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May 20, 2004
Who Needs Sex?
Is there another way to mix genes besides sex?
By Scott Anderson
An intriguing idea percolating through the scientific
community has the power to upend a lot of biology, genetics and
evolution. For that reason, scientists are treating it delicately.
They are poking at the theory (because they must), but from a respectable
distance. The idea, called "horizontal gene transfer,"
makes a terrific sci-fi premise but it may also be true.
We're used to the idea that our genes come from our
parents, who mixed and matched their own genes to create each of
us as a unique individual. That's certainly what Mendel showed with
his pea studies, and what countless follow-up experiments have amply
confirmed. You can illustrate these experiments with genetic trees
showing children branching off from their parents and having more
children, etc.
Scale the tree up to include all the species, and you
have a tree of life.
There are two things to notice about a standard tree
of life. One is that it has a single starting point at the base
of the trunk, which presumably represents the original cellular
life-form from which all subsequent life evolved. Around 3.5 billion
years ago, this original prototype cell must have bubbled up out
of the primordial sludge and mutated into different cells that eventually
established the basic domains (also called kingdoms) like bacteria,
plants and animals.
The second thing to notice about the standard tree is
that the branches inexorably go up and out. After a species splits
off, it never looks back. In fact, that's what we mean by species:
creatures of the same species can successfully mate and produce
offspring, but after the split has been made inter-species mating
is sterile. The branches spread out and the genes never again get
a chance to mix.
Classic Darwinian genetics is a paragon of patience.
Tiny changes slowly accumulate over many eons, finally converting,
say, a brown-eyed gene into a blue-eyed gene. The changes are presumed
to be random, but over a sufficient period of time, certain genes
demonstrate a statistically reliable rate of change. That rate can
be used to calibrate a kind of clock: if a gene averages one change
per millennium and your two samples have ten differences, then they
probably differ in age by ten millennia.
Having sequenced so many genes, and armed with this
genetic clock, we should be able to a bang-up job on the tree of
life. We should be able to pinpoint with reasonable precision when
each species split off and even to quantify how different it is
from its ancestors and cousins. But in working on the tree, a perplexing
anomaly has surfaced.
The problem is simple to state: the genes of many species
seem to be younger than the species themselves. That's a big problem;
if we want to use genes to refine the tree of life, it would be
handy if they actually correlated with the species. Worse yet, certain
genes seem to be popping up in more than one species perhaps even
more than one domain at about the same time.
It's almost as if entire genes had been packaged up
and transferred to other species. But that couldn't be there are
just too many cellular processes designed to stop this very thing.
If genes were that promiscuous, it would throw biology for a loop.
Besides, how could something as dramatic as wholesale gene transfer
be overlooked by the last seventy years of molecular biology?
Recognizing gene transfer, however, is not so simple.
Before all the genes had actually been mapped and logged for analysis,
seeing the patterns was a matter of serendipity. However, once the
data started flowing in, an interesting picture started to emerge
and it wasn't what anyone had expected.
The first hints that whole-gene transfer was possible
came from studies of antibacterial resistance. Antibacterial action
was discovered in 1928 by Alexander Fleming, who noticed that a
spot on mold in a petri dish was killing his colony of staph bacteria.
Fleming isolated penicillin from the mold and created the first
mold-based antibacterial.
Many more antibacterial extracts were discovered, and
these had a huge impact on the health of humans around the world.
But within years of using some of these antibacterials clinically,
the bacteria started to develop resistance. At first a mystery,
the cause of the resistance was finally traced to genes on a circular
loop of DNA called a plasmid. These loops of DNA are passed back
and forth by the bacteria as casually as you would loan a DVD to
a friend. And, as with a DVD, the DNA is standardized and ready
to "play" in any other bacteria. If the plasmid confers
resistance to a particular antibiotic, any cell that receives it
is then protected. The bacteria without the gene die off, leaving
a population of "super bugs" that can't be treated with
that particular antibiotic.
Okay, thought the researchers, that is certainly gene
transfer, but a bacterial plasmid is nothing like the nuclear DNA
in more advanced organisms. What's true for bacteria surely has
nothing to do with eukaryotes (the so-called "true" cells
of plants and animals). Eukaryotes, it was certain, only mixed genes
during the cross-over event of sexual reproduction. In fact, thanks
to the pioneering work of people like Barbara McClintock, scientists
had actually succeeding in nailing down just where each gene resided
on the chromosomes. If there was ever an orderly, static place for
storing information, it was the stately DNA molecule.
But then in 1951, McClintock, who clearly didn't know
how to rest on her laurels, noticed something in a special variety
of corn that is still creating ripples throughout biology today:
some of the genes were jumping around to different locations on
the chromosomes. Not only that, but there were other genes helping
them do it. McClintock called it transposition, and the jumping
genes became known as transposons.
This news didn't go down easily. Many scientists insisted
that the effect must be limited to that specific corn variety
a freak of nature, certainly not the norm. But Dr. McClintock disproved
that notion when she discovered more transposons in other varieties
as well. That should have settled the case, but many scientists
remained unconvinced and minimized the importance of jumping genes.
Even though she received a Nobel prize for her work, Dr. McClintock's
experiments are still little known outside of biology labs.
In the 1960s, Lynn Margulis declared that organelles
(tiny structures in cells like mitochondria or chloroplasts) are
most likely trapped bacteria that have come to live symbiotically
within eukaryotic cells. Once again, biologists were intrigued but
wary. Bacteria seem to be our enemies, and yet here was Dr. Margulis
suggesting that we had let the enemy in the front door and were
setting up house with them. So now, it seemed, not only genes were
being transferred, but whole organisms were being co-opted. The
Darwinian struggle was starting to look more like a love fest.
In 1976, Susumu Tonegawa at MIT discovered that mouse
antibody genes change their positions on the chromosomes, in effect
randomizing the antibodies. By shuffling the genes like this, millions
of different combinations are generated, allowing antibodies to
attack a wide range of invaders. This is a case where jumping genes
are used to promote parsimony; to actually encode each antibody
as a unique gene would easily quadruple the size of the chromosomes.
In the 1980s, Harvard's Dr. Michael Syvanen couldn't
stop thinking about the many different ways that a gene might be
passed around from species to species. For instance, as well as
using plasmids to transfer genes, bacteria were known to pick up
genes merely by eating a fellow bacteria even one from a different
species. You are literally what you eat, at least when it comes
to bacteria.
And if bacteria can easily incorporate genes from their
surroundings, they may pick up animal genes as well. In fact, certain
strains of luminescent bacteria are known to have an animal variety
of a gene called superoxide dismutase. Presumably, the gene was
picked up from the ponyfish that, over the ages, have provided a
symbiotic home for the bacteria.
That conjures up some unsettling scenarios. Bacteria
are, after all, responsible for decay, the system by which all flesh
is ultimately converted to compost. Just by consuming animals, bacteria
may pick up genes from those animals. And if, say, a vulture dines
on that rotting flesh, those bacteria may take up residence in the
bird and possibly even pass a gene from the dinner to the diner.
Like I say, a good premise for a sci-fi story.
As well as bacterial vectors, Dr. Syvanen knew that
retroviruses can also inject whole genes by hijacking the cellular
reproductive machinery and splicing the gene into the cell's own
DNA. There is also some evidence that viruses, like bacteria, can
pick up genes from a host. Might they then pass these on to another
host?
When the human genome was sequenced, the tally was incredible:
humans were found to have at least 98,000 of these spliced-in viral
genes liberally peppering our chromosomes. How did they get there?
Apparently, a virus infected a precursor to a germ cell (such as
a sperm), which incorporated it into its nuclear DNA and then passed
it on after fertilization to its progeny. And, apparently, that
has happened about a hundred thousand times throughout our genetic
history.
Some of these genes are implicated in cancer and auto-immune
diseases, although most of them seem to be inactivated. Nevertheless,
if any more proof of gene transfer was needed, this would seem to
cinch the case.
But dogma can be surprisingly tenacious, especially
when the very essence of humanity is concerned. Are we just a hodge-podge
of foreign genes and body parts tossed together from various sources?
As ideas go, they don't come any more preposterous than that. It's
insulting to the human species to suggest that we are pasted together
like some crude ransom note, using arbitrary bits and pieces snipped
out of other creatures.
And yet, as Dr. Syvanen (now at UC Davis) and others
have pointed out, this preposterous theory explains so much. For
instance, why is the DNA code the same for all creatures, no matter
how many billions of years ago they separated? Why are the same
20 amino acids encoded pretty much the same way for all creatures?
It doesn't seem to square with simple thermodynamics (things break
down over time), let alone popular notions of biological diversity.
But if genes are being passed around like shared DVDs, they would
all need to run on the same operating system to be useful. Any creature
that couldn't share the genetic information would be marginalized
and could even become extinct, and that would exert a Darwinian
pressure for conformity to a single code. It is a rather elegant
theory.
Along with the captured organelles of Dr. Margulis,
it implies a less cut-throat environment for evolution. Instead
of an all-out brawl, there are firm guidelines that most organisms
follow, and opportunism abounds. A gene or even an entire creature
is as likely to be exploited as exterminated. Instead of a fight
to the finish, networking is the order of the day.
Gene transfer also helps to explain the sudden changes
noted in the fossil record. Typically, rather than the stately progression
of "ordinary" Darwinian evolution, relatively fast changes
occur between long stretches of stability. Niles Eldredge and Stephen
Jay Gould called it punctuated equilibrium, and argued that it represented
new species splitting off and changing over tens of thousands of
years. That is slow enough that no single individual would even
perceive it, but by geological scales, it's an eye-blink.
The popular explanation for how a species splits involves
physical separation between two populations, say by a flood-swollen
river. Over time, if not exposed to each other, they could diverge
genetically. But what if wholesale gene transfer were able to split
a species in two without further ado? Could gene transfer be another
agent of speciation, a kind of instant genetic barrier that ends
up separating two populations molecularly?
Dr. Syvanen goes even farther. As every budding biologist
learns, early human development looks a lot like monkey, chicken
or even shark development. Human embryos have tails and gills that
later disappear or morph into something else. Why the commonality
of development? If Dr. Syvanen is right, the persistence of these
similar forms provides a valuable platform for gene transfer. It
might allow a shark gene to be expressed in a human being at least
during some phase of development. If so, there would be a strong
evolutionary pressure to ensure that this platform for gene transfer
was maintained. Without it, a major possible mechanism of cross-species
genetic updating would be lost.
If gene transfer is common, it has far-reaching implications.
Just as one instance, current genetically modified (GM) food crop
experiments are being challenged because they threaten to spread
their genes to other nearby crops. Dr. Syvanen's work would seem
to support these concerns.
Currently, in order to create a GM plant, scientists
use plasmids that contain the gene of interest connected to a gene
for antibacterial resistance. After getting the plant to take up
the plasmid, the researchers need to separate the plants that actually
express the gene from those that didn't incorporate it properly.
They do that by dosing the cells with antibiotics. If the gene of
interest has been properly inserted, odds are the antibacterial
gene will be too, and those cells will survive while the rest die
off.
That means that most GM crops, simply as an artifact
of their laboratory creation, have antibacterial genes. Can these
transfer to bacteria in the soil? After what we've learned so far,
it would be surprising if they didn't. In fact, that's just what
people are finding when they look at the bacteria around the roots
of GM crops.
But if gene transfer is really that profligate, then
perhaps GM foods are not so special after all. It might seem totally
wacky to put jellyfish genes into tomatoes, but it wouldn't be surprising
if nature had already beat us to the punch. In fact, given the evolutionary
gauntlet that genes must endure, it would be quite surprising if
mere humans were able to put forward a novel gene that could possibly
compete with the reigning champs.
In other words, nature is resilient, and genetic engineering
may not be the sole province of human researchers. Mother Nature
likes to mix and match too, and she has a few billion years on us.
That's not to say we should feel free to muck things up. Certainly
we can damage ecosystems by popping in the wrong gene. Due to the
ruggedness of nature, we probably won't cause any runaway genetic
meltdown, but we could easily make a mess if we don't take gene
transfer seriously.
The lesson for GM researchers may be that the reason
it is possible to insert genes in the first place is that life is
built for swapping but it doesn't stop at the lab door. The genes
we introduce may spread throughout an ecosystem, so we should be
circumspect about which genes those are.
If our genes are really jumping around, we need to rethink
many things. The molecular clock we've been depending on to date
all things biological may need to be recalibrated. Evolution, commonly
thought of as the accumulation of billions of tiny changes, would
be radically speeded up if whole genes are exchanged. And the whole
tree of life starts to look more like a web, where the horizontal
lines represent genes that have jumped from one species to another:
This is truly a remarkable picture with far-reaching
interpretations. If viruses and bacteria are indeed vectors for
transferring genes, then their collective status as mischief maker
should be revised to include species maker. Perhaps viruses and
bacteria have more central roles in evolution than previously appreciated.
Jumping genes may also play a part in development, as
stem cells morph into adult cells. There is accumulating evidence
that contrary to what most of us learned in school, each cell does
not have the same DNA. Instead, through a series of adjustments
and jumping around, the genome is rearranged to provide a unique
blueprint for each cell type.
Recent research has indicated that developing embryos
produce reverse transcriptase. This is the protein used by retroviruses
to sneak their genes into the host DNA. Why is a virus protein expressed
during animal development? Based on what we've learned so far, we
couldn't be blamed for thinking it's to help shuffle the genetic
deck. In the process of shuffling, the subsequent daughter cells
would differ from their mother they would differentiate, which
is the beginning of development.
Scientists already have theories to explain how a daughter
cell can be different without invoking jumping genes. It's pretty
easy to roll up a segment of DNA so that it is effectively neutered,
and that should also give rise to differentiated cells. But what
if both mechanisms (new genes and neutered genes) are needed?
Did a virus infect an early cell and inadvertently confer
upon it the ability to specialize, thus giving rise to the first
complex creatures?
Could these mechanisms have grown up together, one changing
genes on the short scale of development and the other on the long
scale of evolution? And, if the same mechanism underlies both phenomena,
could gene transfer offer yet another way to explain why development
echoes evolution?
Many more experiments and observations are needed to
measure the full impact of gene transfer, but some biologists are
still dragging their feet. A recent article in the prestigious journal
Nature speculated on the origin of life as a sort of communal soup.
There was not a single mention of horizontal gene transfer. I asked
Dr. Syvanen about the slight, and he said that he has submitted
several papers to Nature, but they have never been accepted. When
I asked him if he was running into resistance from people whose
timelines would have to be recalibrated, he said, "Major resistance.
You are right. It would change the field of taxonomy, maybe not
too seriously with the metazoans but with plants and the higher
taxonomic issues it would."
Nevertheless, as with the theories of McClintock and
Margulis, the final arbiter of biological truth is not a committee
of smart people, but rather nature herself. As much as it pains
us, many of the things we learned in school were just plain wrong.
That is, paradoxically, a mark of success for the scientific method.
When it comes to mixing genes, sex is a great, time-honored
technique. But it may not be the only way. The next time you get
the flu or an infection, stay alert to the possibility that your
genes may be getting an update. For the sake of you and your future
children, let's hope it's a good one.
Copyright © 2000-2004 by Scott Anderson
For reprint rights, email the author:
Scott_Anderson@ScienceForPeople.com
Here are some other suggested readings in gene
transfer:
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