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Unit 9: Human Evolution
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Ajit Varki, MD

Ajit Varki, MD
Ajit Varki, MD, is a Professor of Medicine and Cellular Molecular Medicine and Director of the Glycobiology Research and Training Center at the University of California at San Diego. He studies the medical and evolutionary applications of glycobiology (the study of glycans, sugar chains that regulate many cellular functions).




Could you define the word Hominid?
The term hominid was traditionally used for all the different species that existed after the time that we had a common ancestor with the great apes, the chimpanzees and the bonobos. And so all the different ancestors of humans are all considered hominids. Usage of the term has changed recently to include all humans, and all of the great apes.

Talk about the inheritance of mitochondrial DNA.
Most of the DNA that you hear about is in the genome; it is in the nucleus of the cell, but there's also a small amount of DNA in the mitochondria, which are the "powerhouses" of the cell. And this mitochondrial DNA is typically inherited from the mother, because the mitochondria come from the eggs of the mother - and so this mitochondrial DNA is sometimes used to follow the genealogy of individuals based on a maternal inheritance.

What is the Regulatory hypothesis?
The regulatory hypothesis for explaining humans originated from Mary-Claire King and Alan Wilson in the 1970s, when they noticed that the early evidence available at the time showed that there was hardly any difference between chimpanzees and humans at the level of gene or protein sequence. So, they suggested that possibly in fact there may be no gene or protein differences, and that all the differences are due to differences in how genes are expressed.

Maybe an analogy one can use is, if you say the genome is a recipe book - the recipe book doesn't do you any good till you decide which recipes to use. In the same manner, you have to express genes, and not all genes are expressed in all places.

So simply by regulating the expression of the number of genes and types of genes in time and space, one could imagine a situation where in fact there were no differences between chimps and humans in terms of the actual genes and everything was due to just regulation. Now in fact as it turns out now, we know that that hypothesis is partly true, but many other possibilities also exist.

What is messenger RNA?
The sequences coding for proteins are present in the DNA in the genome, but they first have to be transcribed into RNA in the form of RNA sequences, and a portion of this RNA provides a code for translation into proteins - and that portion of RNA produced from the DNA that codes for proteins is called "messenger RNA."

How would you define glycobiology?
The field of glycobiology is a relatively new field. The term was only coined in the late 1980s. It was known from the early days of biology and biochemistry that cells are not just made up of DNA, RNA, proteins and lipids(or fats), but that there are also a lot of sugars.

Now some of these sugars are involved in energy metabolism, but a large number of different kinds of sugars are found coating the surfaces of all cells, of many proteins, both inside and outside the cell, and there's a rather large amount of them. But the study of these sugars got left behind in the molecular biology revolution, because they were much more complicated to study, unlike DNA and RNA and proteins that run in straight lines, in strings. These sugars on the other hand have complicated branching structures, and so it became very difficult to study them.

So only recently, in the 1990's really, did the technology to study these sugars in the same way that one studies the other molecules become available, and so somebody coined the term "glycobiology" which is now popularly used. In a sense, glycobiology is really a subset of classical molecular biology and perhaps one day it'll re-merge back into molecular biology. But for the moment, because it's somewhat specialized, there's a need for this specialized field.

How did you get involved in this subfield?
I'm actually originally trained as a physician, and I specialized in hematology, which is the study of blood cells and blood diseases; and oncology is the study of cancer and treatment of cancer.

So early on, when I was training in research, I noticed that some of the blood cells, like red blood cells and white cells in the blood, were known to be covered with this coating of sugars, and the more I read about it I realized that it's not just a few sugars. It's a thick coating. It's like an icing on a cake. Another analogy would be that if you look at the Amazon jungle and that was the surface of a cell everything that's green would be the sugars. That's the sort of density we're talking about. So this was in the late 1970's to early 1980's, and I just thought this was fascinating, and I got into studying these sugars, and I decided not to do what everyone else is doing which, is studying DNA, RNA and proteins, and later on, it turned out that this became a field called glycobiology.

Talk a bit about the research you do.
The surface of all cells is covered with these sugars, and if you were to go to the outermost tips of the sugar coating, the part that really faces the outside of the cell, you would find a particular family of sugars called sialic acids.So there are these acidic sugars right out of the tips of all these sugar chains. And this is a family of sugars that I got very interested in. That's the primary focus of work in our lab.

Now we study the role of sialic acids, in how viruses bind to cells, how cancer cells get around the body and how the immune system works. But in early work we ran into a finding that suggested that this had something to do with human evolution, and it actually came from my background in hematology. It's known that when you give animal serum to humans, which still has to be done in some circumstances-for example, horse serum is given in certain circumstances to help certain situations-the patients will develop an immune response naturally, given a foreign serum.

But round about the early 1980's, when I was seeing a patient with that circumstance-it's called "serum sickness"-some other people reported that part of the reaction that patients had against animal serum was against a particular kind of sialic acid. One thing then led to another, and I began to realize that this probably meant that humans didn't have that sialic acid that they were making an immune response to.

And so in the late 1980's, I started approaching this question, and along with a colleague, Elaine Muchmore, we decided to go looking. We found that humans didn't have this one particular sialic acid which has the rather long name of N-glycolylneuraminic acid, or Gc for short, if you like. While humans didn't have it, all of the animals we studied had it. And it's really only in the 1990s that we got around to studying our closest evolutionary relatives, the chimpanzees and the bonobos and the gorillas, orangutans, the other great apes, and we found that they all had it. So in that respect, the pig and dog and cat and chimpanzee are identical and humans are different.

It's only in the late 1990's that we finally figured out the genetic basis for this and it turned out that all humans on the planet are mutants, in that we are missing a gene responsible for making this particular kind of sialic acid called Gc.

Now there are actually two major kinds of sialic acids in, say, an ape cell. One is called N-acetylneuraminic acid, or for short, Ac. The other one is Gc. But Gc comes from Ac, and so this gene produces an enzyme that can change the Ac to Gc. So actually humans are missing the enzyme, and there are really two differences. Humans don't have Gc, but we have excessive Ac, the precursor form. So we have the same total amount of sialic acid, but the sialic acid pattern of the cell surface is very different because you have this one sialic acid that's missing and too much of another kind.

That led us into getting interested in human evolution, and there have been many different ramifications of this. It has also led me into a more general interest in the issue of differences between chimpanzees and humans because it turned out that this was one of the first known genetic differences between humans and chimpanzees, quite different from the regulatory hypothesis that we discussed.

So what's the significance of the missing Gc? How much do the animals express?
It seems to vary a lot between species. Every other species we've looked at-with the possible exception of some birds; we haven't fully examined them-have Gc, and it just varies in amount in different cell types and different lineages, and it seems like something regulated in many different systems. I mean I'm not sure exactly why. But especially in the great apes and the primates, we find generally about equal amount of Ac and Gc. So, since the time that we had common ancestors with the great apes and other primates, we have undergone a pretty significant change.

What can Gc knockout studies tell us?
They're underway, but there's no call to do this kind of study in primates, - in fact I would consider it unethical to do a study of any kind of gene knockout in a chimpanzee. The only model we have right now is the mouse. In the mouse, as you know, it's quite possible to eliminate genes or over-express genes and so on. So we have now a mouse in collaboration with a Japanese group, where this gene has been knocked out, sort of like one sees in the wild type human. We've just being to study that mouse.

We have been trying to make a mouse, for reasons that we can get into later, that over-expresses this gene, particularly in the brain, and there actually we've had great difficulty making such a mouse, and we don't know what the difficulty is. Is it just technical? Or is it in fact telling us something about the system? Unfortunately, at this point I don't have any conclusions I can relate on either front.

How does all this relate back to histology?
These sugars, as I said, are scattered on the cell surface, and each cell type is different. So if you were to just take an organ like the liver or the brain and take a piece of it and grind it up and extract the sugars, you wouldn't know which sugars came from which cell type because there are multiple cell types in any tissue. So it becomes really valuable to go in and actually look at tissues directly, at sections of tissues, and probe them with different probes that pick up different kinds of sugars. This, in a general sense, is glycobiology and it is very valuable. It just so happens that there are many such proteins that recognize specific sugars that come from plants and animals, and we have many of these probes. So I'm very fortunate that my spouse and collaborator Nissi Varki is an expert on this kind of histology, and so she does a lot of these kinds of studies, and we've made comparisons between humans and great apes and so on. Specifically with regard to Gc, we have raised some very specific antibodies against the Gc, and so we can probe human tissues and actually Nissi has recently found that there may be a little bit of Gc in humans using this specific antibody. So, it's a very powerful approach to tell a lot about what's actually happening at the cellular level in a complex tissue.

What is the definition of histology?
Histology consists of sectioning a tissue sample, an organ sample. You cut a very thin slice of it, and put it down on a slide, and then fix it to the slide, and then you come in and stain the tissue in various ways, either with a generic stain just to see cells, or you might use a specific antibody or a probe to pick up a particular sugar, and so on. And then you would look under the microscope.

Now here's where the expertise of the person looking under the microscope becomes very important. You require somebody who is an expert at understanding what they see. It's very complicated, the way the tissues look, identifying each cell type, and also being sure that anything that's being seen is a true finding and not an artifact. There's a lot of potential for artifacts in doing that kind of work. So, again, we're fortunate in our group to have expertise in dealing with that.

How are immunohistochemical assays converted to an histopathological interpretation?
Immunohistology consists of taking that tissue section and putting down, for example, a specific antibody that binds to a particular kind of structure, and then washing away the excess antibody and detecting where that antibody bound labeling it with certain colors and so on. So that's Immunohistology.

And histopathology simply means that you take the tissue and stain it with some generic stain that lights up the membranes and the nuclei and so on, and then you really need an expert who knows what they're looking at to tell that this histology, the organization of the cells or the types of cells and patterns, are not normal; that they're abnormal. And so this is what a pathologist does.

Can you talk about your work with Svente Paabo's team on protein expression?
This was a study that originated to try to test the regulatory hypothesis, to look for differences in gene expression between chimpanzees and humans. Elaine Muchmore and I initially did a study like that here at UCSD, when we found that Svente Paabo and his group at the Max Planck Institute in Germany were doing a similar kind of study. And, given our resources and expertise here, and the resources and expertise that Svente had, we decided it made more sense to collaborate with him.

So we basically obtained the chimpanzee and human messenger RNA's from different tissues and qualified them and checked that they were good and so on. And Wolfgang Enard in Svante's group really did the actual work of the microarray, which consists of seeing which genes are being expressed, so it's not really protein expression. It's gene expression. You're looking at messenger RNA.

So what was done, then, was to take tissues like liver or blood, where we don't seem to find a lot of functional differences in humans and chimpanzees. I mean if you do a typical blood test in the hospital on chimpanzees, there are very few differences you can pick up compared with humans. If you didn't know better, you'd think it was a human sample.

Likewise, there's not a lot known about any differences in the liver. On the other hand, the brain is a place where, at least functionally and in size, we'd say there are differences.

So the comparison was made between gene expression, between individuals, between species, and between organs, and so on.

And the long and the short of it is, as expected, there are a certain number of gene expression differences in the liver or the blood. In the brain, there are more gene expression differences. But you still could argue that this is something that is special about the chimpanzee, not the human. So what was done was to get similar samples from the rhesus monkey, which shared a common ancestor with the common ancestor of the chimpanzee and human probably 25 million years ago or so.

So it turned out that if you looked at a gene expression differences between the rhesus monkey and the human and the chimp, if you were looking at the liver or the blood, you got the expected pattern. That is, humans and chimps look very similar to each other, and the rhesus monkey looked very different. The term used is "outgroup." The rhesus monkey seemed to be the outgroup. But when you looked at gene expression in the brain, the chimp and the rhesus looked relatively similar, of course with some differences, but humans looked somewhat different.

So that favors the regulatory hypothesis: that gene expression differences in the brain have occurred, and that these may be partly responsible for the differences in the function of the brain between humans and chimps and rhesus monkeys. And of course that's just part of the story, and we only looked at adults - and of course many of the samples came from autopsies and so one could certainly argue about whether this tells you too much. On the other hand, the result is in the direction predicted by the regulatory hypothesis.

What can gene expression in the brain tell us about human evolution?
I think we only compared the liver, blood, and brain, and we chose liver and blood because they were organs and systems where there didn't seem to be many differences. Now there are many other situations where there are rather dramatic differences. For example, the skin is the obvious one. The skin is obviously very different from that of the chimp, and hair and other things like that. There's some evidence that the reproductive system is somewhat different.

For example, the breasts are very different. Other tissues where there are differences might be in the muscle. Chimpanzees are much stronger than humans. They seem to be much stronger for reasons that are not clear. There are structures like the sinuses, and things like that, which are different. So there are many other organs where there are differences between humans and chimpanzees, and of course brain is the one that we all tend to be primarily interested in. In fact I have the view that it's not going to be easy to figure out. It's going to be a very complicated problem.

I think that comparing some of these other tissues may give us indirect clues. After all, if a gene changes expression for example, and changes the distribution of hair on the body, that might be the same gene whose expression or structure change, resulted in a change in some function of the brain, and it's much easier to study skin, for example, so I think it's worthwhile considering that there are other tissues and cell types that are different too.

Would you say that chimps and humans are really so different, given our genetic similarities?
I think it's a very popular notion to say that chimps are so similar to humans and I think it's an appropriate notion, because in times past we always had this view that humans were so different and unique and special. And clearly it's been shown over and over again, at the biological and the functional and behavioral levels, that in many respects the chimps are very similar to us. And that makes sense, because after all we evolve from a common ancestor.

On the other hand, I personally think that that notion has gone too far, to the point of saying that there's not much difference at all. I think an average layperson will tell you that there are differences, but even if you are a little more careful with the specific features, I think that you can show that there are several aspects of humans where we are different in situations where the chimp is similar to the gorilla and similar to the orangutan or the other great apes — and yet humans are the ones that are different.

So I personally think that there are differences to be explained, and they're quite significant. In fact, there's one school of thought that I subscribe to, that the great apes, as a group, are a group of animals who have been evolving slowly - they're relatively conservative, if you will. As a group, they haven't undergone dramatic changes.

A friend of mine, Maynard Olson in Seattle, would point this out and say that humans are the ones that have really changed a lot, and I think Christopher Wills, who you're going to talk to, can address this further. Actually, Chris and I did some work together but never published it. In his book he would say humans "stick out like a fishing pole" the term he uses.

There's another classic term. I forget who said it, but somebody pointed out that humans are like "hastily made over" apes, as if evolution had quickly done some multiple changes resulting in what is "human". And of course, in the end, I don't disagree with the people that say we're very similar to apes. I just say that I'm interested in the differences. That's what I want to study. And that admittedly is an anthropocentric view. It's a view coming from a human, but I'm a human, and I want to know what makes me human.

What are the latest estimates of when humans split from the apes?
Estimates are that we shared a common ancestor with the orangutans about 13 million years ago; with the gorilla about eight million years ago, and with the chimp perhaps six or seven million years ago. The chimp and the bonobo are sister species. And there's not a lot of other work to really indicate where the gene expression differences have been major contributors to human evolution, only this recent work that we were involved in, and so it remains to be seen.

On the other hand there is an alternative view. Actually Maynard Olson is part of this, what he calls "less is more". The notion is that when you have a very conservative lineage of species, if you want to make sudden changes it's easier to make the changes by eliminating genes than by gradually tweaking or changing existing genes slightly. And there's evidence for that.

Obviously we have one case where there's a gene knocked out in humans: the Gc sialic acid. In fact, we have a second case of a gene that's knocked out in function in humans related to sialic acid biology, and I think Maynard would predict that they're going to find some gene expression changes. Of course there's some value to the regulatory hypothesis, but we also may find multiple gene losses in the human lineage. And we'll know when the chimpanzee genome is completely sequenced what exactly the situation is, if that is really true.

Is that sequencing work under way?
Yes, in fact, the chimpanzee genome has recently been accorded high priority by the National Human Genome Research Institute. Francis Collins asked the scientific community to submit proposals for various genomes, and I was involved in two of the proposals that were written favoring the chimpanzee genome - although we really preferred a combination of the chimpanzee and the rhesus monkey genomes, because we feel that when you find the differences, you need an outgroup to tell whether the difference is a chimpanzee difference or a human difference.

But anyway the long and the short of it is that the chimpanzee genome is in a current high priority and the rhesus genome, I believe, is right now only a moderate priority. And they will both get done in time, I'm sure. So at least in the next few years, one can anticipate seeing the chimpanzee genome coming onboard.

How can messenger RNA tell us about the changes between species?
When you have a common ancestor, and then you develop different species, there are many theories of speciation. One of them is the simple geographical separation of groups. But eventually, as two lineages evolve away from each other, you are going to get differences of all kinds. There may be gains of genes, there may be losses of genes, there may be changes in specific sequences of genes and changes in the amino acids, changes in their function, and there may be changes in messenger RNA.

And given that human evolution occurred over maybe six million years and took place in many steps, the fossil evidence clearly says that there were many, many steps along the way. My own feeling is that all of these theories are going to turn out to be right, that we're going to find examples of each, and it's all of them working together over a very long period of time that have resulted in the present situation, and of course I should immediately say that genes are not everything, and that without the environment, including the physical and the social and cultural environment, genes are meaningless. Like I said, the genome is like a recipe book. Genes to be expressed need to respond to something, and so eventually it's really interaction between nurture and nature, as they say, that gives rise to the human.

Now chimpanzees and bonobos have evolved in their own way and we know much less about their evolution, and so it's also important to put aside the sort of common notion that we evolved from a chimpanzee. That's not the case. We shared a common ancestor with the chimpanzee. The chimpanzee has been evolving itself during the last five to six million years. And what exactly is the nature of that common ancestor is something that people try to predict.

I guess one can say the limited information is that the fossils that are closer to that six million year time point, the human ancestor fossils look more chimpanzee-like, but you can't really say what the common ancestor was like.

What can you say about the recent fossil finds in Chad and Georgia?
The original molecular clock calculations used DNA, and many of them have suggested that we share a common ancestor with chimpanzees about five to six million years ago. That's the number you'll find in literature. And the early fossils that became available suggested that our ancestors stood upright-became bipedal, as they say-only about four million years ago, and that was the view until probably five years ago.

And then various fossils that have come out, some from Tim White at Berkeley, and from one of the groups in France, that have suggested that this time of bipedalism, standing upright, should be pushed back further. And so even prior to the recent fossil findings in Chad, we were already pushing back the timing of this bipedal state to five and a half million years or so.

And the fossils from Chad, as I understand it-I'm no expert on this-suggest that they're very much hominid, and they're pretty accurately dated, as I understand it, between six to seven million years ago. So if that is the case, I think we have to push back the common ancestor back into that upper bound of the original estimate, which used to be five to seven million years ago. So it says that.

It also says that, although there's no evidence for bipedalism, because the appropriate bones are not present, reported from those fossils, there are other fossils that are claimed to show bipedalism at six million years ago, and some of that work is still not published I think.

If that's the case, then relatively soon after a common ancestor with the chimpanzee, we began to be bipedal, but the brain size did not change, and so those bipedal ancestors-perhaps one of the most famous ones you hear about is Lucy-had brains the size of chimpanzee brains, and so brain expansion only began about, as far as we can tell, about two to two and a half million years ago.

We have a paper coming out next week showing that this gene mutation that we have been studying occurred about two and a half to three million years ago. [Dr. Varki is referring to the following paper in these sections: Chou et al. Inactivation of CMP-N-acetylneuraminic acid hydroxylase occurred prior to brain expansion during human evolution. (2002) PNAS 99(18): 11736-41.] We used multiple different techniques to do this. It tells us is that this mutation has nothing to do with standing upright or changing the way the hands and the feet and the structure of the body work, but it could have something to do with brain expansions, since brain expansion occurred just after this mutation. But that's still just something that gives us a clue as to what to study.

What can the Neanderthals tell us about our evolution?
Svante Paabo's group, and then subsequently some other groups, have successfully extracted mitochondrial DNA from fossils and shown that the Neanderthals appeared not to have mixed with humans a lot, if any, and that we simply shared a common ancestor with the Neanderthals about 600 to 500,000 years ago.

So when we wanted to look for our mutation, we thought of looking for DNA but as Svante and others have shown, Jurassic Park notwithstanding, you can't get DNA from fossils that are more than a hundred thousand years old.And since our own species-modern humans-is probably at least a hundred thousand years old, there was no question of getting the answer by DNA.

So we took the chance that the sialic acids might be present in fossils. First we studied bones from chimpanzees and humans-modern bones-and developed a technique to extract sialic acids and showed that we could easily tell apart the chimpanzee and human bones, because human bones had one kind of sialic acid; the Ac, and the chimpanzee bone had Ac and Gc in about equal amounts. So they reasoned that even if the total amount of sialic acid fell, since both these were equally stable or unstable, we would soon be looking for a species that had Ac versus the one that had both Ac and Gc.

So I first went to the Arizona Fossil Show and obtained some inexpensive fossils of ancient horses and whales and so on, and we studied those, and found in fact in some cases that we could find sialic acids in the fossils, and we could tell whether there was Ac and Gc and so on.

The next step then was to look at human fossils, and as it happened when we read the paper from Svente Paabo on his work in extracting DNA from the Neanderthals, we realized that when he extracted the DNA, he had another fraction that he was not studying, which would contain sialic acids if it were there, and it turned out that he had saved all that in his freezer. So we were able to collaborate with him and obtain these side fractions from the DNA extraction and we were able to find sialic acids in at least two of the three samples we studied. And in both cases, they were very clearly like humans. They only had Ac; they didn't have Ac and Gc.

So based on this we can say that the common ancestor of the Neanderthals and humans already had this mutation. They just had Ac. So then we had to go back further in time, and we contacted Teku Jacob and Etty ndriati in Indonesia-the people who have the custody of the Java man.

It's not easy to convince somebody else that you want to sample their very precious fossil samples, so actually my graduate student flew out there and gave them a lecture about what we were doing. We provided them all the information. They agreed to sample the Java man.

We did that, but unfortunately there were no sialic acids at all in that sample. So we wondered whether that had something to do with the tropical climate and so on, and we meanwhile had also contacted Meave Leakey in Kenya to ask about the fossils in Africa. Given the result of the Java man fossils, we agreed with Meave that we should first study less precious animal fossils from the same sites. So Meave went out and collected animal fossils from exactly the same strata, dates, and time and location of the famous Hominid fossils, but we found no sialic acids.

So actually, our conclusion so far is that, when it comes from tropical climates as opposed to the Neanderthals who fossilized up in Europe, it may not be possible to find sialic acids. So we couldn't go further with that route. We then turned to molecular fossils, so to speak, and molecular fossils are genes that have died, or pieces of DNA that are left behind in the genome. In a sense, they're like fossils; they also change with time and you can study them.

We initiated a collaboration with Naoyuki ("Yuki") Takahata in Japan, which took advantage of two facts. One is that when the gene in humans-this gene that produces Gc-died, it was no longer a gene. It's now what's called a "pseudogene." And a pseudogene is susceptible to just random mutation because there's no reason to conserve it in any way. Whereas the equivalent gene, which is intact and normal in the chimpanzee, gorilla, bonobo, and the orangutan, would be expected to remain highly conserved, not undergo these random changes.

And so we sequenced a whole bunch of these pseudogenes of individual humans and great apes, and sure enough we found that the human pseudo gene had many, many more mutations. But now what could be done with it, by somebody with the expertise of Yuki Takahata, is to take that data and construct a sort of a tree in a clock and say, well, based on all various kinds of information, this must have happened at approximately this time. And they came up with a number that was 2.5 million to 3 million years ago, so that was one number, and that fit with the Neanderthal data that said that it was before half a million years.

But there's a certain amount of error in this calculation, so we needed a third method. And for the third method, we took advantage of the fact that we know how the human gene mutation was caused. Ten percent of the human genome consists of these little pieces of DNA called "Alu" sequences, which are simply parasitic DNA that's multiplying and landing in various parts of the genomeTthis in fact is part of what is normally called "junk DNA."

Toshiyuki Hayakawa, who is a student with Yuki Takahata, noticed that at the place where we had found our mutation there was an Alu sitting on top of it, and in fact that Alu is a human specific Alu. It's a young Alu sequence. So that Alu landed on one copy of somebody's DNA at some time and knocked it out, and now we all have that situation in common. We all inherited that mutation.

That Alu has a lot of cousins in the genome, so when the human genome came along, we could scan the human genome and say, which are all the close cousins of this Alu? And there are at this time about a hundred of them in the human genome.

And now Yuki could construct a family tree of these Alu sequences, because they're all cousins of each other, based on their sequence difference. So he constructed the family tree of these Alu sequences, and we look at that and say, okay, so what is the age of this particular Alu that hit our Gc producing gene? It turns out it's about two and a half to three million years ago, which fits with the other estimate.

So even though there's still some potential error in this, and we can't say we've nailed an exact time, we can roughly say that this mutation occurred long after standing upright, but before the brain began to expand. And so with that and some other clues that we have, we started looking to the possibility that this mutation may have contributed in some way to brain expansion, but I have to qualify that by saying it's just a hypothesis right now. We're studying it. So that was basically a summary of the paper that just came out.

Can using these multiple techniques help to unify theories of human evolution?
In the early days of paleontology and molecular anthropology, there was a lot of conflict between the two approaches, because both were incomplete. The fossil data set was limited, and the sequence analyses were based on very few examples and methods.

But now, more and more, the methods are getting to the point where we can compare things, and the additional thing added into here is the ability to take molecules out of fossils. Obviously that's been done with DNA, and now we've done it with sialic acids, and we would suggest that maybe we could look at more molecules, even though fossils really effectively rot away and lose a lot of their organic material, there's a field of people that know how to study these things and there are molecules in fossils, and others are extracting different kinds of molecules, so I think all these techniques are coming together.

What prompted you to meet with the interdisciplinary group of scientists about human evolution?
I actually got interested in what makes us human when my daughter was born 18 years ago, and it's obviously something that fascinates all of us, but it's only in the late 1980's that I got into studying this question at a molecular level.

And I found that in reading the general literature on the subject, it's very hard to really understand it all, because it ranges all the way from linguistics to anthropology to molecular biology to neuroscience; almost every field of basic research is somehow involved in explaining human evolution. And so, I decided to talk to other people. The La Jolla area is a wonderful area to have people get together, and so the long and short of it is, I formed a group of people that are officially called the UCSD Project for Explaining the Origin of Humans, where we bring together people from all these different backgrounds and try to have them talk to each other.

And, as you can imagine, the terminology that a linguist uses and a molecular biologists uses are very different, and the challenge is to get them all to understand each other, because I think this is really one of those examples of a truly multidisciplinary problem. We need all these different fields to contribute before we can even begin to think of explaining humans. But I also happen to feel that the time has come to start doing this, if it's possible to do it. So that's basically the project. We have chosen to maintain it as a relatively low-key enterprise, because it seems to work better that way.

The UCSD project also has recruited experts from all over the world, and different people in these different fields, just a few people that we happen to know, and so that has helped also to increase the critical mass in different fields.

Do you see a danger towards perhaps one "umbrella hypothesis" of human evolution?
This problem of " umbrella hypotheses", has been common in the literature going back a long way in studies of human evolution. And a lot of people like to come up with one explanation that's going to explain humans, and so this is what's called "umbrella hypothesis."

And the problem is that often many of theories begin with a very good idea, which may actually have some truth to it and, in fact, may be quite on target, but then they may attempt to explain all of human evolution based on that one molecular mechanism, or whatever the case may be. And you just have to look at what happened in human evolution to realize that there's no way that that's possible. It must have been multiple, multiple events that occurred.

So I don't discount the ideas behind a number of umbrella hypotheses. In fact, I think we should take them very seriously, but I don't like to make them into an umbrella. And as I said before, I think it's going to be a combination of many of these theories are going to be correct, and they're all going to be contributors to the process of human evolution.

What is the utility of molecular clocks?
The basic idea is that, with time, DNA accumulates mutations, and so although the rate of these mutations to accumulate is going to vary, if you can anchor some time points in evolution just by looking at the number of differences in mutations between one lineage and another, you may be able to compute when they had a common ancestor, and so on, so that's the general idea of molecular clock but I'd not be the right person to give the expert answer on this.

Have they added value to the study of fossils?
I think that studying fossils has been extremely valuable, and studying molecular clocks has been extremely valuable but, there's an additional arena that is just beginning to be studied, and that is to study the biology of humans in comparison with chimpanzees. The group at the Yerkes Primate Center at Emory University has suggested-in fact they've started a little center called the Living Link Center-with the idea that we're all studying the quote, "missing link," although there's no such thing really, and the point is, "what about these living links?" We have a species that's a very close evolutionary cousin that's very, very similar to us, so by comparing the two couldn't we find out more, and we're doing this in as completely ethical a fashion as possible.

So now, I think, there's the entire area of studying not only the chimp and the human genome, but what I call the "phenome," that is the phenotype, because you need that information. We know a lot about humans because we study ourselves both from a normal and disease point of view, but we know very, very little about chimpanzees and great apes.

And a group of us has suggested that the chimpanzee genome project is not going to be so effective unless we also have a parallel "great ape phenome project", where studies are done using the same ethical principles that are used to study humans - to examine the great apes all the way from the molecular to the physiological to the behavioral level and make comparisons. In the end you need that information because otherwise no amount of fossils or molecular clocks or basic molecular biology is going to solve or even approach the whole problem. So we need to approach those issues too. And I think in recent times, more and more people are getting interested in this.

In fact, I've yet to meet a human being who's not interested in this matter. It was previously a field where there were relatively few scientists actually working in it from the paleoanthropology and molecular anthropology communityies. But now I think more and more scientists from other fields are getting interested-all the way from cognitive science to molecular studies.

Is it in part glycobiology that makes that possible?
In some ways, you would not have expected that an obscure field like glycobiology would provide some of the examples. But glycobiology is a field that studies possibly a couple of thousand of the tens of thousands of genes in the genome that are responsible for making all these sugars -and it so happens that we've already found two mutations, and actually have further unpublished data showing additional sialic acid differences between humans and great apes that we're working on. So I don't know about the rest of glycobiology, but it seems that at least the sialic acid aspect of glycobiology may have something to contribute.

But it's important to qualify that. When we find differences today in modern humans there are three possibilities. One is that these differences are responsible for what we are today and actually are functional today. The second possibility is that they were important in the past, and some point in human evolution that got us through some particular time and they're not important anymore. The third possibility, unfortunately, for any genetic mutation in humans, is that there is evidence from other experts that the average population size of humans was very small for a very long time. As someone said, "We were an endangered species for a long time."

Now when that happens, my understanding is that a particular mutation could also become fixed in the population, that is, it could be present in everybody in the population, just by random chance. So what we're studying. could be random chance, it could also be something very, very important and we just have to find out which is the case.

How about the issue of singularity in terms of an event that led to human evolution?
In thinking about how human evolution came about, I think we have to take into account the fact that it only happened once, although there are clearly other species like whales and parrots, and so on, that have developed pretty advanced cognitive abilities. From at least the human perspective, I think we feel that humans are an unusual case.

Now, in other words, some people might use the term that humans are a singularity. We only happened once in the history of this planet. So when you're studying something that happened only once, it does not necessarily follow that it happened in the most logical possible sequence. So there's a limit to how much you can use logic and probability to try and decide what is the most likely cause of human evolution.

After all, when something only happens once, it might have happened by the most improbable series of events you could possibly imagine, and you'll never know how. So for that reason, I think that one really needs to keep an open mind. There's a tendency to debunk ideas that seem improbable, and to favor the ideas that seem very probable, and that's part of science. We have to do that to some extent. We can't pay attention to every possibility. On the other hand, I prefer to keep an open mind, because it may be that some very improbable things happened, leading the course of evolution towards humans.

What are the major events that you think were most important in human evolution?
Looking at human evolution from the early times, obviously bipedalism, standing upright, and thereby freeing the hands to do different things, is a very major event, very uncommon in nature to find that happening. That's a very interesting event.

Then the next big thing that one recognizes, or at least one is interested in, is the beginning of the expansion of the brain, which then progresses through to several series of expansions of the brain and that's very interesting. How did that happen? Coincident with that, there is the appearance of tools. We all know now that chimpanzees use tools also, and so do many other animals, but that more sophisticated tools and more complex tools emerged in hominids. So the appearance of that is very interesting.

And then, the thing I find very interesting is the fact that the size of the human brain achieved its current day size more than 200,000 years ago, and our cousins the Neanderthals had brains if anything bigger than ours. So large brains are already present probably more than 200,000 years ago, but the individuals that had these large brains were still doing very much the things that were being done in the previous times, and were not leaving behind tangible artifacts like art or decorations of beads, or burial of the dead, and so on and so forth. So these sort of features that would suggest some higher cognitive ability similar to humans, all of that really only appears some time maybe 60-70,000 years ago, as I understand from current information in Africa, and then gradually increases and then you find it all the way from Europe to Australia.

The first crossing of a major ocean to Australia was probably 40-50,000 years ago and many of these other features are found in the people there. So I think there's another puzzle, which is what is called the "emergence of modern humans." So somewhere probably in Africa, a group emerged and spread across the world that, as far as we can tell, replaced everybody else, and although there are some alternative hypotheses out there, I think I favor most of the data suggesting that there was a replacement. We don't know the mechanism of the replacement either. It may have been just simple competition. So I think that's a fascinating thing.

Now when you come to modern humans, there are obviously many other things, like language or skin or hair or things that we have mentioned, the differences that don't leave behind any fossil trails so it's hard to tell when they changed. So many of the human-chimpanzee differences are going to be very hard to trace as to exactly when they occurred so all we can do is look at the modern situation.

But then, finally, there's also something I'm interested in from the biomedical perspective. I spent a month at the Yerkes Primate Center in Atlanta after this research started, to learn all I could about chimpanzees, and basically picked the brains of all the experts there. I came away realizing after talking to the veterinarians there that, while chimps are very similar to humans-and in fact they use the human textbook of medicine to take care of chimps-there are several interesting differences, and they happen to be in diseases like HIV, some kinds of malaria, possibly some kinds of cancer, possibly Alzheimer's disease-many of the diseases that are major killers right now.

And in fact Maynard Olson likes to suggest that this is because we are "degenerate apes,". We have lost genes, and maybe made ourselves more susceptible to these diseases.

But whether or not that's the case, it still remains to be said that by comparing humans and chimpanzees, we might be able to address the nature of these differences, and perhaps that could lead to treatments. And also it could lead to better care for the great apes, because after all, the great apes are being taken care of using the human textbook of medicine and they're clearly quite different -and I think that given that they are endangered species they deserve to have better medical management as well.

So I guess those are the major things that interest me, but different people will have different interests. Things like art and music, are obviously truly fascinating, and in the end, a lot of that comes down to understanding how the human brain works and how the human brain is different from that of a chimpanzee brain. And, again, to emphasize, it's not going to be just genes. It's the environment acting on the genes in the brain, so those things are important too.

What do you most want this audience to understand?
Well, in general about human evolution, I'd like people to come away with the idea that we evolved from a common ancestor with the chimpanzees and bonobos and that, this process occurred in multiple, multiple steps involving probably many dead ends and branches and eventually resulting in modern humans, that there are probably many, many steps along the way to be studied, and that we can learn just as much from studying the steps as from comparing great apes and humans to each other and with other primates and other species.

From the point of our own work, I guess the fact that we found the first genetic difference doesn't necessarily mean it's the most important one, and there are still many caveats, but we have found, as I said, multiple differences between humans and great apes, and we're trying to sort out what it means. And it remains to be seen if these differences can explain modern humans, and why they're different from great apes.

What do you see as the future of human evolution?
The future of human evolution is an interesting topic. Many people have many opinions about it. I think one thing one can clearly say is that we have changed the rules of evolution: whereas evolution previously occurred by chance and selection from a variety in a population, we have changed all those rules because we changed the outcome of survival of individual substantially based on the ways we intervene in various ways.

So I think it's safe to say that we have changed evolution. Whether or not we have actually arrested evolution by this manner or not, I don't know. So I don't think I'm really expert enough to make further predictions on that, but after all, when we have this very large population size spread across the globe it's hard to imagine evolution affecting the entire population. If you want a futuristic scenario, I could imagine a subgroup of humans going away and populating another planet and then being separated for a long, long time. Under those circumstances, I would imagine that human evolution might proceed further, if in fact there were selections.

But evolution by natural selection may not be as active in humans, but then we are imposing other kinds of selection, which are not part of the natural selections, so I think it's an interesting thought, but I think given the size of the world population I'm not so sure that it's going so rapidly anymore.



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