Word from the complaints department has it that my recent post “What Bioethicists Don’t Do” was so long and turgid (ahem) that it was well-nigh unreadable. The problem was duly noted, and is being addressed, right here and now.

I’m going to run it past you again in an even more severely whittled down form (with some helpful interpolations), followed by my own humble and halting summary translation. If you want to skip the block quotes and jump ahead to the end, I may not respect you in the morning. But I’ll understand.

Mitochondria are intracellular organelles found in almost all eukaryotes, derived from ¦Á-proteobacteria and possessing their own genome...They are involved in many biochemical processes…

Mitochondria are vital working parts in most of the cells in your body. If they stop working correctly, you die…

In each cell there are usually between 1,000 and 100,000 copies of mtDNA [mitochondrial DNA], on average 4,900 mtDNA genomes per nuclear genome…

A nuclear genome is what most of us think of when we hear the word DNA. That is, the coiled helix of DNA which resides all comfy and protected inside a cell’s nucleus, the primary determinant of our heredity. But a cell has more than one genome. Many more, in fact. Each little mitochondrion in your body packs its own little genetic blueprint, inherited from your mother.

Therefore, there are many more mitochondrial genomes (thousands) in any given cell than there are nuclear genomes (one). And since there are so many of them, riding around all exposed and vulnerable outside the cellular nucleus, they have many more chances to get screwed up.

The presence of a mutation in 100% of the genomes is termed homoplasmy, while heteroplasmy is a mixture of mutated and wild-type sequences for a given locus.

Here, the authors simply point out that there are two kinds of mitochondrial mutation; those that are found in every mitochondrion (the homos), and those that aren’t (the heteros). This will be important later.

Since uncorrected accumulation of mutations would within a very small number of generations become incompatible with survival, there are mechanisms for selection against mtDNA mutations… there are many conditions where this cleansing mechanism fails...

Too many mutations, alterations in the DNA, and your mitochondria will stop working. Then you die. Natural repair mechanisms exist, to stave off this unfortunate event. But they’re not perfect.

We implicate…mitochondrial microheteroplasmy, as a candidate for the principal component of aging.

Which is a main point of this paper.

Microheteroplasmy is the presence of hundreds of independent mutations in one organism, with each mutation usually found in 1 - 2% of all mitochondrial genomes.

They already defined heteroplasmy, but now we’re talking about microheteroplasmy, heteroplasmy on a very small scale.

Despite the low abundance of single mutations, the vast majority of mitochondrial genomes in all adults are mutated…

Which is not good news.

A molecular substrate of aging…would have to persist for decades and accumulate change over this time. The nuclear and mitochondrial DNA appear to have the requisite characteristics...

They appear to, but there are problems, which we shall address either lightly or not at all. The primary cause of aging is still unknown, though many theories have been advanced to date.

Oversimplifying, we could divide those theories into two main camps, “Wear and Tear” versus “Planned Obsolescence”. Compromises and combinations are possible. Our authors think that they’re onto a new causative agent which may put an older wear and tear theory back in the running.

...while there may be other molecular mechanisms for long-term accumulation of change important in some contexts...DNA appears to be the most likely candidate for the substrate of aging.

Which only makes sense. Different species age at different rates. A chimp is old at fifty, a rat at two. Meadowlarks. Mayflies. You get my drift. Why are they different species? Because their DNA has changed over time. Different DNA equals different life expectancy. Supporting this supposition is the following fact. When scientists alter the DNA of laboratory animals in certain specific ways, they can alter that animal’s life expectancy, both positively and negatively.

…aging should be conceptualized primarily as a disease of our somatic cell DNA, where mutations accumulate with time, and lead to cellular dysfunction. Thus, aging is an integral of information loss over time...

Again, like so many new theories, this sounds plausible. As mutations accumulate over time, your DNA becomes ever less able to do its job, i.e. provide necessary instructions to the cellular machinery. Eventually, the program becomes so bug-ridden that it can no longer provide the needed information. For want of uncorrupted data, the elegant mechanisms of the cell grind to a halt. Or worse.

The rate of accumulation of mutations in mtDNA will determine the timing of onset...thus acting as the principal component of the molecular clock of aging.

Except that, until now, there was no easily observable correlation between discernable mitochondrial changes and the external signs of aging.

Usually, mitochondrial DNA is used as a template for PCR [polymerase chain replication, a technique for taking a small sample of genetic material and turning it into a large sample], and the amplified DNA is directly sequenced.

This method allows only the reliable detection of mutations present in no less than 30% of mitochondrial genomes…it is possible to increase sensitivity to about 10% heteroplasmy but…this is still well below the sensitivity needed to detect the class of mutations which are the focus of this article.

Another technique used to analyze mutations is denaturing HPLC…but even there the sensitivity is usually not better than 3%...

Here’s where the distinction between the two kinds of mutation mentioned earlier becomes important. Homoplasmic mutations are relatively easy to detect, which shouldn’t be surprising, as there are so many more of the little buggers. Finding the much less frequent heteroplasmic mutations is a real chore, both tricky…

The other form of mtDNA mutational load, low-level heteroplasmic mutations (microheteroplasmy), is more difficult to detect.

…and expensive.

With cloning…the percentage of mutation can be calculated from the ratio of wild-type vs. mutated clones. This procedure is more than a hundred times more expensive than direct PCR sequencing.

Until recently, it couldn’t be done at all.

Consequently, there is much less data on microheteroplasmy. Available studies indicate that microheteroplasmy is present in all tissues, at all ages examined, and in all subjects...

With hundreds of different mutations in each patient their total burden adds up to a level comparable with the mutation loads present in classical mitochondrial disorders.

Like the Land Unknown emerging out of the mists, we see a sweeping vista opening before us. Can you hear the dinosaurs?

…in stark contrast to the frequently quoted estimate of 0.1% mutated mitochondrial genomes the true mutational load is orders of magnitude higher.

Not good news. Where once we saw sturdy cellular timbers propping up the foundations of our lives, we now see rotted, vermin-infested punkwood. Still, it’s better to know than to not know.

As alluded to in the introduction, this finding has important methodological implications [since] the, literally, thousands of studies looking at mtDNA with direct sequencing of PCR products were for technical reasons alone incapable of detecting the majority of mutations.

We’ve been flying blind. Just like always.

To summarize the data on the mitochondrial genome: It has the characteristics necessary for the molecular clock of aging, accumulates mutations both through inheritance and during aging in all humans, at levels sufficient to explain phenotypic [bodily] change, and in some cases the acquired mutations already have been shown to correlate with, or explain age-related disease.

Which was not clear before due to technical shortcomings.

The primary obstacle in the acceptance of the mitochondrial theory of aging and age-related diseases was heretofore the lack of a set of mutations which would be detectable in all aged adults at levels sufficient to explain the physiological derangements.

But that may be changing.

…microheteroplasmy affects the vast majority of genomes in adults, with at least 90% of genomes in every aged adult predicted to have at least one amino-acid changing mutation per genome.

Even if some fraction of these mutations is innocuous, the total level is on par with levels of deleterious mutations sufficient to cause severe phenotypes in classical mitochondrial conditions.

Oops. Our foundation has lots of termites.

The mutations are present in all tissues examined so far and in every individual, making them the suitable substrate for a ubiquitous clock. Mutations levels are lowest in the neonate, and smoothly increase with age, exactly as would be expected from a time-measuring quantity (or perhaps more precisely, an integrator of damage over time)...

The dearth of mutations in previous studies of mtDNA is due to the methodology used for their detection, which lead to erroneous conclusions, much like reliance on the light microscope might lead one to deny the existence of viruses.

We postulate that microheteroplasmy accumulation in tissue-specific stem cells is the primary cause of the exhaustion of the tissue renewal capacity in advanced age…

Okay, to summarize…

Most of the cells in your body (seventy trillion or so, by some counts) contain thousands of organelles called mitochondria, the “power plants of the cell”. Each of these mitochondria, in turn, has its own onboard complement of DNA, doing important DNA-type work, keeping that mitochondrion alive and working. When the mitochondria stop working, so do the cells.

One theory (out of many) implicates mitochondrial failure (brought on by mtDNA mutations) as a primary cause of aging. Evidence to date has not supported this theory. Nobody saw enough mutations to account for the observable symptoms. This situation may be changing.

New observational techniques are now capable of detecting mitochondrial DNA mutations that were heretofore unsuspected. There are a lot of them. Individually they don’t look like much. But add them all together and these mutations look like they may be sufficient in number to account for the degeneration that we can see at the macro level.

They may supply a unifying story with enough explanatory power to fit all the facts. So far that hasn’t been done yet.

So far, so good. Knowledge is power. Better to know than to not know, and all that.

On the other hand, there’s not a lot we can do about it, right? Tiny little bits of us get sick and die, dragging the rest of us down with them. It’s not like we can do anything about it. Hell, we can barely even see them. But let’s not be unduly pessimistic.

Today our team confirmed our previous preliminary data showing that we can achieve robust mitochondrial transfection and protein expression in mitochondria of live rats, after an injection of genetically engineered mitochondrial DNA complexed with our protofection transfection agent. A significant fraction of cells in the brain is transfected with this single injection even though we so far did not optimize the dose.

These guys have just demonstrated the successful genetic manipulation of mitochondria in living animals. That’s a hopeful thing, a very hopeful thing.

This achievement has important implications for medicine: protofection technology works in vivo, and should be capable of replacing damaged mitochondrial genomes.

We can do more than just see them now. We can reach our grubby little paws down and mess with them, maybe even fix them. Most folks would call that good news.