ALS Ice Bucket Challenge Donations Lead to Significant Gene Discovery

You might be interested in this http://www.sandiegouniontribune.com/news/2016/jul/06/NIH-scr...

The military has databases like this that could lead to a lot of interesting research, in theory. They do DNA testing for body identification purposes as well as tracking long term health through the VA.

How is that different than sequencing genes from individuals and correlating that to their (fairly detailed) recorded medical history? If I'm not mistaken, that's what's currently being done.

I feel like problem intractability would be a hol' up.. on the other hand I just remembered that 23andMe is sort of attempting this

Kaiser Permanente has just such a project: http://digitalrepository.aurorahealthcare.org/jpcrr/vol2/iss...

yeah, you just invented GWAS (genome wide association studies), something done on huge scale but obviously you always need more data and better features.

It' so wide spread to be considered a belief on its own: http://www.theallium.com/biology/us-government-to-officially... ;)

I think the fundamental thing you're missing is that a gene's behavior throughout your life depends on more than just its sequence. Everything else that goes on in your body, and in particular everything that goes in and comes out of your body, can impact when genes are triggered to form proteins, how those proteins fold, and what effect the proteins have.

At best, gene sequence data like you describe could provide rough probabilities for some health conditions. That's as likely to lead to over-treatment for a non-problem as catching a real problem early.

Sure, there would be some cases where everyone who has a certain sequence winds up with the same disease, and it'd be good to discover those early in life. (Ex: my wife was born with Wilson's Disease, which causes liver failure by early adulthood 100% of the time without treatment.) But those cases would probably be very few compared to the number of people who get freaked out by things that might become an issue, but probably won't, and the cases where the correlation is too weak to provide a warning, but a health problem occurs.

Besides the actual sequencing this is what LifeGene http://lifegene.ki.se/ does. I.e. long study with check ups every 10 years, lots of tests and lots of data about person's environment, living conditions, etc.

this is happening: http://www.personalgenomes.org/

> With a large enough sample pool, we'd be able to correlate features with obscure genes, wouldn't we? Am I missing something fundamental?

Nature vs Nurture.

You'd find a huge sampling error because of epigenetics. The same genes in different people don't always kick in and do something.

However, finding out which gene + which life-style == bad stuff might still work out as a possibility.

Even those might not be repeatable in the future - I grew up running around in leaded gasoline land and the same genes will probably never have to deal with so much lead in the air in my kids. Does it matter that I might have special tolerance genes which protect my brain lead fumes?

The study would throw up interesting results, but not "feature -> genes", but maybe "genes -?-> features" (necessary but not sufficient).

Various national level projects have begun. The Scandinavian countries have begun taking biological samples for later sequencing, which can then be cross-referenced with their fantastic population-level databases. The UK Biobank has been doing that for hundreds of thousands of UK people, and has been responsible for many important recent genetics papers. The Obama administration has been funding a similar project which is planning to collect 1 million genomes and has gotten press recently.

Such a program is a major part of President Obama's Precision Medicine Initiative. The NIH is funding 5 research pipelines throughout the country (4 at universities, 1 at the NIH) with the intent of collecting the full genomes and accurate phenotypes of one million individuals, with ability to recontact for further information if needed. The NIH just announced the grant winners two weeks ago so the grant recipients are just starting to work on the full protocols/pipelines now.

As someone who works in the field, the lack of phenotypic data available accompanying genome sequences is currently one of two major roadblocks in advancing genomic science (money is the other problem, of course).

Yes and no.

What you describe would be useful, but the scope of its usefulness is likely far less than you might think. Basically, you'd only be capturing some long term effects that have very high effect sizes / strong correlations. The sheer complexity, variability, and size of the dataset means that you won't be able to pull out subtle interactions, even with a large number of individuals. Barring fundamental advances in GWAS methods, you're looking at huge expense for very little benefit.

Now, collecting and organizing disparate datasets that are already being generated is worthwhile. Comparison is difficult due to the different methods used, but a good investigator will be able to do a lot of in silico work to, at least, do some preliminary work on hypotheses. On a personal note, this is actually a lot of fun because you can often come across from very exciting hints to follow up on, all with a quick feedback cycle conducive to 'flow'.

Ultimately, and this gets back to science fundamentals, this would amount to a big fishing expedition. Good science will always be strongly hypothesis driven. Good bioinformatics is built upon good datasets, and that only comes from very careful hypothesis consideration, solid methods, and a good understanding of the biology involved.

The US military is doing this with its personnel.

The US military got stung very badly in Desert Storm I with people coming home sick with no way to see what went wrong. They decided not to repeat that mistake.

There are many rare variants in each individual. Establishing the significance of these variants in a particular environmental context, and dealing with the myriad of potential interactions with other variants is probably not tractable with the experimental design you describe.

High throughput phenotypic screens which test the cellular affects of inserting particular variants could help, as they would prune the number of potential variants, but the false negative rate is high.

Genomic determinism may not exist in a useful sense in the current era.

Well there is the Dunedin Study [0], which is similar to what you're talking about.

https://en.wikipedia.org/wiki/Dunedin_Multidisciplinary_Heal...

While it may seem esoteric to some, I believe significant effort should be put into the sequencing and analysis of dogs genetics. Their selective breeding is truly the greatest genetic experiment ever performed: from to Chihuahuas and Great Danes to Scent Hounds to Sight hounds to retrievers to herding dogs. We have crazy-detailed knowledge we have of them including their behavior, differences in morphology (e.g.,size), diseases (cancers, neurological disorders, musclo-skeletal disorders, metabolic diversity). Genetically, an amazing range of diversity exists, with subsets in a spectrum from extremely inbred breeds to totally outbred mutts scatter throughout the world. This diversity dwarfs that of humans, with nearly none of the informed consent and data privacy challenges that will-and should--go with a human study. There are legions of fanatical dog owners that are easy to find that would likely be enthusiastic in having their pup participate. While I sit here with mutt at my feet, my primary motivation is the correlation of genetic variations with diversity in behavior, stature, health, and disease. I know good work is already being done in this area, but a lot more can be done with relatively modest resources compared to what is required for human studies, and the results would provide an amazing benchmark by which to help interpret the human data as we collect it.

Associations between genetics and traits (such as diseases, height, etc) are already very common in science. One of the main problems is that you need extremely large sample sizes to see any effect. These kind of studies are called genome-wide association studies. Many common traits need hundreds of thousands of individuals if the genetic link is suspected to be weak (which is the case for most common diseases), making such studies extremely expensive, not to mention time-consuming.

I guess you could count self-help groups as a huge benefit. Or information distribution within towns/cities.

they have merely established a correlation. I wouldn't pin my hopes on it.

Crowdfunding and crowdsourcing are often social network based, are they not?

Twitter has rather famously been a means of real time communication during times of political turmoil/important current events. See The Arab Spring or the Ferguson, MO protests.

There's nothing wrong on making money even in this space: http://www.ted.com/talks/dan_pallotta_the_way_we_think_about...

My brother was recently diagnosed with ALS. Is there anyway I can get in touch with you to have a chat about that video?

Yep, that's what pretty much all genomic discoveries are these days. Since the Human Genome Project [1], which set out to map all genes in the human genome, was considered complete in 2003, most studies these days seek to find the correlations between genetic mutations and diseases.

[1] https://en.m.wikipedia.org/wiki/Human_Genome_Project

And to add to this, we cannot know, if the funding wouldn't have happened non the less if IBC didn't happen.

And also to quote from the article: "NEK1 was discovered through a genome-wide search for ALS risk genes in over 1,000 ALS families, and was independently found through different means in an isolated population in The Netherlands. "

So they already knew about the gene and in time would have found out more on it non the less. So the influence of the IBC seems less and less important, while reading the piece.

Sad isn't it?

The end result is what matters for most people, not the politics. Discovering a cure for ALS would be an amazing medical feat.

To answer your question, the ALS association raises public awareness about ALS, provides care services to ALS patients and distributes funding to research projects on ALS. The politics to when one of these research facilities discover a cure for ALS is up to them. They are just receiving grants from the ALS Association.

There is a long distance between the research ALS foundations pay for and a drug.

Obviously yes, if the alternative is no campaign and no funding at all.

A chance reasonably larger than zero is better than a chance very close to zero.

I think it's more about being critical of people who were critical for no reason.

That's a... very upside-down way of looking at it. The alternative is that those funds would not have been received at all.

Normally, large amounts of people donating to a good cause is seen as a universal positive...

"May or may not succeed" applies to the research itself, regardless of how it is funded. I imagine the subtext of your comment is that ALS (or gene sequencing?) should receive more public funding, but they both already receive a lot of public funding. It's the overall sustained effort in medical research that leads to results, for ALS this time and maybe for something else next time.

Funding should be left to wherever it can come from. If you try to get a single X to fund everything, X will quickly become bankrupt.

If that's not your point, that funding should only come from a certain X, then is your point the even more absurd remark analogous to saying after the discovery of Penicillin by Fleming "should such critical advances be left to serendipity and solo poor communicators who may never discover anything"?

This is the announcement of a correlation. The question would be whether knowledge of the gene is useful in dealing with the disease.

The difference is probably that they sequenced full genomes, whereas 23andme (mostly?) looks at known genes.

A slightly different perspective from the other comments: as far as I know, 23andMe only works with single-nucleotide polymorphisms (SNPs). While far better than nothing, this covers a combinatorially small subset of genetic variation, and, as such, is unable to detect the majority of genetic phenomena (although an approach that synthesizes data from multiple SNPs may expand its scope).

I can't read the full text of the research in question (http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.3626....), but I suspect that they have done a much more expansive analysis than 23andMe's SNP-only approach permits.