(delicate piano music)
- [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.
(upbeat electronic music)
- Good afternoon.
Comparative medicine has a long and strong tradition
at UC San Diego,
going back to one of the godfathers of the field,
Kurt Benirschke,
who was actually one of the founding members of CARTA.
But comparative medicine tends to focus on
similarities in diseases between different species.
But when it comes to anthropogeny,
we are more interested in differences
between humans and our closely related cousins,
the great apes.
So, my own interest in this area
began in studies of sialic acid biology,
which covers the surface of every cell in the body,
in which we discovered a gene that was inactivated
two to three million years ago in the human lineage,
changing all the cells in our body
in many different ways, but that's a different story.
That got me interested in human origins,
and then raised the question,
given my medical background,
are there human specific diseases,
and what would be the criteria of such diseases?
It should be very common in humans
but rarely reported in closely related species,
such as great apes, even in captivity,
and it could not be experimentally
reproduced in such species in the days
when such studies were allowed.
The caveat is that reliable information
is limited to data on a few thousand
great apes in captivity, mostly chimpanzees.
But these chimpanzees were cared for
in NIH-funded facilities with full veterinary care
and thorough necropsies at death.
So they have very good records on these chimpanzees.
So, my work in this area could not have been possible
without my spouse and long-term collaborator,
Nissi Varki, a comparative pathologist
who actually trained with Kurt.
And over the years, we have visited
several of these primate centers
and tried to learn about human-chimpanzee diseases,
done some work in the lab,
and published papers such as these.
And updated to today, we have this long list of candidates
for these human-specific diseases,
divided into definite, probable, and possible,
only some of which I can comment on,
with some focus on our own work.
Perhaps the most dramatic difference is in heart disease.
When I first went to visit the Yerkes Primate Center,
I asked the veterinarians,
what's the commonest cause of death in chimpanzees?
They said heart attacks and heart failure.
I said, oh, that's just like humans.
Nissi went later and said, "No,
"you didn't look at the pathology.
"It's a different disease."
And it turns out that heart disease
is common in humans and chimpanzees
but is caused by very different pathological processes.
So, the process we're familiar with in humans
is called myocardial infarction,
coronary thrombosis blocks the blood vessels
to the coronaries and causes loss of heart muscle.
And the chimpanzees, and all the other great apes, actually,
it turns out they get massive scarring
of the heart muscle.
And that's what they really die of.
So actually, the commonest cause of human death,
in fact, probably going to be the commonest cause of death
of people in this room, unfortunately,
does not occur in chimpanzees, great apes,
or any other animal that we can come across,
except in very contrived experimental situations.
So, this is actually not new,
it's just, we wondered why this is not reported,
and it turns out the reason is that
chimpanzees were placed in captivity for NIH
as models for human diseases.
So whenever things are similar, we find a lot of reports.
Whenever they're different, they didn't say much about it.
But in fact, the veterinarians
are very familiar with this problem,
and since then, there's been this formation
of this great ape Heart Project,
which strives to address this issue.
And there are two mysteries:
why do we not suffer from this fibrotic heart disease
which is clearly present in
the common ancestor of great apes,
and conversely, why do they not get
the disease that we get?
So, this is ongoing work that we and others are doing.
Another classic human-specific disease
is malignant malaria, Plasmodium falciparum.
Horrible studies done in the 20's and 40's
with a two-way cross-transfusion between chimps and humans,
infected or non-infected with malaria.
No evidence of cross-infection.
And the conclusion was, while the parasites
look the same in the microscope, they are different.
An updated view of this is something that
Pascal Gagneux and I summarized in the work of many people.
It appears that there are many common
mild malarias occurring in great apes in Africa
which are not transfers for a human,
because they bind the non-human siliac acid.
That may be one of the reasons.
And perhaps, when we lost this target,
we had a free ride from malaria
for a million years or so.
That's of course speculation,
but the parasites always win in the end.
(faint laughter from audience)
And a single transfer from a gorilla to a human
at some point, probably 30, 40, 50,000 years ago,
came in with a parasite that is now binding
the human rich sialic acid.
And then, of course, we spread across the world
and took mosquitoes with us,
and expanded their base and so on,
and the rest is,
is malignant malaria.
Another classic example is typhoid fever.
Again, horrible studies done in the 1960's,
large dose of S. typhi did not give
severe complicated forms of typhoid fever in chimpanzees,
and the bug didn't survive a long time
in the chimpanzees.
And they were much less sensitive to the typhoid toxin.
The toxin is the secret.
So, if, as my collaborator, Jorge Galan, likes to say,
if any of you get a garden variety salmonella
from contaminated dairy products,
you'd think you're going to die.
If you get typhoid fever, you are going to die.
It's, in fact, a very high mortality untreated.
And the reason is is that there's a very potent toxin
produced only by this one strain of S. typhi
that infects humans,
and it has adapted itself to humans.
And the summary of a lot of work
with other collaborators suggests
that what's happening is this toxin
has become highly specialized in seeing
the human cell surface, and doesn't react very well
with the ape cell surface.
Another dramatic example is cholera,
one of the most deadly diseases that afflicts,
still afflicts, many populations.
Many of you are probably familiar with
Robert Koch's postulates for microbial diseases.
Microbes should be found in abundance
in all organisms suffering from the disease,
should be isolated from that organism,
grown in pure culture.
Should then cause the disease
when reintroduced into healthy organisms.
And should be re-isolated and shown to be identical
to the original agent.
Robert Koch had one failure to fulfill his postulates.
In 1884, he complained,
"Although these experiments were constantly repeated
"with material from fresh cholera cases,
"our mice remained healthy.
"We then made experiments on monkeys, cats,
"poultry, dogs, various other animals,
"never able to arrive at anything in animals
"similar to the cholera process."
And to date, cholera does not cause diarrhea
in any adult animals.
There are a few unusual models of baby rabbits, models,
but basically no other animals.
And we don't know the final answer,
but again, this sialic acid difference being studied,
we've recently published suggesting
that this is one of the major reasons,
and the various mechanisms I won't go into.
Gonorrhea.
Sexually transmitted disease, 100 million new cases a year.
One third are multi-drug resistant,
high-frequency of asymptomatic infection in females,
causes pelvic inflammatory disease and infertility,
no occurrence in other species in nature.
Early disease model in chimpanzees
in the days when that was allowed was not successful.
We now have molecular evidence, we and others,
that human factor H is selectively bound
by the gonorrhea organism, not the chimpanzee,
and we are studying Human Innate Immune Receptors
that are engaged by human Siglecs,
and not by chimpanzee Siglecs on the gonorrhea organism.
Again, this is a very recent publication of interest.
And again, I'm not suggesting we've found the answers,
but we found some of the components of the answers.
In the probable category, perhaps the most fascinating
is carcinomas.
To date, no captive great apes
have been reported to have spontaneous carcinomas
of the esophagus, lungs, stomach, pancreas, colon, uterus,
ovary or prostate.
A few liver cancers associated with
experimental chronic active hepatitis in chimpanzees
in the days when that was allowed.
So, Nissi and I looked into this literature,
contacted various primate centers again,
and wrote about the apparent rarity of epithelial cancers.
And we conclude that while this relative risk
is a likely difference between humans and chimpanzees
and possibly other great apes,
the zoos have much less numbers,
a more systematic survey is required
for validation of this claim.
And we have potential mechanisms
we and others are working on for this.
But in fact, as I said, these differences
are actually well known to veterinary pathologists.
In recent times, they've gone back and done
really more systematic surveys than we've done.
And these are two recent reviews from
well-known veterinary pathologists
and veterinarians.
And they come to the same general conclusions
that we come to.
So, comparative medicine of humans and great apes,
what do we know for certain?
What are we reasonably sure about?
Most reliable information arises from careful studies
in captivity,
but numerical significance is limited to chimpanzees.
Of course, there are distinctly human conditions
related to upright posture that I have not mentioned,
like difficult childbirths, spine and back problems,
and other anatomic features of humans,
where unusual skin, sinuses, breasts, airway anatomy,
and so on, that result in certain diseases
which I have not gone into.
Some major infectious diseases, common ones,
appear unique to humans.
We humans appear to have hyper-active immune responses,
and by various criteria.
This heart attack of the human type
appears to be much more common in humans.
Some great ape diseases relate to
their own unique anatomies.
For example, the air sacs that they have.
Unlike most African primates,
this is for the aficionados,
the human lineage eliminated
endemic infectious retroviruses.
How did that come about?
What do we think we know?
What are we not sure about?
To what extent are these disease differences
related to aging and lifespan?
What extent are they related to
prolonged post-reproductive lifespan that we hear about?
Are we really at greater risk for developing common cancers?
Are we more prone to auto-immune diseases?
Do we react more to chronic viral infections
resulting more commonly in AIDS?
A series of human female reproductive conditions
not reported in great apes to date,
common in humans.
And they're listed there, which I won't read.
Pathology and progression of neurodegenerative diseases,
like Alzheimer's disease, appear more advanced in humans.
How do we proceed?
We need more mechanistic explanations
on both sides of the coin.
Are there great ape equivalents
of human psychiatric diseases?
We should hear about that hopefully shortly.
Can study of ancient hominin DNA that was mentioned
tell us about the emergence of unusual human diseases?
Also by distinctive genomic signatures
in the hominin genomes.
Can we search this microbial contamination,
as has been mentioned?
Are there diseases similarities more prominent
in great apes?
So, disease profiles of human and chimpanzee
are rather different.
Understanding the differences has implications
for anthropogeny.
Chimpanzees are poor models of human diseases.
Humans are likely to be poor models
of many chimpanzee diseases. (faint chatter from audience)
And there are serious ethical issues.
Pascal Gagneux, Jim Moore, and I wrote in 2005
that we should be allowed to conduct research on great apes
following principles as similar as possible to those
accepted for human research. (faint laughter from audience)
And we suggested the human researchers should volunteer
to be subjects in the same studies.
(laughter from audience)
But the pendulum has now
gone full swing to the other extreme.
NIH has ended all support
for research on chimpanzee diseases.
And the question is, will the ban on chimpanzee research
actually do more harm than good?
And so, we've gone from being highly inappropriate
to almost impossible to do what would be done in humans.
Can we find ethically acceptable compromises?
Can this aid conservation of apes in the wild
and care in captivity?
So, final corollary
is that chimpanzees would benefit
from more ethical studies of their own diseases.
And so, (clears throat)
I think that's a good point on which to end,
to acknowledge the great debt
that we all owe to chimpanzees
for what they've taught us about our diseases,
and not much about their own diseases.
Thank you.
(audience applauds)
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