Power, Sex, Suicide: Mitochondria and the Meaning of Life (9 page)

Despite their love of extreme environments and unique characteristics, the archaea also share a mosaic of traits with both bacteria and eukaryotes. I say ‘mosaic’ advisedly, as many of these traits are self-contained modules, encoded by groups of genes that work together as a unit (such as the genes for protein synthesis, or for energy metabolism). These individual modules fit together like the pieces of a mosaic, to construct the overall pattern of an organism. In the case of the archaea, some pieces are similar to those used by eukaryotes, while others are more reminiscent of bacteria. It is almost as if they were selected at random from a lucky dip of cell characteristics. So, for example, even though the archaea are prokaryotes, easily mistaken for bacteria when viewed down the microscope, some of them nonetheless wrap their chromosome in histone proteins, in a very similar manner to eukaryotes.

The parallels between archaea and eukaryotes go further. The presence of histones means that archaeal DNA is not easily accessible, so, like the eukaryotes, archaea need complicated transcription factors to copy or to transcribe their DNA (reading off the genetic code to construct a protein). The detailed
mechanism of genetic transcription in the archaea parallels that in eukaryotes, albeit in a simpler fashion. There are also similarities in the way that the two groups construct their proteins. As we saw in the Introduction, all cells assemble their proteins using the tiny molecular factories called ribosomes. The ribosomes are broadly similar in all three domains of life, implying that they share a common ancestry, but they differ in many details. Interestingly, there are more differences between the bacterial and archaeal ribosomes than there are between archaeal and eukaryotic ribosomes. For example, toxins like diphtheria toxin block protein assembly on ribosomes in both the archaea and eukaryotes, but not in bacteria. Antibiotics like chloramphenicol, streptomycin, and kanamycin block protein synthesis in the bacteria, but not in the archaea or eukaryotes. These patterns are explained by differences in the way that protein synthesis is initiated, and in the detailed structure of the ribosome factories themselves. The ribosomes of eukaryotes and archaea have more in common with each other than either do with bacteria.

All this means the archaea are about as close to a missing link between the bacteria and the eukaryotes as we are ever likely to find. The archaea and the eukaryotes probably share a relatively recent common ancestor, and are best seen as ‘sister’ groups. This seems to back up Cavalier-Smith’s view that the loss of the cell wall, possibly in the common ancestor of the archaea and the eukaryotes, was the catastrophic step that later propelled the evolution of eukaryotes. The earliest eukaryotes may have looked a little like modern archaea. Intriguingly, though, no archaea ever learnt to change shape to scavenge a living by engulfing food in the eukaryotic fashion. On the contrary, instead of developing a flexible cytoskeleton as the eukaryotes did, the archaea developed quite a stiff membrane system, and remained nearly as rigid as bacterial cells. So there is more to being ‘eukaryotic’ than just lacking a cell wall; but might it be no more complex than lifestyle? Were the ancestral eukaryotes simply wall-less archaea, which modified their existing cytoskeleton into a more dynamic scaffolding that enabled them to change shape and eat food in lumps, by phagocytosis? Might this alone account for how they came by their mitochondria—they simply ate them? And if so, might there still be a few living fossils from the age before mitochondria lurking in hidden corners, relics of those primitive eukaryotes that shared more traits with the archaea?

According to the theory put forward by Cavalier-Smith as long ago as 1983, some of the simple single-celled eukaryotes living today
do
still resemble the earliest eukaryotes. More than a thousand species of primitive eukaryotes do not possess mitochondria. While many of these probably lost their mitochondria
later, simply because they didn’t need them (evolution is always quick to jettison unnecessary traits), Cavalier-Smith argued that at least a few of these species were probably ‘primitively amitochondriate’—in other words, they never did have any mitochondria, but were instead primitive relics of the age before the eukaryotic merger. To generate their energy, most of these cells depend on fermentations in the same way as yeast. While a few of them tolerate the presence of oxygen, most grow best at very low levels or even in the complete absence of the gas, and thrive today in low-oxygen environments. Cavalier-Smith named this hypothetical group the ‘archezoa’ in deference to their ancient roots and their animal-like, scavenging mode of living, as well as their similarities to the archaea. The name ‘archezoa’ is unfortunate, in that it is confusingly similar to ‘archaea’. I can only apologize for this confusion. The archaea are prokaryotes (without a nucleus), one of the three domains of life, while the archezoa are eukaryotes (with a nucleus) that never had any mitochondria.

Like any good hypothesis, Cavalier-Smith’s was eminently testable by the genetic sequencing technologies then reaching fruition—the capacity to work out the precise sequence of letters in the code of genes. By comparing the gene sequences of different eukaryotes, it is possible to determine how closely related different species are to each other—or conversely, how remote the archezoa are from more ‘modern’ eukaryotes. The reasoning is simple. Gene sequences consist of thousands of ‘letters’. For any gene, the sequence of these letters drifts slowly over time as a result of mutations, in which particular letters are lost or gained, or substituted one for another. Thus, if two different species have copies of the same gene, then the exact sequence of letters is likely to be slightly different in the two different species. These changes accumulate very slowly over millions of years. Other factors need to be considered, but to a point the number of changes in the sequence of letters gives an indication of the time elapsed since the two versions diverged from a common ancestor. These data can be used to build a branching tree of evolutionary relationships—the universal tree of life.

If the archezoa really could be shown to be among the oldest of eukaryotes, then Cavalier-Smith would have found his missing link—a primitive eukaryotic cell, that had never possessed any mitochondria, but which did have a nucleus and a dynamic cytoskeleton, enabling it to change shape and feed by phagocytosis. The first answers became available within a few years of Cavalier-Smith’s hypothesis, and apparently satisfied his predictions in full. Four groups of primitive-looking eukaryotes, which not only lacked mitochondria but also most other organelles, were confirmed by genetic analysis to be amongst the oldest of the eukaryotes.

The first genes to be sequenced, by Woese’s group in 1987, belonged to a tiny
parasite, no larger than a bacterium, which lives inside other cells—indeed, can
only
live inside other cells. This was the microsporidium
V. necatrix
. As a group, the microsporidia are named after their infective spores, all of which come replete with a projecting coiled tube, through which spores extrude their contents into a host cell, then multiply to begin their life cycle afresh, ultimately producing more infective spores. Perhaps the best-known representative of the microsporidia is
Nosema
, which is notorious for causing epidemics in honeybees and silkworms. When feeding inside the host cell,
Nosema
behaves like a minute amoeba, moving around and engulfing food by phagocytosis. It has a nucleus, a cytoskeleton and small bacterial-style ribosomes, but has no mitochondria or any other organelles. As a group, the microsporidia infect a wide variety of cells from many branches of the eukaryote tree-of-life, including vertebrates, insects, worms, and even single-celled ciliates (cells named after their tiny hair-like ‘cilia’, used for feeding and locomotion). As all microsporidia are parasites that can survive only inside other eukaryotic cells, they can’t truly represent the first eukaryotes (because they would have had nothing to infect) but the diverse range of organisms that they do infect suggests that they have ancient origins, going back to the roots of the eukaryotic tree. This assumption seemed to be confirmed by genetic analysis, but there was a catch, as we shall see in a moment.

Over the next few years, the ancient status of the three other groups of primitive eukaryotes was confirmed by genetic analyses—the archamoebae, the metamonads, and the parabasalia. All three groups are best known as parasites, but free-living forms do also exist, perhaps fitting them better than the microsporidia as the earliest eukaryotes. As parasites, these three groups occasion much misery, illness, and death; how ironic that these repellent and life-threatening cells should be singled out as our own early ancestors. The archamoeba are best represented by
Entamoeba histolytica
, which causes amoebic dysentery, with symptoms ranging from diarrhoea to intestinal bleeding and peritonitis. The parasites burrow through the wall of the intestine to gain access to the bloodstream, from where they infect other organs, including the liver, lungs, and brain. In the long term, they may form enormous cysts on these organs, especially the liver, causing up to 100 000 deaths worldwide each year. The other two groups are less deadly but no less smelly. The best-known metamonad is
Giardia lamblia
, another intestinal parasite.
Giardia
does not invade the intestinal walls or enter the bloodstream, but the infection is still thoroughly unpleasant, as any travellers who have incautiously drunk water from infected streams know to their cost. Watery diarrhoea and ‘eggy’ flatulence may persist for weeks or months. Turning to the third group, the parabasalia, the best known is
Trichomonas vaginalis
, which is among the most prevalent, albeit least menacing, of the microbes that cause sexually transmitted diseases (though the inflammation it produces may increase the risk of
contracting other diseases such as AIDS).
T. vaginalis
is transmitted mainly by vaginal intercourse but can also infect the urethra in men. In women, it causes vaginal inflammation and the discharge of a malodorous yellowish-green fluid. All in all, this portfolio of foul ancestors just goes to prove that we can choose our friends but not our relatives.

For all their unpleasantness, the archezoa nonetheless fitted the bill as primitive eukaryotes, survivors from the earliest days before the acquisition of mitochondria. Genetic analysis confirmed that they did branch away from more modern eukaryotes at an early stage of evolution, some two thousand million years ago, while their uncluttered morphology was compatible with a simple early lifestyle as scavengers that engulfed their food whole by phagocytosis. Presumably, one fine morning, two thousand million years ago, a cousin of these simple cells engulfed a bacterium, and for some reason failed to digest it. The bacterium lived on and divided inside the archezoon. Whatever the original benefit might have been to either party the intimate association was eventually so successful that the chimeric cell gave rise to all modern eukaryotes with mitochondria—all the familiar plants, animals, and fungi.

According to this reconstruction, the original benefit of the merger was probably related to oxygen. Presumably it was not a coincidence that the merger took place at a time when oxygen levels were rising in the air and the oceans. A great surge in atmospheric oxygen levels certainly occurred around two billion years ago, probably in the wake of a global glaciation, or ‘snowball earth’. This timing corresponds closely to that of the eukaryotic merger. Modern mitochondria make use of oxygen to burn sugars and fats in cell respiration, so it is not surprising that mitochondria should have become established at a time when oxygen levels were rising. As a form of energy-generation, oxygen respiration is much more efficient than other forms of respiration, which generate energy in the absence of oxygen (anaerobic respiration). All that said, it is unlikely that superior energy generation could have been the original advantage. There is no reason why a bacterium living inside another cell should pass on its energy to the host. Modern bacteria keep all their energy for themselves, and the last thing they do is export it benevolently to their neighbouring cells. Thus while there is a clear advantage for the ancestors of the mitochondria, which had intimate access to any of the host’s nutrients, there is no apparent advantage to the host cell itself.

Perhaps the initial relationship was actually parasitic—a possibility first suggested by Lynn Margulis. Important work from Siv Andersson’s laboratory at the University of Uppsala in Sweden, published in
Nature
in 1998, showed that
the genes of the parasitic bacterium
Rickettsia prowazekii
, the cause of typhus, correspond closely with those of human mitochondria, raising the possibility that the original bacterium might have been a parasite not unlike
Rickettsia
. Even if the original invading bacterium was a parasite, the unbalanced ‘partnership’ may have survived, as long as its unwelcome guest did not fatally weaken the host cell. Many infections today become less virulent over time, as parasites also benefit from keeping their host alive—they do not have to search for a new home every time their host dies. Diseases like syphilis have become much less virulent over the centuries, and there are hints that a similar attenuation is already underway with AIDS. Interestingly, such attenuation over generations also takes place in amoebae such as proteus. In this case, the infecting bacteria initially often kill the host amoebae, but eventually become necessary for their survival. The nuclei of infected amoebae become incompatible with the original amoebae, and ultimately lethal to them, effectively forcing the origin of a new species.

In the case of the eukaryotic cell, the host is good at ‘eating’ and through its predatory lifestyle provides its guest with a continuous supply of food. We are told that there is no such thing as a free lunch, but the parasite might simply burn up the metabolic waste-products of the host without weakening it much at all, which is not far short of a free lunch. Over time the host learned to tap into the energy-generating capacity of its guest, by inserting membrane channels, or ‘taps’. The relationship reversed. The guest had been the parasite of the host, but now it became the slave, its energy drained off to serve the host.