The Boy Who Wasn't Short

by Kirk, Edwin;

  And now something truly strange happens. Your family tree splits. Even though you had followed mother after mother after mother, choosing just one parent at each generation, and continued to do so until you reached, perhaps already, the origins of sex itself … now there is a double row of portraits stretching out along the wall.

  You’ve just walked past a pictorial history of one of the most important events in evolution, happening in reverse as you backtracked through your ancestry. What happened, nearly two billion years ago, was a joining of forces between two primitive organisms. One, the larger, was from a line that had already been building in complexity. Around the same time as this remarkable union, the nucleus formed. The larger partner was one of the first of the eukaryotes, the group of organisms that includes almost everything that isn’t a bacterium. After perhaps a billion years of nothing much happening, an evolutionary cataclysm was underway. The other partner was a much smaller and simpler organism, but had a neat trick up its sleeve (not that it had sleeves, of course. Or arms).

  The smaller creature’s neat trick was that it was really good at harvesting energy from food. Its new host could do this, too, but much more slowly and less efficiently. So there was a win for both sides in the new arrangement. The smaller partner gained protection from others who would eat it, and perhaps a steadier supply of raw materials than it could forage on its own. The larger gained a burst of energy that would fuel the next two billion years of evolution.

  Not that long after this event, in another line of cells from ours, the same thing happened again. This time, the new cell that took up residence had a different specialty: it could take water and carbon dioxide, and, using energy from the sun, manufacture food. The first plant had been born.

  Now, we call the remnant of that small invading bacterium the mitochondrion (the second set of invaders, which make a plant a plant, are called chloroplasts). Mitochondria have changed a great deal since they first took up residence in our cells, but, in some ways, they are still independent creatures, with their own DNA, their own slightly different metabolism, and their own reproductive cycle. We are utterly dependent on our mitochondria — we need them to survive and thrive. When things go wrong for them, they go wrong for us — often very badly indeed.

  There is something fundamentally odd about this arrangement. It’s as if you went swimming one day, and a small but particularly aggressive eel latched onto your belly and managed to eat its way inside you … and then took up residence. Then, instead of killing you, the eel became one of your most important organs. In this imaginary world, the eel regards this as an exceptionally good deal. Did I mention that it was pregnant at the time, and now it has a nice safe place to raise its babies? But everything’s okay, because you are also happy about the situation.

  I don’t know about you, but I can never quite get used to this idea.

  We should not imagine, by the way, that this was a one-off event, a happy chance that worked out perfectly the first and only time it occurred. Countless small blobs of life consumed even more numerous, smaller blobs of life, over and over for hundreds of millions of years. During that time, there must have been many occasions when a partnership almost formed, when for perhaps as many as a few generations of cells something close to stability was generated — only for the big blob to lose patience and consume the smaller, or for the small to grow too fast and consume its host from the inside. But in the end, the partnership formed and was a roaring success. Look around you: everything you can see that is not rock, sand, or water is the result of that partnership. Every bush, every tree, every coral reef, every house, road, ship, and plastic bag … all exist only because of this union between your ancient ancestors, tiny dots of life that were just that bit more successful working together than apart.

  Over the millions of years, our mitochondria have settled down and really made themselves at home. Gradually, they handed some key tasks over to the nucleus of the cell, and long, long ago lost the ability to exist as free-living organisms. They have kept one reminder of their free-living past: their own small genome. In humans, this is tiny: only 16,569 bases long and containing just 37 genes. Compare this with the genomes of modern bacteria: free-living bacteria seem to need at least about 1,500 genes, spanning about 1.5 million bases of DNA, and some have genomes five times that size. There are some bacteria with smaller genomes, but they depend on other organisms for their existence. Take Mycoplasma genitalium,1 which has only about 470 genes. It can’t break food down into components it can use, so it exists only as a parasite inside other cells. There are quite a lot of parasites like this — perhaps they are the near-misses of evolution, the scenario in which the ‘one organism living inside another’ arrangement worked out better for one partner (the parasite) than the other (the host).

  [1 As its name suggests, it likes to live in human genitals. You definitely don’t want it living in yours.]

  So, the mitochondrial genome is a ghost of what must have been its former self. Of its 37 genes, only 13 code for proteins — the rest produce machinery needed to make those proteins, running a slightly different biochemistry from the nuclear genome in order to achieve this. It’s possible that, eventually, all of those 13 genes will transfer across to the nuclear genome, and the mitochondrial genome will lose its function.2 In the meantime, mitochondria carry on behaving a bit like they are a separate organism. Each cell contains hundreds to thousands of mitochondria. Each mitochondrion contains multiple copies of its genome,3 which exists in the form of a ring of DNA — like the genomes of bacteria, and quite unlike the chromosomes in the nucleus. The mitochondria live their own little lives, semi-independently from the rest of the cell. They divide into two just like bacteria; they grow and age and die at their own pace. When cells divide, the new daughter cells share the mitochondria from the original cell between them. In order for dividing mitochondria to have their own copies of the mitochondrial genome, that, too, has to be copied, and there is a special set of cellular machinery for that. Like any DNA that is being copied, there is a chance for mistakes — and so there can be mitochondrial mutations. They have some special properties, as we shall see.

  [2 The degeneration of both the Y chromosome and the mitochondrial genome has been ascribed to Muller’s ratchet. The ratchet is a gradual accumulation of harmful mutations in situations where chromosomes can’t trade information. During formation of eggs and sperm, chromosomes 1–22, and the X chromosomes in egg production, undergo a process called recombination, in which material is exchanged between the two versions of the chromosome. The Y can only do this in a very limited way, and mitochondrial DNA can’t do it at all, leaving them vulnerable to decay over the millennia.]

  [3 There’s a special case, though: in the egg, each of the 200,000 or so mitochondria contains just one copy of the mitochondrial genome.]

  We depend on our mitochondria: they do many tasks, but, most importantly, they are like generators making the energy our cells require. The digestive system, including the liver, breaks food down into its component parts. We can use some of those parts for energy: sugar, fat, and (at a pinch) protein can be burned for fuel. These raw materials get passed to the mitochondria for conversion into a form of instant chemical energy the cell can burn to do whatever it needs to do. This means the cells that use the most energy — brain, muscle, heart, and so on — are the most vulnerable if something goes wrong with the mitochondria. By contrast, cells that don’t need a lot of power — skin cells and fat cells, for instance — can cope relatively well when their mitochondria fail.

  *

  Something was wrong with Felicity’s mitochondria, and had been for her whole life. It was only now, though, in her late 30s, that the first signs of this were beginning to show themselves. The progression was so subtle, so insidious that Felicity didn’t even notice, until one day her husband pointed out that her eyelids had begun to droop. She saw an eye specialist, who realised that the probl
em wasn’t just in her eyelids. Her eyes were not moving as well as they should, because slowly her eye muscles were getting weaker. Eventually, she would not be able to move her eyes at all, and would have to turn her head to look to the side. Otherwise, though, she was completely well.

  Ahmed had always been a clumsy child, and had struggled to keep up with his friends in the playground. From the time he was about ten, his mother started to worry that he was increasingly unsteady on his feet, and he had begun to walk on his toes. He wasn’t doing well at school — everything seemed more difficult for him than it had when he was younger. His mother took him to a paediatrician, who found that Ahmed had some muscle weakness, and that he was walking on his toes because of tightness in his Achilles tendon, which made it hard for him to get his feet flat to the ground. Ahmed, too, had drooping eyelids and could not move his eyes normally.

  Jacob did not live to see his first birthday. Very early in life, he was found to have anaemia — his bone marrow could not make enough red blood cells to meet his body’s needs. It was so severe that he needed regular blood transfusions. His pancreas did not work as it should, so that he could not absorb food well. There was a high level of lactic acid in his blood, and his liver was sick from the day he was born, until it failed him completely late in his first year.

  Jacob, Ahmed, and Felicity, although so different, all had exactly the same underlying problem: some of their mitochondria were missing a wedge from their circular DNA. For reasons we don’t understand, if you are missing a large part of your mitochondrial DNA, you’re quite likely to develop one of these three related conditions — chronic progressive external ophthalmoplegia (CPEO),4 like Felicity; Kearns-Sayre syndrome, like Ahmed; or Pearson syndrome, like Jacob. Had Jacob survived infancy, he, too, would almost certainly have eventually developed similar eye problems to those that Ahmed and Felicity had. Although these three conditions have different names, really it’s all one condition with differing degrees of severity, from CPEO at the mildest end to Pearson syndrome at the most severe.

  [4 This sounds daunting, but it’s just jargon. Chronic means present over a long time. Progressive means getting worse over time. External means outside. Opthalmo refers to the eye. And plegia means weakness, as in paraplegia. Put that together and you have a long-term condition that gets worse over time and affects the muscles on the outside of the eyeball (the muscles that move the eye).]

  Genetics is full of situations in which changes in DNA that you might expect to have wide-ranging effects instead produce oddly specific manifestations, and this is a typical example. Having a change in just one of the 16,569 bits of DNA that make up the mitochondrial genome can have a devastating effect on multiple organs, sometimes causing death in the first days of life. So why on earth should removing as much as three-quarters of the mitochondrial DNA lead to someone having only an eye condition, and one that takes decades before it becomes noticeable? And why is it that Jacob died in infancy, Ahmed had significant and varied medical problems in childhood, and Felicity was completely healthy apart from her eye condition?

  We only partly know the answer to these questions. The bit that we understand best has to do with the fact that the mitochondrial genomes inside a cell are independent from each other. This means that it is quite possible for a single cell to have more than one version of the mitochondrial genome. That could mean harmless variation — or it could mean that there are some copies that are normal, while others have something wrong with them, such as a missing piece. There’s a term for this type of mixture: heteroplasmy. It’s easy to imagine that, if most of the copies of the mitochondrial genome are normal, that might lead to milder problems than if almost all of the mitochondrial DNA is abnormal.

  At least in part, that explains the difference between Felicity and Jacob: if we could go inside each of their cells and count normal and abnormal copies, Felicity would very likely have many normal copies, but Jacob would mainly have abnormal copies. The fewer normal copies that are present, the worse the function of the mitochondria, with correspondingly more severe health problems that start earlier in life.

  That leads to another question. How was it possible for Felicity to be perfectly fine for decades, despite her cells containing at least some faulty mitochondria? The answer is that as we age, our mitochondria accumulate damage, including deletions like those seen in CPEO. Felicity started life with a certain percentage of damaged copies of the mitochondrial genome. She had enough normal, functioning copies for the cells of her eye muscles to work just fine. Over the years, damage accumulated and those cells passed some threshold of damage, past which they could no longer cope. Slowly, her eyelids began to droop. Poor Jacob was born with his cells already past the redline — most of his mitochondrial DNA was abnormal.

  Different types of cell are better at tolerating this problem than others, which explains the different pattern of symptoms in our three patients. In Jacob, many different tissues were struggling from the start, because their cells were beyond the level of faulty mitochondrial DNA at which they could cope, and there was no way back. Ahmed was in between the two extremes. The mild clumsiness his mother had noticed early on was a sign that there were some nerve cells that were struggling a bit. Even from birth, he must have had many cells that were only just keeping up with the demand for energy. Just a few years later, a little extra damage had happened and his symptoms began.

  At this point you might be wondering about your own mitochondria. Are they also accumulating damage? You bet they are. In a 2006 study, researchers from the University of Wisconsin looked at muscle samples taken from people aged from 49 to 93 with no known mitochondrial condition. They found muscle fibres with faulty mitochondria in all of the people they studied, and the older the person, the worse the problem. In people in their late 40s and early 50s, about 6 per cent of muscle fibres showed abnormalities; for those in their 90s it was 30 per cent. They also found a steady increase in the level of deletions similar to those seen in people like Felicity, Ahmed, and Jacob (but at much lower levels). The loss of muscle strength we all experience as we age is partly down to this gradual decay of mitochondria. You can’t expect a faulty powerhouse to supply the energy a muscle needs.

  If individuals accumulate mitochondrial damage, what about the species as a whole? How is it possible for generation after generation of people to be born and live their lives, mostly not having any sign of mitochondrial disease, if their mitochondrial DNA is constantly decaying? Why didn’t we all go extinct millions of years ago?

  Strangely, the answer lies in the neck of a bottle. In this case, it’s a figurative bottle: the mitochondrial bottleneck is an event, rather than a physical thing. It’s an event that happens very early in a woman’s life, before she is even born, and it has to do with the number of mitochondria in the egg. A typical cell has thousands of copies of the mitochondrial genome, but a human egg cell has about 200,000 copies. After the egg is fertilised, the cells divide faster than the mitochondria can keep up, so that the number per cell drops quickly towards a more ‘normal’ level. Among the many different types of cell in the growing (female) embryo, there is one type that will eventually become the future eggs; the next generation is being plotted almost from the start.

  This process involves many cell divisions. Somewhere along the way, the number of mitochondria drops dramatically and then expands again: this is the bottleneck. We’re not sure quite how low the number goes — how tight the bottleneck is — or even if it is a single bottleneck, or rather a process of widening and narrowing, a sort of wavy bottleneck. Regardless, the idea is that if you have a small number of mitochondria — maybe a couple of hundred — which are then multiplied to become 100,000, anything dangerous that lurks in the mitochondrial DNA in those 200 will also be multiplied. That might seem a bad idea, but it means that a slow accumulation of damage over generations can’t happen.

  The reason for this is that if any damaged DNA slips thro
ugh the bottleneck, it will be amplified up and is likely to become a significant proportion of the resulting egg’s complement of mitochondrial DNA. An egg with a high burden of damage is very likely to be prevented from passqing that damaged DNA to the woman’s descendants. In the ideal world, this would be by making the egg non-viable — incapable of being fertilised, or of dividing and becoming an embryo. Perhaps that is what usually happens. But from the point of view of survival of the species, it doesn’t make a great deal of difference if an occasional baby is born but never grows old enough to have children of her own. As long as that heritage of damaged DNA is not passed on, the species is saved from its effects and can continue. From this perspective, the existence of mitochondrial disease is the price we all pay for continuing to exist.

  It is a harsh price for those who have to pay it personally. We don’t know for certain why, but the kind of mitochondrial deletion that causes the problems we saw in Felicity, Ahmed, and Jacob is almost never passed on from mother to child. It seems likely that the bottleneck is very efficient at removing these deletions. This is not true for other types of mitochondrial mutation, however. A change in a single base of mitochondrial DNA can cause problems every bit as severe as those seen in Jacob, with the same variability due to different mixes of healthy and mutant mitochondrial DNA. A lot of the time, this seems to happen as a one-off: a particular line of cells gets unlucky and produces a single egg with a high load of abnormal mitochondrial DNA, and it never happens again in that family. Sometimes, though, we see multiple siblings affected, and even passage through several generations.