(Science Photo Library)
More than a century after their discovery, we still don’t know what
blood groups like O, A and B are for. Do they really matter? Carl Zimmer
investigates.
When my parents informed me that my blood type was A+, I felt a
strange sense of pride.
If A+ was the top grade in school, then surely
A+ was also the most excellent of blood types – a biological mark of
distinction.
It didn’t take long for me to recognise just how
silly that feeling was and tamp it down.
But I didn’t learn much more
about what it really meant to have type A+ blood.
By the time I was an
adult, all I really knew was that if I should end up in a hospital in
need of blood, the doctors there would need to make sure they transfused
me with a suitable type.
And yet there remained some nagging
questions.
Why do 40% of Caucasians have type A blood, while only 27% of
Asians do? Where do different blood types come from, and what do they
do?
To get some answers, I went to the experts – to haematologists,
geneticists, evolutionary biologists, virologists and nutrition
scientists.
In 1900 the Austrian physician Karl Landsteiner first
discovered blood types, winning the Nobel Prize in Physiology or
Medicine for his research in 1930.
Since then scientists have developed
ever more powerful tools for probing the biology of blood types.
They’ve
found some intriguing clues about them – tracing their deep ancestry,
for example, and detecting influences of blood types on our health.
And
yet I found that in many ways blood types remain strangely mysterious.
Scientists have yet to come up with a good explanation for their very
existence.
“Isn’t it amazing?” says Ajit Varki, a biologist at the
University of California, San Diego.
“Almost a hundred years after the
Nobel Prize was awarded for this discovery, we still don’t know exactly
what they’re for.”
Transfusion confusion
My
knowledge that I’m type A comes to me thanks to one of the greatest
discoveries in the history of medicine.
Because doctors are aware of
blood types, they can save lives by transfusing blood into patients.
But
for most of history, the notion of putting blood from one person into
another was a feverish dream.
Renaissance doctors mused about what
would happen if they put blood into the veins of their patients.
Some
thought 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
colour 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 died.
Still,
the experience convinced 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).
Prize discovery
Blundell
was correct in believing that humans should only get human blood.
But
he didn’t know another crucial fact about blood: that 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 categorise 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.
Distinguishing features
It’s
this clumping that makes blood transfusions so potentially dangerous.
If a doctor accidentally injected type B blood into my arm, my body
would become loaded with tiny clots.
They would disrupt my circulation
and cause me to start bleeding massively, struggle for breath and
potentially die.
But if I received either type A or type O blood, I
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.
In my type A blood,
for example, the cells build these molecules in two stages, like two
floors of a house.
The first floor is called an H antigen.
On top of the
first floor the cells build a second, called the A antigen.
People
with type B blood, on the other hand, build the second floor of the
house in a different shape.
And people with type O build a single-storey
ranch house: they only build the H antigen and go no further.
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 centres.
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 houses?
And why do
people have different houses?
Solid scientific answers to these
questions have been hard to come by.
And in the meantime, some
unscientific explanations have gained huge popularity.
“It’s just been
ridiculous,” sighs Connie Westhoff, the Director of Immunohematology,
Genomics and Rare Blood at the New York Blood Center.
Crash diet
In 1996 a naturopath named Peter D’Adamo published a book called Eat Right 4 Your Type. D’Adamo argued that we must eat according to our blood type, in order to harmonise with our evolutionary heritage.
In 1996 a naturopath named Peter D’Adamo published a book called Eat Right 4 Your Type. D’Adamo argued that we must eat according to our blood type, in order to harmonise with our evolutionary heritage.
Blood
types, he claimed, “appear to have arrived at critical junctures of
human development.”
According to D’Adamo, type O blood arose in our
hunter-gatherer ancestors in Africa, type A at the dawn of agriculture,
and type B developed between 10,000 and 15,000 years ago in the
Himalayan highlands. Type AB, he argued, is a modern blending of A and
B.
From these suppositions D’Adamo then claimed that our blood
type determines what food we should eat.
With my agriculture-based type A
blood, for example, I should be a vegetarian.
People with the ancient
hunter type O should have a meat-rich diet and avoid grains and dairy.
According to the book, foods that aren’t suited to our blood type
contain antigens that can cause all sorts of illness.
D’Adamo
recommended his diet as a way to reduce infections, lose weight, fight
cancer and diabetes, and slow the ageing process.
D’Adamo’s book has sold seven million copies and has been
translated into 60 languages.
It’s been followed by a string of other
blood type diet books; D’Adamo also sells a line of blood-type-tailored
diet supplements on his website.
As a result, doctors often get asked by
their patients if blood type diets actually work.
The best way to
answer that question is to run an experiment.
In Eat Right 4 Your Type
D’Adamo wrote that he was in the eighth year of a decade-long trial of
blood type diets on women with cancer.
Eighteen years later, however,
the data from this trial have not yet been published.
Recently,
researchers at the Red Cross in Belgium decided to see if there was any
other evidence in the diet’s favour.
They hunted through the scientific
literature for experiments that measured the benefits of diets based on
blood types.
Although they examined over 1,000 studies, their efforts
were futile.
“There is no direct evidence supporting the health effects
of the ABO blood type diet,” says Emmy De Buck of the Belgian Red
Cross-Flanders.
After De Buck and her colleagues published their
review in the American Journal of Clinical Nutrition, D’Adamo responded
on his blog.
In spite of the lack of published evidence supporting his
Blood Type Diet, he claimed that the science behind it is right.
“There
is good science behind the blood type diets, just like there was good
science behind Einstein’s mathmatical [sic] calculations that led to the
Theory of Relativity,” he wrote.
Different strokes
Comparisons to Einstein notwithstanding, the scientists who actually do research on blood types categorically reject such a claim.
“The promotion of these diets is wrong,” a group of researchers flatly declared in Transfusion Medicine Reviews.
Nevertheless, some people who follow the Blood Type Diet see positive results.
According to Ahmed El-Sohemy, a nutritional scientist at the University of Toronto, that’s no reason to think that blood types have anything to do with the diet’s success.
El-Sohemy is an expert in the emerging field of nutrigenomics.
He and his colleagues have brought together 1,500 volunteers to study, tracking the foods they eat and their health.
They are analysing the DNA of their subjects to see how their genes may influence how food affects them.
Two people may respond very differently to the same diet based on their genes.
“Almost every time I give talks about this, someone at the end
asks me, ‘Oh, is this like the Blood Type Diet?’” says El-Sohemy.
As a
scientist, he found Eat Right 4 Your Type lacking. “None of the stuff in
the book is backed by science,” he says.
But El-Sohemy realised that
since he knew the blood types of his 1,500 volunteers, he could see if
the Blood Type Diet actually did people any good.
El-Sohemy and
his colleagues divided up their subjects by their diets.
Some ate the
meat-based diets D’Adamo recommended for type O, some ate a mostly
vegetarian diet as recommended for type A, and so on.
The scientists
gave each person in the study a score for how well they adhered to each
blood type diet.
The researchers did find, in fact, that some of
the diets could do people some good.
People who stuck to the type A
diet, for example, had lower body mass index scores, smaller waists and
lower blood pressure.
People on the type O diet had lower triglycerides.
The type B diet – rich in dairy products – provided no benefits.
“The
catch,” says El-Sohemy, “is that it has nothing to do with people’s
blood type.”
In other words, if you have type O blood, you can still
benefit from a so-called type A diet just as much as someone with type A
blood – probably because the benefits of a mostly vegetarian diet can
be enjoyed by anyone.
Anyone on a type O diet cuts out lots of
carbohydrates, with the attending benefits of this being available to
virtually everyone.
Likewise, a diet rich in dairy products isn’t
healthy for anyone – no matter what their blood type.
Monkey business
One of the appeals of the Blood Type Diet is its story of the origins of how we got our different blood types.
One of the appeals of the Blood Type Diet is its story of the origins of how we got our different blood types.
But that story bears little
resemblance to the evidence that scientists have gathered about their
evolution.
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 my type A blood doesn’t necessarily mean that
the monkey inherited the same type A gene that I 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
floor of the blood type house.
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 storey on the blood type
house.
These mutations have turned blood types from A or B to O.
“There
are hundreds of ways of being type O,” says Westhoff.
Bombay puzzle
Being type A is not a legacy of my proto-farmer ancestors, in other words.
Being type A is not a legacy of my proto-farmer ancestors, in other words.
It’s a legacy of my monkey-like ancestors. Surely, if my blood
type has endured for millions of years, it must be providing me with
some obvious biological benefit.
Otherwise, why do my blood cells bother
building such complicated molecular structures?
Yet scientists
have struggled to identify what benefit the ABO gene provides.
“There is
no good and definite explanation for ABO,” says Antoine Blancher of the
University of Toulouse, “although many answers have been given.”
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-storey buildings, and O is a one-storey ranch
house, then these Bombay patients had only an empty lot.
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.
“There are still many associations being found between blood groups and
infections, cancers and a range of diseases,” Pamela Greenwell of the
University of Westminster tells me.
From Greenwell I learn to my
displeasure that blood type A puts me at a higher risk of several types
of cancer, such as some forms of pancreatic cancer and leukaemia.
I’m
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.
Virus scan
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 recognising infected blood cells if they’re type O rather than other
blood types.
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 diarrhoea.
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.
As I contemplate this
possibility, my type A blood remains as puzzling to me as when I was a
boy.
But it’s a deeper state of puzzlement that brings me some pleasure.
I realise that the reason for my blood type may, ultimately, have
nothing to do with blood at all.
For more about the issues around this story, visit Mosaic’s website here.
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