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Secrets of our first seven days

What exactly is gene editing? Why is it important in medical research? Last year, developmental biologist Dr Kathy Niakan got the first ever licence to carry out gene editing in very early human embryos using a new technique called CRISPR-Cas9. She explains all.

Tell us about your research and what you’re trying to find out?

Our lab, at The Francis Crick Institute in London, is really interested in understanding how human embryos develop during the first seven days of development.

We all start off as a fertilised egg, which then divides to form two cells, then four cells, eight cells and so on until it forms a structure called a blastocyst at around day six. At some point around the eight cell stage we think that some of these cells are being set aside. These few cells divide to produce about 20 clumps of cells which go on to become the embryo, while the vast majority of the other cells will be set aside to form the placenta and yolk sac.

What fascinates us is, how does this happen? From this group of cells which all had an equal chance of becoming either an embryo or placenta and yolk sac, how are these cells set aside? They’ve all inherited the same DNA blueprint, it’s just that they are reading that DNA differently. So we want to know what is the key gene that ‘flips the switch’ and decides their fate?

Interesting stuff – but how might that ultimately help people?

Well, first of all, it has importance for stem cells. If we could better understand how these 20 clumps of cells are set aside to form the embryo that could allow us to significantly improve upon methods for maintaining these cells indefinitely in a petri dish – as a type of stem cell called human embryonic stem cells (hESCs). Such cells would be truly ‘pluripotent’ ie could go on to form any cell in the body. That has a huge array of potential applications for research and for health, for example growing nerve cells to study Parkinson’s disease or making insulin-secreting cells to treat diabetes.

The other reason why it’s so important is for improving the success rate for in vitro fertilisation (IVF). Currently only about 40% of IVF embryos make it to the blastocyst stage. Typically only half of those blastocysts will implant into the uterus, and not all of those will result in a live birth – so for a woman going through a cycle of treatment there’s less than a 20% chance of a successful pregnancy.

If we can understand more about the molecular processes going on in the blastocyst we might be able to find biomarkers to pick out the embryos with the highest probability of survival and thereby boost IVF success rates.

So what is CRISPR-Cas9 gene editing and how are you using it in your research?

It’s often been often described as a pair of ‘molecular scissors’ to cut strands of DNA in a very precise way. The technique consists of making a ‘guide RNA’, a molecule that’s complementary to a particular section of DNA (for example a gene), that we want to target. The guide RNA finds the chosen section of DNA and directs the Cas9 enzyme to cut the strand of DNA. The DNA repair mechanisms that exist in all of our cells can be error prone, and, while trying to repair the cut to the DNA, it inactivates (or ‘knocks out’) the gene we’re interested in.

In our research we want to use CRISPR-Cas9 to ‘knock out’ a gene called Oct4, which we suspect is important in allocating the cells that go on to become the embryo. If we are able to remove the Oct4 gene at the one-cell stage and then allow that embryo to develop up until day seven, we’ll be able to test whether the blastocyst will still develop without Oct4. If it does, we can find out whether those 20 cells are normal or affected negatively in some way.

Listen to the audio clip above to hear Kathy’s answers to quickfire questions about her inspirations and philosophy.

Why did you pick Oct4?

Lots of previous research has shown that Oct4 works to keep human embryonic stem cells pluripotent. It’s the most likely gene to have a very overt, obvious effect on the embryo so it seemed like a good candidate to test whether using CRISPR-Cas9 is effective or not. Basically we wanted to pick a gene where it would be very obvious to us that our methods were working.

But haven’t scientists already been able to alter DNA for a long time? What’s special about CRISPR-Cas9?

Its effect can be seen really quickly and the probability of actually being able to ‘knock out’ the function of a given gene is much higher. Other methods for gene editing exist, for example something called homologous recombination. But those methods are just orders of magnitude less efficient. With CRISPR-Cas9 we would need to use far fewer embryos to be confident that we’d actually affected Oct4 function, and I think it’s really important that we don’t waste human embryos using inefficient methods.

It’s just an amazing system. It’s transforming pretty much every field in basic biology.

Why do you need to use human embryos? Couldn’t you have used animal embryos instead?

We should never underestimate the difference between early human embryo development and that of other organisms. Research data show that there are fundamental differences in the timing of gene expression between human and animal embryos, for example.

It would have been so easy for us if the genes and when they are expressed during early development was the same in humans and in established animal models like mice, but that’s not the case. The only way to discover the true picture of what’s going on is to study human embryos.

It’s been a year since you were granted the licence. What have you done so far?

Well, we can’t justify using any human embryos until we are absolutely sure about the methodologies. For example we weren’t clear on how to design the right guide RNA, so we’ve spent the better half of a year optimising that, methodically testing every single possible guide RNA in human embryonic stem cells. We were also uncertain about how to inject the guide RNA into a one-cell embryo so we’ve been working with lots of very generous people across the world who have pioneered this technique in other contexts, who shared with us their pre-published data.

We just want to start from scratch and make no assumptions. So that’s all done before we even go near a human embryo. From the start we’ve agreed that if any of these pre-embryo studies at all raised a red flag, then we won’t proceed. Because it’s not justified.

Is there a risk that use of CRISPR/Cas9 in human embryos could open the door to the creation of so-called ‘designer babies’ where people get to, for example, pick the eye and hair colour of a child?

No. Here in the UK there is so much oversight from the regulators of what scientists who’ve been granted licences are doing. The Human Embryology and Fertilisation Authority regularly come to our lab to inspect our work. And there is a very clear boundary is between what is legally permitted and what is not. It’s not possible to cross that line. It would be a criminal offence. The only way that gene editing could move in any other direction is if society agrees to that, and if the laws were changed.

Further reading: The Nuffield Council on Bioethics published an ethical review of genome editing in September 2016.

Also published on Medium.

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