[applause] Eric Green:
Thank you very much. It's certainly a pleasure to be here. I want to welcome everybody here this evening
on behalf of the National Human Genome Research Institute, one of the 27 institutes and centers
that make up the National Institutes of Health. As you heard, this is one part of a series
of programs that are associated with this wonderful exhibition in Hall 23 of this great
museum, Genome Unlocking Life's Code, which really reflects this great new partnership
between the NIH and the Smithsonian Institution. And it's a real pleasure to be a part of this
program tonight, but also this entire series. And it has proven to be remarkably enjoyable
and productive to be working so closely with the Smithsonian Institution and also the Smithsonian
Associates Program for putting together programs such as this, which really have brought in
some spectacular guests and speakers to help round out what you can learn from visiting
the exhibition itself. So my role here was simply to welcome you
and tell you it's really a pleasure for our institute and for NIH to be involved in programs
such as this, and also to introduce Dr. Rick Potts, who's going to in turn give a more
detailed introduction of tonight's special guest. Just by way of background, as you heard, Rick
Potts directs the Human Origins Program here at the Smithsonian's National Museum on Natural
History, where he holds the Peter Buck chair in human origins. His research investigates Earth's environmental
dynamics and how human adaptations have evolved over the past six million years. Bridging many research disciplines, Rick leads
field projects in the East African Ridge Valley and in Southern and Northern China. He's also a curator and a visionary for the
Smithsonian's Hall of Human Origins and is the author of the companion book, "What Does
it Mean to Be Human?" So with that as background, please welcome
Dr. Rick Potts. [applause] Dr. Rick Potts:
Thank you very much, Eric. And I don't know what it is but as I was stepped
out into the lobby and came back in here there was such a feeling of excitement about tonight. Maybe it's snow, but I have a feeling it's
Neanderthals or something like that. [laughter] Anyway, I wish to offer my gratitude to Dr.
Eric Green and the extraordinary partnership that's already been alluded to, the partnership
that developed surrounding the human genome exhibition, a partnership between the Smithsonian's
National Museum of Natural History, and the National Human Genome Research Institute,
which Eric leads and directs at the NIH. Great thanks also to the Smithsonian Associates
for organizing tonight's event, which is absolutely thrilling to me, as it would be to anyone
who was involved in the study of human origins. Dr. Svante Pääbo has led the effort to create
a new field of discovery directly relevant to the subject of human evolution. The study of ancient genomes has offered a
novel means of delving into the actual genetics of early human lineages, beginning with the
Neanderthal Genome Project. Dr. Pääbo's research team wowed his fellow
scientists and the public by mapping the molecular foundation of what it means to be a Neanderthal. And with that, with those findings, those
findings have shed great light on the genomes of many people alive today, as well as the
complexity of the later phases of human evolution. And for his work and for his earlier research
in genetics, Dr. Svante Pääbo has received numerous recognitions and awards. In 2007, "Time Magazine" named him one of
the most 100 influential people in the world for that particular year. And I think that continues because that was
three years before his team produced the first draft of the Neanderthal genome. More recently he received the Theodor Bucher
Medal from the Federation of European Biochemical Societies. And last year Svante received the Gruber prize
in genetics for his pioneering research and leadership in the field of evolutionary genetics. In addition to the Neanderthal genome project,
the further discovery of the denisovan genome is equally amazing. Svante is here to tell you about it all himself. One of the great adventure stories in modern
science told at the molecular level and guaranteed to inform our evolutionary history and the
distinctiveness of being human. It is my considerable honor to ask you to
welcome Dr. Svante Pääbo. [applause] Dr. Svante Pääbo:
Thanks. Well, first of all, let me thank you very
much, Rick, for that very kind introduction and for the invitation to come here and also
see this amazing exhibition that I actually heard a lot about all the way to Europe. And what I wanted to do today is use my time
so that I first talk a little bit about our efforts in general to retrieve DNA from old
fossils in particular from Neanderthals, then discuss Neanderthal [unintelligible] in detail
and what has that taught us, and also the genomes of this relative of Neanderthals from
Siberia. And in the last third of my time or so I'd
like to discuss where we're going from here, how we will exploit the knowledge we now have
to go further. And please tell me if it's not loud enough
and you don't hear me. I can't gauge how loud I am. But before starting all this then, I just
want to remind you at what I think you all already know, that our genome, our genetic
material is stored in almost all cells in our body on the chromosomes and it's stored
in this famous double helical DNA molecule. And when a new cell divides, a [unintelligible]
of interest is then in our germ line where new germ cells are formed, so new individuals
may appear. There are [unintelligible] that unwind these
two strands and synthesize new strands with the old as templates. So there appears two molecules which are more
or less exact copies of the earlier copies -- version of our genome. And this is a very exact process, but nothing
is of course absolutely perfect in nature. So now and again an error is made. For example, instead of building in what should
have been a "G" here, an "A" is built in. And if that's not repaired fast enough before
the DNA replicates again, it will appear as a mutation in the next generation. And you can then discover these mutations
as sort of consequences of these mutations when you compare DNA sequences from two individuals. So if you compare the genomes of two people
in this room we will find a difference every 1,200, 1,300 such letters in nucleotides approximately. If you add in the [unintelligible] "C" here
we will find a lot more differences, one every 100 nucleotides approximately. And we can then use our models for how we
think these mutations occur to reconstruct the history of the whole genome or a part
of the DNA sequence. And we generally depict that in the form of
trees like this. In this case it's very simple. The two human sequences go back to common
ancestor quite recently. Much further back is their common ancestor,
[unintelligible]. So our genome, as you also know, is over 3
billion base pairs. So we have something in the order of 3 million
differences between any two people in the audience or between the two versions of the
genome that you inherited from your mother and from your father. So there's a lot of information there to begin
to reconstruct human history. And if you do that on a world-wide scale,
what you will find is that most variation is found in Africa. So although there are a lot less people living
in Africa than outside Africa, the total amount of variation outside is less than you'll find
inside Africa. And not only that, for most of the variants
you find outside Africa, you have closely-related variants of DNA sequences inside Africa. But there's a component of the variation in
Africa that you don't find outside. And the interpretation of this is that modern
humans, humans that are essentially as us, evolved in Africa and a part of the variation
that existed there sort of went out and colonized the rest of the world. And by some genetic tricks, for example, looking
at how associated variants are with each other along the chromosome, you can also estimate
approximately when this happened. And it's in the order of 100,000 years ago,
so quite recent in terms of human evolution. So this is the recent African origin of modern
humans. But there's a problem, if you like, with this
model and that is that 100,000 years ago there were not only modern humans around. There were many other forms of humans. And outside Africa most famously Neanderthals
in Western Eurasia and in Eastern Asia other forms that are less well-described. So big question has always been what happened
with these other forms of humans? Did they contribute to people who live today
or did they go extinct without any sort of [inaudible]. And most interest has been focused on Neanderthals. Here are some reconstructed skeleton of a
Neanderthal compared to a modern human. As you may also know, Neanderthals appear
in the fossil record depending on how you define a Neanderthal, maybe 300, maybe 400,000
years ago, and they exist until about 30,000 years ago when they become extinct about the
same time in different areas when modern humans appear. So there have been these two ideas around
in paleontology for decades about what happened when modern humans appear in Africa and come
out, one idea is a sort of total replacement idea where Neanderthals in Europe and other
forms in Asia become extinct without any contribution to present-day people. Another one -- idea is a simulation called
here, where modern humans come, mix with Neanderthals before they become extinct so they contribute
to people in Europe today and the same in Asia. So you can regard these two ideas on a sort
of sliding scale where total replacement would be zero contribution from these earlier forms. And you could have more and more of contribution
until total continuity that I think no one really believed in until quite a while ago
already. So we got a first chance to sort of test this
with molecular means back in the mid-90s when we got access to this fossil, which is [unintelligible]
and in the Neanderthal, it's sort of the Neanderthal that was found in Neanderthal in 1856 and
yet it's named to the [unintelligible] of humans. So we got a sample from the arm bone here. It was an extracted DNA under really clean
room conditions to avoid contamination from yourself or from dust in the air or from chemicals
into your experiments. And with great effort at that time with a
message we had a [unintelligible] at a particular variable part of the tiny piece of the genome,
the mitochondrial genome, which is inherited from mothers to offspring. So it gives a very one-sided version of history,
if you like, just a female side and it's also a tiny little piece inherited as a unit so
very much influenced by chance. But it has advantage that occurs many copies
of this [unintelligible]. It's a bit easier to retrieve. It's a bit like some fragments of it have
survived. So we've [unintelligible] reconstructed piece
of this by shorter little pieces. You could retrieve believing the things we
could reproducibly find and reconstruct in such a tree as I showed before. And if you look at the mitochondrial genomes
of present-day people -- now the pointer has died -- of the modern humans there, they go
back to common ancestor between 100 and 200,000 years ago. The Neanderthal mitochondrial genome was found
to go back much further in time, about half a million years or so. And since then we and others have looked at
other mitochondrial genomes from other sites and they all go back to common ancestor outside
a [unintelligible] of modern humans. So the [unintelligible] there's no battery
in this. It doesn't forward either. So in this scale of thing it's quite clear
that no one today runs around with a mitochondrial genome from a Neanderthal. So it's total replacement. And this mitochondrial genome also gave us
another piece of information. It suggested that the split between Neanderthals
and modern humans -- wow, that is really nice, wonderful, thanks a lot, great -- split about
a half a million years ago or later because that was the time we had between the mitochondrial
genomes there. So this was what you could see from this tiny
little piece of the genome. But it was of course clear to us and everyone
else that the full story would be hidden in the nuclear genome because then we could really
study all parts of the genome and also find things that would have appeared more recent
than humans since we separated from the Neanderthals here. And I think I'm on the published record something
like eight years ago saying we will never see a nuclear genome of a Neanderthal. It's too degraded. It's too little there. It's impossible. [laughter] And you should, of course, never say things
like that because generally you're overtaken by technology. And in this case it was quite clear it was
high through-put DNA sequences -- sequencing that changed it -- machines and techniques
that came around to sequence millions of DNA molecules really rapidly and inexpensively. So you could then instead of trying to find
a particular little piece of DNA you're interested in, simply extract all the DNA from the fossil
and sequence all the fragments you had there, all the pieces of DNA, make up a little database
and then start looking through that database and see what parts fit to the human genome. So they might count from the Neanderthals
which parts -- which fragments are from bacteria and so on. And the first place where this worked was
in Croatia, a beautiful site in southern Europe, and from this little bone, which is 38,000
years old, this part of the bone there. And the first thing one sees and when one
looks at the DNA sequence is that they are indeed very short. It's tiny little pieces, hardly anything as
big as 200 base [unintelligible], average 50, 60. The other thing you will see is that the vast
majority of the DNA in such a piece of bone is not at all from the Neanderthal. Our very best bones have something like up
to 3, maybe 4 percent of Neanderthal DNA. The rest is all from bacterial and fungi that
colonized the bone when it was deposited in the cave. So we started a project where over a couple
of years worked a lot on improving the efficiency with which we come from the DNA and the bones
to something we can feed into the sequencing machines. The machines got more efficient in that time
in terms of how many molecules it could sequence. We looked through many, many sites and many
bones to find the ones with the most Neanderthal DNA in them, found three ones from that site
in Croatia that were then used and sequenced a little over a billion DNA sequences from
them. The vast majority of [unintelligible] do not
come from the Neanderthal, but from bacterial. But -- so we sort of matched these fragments
to the human genome until we had gotten together about three billion base [unintelligible]
Neanderthal DNA. So that means you had random fragments here
that together would add up to three billion base [unintelligible] the size of the human
genome. But these fragments were of course from random
places in the genomes. So sometimes we had fragments that we saw
a piece twice, sometimes even three times, but were lots of pieces we also just missed
by chance. So the genome we had back in 2010 covered
around 55 percent of the Neanderthal genome. But it allowed us to have a first overview
and start to ask some questions. And one of the first questions -- we were
interested in [unintelligible] question. Was there interbreeding with modern humans
when they came out of Africa? And we tried to ask that question in many
different ways. I'll just present one here. And that is saying that if modern humans came
out of Africa and would mix with people, Neanderthals in Europe, we would expect people in Europe
today to share more genetic variants with Neanderthals than people in Africa, where
there have never been Neanderthals. So we were then looking for tiny little signals
in the genomes. So we're very worried about errors in our
sequences. So we went out and sequenced five people that
live today to compare with so we would know the spectrum of errors would be exactly the
same in them. So one person from Europe and to us -- sorry,
that is actually the Neanderthal we sequenced, one person from Europe, here, and to us, of
course, our typical European is a French person, so this is a French person here. [laughter] We have two African individuals, one person
from China, and one from Papua New Guinea. And then we did a very simple analysis where
we just took two of these modern genomes to test it first to Africans and looked for all
positions where those two present-day Africans differ from each other. And we'd take the Neanderthal and count how
often does a Neanderthal match that African or that African? And it would be 50/50 right because Neanderthals
had never been in Africa, there is no reason to assume that it would be closer to one African
than the other. And indeed, it's about a little less than
100,000 matches to this one and to that one. Then we do the same analysis with a European
individual and an African individual. And to my surprise, I would say, we actually
found statistically significantly more matching to the European individual than the African
individual. Even more surprising to me was that when we
looked in the Chinese individual there was again more matching than to the African, and
even in Papua New Guinea that was also the case. So I was actually biased when we started doing
this, thinking there had been no mix with the Neanderthals, but if there was one, I
would expect it in Europe, where the Neanderthals had actually lived. But we now found that in China and in Papua
New Guinea. So the model is sort of supposed to explain
that, that has since been borne out by work by others, is that if you assume that modern
humans came out of Africa, the first -- they probably passed through the Middle East and
we know there were Neanderthals in the Middle East. So if these modern humans there mixed with
Neanderthals and then went on to become the ancestors of everyone that live today outside
Africa, they would have sort of carried with them this Neanderthal contribution out to
the world, [unintelligible] the parts where there were no Neanderthals to the extent that
up to a maximum, perhaps 2-and-a-half percent or so of the genomes of people outside Africa
come from the Neanderthals. We could also calculate with various tricks
about when this inflow from the Neanderthals had happened between 40 and 90,000 years ago,
fitting with the time when we believe modern humans came out of African and started spreading
seriously over the world. And there has since been a lot of follow-up
work of this by other scientists, but I can sort of never stop myself from pointing out
that the public is also very interested in what we do, and started writing to us in 2010. Many people wrote to us and self-identified
as Neanderthals. [laughter] And after a while I started seeing a pattern
in this correspondence. It was almost exclusively men who wrote to
me. [laughter] And there were very few women who self-identified
as Neanderthals. [laughter] So I do no real lab work myself anymore, so
I presented this to my group as sort of my research counting emails. [laughter] And they're, of course, very critical particularly
when I present something. So they said this is just as a payment, women
are not interested -- less interested in molecular genetics than men, so only men will write
to you. [laughter] But I went back to my correspondence and found
that that was not at all true because there were plenty of women who wrote to me and said
their husbands were Neanderthals. [laughter] Whereas, not a single man has written and
said that his wife is a Neanderthal. [laughter] And this is, of course, extremely interesting
for geneticists so that's sort of something I have to look into. But we, of course, do a few other things than
counting emails. So something we're interested in is other
forms of extinct humans. There are, of course, many, many forms of
humans that we don't find in the fossil record and we don't really know how they're related
to present-day people and to Neanderthals. And we are particularly lucky to work together
with Professor [unintelligible] Yankel [spelled phonetically] and his associate, Professor
[unintelligible] excavated many sites in Siberia, particularly they excavated this site in southern
Siberia on the border to Mongolia and China. It's a beautiful place and they excavate since
a number of years. And in 2008, they were actually very skilled,
I think, to find and recognize a tiny little bone and realize that it might come from a
human. So it's a fragment of the last phalanx of
the pinkie. So we extracted the DNA from this bone and
found, to our surprise, that it was extremely well-preserved. As I said, our best Neanderthal bones are
4 percent indigenous to [unintelligible] 70 percent. So it allowed us to produce a genome from
this individual about the same quality as the Neanderthal genome. And to our great surprise we found that it
was not really Neanderthal. It went back to common ancestor shared with
Neanderthals but far, far back. Neanderthals had a long, independent history,
longer than say the history deepest divergence as we have among present-day people. So we defined this as a sort of new group
of extinct [unintelligible] and based just on the genome sequences and we named them
denisovans after the Denisova cave, where they were first found just like Neanderthals
are then called Neanderthals after Neanderthal, where they were first found. What has then happened in the last three years
since that time is that we have improved our methods for retrieving tiny amounts of damaged
DNA very much. There are many parts to that, but one particularly
interesting one is that you extract across a double-stranded DNA from your fossil. And normally you then try to modify the [unintelligible]
so that you can go on and sequence it. But many of these molecules are chemically
modified so that you cannot actual replicate them or sequence them. So something that [unintelligible] in the
laboratory invented was that he actually starts by separating the two DNA strands, then ligate
on the synthetic piece of DNA and immobilize it here so that each of the two strands independently
have a chance to end up being sequenced. So that means if you have a chemical modification
of one strand that inhibits analysis, the other strand can still make it. So with this method and other modifications
we've been able to go on in the denisovan genome first that you have this slight overview
over where many pieces were missed, to now sequence it so deeply so that we actually
see all the positions to which we can map these short fragments, which is about two-thirds
of the genome, but with great accuracy. So you can do a lot of things then when you
have a very accurate genome. You can, for example, distinguish the two
variants that this individual inherited from its mother and its father. Just to illustrate that there is a genetic
variant at high frequency in Asia and Native Americans that's responsible for straight
hair and some other sort of texture of the hair. It's very common among people in China and
East Asia today. It's not in Europe or Africa and when we now
look at this denisovan individual it doesn't carry it either. And that's actually a common pattern. This individual doesn't seem to have any special
relationship to people in Asia today. But you can do much more than that. Since we have the sequence of the two chromosomes,
we can sort of estimate for a part of the genome here the time back to common ancestor
by making a little tree like that. And you can then go across a genome and do
that for many, many parts of the genome. And you can then use by a method developed
by Hennly [spelled phonetically] and Richard Durbin this to estimate population size over
time. Because when you have two chromosomes like
that, when they go back to common ancestor they would be more likely to go back to common
ancestor at a time when the population was small. So in this example here we would expect the
population size to have been small at this time where many of the chromosomes have a
common ancestor. So from a single individual the two genomes
and that we can estimate the population history of the entire population from which this individual
derives. So if we do this for present-day people you
will see very nicely it's past here, you go to the present here, and everybody, no matter
where we live on the planet, share a reduction in population size, an increase in population
size, and only the last 100,000 years or so do we start seeing a difference between Africans
we have more variation than non-Africans due to this bottleneck of coming out of Africa. And we could now add this individual and look
what its population history was. You then find that, if anything, it's a bit
bigger population size there for a time, but then it crashes and goes down and becomes
extinct. So this was very fascinating to me. This individual had a very different population
history from anybody who is around today on the planet. Something else we can do when we have very
accurate genome sequences, is that we can begin to see that this individual lived long
ago, so actually it's missing mutations when we compare to present-day humans. So we could see that it missed something like
1 to 1.3 percent of the mutations relative to present-day humans here. So we can then if we assume that the common
ancestor with the chimp is 6.5 million years, we'd miss 1.2 percent of the mutations here. We can estimate how old this bone is. And in this case it would be something like
60 to 80,000 years old. Now there are many caveats about this, particularly
about sequencing errors among present-day human genomes. They actually vary in age by about 20 percent
of this here or that we know they all live today. But I think it's an indication of what will
come in the future, that when we handle genome sequencing even better than now, that from
bones where we can retrieve a genome, we can actually date them. And in this case even more from a bone so
small that you could actually not use carbon dating, for example, on it. So we can, of course, with a genome ask just
for the Neanderthals, have these denisovans contribute to present-day people and indeed
they have. But surprisingly not in central Asia or Siberia,
but out in the Pacific, particularly aboriginal Australians, Papua New Guineans, and so on. So this then suggests that probably these
denisovans were more widespread in the past and was also in Southeast Asia. So this is a copy again of this bone. And I think it sort of indicates something
that will become more common in archeology in the future. They're from tiny, little remains like this. You can reconstruct a lot of population history,
even dates and often frustratingly. Like in this case we don't know how these
denisovans looked morphologically or what stone tools they made or any other things
we would traditionally know. So, just to summarize before coming to the
last part here what we think we know then about the origin of Neanderthals and modern
humans. And Denisovans -- we think that Neanderthals
and Denisovans have a common ancestor sometime in the order of half a million years ago in
Africa. They come out, they evolve in Western Eurasia
to what we call Neanderthals. In Eastern Eurasia somewhere to what we call
Denisovans. This is not to say that they were this widespread,
also not that they were the only hominins there at that time. We know there were other hobbits Homo floresiensis
in Indonesia, for example. We also don't know the border between these
two groups. We do know that in this region in the Altai
Mountains, at sometimes there were Neanderthals, at another time, Denisovans. Then modern humans evolved in Africa come
out and presume [spelled phonetically] in the Middle East mix with Neanderthals. They continue to spread around, and there
is now a paper that appeared in January that convincingly showed that there seems to have
been a second occurrence or mixing with Neanderthals in -- somewhere in Central Asia or so because
people in China, for example, have slightly more Neanderthal contribution in their genome
than people in Europe. There is then this mixture with Denisovans,
presumably somewhere in Southeast Asia by people that then spread out in to the Pacific. And these archaic humans then become extinct,
but they live on a little bit today if you'd like so that something like 1 to 2-and-a-half
of percent of the genomes of people in Eurasia comes from them. And you add on another 5 percent from Denisovans
in the Pacific. Now we've sequenced two genomes from extinct
hominins, found two cases of that mixture. I wouldn't be surprised if, for example, in
China one found other cases. I also don't think there is an absolute difference
between Africans and non-Africans in that Africans would not have a contribution. Clearly, Neanderthals -- sort of modern humans
appeared somewhere in Africa and also spread across Africa. And there is some indication from present-day
variation that there might have been a contribution from earlier forms of hominins also there. So we've clearly rejected the sort of total
replacement model for modern human origins. We have up to 7 and a half percent contribution
from other forms. But the big picture is still one of replacement. So we has to sort of have a name for this. I find sort of lethal replacement perhaps
a good idea. [laughter] So I would then like some bring up three things
that are sort of in the works. The first one is actually now accomplished;
we need a good Neanderthal genome. And we know have that since January when we
published it. It's again from the same site in the Altai
Mountain from Denisova Cave. We even found a finger bone, and deeper down,
two years later, they found a toe bone that looks like this. And we sequenced the DNA from it, and again
to our surprise, it was not Denisovan, but it was very close to other known Neanderthals
there. So this is a Neanderthal, and we sequenced
this genome to high coverage, again very high quality. We can compare it to present day people. For example, look over all how much variation
is it between the two genomes these individuals have inherited from their parents. So here are Africans that have more variation
than non-Africans today. And these are the Denisovan finger bones and
the Neanderthal toe bone that have dramatically less variation. But not only that, we also found something
very surprising. When we worked along the chromosomes in this
Neanderthal genome on the bottom here, we found large stretches, one here, of 19 million
base pairs where the two chromosomes were absolutely identical. And this of course indicates that the parents
of this individual was -- were closely related. So you can -- where we find much less of that
in the Denisova finger. So you can then model what relationships must
have occurred [spelled phonetically] been the case for the parents of this individual
here, the Neanderthal individual. The parents have been either, say half sibs
or grandfather granddaughter. Don't ask me to explain what double for double
fir castles [spelled phonetically] -- [laughter] -- this because I can't. But one of these four scenarios must have
been the case. So you begin to get some idea about socially
what happened in that cave quite a long time ago. And I think it would be very interesting in
the future to see in other Neanderthal sites if this is a typical pattern for Neanderthal
or something special here. You could, again, do the same analysis with
a Neanderthal here, comparing it to present day humans and Denisovans. And its population history matches that of
the Denisovans very closely. This difference here is probably just due
to that this bone is actually older than the Denisovan bone, but we don't know how much
older it is. We now then have two good genomes of a Denisovan,
of a Neanderthal. We have some sort of overview genomes from
Croatia and a place in the Corcuses [spelled phonetically]. So we can now begin to look at interactions
not only the present day people but also with anon between Neanderthals and the Denisovans. So if we do that, we find this contribution
from Neanderthals to present day people outside Africa that we know about or wanted to present
contribution from Denisovans, the people out in the Pacific of about 5 percent. We now find a tiny contribution Denisovans
also from mainland Asia in China for example of .2 percent. So a lot less. But we also see a contribution from Neanderthals
to Denisovans, and quite interestingly we see an old component in the Denisovan genome
that we do not see in the Neanderthal genome that comes from something else, that diverged
much earlier than these guys want to 4 million years ago from the human lineage. So it's very tempting to speculate that this
is Homo-erectus or something like that in Asia that contributes to the Denisovan genome. And I think future work will look more into
that. So a conclusion from this is that human forms
have always mixed with each other at least to some extent. We find no, sort of wholesale contributions
of 30, 40 percent from one into the other. It seems to be generally small extent. What you can also do now then, and there were
two papers that appeared in January. One of them we were involved in, and the other
was one from Josh Akey's group in Seattle where they had looked at contributions in
present day European genomes and East Asian genomes from Neanderthals. And they then find in some regions high contributions
from Neanderthals, very high percent of present day people carry fragments from Neanderthals
in certain regions of the genome. And if you look what genes are particular
present in such areas, one group of such genes are those that are involved with structured
proteins in the hair and the skin. So there seems to be that Neanderthals have
contributed something in the skin or hair to quite a lot of people that exist today. And now the group of genes that come from
Neanderthals and Denisovans was shown already in 2011, but Peter Parham's group that they're
involved in regulation of the immune system. So I can imagine that there were sort of Neanderthals
had resistance to certain infectious diseases that they had adapted to over hundreds of
thousands of years. And when modern humans from Africa picked
up this variance, they were of advantage to them, so they increased in frequency. I was quite fascinated by a paper that appeared
from David Altshuler's group, a big consortium that appeared in December where they found
a new risk allele for Type 2 diabetes, the type of diabetes you get in old age. And that risk allele was existed at high frequencies
in East Asia and in Native Americas. And when you look at this -- a tree of this
risk allele versus non-risk alleles, you find that the Neanderthal allele is right in there. So this is a variance that one has picked
up probably in Asia from Neanderthals into high frequency, perhaps because its variance
were of an advantage in a situation of starvation. And today when we have ample nutrition all
the time, it results in type two diabetes. So some of the sort of contributions may actually
have consequences also, medical consequences today. What you can also look across is genomes of
present day people. They stand for areas where there is no contribution
from Neanderthals, so areas that seems to be resistant to Neanderthal contribution when
we would expect statistically to see Neanderthal DNA in some people, but we don't see it. They are of course interesting because they
might point to things that we sort of don't accept from Neanderthals in the modern human
gene pool. And if we look in such regions of the genome
for what genes are particular present there, it turns out that is genes that are expressed
in the male germ [spelled phonetically] and in testicles. So it makes it very tempting to suggest that
in the hybrids -- Neanderthal-human hybrids, there may have been a problem with male fertility. And that's actually not uncommon when closely
related species or populations come together and make hybrids, be that say donkeys and
horses. It's a male offspring that's infertile, and
the female offspring generally is fertile. So it may actually be that there was some
biological problems when this happened. So something else that we then work on is
to apply this super sensitive techniques, particularly that single strand library techniques
to all the remains of hominins. So far we've sort of always said that we have
to stay within the last 100,000 years or so of human history. But we now apply this and try older things,
and we've been very lucky to work at a site in Spain called Cema de Luesos [spelled phonetically]
in Atapuerca. It's a deep cave, 30 meters down, so it's
very constant conditions where they find very many bones of something that most people would
call Homohydobergensas [spelled phonetically], so maybe an ancestor of Neanderthals. And from this femur here, we were able to
get -- we got samples, extracted DNA and are very degraded, very short pieces. We have so far been only able to retrieve
this mitochondrial genome that exist in many cultures per cell. And just to give you a feeling for this, we've
sequenced about 500,000,000 DNA sequences from this bone, and sift them down to be in
the end analyzed in the order of 10,000 to reconstruct the mitochondrial genome. But we were able to do that. And quite surprisingly we found that this
mitochondrial genome was related not to the mitochondrial genomes of Neanderthals, but
to the Denisovan mitochondrial genomes, but far back here of course. So it's very surprising, of course, that we
now find in Spain something that's related even though far back to the Denisovan mitochondrial
genome and not those of the Neanderthals that have been sequences. So one explanation for this may be that 400,000
years ago, we're simply so far back. So we're somewhere in the common ancestral
populations of Denisovans and Neanderthals and modern humans that they have variance,
that they're related to all of these. We may see other types of mitochondrial DNA
when we sequence more individuals from there. Another possibility is that this actually
comes from gene flow from some other group of humans into the ancestors here in Cema
de Luesos. And it's them only the nuclear genome that
would be able to clarify that. And we're sort of working hard to try to retrieve
at least parts of the nuclear genome. But what is really exciting to me is that
these techniques now allow us to go further back. Somewhere maybe to within the last million
years or so in the rare sites that well enough preserved for this. So finally then, the third thing that has
[spelled phonetically] a very excited about is to actually look on the sort of functional
implications for modern humans from what we can now see from the genomes. So for example looking in this regions that
lack Neanderthal contributions to see what hides there more than this male gene's expressed
in male germ line. So looking for things and that has appeared
in humans very recently since we separated from Neanderthals. In particular, those things that have become
fixed and are present in all humans today. So if we take a very strict criterion and
say what changes in the genome can we find that exist to -- in everybody today, no matter
where we live on the planet, but where the Neanderthals, Denisovans look like the apes. So things that changed here and spread to
everybody. That's if you like a genetic recipe for being
a fully modern human when we then compare ourselves to our very closest relatives. The interesting thing that this catalog of
such changes that flow could define us genetically as a species relative to Neanderthals and
Denisovans is not very long. It's not very long. It's a total of a bit of over 30,000 single
nucleotides that have changed, and some insertions and deletions. So you can actually look through it in an
afternoon in the computer. You can then of course say some of these we
have some inkling what they may be involved in. So there are something like 3,000 changes
in well-defined regulatory regions. And if we look at things that change amino
acids in our proteins in our body, we'll focus on that for a minute just to give you a sense
for how we can look this now. It's just 96 amino acid changes that have
changed. And they occur in just 87 different proteins
because some of them have multiple changes. So it's of course very interesting to look
at this and say is there some function that hides that may be behind what set modern humans
on this very special trajectory: the fact that we are 7 billion people on the planet,
and not in the hundreds of thousands that -- the hundreds of thousands that the Neanderthals
were. We're particularly interested of course in
things expressed in the brain. So it was quite interesting to see that if
we look for those 87 proteins and see where they're expressed in the developing human
brain, we actually see an enrichment of them in the proliferative zone in the developing
brains where new neurons are born in fetal development. And quite surprisingly, of these seven genes
that are expressed here, three of them actually turn out to be part in the machinery that
pull chromosomes apart during cell division. So that was quite surprising to me. I thought that was a very concerred [spelled
phonetically] function that would not have changed recently in human history. But there also indications that how cells
divide, how the stem cells divide in the developing brain, determines what types of neurons are
form and how many of them you form. So it may actually be that these three genes
are particularly interesting, that one should now go on study, but that's, of course, work
that will be very -- take a lot of work over many years by many biologists to do that. But I just wanted to end up saying how would
we do that? How would we take the next step to investigate
such human-specific traits? Because the problem is, of course, we have
no animal models. When we now want to study something that's
unique to humans. So I've gone a long sort of that is the question. And I've sort of spent many years going around
making jokes when I give talks and saying what we want to do is put Neanderthal variance
into transgenic humans. And human variance into transgenic chimps,
and then analyze them. And I've sort of said that that is impossible
-- [laughter] -- and would never be done. But this is sort of subtly not so much of
a joke anymore because there are people, there's even a very famous professor of genetics in
Harvard, George Church, that goes around and suggests that one should go much further than
what I suggested here. We should clone Neanderthals. We should engineer all these changes we found
in the Neanderthal genome into human stem cell and create a Neanderthal. And I think I'm sort of tired of discussing
it. I think it's technically impossible and ethically
totally, absolutely impossible. So why are we really thinking about it? But it's, anyway, a serious question. How will we go on with this? And I think there are some ways that I just
want to mention. I think that the human genome and I think
Eric is a perfect person to discuss this is a small enough place that all mutations that
are compatible with human life actually exist there out in the population. Every baby that's born has something like
50 or 100 mutations -- new mutations that are not there in the father nor the mother. The genome is 3 billion base pairs, we are
7 billion people on the planet, everyone has 50 or 100 mutations. So we will -- in the future when we sequence
millions and millions of people when you just walk into your doctor's office, I think we
will be able to find back mutations to the ancestral state. And probably it will be possible to work out
ethical ways to then study that. Something else that will come and we and others
are already in the process of doing it is engineering these interesting changes into
human stem cells and differentiate in two different forms of cells in the tissue culture
in the laboratory and study their effects in cells in culture. And I think something else one would also
be able to do is sort of put them into mice, maybe several of them together to study the
effects of particular biological systems. Before ending, I should also say there have
been many, many people involved in this. Many more people than I can mention. I then just want to put up one person here,
Matthias Meyer, who developed the single strand library method that -- without which we would
never have been able to get these high quality Neanderthal and Denisovan genomes. It's really transformed what we can do. Many people have helped in analyzing this,
particularly Jim Mullikin at the NHGRI here in the TESTA [spelled phonetically]. And before ending, I should also say that
some of the things I've described is also in a book where I sort of also describe the
dirty, little secrets of how this all happened. And I thank you very much for your attention. [applause] [laughter] [inaudible commentary] Male Speaker:
Very good. Am I on? Do -- hear me okay? Excellent, excellent. Terrific Svante, and my head is swimming,
not because of the complexity of the subject, but because that it's been done [laughs] and
is continuing to go on. And I just can't -- personally, I can't wait
to see what a Neanderthal mouse looks like. [laughter] The -- so what we'll do here is we'll have
about 20 minutes of conversation and maybe before our -- as we're winding that part of
it up, I'll mention that if you have questions, we have two microphones that are available. Don't get up now and get there -- and line
up for your question yet, but I'll announce when we're going to start to take questions
from the audience. I love the idea of liki [spelled phonetically]
replacement with regard to the variety of models that you've suggested. And, you know, I'm a bones and stones person. And those of us in that area of paleoanthropology
-- we love our categories. We like to slap the species name on things. And I think that most people also enjoy, you
know, what box do I put things in? Whether it be a woman put her -- putting her
husband in a Neanderthal category, or whatever, which is terrific. In any case, to what degree would you then
say that Neanderthals -- that the Neanderthal lineage and the lineage of living people were
reproductively isolated? Because I think this is one of the questions
that as -- in our hall of human origins that I get, that our volunteers who are the docents
who work there get a lot. Do we call Homo -- do we call Neanderthals
Homo-neanderthalensis as a separate species? And particularly of interest to me is that
for about -- what was it, be about 10,000 years that -- or maybe 15,000 years that Neanderthals
and Homo sapiens were both in Europe. But apparently you see no evidence, no echo
of interbreeding during that time? Svante Pääbo:
Yeah, so -- I mean we see this what I found it very fascinating this thing that we do
see something that the most reasonable explanation was that there was some problem with fertility
in the offspring, probably that the men had reduced fertility. So it wasn't just a sort of two groups that
totally -- they were perhaps even on the verge of becoming reproductive isolated that when
they came together. Then it's another thing that we as humans
and perhaps particularly as professors in academics you want to put things into boxes
and feel very uncomfortable if you can't put everything in boxes. To some extent I would say it's a sterile
discussion. Are we calling them a species or a sub species
if we now describe that they contributed 1 or 2 percent to the genomes of people today. In a way that is the interesting information. I think it's up to everybody if you want to
call them one or the other. We actually -- I never use these Latin names
because then I have to take a stand on it. I have the feeling if I say Neanderthals,
if I say Denisovans, modern humans, people know pretty much what I'm talking about and
I don't need to have a long discussion -- Male Speaker:
Yeah. [laughs]. Svante Pääbo:
-- but is chickening out. Male Speaker:
So noted [laughs] as a paleoanthropologist. I'm interested in the matter of the chromosomal
evolution that has occurred in humans since the separation from our last common ancestor
with a living species, chimpanzees. And all of the great apes have 48 chromosomes,
24 pairs; humans have 46 chromosome, 23 pairs. And as I understand it, the change that occurred
was where two chromosomes both that have -- that are the strands are joined together at the
end merged into one that joins at the middle: a fusion of two chromosomes into one. Are we pretty certain that the Neanderthals
had 23 pairs of chromosomes as you've shown? And how would we be able to detect? And do you have ideas about when that possibly
very important change in genetic evolution but at the chromosomal level occurred? Svante Pääbo:
Yes, they're more actually now sure that that fusion that created our chromosome two had
happened before we separate from Neanderthals. Because we can find this junction fragment
that of course created a piece of DNA that's unique to humans relative to the apes. Where one chromosome ends, the other one start
and fuse to each other. And we can look in our high quality genomes,
but the reads we have there for this junction fragment, and we find it many, many times
over. So that had actually -- so from that point
of view -- if two groups of different chromosome numbers have offspring, you'll often also
have problems in fertility in the hybrids. But that is not a risk-taking -- [spelled
phonetically]. Male Speaker:
[affirmative] And do you -- are you quite certain at this point that in the Atapuerca
material that goes back to about 400,000, that again the chromosomal fusion occurred
before then? Svante Pääbo:
That we don't know. That there we have so little information. We only have the mitochondrial genome. But there are studies on that sort of fusion
region that suggests that this is at least 700,000 years ago or more. Male Speaker:
[affirmative] The number that you put up here, and there were a lot of numbers that we've
heard tonight. But one of the ones that I think may be surprising
to many people. I find that when I crib from your articles
and things like this and mention this to people that people are quite amazed at the number
of base pairs in our DNA and that, as I understand it, between any two individuals, there would
be about 3 million base pair differences. Could you put a number on the number of base
pair difference between any two Neanderthals? And what does that indicate about the genetic
diversity of Neanderthals compared with the genetic diversity of human beings today? Svante Pääbo:
Yeah, so as I showed there, there is much less genetic diversity among Neanderthals
than among present day people. Now that said, we sort of study late Neanderthals
here, of course. So it may -- but they have something like
-- I shouldn't put a number on this because I don't really have it in my head. But they have something like a third of the
variation that we have today. They are among the least variable groups of
organisms we have among mammals so far. But again, these are late Neanderthals. Some of it is rather extreme as we saw the
perils of this in Neanderthals where [inaudible]. And there is also indication that there have
been close relatives further back in the generations of this individual also. Male Speaker:
Well, that's interesting, because one of the things that as I understand it come out from
the study of genetics of all living people is that the genetic diversity of living humans
is actually quite small relative to other primates. And it is been speculated that -- not speculated
exactly, but one part of the spectrum of thinking on that is that there is -- was a genetic
bottleneck in the evolution of our own species. Others might see that it was a low population
size over a long period of time. Do you think that the Neanderthals also underwent
a genetic bottleneck? And might this be a fairly common phenomenon
for the precarious nature of human evolutionary history? Svante Pääbo:
Yes, but sort of with a caveat that I don't know if that bottleneck had to do with the
origin of Neanderthals or say, the last Asian [inaudible]. We also see that we have now Neanderthals
from Spain; we have them Croatia; we have them from the Corcuses; we have them from
the Altai Mountains. But not only do they have little variation,
they also are quite distinct from each other. I mean, our interpretations relay that they've
been quite small but separated, isolated groups from each other. Male Speaker:
[affirmative] The idea of cloning a Neanderthal -- I'm glad you mentioned what you did and
had your thoughts about this. There is a gentleman named -- who's quite
famous named Stuart Brand who's also very strongly in favor of well, let's bring back
-- let's bring back the extinct forms of organisms. And one day at -- about three years ago at
dinner, he said, "You're a paleoanthropologist. Don't you want to see a Neanderthal?" And I said, "Well, yeah. I would love to see a Neanderthal, but give
me -- give me a time machine to go back rather than trying to bring one up to speed now." I'm interested that George Church at Harvard
also is in favor of this. You mentioned that you thought not only is
it ethically questionable at best, but is it technically possible given that every aspect
of biology needs an environment? Even the genome needs a molecular environment
in which to actually produce the organism for which those instructions have evolved. And is it possible to actually take the genome
of the Neanderthal that you and your team and others around the world have produced
-- and is it technically possible to bring back a Neanderthal? Svante Pääbo:
First of all, as I said at one point there, what we study is actually the single copy
part of the inner parts of the genome that occur only once -- that's where we're going
to have this very accurate sequence now. For about a third of the genome is actually
repeated; the sequences occur twice or more times; [unintelligible] fragments where they
fit, to which copy they fit. So we can only statistically say there were
this many copied numbers of this version, but we don't know how they are arranged. And we know that those parts of the genome
are also very important in many respects. So for a third of the genome we cannot do
it at all. For the other parts, I mean, in reality we
struggled just to put in two or three changes today, accurately in a stem cell. We can do it in one with great effort; putting
in more is much, much harder. And we're now talking about putting in, say,
30,000 back to the common ancestors and another 30,000 to make the Neanderthal and put them
in on both chromosomes. I mean, this is way [unintelligible] what
George Church can do. Male Speaker:
Have you just said, "never"? Svante Pääbo:
I haven't said quite never, but yes. Male Speaker:
I thought I should ask. Okay, I'll have perhaps one or two more questions. If you'd like to think about questions you'd
like to ask Dr. Pääbo. We have the two microphones here and you can
-- please stand up, don't be shy, and go to a microphone and ask your question. And one of the final questions I have that's
on my mind is that, as a person who does his research largely focused, not entirely focused,
but largely focused in Africa, you know, we tend to think that Africa is the happening
place for changes for the developments in human evolutionary history that have been
so important related to the origin of our species. And, yet, there are problems, as I understand
it, in warmer climates with regard to DNA degradation. Are there some steps, do you see some technologies
that you see clearly, or vaguely, down the road that can help deal with that? And allow the rich fossil record of Africa
and other tropical areas to be decoded? Svante Pääbo:
So, of course with these new sensitive methods, some things work that have previously not
worked for us. I think it's still the situation that there
have been very disappointing to try things in the Middle East, for example. I would really hope for areas of Africa with
a colder climate, be that southern South Africa, or Ethiopian Highlands, or deep cave sites,
if there are such things, with constant conditions, would probably be the best things. Male Speaker:
Right, right. I had the pleasure of visiting Svante's lab
several years ago and bringing a fragment of our Shanidar 3 Neanderthal from Shanidar
Cave in northern Iraq to his lab, but unfortunately there were only contaminates or hardly any
DNA in it at all. What was there proved to be contaminates. So that's the fossil that you can see out
in the human origins hall there, but, you know, with the kinds of remarkable developments
that you and your team and others around the world have been able to make, I remain, at
least hopeful that and other bones from more southerly locations, more near the equator
locations will someday be susceptible to study in this way. So, why don't we begin, and we'll just go
back-and-forth, and why don't we start over here. Please, sir. Male Speaker:
Yes, you showed the nice little pinky bone from the Denisovans. Can you say something about what fraction
of that tiny bone you actually had to destroy in order to do this experiment? And will there be plenty of that left in the
future for, let's say a decade from now when even your techniques will be more highly developed? Svante Pääbo:
So we used almost all of that. We used a sterile dentistry drill and we drill
inside; we just barely kept the surface of it. Of course we do micro-CT on things before
so that the more [unintelligible] is at least sort of preserved. Now actually there's another part of the story,
too, that I don't know if I dare tell, but it's in the book, so I can also still say
it. There was another part of that bone that was
given to another laboratory and so there is, but nothing ever really came out of that,
but there is another part of that bone that could perhaps be used for other analysis. There's also been two teeth found in the cave
that we have shown contained Denisovan DNA, but much, much less than the finger bone. So we have some idea about the dental morphology
of this Denisovans. Male Speaker:
Please. Female Speaker:
Thank you for a lovely talk. In written human history, we know that infectious
disease has had a major role in forming societies and really having major impacts on different
populations around the world. And I was really heartened to see that you
were analyzing aspects of the Neanderthal and Denisovan genomes that involve the immune
loci. Can you, maybe, tell us what you can extract
as information for how perhaps infectious disease may have impacted these early hominids
as well? Svante Pääbo:
Yes. That sort of is a good question. We can of course imagine that infectious disease
has played a big role. We have not anything really to say about this. It's quite hard to study this immune responses
because they are so repeated it's just sort of really hard to see which fragments come
from which. And Peter Parham's group at Stanford are really
the experts in these groups of these and it's their study I had that figure [unintelligible]
from there. The problem is a disease has genes that regulate
an immune response, it's a count of high frequency, but you do not know what pathogens [unintelligible]
that were responsible for this. There has been work recently from a previous
student of mine who is now a professor who studies the DNA of infectious diseases of
the Yersinia pestis, for example, and of other pathogens. So it might be the chance there are, for example,
some Neanderthal remains with what seems to be tuberculosis lesions. So, it may well be that one will be able to
study the evolution of these pathogens even back to part of our archaic continents. But unfortunately I have nothing really concrete
to say. Male Speaker:
I was wondering if the geographic range of the Neanderthal extended into areas were then
and maybe still are permafrost? What I'm getting at is there a finite, but
maybe infinitesimal possibility a preserved body could be found or maybe an Ӧtzi or maybe
a bog person in a temperate climate? Svante Pääbo:
I [unintelligible] find a permafrost Neanderthal is the question. I think there is a realistic chance of that. Unfortunately, one has not done that yet. But, if of course things are melting, we've
actually started collecting bones from people who collect mammoth ivory from the river systems
in Siberia. They find a lot of bones on the banks of a
river; they are there for the ivory. But one can sort of get them to sort of pick-up
what looks like human bones and it might be that we'll find things there that are of interest. That's not permafrost, but yes. Male Speaker:
Actually, as a follow-up to that, I'm wondering is there any possibility ever, do you imagine,
of finding DNA say to the place where you hold a stone tool? Svante Pääbo:
Yes, maybe, I would be skeptical. Or from blood stains on stone tools or things
like that, maybe, maybe. Male Speaker:
Dr. Pääbo, thank you again for such a lovely talk. And, it's very now interesting to think about
what it means to be a modern human considering your findings. And I was wondering, in reference, this is
more of a philosophical question, I guess. In reference to the findings that you identified,
there are contributions of Neanderthals and Denisovans that have been made to our modern
genome and considering that some of the subpopulations of modern humans have these while others don't,
I was wondering what sort of implications, if any, does this have for the definition
of what it means to be a modern human? Svante Pääbo:
Yes. To me, the definition of being a modern human
must be in the parts that we don't have from Neanderthals. In those regions when Neanderthals don't seem
to contribute, the Denisovans also don't contribute. It must, in a way, be in this catalog we presented
there; that is now a very strict catalog saying, "This would be genetic changes that are there,
as far as we can tell today, in 100 percent of humans on the planet." Can I of course relax that to say 90 percent
then that catalog gets about a bit more than twice as long, but it's in that catalog I
would see the genetic definition of it being a fully modern human. Because all of us, that is to say, we are
all modern humans, right, even if you don't have any Neanderthal contribution, if you
are from Africa and don't have any Neanderthal contribution, right. But this is a surprisingly short list to me. It is extremely interesting if some of these
have functional consequences I think. And I think many people work on this other
than us in the world. Female Speaker:
When I was a student, Neanderthals were depicted as being these hairy, shambling, brutes with
low brows and corresponding low IQs. I was wondering from your studies, and this
is highly speculative, if you clean them up and put them in a suit and so forth and put
them on the metro, would they stand out? [laughs] What would people say, "This is a
human being or this is a, I don't know what this is"? Svante Pääbo:
Probably you are better than I can answer this. [laughter] I would tend to think one would look twice. Male Speaker:
Yes. I would agree with that. Svante Pääbo:
Maybe not in a New York subway. [laughter] Male Speaker:
Thank you. I happened to have bought your book and read
it and it's fascinating. I would invite everybody [unintelligible]
I would invite everybody to read it. It's very interesting. Thank you. My question is more on the statistical side. Both in your presentation and your book and
what you say, it appears that you have very, very fine statistics. And we're talking about one out of 10,000
or 1 percent, half a percent. I come from the engineering side and the financial
side and these are just, in my universe, just not significant. The likelihood of error, the lack of certainty
on such a fine number of differences over a very large population, I've done a bit of
statistics, leads me to think that the statistics that you use must be very, very precise or
powerful. So, my question is very simple, do you really
trust the statistics and why do you trust them when they are so fine as to be infinitesimal? Svante Pääbo:
Yes, [unintelligible] of course should be skeptical about this. Of course, in the statistics, we sort of try
have as good models as we can. But it's of course not just a statistical
thing we have. You can also go in the genome and find pieces
of DNA that are 30, 40, 50 thousand [unintelligible] that are almost identical to the Neanderthal
genome, where the eye, for example, is almost identical to the Neanderthal genome and very
different from other people from over in Europe. So, you can sort of actually see with your
own eyes that there is evidence of this and that you don't find this in African genomes. So that is sort of [unintelligible] intuitively
direct answer to your question. We can also formalize that more where we,
for example, do analysis where we see that if you walk across a genome of me and I sort
of plot when I get closer and closer to the Neanderthals, most of that is simply a counterpart
of genome with a mutation, right, is rather low, but then I see that in those regions
where I get closer and closer to Neanderthal, I also get closer and closer to you because
we just have a low mutation rate in those parts. But then when I get to the regions where I'm
very close, almost identical to Neanderthal, I'm suddenly very different from you. So that also convinces us that there is a
population of sequences there that is really derived from Neanderthals. There are several lines of evidence like that,
actually. And I mean, this is so [unintelligible] I've
almost waited for someone in the world to publish something and say it's wrong. [laughter] Male Speaker:
Now there's a challenge, isn't it? Please. Female Speaker:
Thank you for coming tonight, I really enjoyed your talk. And first off, I'd like to tell you the Arkansas
definition of a double first cousin, brothers marry sisters, their offspring are double
first cousins. Two brothers marry two sisters, each set has
children, the cousins are then first cousins from both sides. Svante Pääbo:
These are double first cousins? Female Speaker:
Arkansas double first cousins. [laughter] Svante Pääbo:
Ah, yeah, cool. Female Speaker:
My question is -- Male Speaker:
Someone write that down, please. -- [laughter] Female Speaker:
-- a lot of the mutations, you said, are transferred from Neanderthal to modern human being with
the immune system. Do you think there's any way we can maybe
pull some more out and have maybe some new gene therapies and stuff to fight disease;
Alzheimer's, cancers, whatever. Svante Pääbo:
I don't -- so the question is, do we think that we can somehow learn from these variants? Female Speaker:
Maybe even manipulate modern human to go back to Neanderthal to fight off things maybe,
you know. Svante Pääbo:
Yes, I would be extremely, yes, for all these reasons that we don't clone Neanderthals;
I would also not go and manipulate the genomes. Even with the view to fighting diseases like
that. [inaudible commentary] Svante Pääbo:
That maybe something that's an earlier branch off [unintelligible] the real sort of attempt
to do that, after lots of discussions and negotiations with six, seven years ago, to
drill a little bit in the root of a tooth and we couldn't get any DNA out of that at
that time. Now that said, we are better at it now, but
it's also very humid, and very warm. I suspect it's actually not preserved. The majority of fossils, especially from such
climates, don't contain any DNA. That's not that this can be applied to everything,
unfortunately. Female Speaker:
Hi, I have a question about another human ancestor that's also a recent new comer to
our whole hominid species, Australopithecus sediba. So, I've been teaching anthropology at the
high school level for eight years and it's been really exciting because we keep getting
new species, like sediba. And so I heard, it's almost like rumors, that
there might be on some of those fossils some actual flesh or they think there might be
a little bit of something like that, and so would you be able to get DNA out of that? If that, sort of rumor, is actually true? Svante Pääbo:
So what was the rumor? [laughter] Female Speaker:
So, I've heard, I just took, actually, a course through Coursera with John Hoch at the University
of Madison and so he interviewed somebody who was working with the sediba fossils and
they think there might be some bit of, you know, actual material -- Svante Pääbo:
Soft tissue -- Female Speaker:
-- yeah, soft tissue. Male Speaker:
And that rumor is true in that it is a rumor. Svante Pääbo:
I mean, I would still think, so how old is sediba? Male Speaker:
1.9 million years. Svante Pääbo:
I would be very skeptical. I don't think it would be justified to sort
of sacrifice any of it to try to get DNA. But animal remains from similar place, [unintelligible]
attempt but I would almost think it was a waste of your time to do that today. Male Speaker:
So we know the Neanderthals buried their dead; we know that they created musical instruments;
we know that they painted; do you have sense of that portion of the non-African population,
what the DNA, the genomes contributed to modern people? So, blonde hair? Blue eyes? Musical ability? Svante Pääbo:
No, actually. All we know almost is just what I presented
there, unfortunately. I think there will be a lot more knowledge
in the future. I know that there are studies underway, for
example, where [unintelligible] look at cranial forms, [unintelligible] what Neanderthals
looked like from FMRI studies, medical studies. We also have genome sequence from individuals
to look at and now look at what Neanderthal proportion part of the genome that people
have and does it correlate with the features in the cranial [unintelligible]. So I think there will be some things like
that that will be known in just the next few years. But there has been a claim that red hair came
from Neanderthals. There's even a, sort of study, so, but those
mutations in the Neanderthal genomes we have, we don't see the mutations that now give red
hair in Europeans, so far. Male Speaker:
So it's a kind of a parallel evolution of red hair, is what you're suggesting? Svante Pääbo:
A parallel? I mean, we don't know if Neanderthals had
red hair. Male Speaker:
Ah, right, okay. Please. Female Speaker:
Hi, my question may be a little bit similar. I'm actually a cultural anthropologist so
I'm a little of my realm here. But, is there any potential benefit to having
either Neanderthal or Denisovan DNA. And, for example, if I'm looking for a husband,
should I seek out or avoid men with Neanderthal or Denisovan? [laughs] It's more about, is there any potential
benefit? Is there any something different about people
who have the Neanderthal? Svante Pääbo:
No, everyone we've looked at outside of Africa have Neanderthal contribution, but we have
different pieces, each of us, right. So you can actually walk around people in
this room and parcel together the Neanderthal genome by jumping from person to person, so
to say. And you can get something like 35 percent
of the Neanderthal genome that way. But, yes, we're just at the beginning of associating
any of the variants with anything in how we look, or behave, or things you might look
for in your husband. [laughter] Male Speaker:
That may not have been a question a scientist would ask, but it certainly is a very human
question. Please. Male Speaker:
My understanding is you worked primarily with mitochondrial DNA? Svante Pääbo:
Not anymore. Whenever we can, we really try to look at
the nuclear genome because it gives us so much more information. Male Speaker:
I wonder is it possible to use the male chromosome? Is that accessible, I mean, is it preserved
enough to use? Svante Pääbo:
So, by funny quirk of nature, these are females in the Denisovan high-coverage genome and
Neanderthal high-coverage genome, but when we find a male and we have one in Spain now,
one will be able to study the Y chromosome. At least those parts of them that are single
copy, the large part of them that are repeated we'll have problems with. Male Speaker:
Thank you. Male Speaker:
We'll take two more questions. Eric Green has a question. Eric Green:
So I'm going to actually ask a question of the moderator because I actually have something
that I think you might be able to answer to shed some light on. Everything Svante talked about has been made
possible because of remarkable technological breakthroughs in DNA sequencing to allow exquisite
sensitivity to be able to reconstruct genomic information from highly degraded bits of DNA. But, he'd be the first to admit, you even
heard in some of his answers, that what limits him now, will be some technical advances and
computational methods will get better, but really what limits him from doing some things
that even come up in the questions and answers of "wouldn't it be great if?" are better specimens and better preserved
materials. And one can't help wonder if somewhere in
this earth are better preserved samples where the DNA is more intact and we can get much
more accurate and complete genomic information from those specimens. But, we can't find it. So just as we've seen genomic technologies
advance this field significantly, are there new technologies on the horizon for finding
better specimens that can then be analyzed? Male Speaker:
Yeah, that's a good question. Well, if you look at the comparison of the
extent of genomic coverage of the Denisovan DNA compared with others from Vindija Cave,
caves are a good place to look. Caves in colder environments, so far, have
been very good to look. I know that in our excavations right near
the equator in Kenya that there have been times when I have been excavating, for example,
the fossil elephant butchery site that's featured in one of the snapshots through time in our
exhibit on human origins, whereas while we were digging we were actually seeing oxidation
of plant roots, of ancient plant roots right before our eyes as we were digging. At that point, we changed over to excavating
with gloves, sterile gloves and implements that we have not excavated with before or
handled in order to try to see is there something from the stone tools that we could recover. And we were able to actually see amino acids
related to keratin in hair on them. So that's an example of something where if
you, and this has gone on in one of the Spanish sites where you've worked on the Neanderthals,
El Sidrón, is that the name of it? Svante Pääbo:
Yes. Male Speaker:
Where people went in there, the excavators went in there with gloves in sterile conditions
in order to recover these things. I would say that the best place to look would
be caves. And the question is whether there are caves
that have been sealed enough in areas that are closer to the equator, places in Africa
for example, where one might try to look, but I think it's, you're work has shown, that
it's a little bit like looking for a needle in a haystack. Eric Green:
Are there better imaging technologies that are becoming available that can allow you
to find the sites to then try to dig -- Male Speaker:
Yeah, I mean, satellite technology has been great to be able to see exposed sediments;
exposures of sediments; places where the vegetation coverage is such that you can actually go
and you can see eroded hills and gullies to recover things. But, even there, when you get to outcrops
where you can dig, where nature does the first excavation, and you go in and you help nature
along by excavating a bit, we find the degradation of pollen; we find the degradation of organic
materials; and so one of the questions that could be really, you know, that would get
around that is if you could drill down like we've drilled a core for environmental purposes
out of the east African rift valley. But, the chances of hitting hominid bone in
a drill core that's four centimeters in diameter going down are quite remote, so there's going
to have to be some continued luck on the paleo-anthropological side and where possible, the use of sterile
techniques. Yes, last question. Male Speaker:
Thank you very much for an excellent presentation and also for an excellent book that you wrote
that talked about the decades of effort it took to develop these techniques, especially
dealing with such small fragments of DNA and the extensive amount of contamination. Early in your book you talk about the examination
of Ӧtzi, the Paleolithic man that was found in Europe, but you don't follow-up with what
we've learned later. And, I assume we've learned a great deal. One of the interesting questions perhaps you
could shed some light on is, to what extent is Ӧtzi different from us? He's clearly not a Neanderthal, he's much
closer to us, but is there a field of study of worth in looking at human beings using
the techniques you've developed since the last breaks 3,000 plus years ago now that
you've got these techniques to the point where they can look so specifically at individual
genes and get pretty good DNA registers and apply them perhaps on things in the last five
to seven thousand years. Svante Pääbo:
Yes, I think that's a sort of area that's expanding very drastically. There are many laboratories now that study
sort of Neolithic, Paleolithic, the transition to agriculture in Europe. So I think that will be extremely illuminating
and [unintelligible] first insights are coming suggesting there's quite an influx of populations
that came with agriculture. But, in northern Europe, there's also big
contribution from earlier hunter/gatherers to present day populations. So I think there will be a lot of things in
that timeframe that will come. That is obviously very, very close to us today
compared to Neanderthals, particularly. Had we sequenced this [unintelligible] person
today, we would not have reacted and said this couldn't be a person on the street today. Male Speaker:
In addition to the fossil Neanderthal from Shanidar Cave that we have on display, we
do have, here in the department of anthropology in this museum, one other fossil hominid from
a site in Afghanistan. And, I'm glad to say Svante's going to, I
think, go away with it in his luggage in a couple of days. Svante Pääbo:
You'll get most of it back. You'll get most of it back. Male Speaker:
We don't know how old it is. It comes from a site called Dari Ekor and
there's a plan to date the specimen and have to Svante's group sample the bit of cranial
bone and see what it means for, not only our collections, but for the study of human evolution. As a follow-up to that, I just have a question. How many fossil human specimens do you have
in your lab right now that you're working on? Svante Pääbo:
We have milligrams of bone material from hundreds of specimens that we have had. But many sites are of course many, many bones
for example. Male Speaker:
Where can one get your book? Svante Pääbo:
In a bookstore. [laughter] Svante Pääbo:
Amazon. Male Speaker:
And there is a bookstore in this museum and of course all around. Are you doing a signing by any chance, while
you're here? Svante Pääbo:
Not that I know of. Male Speaker:
Not that you know of. Okay. So in any case, well, I hope that we have
it in our bookstore. Does anyone know whether... Audience:
Yes. Male Speaker:
We do, okay, good, good, excellent. That's a thumbs-up on that. So, well, in any case, I can say it, Svante
can't, go buy his book. I want to thank you all for coming out on
a snowy evening and contributing to a great evening here together. And a tremendous thanks to Dr. Svante Pääbo. [applause] [end of transcript]
