We are the paradoxical ape.
Bipedal, naked, large brain,
long the master of fire, tools, and language,
but still trying to understand ourselves.
Aware that death is inevitable.
Yet filled with optimism,
we grow up slowly.
We hand down knowledge,
we empathize and deceive.
We shape the future from
our shared understanding of the past.
CARTA brings together experts from diverse disciplines
to exchange insights on who we are and how we got here.
An exploration made possible by the generosity
of humans like you
Greetings.
Today, I will talk about ABO blood groups and we
will explore to which
extent this system is unique to humans.
Blood groups are discovered 120 years ago by a doctor in
Vienna who observed curious patterns
when he was mixing serum,
the fluid from coagulated blood with
red blood cells of certain individuals.
You can see here an example of bloods that don't react,
and serum and blood cells that
react in a reaction called agglutination,
where antibodies in the serum are
coagulating the red blood cells of another individual.
He observed by mixing
blood pairwise from six mothers
that had just given birth,
six healthy women, postpartum women.
That blood's of different pairs
reacted in particular ways.
He verified that by also doing the same thing
with blood cells from six healthy men and
discovered that there were patterns of
reaction between the antibodies
in the sera of certain individuals
and the red blood cells of others.
He described three blood groups,
which he named A, B, and O.
These differ by presence and
absence of certain antibodies and
certain antigens molecules on
the surface of red blood cells.
It took him several more years to describe
a fourth much rarer blood group called AB blood group,
where there was no antibodies present,
but both types of antigens
were present on the red blood cells.
Now for most of the 20th century,
it was observed that unlike humans,
where four blood types exist four ABO blood types A,
B, AB, and O.
Our closest living relatives,
the African great apes,
had only A and O types in common chimpanzees,
only a type in bonobos and only be type in gorillas.
Of course, in the case of humans,
in the context of transfusion medicine
and transplantations,
these ABO blood groups have
become extremely important clinically
because it is a matter of life and death not
to infuse a patient with mismatched blood groups.
Now, what are blood groups?
Blood groups are defined as inherited differences in
biochemical composition of blood
and other tissues, it turns out.
What I have here is a cartoon of
a red blood cell and erythrocytes,
and all these red blood cells, not to scale,
you can find a variety of proteins, lipids,
glycoproteins, glycolipids, and these,
it turns out, can differ between
individuals based on their genetics.
Blood groups often also include the presence of
antibodies against molecules that
are not present on our own blood cells.
The topic of today is the ABO blood group,
which it turns out is only one out of
40 different blood groups
involving over 400 different molecules.
As I mentioned, it was the first one to be
discovered over 120 years ago,
and it involves natural antibodies that appear in
early life after the baby's exposure to gut microbes,
and it's clinically most relevant.
Many of you are familiar with
the plus-minus that often is written after A,
B, or O, plus-minus.
That refers to recess,
which is a protein on the surface of red blood cells,
and I shall not discuss that today.
Today's topic is ABO,
which is defined as
little sugar chains on the surface of red blood cells,
they can sit on glycoproteins or on glycolipids.
Now, let's look at our red blood cells to scale.
We make ourselves very small
and zoom in on the surface of one of our red blood cells.
What we could observe if we
could make ourselves this small,
is the red blood cell surface is covered with
a complicated array of molecules that are
short sugar chains or oligosaccharides,
also known as glycans,
and ABO antigens turn out to be short sugar chains.
They are present at a number of
about two million per red blood cell,
and to give you an idea,
there are other sugars that are even
more common on red blood cells.
For example, sialic acids that are present at
10 times that number 20 million per red blood cell.
The ABO system was discovered in 1901,
but it took over 60 years
for biochemists to actually zoom
in on the biochemical nature of these antigens,
and another 30 years to discover
the genetic basis that determines whether you are A,
B, O, or AB, and your blood type.
Now, it turns out that the genetic basis
is remarkably simple.
It is a single gene that is located on chromosome 9.
The gene does not encode for sugars. Like genes,
it is a protein-coding gene that encodes for an enzyme,
a protein called a transferase.
It's a glycosyltransferase
that can transfer monosaccharide sugars,
too little growing chains of sugars.
Now, based on the DNA sequence, we each have at this gene,
you can produce a little oligosaccharide that ends
in one type of sugar or another type of sugar,
galactose instead of an N-Acetylgalactosamine,
or your enzyme might have mutations
that render it inactive and loss of function,
in which case, you do not add
a sugar and that would be blood type O,
the antigen of blood type O is called H antigen.
The loss of function,
whether you make no protein
or you make an inactive protein,
turns you into blood type O.
Now, it turns out that it was only
less than 10 years ago that a group in Chicago,
Molly Przeworski and colleagues,
looked at a phylogenetic comparison of
these ABO genes across primates. Lo and behold,
what they found is that it seems that the system of
diversity between individuals within
one species that we call ABO polymorphism
is really old, is as old as primates,
more than 20 million years old.
It's somewhat curious that
the African apes seem to lack the full system,
but many of the other non-human primates you can see
have all alleles and
they can make the different blood groups.
Based on this wider phylogenetic comparison,
it's really clear that
the ABO system is in fact not uniquely humans.
It's a widespread system
of maintaining diversity within populations.
If we look at humans and
the distribution of
the different alleles across different populations,
we can see that in many populations
around the world, you find all three alleles.
There are some interesting places such as
in native population of South America,
where almost everyone has the O alleles.
But in modern countries around the world,
you find all four blood types.
This is allele frequencies over here,
and this is phenotype frequencies,
the actual blood type.
You can see that most countries
have people with all four blood types.
Of course, that's very relevant for clinical use.
We need different blood types in blood banks so we
can save people's lives when we transfuse blood.
Now, this system is
a co-dominant system of
inheritance where you can have two different alleles,
which allows you to be AB or
A even if you carry an O allele.
Now, one question is,
what evolutionary forces maintain this?
Did this evolve to complicate
blood transfusions? Very unlikely.
It turns out that pathogens and parasites don't seem to
be able to infect
people of different blood groups
with the same efficiency.
ABO blood types are known to affect
the susceptibility in
many different pathogens and parasites.
Take viruses, for example,
different strains of viruses will
specifically infect only people
of one or another blood type.
Among bacteria, depending on the bacteria,
whether it's the cholera bacteria or
Helicobacter that can cause ulcers or
Campylobacter or group A or
group B streptococci or staphylococcus,
different species of bacteria
have a preference for certain blood groups,
and it goes in all possible directions.
These pathogens and parasites have
selected our ancestors in different directions.
The same is true for protozoa such as
the really important causes
of agent of a malignant malaria,
plasmodium falciparum, that prefers
A and B individuals over O individuals.
It's also true for fungi and
even for helminths such as schistosomes,
where there are different preferences
of one blood group over the other.
An additional complication, you might have
heard people use the word histo-blood group,
not just blood group,
has to do with the fact that it is now
understood that this molecular diversity,
this biochemical identity,
that we differ in between individuals,
can also be present in other tissues than the blood.
About 80 percent of us make ABO antigens,
the short oligosaccharides,
that sit on glycolipids and glycoproteins.
We also make those in
our bodily secretions, in our lungs,
in our gastrointestinal tracts,
and in our reproductive tracts.
Twenty percent don't make them.
These people are called non-secretors,
and this is based on a different gene,
the gene that attaches this fucose sugar to this chain.
If this gene is inactive,
then you do not produce
these secretions in your saliva
and other bodily secretions.
Human individuals also differ with respect to whether
they maintain this polymorphism
just within the vasculature,
or whether they also present
it in their lungs and so forth,
which are important landing places for infectious agents.
ABO is not expressed in connective tissues,
muscle, or central nervous tissue.
Many years ago, Ajit Varki and I
wrote about the evolution of glycogen diversity.
One of the questions we entertained is that,
glycan seem to be specifically
involved in maintaining diversity.
Immunologists have long talked about GOD, G-O-D,
as generation of diversity,
with the idea in mind that diversity can be protected.
What you see here is just an attempt by Ajit and
me to propose a very simple model,
where we have individuals of
just two types simpler than ABO.
One type is susceptible to
this little pathogen here that likes corners,
but doesn't like round things,
and if you have a mixed population that
differs in composition individuals of two kinds,
then what can happen is that
the non-susceptible individuals that differ,
actually produce a type of herd immunity,
and they protect other susceptible individuals
against a population wide infection.
This is this idea of protective diversity,
and it seems that ABO is involved in that,
and it's not just recognition,
a lot of pathogens use the very sugar chains that
define ABO to attach to the host and infect.
It turns out most viruses,
including the current SARS-CoV-2
that causes the current epidemic,
pandemic are enveloped viruses.
Enveloped viruses that come out of one individual,
say they come out of Pascal,
my blood type is A,
will carry little sugar chains
are the A antigen on their surfaces.
I would invite you to think of infection
by enveloped viruses as a type of nano transplantation.
It turns out during initial infection,
when a virus coming out of
A type individual tries to infect a O type individual,
the O type individual has a huge advantage because she or
he is making both antibodies against A and B,
and so if an enveloped viruses with A
or B determines on its envelope arrives,
it is tagged for destruction by
the existing antibodies of the O individual.
This effect, of course,
only takes place at the beginning of an epidemic.
As soon as we have enough of each blood type infected,
the viruses will find a host that is more compatible.
There's actually quite a lot of evidence for this for
both experiments and epidemiology
for viruses such as measles,
influenza A, HIV, and SARS-Cov-2.
Now, humans of course,
are cultural species,
we have medical technology,
and blood transfusions are incredibly important globally.
Based on WHO data,
there are over 180 million blood donations a year.
That corresponds to about 20 Olympic swimming pools
of blood that are being given,
and then transfused into people,
and it turns out it is still
not enough to cover the demand.
Just like the current vaccine roll out,
you can see from this map,
that many places actually are under-served
in terms of badly needed blood banks.
Now, in the early 20th century,
people like Arthur Mourant,
who was a hematologist in England,
went around the world and collected blood samples from
so-called Aboriginal populations that were quite
ill-defined and the collections
were far from ethical by today's standards.
But they generated some very interesting data
showing that across the world,
human populations differ in
the relative frequency of certain alleles,
very strikingly South America, for example,
is almost completely fixed for the blood type O allele.
We still don't know the reason for this.
It could have to do with founder events and demographics,
but it could also have to do with recent selection.
Unfortunately, as with many other enterprises
in anthropology, back then,
several 20th century European anthropologists
decided, well,
look at A group seems to be very common in Europe.
They immediately jumped to conclusion
that the A blood group must be superior,
with absolutely no evidence.
But that just highlights
the danger of studying ourselves,
and then being biased to finding
something that makes us look better than our neighbor.
This was for a long time,
people were very focused on proving that
A group was better than they own O or AB.
Unfortunately, this persists.
There is plenty of evidence of
surviving pseudoscience with regard to ABO.
Some of you might have heard about the ABO diets,
which are based on patently wrong theories,
and actually have been debunked several times,
and warned against by the British Dietetic Association.
Similarly, there is a type of
ABO astrology quite popular in Japan,
that is known as ketsuekigata
or blood type and personality,
even predicting how you will study for
your college exams based on your ABO blood type.
It's used traditionally for
matchmaking with belief in inconsistencies,
incompatibilities between different ABO blood groups.
In summary, the idea of
histo-blood groups are not human-specific because they
have persisted for millions of years as
something that is known as a balanced polymorphism.
Whenever one blood group becomes rare,
another one has an advantage,
it becomes more common until
most pathogens target that one,
it becomes rare again.
Of course, since the development of
modern medicine based on human culture and technology,
ABO histo-blood groups have become very important
clinically for the many millions of blood transfusions,
and hundreds of thousands of
organ transplantations per year.
What this highlights really is that this is
an example where the ABO blood groups,
our unknown topic from comparative anthropology.
We only realized that once we look at a wider comparison,
including other non-human primates,
they initially based on
just comparisons of humans and African great apes,
it looked like it was
a uniquely human feature, but it is not.
This highlights the importance of
wider phylogenetic comparisons when we
ask ourselves questions
about distinctly human phenotypes.
I thank you very much.