Because only one in every 6m people has the Rh null blood type, British researchers are now trying to grow it in the laboratory in the hope it could save lives, reports BBC News.
Blood transfusions have transformed modern medicine, but not everyone is able to benefit from this remarkable procedure. People with rare blood types struggle to find donated blood that will match their own.
One of the rarest – the Rh null blood type – is found in just 50 known people in the world, and their chances of getting a transfusion, should they ever need one, are slim.
Those with Rh null are instead encouraged to freeze their own blood for long-term storage.
But, despite its rarity, this blood type is also highly prized for other reasons. Within the medical and research community it is sometimes referred to as “golden blood” due to how it can be used.
It may also help to create universal blood transfusions as scientists search for ways of overcoming the immunity issues that currently restrict how donated blood is used.
The type of blood circulating around our bodies is classified based on the presence or absence of specific markers on the surface of our red blood cells. These markers (antigens), consist of proteins or sugars which stick out from the cell surface and can be detected by the immune system.
“If you get transfused with donor blood containing different antigens from your own blood, you’ll make antibodies to that blood and attack it,” says Ash Toye, Professor of Cell Biology at the University of Bristol. “If you get transfused with that blood again, it can be life threatening.”
The two blood group systems that evoke the largest immune response are ABO and Rhesus (Rh). A person with an A blood group has A antigens on the surface of their red blood cells, while someone with a B blood type has B antigens. The AB blood group has both A and B antigens, with the O group has neither. Each group can be either Rh positive or Rh negative.
People with O negative blood are often described as universal donors, as their blood contains neither A, B, or Rh antigens. However, this is an over-simplification.
First, there are currently 47 known blood groups and 366 different antigens, as of October 2024. That means someone receiving an O negative donation could still have an immune reaction to any of the other antigens present – although some antigens provoke more of an immune response than others.
Second, there are more than 50 Rh antigens. When people talk about being Rh negative they are referring to the Rh(D) antigen, but their red blood cells still contain other Rh proteins. There is also a huge diversity of Rh antigens worldwide, making it challenging to find true donor matches.
People with Rh null blood, however, lack all 50 Rh antigens. While they cannot receive any other blood type, Rh null blood is compatible with all of the many Rh blood types – making O type Rh null blood extremely valuable, as most people can receive it, including individuals with all variants of ABO.
In emergencies where a patient’s blood type is not known, O type Rh null blood could be given with a low risk of allergic reaction. For this reason, scientists worldwide are looking for ways to replicate this “golden blood”.
Origin of Rh null blood
Recent research has revealed that Rh null blood is caused by genetic mutations affecting a protein that plays a crucial role in red blood cells, known as Rh associated glycoprotein, or RHAG. These appear to shorten or alter the shape of this protein, causing it to disrupt the expression of other Rh antigens.
In a 2018 study, Toye and colleagues at the University of Bristol recreated Rh null blood in the lab. They took a cell line – a population of cells grown in a laboratory – of immature red blood cells – and then used the gene editing technique Crispr-Cas9 to delete genes coding for the antigens of the five blood group systems that collectively are responsible for most transfusion incompatibilities.
This included the ABO and Rh antigens, as well as other antigens called Kell, Duffy and GPB.
“We worked out if we knocked out five, that would create an ultra-compatible cell, because it had five of the most problematic blood groups removed,” says Toye.
The resulting blood cells would be compatible for all the major common blood groups but also for those with rare types like Rh null and the Bombay phenotype, which is carried by one in every 4m people. People with this blood group cannot be given O, A, B or AB blood.
Using gene editing techniques, however, remains controversial, and it could be some time before this ultra-compatible type of blood might become clinically available. It would need to go through many rounds of clinical trials and testing before being approved.
Meanwhile, Toye has co-founded Scarlet Therapeutics, which is collecting blood donations from people with rare blood groups including Rh null. The team hope to use that blood to create cell lines that can be lab-grown to produce red blood cells indefinitely. This could then be frozen in storage for emergencies should those with rare blood types need it.
Toye hopes to create banks of rare blood in the laboratory without using gene editing, although the technique could play a role in the future.
“If we can do it without editing, then great, but editing is an option for us,” he says.
“Part of what we’re doing is carefully selecting donors to try to make all of their antigens as compatible as possible for most people. Then probably we’ll have to gene edit to make it compatible for everybody.”
Other researchers are also racing to make Rh null blood in the laboratory.
In 2021, immunologist Gregory Denomme and colleagues at the Versiti Blood Research Institute, in Milwaukee, US, used Crispr-Cas9 gene editing technology to create customised rare blood types, including Rh null from human induced pluripotent stem cells (hiPSC). These stem cells have properties similar to embryonic stem cells and have the potential to become any cell in the human body, given the right conditions.
Other scientists are using another type of stem cells that are already pre-programmed to become blood cells but haven’t determined which kind yet.
For example scientists at Laval University in Quebec, Canada, recently extracted blood stem cells from donors with A positive blood. They then used Crispr-Cas9 technology to delete the genes coding for the A and Rh antigens, producing O Rh null immature red blood cells.
Researchers in Barcelona, Spain, also recently took stem cells from a Rh null blood donor, and used Crispr-Cas9 to convert their blood from type A to type O, making it more universal.
Nevertheless, despite these impressive efforts, creating artificial lab-grown blood on a scale where people could use it is still a long way off.
One difficulty is to get the stem cells to grow into mature red blood cells. In the body, these are produced from stem cells in the bone marrow, which produces complex signals to guide how they develop. This is difficult to replicate in the laboratory.
“There is the added problem that when creating Rh null or any other null blood type, the growth and maturation of the red blood cells can be perturbed,” says Denomme, now a Medical Affairs Director at Grifols Diagnostic Solutions, a healthcare company specialising in transfusion medicine.
“Producing specific blood group genes might result in the cell membrane falling apart, or a loss of producing red blood cells efficiently in cell culture.”
For now, Toye is co-leading the RESTORE trial, the world’s first ever clinical trial testing the safety of giving healthy volunteers red blood cells that have been artificially grown in the laboratory from donor blood stem cells.
The artificial blood in the trial wasn’t gene edited in any way, but it still took 10 years of research to get to the stage where scientists were ready to test it in humans.
“At the moment, taking blood out of somebody”s arm is so much more efficient and cost effective, and so we will need blood donors for the foreseeable future,” says Toye.
“But for people with rare blood types where there are very few other donors, if we can grow them more blood, that would be really exciting.”
BBC article – The magic of the world's rarest blood type (Open access)
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