Dr Tim Satchwell working with CRISPR erythroid lines

New gene tech being used in Bristol to try to solve transfusion problems for rare blood types

From his lab based in the University of Bristol, Dr Ashley Toye hopes to use CRISPR technology to create ‘universal’ red blood cells
15th January 2018

The NHS needs over 6,000 blood donations every day to match the treatment needs of patients in England, but there is a shortage of donors, especially those of ethnic minorities and those with rare blood types. Even after blood has been donated, there are sometimes issues that arise. The transfusion can be unsuccessful or problematic, for example, an unforeseen mismatch between donor and recipient. So how can we ensure that there is suitable blood available for all, exactly when they need it?

NHSBT Principle Investigator and BrisSynBio member Ash Toye

NHSBT Principle Investigator and BrisSynBio member Ashley (Ash) Toye (pictured right) is hoping to find a solution using a popular gene-editing tool to make a more compatible form of blood cell.

“If we want to change one blood group to another we need to change the proteins on the outside of the cell”

 

Blood type is determined by the proteins expressed on the red blood cell membrane. People with rare blood types have specific changes to the membrane proteins or sugars on the outside of the cell that make it harder to find a suitable donor. There are also patients who have had so many blood transfusions that their body sometimes generates antibodies that attack the incoming red blood cells due to detecting very small blood type differences.

Ash conducts his research in the University of Bristol, within the Bristol BioDesign Institute, a research centre that works to provide solutions to the challenges we face in the 21st century. He is a member of BrisSynBio, part of the institute which focuses on using biological engineering and design to tackle global problems.

The gene-editing tool box

Ash uses a technique known as CRISPR (or Clustered Regularly Interspaced Short Palindromic Repeats). It is a method that was originally used in nature by bacteria to attack invading viruses. By using RNA guides – single-stranded RNA that matches a section of the virus’s DNA – the bacteria is able to detect the virus. The bacteria then uses a particular type of enzyme that can cut DNA called Cas9. Once a section of the virus’s DNA has been cut it becomes useless and thus the bacteria has stopped itself from being invaded. You can see this in more detail in the video below:

Scientists studying this bacterial technique realised that it could be applied to other types of DNA, including human genes. “There are two possible outcomes when using CRISPR in the lab,” Ash explains, “after the enzyme has cut the desired DNA, the cell will either repair the cut DNA and make a mistake which then leads to the protein not being expressed – called a knockout – or, if scientists have provided the cell with a new copy of DNA, this would be used to repair the gene and so can be used to make alterations or new functions.”

This latter outcome is the hardest to do and is usually less efficient. A knockout is the mostly likely scenario and this is what Ash and his team are hoping to achieve with their work in red blood cells.

“CRISPR might be able to add extra functionality to blood cells… it’s an amazingly powerful technique”

 

“If we want to change one blood group to another we need to change the proteins on the outside of the cell, as this is what determines the cell’s blood type. If we can stop a gene from being expressed by ‘knocking it out’ that will mean none of the problematic membrane protein or sugar residue is there, so the patient’s body would not reject the transfusion.”

Ash recognises how incredible this gene technology is, explaining that “the CRISPR field is moving extremely fast, with new versions of the enzymes coming out all the time that do even more amazing things. From enabling the DNA to light up or glow to tell you if your edit has been successful, to engineering small changes that repair a person’s DNA to make the difference between them having a disease or not.”

The unlimited possibilities of cells

The CRISPR technique has changed the way scientists experiment with gene editing. “You can keep adding new changes to a cell’s DNA and then see what the effects are on the final red blood cell that is made.”

“We hope that one day we can make cells that can be used by pretty much everyone – a ‘universal’ red blood cell”

 

Another exciting thing CRISPR might be able to do is add extra functionality to blood cells. “Blood is beautifully designed by nature to travel the body for 120 days, so we are re-engineering them to try to make them last even longer, carry medicines or have enzymes which clear toxins. It’s an amazingly powerful technique.”

Collaboration of all kinds

Ash’s work is highly collaborative. The team who grow blood without CRISPR changes are running a clinical trial involving people from Bristol University, NHS Blood and Transplant, Cambridge University, Warwick and Bath. Ash has also worked with computer modellers, other scientists and clinicians at Bristol, in Europe, and around the world on lots of different projects.

BrisSynBio has an active programme of events as part of Bristol University’s public engagement, and has worked with artists who are inspired by the lab. Katy Connor is the latest artist to collaborate with Ash and his team, and she exhibited her work entitled ‘Reimag(in)ing life at a cellular scale‘ earlier this year.

To follow Ash’s work with red blood cells take a look at the BrisSynBio website.

If you haven’t yet signed up to become a blood donor, you can do so now by visiting the NHS Blood and Transplant website.

Image credit: Ash Toye