Book Review: Power, Sex, Suicide

 

Introducing the Mitochondria

“The mitochondria is the powerhouse of the cell” - Variously attributed

Everybody learns something about Mitochondria in grade school.  That they are an organelle inside your cells.  That they let your body break down sugar and create ATP using oxygen in a way that’s far more efficient than fermentation without oxygen.  That’s clearly an important role, when we’re drowning, say, and can’t get the oxygen needed for aerobic respiration we die.  However, they’re a lot more than that too.  Mitochondria used to have independent bacterial lives charting their own fates.  That their existence came to be so enmeshed with their hosts is arguably the most unlikely but important event in the history of life on Earth and has some implications.

Pump and Dump

Aerobic Respiration

Essentially all life lives by extracting energy from a difference in the concentration of hydrogen across a lipid membrane.  Let’s say you’re a mitochondria or a bacteria that lives off of sugar and oxygen.  The process of eating looks like this.  You take a tasty glucose molecule and do some glycolysis, breaking it up to net you a couple of the basic energy currency of your cell called ATP.  The remains are chewed up in a whirling reaction called the Krebs Acid Cycle.  But most of the energy comes from elsewhere.  Pairs of electrons stiripped off of the glucose travel down a chain of stations, pumping protons uphill each time they proceed, until finally grounding out in the process of reacting hydrogen with oxygen to make water.  

Ok, you many ask, so I’ve got a proton gradient.  So what?  Well, just like you can let water stored in a pond at the top of a hill flow down through a turbine so you can let the protons flow down hill, forced by the voltage they’ve built up, and go through a turbine which assembles ADP into ATP.

A literal turbine that spins and everything

A typical voltage that the protons get pumped up might be somewhere around 150mV.  Compared to batteries you’re used to, let along power lines, that might seem pretty small.  But that voltage is basically just across a single lipid membrane layer and in that context it’s crazy high.

Mostly the potential energy of that lake of protons is just used to drive ATP creation but it can do other things as well.  Pumping things across the membrane is one common use, say the phosphate to combine with ADP to make ATP.  Or, in another literal turbine, they can spin the flagella to make bacteria able to move.  

This isn’t the only use of protons gradients in living metabolism.  Photosynthesis works the same way, pumping protons across a membrane with electrons given a jolt of energy from a photon.  And so do most of the weird metabolisms that bacteria or archaea might use except fermentation.  But even organisms that don’t use a proton gradient for their metabolism still have one and maintain it.  

There aren’t that many things that are common to nearly all life on Earth.  RNA encoding for proteins is universal.  Creating a membrane to encapsulate yourself is universal but the two prokaryotic kingdoms, bacteria and archaea, have entirely different formulations for these membranes making it look like their earliest common ancestor didn’t make its own but found it laying around in its environment.  So one obvious hypothesis about the conditions giving rise to the first life might have involved something like microtubules with lipid membranes across them and some geologic process providing a supply of fresh hydrogen on one side.  But if you’re interested in that I’d point you at Professor Lane’s book Life Ascending, his speculation around the issue is only touched on in this book.

Internalizing the Profits

The Eukaryotic Revolution

Most life on Earth isn’t lucky enough to be Eukaryotic and be able to conduct their metabolism in the middle of themselves.  Instead they breathe over the surfaces of their skins, also known as their plasma membranes.  That’s pretty clever in a way, since you don’t have to have a bunch of extra membranes inside yourself when you can just re-use the same membrane that keeps your insides inside. That makes a certain amount of sense but it comes with one crucial disadvantage.  If you double yourself in size along every dimension the surface you can respirate over will quadruple in area but you will octuple in volume.  

If you look at an array of all the types of eukaryotic cells on this Earth and another array of all the prokaryotic cells one thing will jump out at you first.  The eukaryotes are a lot bigger.  Not literally all of them, the smallest eukaryote is smaller than the largest prokaryote.  But your typical eukaryote has something like 10 to 100 times the length and 10,000 to 100,000 times more volume than the typical prokaryote.  And with larger size comes more stuff.  Eukaryotes have larger genomes too, to an extent roughly comparable with their greater volume.  And because they can have so many genes the genome doesn’t have to be kept simple but can include more regulatory structure and means of splicing different sequences together to code for particular proteins.  They’ve got nuclei too, a cytoskeleton to hold them rigid even without a cell wall, membrane enclosed organelles, sexual reproduction, and other features.

All of this is a pretty big deal.  Especially the genome size bit.  For a bacteria trying to reproduce each gene in its genome is a pretty expensive things to copy when its going to reproduce.  In an environment where a certain gene isn’t needed that creates a pretty strong selective pressure to get rid of it to reproduce faster.  In his book about his time inside the Soviet biological warfare program, Biohazard, Ken Alibek complains about this.  While it might be a simple matter to add genes to anthrax or tularemia to make them resistant to common NATO antibiotics if Soviet researchers tried to add genes to protect against all five of the most common antibiotics the darn bugs reproduced so slowly they just weren’t able to keep enough virulence to be worth while as weapons.  So there’s a pretty strong pressure to drop those extra genes when in an environment where antibiotics aren’t present.  Though I should say that antibiotic resistance is still going to be present in the bacterial population for a long time after it’s gone from most individual bacteria.

So in order to get larger cells with more complex genomes we needed to find a way to let cells get out of the geometric trap they were in, but that’s easier said than done.

From Wikipedia, of course

What should jump out at you looking at this is that it really didn’t take all that long from Earth to go from a dead to alive after the Late Heavy Bombardment stopped and the Earth figured out how to be a little bit less molten, on the outside of course.  4 billion years ago isn’t even a clear date for the first life but for the first life that left a mark in the fossil record, things could have been getting their act together for a while before that.  

And the second thing to jump out at you should be that it took a very long time for the first Eukaryotes to come around, and that things started moving a lot faster when they did.

And that sort of makes sense.  Evolution mostly likes smooth gradients to ascend.  If you’re an organism lucky enough to have some complicated feature then chances are it evolved from some less complicated feature.  And if your wonderful, complicated eyes evolved to have their nerves between the light and the photoreceptors (unlike octopus eyes, say), well, that made sense at the time but evolution can’t just swap out one complicated mechanism for another equally complicated mechanism even though the later makes more sense now.

But if a species went blind for a thousand generations while they redesigned their eyes, well, they’d almost certainly go extinct but it wouldn’t be an absolute certainty.  Dropping respiration over your exterior membrane while you work on respiration over interior membranes isn’t nearly so survivable.

So something weird had to happen.  Luckily we know what it was.  

You Married a What!?

Mitochondria Through Endosymbiosis

Before the eukaryotes came along there were two similar but distinct domains of life, the bacteria and the archaea.  Both are prokaryotes, limited in size and look pretty similar if you squint but chemically there are huge differences in what their membranes are composed from, how proteins are synthesized, and only archaea sometimes wrap their DNA in histone proteins for protection.  We tend to run into archaea less in our lives because they tend to be extremophiles living in geysers, in oil wells, or in the oxygenless bottoms of marshes where they release methane marsh gas.  These two kingdoms of prokaryotic life seem to have diverged right at the very beginning of the history of life with none of the horizontal genetic transfer you see so often in prokaryotes.  And Eukaryotic cells seem to be a mixture of both.

A eukaryotic ribosome translates RNA into proteins in a manner far more similar to an Archaea.  But our cell membranes have fatty acid tails like bacteria membranes.  And our DNA is protected by histone like archaea DNA is.  Looking at our genes themselves some, mostly related to information like copying DNA, comes from archaea and some, usually more functional genes related to creating useful proteins, comes from bacteria.  So somehow an archaea and a bacteria evolved such a close symbiosis that they eventually merged into one single organism.  And it looks like one of the symbiotes was specifically the ancestors of mitochondria which still have a small genome which looks more bacterial in nature.  A bacteria somehow ended up inside an archaea and became so codependent that it transferred hundreds of its genes to the host’s nucleus, keeping only a bit more than a dozen.

For how this happened the book argues for something called the hydrogen hypothesis in this book.  The idea is that you have a bacteria of a species that consumes various materials and releases hydrogen as a byproduct of its metabolism.  It teams up with a methanogen archaea which consumes the hydrogen to produce methane in its metabolism.  Chains like this happen pretty often in real microbe populations, the question is how the proto-mitochondria ended up inside the archaea.  One appealing aspect of the theory is that some eukaryotic cells have hydrogenosomes, organelles with the same descent as mitochondria that release energy by breaking down organic materials into hydrogen and acetate to release energy.  Genetically, it looks a lot like hydrogenosomes have the same ancestor as mitochondria and they all seem to break down things into hydrogen the same way, genetically, so it looks like whatever bacteria got swallowed could do both forms of respiration.  And maybe later the oxygen hating archaea host relied on its passengers to deal with the oxygen it encountered as it moved to new areas?  As global oxygen levels were rising rapidly at the time this would be important.

As you might expect, in the nearly two decades since the book came out we’ve learned a lot on the topic especially given how quickly the technology behind reading genomes has been advancing.  When the book was written we’d already nailed down the bacterial ancestor of our mitochondria as a member of the Rickettsiales order, a relative of the bacteria that invades our cells to cause typhus.  But we’ve made a lot of progress on the archaeal ancestor, in 2015 some samples from sediment near a hydrothermal vent called Loki’s Castle revealed a new group of archaea named after norse gods which is the closest relation to eukaryotes yet found, containing genes for proteins that had only ever been seen in Eukaryotes before.

Maybe not the prettiest microorganism.

In 2019 we were able to culture one member of the family in a lab to actually get a picture of what it looked like.  The genome had spoken about a mobile cytoskeleton of the sort that eukaryotic amoebas use to swallow prey but I don’t think anyone was expecting tentacles like that.  Apparently it digests amino acids and releases hydrogen as a byproduct which it feeds into bacteria it’s grabbed who use it to make methane, in a neat reversal of the hydrogen hypothesis theory.  Of course this is just the one we’ve been able to culture and who knows what we may discover next but the…grabiness of this boy suggests this might be the right track.

In any event, once the two organisms were unified into one the genes from the bacteria started migrating to the nucleus when it evolved.  It’s dangerous in a power plant and gene transfer between simple prokaryotes really isn’t that weird.  The difference in ribosomal codes would have slowed it down but not stopped it.  Hundreds of genes were able to make the transition over time leaving only a handful.  Why a few left?  A mystery for a future section.

Memento Mori

Apoptosis and Multicellular Organisms

Besides energy generation mitochondria also have another very important job they perform for the host cell.  Murdering it.

Your body has more than 30 trillion cells that are supposed to all be working in harmony for their common goals. But things don’t always work out like that.  One relatively innocuous failure is that a cell just breaks down in a way that means it can’t accomplish its mission any more.  Better the cell stop taking up resources than hang around uselessly.  Worse, a cell might be on its way to becoming cancerous and have to be put down for that reason.  Figuring out how to diffuse the apoptotic self destruct system is one of the many challenges a cell has to overcome before it can become a cancer.  Or a cell might realize it's been infected by a virus and off itself for that reason.  This last seems like it might have been the reason apoptosis was kept around by single celled organisms.  If you’re a cell and you just got injected by a virus that’s a lot like having been bitten in a zombie movie.  You’re certainly dead soon but by taking matters into your own hands you can avoid endangering your friends and relatives.

Not all apoptosis is for unusual circumstances either.  When your body is developing there’s a lot of scaffolding that gets built that has to be taken down for the full organism to work. When your fingers are growing out they’re all webbed together but when they’re ready that webbing goes away through apoptosis.  Even in the simplest model organism of them all, c. elegans, 131 of the 1090 non-reproductive cells created during development go away.  And even when you’re an adult apoptosis is still part of your ordinary existence.  Through the magic of somatic hypermutation your immune system is constantly experimenting with cells producing new antibodies that it hopes will attack its enemies.  If it works, great, clone it with variations.  If the antibodies attack the body's own proteins, however, the cell that makes them is forcibly retired.

Don’t fear the little reapers inside

So it’s pretty hard to imagine multicellular creatures arising without cell suicide built in.  But how would this evolve and why would the mitochondria, of all organelles, be responsible for pulling the trigger?  That would naturally arise from the mitochondria’s previous existence as an independent creature.  It’s natural that the mitochondria early in their symbiotic relationship might not want to die if their host cell starts to have problems.  And so, like rats, they’ll want to flee the sinking ship and apply dynamite to any walls standing in their way (here the metaphor breaks down).  As living creatures they had their own interest in living and anyways the members of their family who were parasites infecting other cells already had great experience blowing up cells from the inside.

I use explosions as a metaphor above, but really apoptosis is a quiet, relatively dignified process.  The release of cytochrome c from the mitochondria triggers its mechanisms throughout the cell and soon throughout the cell, without any fuss, resources are packaged up and removed for other cells to use.  10 billion of your cells are reaped this way every day and you never even notice.

Radical Uprising

Balancing a mitochondria

You’ve probably heard of free radicals, and the antioxidants that are promised to fix them.  The situation might be like this.  Your cell has plentiful glucose and oxygen so it breaks down a glucose molecule and dumps some electrons at the top of the respiratory chain where they’re supposed to help pump some protons uphill.  But the cell hasn’t been using much energy lately, the proton reservoir is full, and the electrons are having a hard time pushing more protons uphill.  So when one sees a passing oxygen it jumps off to form an unbalanced reactive molecule that goes caroming around leaving breakage in its wake.  Antioxidants are molecules that can absorb these free radicals safely without them bothering the rest of the cell.

This is the danger to the mitochondrial DNA that led to so much of it migrating to the nucleus rather than stick around.  Do antioxidants help?  Well the empirical evidence is “not really.”  Despite a lot of investigation going into the theory nobody has been able to show that taking antioxidants gives any sort of benefit.  Which makes a sort of sense given the ubiquity of homeostasis in the body.  Lots of antioxidants floating around?  Well, I guess the cell can slack off on making more then.  The only sort of antioxidant intervention that’s been shown to work is genetically engineering a mouse’s mitochondria themselves to make more and even that didn’t help too much.

And this partially goes back to the whole problem of control that exists with mitochondria.  Free radicals cause damage but they also act as a signal about the state and problems of a mitochondria.  Much more so than most organelles they have to be able to ramp their activities up and down very quickly.  In metabolism electrons have to flow down a balanced chain from one complex to another and if a given mitochondria is short on Compex IV it doesn’t help to build each of every complex or to send more Complex IV sites to every mitochondria in the cell.  This is why the author thinks that mitochondria still have some genes.  They can’t code for every gene in Complex IV but they can create the central protein and once that’s laid down in the mitochondria’s membrane the rest of the proteins needed can find their way there and assemble around it, giving a response that’s both fast and responsive to the specific needs of that mitochondria.

Not everyone agrees.  Some researchers think that the way the proteins coded by these genes fold immediately after assembly makes them harder to import through the mitochondria’s membranes.  The SENS foundation has plans to try importing these genes to the nucleus to protect them from damage and slow mitochondrial aging.  I think I’m more convinced by the control explanation but it’s possible that nuclear genes would give people longer lives at the expense of athletic ability and that this is a tradeoff some people would be happy to make.

There is one thing already out there that has been well shown to allow a creature of a given mass and resting metabolic rate to live much longer than normal: being a bird.

Look into those ageless eyes

Birds typically tend to live three times longer than the equivalent mammal, despite having the same levels of antioxidants and having roughly the same number of genes in their mitochondria.  It looks like their secret is their high metabolic rate when flying and their associated high number of mitochondria in total.  Now, you’d think that if the metabolic demands of flying were their secret you’d see the same relatively long lifespans in bats and, sure enough, you do.  It looks like just having more respiratory chains helps 

For those of us looking to live longer it’s hard to take up flying as a hobby without technological assistance but exercise can lead to low levels of ATP in your cells which tells your mitochondria to build more metabolic chains, so there’s that.  Which is to say that through deep inspection of the inner workings of the cell we’ve learned what we always already knew and that it all adds up to normality.  But it’s still nice to have that confirmed.

A Firmer Handshake

Metabolic Coupling

For a long time people thought that there hadn’t been any interbreeding between humans and neanderthals.  There are hundreds of mitochondria in the typical cell and they have multiple copies of their genes, so it’s a lot easier to get a good read of an individual's mitochondrial DNA than their nuclear DNA especially if the DNA has been through a rough time, for instance if they died several thousand years ago.  But of course now that we can read Neanderthal’s nuclear DNA we know that a lot of interbreeding happened.  So what happened to all that Neanderthal mitochondrial DNA?

The problem is that high voltage (for a cell) electron transport is a delicate business.  If the different proteins of a complex don’t mesh together well you can easily lose the electrons rather than shuffle them along to where they’re supposed to go.  In one experiment a mitochondria in a mouse cell had all its mitochondrial DNA replaced with a rat’s.  The resulting proteins could be transcribed just fine by the mitochondria, but when they tried to work together with the proteins from the mouse’s nuclear DNA electrons wouldn’t flow and respiration ground to a halt. Children of a neanderthal mother will have half their nuclear DNA designed to work well with their neanderthal mitochondria, but entering a larger sapiens population the mitochondria can’t count on being in that situation long so it makes sense that they’d be selected against along with several other parts of the neanderthal genome.

There’s another sense in which coupling in mitochondria can be looser, how easy it is for protons to leak out of their reservoir when it gets too full.  A proton that leaks isn’t driving the creation of more ATP and so is metabolically wasted energy in one sense.  But if it prevents the electrons on the metabolic chain from backing up and releasing free radicals that’s an advantage.  There’s some evidence that people whose maternal ancestors came from colder climates have mitochondria which are more loosely coupled or more prone to let protons out when the reservoir is full.  My maternal line has the U5 haplogroup (shred with Cheddar Man!) which is a branch of mitochondria which are apparently a bit notorious for relatively low coupling.  Maybe that’s why I don’t get cold easily?

Maybe he didn’t get cold easily either?

And I should point out here that mitochondria have gotten the limelight once before here, back in the Slate Star Codex days.  Having a really high bypass ratio that leaks protons easily will tend to burn a lot of energy doing nothing but generating heat.  That’s great for not freezing to death or losing weight fast, but our previous drug for that, DNP, had a whole lot of other terrible side effects.  But when a new drug came along that promised to help you lose weight without the side effects, he was happy to shill for it.

Darwin Among the Mitochondria

Looking at Mitochondria as populations inside cells

The classical model of accelerating damage to a mitochondria looks like this.  A free radical leaks and damages a mitochondria’s DNA a little.  This makes its respiratory chain a bit less efficient, so more leakage happens.  The extra leakage causes extra damage which causes extra leakage, etc, etc, etc in an accelerating cycle that eventually kills the mitochondria.  

That seems to be what happens as far as it goes, within a mitochondria but it’s not so important at the level of the cell.  Cells have populations of mitochondria which reproduce under selective pressure which kills off the least efficient mitochondria, so in general the population of mitochondria in a cell can remain healthy while individual mitochondria spiral into breakdown.

This isn’t to say mitochondria are immune to problems.  Population genetics gives us equations for how likely a new trait is to replicate enough to become prevalent throughout a population.  If the population is just a few hundred a bad trait probably won’t spread throughout it, but its not nearly as unlikely to happen as if the population was a few million so just the force of darwinian selection isn’t enough to reliably combat small reductions in a mitochondria’s efficiency.  Also, occasionally, it seems like large mutations occur which blow out a mitochondria’s ability to conduct respiration at all.  In that case it isn’t shedding any free radicals at all which apparently gives it a big advantage in reproduction and so we see mitochondrial populations like that taking over a cell way more often than would be explicable by chance.  

But in general darwinian selection is a huge brake on how often bad mutations accumulate in mitochondria and when we look at things like the ratio of mutation that affect how proteins are expressed to mutations that don’t affect that we see a huge influence of selective pressure reining in the former.

When you have two diverse populations then evolutionarily that’s a cause for conflict in the long run.  If one population evolves a way to kill off the other then that’ll give victory to the aggressor giving it a huge evolutionary advantage as the two populations battle for dominance.  But thankfully that never gets the chance to evolve.

The battle for supremacy

During your lifetime you mitochondrial populations just don’t have time to develop dastardly tactics like that.  Sometimes in humans a sperm’s mitochondria make it into an embryo but that also doesn’t give mitochondria enough incentive to detect this circumstance and evolve the means to wage war on divergent populations.  But there are some species where there is no distinct mother to be the sole contributor of mitochondria.  

Take the sea lettuce, which produces unisexual gametes which fuse to produce offspring.  Each brings its own population of mitochondria and chloroplasts which presumably long ago contributed to half the populations of the offspring.  But a long time ago one of these organelles developed a mutation which caused it to produce chemicals killing off the other population of organelle, leaving its descendants to completely fill its niche in its cell’s descendants.  This trait would be a huge evolutionary advantage, leaving its descendants to quickly eliminate all non-murderous varieties.  So now, when two sea lettuce reproduce, their respective mitochondria and chloroplasts being a war which will only leave one population of survivors.  Most of these organelles will die off, leaving the host cell with a large deficit for a while, but to the victor mitochondria or chloroplast go the spoils.

This is great for the mitochondria with the more lethal chemical weapons, but terrible for the host cell.  So its no surprise that almost every sexually reproducing species has figured out some means for preventing this conflict from happening.  In mammals it’s pretty simple.  Males contribute half the nuclear genes.  Females contribute the other half of the nuclear genes and all the mitochondria.  Occasionally a few mitochondria from the father make it into the embryo but so infrequently that it’s not worth the effort for any mitochondria to evolve into murder-mitohondria.

We don’t have to evolve all the way to murder-mitochondria to have problems.  Simply mitochondria that reproduce faster at the expense of metabolic efficiency can cause the same sort of problem.  But it's the same sort of problem and keep up the selective pressure for long enough and you get murder.

This does lead to the distinct disadvantage, though, that of the other members of your species you might happen to run into you can only reproduce with half of them.  Other species do this differently.  The fungus Schizophyllum commune, for instance, has 288 variations in one trait and 81 in another.  If another member of its species is different in both traits, 22,960 individuals for every 23,328 it encounters, it can mate with them and they’ll be able to work out whose mitochondria get to reproduce.  Pretty good odds!

So different sexes evolve because cells need some way of preventing dog eat dog competition from evolving among their organelles, keeping everything harmonious so Moloch never gets her foot in the door.

Ad Astra per Respira 

Implications for distant life

That’s what’s in the book. What else does it make me think about?  Well, first of all that damn did life on Earth luck out.  Despite the Hydrogen Hypothesis or related mechanisms it took much, much longer for eukaryotic cells to evolve on Earth than life did in the first place.  

Let’s imagine life evolving on Europa.  There’s enough liquid water there and enough tectonic activity that you can have free chemical energy around for a self reproducing chemical reaction to start up reproducing itself.  But with the dim sunlight making its way out Jupiter-wase and the thick shell of ice around the moon you can’t expect photosynthesis to ever get started.  And with such a correspondingly small biosphere and without an oxygen-rich environment to reward large scales can you see eukaryotic life taking off there?

Or take Mars.  Once warm and covered with water like Earth but smaller.  The surface of Mars is only one third as large as that of Earth’s, so on average it should take three times as long for anything to evolve on Mars as on Earth in theory.  So it should have taken photosynthesis maybe 1.5 billion years instead of only 500 million.  Except with a lower gravity and with no photosynthesis to create an oxygen rich atmosphere to create an ozone layer Mars lost so much hydrogen to the solar wind in its early days that it was a desiccated dessert by that point which wasn’t in much of a position to evolve photosynthesis any more.

And what if Earth had taken just another billion years between evolving life, photosynthesis, mitochondria, etc.  Well, in another billion years the sun will get bigger.  It will be brighter and closer to the Earth.  And all the liquid water on Earth will be gone.  It took 4 billion years or so to go from the first life to us but if it had taken 5 billion instead it wouldn't have mattered because our planet would have missed its chance and some other solar system somewhere out there would have had to fill in.

Mitochondria can’t evolve in space

This all makes me pretty pessimistic about how often complex life might evolve out there but again, it all adds up to normality and with the Fermi Paradox we probably already knew that.  But on the flip side, it makes me more optimistic about our ability to find simple life out there.  Colonies of chemosynthetic life bound to deep sea vents on icy but geologically active moons in the outer solar system.  Or life that once arose on Mars but died out when the surface water went away.

We were lucky that life on Earth found the merger that let cells grow to a size where they weren’t ruthlessly pruning down their genome to the bare necessity.  And we’re lucky that in that process they found the terminal sanctions that let them keep trillions of cells in line to create huge organisms like us.

And it makes me appreciate how much of what makes us up is a local maximum, where simple ideas any human engineer could think up to get beyond square cube laws took billions of years to evolve.  How much is left out there in biology to be discovered by engineering rather than a process that only works by feeling one step ahead at a time?