We Can Be Heroes

Consider the complexity of the human genome. Three billion individual DNA “base pairs”, 23 chromosomes, 200,000 protein coding genes and a whole lot of mystery. Now visualize a gargantuan encyclopedia of 23 volumes, three billion characters long, with only 1.5% of these characters spelling 200,000 “expressive” words.

With this in mind, it’s not difficult to appreciate the level of diversity human genetics allows.

Today sees the airing of Marvel’s Agents of S.H.I.E.L.D. – the first television series to take place in the “Marvel Cinematic Universe”. This particular world is one of many that sit under Marvel’s grand umbrella of comic book existences. Stack Marvel’s collection of universes atop the universes of other superhero comic book publishers and the result is a series of complex and often convoluted modern mythologies, each containing myriad characters of varying abilities with their own individual history and lore.

But where does the fiction, the mythology of Marvel’s universe start? And where does the truth, the real world inspiration end? Molecular genetics obviously hasn’t featured in humanity’s greatest myths and legends, but stories of humans performing feats above and beyond the accepted limits of human capability have likely existed since the dawn of language itself.

Every aspect of the human body and mind has some basis in genetics, and it’s said that all myths have a basis in truth, so could the human genome allow for individuals with extraordinary powers? If so, what is the genetic basis of these amazing traits, and what do they say about human kind? Could we be heroes?

The ubiquity of “super strength” among fictional heroes is far from surprising. Humanity has celebrated the amazing physical feats of Olympians for millennia and still travel from across the globe to witness them lift immense weights, launch themselves over great distances and travel at incredible speeds. But do these men and women possess an “athletic” genetic profile predispositioning them to the growth of greater and more efficient muscles? Fortunately, the genetic basis of mammalian muscle growth is well understood, taking us to our first target, the gene MSTN.

A perfectly healthy boy with scarce body fat and body builder-like musculature.

Coding for the hormone myostatin, MSTN is responsible for skeletal muscle growth regulation in the embryonic stages of development and beyond. Myostatin itself binds to cellular “receptor” molecules, named activin type II receptors, which initiates a chain of biochemical reactions preventing newly formed muscle cells from maturing.

“Double muscled” cattle containing mutated forms of bovine MSTN have been selectively bred
for centuries for their 40% increase in muscle mass. The speedy whippet harbors a similar canine MSTN mutation and lab mice have been created with defective murine MSTN, resulting in the muscular “mighty mouse” strain. But could an MSTN related mutation lead to a favorable human trait?

Well, just ask Liam Hoekstra.

Born in 2005, Liam experienced a brief moment of stardom for his rare variant of an already
rare condition known as myostatin-related muscle hypertrophy – where a MSTN mutation causes increased muscle bulk. In Liam’s case, his MSTN gene is normal, but his activin type II receptors are misshapen, hindering myostatin binding. The result? A perfectly healthy boy with scarce body fat and body builder-like musculature.

Unlike the action-oriented Agents of S.H.I.E.L.D. , Liam’s contribution to mankind doesn’t come from his actions, but from the insight his body gives on those with less favorable genetic makeups. In fact, research is already underway to create a myostatin inhibiting drug to help delay the effects of various degenerative muscle diseases.

IGF-1 is another hormone involved in muscle growth, the production of which is stimulated by the well known “growth hormone”. When bound to the correct cellular receptor, IGF-1 instigates the proliferation of almost every human tissue, with the most dramatic effects occurring in skeletal muscle and bone. However, those born with Laron syndrome, a rare form of dwarfism, produce no IGF-1 at all.

The cause of these individuals’ dwarfism isn’t the result of an IGF-1 gene mutation, but instead an irregularity in the gene GHR which codes for the growth hormone receptor (GHR). No GHR – no cellular recognition of growth hormone and no IGF-1 production – resulting in the characteristically smaller form. But in 2011, after a 24 year long study of 99 Ecuadorian villagers with Laron syndrome, it was discovered that the lack of IGF-1 in their systems resulted in an extraordinary resistance to diabetes and cancer.

The lack of IGF-1 in their systems resulted in an extraordinary resistance to diabetes and cancer.

But IGF-1’s role in general age-related morbidity doesn’t stop at humanity’s two most prevalent, age associated diseases – disabling the equivalent forms of GHR in lab mice and the C. elegans nematode worm results in a 40% and 100% increase in life span respectively. So, is IGF-1 the key to unlocking the secret of superhero-esque longevity? Perhaps. But, if anything, the Laron syndrome dwarfs of Ecuador have provided a valuable lead in the pursuit of preventative cancer and diabetes treatments.

There’s no doubt that the genetically gifted heroes of our world have helped increase our understanding of human genetics, despite their inability to protect us as comic book heroes would. But even with their incredible powers there’s still one aspect of humanity that many modern fictional superheroes are unable to overcome: rage.

Wolverine and Hulk are two good examples of popular Marvel characters who are generally heroic, yet suffer from violent and destructive bouts of uncontrollable rage. It seems fitting for this article then that Logan’s personal demons are partly inherited from his father and that Bruce Banner’s enraged alter ego emerged following his genome’s bombardment with gamma radiation.

But does extreme aggression in seemingly healthy individuals really have a genetic basis? It’s a controversial topic, but some would argue that the answer lies in the gene MAOA, dubbed by the media as the “warrior gene”.

MAOA the gene codes for monoamine oxidase A (MAO-A) the enzyme – a catalytic molecule that helps break down surplus neurotransmitters including serotonin, adrenaline and dopamine. Considering the effect these neurotransmitters have on our mood and behavior, their regulation by MAO-A has a crucial role in maintaining a balanced state of mind. Conversely, a MAO-A deficiency can lead to abnormally impulsive and aggressive behaviors in those affected.

But as is the case with many human genes, several commonly occurring variants of MAOA exist, including one set of low-expression variants collectively known as MAOA-L. While an individual’s possession of a MAOA-L variant does not predisposition them to a life of crime and violence, several studies show a correlation between those with MAOA-L variants and a history of child abuse and overly aggressive behaviors.

In 2009 Bradley Waldrop, charged with the attempted murder of his wife and the first degree murder of her friend, avoided the death penalty following the defense’s successful plea to have the jury consider Waldrop’s former child abuse combined with his possession of the most potent MAOA-L variant, MAOA 3R. The case was a controversial one, but is nonetheless a prime example of the complex role molecular genetics will inevitably play in all aspects of civilized society – for better or for worse.

At least for now, research into MAOA and the MAO-A enzyme has resulted in beneficial medicinal uses – MAO-A inhibitors are found within numerous anti-depressants and anti-anxiety drugs to boost neurotransmitter levels. Unlike our favorite emotionally conflicted superheroes, those with pronounced, genetically attributed mental health problems are able to help – albeit indirectly – the many suffers of similar afflictions.

It’s a pity that the identification of superhumans in Agents of S.H.I.E.L.D. is carried out in the name of international security while the superhumans of our world offer significant genetic and medicinal insights. However, it mightn’t be long before we also need to become aware of those who would dishonestly use and abuse our cumulative scientific knowledge for their own personal – and genomic – gain.

In 2004 the home of German track coach Thomas Springstein was raided by police and in 2006 he was was given a 16-month suspended sentence for administering performance-enhancing “drugs” to a minor. Little did Springstein know that he’d unwittingly opened the Pandora’s box of what sports journalists around the world have dubbed “the era of gene doping“.

Humanity is inching ever closer to obtaining a complete working knowledge of the human genome

In the case of Springstein, he’d attempted to obtain an experimental gene therapy treatment which inserts an oxygen sensitive EPO gene – which codes for the hormone erythropoietin – into the genome of any tissue it’s injected into. The treatment, named Repoxygen, is intended for use with sufferers of anemia to perpetually boost the the production of erythropoietin and the red blood cell proliferation it’s responsible for. Athletes administering themselves with illicit erythropoietin is nothing new, but the permanent and self-regulating effects of Repoxygen make detection extremely difficult – though the World Anti-Doping Agency hopes to have a reliable test ready for the Rio 2016 Olympic Games.

Repoxygen is comprised of modified viruses stripped of their virulent genes, “repackaged” with EPO and “reprogrammed” to splice the gene directly into a host genome at a predetermined location. But researchers use the same method with human, non-human and synthetic genes in the pursuit of effective treatments for cystic fibrosis, Huntington’s, Alzheimer’s, HIV and many other prevalent genetic diseases. This being said, gene therapy could, in theory, be performed on healthy individuals to boost athletic performance, alter mental states or increase longevity using variants of MSTN, IGF, GHR, MAOA-L, or any other gene.

Humanity is inching ever closer to obtaining a complete working knowledge of the human genome, and although the accompanying medical advances will be immense, so too will be the ethical, legal and social implications of non-medicinal applications of genetic technologies. In a way, the investigators of Agents of S.H.I.E.L.D are lucky – they only deal with isolated incidents of superhuman activity. In the not too distant future, our mastery of nature’s most cryptic of codes may lead to a world where we can all be heroes – or villains – or something in between.

Michael Westgarth is a freelance writer and geneticist for hire. Discover more of his work on his blog MegaWestgarth and pick his brains through Twitter @MegaWestgarth.