“Golden blood”: Why are scientists trying to grow the world’s rarest blood in the laboratory?

“If you receive a blood transfusion from a donor that contains different antigens to your own blood, your body will generate antibodies against that blood and attack it,” explains Ash Toye, professor of cell biology at the University of Bristol.

“If I had another transfusion of this blood, it could be fatal.”

The two blood group systems that cause the greatest immune response are ABO and Rh. A person with blood type A has A antigens on the surface of red blood cells, while a person with blood type B has B antigens.

Type AB blood contains both A and B antigens, while type O blood contains neither. Each Rh group can be Rh positive or Rh negative.

People with type O negative blood are often described as universal donors, since their blood does not contain A, B or Rh antigens. However, this is an oversimplification.

First of all, as of October 2024, there were 47 blood types and 366 different antigens known. This means that a person who receives an O-negative blood donation may still have an immune reaction to any of the other antigens present, even though some antigens elicit a greater immune response than others.

Second, there are more than 50 Rh antigens. When we talk about being Rh negative, we are referring to the Rh (D) antigen, but the red blood cells still contain other Rh proteins.

Furthermore, there is enormous diversity in Rh factor antigens around the world, making it difficult to find compatible donors, especially for people from ethnic minorities in a given country.

People with Rh-null blood lack all 50 Rh antigens. Although they cannot have any other blood type, Rh-null blood is compatible with all Rh blood types.

This makes O Rh free blood very valuable as it is accessible to most people, including those with all types of ABO system.

In emergency situations where the patient’s blood type is unknown, Rh-null O blood can be given with a low risk of allergy. For this reason, scientists around the world are looking for ways to clone this “golden blood.”

“Rh antigens trigger a massive immune response, so if you don’t have these antigens, there won’t be anything to respond to in terms of Rh,” says Professor Toy.

“If your blood type is O and Rh is null, compatibility is practically universal. But there are still other blood types to consider.”

Recent research has revealed that Rh-negative blood is due to genetic mutations affecting an important protein in red blood cells, known as Rh-associated glycoprotein (RHAG).

These mutations appear to shorten or change the shape of this protein, causing it to interfere with the expression of other Rh antigens.

In a 2018 study, Professor Toye and colleagues at the University of Bristol recreated Rh-null blood in the laboratory. To do this, they used a cell line — a group of cells grown in a laboratory — made up of immature red blood cells.

The team then used CRISPR-Cas9 gene editing technology to knock out genes that encode antigens for the five blood group systems that together are responsible for the majority of transfusion incompatibilities.

This included ABO and Rh antigens, as well as others called Kell, Duffy, and GPB.

“We found that if we deleted five genes, it would create a supercompatible cell, because it would lack five of the most problematic blood types,” Professor Toy explains.

The resulting blood cells will be compatible with all the major common blood types, as well as those with rarer types such as Rh null and the Bombay phenotype, which one in four million people have.

People with this blood type cannot receive blood transfusions from groups O, A, B, or AB.

However, the use of gene editing techniques remains controversial and strictly controlled in many parts of the world, meaning it may be some time before this highly compatible blood type becomes clinically available.

It will have to undergo several rounds of clinical trials and tests before being approved.

Meanwhile, Professor Toy co-founded Scarlet Therapeutics, which collects blood donations from people with rare blood types, including Rh-null.

The team hopes to use this blood to create cell lines that can be grown in the laboratory to produce red blood cells indefinitely. This laboratory-grown blood can be frozen and stored for emergency situations, in case people with rare blood types need it.

Professor Toy hopes to create blood banks for rare species in the laboratory without resorting to gene editing, although this technology may be useful in the future.

“If we can do it without editing genes, that’s even better, but editing is a choice,” he says.

“Part of our job is to carefully select donors to try to make their antigens as compatible as possible with most people. We will probably then have to modify the genes so that they are compatible with everyone.”

In 2021, immunologist Gregory Denomme and colleagues at the Versiti Blood Research Institute in Milwaukee, US, used CRISPR-Cas9 gene editing technology to create personalized rare blood types, including Rh-null, from human pluripotent stem cells (hiPSCs).

These stem cells have properties similar to those of embryonic stem cells and have the potential to become any cell in the human body, under the right conditions.

Other scientists are using another type of stem cell that is pre-programmed to become blood cells, although they have not yet determined what type. For example, scientists at Laval University in Quebec, Canada, recently extracted blood stem cells from donors with seropositive blood.

They then used CRISPR-Cas9 to knock out the genes that encode the A and Rh antigens, resulting in the production of Rh-null O immature red blood cells.

Researchers in Barcelona, ​​Spain, also recently obtained stem cells from an Rh-null blood donor and used CRISPR-Cas9 technology to convert their blood from type A to type O, making it more universal.

However, despite these impressive efforts, it is important to note that the production of laboratory-grown synthetic blood on a scale that allows for human use is still far from reality.

One difficulty is getting stem cells to develop into mature red blood cells.

In the body, red blood cells are produced from stem cells in the bone marrow, which generate complex signals that direct their development. This process is difficult to replicate in the laboratory.

“An additional problem is that by creating Rh-null blood or other null blood type, the growth and maturation of red blood cells can be altered,” says Denomy, who is currently director of medical affairs at Grifols Diagnostic Solutions, a healthcare company specializing in transfusion medicine.

“Production of blood type-specific genes can lead to rupture of the cell membrane or decreased efficiency of red blood cell production in cell cultures.”

Currently, Professor Toy is co-leading the RESTORE trial, the world’s first clinical trial to evaluate the safety of giving healthy volunteers red blood cells artificially grown in the laboratory from donated blood stem cells.

The artificial blood used in the experiment was not genetically modified, but it still needs 10 years of research to reach the stage where scientists are ready to test it on humans.

“Drawing blood from the arm is now more efficient and less expensive, so we will still need blood donors for the foreseeable future,” Professor Toy says.

“But for people with rare blood types, for whom there are very few donors, if we can culture more blood, that would be really promising,” he adds.