to drugs that suppress the patient’s immune system, and also to prevent them attacking normal patient cells

– Professor Adrian Thrasher, Institute of Child Health, London

Her doctors used gene editing to engineer immune cells in the lab so they could seek out and attack cancer cells when injected into Layla’s body (an approach we’ve written about here). It’s too early to say how effective the treatment will be in the long-run, but Layla’s initial response was extremely encouraging, and made headlines worldwide.

“The beauty of this treatment was the fact that the cells were edited in a way to make them invisible to drugs that suppress the patient’s immune system, and also to prevent them attacking normal patient cells,” says Professor Adrian Thrasher, from the Institute of Child Health and whose team treated Layla.

“So these cells, which were made from a donor, can be used to treat many patients. This is something that we wouldn’t have been able to do before without these new gene editing techniques.”

While not carried out by CRISPR, Layla’s treatment was created using a similar, slightly older gene editing toolkit called TALENs.

As Saurian explains, while TALENs used to be one of the ‘hot’ gene editing tools, CRISPR has really stolen scientists’ hearts. “When TALENs came along, experiments were difficult and expensive to set up,” he says.

“For a small lab, it took two the three months to get them working in cells reliably. But with CRISPR, I can get the same cells edited and growing in the lab in just one week.”

If this technology is to have any impact in terms of treatment, a boost in efficiency like this could be really important.

And early research from the US is beginning to show how CRISPR might help make the type of immune therapy used to treat Layla more efficient – and thus, perhaps cheaper.

A family affair?

As with any exciting new technology, it’s easy to get a bit overexcited in prophesying what CRISPR might be used for.

From engineering malaria-fighting mosquitoes to gene editing crops to be resistant to pests, there’s lots of potential. There has even been talk of resurrecting the woolly mammoth (although this is perhaps rather further off). And, of course, there has also been interest in how this type of approach might one day be used to tackle genetic disorders, including cancer.

But to echo Jurassic Parks’ Dr Ian Malcolm – played by Jeff Goldblum in the movie – it’s really important to consider both the ‘could’ and the ‘should’. And experts across the worlds of research, policy and ethics are taking this very seriously, including promoting the need for clear public discussions on these technologies.

But while the debate rages, if we allow our minds to wander, we can speculate that if this technology became accurate enough, it might one day be possible to edit cancer risk out of a family’s genome.

Some families carry gene faults that put them at particularly high risk of developing cancer. And over the last few decades, researchers have uncovered hundreds of weaker but more common genetic variations, called SNPs, which influence everyone’s risk of developing cancer to some degree.

We need to understand the impact of these genetic changes first. Then we can think about correcting them

– Dr Maya Ghoussaini, University of Cambridge

Editing out this cancer risk sounds like Sci-Fi – and so far it is.

But researchers are using CRISPR to find out just how important these faults are. “We have this big catalogue of genetic changes that increase the risk of cancer,” says Dr Maya Ghoussaini, whose team at the University of Cambridge is studying genetic changes associated with breast cancer. “But we don’t know how they increase the risk.”

Ghoussaini is editing the faults seen in cancer patients into lab-grown cells, and looking at how this affects gene expression and cells’ behaviour.

And she believes this approach could one day work the other way around, offering the potential to correct the faults that matter in patients’ DNA. But she stresses that “we need to understand the impact of these genetic changes first. Then we can think about correcting them”.

For this type of approach to come even close to the clinic, the technology would need to become even more accurate. And years of research in the lab would be needed to test the idea and prove it was safe and effective.

“We still don’t know how efficient CRISPR will need to be to fix faulty genes in people,” says Ghoussaini.

“There are exciting years to come, but figuring out how this might one day work in people is going to be a big challenge.”

And there would also be a number of hugely important ethical questions to consider, including the implications of making changes to the human genome that can be passed on from generation to generation.

And because this type of therapy – even if you can define it as that – would involve editing human embryos destined to become babies, it would also need to be proven that no alternative method could achieve the same result without altering embryos.

But as things stand, any attempt to carry out this type of human cell editing outside the lab is illegal in the UK.

So, as exciting as this idea is, and as fast as the field is moving, this is still – we think – one for the longer term future. But that just reinforces the need to have these important conversations now.

A final edit

So what of today’s announcement? Is it a cause for concern? UK laws are among the most rigorous in the world when it comes to research using human embryos. And the decision about the proposed research at the Francis Crick Institute underscores this.

In the UK, the balance – we think – has been struck well between proper regulation and research progress. The team at the Crick has the potential to carry out research that will uncover the details of the earliest moments of human development – vital information that could one day lead to new ways of improving IVF and limiting miscarriages.

For now, this won’t directly offer insights into cancer. But the potential is there as the technology develops, which is why we have signed up to a joint statement describing the use of this technology in human cells and committing to public discussion.

Editing humans – whether for improvements in fertility or to tackle cancer – is a big challenge, with huge responsibilities. If CRISPR is going to help researchers and doctors get there, experts and the public will need to be absolutely sure it’s up to the job. In the meantime, for researchers working day-to-day to study human disease, this ground-breaking new technology looks set to revolutionise our understanding. And that can only be a good thing.

Nick

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