Saturday, March 19, 2016

The surprising real genetics behind the X-Men

The X-Men – everyone’s favourite mutants – are hugely popular, thanks to seven feature films since 2000, with more on the way, and to the enormously successful comics that have been running for over 50 years. With that kind of exposure, they can have a real influence on the public perception of genetics, grounded as they are in ideas of mutation and evolution of the “next stage of humanity”. So, is there any real scientific basis underlying these stories? Well, to a geneticist, most of the supposed mutant abilities of the X-Men and their mutant brethren are frankly ludicrous. No matter how mutant you are, the laws of physics will still apply! (Except for Entropy Man of course). But some of them are less far-fetched, reflecting the strange and wonderful world of real-life biology. And underlying them all is a much deeper mechanism that has, in the real world, a profound effect on how mutations contribute to evolution.

The X-Men were created in 1963 by Stan Lee at Marvel comics. He had already done the Fantastic Four and the Hulk and Spider-Man but wanted to create a new team of superheroes, with a bunch of different powers. And when it came to their origin story, he was, by his own admission, just being lazy. He realised he couldn’t have everyone exposed to cosmic rays or gamma rays or bitten by a radioactive spider – you’d quickly run out of radioactive animals to bite people that would be in any way cool – Mosquito-Man or Bed Bug-Man just don’t sound that awesome (though The Tick has always been a personal favourite).

So, he decided he would simply make them all “mutants” – they were all just born that way. That way he could have one have lasers coming out of his eyeballs and another able to control the weather and another able to turn into ice and just say it was all down to mutation.

He actually wanted to call the comic The Mutants, but he was over-ruled on the basis that no one at the time really knew what mutants were – the word was in the air, perhaps, linked to the ever-present threat of radiation that loomed large in the public consciousness during the Cold War, but it wouldn’t have been widely understood. And it seems from looking at some of their abilities that Stan Lee didn’t really know what mutants are either, because a lot of those powers are just absurd.

I mean, some animals can manage a dim glow that you can see in the darkest depths of the ocean but lasers out of your eyeballs like Cyclops is a bit of a stretch. Where would the power come from? And while we’re at it, how is he supposed to see anything?

Or controlling magnetism like Magneto – again, some animals can emit very weak electromagnetic fields – duck-billed platypuses do that to detect their prey, for example – but the idea that a mutation could let you lift an aircraft carrier is just silly. (It’s inspired silliness, but still). On the other hand, if you want an origin story for a character with the ability to manipulate magnetism, I suppose it beats being bitten by a radioactive platypus.

Many of the other abilities also require suspension of the laws of physics (a big ask for a little change in your DNA), but a few of them actually have some grounding in real biology.’s take everyone’s favourite mutant, Wolverine. His main power is his super-healing ability, which actually is quite plausible (in kind anyway, if not in degree). There are, in fact, strains of mice called “super-healing mice” (AKA Murphy Roths Large / lymphoproliferative mouse strain!) where something very similar has been found. These strains were initially of interest because they are prone to autoimmune disorders. Their super-healing ability was discovered quite by accident when researchers noticed that the ear punches they used to keep track of individual mice were healing over completely! These mice show increased wound healing generally, with much reduced scarring and even more rapid healing of broken bones. It’s still not really known why this is or which genes are responsible, however.

Wolverine is also ferocious (a berserker, in fact), and something like that can also be caused by mutations. In fact, there are many mutations that affect aggressiveness, (having a Y chromosome certainly does), but the ones with the biggest effect in mice are in a gene called NR2E1, which is involved in brain development. A line of mice with mutations in this gene are called “fierce” because they’re so aggressive, with both males and females viciously attacking other mice or even anyone foolish enough to put their hand in the cage.

Beast is another mutant whose abilities are not completely ludicrous. There are mutations that
can make you super-strong, in genes called myostatin or activin, which normally act to restrict muscle growth. When these genes are mutated, in cattle, mice or humans, muscle growth can increase by two-fold or more, with concomitant increases in strength. And there are also mutations that can make you grow hair all over your body (a condition called hypertrichosis, or, less sympathetically, werewolf syndrome).

Now it’s not usually blue hair, like Beast’s, but there is another mutation that does cause shockingly blue skin coloration, in a condition called methemoglobinaemia. It is famous from a particular kindred from the wonderfully named town of Troublesome Creek in the Appalachian mountains of Kentucky. They are known as the “blue Fugates”, that being the most common last name in the clan, and they really do have skin close to the colour of Mystique or Nightcrawler. No signs of shape-shifting or teleportation, though (although you never know with people from Kentucky – they’re tricksy…)

Let’s see, how about Professor X? He’s a telepath, of course, with an ability to read minds and manipulate people. As crazy as it sounds, there is a genetically distinct group of people who are much better than the rest of the population at reading minds – they’re called women. On average, women score higher than men on measures of empathy and performance on tasks like “reading the mind in the eyes test”. People with autism tend to do very poorly on such tests, but so does a sizeable proportion of the general male population. Whether there are people at the other end of the spectrum, with really heightened abilities – super-empathisers – remains unknown, though it seems plausible enough.

So, overall, most of the X-Men abilities are completely nuts but a few are only wildly exaggerated, like super-strength or super-healing or being blue or hairy. But here’s the thing – all those things arise from mutations in different genes while the X-Men are all supposed to have inherited a mutation in the same gene – the “X gene”, yet they have very different abilities. So how could that be?

Despite not actually knowing anything about genetics, Lee stumbled onto an idea that actually exists and that, in fact, plays an important role in evolution. There really is a gene that, when mutated, causes all kinds of different effects in different individuals.

This gene is called Hsp90 and it encodes what’s known as a “heat shock protein”. Heat shock proteins are turned on in cells when they are under stress – like when you suddenly raise the temperature. Their job is to help the cell deal with that stress and in particular to help other proteins in the cell to fold into the right shapes.

We have about 20,000 different proteins in our cells, each one encoded by a different gene. Each protein is made from a string of subunits called amino acids – there are twenty different kinds that are strung along in a specific sequence encoded by the DNA sequence of that gene. As each protein is being made, that string of amino acids folds back on itself in a kind of molecular origami, making a complex three-dimensional structure, the shape of which depends on all the forces between all the atoms in those amino acids. The particular 3D shape of each protein is crucial for it to do its job.

Now, when the temperature goes up, this distorts those forces and it disrupts the folding, so that many proteins become non-functional (which is very bad for the cell or organism). The job of Hsp90 and other heat shock proteins is to help them to fold into the right shape – it (almost literally) grabs hold of them and shakes them up and gives them a chance to make the right structure.

So, Hsp90 can help a cell deal with sudden stress by detecting and correcting wrongly folded proteins. But the other thing that can make a protein fold wrong is if it has a mutation in it. If you mutate the DNA sequence of a gene you can change the instructions so the wrong amino acid is inserted into the protein at a particular position and that can stop it from folding properly. But if it’s given a good shake by Hsp90, then it can snap out of it and pull itself together.

That sounds great – Hsp90 can protect the cell from the effects of mutations that alter protein folding. But there’s a dark side – the result is that those kinds of mutations then start to accumulate in a species, because Hsp90 is there to make sure they don’t have any effect. Indeed, all of us have mutations in all kinds of genes that aren’t having any effect because of Hsp90 and genes like it.

Now, do you see where I’m going? What happens when Hsp90 gets mutated? Suddenly all those other mutations – whichever ones were in the background in any particular individual – can have an effect. And that’s exactly what people saw when they mutated the Hsp90 in fruitflies – they started seeing flies with all kinds of different phenotypes: deformed or missing eyes, misshapen wings, altered pigmentation, extra bristles, duplicated body parts.

All kinds of freaky stuff, just from mutating that one gene – all the genetic variation that was being buffered and not having any effect was suddenly released. And not only that, when they put the animals under stressful conditions (high temperature) it got even freakier. Which is another central part of the X-Men mythology – the idea that, while they are born mutants, their abilities often lie latent for years and only come out at times of high stress. Often this is when they’re teenagers, because, as well know, being a teenager is, like, OMG, sooooo stressful!

In evolution, this kind of mechanism is hugely important – it allows so-called “cryptic genetic variation” to accumulate in a population without affecting the phenotypes of the individuals. But if the environment changes (or the organisms move to a new environment), the stresses associated with that may “release” some of that genetic variation, so that it starts to affect the traits of individuals. And somewhere among that pool there may be some changes that are adaptive to the new environment. Those differences may be selected for in the new environment so that the species (though not all the individuals in it) can adapt more rapidly than they would have if they came in with a clean slate, as it were, and had to wait for new mutations to arise. The cryptic genetic variation is thus a source of evolutionary potential.

So, despite the fact that Stan Lee seems to have known very little about genetics, the central premise of the X-Men isn’t that far-fetched after all and actually reflects a mechanism that is central to how species evolve and adapt to new conditions.

Still doesn’t mean we’ll have laser-beams shooting out of our eyeballs any time soon, though…