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The Times Literary Supplement, June 2005

Assisted apoptosis

Jonathan Hodgkin

All animals and plants survive on the earth only as a result of a symbiotic relationship, established more than a billion years ago, between large host cells with distinct nuclei and complicated internal structures, and small passengers called mitochondria, which supply energy to the rest of the cell. This idea was once controversial, but it is now universally accepted that mitochondria are degenerate bacteria. They have retained a few genes which confirm their bacterial ancestry, but long ago transferred most of their DNA to the nuclei of the host cells. As a result, they are now completely incapable of independent existence, but they are indispensable to their hosts, so that the symbiotic relationship seems stable and essentially immutable.

Mitochondria are not very exciting to look at: they are (usually) small sausage-shaped bodies, with a smooth outer membrane and a pleated inner membrane, and present in every plant or animal cell in numbers ranging from one to thousands, depending on the nature of the cell concerned. Their importance for energy production is well known, but it is increasingly recognized that they have many other roles.

Nick Lane's impressive Power, Sex, Suicide sets out to convince us that there is far more to mitochondria than the conventional view allows. According to him, they are intimately bound up with every major aspect of biology: the origin of life, evolution, complexity, sex, growth, size, death, ageing and the rest. This is a polemical book, and like all polemics it tends to omit alternative views and awkward facts, but it is readable, provocative and often persuasive. Although written for the general reader, it manages to cover its enormous range of topics in considerable depth, and the technical details are very well managed.

The flamboyant title captures some, but by no means all, of the major themes of the book. Power comes first, and power generation is the most obvious feature of mitochondrial biology; the textbook view is that mitochondria are there simply to generate ATP, the main energy currency of the cell. But they, and their bacterial cousins, achieve this ATP production in a peculiar way, by first pumping protons across a membrane, creating a gradient which is then used for ATP synthesis. These trans-membrane proton gradients seem to be the primordial energy currency, and the gradients and associated membranes may even have been essential for the origin of life. The mechanisms involved are very different from the usual kinds of chemical reactions that biochemists studied in the first half of the twentieth century, and the notion that a "proton motive force" was responsible for ATP production met with huge resistance when it was first proposed by Peter Mitchell. The Mitchell hypothesis came to prevail, however, in one of the few examples of a genuine Kuhnian revolution in biology. It still seems distinctly odd, and we still don't understand how the membrane-based energy mechanism could have arisen in the first place. Lane subscribes to the interesting theory that the earliest membranes of primitive cells were not even organic, but made from iron and sulphur.

Power is essential for survival, but additional power is also needed for doing anything fast and complicated, like eating your neighbour, and one idea is that the symbiotic pairing of two kinds of bacterial cell made it possible for cellular predators -eukaryotes -to evolve for the first time. One partner provided the muscle, and the other provided the moves. Once predation became possible, all sorts of other changes in size and complexity may have evolved as a consequence, with the initiation of evolutionary arms races.

Accordingly, one of the big mysteries in evolutionary biology is the origin of the eukaryotic cell. For billions of years, the only organisms present on earth were two great kingdoms or empires of bacteria, called the archaea and the eubacteria.

The third empire, the eukaryotes (which includes all plants, animals, fungi and protozoa), arose only latterly, probably as a result of a critical symbiosis between archaea (the ancestor of the nucleated host cells) and eubacteria (the ancestor of the mitochondria). Exactly how and why this symbiosis happened is vigorously debated, and Lane provides an excellent, if partisan, account of the possibilities and problems involved.

Sex brings in another set of evolutionary mysteries: why did sex evolve, why are there two sexes, and why are their gametes (eggs and sperm) so dissimilar? Again these are very controversial areas, and again there are scenarios in which mitochondria might be very important. Some of these also seek to explain the maternal inheritance of mitochondria: we inherit our mitochondria only from our mothers, not from our fathers, like a maternal surname. Why should this be? Lane suggests there has to be a mutual tuning of the maternal mitochondria and the maternal genome, to achieve an optimal fit, and the addition of another set of mitochondria from the father would disturb this, so it is prevented. There are obvious problems with this theory, which he eventually concedes in a footnote.

Theory aside, the effect of putting different sets of mitochondria together is currently a hot topic in human reproduction, with the advent of "babies with two mothers". Lane would argue that the technique of supplying extra mitochondria by ooplasmic transfer, in order to correct maternal defects, is inherently dangerous; not all would agree.

The "suicide" part of the title refers to yet another facet of mitochondrial biology, which is the role of mitochondria in cell death, in particular the specialized form of cell suicide known as apoptosis. Once again we are dealing with a major evolutionary transition, this time the transition from selfish unicellular existence (every man for himself) to multicellular life, for which some kind of cooperation between cells is needed. Suicide for the greater good of the whole organism is the most extreme kind of cooperation. Transitions to multicellular life have happened multiple times in evolution, even before the advent of complex eukaryotic organisms, and every time some form of controlled cell suicide has evolved in parallel. However, these are clearly independent events, and the molecules involved in suicide are not always the same. Lane would have you believe otherwise, and furthermore that mitochondria are always central to cell death, but his arguments here are not compelling. Mitochondria are certainly important in mammalian apoptosis, but it can be argued that they have acquired this role relatively recently in evolution, and act only as amplifiers of the suicide signal, rather than controllers of the decision to die.

Mitochondria provide the power that keeps us going, but they also generate the poisons that kill us in the end. Respiration, the main metabolic function of mitochondria, can also create dangerous molecules called free radicals, which cause cumulative cellular damage. Consequently, a vast amount of research and industry is devoted to testing free-radical theories of ageing, and to the use of antioxidants as possible anti-ageing drugs. Lane rightly emphasizes that such drugs are generally useless, because they cannot target the key cellular sites where the damage is being done. He provides a valuable and critical discussion of mitochondrial theories of ageing, and comes up with his own variations on these themes. This leads him to propose, with a final flourish, his panacea and cure for old age: simply making more mitochondria. How this might be achieved therapeutically is not obvious, but there is even a tiny piece of evidence in favour of the idea, in the form of an association between greater human longevity and a mutation that may allow mitochondria to multiply more rapidly.

Perhaps only the most ardent devotees of mitochondria would go along with every one of the numerous theories that Lane supports or proposes. Nevertheless, much of what he says is plausible, very well explained, and undoubtedly important. This is an exciting and unusual book.

 

Jonathan Hodgkin is Professor of Genetics at Oxford University

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