Scientists Are Trying to Recreate the World’s Rarest Blood Type

The Rh null blood type is extremely rare — occurring in roughly one out of every six million people. Today, scientists are attempting to produce it in the laboratory to help save lives.

Only 50 people are known to have one of the world’s rarest blood types, Rh null. If any of them were to end up in a situation requiring a blood transfusion, their chances of receiving compatible blood would be extremely low. People with Rh null are advised to freeze their own blood for long-term storage.

But despite its rarity, this blood type is highly valued for other reasons as well. In the medical and scientific community, it is sometimes referred to as “golden blood” because of how it can be used. Scientists are also searching for ways to overcome immune complications that currently limit the use of donor blood, and Rh null may help in creating universal blood for transfusions.

Recent studies have shown that Rh null blood is caused by genetic mutations that affect a protein that plays a key role in red blood cells, known as the Rh-associated glycoprotein, or RHAG, the BBC reports.

These mutations appear to shorten or alter the shape of this protein, preventing the expression of other Rh antigens.

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

The team then used Crispr-Cas9 gene-editing technology to remove the genes encoding antigens from five blood group systems, which together account for most cases of transfusion incompatibility. These included ABO and Rh antigens, as well as others known as Kell, Duffy, and GPB.

“We found that if you remove all five, you get an ultra-compatible cell because it lacks the five most problematic blood group systems,” Professor Toy says.

The resulting blood cells would be compatible with all major common blood types, as well as rare ones such as Rh null and the Bombay phenotype, which occurs in one out of four million people — individuals with this type cannot receive blood from groups O, A, B, or AB.

However, the use of gene-editing methods is still considered controversial and is strictly regulated in many countries. This means that this ultra-compatible blood type will not become available for clinical use right away.

Before gaining approval, it will need to undergo extensive clinical trials and testing.

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

His team hopes to use this blood to create cell lines that can be grown in the laboratory to produce red blood cells. This lab-grown blood can be frozen and stored for emergencies when needed by people with rare blood types.

Professor Toy hopes to create a bank of rare blood types in the lab without using gene editing, though this technique may still play a role in the future.

“If we can do this without editing, that would be wonderful, but we see editing as an option,” he says. “Part of our work involves carefully selecting donors to make their antigens as compatible as possible for most people. Then we may need to resort to gene editing to make them compatible for everyone.”

In 2021, immunologist Gregory Denomme and his colleagues at the Versiti Blood Research Institute in Milwaukee, USA, used Crispr-Cas9 gene editing to reproduce individual rare blood types, including Rh null, from human induced pluripotent stem cells (hiPSCs).

These stem cells have properties similar to embryonic stem cells and can, under certain conditions, develop into any cell in the human body.

Other scientists are using a different type of stem cell — ones that are already programmed to develop into blood cells but have not yet determined which specific type. For example, researchers at Laval University in Quebec recently extracted blood stem cells from donors with A+ blood. They then used Crispr-Cas9 to remove the genes encoding the A and Rh antigens, producing immature red blood cells with Rh null and type O blood.

Researchers in Barcelona recently took stem cells from a donor with Rh null and used Crispr-Cas9 to convert their blood type from A to O, making it more universal.

However, despite these impressive achievements, it is important to note that large-scale production of usable lab-grown artificial blood is still far off.

One challenge is producing mature red blood cells from stem cells.

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

“There is an additional challenge: when creating Rh-negative blood or any other blood type lacking certain antigens, the growth and maturation of red blood cells may be impaired,” says Denomme, now Chief Medical Officer at Grifols Diagnostic Solutions, a company specializing in transfusion medicine. “Producing certain blood group genes can lead to membrane instability or loss of the ability to effectively produce red blood cells in culture.”

Currently, Professor Toy is one of the leaders of the world’s first clinical trial testing the safety of transfusing lab-grown red blood cells into healthy volunteers.

The artificial blood used in the trial was not genetically edited, but it still took 10 years of research for scientists to be ready to test it in humans.

“For now, drawing blood from a person’s arm is far more efficient and cost-effective, so we will continue to rely on blood donors for the foreseeable future,” Professor Toy says. “But it would be truly remarkable if we could grow blood in the lab for people with rare blood types, for whom donors are extremely scarce.”

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