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CRISPR – the future of genetic research at Manchester?

Clustered Regularly Interspaced Palindromic Repeats isn’t something that rolls off the tongue, yet it is set to be the biggest scientific breakthrough of the 21st century. Better known as CRISPR, this technique allows scientists to modify and change the genetic makeup of cells, possessing far-reaching potential to treat genetic disease and enhance human health.

CRISPR is quite literally changing the world around you – and Manchester is leading the way.

In fact, the University’s Transgenic Unit is the only core facility in the UK that not only uses CRISPR-Cas9 but also trains others to do so, making The University of Manchester the place to be for gene editing research.

How does CRISPR work?

CRISPR is a re-purposed bacterial immune system. Bacteria are able to destroy invading viruses by cutting up their DNA, and it is this DNA cutting property that scientists at Manchester are using in their research.

CRISPR acts like a tiny pair of scissors, cutting target DNA at a specific point which we can then exploit to make a desired change. This could be the removal of an entire gene from the cell, or very specific, small changes to mimic human genetic diseases, in either cells in a dish or mice.

The ease and speed of application makes CRISPR vastly more user friendly than previous methods, and now researchers can rapidly generate far more accurate experimental models, with obvious improvements to the validity and rate of research.

Dr Antony Adamson is a senior experimental officer at the Transgenic Unit.

"When I first came to the University nine years ago as a postdoctoral researcher, editing genes directly wasn’t really possible or widespread. Now, 99% of the work that I do uses gene editing in the form of CRISPR-Cas9 in some way”, says Antony.

“Almost overnight we went from traditional methods of transgenic work to using CRISPR.

“Working alongside colleagues all over the world, we have managed to iron out some of the problems the early use of CRISPR had and now it is very easy to produce accurate models in a time that would have been unthinkable 10 years ago.”

The explosion in use of CRISPR-Cas9 can be seen with the recent expansion of the Unit, which has now recruited extra staff to deal with increasing service demands.

Using CRISPR to teach the next generation of scientists

The Unit has also teamed up with teaching colleagues to put CRISPR on the syllabus.

“CRISPR has revolutionised genome engineering and must stand as one of the most important technological developments in genetic research of recent times”

A specialist module in Disease Modelling and Genome Engineering can be studied at the University as part of the MSc in Genomic Medicine, or as a standalone courses for continuing professional development.

This sees Antony and lecturer Dr Forbes Manson teach students how to set up a CRISPR experiment and the scientific techniques needed to run it.

“CRISPR has revolutionised genome engineering and must stand as one of the most important technological developments in genetic research of recent times”, says Forbes.

“The technique has huge implications for the study and treatment of human genetic disease and as a result it is vitally important that current and future researchers in the field have an understanding of its many applications and how to use it.”

The module reviews the theory and practical application of CRISPR genome engineering, which includes a practical session on designing CRISPR reagents.

“Students and researchers who take this module will leave with the skills and knowledge to contribute to this fast moving and hugely important field”, Forbes explains.

experiments

Case study: CRISPR in action

The Brough Lab, led by Dr David Brough, recently published a paper which used CRISPR to examine inflammation more closely.

Published in Nature’s Scientific Reports, the team modified the gene that codes for a molecule called Interleukin-1 (IL-1α), which is thought to play a role in the development of many brain diseases such as stroke and Alzheimer’s.

IL-1α is unusual compared to most inflammatory proteins. On the protein, there is a small sequence that directs IL-1α to a part of the cell that most inflammatory proteins do not go – the nucleus. The team wanted to find out why this peculiar property exists and better understand the mechanisms by which IL-1 α interacts in cells.

To do this, they used CRISPR and targeted the DNA code responsible for the transport of IL-1α to the nucleus. In doing this, the team discovered that CRISPR was much less selective than previously thought and can lead to unexpected effects via the non-coding region of the molecule.

Cellular DNA comes in two parts: the coding region and the non-coding region. The coding region is the parts of the DNA code that are active and are used as instructions to build proteins. The non-coding region is 'inactive' DNA; DNA that is not read and so does not go on to produce proteins.

The team gave CRISPR the directions for what they wanted it to target and set it loose on the IL-1α gene. However, CRISPR mutated regions in both the coding and non-coding regions of DNA. The team quickly discovered that instead of producing a modified version of IL-1α that does not transport to the nucleus, IL-1α was no longer being produced at all.

"My heart skipped a beat when I realised we’d lost expression of IL-1α" says Mike Daniels, a PhD student, who played an integral part in the study. "Thankfully we were able to chase it up and, in the end, make a really important discovery".  

"This result seemed like a failure at first", says David. "We were able to use this set-back not only to discover that small changes to non-coding DNA can stop production of proteins but also to give greater insight into the CRISPR technique."

The team have used this experience to send an important message to scientists across the world. CRISPR can lead to unexpected results and precautions must be taken to prevent these.

"We hope that this discovery will improve CRISPR success-rate and help the development of this ground-breaking technique", says David.

In just six years, CRISPR has gone from an interesting and understudied system in bacteria to being the centre of the University’s Transgenic Unit and a key part of a flagship master's programme.

This year, as CRISPR moves from its exciting early stages into human clinical trials, the University is set to play a pivotal role in refining CRISPR and creating the tools needed for real biomedical applications.

99% of transgenic experiments at the University now use CRISPR.

PhD student Mike Daniels has also written a comprehensive blog on the case study.