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11 September 2007

Power, Sex, Suicide Mitochondria and the meaning of life

Power, Sex, Suicide
Mitochondria and the meaning of life
Nick Lane 2005 OUP http://pages.britishlibrary.net/nick.lane [link no longer works]

This book is unusual in that it proposes a rare, indeed singular, and extremely unlikely event in the history of life. Its premise and arguments thereby suffer, in a scientific sense, ie they are non-repeatable. Also, extraordinary claims require extraordinary evidence.
NL puts forward a bunch of possibilities that are fascinating and well worth a look. One review calls the book a polemic, which omits opposing arguments. (No ref for that review)
Mitochondria [m.] are organelles 1 -4 microns long found in most (all?) Eukaryotic cells.
They generate energy in the form of ATP which they export to the cells in which they live

P4 "Each mitochondrion contains 5 to 10 copies of its genes"
P5 "m. can even form branching networks, communication among themselves"
P5. "M. have a bacterial ancestory … Lyn Margulis [LM] made this once controversial thesis familiar in the 1970s…
Today accepted as fact."
"Apoptosis, or programmed cell death… is not governed by genes in the nucleus… but by the mitochondria"
"It may be that multicellular organisms could not exist without mitochondria…
"All multicellular plants and animals do contain m.. It looks as if all known eukaryotic cells either have or once had (and then lost) m."
- This is contentious LM clams there are many a-mitochondrial Eukaryotes
P7 "the mechanism ,by which m. generate energy, by pumping protons across a membrane (chemiosmosis), is found in all forma of life, including the most primitive bacteria…. 'not since Darwin has biology come up with an idea as counterintuitive as those of, say Einstein, Heisenberg, or Schrödinger'… this idea won Peter Mitchell a Nobel prize in 1978
- Massey University in 1967 was well ahead in accepting chemiosmosis, but DNA technology wasn't then advanced enough to do much about m. DNA
"all species with m. have retained exactly the same core contingent of m. genes"
- This is contradicted later in a few cases, but seems generally true
"the m. genes encode only 13 proteins.. along with all the genetic machinery need to make them."
"the acquisition of m. was the pivotal moment in the history of life"
"..the eukaryotic [e.] cell evolved only once… the origin of the e. cell looks far more improbable than the evolution of multicellular organisms… "
Bacteria will not evolve much beyond slime.. anywhere in the universe.. the secret of complex life lies in the chimeric nature of the e. cell - a hopeful monster, born in an improbable merger 2000 million years ago.
- 'complex' here meaning visually or behaviourally complex. Big animals and plants are usually described as more 'complex' that bacteria, but bacteria can perform many complex biochemical operations than animals and plants cannot. Only bacteria can fix Nitrogen. Caveat: in the root nodules of the pea, the pink colouration is caused by a variety of haemoglobin. The pea's symbiont bacteria produce the haem, the pea produces the globin protein which holds the haem. So the pea uses bacteria in an intimate way to fix atmospheric nitrogen]
'hopeful monster' idea in 1940 Richard Goldschmidt, tiny mutations can't explain the origin of species
- Note that Darwin's book 'Origin of species' posits an evolutionary mechanism, but does not explain the origin of species
Origin of the e.cell: 2 ideas: 'mainstream' and 'the hydrogen hypothesis'
According to Cavalier-Smith, phagocytosis is the defining feature that sets the e. apart from bacteria
Only two groups of cells have [no] cell wall - e. and Archaea a few microns across .. single circular chromosome.. 30% of archeal genes are unique.. we now classify all living things into three domains bacteria, archaea and eukaryotes
- LM differs here, she has five kingdoms
Archaea ribosomes differ more from bacterial ribosomes than e. ribosomes
A thousand species of primitive (sic) e. do not possess m. … many lost their m. … Cavalier Smith argued that at least a few were 'amitochondriate' - they never did have any.
- LM agrees, but NL's thesis depends on no e. being truly 'amitochondriate'
4 parasites, … Entamoeba, Giardia, Trichchomonas… have no m. , thought to be ancient [NL has a habit of describing a ,standard model' as if proven, then later 'but wait, its been disproven' which must be confusing for the novice reader]
1998 Siv Andersson U Uppsala: m. genes similar to parasitic bacterium Rickettsia prowazekii - typhus [later NL contradicts this???]
The above story reversed; the above parasites, not so ancient,. Entamoeba has in its nuclear genome 2 genes that 'almost certainly' derived from the original m. … so far all the 'archezoa' (quotes in original) tested had m. and lost them later.
- LM still maintains that 'amitochondriate' eukaryotes exist. NL may hold the minority view here, but its central to his 'singularity' theory
m. are related to α-proteobacteria
1998 & 2004 Maria Rivera, UCLA : e. have 2 classes of genes, informational & operational. . almost all operational genes come from the α-proteobacteria , presumably by way of the m.
Informational genes .. strong resemblance to genes in archaea methanogens
e. histones resemble methanogen histones… the original host in the e. merger was a methanogen.
- LM may agree - check this. Also check: only methanogens have histones?
The (orthodox?) Ox-Tox hypothesis for e. - m. merger: the m. consumes toxic oxygen.
"Its unlikely that superior energy generation could have been the original advantage." …[ bacteria don't leak energy, or export energy … the e. had to evolve a pump to get ATP out of the mitochondria. Some other authors talk about bacteria leaking energy, but NL is probably correct here]

The hydrogen hypothesis:
- NL admits that this is improbable, but turns that around to bolster his claim that the origin of the eukaryotic+mitochondrial cell was a singular, extremely unlikely event. He thus automatically defuses criticism, but his thesis must remain speculative, if fascinating.
Hydrogenosomes [h.] m. -like organelles found in primitive single-celled e. (including Trichomonas vaginalis) energy generation by releasing hydrogen gas… e. containing h. sometimes host tiny methanogens. Aligned [nice picture p54] Methanogens can generate all the organic compounds they need, as well as all their energy from carbon dioxide and hydrogen… there is a spectrum … aerobic to anaerobic m.
"if the ancestral bacterium was metabolically sophisticated, then it was in a position to hand down specialized genes directly to its ancestors "(sic) [ this simple erratum (p55) perhaps indicates a certain breathlessness in NL's arguments here]
"Rhodobacter [which can do both oxygen respiration and hydrogen] might therefore resemble the ancestral m. better then does Rickettsia" [check LM on this]
"Why did they [Rickettsia and m.] become so similar… by convergent evolution … in both the spectrum of their surviving genes and in their detailed DNA sequence." P57
- This may be the weakest link in NLs argument. Convergent evolution may produce similar functionality, but the odds of similar DNA sequences arising from convergence are vanishingly small. The entire field of DNA species typing, which NL himself uses, would be invalidated if DNA could converge.
"how did a merger that could only work under anaerobic conditions … bring about the e.?... if the film of life were to be replayed… would the same events be repeated. I doubt it"
- NL claims that 'complex' (ie multicellular, large, intelligent) is unlikely anywhere else in the universe, precisely because his theory is so improbable. It's a bold way to present a hypothesis. He may be correct, but I would like to give life's schemes the benefit of the doubt.
"the α-proteobacteria has now found itself inside a methanogen [NL is strong on the idea that bacteria do not phagocytose so how it got inside is a bit of a gradual fudge] the α-proteobacteria had all the genes for absorbing food, so it could hand them over to the methanogen … ["handing over" genes, another part of symbiogenesis that produces novelty outside the neo-Darwinian model]
"all the genes needed for oxygen respiration must have survived intact… despite falling into prolonged disuse. [NL admits this as a major difficulty for his 'hydrogen hypothesis'] "the right combination of probability and improbability to explain the fact that the e. arose just once. [note the circular logic, but it is very likely that e. did arise just once. Its possible that slime, or stromatalites, is the best that is out there in 10ˆ11 galaxies]

Part 2 proton power:
Human energy: 2mJ/g/sec
Sun: 0.2µJ/g/sec - 10,000 less than human flesh
"some energetic bacteria such as Azotobacter, generate 10 Joules/g/sec" [ this throw-away remark confuses me somewhat. The central thesis of this book is the e. with m. cells have a great energy advantage over bacteria and here is Azotobacter 500 times more energetic than animal flesh ]
1790 Lavoiser ( as in 'the revolution has no need of') "respiration is a slow combustion of carbon and hydrogen.. similar in every way.. to a lighted candle"
Respiratory complexes: 4 huge molecular complexes embedded in the inner membrane of the m. … m. genes encode some of the proteins, nuclear genes encode others. The complexes act as electron carriers… electrons are transferred from carrier to carrier at a rate of about 1 electron every 5 to 20 milliseconds [200 - 500 Hz]

[The gradual elucidation of the detailed atomic-level structure, by X-Ray crystallography, was a big excitement from the 1960s on. Its difficult to get a mental picture of electrons being handed on from glucose remnants to complex to complex. There remains an opportunity to produce visualizations of the rod & hinge plus electric field gradients involved. Much great computer molecular modeling software exists, but a decent narrative DVD movie for the non specialist is yet to appear. Some asides can assist: eg Protons in water are described as being pumped or concentrated, but one lecturer casually told me that of course protons don't exist alone, they occur as H3O+]
[aside: many reactions in the cell are slow by chemical standards, diffusion limited… many reactions operate at audio frequencies, eg. DNA bases added at about 2000Hz I often wonder if audio sounds, even music, can effect cellular reactions by resonances at these frequencies]

The electrons are obtained from Glucose in the Krebs reaction… [these electrons are 'high energy' and each transfer is to a lower redox potential]
"perhaps the most important question remained unanswered - how was energy conserved?"
1897 the belief that living yeast was necessary for fermentation was overturned by Eduard Buchner, … ground yeast squeezed using a hydraulic press… if sugar was added.. the mixture evanesced alcohol and carbon dioxide in the same proportions as live yeast… Buchner proposed biological catalyses he named enzymes… the end of vitalism.
1929 ATP discovered by Karl Lohman… splitting off the terminal phosphate from ATP releases energy that can be used to power work…
Fermentation of one molecule of glucose regenerates two molecules of ATP
Respiration releases up to 38 molecules of ATP from a single molecule of glucose.
[this extra yield is the e. advantage]
"In the average person ATP is produced and consumed at a turnover rate of 65kg every day.
How ATP is produced: a chemical intermediate was presumed to be involved. "
ATP is formed by a giant complex ATPase … 30,000 stud the inner mitochondrial membrane.
[the inner membrane is wrinkled like a prune, to increase surface area. The outer membrane holds the 'proton cloud' the H30+, the chemiosmotic gradient. Obviously both membrane must have a variety of selective channels for ATP, proteins, etc etc]
[I recall in the early 1990s how delighted I was to learn that this spun . The smallest motor.]
"The passage of one pair of electrons down the chain generates between 2 and 3 ATPs: not a round number… how could the production of ATP require a variable and non-integer number of electrons? Another detail also nagged. Respiration requires a membrane…"
1961 Peter Mitchell proposed chemiosmotic coupling … a chemical reaction that could drive an osmotic gradient, or vice-versa… 1965 the ox phos wars [1967 Massey University an early advocate of Mitchell's view]
ATPase: pressure of the proton reservoir on the outside of the membrane forces protons through the drive shaft to °rotate the head.. 3 protons for 1200 … the tensions exerted force chemical bonds to form or break [needed: some decent visualizations of this. A stator is obviously required, spinning alone can produce nothing. Visualization might dispel the last vestiges of vitalism. If we could see the linkages, the mystery might be dispelled] … in humans a complete turn requires 10 protons and releases 3 molecules of ATP"
"bacteria are basically proton-powered" - for some reactions they can use the gradient directly, eg to rotate flagella, without using ATP.
Chapter 6 The origin of life: here NL has a decent stab at yet another origin story…
"the membrane lipids of bacteria .. hydrophobic fatty acids bound to a hydrophilic head by an ester bond. In contrast the membrane lipids of archaea are built up from branching 5-carbon units called isoprenes… numerous cross links giving a rigidity not found in bacteria [nb LM gets irritated when archaea are not described as bacteria. She has a 5 kingdom model which differs from NL's 3 kingdom model]
Archaea: Isoprenes bound to the hydrophilic head by an ether bond
Differences are so fundamental that LUCA (last universal common ancestor) could not have had a lipid membrane…. A radical answer. LUCA might have had an inorganic membrane, a thin, bubbly layer of iron sulphur minerals (Bill Martin, Mike Russell 2002) [this is a hairy idea, echoes of Cairns-Smith and his clay] They have actually made some candidates… "by injecting sodium sulphide into iron chloride ( representing hydro thermal fluid into early oceans) Russell and Hall produced a host of tiny bubbles (nice photos p101) … naturally chemiosmotic, with the outside more acidic … the iron sulphur crystals in the bubbly membrane conduct electrons. [no idea how plausible this is but it makes a great read]
[? A footnote on p100 says "the microbes of the deep hot biosphere … a single cell may take a million years to reproduce" - I don't how this is known, nor how DNA is supposed to last a million years in hot water]

Part 3
Chap 7 why bacteria are simple:
Bacteria need to reproduce fast (but note the deep hot slowpokes above) genomes take time to copy, so bacteria have small genomes… NL hedges this bet somewhat… "Many soil bacteria only manage to produce about three generations in a year" so the need for speed is a bit unclear. Bacteria have streamlined DNA but otoh "unusually among bacteria, nearly a quarter of the genome of Rickettsia is composed of 'junk' DNA" [this is a difficulty in biology: a counter-example to a 'law' frequently fails to disprove the law, it merely shows that a minority can go another way]
Eukaryotes are big and need a lot of DNA (to control all that stuff?, NL doesn't give a reason) so they reproduce slowly, and for them it doesn't matter (why not?) Its all bit muddled, but its clear that in general bacteria have stripped down genomes.
Bacteria can lose un-needed DNA, then get it back if needed by lateral gene transfer using conjugation. [I don't know why the sender (male?) bacteria accepts the signal to send. The receiver may benefit from new or improved DNA, but NL assures us that the sender is not altruistic. Somehow an ESS evolutionarily stable strategy has been 'agreed' upon whereby bacteria will send as well as receive. Sounds like co-operation, and it's a puzzle to me. Maybe there is some machinery where you cant receive unless you also sometimes give. It's a mystery, which NL glosses over]

The stumbling block of geometry. This is the central argument of the book: Proton gradients make energy, they require surface area, and bacteria just cant increase their area. So only Eukaryotes can grow multicellular and have limbs. Eukaryotes can increase their effective energy by having more mitochondria inside. Which they can control via those 13 genes remaining in each m.
"Suddenly, some 2 billion years ago, large eukaryotic cells appear in the fossil record; presumably this must date .. the origin of m. , though they cant be made out in the fossils" - this is the new orthodoxy, I suppose.
"a large energetic cell does not have to spend all its time replicating its DNA… it can turn predator and live by engulfing smaller cells.. it doesn't need to replicate quickly to stay ahead of the competition"
NL is very firm that bacteria don't phagocytose (except for the original mitochondria parasite?]

Chap 8 Mitochondria make complexity possible [all this talk of complexity may make SJGould rotate. He didn't accept the great chain of complexification, it was just staggering away from a wall]
Chloroplast genes are transferred at 1 transfer every 16000 seeds in tobacco - this is fast
The human genome reveals 354 independent transfers of m. DNA to the nucleus in Humans
Origin of the nucleus: the original host should have had archaeal membranes, the m . should have bacterial membranes. Eukaryotic membranes are all bacterial. A problem for the HHypothesis. Maybe the host picked up bacterial membrane machinery in the nucleus and proceeded to churn them out around the chromosomes, hence nuclear membranes … The external membrane got replaced through natural selection, because it was better. [Biology has a danger of descent into handwaving , its there, it must be better, natural selection, don't you know]

Why did m. retain any genes at all. This is the guts of NLs argument. Not one species has lost all its m. genes, they all retain the same core of genes … its about control. Eg if one m. lacks enough cytochrome oxidase it sends a message to the genes "make more cytochrome oxidase" say the genes are in the nucleus, how to know which m. is in need? M. cant have labels because "they are in a constant state of turnover" [Imagine somewhere in the galaxy a bug that has evolved labels for its mitochondria - it doesn't sound absolutely impossible… so the m. don't need genes, they don't even need to be symbionts? So a bacteria, ie a simple cell, could have lots of internal membrane area making proton-gradients - Giant Galactic energetic Bacteria! Seriously folks, I'm always suspicious when a biologist says 'xyz would be impossible to evolve'.
Multicelled life would probably always require discipline but, ie cell suicide (Apoptosis, pronounced apotosis…]
[Aside: David Bolinsky biovisions at Harvard web site? On TEDTalks podcasts talks about truth & beauty in molecular biology visualizations/animations 2007 kinesin - seems to be the kind of stuff required]

This from pharangula, seems to be a tip of the hat to LM:
On Page 8 of a Report from the National Research Council there is an interesting admission:
"Natural selection based solely on mutation is probably not an adequate mechanism for complexity."
Of course the report itself supports the concept of Darwinian evolution. But I think the admission that mutation is an insufficient mechanism is significant. They invoke lateral transfer of genes as the alternate explanation: "More important, lateral gene transfer and endosymbiosis are probably the most obvious mechanisms for creating complex genomes…" Of course this begs the question; where did the genes come from that are being laterally transferred?

M. genes are near the electron chain, hence near damaging free radicals. Hence they mutate 20x faster than nuclear genes [this is why m. eve and her descendants can be dated to within thousands of years]
A failing m. respiratory chain leaks electrons, forming free radicals. These might be a signal to the genes, to eg, make more cytochrome oxidase. If the signal was sent to nuclear genes, there is no way to target a particular failing m. The few genes in the m. may construct a "few core subunits"… they act as a beacon and a scaffold for the assembly of the rest [made via nuclear genes]
…"the m. of plasmodium the cause of malaria have retained just three protein coding genes… they have had to keep all the machinery needed to make these proteins.. all three encode cytochromes - core proteins - exactly as predicted"
- So NL's central argument holds, (note the 13 genes have become 3 in at least one case)
Bacteria can't gain the membrane surface area to pump more protons, because they couldn't control it.
"How might we regain control? One way would be to copy a subset of genes and delegate it to regulate the extra membranes - but how could we choose the right genes? There is no way I can think of that does not involve some kind of foresight… and evolution has none"
- I am very suspicious of arguments that say 'no way I can think of' and of arguments that say something could not evolve. However, it is a fact that in billions of years on Earth, bacteria haven't stood up, and all big life forms have very similar m.
The rule is that multiple genomes in a cell must fight like cats in a bag. NL says that e. have solved the fight by "sealing off the m. genome within a double membrane" Bacteria cant do this because "there would be no way of getting food in and ATP out" - somehow this 'no way' talk seems like special pleading.
"ATP exporters are an e. invention" - sort of like inventing stable doors after housing the horse?

Chap 4 Power laws - small animals burn faster, we don't have a simple explanation, nor a slope for the graph A gram of rats liver consumes 7 times as much O2 as a gram of human liver. Its odd we cant say why. This does not apply to muscle it seems (see below)
Chap10 Even more odd, there is no single, simple explanation for warm-bloodedness. mammals burn 6-100 times as much food as reptiles. The advantage is stamina? What? [one reason not suggested: optimum temperature for diffusion and enzymatic reactions?] Its a scandal we cant state simply why rats burn more than cows than alligators. NL is not scandalized, merely perplexed.

Part 5 Murder or suicide:
P193 "only the genes are passed on to the next generation" - this is an odd thing for NL to say, 2 pages later he has "new m. are always formed from old mitochondria - they cannot be made from scratch" - so genes are not all that life passes on. Odd to think that all the trillions of m. today came from one event 2E9 ybp. Aint we lucky to be here.
In a note on p197 NL says that in her recent book 'Acquiring Genomes' "Margulis is plain wrong to condemn neo-Darwinism as irrelevant" - I'm glad we got that cleared up. However, LM obviously is way more familiar with single celled life than most of her critics, worth attending to.
1972 Apoptosis suggested. (Kerr Wyllie Currie) cells die gracefully, into bite-sized chunks. No inflammation, requires ATP.
1995 loss of proton gradient across the inner m. membrane one main trigger for apoptosis…. Cytochrome c is released from the m. , forms apoptosome, and the cell dies. - an idea greeted with ' general stupefaction' when proposed in 1996 … some other m. proteins also involved… Obviously the outer m. membrane needed a pore. No problem (but note above, the putative bacterial incompetence in pore forming) but then "all known apoptotic proteins released from the mitochondria are bacterial in origin.
Why death signals? Maybe parasites killed failing cells, to jump ship like rats. Gonorrhoeae drill holes when their hosts ATP fails. The bacterial predator Bdellovibrio inside other bacteria also kills failing hosts. "Bdellovibrio has been cited by LM as a possible ancestor of m." NL is now considering parasites, having championed a non-parasitic theory in part 1. "horror of horrors" as he mildly puts it. Obviously m. are not now independent, and would die if their host dies, so no advantage in a single cell. So why the killing machinery? Maybe sex? Bacteria exchange genes but never fuse. [ there's that word never again]. The origin and benefits of sex a mystery. NL mentions Bill Hamiltons 'Red Queen' idea - sex allows known (ie conspecific) packages of immune variety, to keep up with fast breeding parasites. [parasites are defined as things on you that have a shorter life cycle than you… if they lived longer, then I guess you would be the parasite]
[ in future the sex machinery might be slimmed down to just the variable immune genes. Right now males fight for the right to have equal sized genes]
Another reason for sex is to mask bad genes. I had never liked this idea, it seems to me that chances are your mate would have genes as moth-eaten as yours. Recently I have caved. Mask is the keyword, a bad gene is presumably harmless, so grab a set when you can. So Bill's idea may not be the only reason. Another case when a basic, profound biological actuality lacks a single clear explanation.)
Maybe damage is a signal for fusion. (this re-raises my above question: why does the non-damaged partner agree to fuse/swap?) "in yeasts and other simple e. DNA damage constitutes a signal for sexual recombination" In multi-celled organisms sex turned into death. "the very signal for sex is a confession of damage." So multi-celled organisms don't fix sick cells, they kill them, somehow they changed the fuse signal into die. Stressed m. -> free radicals -> damaged DNA.
"All that was required was the insertion of the .. caspase cascade .. inherited from α-proteobacteria…" but in bacteria they don't kill…

"The differentiation of cells is controlled by their Redox state within a 'colony' "(embryo?) - a nice throwaway line.

After fusion, we obviously need to halve the genes .. (mitosis, discussed later? )

Fusion leads to a conflict between the two populations of m. … can compete to the detriment of the fused cell… sexual organisms go to extraordinary lengths to block the entry of m. from one parent [defined
as male] [NL later questions this competition theory. This habit of erecting then demolishing arguments is somewhat irritation, but it keeps you on your TB (theoretical biologist's) toes. ]

Part 6 Battle of the sexes.
Asiatic mole voles: both males and females carry 2 X chromosomes…
1974 first report that m . are inherited from mother only.
"in mice and humans male m. are tagged with ubiquitin, which marks them for destruction in the egg [but why don't they rebel and slough it off?] …

"bats are often heteroplasmic" (ie male and females contribute m.) [why?]

2002 One man found with herteroplasmy: muscle 90% paternal, blood nearly 100% maternal 0.7% of muscle m DNA had recombined. [That sort of rare recombo may explain some odd occurrences in the Pacific].
Important for forensics - at least 10% of humans are heteroplasmic. Much of the mixture appears to come from new mutations, rather than parental seepage"
[ a lot of archeological and forensic DNA is m. , because cells have a lot of m. and hence a lot of m. DNA I have this idea that a few $ would buy the contents of a hotel vacuum cleaner bag, with hundreds of different DNA's. Sprinkle around your crime scene, and hey presto, no forensic evidence!]

Sequences of family members suggest 1 mutation in 40 to 60 generations… but fossil evidence suggests 1 mutation every 6000 to 12000 years. Selection explains the discrepancy?

Mungo girl: 40,000 ybp… worlds oldest m. DNA… no similar … line has fallen extinct. In note: "in fact modern humans do carry a similar sequence in their nuclear DNA - a numt transferred from the m. .. amounts to a DNA fossil as the mutation rate in the nucleus is 20 times slower…

Douglas Wallace , the guru of m. geneticists… underpinned the famous 1987 Nature paper by Cann, Stoneking and Wilson… (inexplicably unmentioned in Sykes Seven Daughters of Eve…) [ there is a better book?]
Geographical distribution of m. genes adapted to particular climates?

..some protozoa such as Trypanosoma edit their RNA sequences to retain the original meaning despite changes in DNA sequence [this kind of statement begs the question of information, where is it stored?. I am also puzzled by the regulatory proteins which supposedly attach to each gene… where is their transcription controlled?, we seem to have an infinite informational regress. I suspect there are combinations of a limited set of regulators… ie. a another code]

Ovarian bottleneck: oocytes in the embryo 100 after 3 weeks, 7 million after 5 months.. at birth 2 million…
[note that this is a huge expansion, followed by a 'bottleneck'. Then spontaneous miscarriage selects further. Somehow this selection has kept animals going for hundreds of millions of years. Astounding that they don't just wither away..]
..it is necessary to test a single set of m. genes against a single set of nuclear genes … [ NL admits that the diploid organism has a double set of genes, so this argument is weak… there also those bats…]

NL is down on anti-oxidant supplements… "they don't affect maximal lifespan at all" - Linus Pauling might have disagreed, he died at 92 regretting he didn't start mega- Vitamin C earlier. LN supposes that we need a minimal amount of free radicals as a signal. Birds have less, and live longer than their small hearts might suggest. "If some of the billions… were directed to the target of free-radical leakage, we could potentially cure all the diseases of old age at a stroke (sic)" . NL is puffing a bit here But the only way to extend human lifespan would to be totally re-engineer m. radical 'leakage' and signaling to be more like birds . Not a near term prospect.

"Lifespan does correlate with the rate of free-radical leakage from the respiratory chain.." Birds need huge energy bursts to fly, so somehow they have learned to leak less and live longer (eg parrots) while still signaling satisfactorily.
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