Neanderthal Genome Offers Clues On Early Humans

Richard E. Green, assistant professor, biomolecular engineering, Baskin School of Engineering, University of California, Santa Cruz, Santa Cruz, Calif.

Richard Klein, professor, anthropology and biology, Stanford University, Stanford, Calif.

Researchers present a draft of the Neanderthal genome in the journal Science this week. Ira Flatow talks with researchers about the results of the genetic analyses, including a new finding that some modern humans have Neanderhtal DNA in their genomes.

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IRA FLATOW, host:

This is SCIENCE FRIDAY from NPR. I'm Ira Flatow.

According to the latest theories, Neanderthals died out in Europe, oh, about 30,000 years ago, give or take a few years, when modern humans began to replace them.

But various theories based on the discoveries of bone remnants have speculated on how Neanderthals and humans may have interacted in the time period and places that they did share.

If you had Neanderthal genome, you could compare it to the human genome and answer some of those questions, and that's what scientists have been trying to do over the years. They've been slowly assembling the Neanderthal genome, piece by piece, using fragments of DNA extracted from ancient bones.

And this week in the journal Science, they've presented the fruits of those labors. It's a draft of the Neanderthal genome, built by sequencing billions of DNA letters, you know, A, T, C, G. And that draft covers what they think is about 60 percent of the entire Neanderthal genome.

Now that they have a sequence, they've been comparing it to our own human sequence with some pretty unexpected results like evidence that humans and Neanderthals, may at some time, have been mating.

My next guest is here to tell us more about that. Ed Green is assistant professor of biomolecular engineering at the Baskin School of Engineering at the University of California, Santa Cruz. He joins us from a studio on the campus there. Welcome to SCIENCE FRIDAY.

Mr. RICHARD GREEN (Assistant Professor, Biomolecular Engineering, Baskin School of Engineering, University of California, Santa Cruz): Hi, how are you?

FLATOW: Hi there. Tell us what you have there. I said it's not a complete sequence, right?

Mr. GREEN: That's right. What we have is we call it about one full coverage of the genome. The data that we get come from these bones that are about 40,000 years old, and there are short, little, sequenced fragments just from some random parts of the genome, and then we map these to the human and chimpanzee genome, kind of to see where they fit in.

But because they're just random bits, we accumulate these data across random parts of the genome, and on average, we've seen every base about one time. But of course, some bases we just see because of stochastic chance more than once, and other places, we haven't seen at all yet.

But this, about 60 percent of all bases we've seen at least once, and on average, we've seen everything about once.

FLATOW: I understand that one of the big problems you have is these bones are really infested with microbes and their own DNA, the bugs, germs on there, right?

Mr. GREEN: Yeah.

FLATOW: So how did you just get Neanderthal DNA out of all of that stuff?

Mr. GREEN: Well, it's not easy, and we rely on the great body of knowledge that's been assembled about DNA sequence in the decades that these data have been accumulating.

We know a lot about what Neanderthal DNA ought to look like because we have the human genome, and we have the chimpanzee genome, and Neanderthal fits somewhere in between those.

So we can take all of these fragments, all these sequence fragments that we get, and use really powerful computers to compare the similarity that human and chimpanzee, and we can also look at all of the microbial sequences that we know about and ask: Does this look like something that is a fungus or a prokaryote, a little, single-celled organism that's been growing in the bone, or does it look like real Neanderthal DNA?

FLATOW: 1-800-989-8255 is our number. You can also tweet us @scifri, @-S-C-I-F-R-I. I mentioned earlier that one of the really surprising things you found was a bit of Neanderthal DNA in modern-day humans from Europe and Asia, implying that humans and Neanderthals may have mated at some period. Can you explain that a bit.

Mr. GREEN: Yeah, sure. So these analyses were done by our great collaborators in the consortium, a guy David Reich at Harvard, and another guy Rasmus Nielson up the road here at Berkeley, and really several lines of evidence point toward this.

So the first thing is really we also sequenced the complete genomes of five modern humans for comparison to Neanderthal: someone from France, someone from China and someone from Papua New Guinea, and then two African samples, a Yoruba and a San Bushman genome.

And what we have done, then, is take the Neanderthal data and compare it to these other genomes at every place where these extant, currently living humans, differ from one another. And making these comparisons, if Neanderthal is just a clean outgroup to everyone, if he is equally distant to everyone, then what we will see is the Neanderthal, at all the places where two humans differ from one another, Neanderthal will 50-50 match any two that we choose to compare.

But what we found, and it was quite a shock, is that there's a small but really statistically significant excess of the Neanderthal matching any one of the non-Africans compared to the two Africans that we've sequenced.

And furthermore, if we compare any two of the two, of the non-Africans to each other, the French versus the Chinese, for example, that the Neanderthal matches both of those about equally well.

So this suggests that there was perhaps an episode of admixture early on, before human population differentiation but subsequent to the time that our ancestors left African and colonized the rest of the world.

FLATOW: So that's why there was no mixing of the African genome, just the European.

Mr. GREEN: That's right.

FLATOW: Yeah, 1-800-989-8255 is our number. How has the research been greeted? There's been some skepticism, is there not?

Mr. GREEN: There has been skepticism. I think it takes time for such ground-shaking new data to really percolate through all of the fields of paleoanthropology that are out there, and you know, some people say of course, that's - we've been saying this for years. And other people say, well, I don't really believe it. And I think we're still seeing the full spectrum of reaction to it come through now.

FLATOW: Let me bring on someone who might add to that spectrum of reaction. Richard Klein is a professor of anthropology and biology at Stanford. Welcome back to SCIENCE FRIDAY, Dr. Klein.

Dr. RICHARD KLEIN (Professor, Anthropology and Biology, Stanford University): Thank you very much.

FLATOW: What is your reaction to this? Is there any fossil evidence that you know of that Neanderthal and humans, early humans, were interacting and possibly breeding?

Dr. KLEIN: Well, the question is more when, rather than whether there is any. I don't see any myself, but that's an arguable thing. The best evidence, the most widely published evidence, is a skeleton from Portugal that dates to about 25,000 years ago, and it's obviously irrelevant to the present issue. It's much after the time when Neanderthals and modern humans would have interbred, and I don't know that we could expect to see Neanderthal features in the skeleton.

It's easy for me to accept the idea that there was a very small amount of gene flow from Neanderthals to modern humans. We're talking about one to four percent, four percent maximum. I don't see any problem with that.

You know, it's perfectly reasonable. You know, it's hard to imagine that these populations didn't come - if they came into contact, that they wouldn't have had some kind of interbreeding, some kind - at least an attempt on one side versus the other.

What is a problem to me, and I've discussed this with Ed Green before, is the timing. And I - I'm just trying to figure out in my own mind, trying to make the archeological and fossil records fit with this evidence for interbreeding insofar as, you know, we have evidence, and when the contact would've occurred.

The only time I can see contact occurring that could've produced this interbreeding is between about 50,000 and 45,000 years ago, and it would've occurred in Western Asia and in Europe. And is that enough time, provided the evidence that we have for gene flow from Neanderthals to modern humans, and why wouldn't there - since the modern human population was expanding very rapidly at this time, even a tiny little amount of Neanderthal gene flow I would think would be much more obvious in modern human populations because the expansion would magnify it.

And I've just been trying to wrap my mind around that, and I don't have the expertise in discussing things like this that Ed Green does.

FLATOW: Ed, can you give some explanation about that question?

Mr. GREEN: Well, what we really bring here is a genetic perspective to this and can't probably answer, to the satisfaction of Richard and other people who study the fossil evidence of where Neanderthals were and where our human ancestors were, to their satisfaction at this point.

But what we really can do is put some constraints on this, that the signal that we can see now appears to - the most parsimonious explanation is that this occurred, this episode of admixture, occurred before the differentiation of the current non-African populations now, because we see this signal to about the same extent in the three modern human genomes that we've sequenced here and compared.

And it must have happened subsequent to the migration out of Africa because, as far as we know, Neanderthals were not found within Africa. More precisely, where exactly this happened and the demographics of this, how long the interbreeding took place and over how many generations and exactly where, is not something that we can address with great precision with the genetic data that we have right now.

FLATOW: If there were - was a mating of both, would we not find some human genome in the Neanderthal DNA?

Mr. GREEN: Well, this is something that we looked for, and there's reason to think - there is some theory that was kind of in place before we ever collected the Neanderthal data and looked at it - but some theory about what signal one might expect to see during this range expansion.

If Neanderthals were in place across Eurasia, and there was an expanding wave front of humans, then this theory predicts that it's much more likely that you see a strong signal within the genomes of the individuals who are coming across this wave front. But that's kind of one explanation, maybe not so satisfying for the pattern that we see.

Another thing that we can't say with much strength at this point, is that we don't see any - we can't rule out that there are Neanderthal, that there are human genes in the Neanderthal genome. Our power to see that direction of gene flow is not nearly as strong as it is to see it in the other direction. So we can't rule that out, at this point.

FLATOW: Richard Klein, what would - what kind of evidence would it take for you to be able to push back that clock as far as you're talking about?

Prof. KLEIN: Well, we'd have to have archeological and fossil evidence that the Neanderthals and modern humans are people who would have modern human genes overlapped in time and space before 50,000 years ago, and there isn't any. All the evidence that we have suggests the reverse, that the first contact was at 50,000. The idea that - to me, the idea that the gene flow was strictly - the detected gene flow was strictly from Neanderthals to modern humans makes perfect sense, given the sample of Neanderthals that's involved here. There are three bones off in Croatia. They - a couple of them dated to the - into the 30,000-year to 40,000-year interval. But those are minimum ages, those are carbon ages, and they could be much older than that.

And if they are much older than that - and the third one, you know, and others certainly are - then these are people - these are Neanderthals who were living in Europe long before modern humans appeared anywhere nearby. And there would be no chance for them to have received modern human DNA. So the only direction that we could observe in modern humans would be from Neanderthals.

FLATOW: Mm-hmm. Do you two scientists speak the same language? I mean, you're a mathematician, are you not, Ed?

Prof. GREEN: Computational biologist and geneticist. I would say that we're learning to speak the same language, and bringing this genetics perspective here. We need to learn this really quickly, and a dialogue like this a great first step.

FLATOW: And because, really, I hear the sub-context of this is - and correct me if I'm wrong, Richard - I'm a guy who deals with bones. I need to look at the evidence. I need to dig them up. I need to date them - you know, as we - as the classic archeologist does, anthropologist. And here you're saying, well, Ed, you know, you're not really in my business. You're just in a mathematical database, genetics business. I really need more data than just that kind of work. Am I far off on this?

Prof. KLEIN: Well, yes and no. I mean, what Ed does is something that is enormously sophisticated. And for somebody trained like me to go out and dig up old stuff, it, you know, I would - it's hard for me to put - wrap my mind around it. And I just accept it, because I accept that Ed knows what he's doing. I have no problem with that. You know, with regard to how the archeological and the genetic evidence, you know, have to fit, they do. I mean, we have to have - these are two different ways of trying to understand whether - how Neanderthals are related to us, and whether Neanderthals and modern humans interbred. And whatever the answer is ultimately, both lines of evidence should provide the same thing. If they don't, then we've got a problem. I mean, I'm sure Ed agrees with that completely.

Prof. GREEN: Yeah. I definitely agree with that completely. But I would just maybe add that what we do is not, hopefully, so refractory to understanding from lots of people, even laypeople. And one of the signals that we see that I think is pretty straightforward to understand and is really compelling is that if one looks at segments of ancestry and current genomes today - and this was an analysis done by Rasmus Nielsen - that most of the gene trees that you can infer across the genome show that the deepest roots are - generally exist only in Africa, or in Africa and outside of Africa, that we can mostly - across our genome - trace the deepest divergences in ancestry just to Africa.

But there are specific regions where this is not the case, where there are very deep divergences that exist only outside of Africa. And in one kind of shocking analysis that was done, we looked just at these regions, these very deeply diverging regions that exist only outside Africa and then ask: What does the Neanderthal look like here? With the hypothesis that perhaps these come from Neanderthal admixture.

And in 10 of these 12 regions, we see that the Neanderthal matches this region of the genome that has a very deep divergence that exists only outside of Africa. And this provides really compelling evidence that there was some gene flow. And that's the thing that we really feel like we can strongly add to - a piece of the puzzle that we can add right now, that there was this admixture. We can...

FLATOW: Let me just remind everybody that this is SCIENCE FRIDAY, from NPR. I'm Ira Flatow. Sorry, Ed, to barge in there, but...

Prof. GREEN: No problem.

FLATOW: So this is what your basic conclusion is about the discovery of the genome here, is how far back it goes and where it flows from.

Prof. GREEN: That's right.

FLATOW: 1-800-989-8255. Let's see if we can get some questions in before we have to take a break. Let's go to Dustin in Oshkosh, Wisconsin. Hi, Dustin.

DUSTIN (Caller): Hi.

FLATOW: Hi, there.

DUSTIN: Thanks for taking my call.

FLATOW: Go ahead.

DUSTIN: It's a little annoying, you know, that chimpanzees and humans have very similar genome. But I've read that - more specifically, the Y chromosome is nowhere near similar to the overall genome. Have you guys have been able to look at the Y chromosome of the Neanderthal at all in comparison to the human or chimpanzee genomes?

FLATOW: Ed?

Prof. GREEN: Yes. Yeah, that's a good question. The Y chromosome just inherited in males, it's what makes us male. Unfortunately, we were not able to see a lot of that with the data we have now. Most of the genome comes from three bones in this Vindija Cave, and unfortunately, they were three women there. So we won't get any Y chromosome data from those guys.

In a previous experiment, we looked at a few polymorphic sites - sites where currently living humans differ - from a different bone from El Sidron in Spain, and we're able to see that the - that particular bone, which came from a male, has a Y chromosome that's more deeply diverging than any current human now. But that's, of course, just one individual and doesn't give us a very global picture of what their Y chromosome looked like.

FLATOW: Thanks, Dustin. In the brief minute we have before the break, Ed, can you tell us how close we are in DNA and genome to the Neanderthals?

Prof. GREEN: Yes. We're very close. Neanderthals are...

FLATOW: One percent.

Prof. GREEN: Well, it's hard to - this is going to be unsatisfying, but it's a bit hard to give an exact number there, because the variation that we see still in - within modern humans today, Neanderthal falls within this for most of the regions of the genome. So Neanderthal can be thought of as a really deeply diverging human population - from a genetic perspective - across most of the genome. So it's something a little more than one in a thousand bases would differ between a human and a Neanderthal.

FLATOW: Well, why wouldn't they be considered human, then, if they're just as diverse as the humans would be?

Prof. GREEN: Well, that's a question I would leave up to others, whether or not they are to be considered human.

FLATOW: Well, and that's the first question I'm going to ask Richard Klein when I get back from this break. So, Richard, stay - standby - and you, too, Ed Green. Talking with Ed Green, who is at UC Santa Cruz, and Richard Klein from Stanford University. Stay with us. Our number: 1-800-989-8255. We'll talk more about this Neanderthal gene when we get back. Don't go away.

(Soundbite of music)

FLATOW: You're listening to SCIENCE FRIDAY, from NPR. I'm Ira Flatow. We're talking about the release of the Neanderthal genome this week with Ed Green, assistant professor of biomolecular engineering at the Baskin School of Engineering at the University of California, Santa Cruz - Richard Klein, professor of anthropology and biology at Stanford University.

And only last left of - Ed was saying that the genome, the Neanderthal genome, differs greater amongst itself than it does between - than humans differ amongst each other. And we - it's closer to humans in diversity than it is with humans amongst each other. And, Richard Klein, why, then, can we not classify Neanderthals as humans?

Prof. KLEIN: Oh, we can. And it is - these are - this is a matter of taste and semantics. I mean, for - it's convenient when you're writing about it. I'm not - I don't this, but other people talk about Neanderthals and humans, they mean modern humans, living humans. And it's, you know, to save them a word or two when they're writing. I - when I write, I write Neanderthals and modern humans, and I call them all humans.

FLATOW: Mm-hmm. And so this is sort of just an artificial construct we've been using over the years.

Prof. KLEIN: Yeah. And I would - I mean, when we talk about human evolution, we mean everybody since they split with chimpanzees, six or six-and-a-half million years ago, including the australopithecines. You know, they're sometimes called humans, too. It's just the way we use the words.

FLATOW: Mm-hmm. Ed, you know, people keep talking about taking genomes and reconstructing wooly mammoths. Would it be unethical to do this with a Neanderthal, bringing it back to life?

Prof. GREEN: Well, I am not an ethicist, but it seems pretty clear to me that not only is it probably not technically feasible at this point, but it would be incredibly unethical.

FLATOW: Mm-hmm. And you agree, Richard?

Prof. KLEIN: Oh, yes. And then we'd have problem of whether the product, you know, should be in a zoo or at Stanford.

FLATOW: Why is it so...

(Soundbite of laughter)

Prof. GREEN: I vote for Stanford.

Prof. KLEIN: Okay.

FLATOW: Well, if, you know, if we can transfer genetic material between humans from, you know, genetic engineering, and if the Neanderthal is human, why couldn't we get the DNA and put it in a human's egg and have it, you know, grow?

Prof. KLEIN: Well, the field of genetic engineering in humans, this is something that is very much in experimental phase right now, and there are technical problems with doing this. As I understand it, this is only done in very rare cases, and the vectors create problems, in many cases. And it's not something that one could just say, if only it were ethical, we could do it today. That's not the case at all. But beyond that, I think the ethical barriers will never move, although the technical barriers may.

FLATOW: Mm-hmm. Ed, what would you like to learn - how far do you have to go in the rest of deciphering the genome and what else - how different are they in other ways from us?

Prof. GREEN: Well, the - getting the genome sequence for a Neanderthal, one of the great uses for this is that it allows us to get a new perspective on our evolution, and it allows us to hone in on regions of the genome where we do differ from Neanderthals - who are, after all, our closest, extinct relatives. And we're using these data now to do that, to find regions where it looks like perhaps there were some important episode of adaptation in our human ancestors not that long ago, even since we split from Neanderthals, that may be - may have been important for, you know, adapting to the environment as we spread out across the world.

And what's interesting is we've identified a few regions, and there are some cool genes in there that have to do, perhaps, with brain function. And the next thing is really to understand what exactly changed there and why and what advantage - benefit it might have had.

FLATOW: Are there any genes you've recognized for appearance, that may have changed our appearance?

Prof. GREEN: Yeah. Well, there's one called RUNX2, which is a gene that is involved in bone development. It's something called a transcription factor, which just means that it's a gene that controls the expression of other genes. And it sits top this regulatory cascade that leads to bone development. And one of the things that we know that's pretty interesting about this gene is that there are people living today who have inherited mutations in this gene that have cleidocranial dysplasia, which is this syndrome that leads to an altered cranial morphology and altered shoulder and rib morphology.

And one of the things that we do know that's different about Neanderthals and humans - all we get are their bones, and we can compare the bones. And, in fact, they never would have been recognized as something different if the bones weren't a little bit different. And there are important differences in the crania and in the - and in ribs. So this is very suggestive that perhaps this could have been conferred some selective advantage, that we're different than they are for some reason. Of course, we don't know what that reason was, but now we know where to look.

FLATOW: And, Richard Klein, he - Ed knows where to look genetically. Do you have any new ideas given this undertaking, this research that published this week about where to look for the fossil evidence, newer places?

Prof. KLEIN: Well, the problem with the fossil evidence is that tearing it up is a matter of luck more than anything else. Tomorrow, somebody could find something that was totally surprising, a Neanderthal in Morocco or something of that sort, and we'd have to go back to the drawing boards and start rethinking this whole question of interbreeding and everything else. I don't think it's very likely to happen.

I think the fossil record is fairly clear on, you know, the separation of Neanderthals and modern humans. They were separate in terms of their evolution, one in Europe, one in Africa, from at least 400,000 years ago. Modern humans had exploded from Africa about 50,000 years ago following a change in their behavior there. And, you know, we're trying - from my point of view, the most interesting question that I think that research can address is what accounts for the fact that modern humans were able to spread from Africa so rapidly, explosively and replace the Neanderthals? Was there something in their genes that gave them an adaptive advantage, maybe an intellectual advantage, who knows what, over the Neanderthals? And the genes that Ed and his colleagues have isolated could include genes that would bear on that.

FLATOW: All right. Thank you. That's a great way to end this segment. Thank you very much for taking time to be with us, Richard.

Prof. KLEIN: Thank you.

FLATOW: Yeah, Richard Klein is professor for anthropology and biology at Stanford University and Ed Green is assistant professor of biomolecular engineering at the Baskin School of Engineering at UC Santa Cruz. Have a great weekend both of you.

Prof. KLEIN: Both of you.

Prof. GREEN: Likewise.

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Hey Good Lookin': Early Humans Dug Neanderthals

Re-creation of a Neanderthal by paleo-artist John Gurche i i

Someone who looks like this could be in your family tree. Chip Clark/Courtesy of the Smithsonian Institution hide caption

itoggle caption Chip Clark/Courtesy of the Smithsonian Institution
Re-creation of a Neanderthal by paleo-artist John Gurche

Someone who looks like this could be in your family tree.

Chip Clark/Courtesy of the Smithsonian Institution

Be careful whom you call a Neanderthal. You may be one yourself. Or at least you may have Neanderthal ancestors.

That's the conclusion of a study being released Thursday that examined DNA extracted from Neanderthal bones more than 35,000 years old.

More Than A Handshake?

There's little question that modern humans and Neanderthals bumped into each other once upon a time.

"The archaeological record shows they overlapped between about 30,000 and 80,000 years ago," says David Reich, a geneticist at Harvard Medical School.

There was some fossil evidence that they may have done more than shake hands in passing, but the initial genetic evidence suggested otherwise.

"And so the big open question was whether they exchanged genes during that time when they overlapped in the Middle East and in Europe," he says.

To find out whether the two human species interbred, scientists from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, launched an audacious effort to sequence all 3 billion letters of Neanderthal DNA. As hard as it may be to believe, fragments of DNA can survive in bones that are more than 30,000 years old. New techniques can sequence those fragments, and new software can line the fragments up.

Neanderthals Crib Sheet

The main strategy for finding whether modern humans and Neanderthals exchanged genes was to compare the Neanderthal DNA with DNA from modern humans — some whose ancestors had remained in Africa, and others who had migrated to Europe, Asia and the New World. If the Neanderthal DNA was more similar to the non-African DNA, it would indicate that Neanderthals contributed their genes after the first modern humans migrated out of Africa.

Reich says that's what they found.

"The non-African is more closely related to the Neanderthal," Reich says. "Quite definitely. Highly statistically significantly overwhelming evidence that they're more closely related on average to Neanderthals."

In other words, Reich and his Leipzig co-authors are totally sure that Neanderthal genes found their way into modern humans when the two species intersected. They report their findings in the journal Science.

"The simplest possible explanation is that it occurred once," Reich says. "But it very easily could have occurred on multiple occasions. Perhaps it's likely that it occurred on multiple occasions."

Reich says it's hard to pin down exactly how much DNA Neanderthals contributed to modern humans. "We estimate about 1 to 4 percent of the genetic ancestry of non-Africans is from Neanderthals," he says.

'Neanderthal' Is No Insult

And just to be clear: Reich says there's no stigma to have a bit of Neanderthal heritage.

"Absolutely not," he says. "In fact, people who have Neanderthal DNA have done just fine in our society."

Now that scientists have the sequence, they can start looking for regions of DNA that differ between Neanderthals and humans.

The bones in the study came from the four archaeological sites shown here.

The bones in the study came from the four archaeological sites shown here. The numbers indicate the dates (before present) from which the bones came. So, the samples from the Vindija site are more than 38,000 years old. Courtesy of Science/AAAS hide caption

itoggle caption Courtesy of Science/AAAS

"And then, once the regions are identified, [we can] look to see what genes are here, what biological sense can we make of this," geneticist Richard Green say.

Green recently left Leipzig to join the faculty of the University of California, Santa Cruz. He says they've already begun to identify genes that have changed — for example, genes that control the tails on sperm, genes that are involved in wound healing, genes that affect the shape of our hair.

Learning About Ourselves

Along with the chimpanzee genome completed a few years ago, the Neanderthal genome will help scientists like Green pin down the genetic changes that made modern humans human.

"Which one of these happened very recently, since we split even from Neanderthals? And which ones of these are much older and happened in the 6 million years or so since we diverged from chimpanzees?" Green says.

Green says for the moment, the real value of the Neanderthal genome is what it tells us about how modern human evolved. John Hawks, an anthropologist at the University of Wisconsin, agrees.

Hawks compares this finding to the first time humans were able to look back at the Earth from beyond Earth's orbit.

"We can say, 'Here's a picture of what we are from the outside — from the distant past,' " says Hawks. "And we can use that to get a new picture of what we are. It's amazing. I can't express how I feel this morning. It's really cool."

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