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.
In keeping with the theme of comparative anthropology,
I'm going to talk about a protein called siglec-11.
It's found in the human brain,
but not in this chimpanzee brain
or brains of other great apes.
The presentation I'm making along
with many people in my group
who worked on this topic over the years
and now this relationship.
This particular one is with Dillon Chen,
a young student professor in neuroscience.
What is a siglec?
A siglec is a sialic-acid
recognizing Ig superfamily lectin,
that's a mouthful. What is that?
These are proteins found on several of cells,
particularly the in immune system.
They're called Type 1 proteins because they pass
through the membrane and the cell one time.
At the other end they have what's called a
V-set domain that bind sialic acid.
We'll come back to that in a minute.
Below that there's some C2-set domain
that extend the protein down to the membrane.
Inside the cell,
you have intracellular signaling motifs.
This is a molecule that can be seen on
the outside and send a signal on the inside.
What is the sialic acid recognition?
Every cell in your body is covered with
dense and complex or with glycans,
and sugar chains like icing on the cake.
On this icing, you find the outerings,
you find these sugars called sialic acids
which are sticking out of the top of sugar chains.
This is a cartoon, of course.
These molecules are primarily
found in animals that deuterostomes lineage.
These are vertebrates and animals
with the backbone like humans.
Curiously, involved is also found in certain bacterial
pathogens that invade deuterostomes.
We'll come back to that in a minute.
There's reason for that. What do sialic acids do?
Given the negative charge and
the high mass huge density on cells,
there are many biophysical roles
affecting all biophysical properties of cells.
Given their location they're
the target to these numerous pathogens,
influenza, malaria, many
coronaviruses, many other bugs,
I could fill the entire screen with
examples of bugs that bind sialic acid,
makes sense, it's sticking out there on the outer into
the surface and they target so many bad guys.
Meanwhile, a bunch of other bad guys,
are coating themselves as sialic acid.
We'll look inside of molecular mimicry,
making them look like you, basically.
There's some evidence for sialic acid involvement in
intraspecies recognition in terms of reproduction.
But for a long time, this role wasn't known.
If this is the sole purpose of sialic acid,
why would it persist for more than 500 million years
of evolution is bad for you, right?
Turns out there are proteins that actually
recognize sialic acid inside your system.
It's critical. More recently,
we and others have been looking at these molecules.
The particular class amount we
will talk about are called siglecs.
Already told you a little bit about them.
What they do at a particular siglec we'll focus in on.
The major role of these siglecs
is to recognize endogenous sialic acid as
self-associated molecular patterns and
dampen innate immune cell responses.
Why would you want them going on?
Because you've got a bunch of immune cells
floating around your body are trying
to attack you all the time.
By having siglec say stop, I'm self.
It's clear recognition of self.
Interactions with self sialic acids is going to
interact both on the same cell.
Cis cells and trans.
When the sialic acid binding occurs,
it triggers what's called
phosphorylation inside of the membrane.
These motifs gets activated
and that keeps the inflammatory genes now offstage.
You've got all these very
strong soldiers spreading around the body,
but they kept off because they keep seeing
this sialic acid [inaudible] self.
Whole bunch of them different on
a different cell types.
The one we're going to look at today is called
siglec-11. The number according
to the time they were found.
Siglec-11, if you look in any tissue of primates,
including humans, you find it in
tissue macrophages in all tissues.
But in the brain, the macrophages called microglia.
You can see here that's siglec-11 in this color patterns,
siglec-11 showing green is
present in the brain and microglia.
[inaudible] would just be an example of
a tissue in a small intestine.
Years ago when we looked at it,
Nissi Varki noticed that while
the brown staining you've seen here
is called macrophages in humans and chimpanzees,
in the brain this brown siglec-11
is only found in microglial brain.
There's little brown dots that you're seeing over that.
Look on the right to chimpanzees,
it's hardly there at all.
Same with the other apes.
That time they actually found what was
the first human-specific protein in
the brain with protein sectors all through the body,
but not in the brain of
other animals, including primates.
But these microglia are like macrophages,
the brain, but they have many other functions.
They don't just clean up
messes or bacteria, anything like that.
They have many functions beyond
pathogen protection and removal of aggregated proteins,
they shape neuron's circuit activity,
effects in development neurogenesis,
they influence neuronal activity acutely and
long-term memory and monitoring of synaptic integrity.
They do a lot of other things besides
just the macrophage function.
Nothing about human siglec-11 is
recognized something called polysialic acid.
Remember I told you sialic acid has one copy.
But if you look in the brain,
particularly in the vertebral brain,
you see this extended chains of sialic acid,
if you can see, heading out called poly-silicon.
These polysaccharides also binds
molecules with efficient recognize BDNF,
FGF-2 to the critical effect on the brain functions.
The expressed on neuronal cells and
they recognize siglec-11,
but they also recognize other important molecules.
Turns out that the brain is
particularly rich in polysialic acid in
the early days of development in the
[inaudible] were actually built and
growth goes down over time.
The human-specific pathogen called i K1,
not the primary E. coli,
especially [inaudible] expresses
identical polysialic acid that you see in the brain.
Like a wolf in sheep's clothing,
it coats itself in polysialic acid getting to the brain.
In fact, 20 percent of cases in
neonatal meningitis called the K1,
as in developing countries, it might be higher.
This is probably making it
some look exactly like the brain.
If you look at the CD33-related
siglec receptors in the brain,
the polysialic acid is taking advantage of
siglec-11 and shutting down
the immune cells in the brain.
Evolution always has more tricks up its sleeve.
There's another group of siglecs
that have the opposite action.
They bind sialic acid with descended positive siglec.
Why would you want that?
It's an evil trend, if you will, of siglecs.
Rather than siglec 16,
it gives you the opposite reaction as it
attacks when it sees the polysialic acid.
The other peculiar thing is if you
look at these two proteins,
if you look at the amino-terminal, front-end,
they're 99 percent identical,
but below that they're only 80 percent identical.
This complicated figure we call a pyelogram, basically,
you expect siglec 11 to be in the same group with
gorillas and chimpanzees, and so on.
But if you look at the upper domain,
there's that identical one, they're within a species.
That's it. It's complicated.
Basically, the idea is what's going on is that genes
codes 11 and 16 are adjacent to the genome.
They stick next to each other side-by-side,
and during process of meiosis
and production of gene cells,
they undergo switching, something called gene conversion.
They keep pasting each other, 11 and 16 keeping
identical in the first two domains.
We have molecules that are identical and
the first two domains are
different than the other domains.
It's in the opposite signal.
These are paired receptors as they call them,
and they modulate inflammatory response
in the opposite directions.
Here's siglec 11 again, here's the E. coli K1,
the bad guy coming in polysialic acid,
binding the siglec-11 and say,
''Shut down, I belong here.''
Along comes siglec 16,
it says, ''We're going to get you,
we recognize everything foreign
because it had the opposite reaction.''
You have inhibitory and activating siglecs 11 and 16,
outgoing opposite responses,
but E. coli k1 is not in the brain,
the vast majority of your life, not at all we hope.
In fact, it's has common brain ligands
mediating other functions in the brain.
The other peculiar part of the story of siglec
16 is that it's found in all chimpanzees and
all the other apes is knocked
out in humans and many humans are non-related primates.
You can find that there are many people,
in fact, majority of you watching
this cannot express siglec 16.
The genes are mutated, it's called a
pseudogene, inactive gene.
A really complicated slide
[inaudible] come back and look at this
later when this is put up by UCTV online in a few months.
Whole series of complicated events occurred where
these two genes modified
each other over time and ended
up with the current situation.
It's all uniquely human events.
When solving a murder mystery,
how all these things happen,
is it specific to humans?
More recently, Masaya Hane from [inaudible] in Japan,
he was in our lab and he looked at
human specific siglec 11 and its effects in the brain.
I won't to go to discuss it in detail,
I'll just summarize what he found.
Human-specific siglec 11 exists in alternate splice form.
It's missing the last set domain
that's specific to human brain again.
If you make a soluble hormone this and look at binding,
it binds better to polysialic acid.
Somehow, once this molecule ended up in the brain,
it figured out a way to curb the last piece,
which makes it bind to polysialic acid even better.
It's also prone to aggregation
affecting ligand-binding ability.
Can also be cut off and secreted
into the extracellular space.
The human-specific microglial variant
doesn't come out by proteolysis,
it comes out in little soap bubbles also called exosomes.
You have siglec 11 and siglec 16
coming out on little bubbles, microglial cell.
These can be released.
There's potential that polysialic acid mediated functions
can be affected at a distance,
not just between two cells.
Siglec 11 and siglec 16 are expressed
as paired receptors in tissue macrophages in humans,
chimps, and other non-human primates outside the brain.
What's uniquely-human features of siglec 11 and 16?
Siglec-11 is converted by pseudogene.
It's a complicated story,
but keep an open reading frame.
That was unexpected, the way that happened.
It's expressed in brain microglia in all humans,
not observed in chimpanzees and other great apes.
It has endogenous ligands in
the developing human brain, including polysialic acid.
Microglia in brain only of
humans have one less C2 set domain than in other forms,
brain-specific, human-specific form.
This form can be secreted as exosomes, like I said,
the little bubbles that come out of the cell,
and therefore, influence function at a distance.
It has endogenous ligands in the developing human brain,
including the polysialic acid.
Likely allows invasion of neonatal brain by E. coli K1,
it seems very likely, but such invasions
may be countered by expression of activating siglec 16.
Siglec 16 is an intact protein only in some humans,
but the messenger RNA is present even
when both alleles have a common deletion.
There's something else going on there,
the RNA is doing something besides the protein.
The other peculiar thing is Siglec-11 and 16 show up in
unusual sites that you don't normally expect them,
probably because of the major change
occurring in this region of genomes.
For example, the uterus of all places and
see what we found that human cervix,
which is the exit part of the uterine cervix,
express 11 and 16.
Other interesting things that happen in 11 and
16 in different parts of the human body,
we haven't really pursued them yet.
Lastly, I just want to point out that this is
not the only case of Siglec changes in humans.
In fact, all these Siglecs that have a star above them,
they have a story about human-specific changes.
These multiple genomic events
altered hominic Siglec biology,
predating the common ancestor
of humans and archaic hominins.
The archaic hominins are Neanderthals,
and Denisovans are closest extinct evolution columns.
If you look at this diagram,
you can see that many of these changes occurred in
the common ancestor of Neanderthal and Denisovans,
before the common ancestor of Neanderthals,
Denisovans, and humans.
But they went on to find that they're human specific,
but mostly apes don't have any of these changes.
This is written up a little in science.
It talked about an ancient
[inaudible] they think the signature,
something that happened maybe 500 millions
ago prior to the common ancestor, Neanderthals,
and humans, but
many changes occurred since then and have been
accumulating in humans and being selected
for or against depending on the impact on human brain.
Some of them,
they're are finding are specific to humans,
not even Neanderthals and Denisovans.
He traced the genetic response
to pathogens back to this common ancestor.
Obviously, there's a lot of
complexity in what I told you about,
but you can tell that there's something.
It's like a murder mystery like I said.
There are many things going on,
we don't fully understand them,
they all fit together in one story.
Apparently, affecting not only
the developing human brain [inaudible] pathogens.
Thank you very much.