The world's first "artificial blood" clinical trial, derived from a 2017 Nature sub-journal paper, may revolutionize the treatment of blood diseases

Blood is the source of life, an indispensable transport carrier for the human body, and can regulate the physiological activities
of various tissues and organs.
When the human body loses too much blood, the tissues and organs are in a state of ischemia and hypoxia, the internal environment of the body is disordered, and normal physiological functions cannot be maintained, and the blood loss will be life-threatening
.

For patients with large blood loss, blood transfusion is currently the most commonly used and effective clinical measure, and these blood mainly come from unpaid blood
donations.
However, over-reliance on unpaid blood donations can easily lead to a "blood shortage", that is, the blood supply of blood banks is seriously insufficient, especially during the winter and summer holidays
when students are on vacation.
In addition, for rare blood type blood loss people, it is difficult to find matching blood
from blood banks.

In order to solve these "blood shortage" problems, recently, the British NHS Blood and Transplant Center, the University of Bristol, the University of Cambridge and other institutions cooperated to carry out the world's first clinical trial
of artificial red blood cells.
These red blood cells are grown entirely in a laboratory
.
The research team isolated 500,000 stem cells from about 470ml of blood donated by healthy people, cultured 50 billion red blood cells on this basis, and finally screened about 15 billion red blood cells
that grew into the human body.

The clinical trial builds on a paper published in Nature Communications in 2017 ^[1].

The study cultured immortalized human adult red blood cell lines (BEL-A) from adult stem cells that can be continuously proliferated, and these immortalized cell lines can be cultured in the laboratory and efficiently differentiated into mature, functional red blood cells
.
Moreover, there were no functional and molecular differences between mature red blood cells differentiated from these immortalized cell lines and cultured red blood cells in vitro, and importantly, no abnormal protein expression
.

This study demonstrates the feasibility of
manufacturing red blood cells from in vitro culture for clinical use.

On November 7, 2022, the British National Health Service (NHS) website released a statement saying that two volunteers had received "artificial red blood cells" transfusions in amounts between
5 and 10ml.
These artificial red blood cells are labeled and can still be tracked
by researchers after they are transfused into the body.
Encouragingly, the two volunteers are currently experiencing no side effects
.

The research team said that at least 8 other volunteers will participate in the trial
later.
All volunteers will receive two transfusions of small red blood cells at least 4 months apart: one artificial red blood cell and one ordinary red blood cell
.

Growing "artificial red blood cells" in the laboratory

If this clinical trial proves to be safe and effective, these "artificial red blood cells" will be useful in the treatment of blood diseases such as sickle cell disease, hematopoietic disorders and rare blood group blood loss
.
In fact, it is currently difficult to find enough matching blood donations for people with these blood
disorders.

For the clinical trial, John James OBE, CEO of the Sickle Cell Society, said the study holds real hope for patients with sickle cells that are difficult to transfuse, and who develop antibodies
to most donor blood types.

In addition, artificial red blood cells are grown directly from stem cells and are "freshly baked", compared to "new" and "old"
red blood cells obtained from blood donors.
This means that artificial red blood cell transfusions will last longer, and patients will need fewer
transfusions in the same amount of time.
This will reduce iron overload due to frequent blood transfusions, which can lead to serious complications
.

At this stage, artificial red blood cells still face many challenges
in clinical application.
First of all, the production of artificial red blood cells is small, so for a long time to come, the main source of blood banks will be blood donation; Secondly, artificial red blood cells are expensive, much higher than ordinary blood transfusions, and their main goal is to provide artificial blood for some patients with special blood
needs.

All told, this world-leading clinical trial lays the groundwork for the creation of artificial red blood cells that can be safely used for transfusions in patients with blood disorders such as sickle cell disease
.
While the vast majority of blood needs still rely on donations, there is no doubt that this work brings new hope
to patients who are difficult to transfuse.

It is worth mentioning that the above research team published a research paper in the journal EMBO Molecular Medicine in April 2018 entitled: Enhancement of red blood cell transfusion compatibility using CRISPR-mediated erythroblast gene editing [2].

The study went a step further, using the CRISPR-Cas9 gene to edit the previously developed immortalized human adult red blood cell line (BEL-A) to enhance its transfusion compatibility
.
It brings new solutions
to the alloimmunization of patients with long-term blood transfusion and the difficulty of matching blood types during "panda blood" transfusion.

The research team used CRISPR-Cas9 gene editing technology to knock out five genes associated with blood group in the immortalized human adult red blood cell line (BEL-A) - FUT1, ACKR1, KEL, GYPB, RHAG, which encode the most common transfusion incompatible antigens
.

After knocking out these 5 genes, these mature red blood cells derived from the immortalized human adult red blood cell line (BEL-A) will be able to give blood transfusions to people with multiple blood types without fear of blood clotting
.

In June 2019, researchers at the University of British Columbia in Canada published a research paper
in Nature Microbiology entitled: An enzymatic pathway in the human gut microbiome that converts A to universal O type blood.

The study found that two enzymes produced by microbes present in the human gut can successfully convert type A blood into universal type O blood
with the addition of extremely low concentrations.
This discovery is expected to change the current situation
of insufficient blood supply.

The red blood cell antigen that determines blood type is a glycolipid molecule, and the microbiota of the human intestinal species can break down various glycoproteins through enzymatic reactions, and the sugars of these glycoprotein species are similar
to red blood cell antigens.
So the team decided to look for better enzymes
in human gut bacteria that can remove red blood cell antigen A.
They collected human stool samples and isolated DNA, which theoretically included genes
encoding bacterial enzymes that digest glycoproteins.
These DNA are then shredded and different DNA fragments transfected into E.
coli, monitoring for any E.
coli that subsequently produces a protein
with the ability to remove antigen A.

They eventually discovered an intestinal bacterium called Flavonifractor plautii, which produces two enzymes that successfully remove red blood cell antigen A from the blood, allowing type A blood to be converted into type O blood
.