CARTA: Implications of Anthropogeny for Medicine – Ajit Varki: Are There Human-Specific Diseases?
1:53 Start of Presentation (Visit: In this talk, Ajit Varki (UC San Diego) offers some surprising examples of common human diseases that …
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– [Narrator] We are the paradoxical ape.
Bipedal, naked, large-brained,
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.
– I'd like to begin by acknowledging
and appreciating the
talk that we just heard,
which really emphasizes
that animals and humans
can get the same diseases
and yet physicians
and veterinarians rarely
consult with one another.
And that human and non-human
can be used to diagnose, treat, and heal
patients of all species.
And I also would like to acknowledge
that this comes as, Barbara pointed out,
from a long lineage
that goes back to Osler,
and one of those steps along the way
was one of our own here.
Kurt Benirschke unfortunately
couldn't be here
because of an illness,
the founding director
of CRESS and professor of pathology here
who really emphasized one medicine.
So, I'd like to flip the coin around,
in science there's always
two sides to every coin,
and say, are there
So what we've been hearing about is
the evolution, biology, and diseases
of a large variety of animals,
mostly warm-blooded social
and you can see an entire lineage here.
Let's zoom in on the
group that we belong to,
primates, and zoom in further.
And among these primates we have
New World monkeys, Old World monkeys,
gibbons, various so-called great apes,
and then us humans.
If we zoom in further here, we can see
that we shared common ancestors with
just a very short time
ago in evolutionary time.
And here's another way to look at it.
In millions of years before present
there's certainly some
discussion about the time frame.
But a very important
point to make here is that
while we classified all these species
as great apes, the main difference between
chimpanzees and bonobos is less than
1% of their amino acid sequence level.
In fact, we are closer to bonobos and
chimpanzees than they are to gorillas.
In fact, we are closer to chimpanzees
than mice and rats are to each other.
So, really, the classification
should be like this.
We are hominids and
then among the hominids
the lineage leading to us are hominins.
So, if you have a species that is 99%
identical to us the protein level,
how could you possibly have anything
that's different between them?
And in fact, when I
first got into this field
I found out that the veterinarians at
the primate centers I went to were using
Harrison's textbook of Internal Medicine.
Same textbook I'd used.
So that made sense.
But if you want to say
there's such a thing
as a human specific disease, it's gotta be
very common in humans, rarely reported
in closely related species.
Now this is very important.
I'm zooming in on this clade, not about
things that happened or distant portions
of evolution, even in captivity
and could not be experimentally reproduced
in such species, and I should warn you,
I'm gonna talk about a few really horrible
experiments that were done a long time ago
that'll never be done again.
So there's a caveat.
Who do you compare with?
In my opinion, reliable information
is limited to data on a few thousand
great apes in captivity,
which are cared for
at NIH-funded facilities with full
veterinary care, probably better
medical care than most Americans get,
and full necropsies.
So this is a reasonable data
set to compare with humans.
I think, comparing with wild chimpanzees
humans isn't that useful,
in this question that we're going to ask.
So when I went to the
Yerkes Primate Center
and other centers and asked, and said,
what's the commonest cause of death
in captive adult chimpanzees,
they said heart disease.
Heart attacks, heart failures.
So I said, oh, it's the same thing.
But then my wife, Nissi
Varki, who is a pathologist
went to see what was going on,
she came back and said, "You fool, it's
"mostly a different disease."
And so we got together with
various experts across,
including Kurt, and wrote this article
that says, heart disease
is common in humans
and chimpanzees, but is mostly caused by
different pathological processes.
So in comparing these two species,
amazingly it turns out that while
we humans, essentially
all of our heart attacks
are due to what you heard
coronary blockage in the arteries,
chimpanzees do get atherosclerosis but
it rarely ever leads
to coronary thrombosis.
Instead, they get this
very peculiar kind of
scarring in the myocardium,
the heart muscle,
fibrosis, so-called interstitial
myocardial fibrosis in great apes.
This gives rise to abnormal rhythms,
heart failure, and heart attacks.
So it looks like humans but at autopsy
it's a different disease.
In fact, since we wrote this article
and others put this out, it has become
so well-recognized that interstitial
myocardial fibrosis is such a major
common in captive great
apes in all the zoos,
that all the zoos led by Zoo Atlanta
have gotten together and found a network
to figure out what is this disease
and why is it killing all our great apes?
And so there are two
mysteries to be solved.
One is, why do we humans not often
get this fibrotic heart
disease that's so common
in closest evolutionary cousins?
Conversely, why do
great apes not often get
the the kind of heart disease we get
that's so common in humans?
Since we're genetically so similar,
there must be very
limited number of reasons.
You'd immediately say,
ah, it's just cholesterol.
In fact cholesterol is the leading thing
that pushes atherosclerotic heart disease.
But look at this figure here.
And look at, above is the black line.
The chimpanzee levels of cholesterol,
even at birth and soon after birth
in the first decade are so high that
they should be on statins.
And they have similar HDL levels.
They have APOE4 ancestral allele,
higher Lp(a) levels, sedentary lifestyles,
hypertension, and so on.
Now to be fair, there are some amino acid
differences in those two
very important proteins
and that may be part of the story.
So based on this kind of work,
Nissi Varki and I went to several of
these primate centers and tried to learn
more about these bio-medical differences.
In this case we are
focusing on differences.
I want to be clear, there
are many similarities,
which I'm not gonna talk about.
And so, we of course work
on sialic acid biology,
that's another story for another day,
but this article also talks
about those differences.
So here's a list of candidates for
that I call definite,
meaning the data so far
suggests that long list.
Obviously I'm not gonna
go through the whole list.
I'll give you a few examples.
The big one of course that I mentioned
is this remarkable difference in
the rates of coronary thrombosis was
interstitial myocardial fibrosis.
In fact, spontaneous coronary thrombosis
due to atherosclerosis seems to be
very rare in other animals in the absence
of experimental genetic
or dietary manipulations.
And the human-specific mechanisms,
undoubtedly as mentioned,
have to do partly
with behavioral and dietary changes,
although I'm looking forward to
the talk from Mike Gurven on this
hunter gatherer heart disease.
These amino acid changes
in these two proteins,
and something I'm not gonna go into,
genetic change in sialic acids that
seems to have made our immune cells
much more prone to inflammation
and also contributes to the effects
of red meat and heart attacks.
But that's, of course, a specialized case.
Here's another disease,
malignant malaria, the big killer malaria.
Horrible, horrible studies done in
the 1920s and 1940s in
the the Belgian Congo.
Two-way cross transfusions between
chimpanzees and humans infected or
non-infected with malaria.
No evidence of cross-infection.
Turned out the parasites looked
the same but are different.
Fast forward almost a century and work by
CARTA member Francisco Ayala and others
showed that all the
falciparum in the world,
this killer malaria, belongs to a
very small clade in the midst of
many, many, many other ape malarias.
In fact, Barbara Hahn later showed
the plasma falciparum probably arose
by a single transfer from
one gorilla to a human,
some time, we don't know exactly when,
a few tens of thousands of years ago.
So Pascal Gagneux summarized it like this,
ape malarias are very common,
and because of the sialic acid change
I'm not going to go into,
we escaped the target
and we had a free ride
for a million years or
so but the parasites
always win in the end.
And finally, the parasite
in that one transfer
switched to bind the
human kind of sialic acid,
and then, of course, we spread the
mosquitoes in our environment
and that rest is history.
Here's another one.
Typhoid fever, big killer throughout
human history until very recently.
And it turns out there's been
a host adaptation to humans.
Again, most horrible
studies done in the 1960s.
Large doses of Salmonella typhi
were given to chimpanzees.
Survival was much better and they were
much less sensitive.
It turns out we found
an explanation for this.
There's a human kind
of sialic acid shown on
this side of the screen,
and the other side
of the screen, Gc is the
chimpanzee type of sialic acid.
And the typhoid toxin only binds to
the human kind of sialic acid.
And so, using most models, we can sort of
show that this is what's going on,
that you have the
sensitivity and resistance.
Robert Koch, the famous
experiments were constantly
"repeated material from
fresh cholera cases,
"our mice remained healthy.
"We then made experiments on monkeys,
"cats, poultry, dogs, and other animals,
"and we're never able to arrive at
"anything similar to a cholera process."
So far, there's nothing
except a baby rabbit model.
Of course, there's an
explanation for this.
Now I've been talking mostly
about infectious disease,
from Jared Diamond and
others, and if you look
in the bottom of the screen you can see
that certain diseases like rabies
can spread throughout many animals.
And then eventually a
disease makes its way
into humans and, by what's
called a Red Queen effect,
becomes highly specialized on one species.
And so some of this is not surprising
but the fact is, there are such diseases.
There's one set of
definite diseases though
that are kind of interesting.
These are gonorrhea,
various other organisms
that infect newborns.
But it appears that what these bacteria
have done is amend the human kind of
sialic acid and quote themselves.
In what my colleague Victor
Nizet calls molecular mimicry,
they are basically wolves
in sheep's clothing,
and they are very successful pathogens.
Okay, so that's some examples,
I haven't gone through all of them,
of human-specific diseases,
that seem to be human-specific.
What about probable ones?
Another CARTA member, Tuck
Finch has written this,
Commentary, is Alzheimer's
disease uniquely human?
But Alzheimer's disease
may be a human-specific
disease was hypothesized in 1989.
considerable amyloid plaques
"after for 40, and age at which these are
"uncommon in humans.
"Despite this early
plaque buildup, ape brains
"have not shown dystrophic
neurites near plaques.
"Aging great ape brains
also have few tangles.
"We cautiously support this hypothesis."
And this is under further investigation.
Carcinomas of epithelial origin.
To date, of these few thousand apes
cared for in captivity,
not a single case of
carcinoma of the esophagus, lung, stomach,
pancreas, colon, uterus,
ovary, or prostate.
And so, Nissi and I looked into this
and concluded that
"while relative carcinoma
"risk is a likely difference between
"humans and chimpanzees and other apes,
"a more systematic survey is needed."
Of course, age is a factor,
not just environment.
And so you'd say, well,
a lot these diseases
we're mentioning have to do with age.
But in fact, chimpanzees in captivity
can live up to the age of 45, 50,
occasionally even up to 60.
And so they're in the age
range, you're looking at
the rates of human cancer here in
human males and females,
well, you might expect
to at least see a few carcinomas,
a few heart attacks of the human kind,
and a few early cases of Alzheimer's-like
disease, but none have been seen.
Another long list.
And here we have what is called
absence of evidence is
not evidence of absence.
We really don't know.
But it's kind of interesting that
bronchial asthma, I've been looking for
a case of bronchial asthma in a great ape,
or for that matter, in a monkey,
and there's no papers about this.
Except there are papers like this.
Here's a paper about the asthma-like
syndrome in a single monkey that says,
"The present case is remarkable in that
"there's a paucity of reports of
"naturally occurring allergy
"airway disease in nonhuman primates."
Now this could have to do with
the hygiene hypothesis, other issues,
remains to be seen.
Anyway, to conclude, disease profiles
of humans and chimpanzees
are rather different
genetically similar we are.
Chimpanzees, contrary to the original idea
of NIH and health sciences,
are poor models of many human disease,
and should not be used
to model human diseases
very often if at all.
Humans, conversely, are likely to be
poor models of many chimpanzee diseases.
So there are huge ethical issues here.
Chimpanzees are sentient beings.
I wouldn't do anything to a chimpanzee
I wouldn't do to a human, and with even
greater care than with humans.
And back in 2005, Jim
Moore, Pascal Gagneux,
and I wrote this ethics
paper, which suggested
that we conduct research on great apes
following principles generally similar
to those accepted for human research.
And we even suggested that the researchers
should volunteer to be
subjects in the same studies.
Since I wrote this, I keep getting
these letters saying,
please sign this document
banning all future
research on chimpanzees.
And my answer is, that's a terrible idea.
Would you ban all future
research on humans?
But unfortunately that's what's happened,
for other reasons, really good reasons of
getting chimpanzees out of not very good
facilities and avoiding invasive research.
The NIH just threw up its hand and has
stopped all chimpanzee research,
And the question is will the ban on
chimpanzee research actually do
more harm than good to both species?
And I'd add a final corollary,
chimpanzees would benefit from
more ethical studies
of their own diseases,
and I'm hoping that we can still keep
this area of research open because
I think it's important both,
for both humans and chimpanzees
and the diseases that we both get.
(contemporary contemplative music)