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Photo: Matthew Cobb

CRISPR – the controversial yet revolutionary gene-editing tool

Every cell in your body contains DNA—the biological template that determines who you are. Ever since the fundamental role of DNA was realised, scientists have dreamed of easily and precisely editing our genome.

Researchers have employed numerous genome-manipulating techniques in the past, but most have proved imperfect, labour-intensive, and expensive. This is where the new genome editing technology, clustered regularly-interspaced short palindromic repeats, or CRISPR, comes in.

CRISPR has taken the world of medical and biological research by storm, as this new power allows scientists to edit the genome in an incredibly quick and precise fashion. What’s more is that CRISPR has been shown to work in any organism, unleashing enormous potential for the technique.

The ease and accuracy of CRISPR will revolutionise genetic engineering, vastly increasing the pace of scientific research.

Dominating recent news headlines, CRISPR brings immense excitement, but also extreme concern. There is now speculation of when the first “CRISPR baby” will be born—a baby that will have started out as the first human embryo to have had a faulty gene edited. Using such a technique on the embryo will ensure the child, and its offspring, never carry the gene for the disease it causes.

Scientists of many disciplines, from all over the world, have rapidly adopted the use of CRISPR. Current discussions are debating the use of CRISPR in a genetic mechanism called a gene drive. This involves the use of CRISPR to genetically edit pest organisms, such as weeds or malaria-carrying mosquitos, to have a lethal gene. The gene drive will then spread the lethal gene throughout the population.

Despite the prospect of revolutionising agriculture and endemic diseases, many worry of the long-term effects of such gene editing on ecological systems.

After his recent BBC Radio 4 broadcast, Editing Life, I spoke to Matthew Cobb, professor of Zoology here at The University of Manchester, to discuss the profound impact, and challenges, of this revolutionary gene-editing tool.

I met with Professor Cobb on a dull Tuesday afternoon, for what I thought would be a quick chat. Conversing in his office for over an hour, amongst an array of scientific literature and toy dinosaurs, it became evident just how broad the applications of CRISPR are. Before exploring these applications, I first wanted to understand exactly what CRISPR is, and specifically why there has been so much excitement surrounding it.

“This [CRISPR] is a naturally occurring system in bacteria, which bacteria have been using for billions of years. It means that they [bacteria] can keep a genetic record of viruses that have infected them, and when those viruses come again, they [bacteria] can mobilise enzymes, called Cas9, to come and snip up the virus.

“CRISPR is a description of what they [the researchers] found in the genome—they found these bits of DNA, which were repeated over and over again, in different clusters, with bits in between them.

“The excitement began around five to six years ago, when people realised that the enzymes that chop up the viral DNA, were guided there by the bits of DNA in the clusters—they [the Cas9 enzymes] knew where to go. It was then realised that they could give it [the Cas9 enzyme] a different DNA target. So the enzymes, metaphorically, act as a pair of scissors, and know where to go. You can give it [the Cas9 enzyme] a sequence of DNA you want it to recognise, give it a guide, and you can then put this in any kind of cell.”

It became evident that the precision of CRISPR was something making it truly extraordinary compared to other techniques: “It [the CRISPR technique] is extremely well targeted, can be used in any kind of cell and organism, is extremely precise, and it can snip out or insert something. It then uses the cells naturally occurring machinery for sticking the sequence back together again. These combinations made people think that this [CRISPR] can be used in all sorts of ways.

“Old techniques are much more cumbersome and slow—CRISPR can be done in a matter of weeks.”

As with many biological techniques, there were originally concerns over potential “off-target effects” of CRISPR—worries that the Cas9 enzyme may act in unexpected places:

“The Cas9 enzyme is being bioengineered, can be fiddled around with to make it do whatever we want. It has been engineered already to be more effective. In a recent article in Nature, it was said that there were no off-target effects at all. This was thought to be a big obstacle towards the safe application of CRISPR, however this has now been removed.”

With CRISPR, the genetic code has never been so easy to rewrite. The recent approval of using CRISPR on a human embryo by the UK’s Human Fertilisation and Embryo Authority (HFEA) has sparked much debate. A team of scientists at the Francis Crick Institute, lead by Kathy Niakan, is utilising the technique to assess questions surrounding fertility. The use of such a technique in human cells seems to not worry Professor Cobb:

“We’ve been allowed to work on them [human embryos] for years. You can only work on them for 2 weeks, and then you have to dispose of them—and you are not allowed to implant them. At the Crick they are working to understand what happens in the early stages of development of the embryo, and when it goes wrong.

“This is the first time CRISPR has been used in the UK on a human embryo, however this already happened in China back in April, and it worked. To be honest, it would be more amazing if CRISPR didn’t work in something.”

I was keen to ask Professor Cobb his opinions on the potential of CRISPR advancing the reality of designer babies: “The things that we’re worried about, like genetic diseases such as Muscular Dystrophy and Huntington’s Disease, are resolvable—creating a master race is not. You can’t just snip out some DNA and all of a sudden we’re going to have a master race, it doesn’t work that way. You could have blue eyes, but I don’t think that’s going to destroy society. Its just going to mean someone has wasted a lot of money on having their child born with blue eyes when they could have had whatever colour.

“The assumption is that someone will make a CRISPR baby somewhere in the world. I’m not worried about it, as it won’t change humanity. It won’t change our relationship with ourselves any more than the soft eugenics we do at the moment—in the form of genetic counselling.

“These are ethical issues that we’ve been discussing for twenty to thirty years. The only issue now is that we can do them really easily. So this changes the sharpness of the discussion, but it doesn’t alter the fundamental questions that are being debated, I don’t think.”

Despite the vast media coverage on CRISPR use in humans, there are several other promising applications of the new gene-editing technology that could revolutionise many aspects of scientific research. As a Professor of Zoology, Professor Cobb seemed extremely excited about the prospect of CRISPR use in ecology: “We want to improve our crops. At the moment we have two ways of doing it: selection, and GM (genetically modified) crops—introducing foreign genes from a different organism. And this (GM) has caused a huge row. Now the crop development people are using CRISPR.

“Those crops (CRISPR crops) will not be GM crops, not in the terms of Europe, as they will have no foreign DNA in them. So, although you need to use the Cas9 to put it in, which is from bacteria so obviously foreign, there are ways of removing this. You achieve your change, then you remove the Cas9, and in fact you now have a pure crop with just a couple of changes. So CRISPR crops will not be GM. This is going to be a much more precise way of getting the desired change without any foreign DNA.”

And what exactly does Professor Cobb find most exciting about CRISPR? “Oh I don’t know—anything! I can’t predict. I think it’s going to transform in biology. We will really be able to move away from model organisms, which aren’t really models of anything. There are many of fantastic organisms out there that have great ecology, and amazing behaviours, and we’ll be able to understand that using this system (CRISPR), as we’ll be able to go in and disrupt the genes and see what happens. CRISPR seems to work in anything. So I think it will broaden our understanding of life, and help us work out why it is the way it is.”

Professor Cobb moved on to explain the potential of CRISPR in enhancing xenotransplantation—a process involving the transplant of organs, or live cells, from a non-human animal source, into a human recipient: “If you can’t get a kidney, the best way is to use a pig, as they are very similar to us in the structure of their kidney—although this can give very bad reactions. CRISPR is being used on pigs, and they’re being altered so that, maybe, you can put them in people.”

CRISPR is being used in many areas of research, but the powerful potential, and ease and pace at which scientists can use the technique raises some questions. I asked Professor Cobb what he finds most concerning about CRISPR: “Now the problems come with the applications of CRISPR—the most obvious one being there’s the possibility of curing genetic diseases.

“Firstly, is it safe? For example, the precision of the enzyme finding its target. If something goes wrong in say a fly, its no problem you just start again. However this is different if this is in a human.

“The thing I’m most concerned about, which is the real need for regulation, is gene drives. What this gene drive does, is that it copies itself [the gene] onto the other chromosome, so you have it in both chromosomes. So very, very quickly the gene will swamp the population.

“Using flies it has been calculated that in twelve generations, everyone would have the same characteristics. This is the ‘genetic bomb’ that people are worrying about.”

Professor Cobb seemed much more concerned about the risk of CRISPR in ecology, than in medicine: “Well on the medical side, what’s the worst that could happen? Someone could die. I don’t think that the medical ethics are posing us with anything new. The problem about whether you should or shouldn’t change the human genome or not, has massive consequences on future generations.

“I think the medical issues are primarily about safety. There is an ethical issue of germline modification, however if you could remove disorders such as Huntington’s Disease, I cannot see why it wouldn’t work. As that [the Huntington’s Disease gene] is not a gene useful to us—it is a mistake that causes tragic consequences. And as far as we can see, removing this gene would have no consequences at all, other than that it would save a life. Anything about improvement, however, that is different.”

The vast applications of CRISPR in controlling the genome have brought the technology under intense ethical scrutiny. Questions are now being raised over who exactly should decide how CRISPR can be used, and how it should be regulated: “Now this is the real issue. There is an argument, suggested by many bioethicists, that this can only be decided at an international level.

“I think the reality will prove to be a mixture of local initiatives, in the UK or Europe perhaps, to say this should or shouldn’t happen, or stating procedures for controlling what’s happening, and for checking.”

After discussing the ethical implications of the technology, Professor Cobb informed me of another debate surrounding CRISPR: “There is also an associated war about credit. So who actually did the work? The head of the Broad Institute, Eric Lander, wrote a big article in Cell called ‘The heroes of CRISPR’, and, if you’ve ever read 1984 you’ll know one of the phrases in there, “he who controls the past, controls the future”, and that’s exactly what he did. So he wrote an aversion of history that’s entirely slanted towards his institution.

“So there’s a huge row going on. There’s money and a Nobel Prize involved. However, if the Nobel committee decides there were too many people involved, they won’t award it to anyone.

“Everyone is very concerned about the patents, as that is vast amounts of money. CRISPR application anywhere in the world would then have to pay money.”

In his BBC Radio 4 broadcast, Professor Cobb discussed current research projects using CRISPR, so I enquired as to whether anyone here at The University of Manchester was utilising the technique: “There is a range of all sorts of interesting things. There are people looking at mucus in frogs, somebody else looking at making new mutants in flies to look at insecticide resistance—basic biology and medicine is going to be transformed as we can manipulate genes in a very precise way.

“Andrew Doige is looking at early onset Alzheimer’s. He’s trying to make the right model to try and understand how that works. Other people are using it in synthetic biology. At the Manchester Institute of Biotechnology, they’re getting it to make E.Coli to make new products.

“Sue Kimber is looking at kidney disease, mutating cells to make them like cells with diseases. Making very precise changes to mirror changes seen in diseased people.”

CRISPR is improving the pace and changing the breadth of scientific discovery, here at The University of Manchester, and around the world. If you would like to find out more about CRISPR, Matthew Cobb’s BBC Radio 4 broadcast, Editing Life, is available on BBC iPlayer Radio.

You can follow Professor Cobb on Twitter @MatthewCobb

Tags: Alzheimer's Disease, BBC Radio 4, CRISPR, Designer babies, DNA, ecology, editing, Gene, Genetic Engineering, malaria, Matthew Cobb, technology

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