This article is taken from the monthly journal Sciences et Avenir – La Recherche #907 of September 2022.
Since the beginning of the year, the French Blood Establishment (EFS) has already asked for help twice due to the state of its stocks caused by the Covid-19 pandemic. 50,000 blood bags per week are used for nationwide health activities. Given their short shelf life (ten days for red blood cells), the EFS calculated that 10,000 French people would have to donate their blood daily to meet national needs. A number that is becoming increasingly difficult to guarantee due to our new remote lifestyle. Should we compensate for this deficiency with an artificial substitute?
Several groups around the world are working on in vitro production of red blood cells or platelets. Over the past fifteen years, they have perfected synthetic methods using so-called primary hematopoietic cells (CD34+) or induced pluripotent stem cells (IPS). In 2011, the team of French hematologist Luc Douai, former head of the hematology laboratory at the Hospital Saint-Antoine in Paris, performed the first transfusion of 2 milliliters of cultured red blood cells made from his own cells into a healthy volunteer.
In the United Kingdom, a team from the University of Cambridge is about to reach a new milestone: 15 people have donated blood for red cell culture and heterologous transfusion, i.e. they will receive synthetic red blood cells compatible with their blood type, but not from their own cells. The first results are expected in October.
Credit: Bruno Bourgeois
From lamb’s blood to milk, centuries of failed attempts
In Japan, Megakaryon and researchers at Kyoto University are testing the safety and efficacy of cultured platelets in ten people with thrombocytopenia, a low blood platelet count due to a bone marrow abnormality, leukemia, or another type of cancer requiring heavy therapy. chemotherapy.
“Today the goal is to succeed in synthesizing specific blood components for a specific function: red blood cells for oxygen transport and platelets for their coagulation ability,” explains Pascal Richard, medical director of the French Blood Establishment. The prospect of replacing the blood in his integrity was discarded.”
However, this is not because we have been trying…for centuries! From William Harvey’s demonstration of blood circulation in the early 17th century, some tried unsuccessfully to administer beer, wine, or urine after hemorrhaging or hemorrhage. On June 15, 1667, Louis XIV’s physician Jean-Baptiste Denis performed the first blood transfusion in Paris by injecting a 15-year-old boy with 300 ml of lamb’s blood. The febrile patient recovers sharply. Now we know that a tiny amount of transfused sheep’s blood has nothing to do with it. Injecting him with a larger amount would be fatal due to the lack of sufficient compatibility of human and animal blood.
At the end of the 19th century, milk transfusion experienced a brief hour of glory when North America faced cholera epidemics. Some prominent experts of the time claim that injectable cow’s or goat’s milk allows white blood cells to fight infection. The observed serious side effects will quickly put an end to this non-curative “milky way”. Moreover, with the discovery of blood groups in 1900 by the Austrian Karl Landsteiner, there are fewer and fewer unsuccessful cases of blood transfusion to a person.
World War II and its countless wounded soldiers underline the interest in a substitute for human blood. However, despite military investment, frustrations are piling up. Blood is especially delicate to study – barely taken, it begins to age and deteriorate – and is very variable in the same person throughout the day, depending on his diet, physical activity, medication … In short, a real mystery. reproduce.
The researchers then focused on one of the most important functions of the blood, oxygen transport, and developed artificial hemoglobins and perfluorocarbons, two options that have since been abandoned due to significant side effects. For all the teams working on these blood substitutes, it is time to scale up and start the first human clinical trials. “There are 2,000 billion red blood cells in a blood bag. If we want synthetic versions of them to be of interest in clinical practice, we need to be able to build a real production plant,” explains Luc Douai, now head of Erypharm, a start-up created as a result of his scientific work on the culture of red blood cells. This requires infrastructure of a completely different scale and huge investments: thus, Erypharm needs to raise 25 million euros, and is facing investor reluctance.
Credit: Bruno Bourgeois
Even an expensive alternative to blood donation is needed
In the context of free blood donation, the additional costs of in vitro blood cell culture are indeed not negligible. “We will never be competitive on a strictly accounting level,” immediately admits Luc Douai, who estimates the cost of producing an erythrocyte (package of erythrocytes) at about 1,500 euros when the French Blood Establishment prepares, stores and redistributes red blood cells from donors at a price of 200 to 500 euro per pill, but from hematopoietic stem cells from a blood sample we could obtain the equivalent of 100 bags of blood in culture, whereas today each donation allows only one bag to be made.”
The production of blood cells on an industrial scale, less dependent on the availability of donors, is not currently intended to replace blood transfusion. Even in Japan, where fear of blood shortages is now a strategic public health issue, as the aging population makes potential donors increasingly scarce and the number of potential recipients increases.
On the other hand, cultured cells would respond to precise therapeutic impasses such as rare blood types or a refractory condition: due to transfusion, the body of some people begins to destroy the platelets they have injected, and it becomes difficult to find immunocompatible platelets. “It would be useful to know how to produce immunologically neutral platelets by suppressing HLA type 1 markers using CRISPR-Cas 9 type technology (molecular scissors capable of targeting elements of interest, editor’s note),” explains Katherine Strassel, Director of Research at EFS Grand Est in Strasbourg.
Not to mention, blood transfusion specialists can no longer fail to foresee the great infectious risk. If Sras-CoV-2 were spread by blood rather than aerosols, the entire planet would have to stop transfusions. Which will revive interest in even more expensive alternatives to blood donation.
In addition to their vital role in blood clotting to stop bleeding, platelets are also important mediators of inflammation, and in the case of cancer, they are in close interaction with metastases. Therefore, the American company Platelet Bio seeks to develop its potential as drug carriers and is working on the synthesis of cargo platelets. These cells, obtained in vitro, can express molecules of, for example, anti-inflammatory or antitumor therapeutic interest. Thus, transfused to the patient, they could “deliver their molecules” directly through the bloodstream to the appropriate organ.