The Ice Bucket Challenge and an Easy Way to Understand Complex Genetics

"Everybody watch me care - I am socially conscientious and a damn good person!"

Remember the Ice Bucket Challenge? The one where attention whores made videos of themselves inexplicably dumping cold water on themselves for ALS? These efforts raised about 100 million dollars. I was meh on the whole thing. It was sweet that people wanted to cure a disease, but the effort was far too small to be effective (the amount of money raised was really not very much in the research world). In the end, I predicted nothing would come of it and moved on. 

 As I predicted, nothing happened... until a week or so ago, when there was an article on ESPN about some breakthrough research that supposedly stemmed from the Ice Bucket Challenge (the thing where you dump cold water over your head and - maybe - donate a few bucks to ALS research). 

Could Noah have been wrong? Short answer: No way. The report was quickly contradicted by people who know what they're fucking talking about. It won't ruin the feel-good message for most people, who viewed the report as a happy addendum to a wonderful, heartwarming story. 

If you're at all interested in understanding how shitty, superficial reporting has mucked up the story, take a look at the original ESPN article, which reports the identification of a "new gene" linked to ALS. 

Sigh. 

First of all, we've mapped every conventional gene in the human genome. There aren't any "new" genes out there, at least not in the sense that the average person on the street would understand. This includes NEK1, the gene purportedly identified in the ESPN article. In fact, it was discovered (and published) in 1992 by these guys: 

Discovered back in the days of MC Hammer...

Interestingly, NEK1 was linked to ALS earlier this year, in May. So the newest "ice bucket" report isn't even the first one to reach that conclusion. Ignoring that, there's a bigger issue here: the findings in the new paper don't even remotely put us onto a cure for ALS, as the ESPN article suggests. Why? Because the authors conducted a genetic linkage study and found that alterations in NEK1 occur in only 3% of ALS cases. In other words, any failure in the NEK1 gene product probably doesn't cause ALS alone. 

So what's with this "new gene discovered" reporting approach? Honestly, I think that reporters are reluctant to believe that the average man on the street can understand potential genetic contributions to complex diseases of unknown etiology with a heritable component. 

That's bullshit though, and I'm going to prove it by explaining complex genetic contribution to diseases in a couple of paragraphs using an easy metaphor I made up less than a minute ago.

Step One: Forget the peas

When we learn about genetics in school, we're given the old story of Mendel and his pea plants, where he figures out dominant and recessive. Punnett squares and all that. 

Remember the punnett square? Big R beats little R, amirite?

The problem is, this has virtually no applicability in the real world. For one thing, there are tens of thousands of genes, which work together in dizzyingly complex ways. For another, big 'R' and little 'r' don't really exist; they represent transcript variants of a gene. Think of them more like flavors than simply dominant and recessive.

In many diseases (often the tough diseases that remain largely untreatable), there seems to be a genetic component. For example, a father with the disease is more likely to pass it on. But it's not 100%, and people who don't have the disease (or even a family history of the disease) can have offspring who are affected. Clearly, there's some genetic component, but it's not remotely clear what it is or where it comes from. 

Step Two: Start Thinking About Planes. 

Here's where a metaphor might be useful. I was at an airshow last weekend. On the drive home, I was pondering how marvelously complex planes can be, and also how incredibly safe they are - the odds of a mechanical failure causing commercial airliner to crash are astronomically small (most crashes are caused by human error). 

In the story, I saw strong parallels to genetics and disease. Planes, like people, are marvelously redundant (by design or evolution, depending on how much magic you believe in). Think of your mother and father as two commercial airliners. Each plane is made up of millions of individual parts. Naturally, most of the parts work but, as I've said, airplanes are complex and there's always something broken. Most of the time, this matters not a whit, because there's a backup system (and occasionally a backup to the backup). So even though bits and pieces don't work, mommy and daddy planes have flown safely (i.e., healthily) their whole lives. 

Now, to make a baby plane, pieces from the mother plane and father plane are copied and reassembled to form a new aircraft. This new plane will, naturally, look like its parents, but will be slightly different, as its components are a mixture of its predecessors. However, new planes are occasionally created who possess a flaw in both the primary and backup system. This occurs when (for example) plane one has a faulty first-line system and a functioning backup, while plane two has a properly functioning main system but a malfunctioning backup. In this cruel twist of fate, the new plane receives one faulty system from each parent plane.

Applying this to biology, it is now possible to see how two fully functioning individuals can be combined to create a person that is functionally screwed. Now replace 'airplane component' with 'gene' and you now have an understanding of biology that surpasses that of most reporters.

Apply this to the current study and the relevance becomes clear. Whatever function NEK1 participates in is, in some way, related to changes in the body that frequently contribute to the development of ALS pathology. IIn the majority of people, the backup system kicks in and we see no disease phenotype (i.e., healthy patient). However, in a small (3%) fraction of people with the NEK1 mutation, the systems that would ordinarily compensate for are broken, resulting in the emergence of ALS. Thus, this finding is important for a number of reasons. For example, determining what NEK1 does (and how it relates to ALS) is tremendously helpful in determining what biological changes trigger the disease. This can get nuanced (and boring) very quickly (ex: there can be 10+ 'backup systems' for some things), but the important takeaways are these: New genes are rarely discovered and people are even more complex than planes.