I've been wondering for some time what the next step is for gene sequencing. Shouldn't someone be working on a 50 year long study where people are brought in at age 20, genes sequenced and dna stored, and an extremely thorough battery of parameters (height, length of each long bone, eye color, etc.) is measured. Tie everything in with medical history. Do the same thing every 10 years for each subject until death.
With a large enough sample pool, we'd be able to correlate features with obscure genes, wouldn't we? Am I missing something fundamental?
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).
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.
I think a great example of gene expression based on environment is that of the himalayan rabbit. Cold temperatures trigger black fur growth whereas warm temperatures allow the fur to be white.
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.
Dogs look different, but in terms of DNA they are very similar. Skin / fir color and size are things DNA optimized to change as quickly as possible which is why Chihuahuas and Great Danes can still interbreed.
The more similar they are genetically, the easier it should be to define and characterize the differences that are responsible for morphology, behavior, and diseases that run among breeds, no?
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.
There's a lot of value on doing this, but GP idea has its value. For starters, there's some survivorship bias, as you cannot map people who have already died.
You may also want to gather more detailed data that the medical history usually conveys, such as sub-clinical conditions and other non-pathological differences.
> 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).
>You'd find a huge sampling error because of epigenetics.
I'm skeptical that, just now that we know of epigenetic effects, they will invalidate all previously existing roughly-Mendelian genetics. It's not like people's eyes change from brown to blue if they're stressed in childhood.
So, you wouldn't necessarily find huge sampling error, you'd find sampling error proportionate to the epigenetic effect on that particular gene. Is that large? I suspect not for many genes we'd be interested in.
>Does it matter that I might have special tolerance genes which protect my brain lead fumes?
I don't think this is how epigenetic effects work.
yeah, you just invented GWAS (genome wide association studies), something done on huge scale but obviously you always need more data and better features.
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.
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.
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.
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.
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.
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.
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.
I know we love to rain on social networks as lacking for one reason or another. But taken together I think they're a large part of the success of the fundraising here. Have we seen other global social benefits from social networks?
Another example of technology's double-edged nature. I'd add the Internet's burgeoning conspiracy theory community to the list of unhealthy outcomes from social networks.
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.
Being able to get a follow up on those donations will help a lot driving donations in the future.
Being able to get a followup and really know what your money is used for, and get confirmed that your money has actually contributed to something significant is incredibly valuable and not enough organizations do it.
That's what helped a lot charity:water, which not only promised to use 100% of the fund to build actual wells in africa, it would tell you exactly which well would get built with your money, where, and then send you a picture of the well.
That's great to see that the whole ice bucket challenge actually helped the cause.
Constructing a narrative around the usage of donations has been something scientific/medical charities have struggled with in comparison with foreign aid charities like World Vision. This article is a smart move for them.
I remain skeptical. Tax records show the Ice Bucket Challenge was extremely profitable to organizers of the non-profit, so there is significant incentive to keep the PR machine going.
Interesting that the gene "discovery" is really just making an association. The gene itself was discovered a long time ago (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC556810/), and associated with other negative outcomes.
Like many that are involved in diseases, the gene appears to be activated in response to DNA damage.
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.
it's kind of amazing that woese managed to discover a whole kingdom of life with just a few RNAs and the best we can do with thousands of genomes is make weak associations.
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.
Medical research has been taken over by this type of hype. It infests the journal articles as well (although the hype there is usually more sophisticated). The signal to noise ratio is very low right now.
Let's say this discovery leads to a drug/treatment for the disease. What happens to it? Does a company get to patent it and then sell it back to the people who paid for the research (with donations)? Does it become public domain? This ambiguity has prevented me from donating to similar causes in the past.
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 are many ALS organizations, some larger than others. They all typically split their money between support and research, but a local ALS chapter will have a larger focus on providing support and equipment for people with the disease in the area.
ALSA got most of the support from the ice bucket challenge, and their focus will be more on research as a national charity, but local ALS chapters do a ton for a rapidly changing and expensive disease.
So it's less about a cure and more about patient services? If it was more advertised that way I'd chip in. I find some "charities" suspect for medical bills. I do some work for an oncology practice and heard a few of the doctors talking about the "charity" they set up. Basicly they find a patient that would never be able to pay the bills that are owed (IE. Patient has no assets, is 90 years old, and owes 200k on a fixed income) and forgives that debt via charitable donations. "It's a way to get paid for things you would not be otherwise" were the exact words I believe.
They have nice little pamphlets that talk about "Give the gift of honor". I find it rather despicable how they use the emotions of relatives of those who have passed on to pad their bottom line.
I can't speak for all the different ALS charities, since they are independent, but as a charity their financial statements will be available. For example, my province's ALS charity spent about $500k last year on equipment loans, while research was only about $20k through donations to ALS Canada. The ice bucket challenge donations were mostly donated for research, as that is what people were expecting to be donating for, and they only have so much patient support they need to give in any year.
I have a family member with ALS and can confirm that they have done a ton to support with various equipment needs and finding the right equipment for them. Support caregivers are only partially paid for (though I can't remember whether that is through the charity or the province).
Why can't the people who develop it reimburse those who donated(with interest) at very least? This is a sector that has rather loud comments regarding it's intellectual property and make no mistake, human beings have died due it's monopoly. Is it not fair to ask for a piece of the action? Wouldn't they?
Understanding NEK1’s role in disease will provide an important new target for therapy development.
I hope that means they will use it to try to map the pathology of the condition and not just develop gene specific drugs.
I do not know why this is being downvoted, but developing expensive drugs without really making progress on understanding the pathology is something they have done with other disorders. Money before patient care. And it is a sucky practice.
Yes, I'm happy that there has been an advance for ALS, but if you take a step back, it does appear that there may be a misattribution of limited research dollars.
Except that the Ice Bucket Challenge did not misappropriate research dollars. They created new research dollars out of thin air. There is not much reason to believe that the people who donated in response to the Ice Bucket Challenge would have otherwise donated those same dollars to some other, more common disease.
The money could have been donated to more common diseases, but probably wouldn't have. Humans are mostly motivated by emotion. The Ice Bucket Challenge captured the imagination of a ton of people and got them motivated to donate. If other common diseases need more money, they should find similar ways to pull at human's heartstrings (obviously they do as well, just not with such a public feelgood novel viral stunt like this).
The question was should we leave funding to internet campaigns, not will we. I can't imagine the OP is arguing that the ALS association shouldn't take the money or that people shouldn't donate. The OP is arguing that they shouldn't have to rely on these kinds of campaigns to solve large problems like this because we should increase public research funding.
No, the upside down part of it is that our systemic mechanisms for research funding are so limited compared to the scale of the problems we face as a species that we need to fall back on silly internet campaigns to fund this work.
Yes, of course it's silly as a funding mechanism. What happens with the money downstream is independent of how it was obtained. The point is that science should not have to resort to this kind of thing in a society that appropriately places knowledge as a coordinated priority.
Your definition of "it works" seems to be circular, based on "what we've got works - otherwise we would not be here". IT doesn't look like you thought about alternatives. "It did something positive (at all, this time)" (and let's ignore the bigger picture altogether) = "it works"?
On the contrary, the raised awareness seems to have increased the public funding. Both houses of Congress passed extra millions of funding just this month.
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"?
"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.
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).
23andMe has contributed to the science described in several dozen articles published in the top journals: https://www.23andme.com/for/scientists/. Is all of that useless garbage?
They have plenty of publications, most of which are "we found genes assoicated with <X>".
Unfortunately, association studies don't tell you much beyond "there is a correlation between X and Y" which typically needs to be followed up with a lot more research. It's not even clear that association studies really pay their way- they cost a lot and produce associations, but the link to disease treatment is often very poor.
it's really a shame nobody has truly shown a very convincing way to convert genotyping/genomics and medical records into better treatment.
>it's really a shame nobody has truly shown a very convincing way to convert genotyping/genomics and medical records into better treatment.
ugh..I am being downvoted for asking what makes this particular discovery significant . I am really curious, what are some of your thoughts on what makes this particular correlation different.
Basically, the reason this is not significant is that there is no way to turn gene-disease associations into treatments. At best, it helps you focus on a gene target, but as you can see, this gene's protein product is an important player that has a role far beyond preventing/causing (or affecting the severity of) disease.
What's different (and it's not particularly different) is that this PR is in response to a social media challenge, the research was partly funded by it. Whether that means anything is hard to say- I don't really see ice bucket challenges scaling up to many diseases.
It's a demonstration that even in a niche most people wouldn't think of, drug administration, there's already dozens of cost-effective medical uses, and the number is going up as more research is done and sequencing goes down.
I am no way qualified to interpret or make any sense those. 23andme has been in existence for over a decade, sure these papers might be great but have they led to anything tangible that a ordinary person like me can benefit from ? I am genuinely curious, i really want to know.
I've been a subscriber for over 7 yrs and have gotten all the upgrades they offered over the years. I am yet to get a single useful peice of data out of it. All my extended family has it too and none of them have gotten anything out of it other than of entertainment value. If they have made significant breakthroughs why I am as a consumer not seeing any benefits in over a decade.
I (correctly) self diagnosed (later confirmed by gastroenterologist) my Celiac disease through 23andme. But that is the easiest 1:1 gene correlation out there. My friend found out he had the same Parkinsons gene as Sergey Brin, and there are potentially things you can do to prepare. Exome testing may or may not be useful, depending on how much you invest in analyzing the results. I think it was of limited value until I ran it through Promethease.
I don't know anybody in the field who thinks that 23andme, on its own or in collaborations, has made any truly signficant scientific contributions. I haven't read all their papers, but I've read some, and have talked to their scientists extensively, and I really haven't heard of anything that is strikingly important that could be solely attributed to 23andme.
Their relative finder feature seems to work pretty well.
With a large enough sample pool, we'd be able to correlate features with obscure genes, wouldn't we? Am I missing something fundamental?
It seems like now is the time to get started.