Vital Questions, Part 3

Week 3 – continued review of The Vital Question by Nick Lane

Nick Lane takes a look at the evolution of life on earth with an eye to explaining large-scale patterns, from a perspective based on the energy metabolism.  In the first week, we talked about the origin of life and the structue of the cell.  In the second week, we looked at the differences between eukaryotes and what came before, and asked about mergers of widely differing species.  In this third and final installment, I want to look at sex and death, and also to advocate for two important concepts that could broaden Lane’s perspective yet further.




Sex is the exchange of genetic material.  It was invented long before the first eukaryote.  Bacteria freely pass circular snippets of DNA called plasmids among themselves, with little regard to where they came from or what they are for.  But in eukaryotes, sex became formalized, with exchange strictly limited to another of the same species (this is the definition of species), and it became compulsory, a prerequisite for reproduction in multi-celled species.  Many plants and some animals are hermaphrodites, with both male and female in one individual.  But most higher organisms have two separate sexes.  Lane proposes to explain all these patterns based on the most fundamental observation:  the mitochondria, having colonized the eukaryotic cell and brought with them their own DNA, have to remain healthy and work hormoniously with the host cell.

bacteria enjoy the benefits of sex (fluid chromosomes) along with the speed and simplicity of cloning. But they don’t fuse whole cells together, and they don’t have two sexes, and so they avoid many of the disadvantages of sex. They would seem to have the best of both worlds. So why did sex arise from lateral gene transfer in the earliest eukaryotes?

This is an (uncharacteristic, for Lane) understatement.  For anyone who thinks in terms of the dominant paradigm of the 20th Century, evolution is all about individual competition and selfish genes.  Plasmids, as selfish genes, make perfect sense.  But the way that sex is implemented in eukaryotes makes no sense from the perspective of selfish gene theory.  The most successful members of the community have combinations of genes that work better than anyone else’s.  What incentive do they have to share genes with their competitors, bringing their fitness down and their competitors’ fitness up?  And the biggest violation of selfish-gene logic is the “cost of males”.   Hermaphrodites have twice the fitness compared to diecious sex (2 separate sexes).

The standard view is that this is a mystery, an isolated phenomenon that has yet to be reconciled with selfish gene theory.  I prefer to think that diecious sex is an unequivocal refutation of selfish gene theory, that evolutionary theory must expand to embrace a notion of fitness more sophisticated than “every gene for itself”.


Origin of Sex

Eukaryotes were around for half a billion years as single-celled protists.  Like bacteria and archaea before them, they were single cells, but the cells were 100,000 times larger and had a great deal of structure and mechanics that the prokaryotes didn’t have.

Lane says sex arose very early in the history of eukaryotes.  He cites as evidence (1) that the long list of traits that all eukaryotes have in common (but that prokaryotes lack) could only have arisen in an inbreeding population; and (2) even the simplest eukaryotes today (giardia is the example that Lane cites) have the genes necessary for meiosis=cell mergers and gene exchange.

Cloning may produce identical copies, but ironically this ultimately drives divergence between populations as mutations accumulate. In contrast, sex pools traits in a population, forever mixing and matching, opposing divergence. The fact that eukaryotes share the same traits suggests that they arose in an interbreeding sexual population. This in turn implies that their population was small enough to interbreed.

In a diverse population sharing genes, it is possible for different lineages to evolve different features, and then these features come together in a single offspring when they mated.

An alternative hypothesis due to Margulis is that these diverse features were too different to have been encompassed in a single species (a single, interbreeding population).  Rather, the the different features that came together in eukaryotes evolved separately and then the separate species combined in rare cell-merger events, a process she wrote about as “endosymbiosis”, or acquiring genomes.

(How different are these two pictures, really?  We know that individuals with very different features must have shared genes; perhaps it is only a subtlety to ask whether these very different individuals were part of one wide-ranging inter-breding population, or of separate demes that might be called different species.)


Sex and Reproduction were Different Functions

In the one-celled eukaryotes, sex and reproduction were separate and unrelated functions.  Reproduction occurred by mitosis, simple cell division, producing two clones.  Sex occurs via conjugation, in which two individuals merge their cells, and merge the cell nuclei temporarily.  Their chromosomes mix, and as each chromosome finds its opposite number, genes can cross over between the two chromosomes.  When the merged cell comes apart, the two individuals that go their separate ways are no longer the same two individuals that came together an hour earlier.  Instead, there are two new individuals, each a hybrid.


Could mitochondria have “agitated for sex”?

Lane sees the cellular invasion by mitochondria as the source of everything eukaryotic.  Sex, as we have seen, is a particularly thorny problem—not just the mechanics, but the fact that (short-term) selective pressures should have been acting against it.  But while sex would not be adaptive for the host cells (in the short run), it would have provided the only effective way for the mitochondrial “infection” to spread.  There must have been a long transition period in which the mitochondria were not fully domesticated, and had their own ideas about what it means to be “adaptive”.  After mitochondria learned to be endosymbionts, they would have trouble surviving outside the host cell, and trouble penetrating the cell walls of other cells, in order to spread from one host to another.  So perhaps it was the genius of the mitochondria to induce some chemical change that would soften the host’s cell wall, and to promote behaviors that would seek other cells to merge with, giving the mitochondria a chance to spread.

My take: this hypothesis has the virtue of being “conservative” in the sense that it fits well within the predominant selfish gene paradigm.  What could be more selfish than for the mitochondria to want to spread themselves?  But at a slightly deeper level, the main thing that the selfish gene paradigm has going for it is that it is supposed to provide an explicit mechanism for natural selection, i.e., that the gene that makes the most copies of itself is the one that prevails.  In this case, Lane’s hypothesis suffers for want of a mechanism how the mitochondria were able to take control of the cell’s behavior and override the interest of the genes in the nucleus for which sex was a liability.


Difference between plants and animals

Mitochondria reproduce within a cell so their DNA is copied many times for each one time that the nuclear DNA is copied.  Furthermore, mitochondria exist in an environment of high-energy chemistry (ROS) that is a constant threat to the integrity of their DNA.  So we expect high mutation rates in mitochondria, perhaps high enough to cause permanent damage and impaired performance.  Somehow, in domesticating its mitochondrial guests, cells had to learn to culture the healthy ones and eliminate the damaged ones.  Otherwise, mitochondria would gradually mutate and degrade over time.

This is a genuine conundrum, about which there are really no cogent ideas in the literature.  If natural selection keeps populations healthy (and even improves them gradually) by filtering out the dysfunctional, where is the selection on mitochondria as they reproduce within a cell?  Most dangerous of all would be the possibility of Darwinian competition within a cell among the different mitochondria.  Some mitochondria might devote less of their metabolisms to serving the host cell and more to reproducing faster than their sisters.  This could produce an evolutionary advantage within the cell for the slackers, the least useful mitochondria.  Selfish evolution of mitochondria is an existential threat to the partnership between mitochondria and host.

Lane devotes a whole chapter to speculation about the resolution of this problem.  We know that nature has managed to keep mitochondria healthy over billions of generations, in all surviving eukaryotes, but we weren’t around to watch how the mitochondria were tamed or convinced to submit to the hegemony of the cell nucleus.  What we have to go on are surviving patterns that may bear the imprint of this ancient battle.  The fact that mitochondria are inherited through the female line only is one piece of data.  A difference in strategy between plants and animals may be another legacy of the battle: any cell of a plant’s meristem can grow into a seed that grows to a new plant, but in animals, the “germ line is segregated”, meaning that there is specialized reproductive tissue, protected from the earliest stage of embryonic development.  Lane relates this difference to the fact that animals have a higher metabolic rate, with more mitochondria that are more active, thus a lower mitochondrial mutation rate.  There may even be a connection to the reason that females lose their fertility earlier than men; the mitochondria become more highly mutated late in life, and it would be a risk to the offspring to launch them into life with a stock of mutated mitochondria.  Males can afford to reproduce later in life because they don’t contribute mitochondria to the offspring.


Aging and death

Lane doesn’t have a lot to say about aging in this volume, but he does note that aging only really became an option once the germ line was segregated.  Germ line cells need to have full capacity for regenerating everything (pluripotency) but cells of the soma have the luxury of specializing, and one option is to differentiate and grow once and for all, creating an organ that must last a lifetime (like a brain or heart).

In the end, Lane’s explanation of aging lands at a place very close to conventional theories based on tradeoffs.  The somatic tissues of the body can’t be simultaneously good at everything, and they are specialized to their differentiated purpose, to the detriment of the ability of regenerate.  Hence they are prone to wear out over a lifetime.  I find this explanation less compelling than many of his other ventures, but this is probably inevitable, since evolution of aging is the area where my own thoughts are most highly developed.

Lane goes on to describe his own version of the mitochondrial free radical theory of aging, which is not an evolutionary theory.  He elaborates why, despite the many well-known failures of this theory in its naive form, he nevertheless finds a core of truth in it.

Conjugation of Ciliates

Sex and Death in Protists Presages Sex and Death in Multicelled Plants and Animals

The mechanics of conjugation in protists looks strikingly like the mechanics of sex in later multi-celled organisms.  The way in which the cells merge, the crossover of chromosomes, the particular genes that are involved all point to a close relationship.  Most striking is the strange mechanism of doubling the chromosome population before dividing it in half, and then in half again.  The very arbitrariness of this behavior, and the fact that we see it both in protist conjugation and in male-female sex, is attests to the fact that latter evolved from the former.

I’ve said that sex and reproduction in one-celled eukaryotes are separate, unrelated functions.  But there does exist one connection in ciliates, an advanced group of protists including the paramecium.  Telomeres get shorter and shorter with each cell division.  This is cellular senescence.  It is permitted to continue, threatening the cell’s viability, because telomerase is repressed, and only comes out to restore the telomere when two individuals conjugate.

Thus, already in the early ciliates, cellular senescence has the purpose of enforcing conjugation.  This ancient form of aging evolved to protect population diversity.  And in higher organisms to this day, cellular senescence contributes to the death of the individual, assuring that the population continues to be enriched by new combinations of genes.  The rationing of telomerase in protists presages the rationing of telomerase in you and me.

(William Clark tells this story in his very readable book, A Means to an End.  My current project is a computer model demonstrating how telomerase rationing evolved on this basis.)

Where to go from here?  Two suggestions

I am an enthusiastic supporter of Lane’s program, trying to understand the broad outlines of evolution, and why life is the way it is.  I offer, from my own experience, two more themes that might complement his program.

  • the conflict between what is adaptive for the individual and what is adaptive for the community, and how evolution has ways to suppress individual competition in order to create cohesive communities that are powerful competitors.
  • adaptations at every level from chromosome structure to ecosystem structure that contribute to evolvability.  It seems that natural selection has been a bootstrapping process, constantly increasing its own efficiency in the long term, even as it is selecting higher fitness in the short term.

Suppression of individual competition has been necessary for evolution to be able to find long-term solutions.  This happens in somas that have the same genome as the germ line, and so their allegience to the germ line is not in question, and even in eusocial insects, where close kin selection helps to support division of labor in a functional community at a higher level of organization than the individual soma.  David Sloan Wilson has devoted his career to the theory of multi-level selection, the ways in which natural selection operates simultaneously at the level of the individual and larger units of families, populations, and entire ecosystems.  Often there are conflicts between what is good for the individual and what is good for the community, and the striking thing (taking the large perspective) is how consistently the communal interest has managed to take precedence, suppressing selfishness.

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Lane doesn’t mention “evolvability” by name, and tends to see it as random, chance event.  “Adaptive” is the operant word, which signifies a Darwinian process,

changes to the genome itself, which might take the form of large deletions, duplications, transpositions or abrupt rewiring as a result of regulatory genes being inappropriately switched on or off. But such changes are not adaptive; like endosymbioses, they merely alter the starting point from which selection acts.

But I would suggest that there are too many of these properties of eukaryotic life that seem to serve not the gene or the individual carrying it, but the long-term viability of the community.  We should expand our notion of a “Darwinian” process, if necessary, to accommodate the reality that evolvability has evolved.  To be explicit:  “Fitness” is the ability to survive and reproduce copiously and robustly.  “Evolvability” is the ability to increase in fitness.  Evolvability is the rate of change of fitness.  We all agree that there is natural selection for fitness.  The controversial idea is that there can also be natural selection for its rate of increase.

I have a personal relation to this idea.  Harvard astrophysicist David Layzer wrote the first modern paper proposing the evolution of evolvability in 1980 when I was his student.  Layzer’s analysis was ignored by the biology community for 16 years, until the time was ripe, and the same idea was re-cast into language more familiar to evolutionists by a prominent evolutionary theorist who teamed up with a creative and versatile computer scientist.  Wagner and Altenberg generated a discussion that has developed and expanded to this day, but the revolutionary implications of this idea for evolutionary theory have yet to be assimilated.  When the central importance of evolvability is fully appreciated, I predict that it will alter the foundations of evolutionary science.

Examples of evolvability adaptations include:

  • Sex imposes a huge cost in individual fitness, but promotes evolvability.  In fact, sex has benefits both for evolvability and for expanding the level of selection.  As practiced by eukaryotes, sex gives each gene a stake in survival of the entire breeding community, and thereby promotes cooperation over selfishness [ref]
  • Hierarchical signaling cascades, “command and control” with HOX genes controlling transcription factors and transcription factors controlling expression of many genes at once.
  • Eukaryotic proteins are modular, with modules that are re-used in different combinations for different purposes.  “Exons” are areas of the chromosome that code for pieces of protein.“Why do eukaryotes have genes in pieces? There are a few known benefits. Different proteins can be pieced together from the same gene by differential splicing…”

Though he never uses the word “evolvability”, Lane gets the message clearly about the benefit of sex, “fending off debilitating parasites, as well as adapting to changing environments, and maintaining necessary variation in a population.”  In my view, he has yet to realize the profound implications of the fact the sex evolved for the sake of its contribution not to fitness but to evolvability.  The fact that natural selection can favor not just fitness itself but also the rate at which fitness increases carries a deep message.  “Evolvability” is not an individual trait of immediate value, but a property of an entire breeding community (a deme), spread through evolutionary time.  The implication is that natural selection can enhance collective fitness, not just individual fitness, and that the long-term health of the community can be favored over the short-term advantage of the individual.

Evolvability is both a result and a cause of natural selection for traits (like aging) that benefit the community over the individual, even at a substantial cost to individual fitness.  Evolution of evolvability is a bootstrap, a self-reinforcing process, a positive feedback system.

Sex in particular helps to elevate the level of selection from the individual to the community, because sex gives each gene a stake in survival of the entire breeding community, and thereby promotes cooperation over selfishness [ref].

This is a further clue, a connection between multilevel selection and evolvability.



I am full of admiration for Lane’s ambition to explain the broad properties of eukaryotic life, and he has made impressive progress pulling together diverse evidence into coherent theories.  Lane is a biochemist and a “strict constructionist”, working within the predominant school of evolutionary theory, sometimes called the “New Synthesis” or “Population Genetics” or “neo-Darwinism”.  My opinion is that to make further progress, he will find it necessary to venture beyond the neo-Darwinian framework to think about levels of selection, evolvability, and evolutionary ecology.

GDF11—Not So Fast

A research report from Novartis may temper our excitement about GDF11, which was a runner-up for Science Magazine’s 2014 Breakthrough Of the Year.


“Heterochronic parabiosis” is the sanitized word for sewing together as Siamese twins two animals of the same species but different ages.  Modern implementation as a research technique was pioneered by Clive McCay in the 1950s, the same McCay who brought us caloric restriction in the 1930s.

The two animals share a common pool fo blood.  What is clear is that the older animal in the pair benefits from young blood.  Healing is improved, and some tissues are rejuvenated.  What is less clear:  what are the elements in the blood that are responsible for the rejuvenation?  Is there a “youth serum”, transferred from the young animal to the old; or in fact is there a blood factor responsible for deterioration, and the old animal is benefiting from dilution of his elder toxins?  Are there a few such blood factors, or too many to form the basis of a practical therapy?

In the last ten years, there has been a diaspora of researchers from the Stanford lab of Tom Rando, young researchers now at Berkeley and Harvard who are pursuing advanced techniques of blood transfer, seeking to isolate the active ingredients.  A consensus is emerging that

  • It is not the red or white blood cells, but dissolved proteins in the blood that make the difference.
  • There are both pro-aging and anti-aging factors in the blood.

The big questions remaining:

  • There are at least several factors of each kind, pro- and anti-aging.  Is the number of essential blood factors small and manageable, so we might hope to make a “bloody Mary” cocktail?  Or is the number so large this is impractical?
  • Will these blood factors reboot the body’s epigenetics so the old body starts producing the young mix itself?  How long must the body be exposed to the young mix before it starts to produce the young mix itself?

Last year in particular saw eye-popping results from the Berkeley lab of Irina and Mike Conboy, and from the Harvard lab of Amy Wagers.  The Conboys claimed that oxytocin is a blood factor promoting longevity.  [ref, my blog]  Wagers identified GDF11 as a blood factor that declines with age, and enhances strength and endurance when administered to muscle tissue in mice.  [ref, my blog]  In humans, GDF11 has been shown to increase nerve growth.


Cousins of GDF11

A rejuvenating role for GDF11 was a surprise because it is in the TGFβ class of hormones, which generally have negative effects on muscles.  In a 2013 blog, I identified TGFβ as one of the blood factors that we have too much of as we age.  Myostatin is the best-known member of this group, and it inhibits muscle growth.  Mice lacking the myostatin gene grow double-size muscles and have better insulin sensitivity.  Creatine is a myostatin inhibitor that is popular among muscle-builders.

Genes for GDF11 and for myostatin are 90% identical.  But mice lacking GDF11 don’t have bigger muscles, and in fact they die soon after birth.  So it’s possible that GDF11 is good and myostatin is bad.


The latest news

Last week, David Glass and a team at Novartis report that they have failed to reproduce Wagers’s results about GDF11.  From a Nature News report by Sara Reardon:

Glass and his colleagues set out to determine why GDF11 had this apparent effect.  First, they tested the antibodies and other reagents that Wagers’ group had used to measure GDF11 levels, and found that these chemicals could not distinguish between myostatin and GDF11. When the Novartis team used a more specific reagent to measure GDF11 levels in the blood of both rats and humans, they found that GDF11 levels actually increased with age — just as levels of myostatin do. That contradicts what Wagers’ group had found.

Glass’s team next used a combination of chemicals to injure a mouse’s skeletal muscles, and then regularly injected the animal with three times as much GDF11 as Wagers and her team had used. Rather than regenerating the muscle, Glass found, GDF11 seemed to make the damage worse by inhibiting the muscles’ ability to repair themselves. He and his colleagues report their results on 19 May in Cell Metabolism.

Woops.  The Wagers results may prove to be an error, or it may be that the story is more nuanced.  It would not be surprising if there is such a thing as too little GDF11 and too much GDF11.

Wagers, however, stands by her findings. She says that although at first glance the Novartis group’s data seem to conflict with her team’s results, there could be multiple forms of GDF11 and that perhaps only one decreases with age. Both papers suggest that having either too much or too little GDF11 could be harmful, she says. She adds that the Novartis group injured the muscle more extensively and then treated it with more GDF11 than her group had done, so the results may not be directly comparable.

 “We look forward to addressing the differences in the studies with additional data very soon,” Wagers says.

Rando expects that researchers will now investigate the finding2 that GDF11 affects the growth of neurons and blood vessels in the brain. “I’m not sure which result is going to stand the test of time,” he says.

Two Unrelated Items of Interest

Life Extension magazine for June claims that fear of Testosterone has been unwarranted, that the benefits of T for strength and heart health do not come at a cost in increased cancer risk or decreased longevity.  (June edition is not yet on-line at LEF, but has been uploaded to Dropbox by a colleague here.)

Low endogenous bioavailable testosterone levels have been shown to be associated with higher rates of all cause and cardiovascular-related mortality…

Testosterone replacement therapy has also been shown to improve the homeostatic model of insulin resistance and hemoglobin A1c in diabetics and to lower the BMI in obese patients. These findings suggest that men with lower levels of endogenous testosterone may be at a higher risk of developing atherosclerosis.

Here is an intriguing news release from Yale about a protein found only in primates that is useful for making ordinary cells into stem cells.



I have a new article at  The bottom line is that pterostilbene may be a “better resveratrol”.  It is better absorbed, stays in the blood stream longer, and has a stronger effect on insulin metabolism and SIRT-1 than resveratrol.  But resveratrol got there first, and there has been much more study of resveratrol in actual animal tests, so it will be a few years at least before we know for sure.  Len Guarente’s MIT lab is where resveratrol got its start, and Guarente has recently launched a corporate spinoff to sell a pterostilbene formula.

Vital Questions — A Book Review

The Vital Question, by Nick Lane, 352 pp, Profile Books, April, 2015

Life has been on earth about 4 billion years.  If we think of each billion as a term at college, then for its Freshman, Sophomore and Junior years, life majored in chemistry.  Every possible chemical environment was probed, drawing its first energy from the warm, hydrothermal vents at the bottom of the ocean, leaving the alkaline silos where life got its start, colonizing the sea and the land, the atmosphere, places cold and hot, wet and dry, acid and base, high in the clouds and deep in rock miles under the earth.

Life as an underclassman was just one cell at a time, and a small cell at that, maybe a micron across, a “prokaryote” that despite its impressive chemical virtuosity had little physical structure and the simplest life cycle.  Divide and conquer.

Before his Sophomore year was over, the precocious chemists had figured out how to use the sun’s energy to pull carbon right out of the air, and the entire atmosphere had been processed, molecule by molecule, from (inert) CO2 to (energy-laden) Oxygen.  The energy economy of the earth was transformed.

Then, about a billion years ago—life was a rising Senior—a once-in-a-lifetime event occurred, a wild fluke.  One of these chemists that specialized in membranes and electrochemistry was invaded and colonized by a parasite that specialized in combustion chemistry—oxidation of sugar, to be specific.  The invader put all that atmospheric oxygen to good use, then spewed out toxic ROS (reactive oxygen species) that almost killed the host, as it had killed many archaeons before.  But this time, the host survived and, over an amazingly short time of just 2 million years, learned not just how to coexist with the invader, but also to domesticate the parasite and put him to work.  The host was already using ATP as an energy source, and the parasite had a talent for producing copious quantities of ATP/energy—more than any archaeon had ever seen before.  Stick with me, kid and we’ll go far.  By the end of Senior year, every plant and animal on earth, every fungus and amoeba, toadstool, jellyfish and (by the way) you and me—every cell in our bodies, all of them are descended from that one sick, infected “hopeful monster”.  Her name was LECA, the Last Eukaryotic Common Ancestor.  Everything we think of as macroscopic biology comprises her progeny, in so many different guises.

Because it was in its Senior year that life first got interested in engineering, cell upon cell.  Pipelines and networks of roadways, electrical circuits, information processing within and between cells. Muscles, bones, shells, levers, motors and other mechanical devices that were made out of living cells!  Locomotion in the sea, on land and air.  The greening of earth and sea, predators and prey, webs of interconnected life—all of this is the realm of eukaryotes.

This story wasn’t written by Nick Lane, but he certainly tells it with a flare.  The story was written by biological visionaries of the last century.  Richard Goldschmidt, Francis Crick, Lynn Margulis, Carl Woese are biologists that I know.  Also Stephen Jay Gould and E. O. Wilson—I’m sure there are others who are equally eminent with whom I am unfamiliar.  Erwin Schroedinger and Freeman Dyson were physicists who also contributed to the canon, speculating about the Great Questions.

In our generation, Nick Lane is the only one I know who is making a bid as heir to these giants.  (I hope that readers of this column will use the comments section to make me aware of others.)  He is a biological visionary who happens to be a great storyteller.  In a series of books since 2005, he is asking the Great Questions about life, how it began, why it is the way it is, how much of life’s history is pure chance, and if we should run into an extraterrestrial life form, how much can we expect it to be like us?  His latest book is called The Vital Question.  Like his previous books, this one takes a bioenergetic view of life. The centerpiece of the present volume is that singular event at the beginning of Senior year:  The fusion of (probably) several bacterial and archaeon individuals to form that one “hopeful monster”, the mother of us all.

Among the traits that all eukaryotes have in common (but distinct from prokaryotes) are

  • a cell nucleus, with multiple linear chromosomes.  (Prokaryotes, by contrast, have their DNA in a single loop and many smaller loops.) “The nucleus is an exquisitely adapted structure, no mere repository for DNA.”
  • genes coded piecemeal, interrupted by introns, a catch-all word for the 95% of DNA that does not code for a protein, and may have many different functions, or possibly none at all
  • within-species genetic exchange (sex) with crossover of parts of chromosomes.  Before eukaryotes, genetic exchange was rampant, promiscuous, and willy-nilly.  Every type of bacteria exchanges genes with every other type.
  • energy generation in mitochondria (the parasites mentioned above)
  • endoplasmic reticulum, a network of membranes that guides transportation of molecules within the cell
  • Golgi apparatus, there are many within the cell, and they serve as post offices, addressing and dispatching packages or protein to their appropriate destination
  • soft, permeable cell membranes that can take in selective nutrients or even engulf and absorb another cell in its entirety (phagocytosis).

Eukaryotes are about 100,000 times bigger than prokaryotes, and there is much more structure and machinery.  Right from the start, Lane frames his narrative with a question about eukaryotes, why they are so different from everything that came before, why they were able to do things that in 3 billion years the prokaryotes never attempted, and why there are no extant “missing links” by which we might trace the evolution from prokaryote to eukaryote.

There is a black hole at the heart of biology. Bluntly put, we do not know why life is the way it is. All complex life on earth shares a common ancestor, a cell that arose from simple bacterial progenitors on just one occasion in 4 billion years. Was this a freak accident, or did other ‘experiments’ in the evolution of complexity fail? We don’t know. We do know that this common ancestor was already a very complex cell. It had more or less the same sophistication as one of your cells, and it passed this great complexity on not just to you and me but to all its descendants, from trees to bees. I challenge you to look at one of your own cells down a microscope and distinguish it from the cells of a mushroom. They are practically identical. I don’t live much like a mushroom, so why are my cells so similar? It’s not just that they look alike. All complex life shares an astonishing catalogue of elaborate traits, from sex to cell suicide to senescence, none of which is seen in a comparable form in bacteria. There is no agreement about why so many unique traits accumulated in that single ancestor, or why none of them shows any sign of evolving independently in bacteria. Why, if all of these traits arose by natural selection, in which each step offers some small advantage, did equivalent traits not arise on other occasions in various bacterial groups?

This story, the merging of very different life forms to create evolutionary revolutions,  is associated most closely with Lynn Margulis.  Lane acknowledges the deep legacy of Margulis, and also parts company with her and diverges from her Story of Life to offer his own version.

Something odd seems to have happened at the very origin of eukaryotes. It looks like the first eukaryotes picked up thousands of genes from prokaryotes, but then ceased to ply any trade in prokaryotic genes. The simplest explanation for this picture is not bacterial-style lateral gene transfer, but eukaryotic-style endosymbiosis.  This is the simplest possible scenario for the origin of eukaryotes: there was a single chimeric event between an archaeal host cell and a bacterial endosymbiont.


Demise of the the Tree of Life

To understand the oddness, we go back to the “tree of life” that was Darwin’s inspiration.

Through evolutionary history, species diverged via mutations and split off from one another, so that one species became two, in a branching process.  In this picture, due to Darwin, relatedness is perfectly defined, and every species has a unique path tracing it back to LECA.

Once genome analysis became possible in the 1980s, it was an early project to try to reverse-engineer the tree.  But the result of that project was a huge surprise.  Tracing different genes produced different trees, until it became clear that there was no tree at all, but rather a web of interconnecttions.  Everywhere there were cross-links in the tree.  Every individual species had acquired genes from many different places.

How can we reconcile this with the common fact of our experience that every cell comes from a single parent that divided in two?  (Yes, there is sexual combination, so a cell can have two parents, but in our experience these two parents are always very closely related, in fact they are by definition of the same species.)

And most problematic of all is the genome of LECA, parts of the genome that all eukaryotes share.  Those genes seem to have come from a dizzying array of very different bacteria and archaeons.  How can that be reconciled with the idea that LECA arose in a single, improbable event?  How can there be both a unique LECA and such a diverse genomic ancestry?

Different genes in the same eukaryotic organism do not all share the same ancestor. Around three-quarters of eukaryotic genes that have prokaryotic homologues apparently have bacterial ancestry, whereas the remaining quarter seem to derive from archaea. That’s true of humans, but we are not alone. Yeasts are remarkably similar; so too are fruit flies, sea urchins and cycads. At the level of our genomes, it seems that all eukaryotes are monstrous chimeras. That much is incontestable. What it means is bitterly contested.

It was this diversity of genes from many origins that Margulis cited as strong support for her thesis that merging of different, unrelated species has time and again seeded evolutionary saltations (times of abrupt change).  But Lane has a different idea.  These diverse genes were acquired all at once during a brief period (~2 million years is Lane’s astonishing claim) around the time of LECA.  The reason that they now appear to be associated with diverse kinds of bacteria is that bacterial genomes are easily mutable via the bacterial brand of promiscuous sex, the exchange of plasmids.  The apparent diversity of bacterial sources for eukaryotic genes is an illusion based on the taxonomic groupings (“species”) of bacteria today, which may be very different from their groupings of old because genomes are continually reshuffled across the diversity of different bacterial “species”.

Neither Margulis’s story nor Lane’s adequately addresses the greatest mystery (as Lane himself is first to admit):  why there are no surviving missing links between the prokaryotes and the eukaryotes?


The Energy Metabolism and the Origin of Life

Lane’s perspective centers on life’s capacity to capture energy and use it for purposes internal and external.  His singular contribution from the past was to remark how strange and curious is life’s universal energy factory: energy is stored and harnessed as a potential difference across an organic membrane.  So it is with all life’s diverse forms adapted to diverse environments.  It was the central insight of Lane’s 2005 book Power, Sex, Suicide that this may be a hint as to how life formed.  There are geothermal vents underwater, where metal oxides are spewed copiously into the sea, creating an alkaline pocket in an acid ocean.  Here are also mineral structures with micro-pores of cellular dimension.  So two of life’s necessities were freely available as foundation for pre-biotic evolution: compartmentalization (micropores) and energy in an appropriate form (gradient of H+ ion concentration).  Lane summarizes and elaborates this story in the new book.

Eukaryotes arose when mitochondria first appeared as an endosymbiont in LECA’s interior, providing a generous and reliable source of energy in the form of ion gradients, with input from biotic fuel and ambient oxygen.  It is Lane’s ambition to explain the broad outlines of eukaryotic life from this one event—the diversity, the behaviors, and the similarities of all plant and animal life, all derived from the character and circumstances of mitochondria.

It means, astonishingly, that mitochondrial variation alone can explain the evolution of multicellular organisms that have anisogamy (sperm and eggs), uniparental inheritance, and a germline, in which female germ cells are sequestered early in development—which together form the basis for all sexual differences between males and females. In other words, the inheritance of mitochondria can account for most of the real physical differences between the two sexes.

Lane even takes a stab at explaining the life cycle, including aging.  I applaud his vision and ambition in stepping back to look at the big picture and addressing the Great Questions.  To what extent are his answers convincing?  I’ll continue next week with some ways in which Lane’s perspective offers fresh new understanding, and some equally Great Questions that he does not address.