A difference in one molecule led physician Ajit Varki to question what sets humans apart from other apes. Bruce Lieberman meets a man who sees a big picture in the finer points.
Bruce Lieberman
The human body does not welcome an injection of horse serum. Ajit Varki discovered this when, as a young San Diego doctor in 1984, he administered some to a woman with bone-marrow failure. The serum was a standard treatment intended to stop the woman's T cells from destroying her bone marrow. But it was also known to prompt a reaction called 'serum sickness' and, sure enough, the patient broke out in hives a week after treatment — the result, Varki assumed, of her immune system's assault on proteins from another species.
Soon after observing his patient's reaction, Varki learned that proteins weren't the only thing to blame. So were sialic acids, sugars that carpet the surface of mammalian cells. Some studies had suggested that the human immune system reacted against one sialic acid called N-glycolyl neuraminic acid (Neu5Gc) in the horse serum. “How can that be?” Varki remembers thinking. “How can you have a reaction against sialic acid? It's everywhere. All mammals have sialic acid.” Varki wondered whether humans might in fact be the only mammal that lacked Neu5Gc.
A physician and biochemist by training, Varki had already embarked on a career in the relatively new field of glycobiology, the study of the sugar chains that decorate many proteins and lipids inside and outside the cell. But it was another 14 years before he got the chance to answer his original question. In 1998, he and his colleagues used high-performance liquid chromatography to analyse blood samples from chimps, bonobos, gorillas, orangutans and humans. They found that humans are indeed the only primates missing Neu5Gc[1] and that human cells are instead rich in another sialic acid, N-acetyl neuraminic acid (Neu5Ac).
A career in evolution
These findings started Varki off on a road that led to his becoming not only a leading glycobiologist but a respected 'honorary' palaeo-anthropologist. He is one of the co-founders and directors of the multidisciplinary Center for Academic Research and Training in Anthropogeny (CARTA) — a research collaboration between the University of California, San Diego, and the Salk Institute in nearby La Jolla. The centre was launched in March this year with a US$3-million grant from the G. Harold & Leila Y. Mathers Foundation, based in New York state.
The 'Anthropogeny' in the centre's title resurrects a term for the study of both the evolution and the individual development of human beings that would have been familiar to earlier generations of anthropologists. To Varki, the word encapsulates some of the biggest questions in the study of human origins, such as how, why and when the human brain evolved its present functions. One of his latest research projects is a collaboration with Spanish palaeontologist Juan Luis Arsuaga, of the Complutense University of Madrid, for the biochemical analysis of 900,000-year-old Homo antecessor fossils from Atapuerca in northern Spain, some of the oldest hominid bones yet found in Europe. What Varki is looking for is evidence that Neu5Gc was lost very early in human evolution. He believes that the fact that humans, and only humans, have lost Neu5Gc could be implicated in the emergence of hominid species.
The journey from glycobiologist to director of a multidisciplinary human origins centre has been fuelled by Varki's insatiable desire for knowledge. “The guy is just an encyclopaedia,” says glycobiologist Mark Lehrman at the University of Texas Southwestern Medical Center in Dallas. “Even though he wasn't trained in anthropology, he's been able to educate himself in this area and become an authority. It's a remarkable gift to be able to do that and do it well.”
Varki initially trained as a general medical doctor at the Christian Medical College in Vellore, India. To pursue a dual medical and research career, he went to the United States, eventually taking up a fellowship under Stuart Kornfeld at Washington University in St Louis, Missouri, in the late 1970s.
Kornfeld was beginning his work on sugar chains, including sialic acids, and Varki was intrigued by the opportunity to contribute to a largely unexplored area of biology. In 1982, he set up his own glycobiology lab at the University of California, San Diego, where he still works today.
On a molecular level, the difference between Neu5Gc and Neu5Ac is tiny — a single added oxygen atom perched on one arm distinguishes one from the other (see graphic). But on a biological level, the difference could be enormous. “We thought if monkeys and all of our closest relatives have Neu5Gc and humans don't, then there must be a molecular basis for that,” Varki says. He subsequently found it in an enzyme that converts Neu5Ac to Neu5Gc, but which is disabled by mutation in humans[2].
Selection pressure
Varki's discovery pointed to a definitive difference that set chimps and humans biochemically apart, says Morris Goodman, an evolutionary biologist at Wayne State University in Detroit, Michigan. It was one of the first such differences to be found, and because sialic acids serve many biological roles, primarily as cell-recognition and cell-adhesion molecules, it might explain some of the unique aspects of human biology. “What we're dealing with here is a gene loss that has an effect throughout the whole body,” says Goodman.
At the time, Varki realized he knew little about human evolution except what he'd learned as an undergraduate or read in National Geographic. So he set out to educate himself. He took a short sabbatical at the Yerkes National Primate Research Center in Atlanta, Georgia. Reviewing the animals' medical records with a veterinarian, he learned that the centre had never seen a case of rheumatoid arthritis or bronchial asthma — common conditions in humans. Chimpanzees don't get sick from the human malaria parasite, Plasmodium falciparum. Conversely, humans can't be infected with P. reichenowi, the malaria parasite that plagues chimpanzees.
“What we're dealing with here is a gene loss that has an effect throughout the whole body.”
Morris Goodman
In subsequent work, Varki and his team showed that the different susceptibilities were due to the differences in sialic acids. P. reichenowi prefers to grab hold of Neu5Gc on chimp red blood cells, whereas P. falciparum favours Neu5Ac[3]. The researchers hypothesized that the selection pressure to evade P. reichenowi may have led humans to lose Neu5Gc and acquire resistance to this parasite — and that this loss may have helped to fuel the emergence of P. falciparum, which could gain entry by latching onto Neu5Ac instead. Other discoveries in Varki's lab — including ten other human-specific genetic changes affecting sialic acid function — may help to explain uniquely human vulnerabilities to conditions such as Alzheimer's disease and multiple sclerosis.
Varki's interest in human evolution soon extended far beyond chimps and their sugars. “I found he was talking with several people on campus,” says neuroscientist Fred Gage at the Salk Institute, a long-time collaborator and friend. “I told him that it wasn't fair that he would have these one-on-one conversations and not share what was being talked about,” he jokes. Reimagining anthropogeny
Gage encouraged Varki to organize a series of informal seminars on human origins at the university. Between 1998 and 2007, the Project for Explaining the Origin of Humans drew in anthropologists, primate biologists, geneticists, immunologists, neuroscientists, linguists and many others. They discussed topics ranging from the evolution of language to the differences between humans, Neanderthals and Homo erectus, the first hominid to leave Africa. Goodman says the interdisciplinary nature of the series made it extremely important to the field. “You really had the chance to explore an issue as it relates to the evolutionary origins of our species,” he says. Differences in sialic acids between chimps and humans alter susceptibilities to some diseases.Differences in sialic acids between chimps and humans alter susceptibilities to some diseases.P. TWEEDIE/CORBIS
Varki's motivations were partly selfish: “One of my goals, my secret agenda, was to educate myself,” he admits. “At the last meeting I asked the people who attended if I could have a bachelor's degree in anthropogeny.” Varki estimates that he has listened to more than 300 talks on various aspects of this discipline. “The idea is the linguist needs to talk to the molecular biologist who needs to talk to the neuroscientist who needs to talk to the psychologist and philosopher about these issues,” he says. “Most areas of human knowledge are somewhere relevant.”
CARTA is a successor to the human origins series. Directed by Varki, Gage, Margaret Schoeninger, a professor of anthropology at the University of California, San Diego, and Pascal Gagneux, a primate biologist and Varki's close collaborator, the centre already has some 40 San Diego-based members and more than 100 in the rest of the United States and elsewhere in the world.
CARTA aims to foster connections between these researchers worldwide, facilitate access to resources for great-ape research, develop a peer-reviewed journal and offer courses on human origins. The project is in some ways comparable to the Leipzig School of Human Origins in Germany, an interdisciplinary PhD programme run jointly by the Max Planck Institute for Evolutionary Anthropology in Leipzig and Leipzig University since 2005. Varki says that CARTA will be more of a virtual organization and that “the
...
>On a molecular level, the difference between Neu5Gc and Neu5Ac is tiny >— a single added oxygen atom perched on one arm distinguishes one from >the other (see graphic). But on a biological level, the difference >could be enormous. “We thought if monkeys and all of our closest >relatives have Neu5Gc and humans don't, then there must be a molecular >basis for that,” Varki says. He subsequently found it in an enzyme >that converts Neu5Ac to Neu5Gc, but which is disabled by mutation in >humans[2].
>Selection pressure
>Varki's discovery pointed to a definitive difference that set chimps >and humans biochemically apart, says Morris Goodman, an evolutionary >biologist at Wayne State University in Detroit, Michigan. It was one >of the first such differences to be found, and because sialic acids >serve many biological roles, primarily as cell-recognition and >cell-adhesion molecules, it might explain some of the unique aspects >of human biology. “What we're dealing with here is a gene loss that >has an effect throughout the whole body,” says Goodman.
Oh the irony of it, our DNA lost genes by mutation on the route from chimp to human!
On Thu, 03 Jul 2008 19:57:05 GMT, Ye Old One <use...@mcsuk.net> wrote:
> A difference in one molecule led physician Ajit Varki to question what > sets humans apart from other apes.
A: Digital wrist watches.
-- http://desertphile.org Desertphile's Desert Soliloquy. WARNING: view with plenty of water "Why aren't resurrections from the dead noteworthy?" -- Jim Rutz
<use_reply_addr...@spamsights.org> wrote: > In message <1bbq64dh9ltk2ctevqvfigkbo68s1bm...@4ax.com>, Ye Old > One <use...@mcsuk.net> writes
> <snip>
> >On a molecular level, the difference between Neu5Gc and Neu5Ac is tiny > >— a single added oxygen atom perched on one arm distinguishes one from > >the other (see graphic). But on a biological level, the difference > >could be enormous. “We thought if monkeys and all of our closest > >relatives have Neu5Gc and humans don't, then there must be a molecular > >basis for that,” Varki says. He subsequently found it in an enzyme > >that converts Neu5Ac to Neu5Gc, but which is disabled by mutation in > >humans[2].
> >Selection pressure
> >Varki's discovery pointed to a definitive difference that set chimps > >and humans biochemically apart, says Morris Goodman, an evolutionary > >biologist at Wayne State University in Detroit, Michigan. It was one > >of the first such differences to be found, and because sialic acids > >serve many biological roles, primarily as cell-recognition and > >cell-adhesion molecules, it might explain some of the unique aspects > >of human biology. “What we're dealing with here is a gene loss that > >has an effect throughout the whole body,” says Goodman. > Oh the irony of it, our DNA lost genes by mutation on the route from > chimp to human!
> I have to ask our creationist friends, does this mean that the chimp > genome has more information than ours?
It would be the common ancestor of Chimpanzees and Humans that had "more information" than us humans (if an oxygen atom is "information"). Or more specifically, a portion of the population of that common ancestory had Neu5Ac, and the rest of that population had Neu5Gc (which went on the human germ line).
Varki _et_all_ hypothesize that a single mutation (an enzime that caused the loss of a single atom in a sialic acid) might be the cause for better reproductive success in the environment that mutation occurred in (a beneficial mutation that resisted disease). If that mutation also caused reproductive isolation, it was a speciation event.
This is very amusing, if valid. It means we not only see a beneficial mutation occurring 2.5 million years ago, but we also observe yet another speciation event. Someone should notify Kent Hovind.
-- http://desertphile.org Desertphile's Desert Soliloquy. WARNING: view with plenty of water "Why aren't resurrections from the dead noteworthy?" -- Jim Rutz
<desertph...@invalid-address.net> wrote: > This is very amusing, if valid. It means we not only see a > beneficial mutation occurring 2.5 million years ago, but we also > observe yet another speciation event. Someone should notify Kent > Hovind.
I must be wrong: the mutation could not be a speciation event because if it was the mutation could not be passed down to descendents.
-- http://desertphile.org Desertphile's Desert Soliloquy. WARNING: view with plenty of water "Why aren't resurrections from the dead noteworthy?" -- Jim Rutz
>> This is very amusing, if valid. It means we not only see a >> beneficial mutation occurring 2.5 million years ago, but we also >> observe yet another speciation event. Someone should notify Kent >> Hovind.
> I must be wrong: the mutation could not be a speciation event > because if it was the mutation could not be passed down to > descendents.
Wow! What an interesting conclusion.... what is the conclusion based on? (citation?; logic; reason; other) Cj
On Fri, 04 Jul 2008 15:52:03 -0400, Cj <C...@mist.net> wrote: > Desertphile wrote: > > On Thu, 03 Jul 2008 22:12:31 -0600, Desertphile > > <desertph...@invalid-address.net> wrote:
> >> This is very amusing, if valid. It means we not only see a > >> beneficial mutation occurring 2.5 million years ago, but we also > >> observe yet another speciation event. Someone should notify Kent > >> Hovind.
> > I must be wrong: the mutation could not be a speciation event > > because if it was the mutation could not be passed down to > > descendents. > Wow! What an interesting conclusion.... what is the conclusion based > on? (citation?; logic; reason; other)
Logic and reason.
-- http://desertphile.org Desertphile's Desert Soliloquy. WARNING: view with plenty of water "Why aren't resurrections from the dead noteworthy?" -- Jim Rutz
>> >> This is very amusing, if valid. It means we not only see a >> >> beneficial mutation occurring 2.5 million years ago, but we also >> >> observe yet another speciation event. Someone should notify Kent >> >> Hovind.
>> > I must be wrong: the mutation could not be a speciation event >> > because if it was the mutation could not be passed down to >> > descendents.
>> Wow! What an interesting conclusion.... what is the conclusion based >> on? (citation?; logic; reason; other)
>Logic and reason.
Logic and reason that ignores the observed facts on sympatric speciation in plants by polyploidy.
Logic and reason that also ignores speciation in asexual organisms.
Logic and reason that didn't quite make the grade (or is it the clade?)
> >> >> This is very amusing, if valid. It means we not only see a > >> >> beneficial mutation occurring 2.5 million years ago, but we also > >> >> observe yet another speciation event. Someone should notify Kent > >> >> Hovind.
> >> > I must be wrong: the mutation could not be a speciation event > >> > because if it was the mutation could not be passed down to > >> > descendents.
> >> Wow! What an interesting conclusion.... what is the conclusion based > >> on? (citation?; logic; reason; other)
> >Logic and reason.
> Logic and reason that ignores the observed facts on sympatric > speciation in plants by polyploidy.
> Logic and reason that also ignores speciation in asexual organisms.
> Logic and reason that didn't quite make the grade (or is it the > clade?)
I disagree, I think Deserphile is right about THIS mutation. Most of the context got snipped, here's what Desertphile originally said about speciation in this instance:
"Varki _et_all_ hypothesize that a single mutation (an enzime that caused the loss of a single atom in a sialic acid) might be the cause for better reproductive success in the environment that mutation occurred in (a beneficial mutation that resisted disease). If that mutation also caused reproductive isolation, it was a speciation event.
This is very amusing, if valid. It means we not only see a beneficial mutation occurring 2.5 million years ago, but we also observe yet another speciation event. Someone should notify Kent Hovind."
If a single mutation in a single individual ape caused reproductive isolation, it couldn't cause a speciation event because that individual couldn't reproduce, right?
-- My 2¢ ß-}
June To email me replace 'go' with 'ville' and remove the .spam.jam
>>> This is very amusing, if valid. It means we not only see a >>> beneficial mutation occurring 2.5 million years ago, but we also >>> observe yet another speciation event. Someone should notify Kent >>> Hovind. >> I must be wrong: the mutation could not be a speciation event >> because if it was the mutation could not be passed down to >> descendents.
>Wow! What an interesting conclusion.... what is the conclusion based >on? (citation?; logic; reason; other)
I'm not sure but I would guess Desertphile realised that the disabling of the conversion gene would not stop the bearers of the mutation interbreeding with the original population, but the mutation would still spread because of the lower parasite susceptibility.
Interesting the *later* immune sensitivity to Neu5Gc may well be a speciation event (as in it probably stops interbreeding with earlier populations) but by the time it happened the entire local population probably had the mutation already, so the newly acquired immune response wouldn't make much difference.
It may well have just changed an isolated population from one that could breed with the original population to one that couldn't, but if it was isolated in other ways geographical (for example, or by an earlier speciation event) then there would be no interbreeding anyway so our species could have quietly separated without anyone noticing. -- sapient_usene...@spamsights.org ICQ #17887309 * Save the net * Grok: http://spam.abuse.nethttp://www.cauce.org * nuke a spammer * Find: http://www.samspade.orghttp://www.netdemon.net * today * Kill: http://spamsights.orghttp://spews.orghttp://spamhaus.org
