Sunday, July 20, 2014

One is a lonely number

I recently came across a very interesting feature article in the New Yorker, "One of a Kind", which describes the dizzying journey parents undertake when their child is identified as the only person known to be affected by a particular genetic condition. The article focuses on one family, the Mights, whose son Bertrand was born with a previously unknown double mutation in one gene, NGLY1, involved in the deglycosylation of proteins - the product of the gene is an enzyme that helps in protein recycling by removing sugar molecules linked to these proteins. It took the Mights several years to learn what exactly was wrong with their son, during which they shuttled from one specialist to the next, trying desperately to map their son's illness while worrying about the damage all the poking and prodding was doing to him.

The conclusion from all these tests was that Bertrand was a complete medical novelty - whatever he suffered from was a disease unknown to medical science at the time. Rather than giving up the battle, the Mights chose to enroll Bertrand in a study designed to test whether genetic sequencing could be used to identify unknown conditions. Genetic sequencing, as most of us are familiar with, is usually designed to test a specific gene for mutations that would explain a medical condition. This only works if you already know that a mutation in gene X causes disease Y. What do you do in a case like Bertrand's, where you have absolutely no idea where in the genome you should be looking?

In this case, the geneticists running the study (at Duke University) used a technique called whole-exome sequencing, which examines only that part of the human genome that actually codes for a protein product - around 2% of the total genetic material. One reason to use this method is that a vast majority of the genetic disorders identified so far can be linked to a mutant protein; the chances of the disease-causing mutation lurking in a non-coding region of the genome are much smaller. Another reason is cost; in 2010, when the study was carried out, whole-exome sequencing had a pricetag of around $7000, while sequencing an entire genome was an order of magnitude more expensive. (Although that might change, with Illumina claiming to crack the $1000 genome). Whole-exome sequencing is now gaining increasing clinical traction as a method of pinning down the genetic causes of previously unknown diseases.

Nearly two years later, the Duke team sat down with the Mights and told them that the likely culprit in Bernard's case was the NLGY1 gene, but without additional patients, they could not pin it down with complete certainty. And here was where they ran smack into the realities of academic research and publishing. In today's "publish or perish" environment, researchers have little incentive to share genetic data from studies unless they are assured of some reward, usually in the form of authorship on a paper in a leading journal. One geneticist is quoted as saying, "The current academic publication system does patients an enormous disservice."

With various research groups and institutions exerting tight control over any genetic data they may own, families like the Mights are often left in the cold. However, in this particular case, Bertrand's father Matt decided to leverage the power of social media to help his son. He posted an essay describing Bertrand's clinical history; since he already had a high social media profile, the essay went viral. Parents and doctors alike began to realize that the constellation of symptoms listed in the essay tallied with their child, or their patient. As a result, the Mights managed to find nine more patients with NGLY1 mutations in just over a year. A huge collaborative paper on the disease was eventually written, and even here the turf wars continued, with some teams dropping out in favour of publishing their own independent papers.

This article held my interest for several reasons. Of course, everyone loves a good detective story, especially one where the culprit (or gene!) is clearly identified at the end. But that was made possible because the Mights had money, and Matt Might had the ability to make sure his message was picked up by social media networks across the world. I can easily imagine his essay being lost somewhere in the vast wastelands of the internet, as it would have been if he hadn't already acquired a fairly high profile online. And $7000 is still a lot of money, enough that whole-exome sequencing isn't going to become routine any time soon. Finally, the story also illustrates the need for more data sharing, which also happens to run entirely counter to the prevailing academic ethos. Having seen many professors fighting hard for tenure and grant funding, I can understand the drive to do whatever it takes to get ahead, including protecting your data fiercely from all competition. While the article describes an NIH-funded initiative to set up a network of centres to handle rare diseases, I think balancing the needs of patients versus researchers is always going to be tricky.

But what fascinated me the most is that once NGLY1 was identified as causing Bernard's disorder, this knowledge gave a huge amount of power not just to the doctors driving his medical care, but his parents as well. Matt Might attributes improvements in Bernard's condition, among other things, to two over-the-counter supplements, cocoa extract and N-acetylcysteine (NAC). NAC, in particular, has been around for years. It's been used extensively in cellular oxidation research (I've used it myself), it's cheap, and it's easily available. It's a tantalizing prospect to think that perhaps patients suffering from other genetic conditions could also benefit from similarly cheap and ubiquitous drugs or chemicals. What could really help is if researchers were able to build an easily accessible database of mutations, and academic and industry groups alike could try and figure out which existing drugs could be useful for a particular case.

All in all, an excellent read, with a lot of food for thought.

1 comment:

  1. Good article Nikki, and a for a change, an article which I could understand fairly well. :p :D