Searching for genetic superheroes

Image Credit: Smoking Airbag by monkeybusiness via Envato

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Searching for genetic superheroes

Like all juicy scientific projects, the search for genetic superheroes started with a simple question with a complicated answer: not why do we get sick, but why do we stay well?

Rather than the conventional approach to understanding how genetic variations influence the risk of disease - which is to take lots and lots of people with a particular condition, then compare their genes to those of people without the condition - Stephen Friend and Eric Schadt at the Icahn School of Medicine at Mount Sinai in New York turned this idea on its head. 

Instead of starting with people who already had a health condition then sifting through their genes, they went the other way: starting with DNA sequences from thousands of people that had been deposited in genetic databases, looking for alterations known to be linked to serious diseases, then finding out whether any of the people with these harmful variations were actually ill. 

They called this idea The Resilience Project, and set out to search for people who were resilient to the impacts of their underlying DNA.

Although it sounds more than a little crazy - and like a lot of hard work - Friend and his colleagues had an inkling that their search might turn out to be fruitful thanks to two patients who had already come to their attention through Mount Sinai hospital. 

One was a woman in her mid-50’s with a change in both copies of a gene called CFTR, which should have caused her to have the serious lung condition cystic fibrosis since childhood. Yet she had never had more than mild breathing issues. There was a 45-year-old man with a genetic variant that meant he should have had Louis–Bar syndrome, a rare and usually fatal neurological disorder, yet he never showed any symptoms. 

And then there’s a man called Doug Whitney, whose family was plagued by early-onset Alzheimer’s disease, which is linked to specific genetic variations. Whitney had watched as his mother, older brother and more than a dozen of his blood relatives succumbed to dementia in their forties or fifties, all of them with the same faulty gene. 

Fortunately, Doug has made it well into his 60s, with no signs of any memory loss or other symptoms of dementia, and thought that he had dodged his family’s deadly genetic legacy. But in 2011 he received some shocking news: after joining a research study, a genetic test revealed that Doug did indeed carry the gene variant that had affected so many of his family.

As Jason Bobe, current principle investigator of the Resilience Project, told me when I interviewed him for a feature about genetic superheroes I wrote for BBC Science Focus Magazine:

“It’s what I like to call a smoking airbag – the opposite of the smoking gun. This guy has had an airbag in his biology that has gone off and we need to find it, but it’s looking for the needle in the haystack. What other genetic or environmental factors in this guy's life has enabled him to escape this disease, where in every other case that we've seen it's been fatal?” 

How many genetic superheroes are there?

Doug and the others aren’t the only superheroes out there. In fact, Friend suspects that around one in 25,000 people has a genetic alteration that puts them at high risk of developing a disease, yet somehow don’t.

So what is it that’s keeping these people well? Is it other variations in their genes? Maybe something in the environment or in their lifestyle? Or is it something else? The only way to know is to find more of these unusually resilient people like Doug -  ‘unexpected genetic heroes’ as Friend originally referred to them, before landing on the catchier ‘genetic superheroes’.

In search of superheroes, the Icahn team trawled databases from previous studies containing information from nearly 600,000 people about their DNA and health. To keep things simple to start with, the team focused on around 850 genes underlying what are known as highly penetrant Mendelian disorders: severe childhood diseases caused by carrying two copies or even just one version of a faulty gene.

To start with, they spotted around 16,000 individuals who looked like they could be heroes, with ‘bad’ alterations in nearly 200 genes linked to more than 160 severe conditions. Narrowing down the search further yielded just 300 potential superheroes. Reviewing each one of these and applying the strictest criteria for their selection left just thirteen people who were resilient to a selection of eight genetic conditions. 

Of this baker’s dozen of superheroes, three were resistant to cystic fibrosis - one of the best-known examples of a highly penetrant Mendelian disease. Another three had gene faults that should have caused major bone abnormalities, known as atelosteogenesis, yet their skeletons were just fine. Two had alterations in a gene called DHCR7, usually responsible for a severe developmental disorder known as Smith-Lemli-Opitz syndrome, but didn’t have the condition.

Another five had their own unique genetic superpowers, and were immune to the impacts of genetic variants known to cause a selection of brain, bone, skin and auto-immune diseases. Yet, as far as the researchers could tell, all of them were well. 

So who were these masked men and women? Frustratingly, we will never know. Due to anonymisation and lack of the right consent to re-contact people in the databases, the researchers weren’t able to track any of them down for further investigation to see if any of them had mild or more serious health impacts as a result of their DNA. There is also still a chance that there could have been some identity mix-ups in the databases, which wouldn’t be unheard of for projects of this scale. 

So are there really any genetic superheroes out there? Excitingly, the answer is yes. While the Icahn team’s paper gathered excitable superhero headlines around the world, another research study definitively confirming the existence of individuals with superhero status had quietly been published two years earlier - proving the power of PR, if nothing else.

Search for the hero inside yourself

Cisca Wijmenga and her team at the University of Groningen in the Netherlands never expected to find superheroes, but they did. They were running a project to sequence the DNA of 250 Dutch families as a baseline for the genetic makeup of the Dutch population, meaning that if any interesting gene variations and faults linked to disease turned up in future studies, they would be able to tell if they were genuinely linked to disease or were just the underlying DNA of Dutchness. 

Two people in the study, both in their sixties, carried two faulty copies of a gene called SERPIN A1, which normally makes a protein that helps to protect the lungs. Without it, the delicate tubes and air sacs start to break down, causing serious breathing problems by the age of 30 to 40. Yet these people appeared to have no serious lung problems. Importantly, unlike the Icahn team’s database trawl, all these people were known and contactable by Wijmenga and her colleagues so they could confirm the finding.

According to their genetics, a number of other people in the study should have had a condition called pseudoachondroplasia, leading to unusually short stature and joint pains. Other conditions on the list include people with genetic variants linked to Wolfram syndrome, which causes high blood sugar, sight and hearing loss; Wilson disease, which comes with liver problems and psychiatric issues; and Niemann-Pick disease, characterised by nerve problems and failure to grow properly in childhood. But most of them were just fine. 

Some populations are likely to be rich hunting grounds for superheroes. A 2015 study showed that nearly one in twelve Icelanders carry two faulty copies of one of more than a thousand genes. Researchers sometimes refer to this as being a ‘human knockout’, similar to so-called  knockout mice that have been genetically engineered to lack specific genes.

Geneticists working with British Pakistani communities in Bradford and East London where marriage between people who are related tends to be more common have discovered a relatively high proportion of people with double faults in hundreds of genes. They’ve also unearthed several superheroes, including a woman with two faulty copies of the PRDM9 gene, which should have made her infertile according to other studies, yet she was healthy and had a child. 

In fact, a study back in 2012 from geneticist Daniel Macarthur and his colleagues showed that typically any one of us has around 100 so-called loss of function variants - genetic changes that seriously affect the function of a gene - with around 20 completely inactivated genes lurking within our genomes. 

So - could we all have a hero inside our cells? Well, maybe. 

Now that we have cheap, large-scale DNA sequencing programmes, the biggest problem is not just identifying healthy people whose genes say they should be sick, but figuring out why they stay well. Just what is it that gives genetic superheroes their health powers? 

The first explanation isn’t exactly glamorous, but it’s important to note. There are plenty of inaccuracies in genetic databases, and associations between genetic variations and diseases found in previous studies can sometimes turn out not to be true, particularly when studied in more genetically diverse populations. 

It’s also important to highlight that the discovery of the existence of genetic superheroes raises questions about what the results of genetic tests for health conditions really mean. 

As Cisca Wijmenga and her colleagues note in their paper about the Dutch superheroes, “Our results highlight the potential pitfalls of interpreting personal genomes.” 

Increasingly, decisions are being made about health based on genetic information, including prenatal genetic testing for conditions like cystic fibrosis. The discovery that it’s possible to apparently carry two faulty versions of the ‘cystic fibrosis gene’ yet be healthy tells us that we still need to know more about how supposedly harmful genetic variants are actually going to manifest in each individual, as well as how their effects might be mitigated. 

Cisca Wijmenga told me, “We’re dealing on a daily basis with patients. “We sequence their genome and find a mutation, and we have to predict what we think that means. It's really important that we have a much better understanding of our genome and when does a mutation matter and when it doesn't. I think in the past we had this kind of black-and-white idea but now there's all the shades of grey.”

One angle for understanding what might be going on is something known as redundancy. We have around twenty thousand genes in the genome, and many of them do similar jobs. So if one of them is faulty or non-functional, another related gene might be able to step in and get the job done. 

For example, the blood condition sickle cell disease is caused by a fault in the gene that makes haemoglobin, the main oxygen-carrying molecule in the blood. But some people with sickle cell disease can naturally reactivate a different gene that makes a type of haemoglobin that’s usually only produced as a fetus grows in the womb, helping to mitigate the impact of the disease. 

As might be expected, there’s now a lot of interest in developing treatments based on gene editing that can help to switch this fetal haemoglobin back on in people who are affected.

Then there’s the related idea of compensation: finding other genetic variations or even things in the environment or lifestyle that might be able to compensate for the effects of faulty genes. Then after that, the challenge is working out how to use this information to improve human health. However, as we’ll see, some of the superheroes who are helping researchers unravel this complex problem aren’t even human in the first place.