Why do humans have different blood types?
Where do different blood types come from, and what do they do? Why do 40% of Caucasians have type A blood, while only 27% of Asians do? There are thousands such questions one might ask. Well, here are some historical accounts that may shed light on some of these questions.
In 1900 the Austrian physician Karl Landsteiner was the first ever to discovered blood types, winning him the Nobel Prize in Physiology or Medicine for his research in 1930. Since then scientists have developed far more evasive tools for probing the biology of blood types and in the process found some intriguing clues about them – through tracing their deep ancestry, for example, and detecting influences of blood types on human health. Despite all this, blood types have retained their enigma, baffling scientists who have yet to come up with a good explanation for their very existence.
“Almost a hundred years after the Nobel Prize was awarded for this discovery, we still don’t know exactly what they’re for.” Professes Ajit Varki; a noted biologist at the University of California, San Diego.
In the present day, because doctors are aware of blood types, they are able to save countless lives by transfusing blood into patients. But for most of history, the notion of putting blood from one person into another was a dangerous and wishful dream.
Renaissance doctors explored the avenue of what might happen if they put blood into the veins of their patients. Some held the view that it could be a treatment for all manner of ailments, even insanity. Finally, in the 1600s, a few doctors tested out the idea, with disastrous results. A French doctor injected calf’s blood into a madman, who promptly started to sweat and vomit and produce urine the color of chimney soot. After another transfusion the man died.
Such calamities gave transfusions a bad reputation for 150 years. Even in the 19th Century only a few doctors dared try out the procedure. One of them was a British physician named James Blundell. Like other physicians of his day he watched many of his female patients die from bleeding during childbirth. After the death of one patient in 1817, he found he couldn't resign himself to the way things were.
“I could not forbear considering that the patient might very probably have been saved by transfusion,” he later wrote.
Blundell became convinced that the earlier disasters with blood transfusions had come about thanks to one fundamental error: transfusing “the blood of the brute”, as he put it. Doctors shouldn't transfer blood between species, he concluded, because “the different kinds of blood differ very importantly from each other”.
Human patients should only get human blood, Blundell decided. But no one had ever tried to perform such a transfusion. Blundell set about doing so by designing a system of funnels and syringes and tubes that could channel blood from a donor to an ailing patient. After testing the apparatus out on dogs, Blundell was summoned to the bed of a man who was bleeding to death. “Transfusion alone could give him a chance of life,” he wrote.
Several donors provided Blundell with 14oz (0.4kg) of blood, which he injected into the man’s arm. After the procedure the patient told Blundell that he felt better – “less fainty” – but two days later he still passed away.
Still, the experience convinced relentless Blundell that blood transfusion would be a huge benefit to mankind, and he continued to pour blood into desperate patients in the following years. All told, he performed 10 blood transfusions. Only four patients survived.
While some other doctors experimented with blood transfusion as well, their success rates were also dismal. Various approaches were tried, including attempts in the 1870s to use milk in transfusions (which were, unsurprisingly, fruitless and dangerous).
Blundell was correct in believing that humans should only get human blood. But he didn’t know another crucial fact about blood: those humans should only get blood from certain other humans. It’s likely that Blundell’s ignorance of this simple fact led to the death of some of his patients. What makes those deaths all the more tragic is that the discovery of blood types, a few decades later, was the result of a fairly simple procedure.
The first clues as to why the transfusions of the early 19th Century had failed were clumps of blood. When scientists in the late 1800s mixed blood from different people in test tubes, they noticed that sometimes the red blood cells stuck together. But because the blood generally came from sick patients, scientists dismissed the clumping as some sort of pathology not worth investigating. Nobody bothered to see if the blood of healthy people clumped, until Karl Landsteiner wondered what would happen. Immediately, he could see that mixtures of healthy blood sometimes clumped too.
Landsteiner set out to map the clumping pattern, collecting blood from members of his lab, including himself. He separated each sample into red blood cells and plasma, and then he combined plasma from one person with cells from another.
Landsteiner found that the clumping occurred only if he mixed certain people’s blood together. By working through all the combinations, he sorted his subjects into three groups. He gave them the entirely arbitrary names of A, B and C. (Later on C was renamed O, and a few years later other researchers discovered the AB group. By the middle of the 20th Century the American researcher Philip Levine had discovered another way to categorize blood, based on whether it had the Rhesus (Rh) blood factor. A plus or minus sign at the end of Landsteiner’s letters indicates whether a person has the factor or not.)
When Landsteiner mixed the blood from different people together, he discovered it followed certain rules. If he mixed the plasma from group A with red blood cells from someone else in group A, the plasma and cells remained a liquid. The same rule applied to the plasma and red blood cells from group B. But if Landsteiner mixed plasma from group A with red blood cells from B, the cells clumped (and vice versa).
The blood from people in group O was different. When Landsteiner mixed either A or B red blood cells with O plasma, the cells clumped. But he could add A or B plasma to O red blood cells without any clumping. It’s this clumping that makes blood transfusions so potentially dangerous. If a doctor accidentally injected type B blood into arm of someone with type A blood, his body would become loaded with tiny clots. They would disrupt his circulation and cause him to start bleeding massively, struggle for breath and potentially die. But if he received either type A or type O blood, he would be fine.
Landsteiner didn’t know what precisely distinguished one blood type from another. Later generations of scientists discovered that the red blood cells in each type are decorated with different molecules on their surface. With A blood, for example, the cells build these molecules in two layers. The first layer is called an H antigen. The second layer is called the A antigen.
People with type B blood, on the other hand, build the second layer in a different shape. And people with type O only build the H antigen and go no further. Different blood types arise as a result of different molecules on the surface of red blood cells. Each person’s immune system becomes familiar with his or her own blood type. If people receive a transfusion of the wrong type of blood, however, their immune system responds with a furious attack, as if the blood were an invader. The exception to this rule is type O blood. It only has H antigens, which are present in the other blood types too. To a person with type A or type B, it seems familiar. That familiarity makes people with type O blood universal donors and their blood especially valuable to blood centers.
Landsteiner reported his experiment in a short, terse paper in 1900. “It might be mentioned that the reported observations may assist in the explanation of various consequences of therapeutic blood transfusions,” he concluded with exquisite understatement. Landsteiner’s discovery opened the way to safe, large-scale blood transfusions, and even today blood banks use his basic method of clumping blood cells as a quick, reliable test for blood types.
But as Landsteiner answered an old question, he raised new ones. What, if anything, were blood types for? Why should red blood cells bother with building their molecular layers? And why do people have different layers? Firm scientific answers to these questions have been hard to come by.
After Landsteiner’s discovery of human blood types in 1900, other scientists wondered if the blood of other animals came in different types too. It turned out that some primate species had blood that mixed nicely with certain human blood types. But for a long time it was hard to know what to make of the findings. The fact that a monkey’s blood doesn't clump with type A blood doesn't necessarily mean that the monkey inherited the same type A gene that we carry from a common ancestor we share. Type A blood might have evolved more than once.
The uncertainty slowly began to dissolve, starting in the 1990s with scientists deciphering the molecular biology of blood types. They found that a single gene, called ABO, is responsible for building the second layer. The A version of the gene differs by a few key mutations from B. People with type O blood have mutations in the ABO gene that prevent them from making the enzyme that builds either the A or B antigen.
Scientists could then begin comparing the ABO gene from humans to other species. Laure Segurel and her colleagues at the National Center for Scientific Research in Paris have led the most ambitious survey of ABO genes in primates to date. And they've found that our blood types are profoundly old. Gibbons and humans both have variants for both A and B blood types, and those variants come from a common ancestor that lived 20 million years ago.
Our blood types might be even older, but it’s hard to know how old. Scientists have yet to analyse the genes of all primates, so they can’t see how widespread our own versions are among other species. But the evidence that scientists have gathered so far already reveals a turbulent history to blood types. In some lineages mutations have shut down one blood type or another. Chimpanzees, our closest living relatives, have only type A and type O blood. Gorillas, on the other hand, have only B. In some cases mutations have altered the ABO gene, turning type A blood into type B. And even in humans, scientists are finding, mutations have repeatedly arisen that prevent the ABO protein from building a second layer. These mutations have turned blood types from A or B to O. “There are hundreds of ways of being type O,” says Westhoff.
The most striking demonstration of our ignorance about the benefit of blood types came to light in Bombay in 1952. Doctors discovered that a handful of patients had no ABO blood type at all – not A, not B, not AB, not O. If A and B are two layers, and O is a one layer, then these Bombay patients had no layers.
Since its discovery this condition – called the Bombay phenotype – has turned up in other people, although it remains exceedingly rare. And as far as scientists can tell, there’s no harm that comes from it. The only known medical risk it presents comes when it’s time for a blood transfusion. Those with the Bombay phenotype can only accept blood from other people with the same condition. Even blood type O, supposedly the universal blood type, can kill them.
The Bombay phenotype proves that there’s no immediate life-or-death advantage to having ABO blood types. Some scientists think that the explanation for blood types may lie in their variation. That’s because different blood types may protect us from different diseases.
Doctors first began to notice a link between blood types and different diseases in the middle of the 20th Century, and the list has continued to grow. For instance, type A Blood, puts them at higher risk of several types of cancer, such as some forms of pancreatic cancer and leukemia. They are also more prone to smallpox infections, heart disease and severe malaria. On the other hand, people with other blood types have to face increased risks of other disorders. People with type O, for example, are more likely to get ulcers and ruptured Achilles tendons.
These links between blood types and diseases have a mysterious arbitrariness about them, and scientists have only begun to work out the reasons behind some of them. For example, Kevin Kain of the University of Toronto and his colleagues have been investigating why people with type O are better protected against severe malaria than people with other blood types. His studies indicate that immune cells have an easier job of recognizing infected blood cells if they’re type O.
More puzzling are the links between blood types and diseases that have nothing to do with the blood. Take norovirus. This nasty pathogen is the bane of cruise ships, as it can rage through hundreds of passengers, causing violent vomiting and diarrhea. It does so by invading cells lining the intestines, leaving blood cells untouched. Nevertheless, people’s blood type influences the risk that they will be infected by a particular strain of norovirus.
The solution to this particular mystery can be found in the fact that blood cells are not the only cells to produce blood type antigens. They are also produced by cells in blood vessel walls, the airway, skin and hair. Many people even secrete blood type antigens in their saliva. Noroviruses make us sick by grabbing onto the blood type antigens produced by cells in the gut.
Yet a norovirus can only grab firmly onto a cell if its proteins fit snugly onto the cell’s blood type antigen. So it’s possible that each strain of norovirus has proteins that are adapted to attach tightly to certain blood type antigens, but not others. That would explain why our blood type can influence which norovirus strains can make us sick.
It may also be a clue as to why a variety of blood types have endured for millions of years. Our primate ancestors were locked in a never-ending cage match with countless pathogens, including viruses, bacteria and other enemies. Some of those pathogens may have adapted to exploit different kinds of blood type antigens. The pathogens that were best suited to the most common blood type would have fared best, because they had the most hosts to infect. But, gradually, they may have destroyed that advantage by killing off their hosts. Meanwhile, primates with rarer blood types would have thrived, thanks to their protection against some of their enemies.
Note: Selected Parts from article, which I’ve provided, were originally published by Mosaic, and is reproduced under a Creative Commons licence. For more about the issues around this story, visit Mosaic’s website.