麻豆传媒

THE YEAR is 1964. A man in the final stages of renal failure lies dying in a
hospital bed in Virginia. His body is bloated with excess fluid, his breathing
laboured. To make matters worse, a human kidney for transplant cannot be found.
As the man鈥檚 condition rapidly worsens, his doctors hit upon an audacious plan.
They decide to use the next best thing: chimpanzee kidneys. They reason that
chimps are more similar to us than any other living animal, so the kidneys stand
a fair chance of working. Indeed, a few years later, molecular biologists will
make a discovery that might have boosted the surgeons鈥� confidence: it turns out
that the genetic make-up of a chimp is 98.5 per cent identical to a human.

So the operation goes ahead, and initially it seems a success. The patient鈥檚
new kidneys filter the fluid from his blood, and his swelling starts to go down.
But all too soon it becomes clear that something is gravely wrong. The chimp
kidneys are spewing out urine far too fast and the patient produces a massive 54
litres of urine in one day. Doctors can鈥檛 pump fluids into him fast enough, and
before their eyes the patient dries up like a raisin and dies of heart failure
three days later.

Maybe it was the seriousness of the patient鈥檚 condition. Or maybe chimp and
human kidneys aren鈥檛 so much alike after all. One thing is clear, however.
Despite their genetic similarities, to even the most casual observer chimps and
humans differ in very many ways

True, we both have large brains, can walk on two legs, use tools, and spend
years nurturing helpless infants. But size for size, the apes are far stronger:
an adult female chimp could lift a 70-kilogram man with one hand. Chimps have
shorter thumbs and much more hair. Female chimps have breasts only when they are
nursing and the males have bones in their penises. And of course, humans are a
lot smarter.

Clearly there is something about that 1.5 per cent of the genome that counts
for a lot. Something that gives Homo sapiens the ability to read
magazines and sing along with the car radio, while our chimp cousins are better
adapted for life in the jungle, climbing trees and fishing for termites with
twigs.

Now a group of geneticists, molecular anthropologists, evolutionary
biologists and primatologists are searching for the genetic changes that make
the difference. They hope that by comparing the DNA sequences of chimps, humans
and other primates鈥攁s well as the fossils of our ancestors鈥攖hey will
be able to get a handle on how we evolved (see 鈥淏ack through the generations鈥�),
and why we are not simply deluxe chimps. 鈥淚t鈥檚 a major question, like the
origin of the Universe or the origin of life,鈥� says Ajit Varki, a biologist at
the University of California, San Diego. 鈥淲e have no idea exactly what we鈥檒l
find,鈥� he says. 鈥淎ll we can do is look.鈥�

The work is only just beginning. But already the researchers have identified
a handful of genes that appear to separate humans from chimps. They speculate
that those genes might one day lead to new treatments for human ailments ranging
from cancer and cholera鈥攈umans appear to be more susceptible to
both鈥攖o certain kinds of mental retardation.

The idea of comparing chimp and human DNA first appeared in print in a 1975
paper by geneticist Mary-Claire King and biochemist Allan Wilson at the
University of California, Berkeley. Using the relatively rough and ready
techniques of the day, based on how similar strands of DNA stick to one another,
the researchers estimated that human DNA is between 98 and 99 per cent identical
to that from chimps. This was confirmed when the original researchers and others
went on to sequence a small number of genes.

The immediate question raised by the finding was what was the significance of
that 1.5 per cent? Did it mean that chimps were nearly human? Not really. Nearly
75 per cent of human genes have some counterpart in
nematodes鈥攎illimetre-long soil-dwelling worms鈥攂ut that doesn鈥檛 mean
that a worm is three-quarters of the way to being a person.

But the 1.5 per cent figure excites biologists because it means that it is
within their technical grasp to identify the genetic differences that
distinguish chimps and humans. They will be able to work out what mutations,
what additions and removals of small bits of DNA, and what rearrangements of the
order of large chunks of DNA occurred when chimps and humans diverged from a
common ancestor.

Still, 鈥渋t鈥檚 definitely like looking for a needle in a haystack,鈥� says Varki.
鈥淣inety-nine per cent of what we look at will be exactly the same.鈥� The human
genome contains very roughly 100 000 genes, so a 1.5 per cent genetic difference
could affect up to 1500 different genes. On the other hand, it is conceivable
that the majority of the differences lie in the roughly 95 per cent of the
genome that does not contain, or control, any genes鈥攖he so-called junk
DNA. That would leave only a few key genes separating humans and chimps.

That is not as incredible as it sounds. After all, within a single
species鈥攕ay dogs鈥攕elective breeding is capable of turning tiny
genetic variations into the difference between a Chihuahua and a Saint Bernard.
And because primate development is so complex it makes it even more possible
that only a very few genetic changes would be needed to turn a common ancestor
into a chimp or a human. A small tweak in a key gene could reverberate through a
developing embryo, snowballing into a big change in the way an animal looks or
behaves, eventually creating a whole new species.

The brain is one organ where the difference between humans and chimps is
clear. It sets the dimmest human apart from even the brightest chimp. 鈥淣ot that
chimps are stupid, by any means,鈥� says Walter Messier, a molecular biologist at
Genoplex, a genomics company based in Denver, Colorado. 鈥淏ut we鈥檙e the ones that
put them in cages, not the other way round.鈥� Yet surprisingly little is known
about how human and chimp brains differ anatomically. We humans clearly have the
edge when it comes to size鈥攐ur brains are twice as big as chimp brains.
What鈥檚 more, the right and left halves of the brain are better connected in
chimps than in humans, although humans appear to have more connections within
each hemisphere鈥攖he finding of a brain imaging study by Thomas Insel and
Jim Rilling of the Yerkes Regional Primate Research Center in Atlanta, soon to
be published in Neuroreport.

A single gene could lie behind either of those differences. 鈥淎 doubling of
neuronal precursor cells would give a chimp a human-sized brain,鈥� points out
David Nelson, a geneticist at Baylor College of Medicine in Houston. And such a
doubling could be prompted by, say, a single gene that ensures cell division is
switched off a bit later in development.

Spot the difference

Messier and his colleagues are searching for just such a gene. They have
sequenced an impressive 10 000 genes that are active in the chimp brain and
compared them to their counterparts in the human gene database. A computer
program flags those genetic differences that might cause a difference in the
activity of the proteins the genes encode. According to Messier, he and his
colleagues have already identified a couple of genes that may be involved in
learning and memory, but they鈥檙e staying mum on what the genes are until they鈥檝e
patented their discoveries. They suggest that their discoveries might just lead
to a drug that could potentially enhance learning or memory鈥攁 product that
would have enormous sales potential.

Genoplex scientists are also searching for the genes that could account for
differences in disease susceptibility between chimps and humans. Chimps, for
example, rarely get cancer, a difference that is unlikely to be due to
differences in diet and environment. 鈥淪olid-tissue tumours, such as prostate
cancers, are virtually unheard of in apes,鈥� says Insel. And blood cancer is
conspicuously uncommon. Until recently it was also believed that HIV did not
cause AIDS in chimps. Now virologists know that the virus can cause the same
disease in chimps as it does in humans
(This Week, 20 February, p 6).
However, chimps appear to be slower to develop symptoms. Messier and his colleagues
believe they know why鈥攖hough as yet they are revealing no more.

Not all the researchers who study chimp-human genetics are quite so
cloak-and-dagger. Last September, Varki and his colleagues at UCSD reported that
at a biochemical level, humans differ from chimps and all other animals that
have been studied in one small but possibly very significant way (
Proceedings of the National Academy of Sciences, vol 95, p 11 751). In most
animals, including chimpanzees, the surface of every cell, except brain cells,
carries glycoproteins that contain one particular member of a family of sugar
molecules called sialic acid. But in humans, a genetic mutation means that this
particular sugar is not carried on any cell in the body.

Sticky issue

Proteins and membrane lipids that sport sialic acid have numerous tasks, such
as helping cells stick to one another. The molecule may also play a role in
disease susceptibility. Sugars such as sialic acid provide a gateway to cells鈥�
interiors for all sorts of infectious agents. And despite the genetic
similarities between them and us, chimps seem to be far less susceptible to
infectious diseases such as cholera and malaria. Biochemists speculate that
having a different form of the sugar on our cell surfaces might be what makes us
more likely to catch those diseases.

The presence of this particular sialic acid on chimp cells might also explain
why all the chimp-to-human organ transplants performed in the 1960s were
unsuccessful. Besides the Virginian patient, about a dozen kidney transplants
failed because of immune rejection. That might have happened, says Varki,
because the patients鈥� immune systems produced antibodies against the 鈥渇oreign鈥�
sugar on the chimp kidneys.

Of course, pinpointing molecules that differentiate chimps from humans would
be simpler if researchers could get their hands on the complete chimp gene
sequence. Several laboratories are now attempting more extensive sequencing of
chimp DNA than just the odd gene. The biggest of these attempts will be led by
molecular geneticist Svante P盲盲bo at the Max Planck Institute for
Evolutionary Anthropology in Leipzig. His team is sequencing two 100-kilobase
regions on the chimp X and Y chromosomes, and plans to compare X chromosome
sequences from large numbers of chimps and humans.

Some gene researchers want to go further. 鈥淭he value of having the chimp
genome laid out in front of us is unquestionable,鈥� says Francis Collins,
director of the National Human Genome Research Institute in Bethesda, Maryland.
鈥淲e ought to do it. But how or when or where the money will come from, I can鈥檛
say.鈥� One possibility is that the ultrafast sequencing centres that are
currently sequencing the human genome will be commandeered once that project is
complete鈥攑erhaps within three or four years. Mice and rats are likely to
be ahead in the queue, but because the DNA sequences of humans and chimps are so
similar, says Collins, sequencing the chimp should be a bargain, 鈥渃onsiderably
cheaper to do than any other mammal鈥�.

Others, however, suspect that focusing on individual genes is the wrong
approach. True, chimp and human DNA may be 98.5 per cent similar, but the way it
is arranged on the chromosomes is somewhat different. Chimps have 24 pairs of
chromosomes, humans 23. Eighteen of the pairs are pretty much identical, but the
rest have been reorganised, with large chunks of DNA moved around. For example,
compared to the chimp, human chromosomes 4, 9 and 12 contain huge inversions. In
the case of chromosome 12, this has the effect of shifting almost a quarter of
its DNA from one end of the chromosome to another. Such rearrangements could
alter the activity of critical genes by moving them closer or further away from
the pieces of DNA that switch them on and off.

Then again, it is possible that these genetic idiosyncrasies amount to
nothing. Lots of people are born with chromosomal inversions and show no obvious
problems. Although certain inversions may cause severe birth defects or even
kill the developing fetus, 鈥測ou don鈥檛 see people with inversions come into the
clinic with too much hair, walking on their knuckles,鈥� says Nelson. In an
attempt to identify genes that may have been affected by chromosome
rearrangements, Nelson and his students are sequencing chunks of chromosome 12
from chimps and humans. 鈥淩ight now it鈥檚 just a fishing expedition,鈥� says
Nelson.

Disconcerting question

Of course, once the full haul of human and chimp genetic information is in,
it鈥檚 anybody鈥檚 guess what it will mean for how we see ourselves and our ape
relatives. Messier says that his learning and memory genes might end up helping
learning-impaired children鈥攂ut supersmart chimps are not on the
agenda.

The simple recognition that changes to such a small number of genes can have
such a profound effect has implications for our understanding of human genetics.
Many molecular biologists publicly dismiss the idea that all it takes is a
handful of genes to change human behaviour, but that stance looks shaky if you
consider that it may only take a gene or two to create two completely different
species.

That leaves a disconcerting question. Why is it that the differences between
chimp and human DNA have thus far been so little studied? It may have something
to do with our overinflated view of ourselves, says Nelson. As humans we think
we鈥檙e so different from chimps that little more than a one per cent difference
in our DNA sequences seems too small to account for our uniqueness, he says. 鈥淲e
think we must be more special than that.鈥�

Working out the genetic differences between chimps and humans is one thing,
but you need to look beyond chimps if you want to understand our evolutionary
origins.

The common ancestor of humans, gorillas and chimps lived eight million years
ago. Around seven million years ago, the gorilla line split off, and two million
years later humans and chimps split into distinct species. Many of the traits we
think of as especially human probably cropped up before this split.

鈥淭hings we consider noteworthy human features,鈥� says Morris Goodman, a
molecular evolutionist at Wayne State University in Detroit, 鈥渉ave deep
evolutionary roots in primates.鈥� A big brain is one such feature. Fossil
evidence indicates that monkeys living 20 million years ago had bigger brains
than the primates of 50 million years ago. Even today, Old World monkeys, apes
or humans have larger brains than New World monkeys such as tamarins and
capuchins. So if you study only chimps and humans you stand no chance of finding
the triggers that led to the evolution of bigger brains.

The same goes for fetal development. Chimps, gorillas and humans have the
longest gestation periods of the primates. This may have something to do with
the evolution of the fetal haemoglobin gene, says Goodman. All primates possess
a cluster of genes that code for different forms of haemoglobin鈥攖he
protein that carries oxygen in the blood. In higher primates, mutations in the
genes allow the haemoglobin that is most adept at handling oxygen to be active
throughout fetal life. This improved oxygen transport may have allowed the
evolution of longer periods of fetal development鈥攑erhaps favouring the
development of a more powerful brain.

By comparing the genes of primates, both living and long gone, researchers
should be able to decipher how and when we came to take on our peculiar
characteristics.