Science: The looming crisis in human genetics | The EconomistThe looming crisis in human genetics
Nov 13th 2009
Some awkward news ahead
Human geneticists have reached a private crisis of conscience, and it will become public knowledge in 2010. The crisis has depressing health implications and alarming political ones. In a nutshell: the new genetics will reveal much less than hoped about how to cure disease, and much more than feared about human evolution and inequality, including genetic differences between classes, ethnicities and races.
About five years ago, genetics researchers became excited about new methods for “genome-wide association studies” (GWAS). We already knew from twin, family and adoption studies that all human traits are heritable: genetic differences explain much of the variation between individuals. We knew the genes were there; we just had to find them. Companies such as Illumina and Affymetrix produced DNA chips that allowed researchers to test up to 1m genetic variants for their statistical association with specific traits. America’s National Institutes of Health and Britain’s Wellcome Trust gave huge research grants for gene-hunting. Thousands of researchers jumped on the GWAS bandwagon. Lab groups formed and international research consortia congealed. The quantity of published GWAS research has soared.
In 2010, GWAS fever will reach its peak. Dozens of papers will report specific genes associated with almost every imaginable trait—intelligence, personality, religiosity, sexuality, longevity, economic risk-taking, consumer preferences, leisure interests and political attitudes. The data are already collected, with DNA samples from large populations already measured for these traits. It’s just a matter of doing the statistics and writing up the papers for Nature Genetics. The gold rush is on throughout the leading behaviour-genetics centres in London, Amsterdam, Boston, Boulder and Brisbane.
GWAS researchers will, in public, continue trumpeting their successes to science journalists and Science magazine. They will reassure Big Pharma and the grant agencies that GWAS will identify the genes that explain most of the variation in heart disease, cancer, obesity, depression, schizophrenia, Alzheimer’s and ageing itself. Those genes will illuminate the biochemical pathways underlying disease, which will yield new genetic tests and blockbuster drugs. Keep holding your breath for a golden age of health, happiness and longevity.
In private, though, the more thoughtful GWAS researchers are troubled. They hold small, discreet conferences on the “missing heritability” problem: if all these human traits are heritable, why are GWAS studies failing so often? The DNA chips should already have identified some important genes behind physical and mental health. They simply have not been delivering the goods.
They simply have not been delivering the goods
Certainly, GWAS papers have reported a couple of hundred genetic variants that show statistically significant associations with a few traits. But the genes typically do not replicate across studies. Even when they do replicate, they never explain more than a tiny fraction of any interesting trait. In fact, classical Mendelian genetics based on family studies has identified far more disease-risk genes with larger effects than GWAS research has so far.
Why the failure? The missing heritability may reflect limitations of DNA-chip design: GWAS methods so far focus on relatively common genetic variants in regions of DNA that code for proteins. They under-sample rare variants and DNA regions translated into non-coding RNA, which seems to orchestrate most organic development in vertebrates. Or it may be that thousands of small mutations disrupt body and brain in different ways in different populations. At worst, each human trait may depend on hundreds of thousands of genetic variants that add up through gene-expression patterns of mind-numbing complexity.
Political science
We will know much more when it becomes possible to do cheap “resequencing”—which is really just “sequencing” a wider variety of individuals beyond the handful analysed for the Human Genome Project. Full sequencing means analysing all 3 billion base pairs of an individual’s DNA rather than just a sample of 1m genetic variants as the DNA chips do. When sequencing costs drop within a few years below $1,000 per genome, researchers in Europe, China and India will start huge projects with vast sample sizes, sophisticated bioinformatics, diverse trait measures and detailed family structures. (American bioscience will prove too politically squeamish to fund such studies.) The missing heritability problem will surely be solved sooner or later.
The trouble is, the resequencing data will reveal much more about human evolutionary history and ethnic differences than they will about disease genes. Once enough DNA is analysed around the world, science will have a panoramic view of human genetic variation across races, ethnicities and regions. We will start reconstructing a detailed family tree that links all living humans, discovering many surprises about mis-attributed paternity and covert mating between classes, castes, regions and ethnicities.
We will also identify the many genes that create physical and mental differences across populations, and we will be able to estimate when those genes arose. Some of those differences probably occurred very recently, within recorded history. Gregory Cochran and Henry Harpending argued in “The 10,000 Year Explosion” that some human groups experienced a vastly accelerated rate of evolutionary change within the past few thousand years, benefiting from the new genetic diversity created within far larger populations, and in response to the new survival, social and reproductive challenges of agriculture, cities, divisions of labour and social classes. Others did not experience these changes until the past few hundred years when they were subject to contact, colonisation and, all too often, extermination.
If the shift from GWAS to sequencing studies finds evidence of such politically awkward and morally perplexing facts, we can expect the usual range of ideological reactions, including nationalistic retro-racism from conservatives and outraged denial from blank-slate liberals. The few who really understand the genetics will gain a more enlightened, live-and-let-live recognition of the biodiversity within our extraordinary species—including a clearer view of likely comparative advantages between the world’s different economies.
Geoffrey Miller: evolutionary psychologist, University of New Mexico; author of “Spent: Sex, Evolution, and Consumer Behavior” (Viking)
For Gallifrey! For Victory! For the end of time itself!!
2 observations.
1.We have much to learn about the way DNA defines us.We've barely scratched the surface in this matter.The only crisis that may loom is the burst of the bubble of unrealistic dreams.Those dreams may still be achieved,but not in a few years.
2.Ideology needs to get out of science.Let's presume that new finds will finally say that we're different.So what.Everybody knows that already.Welcome to real diversity.
Those who know don't speak
Perhaps. Phylogenetics within species ain't easy. You've got to find markers with sufficient variability to make a well defined tree.The trouble is, the resequencing data will reveal much more about human evolutionary history and ethnic differences than they will about disease genes. Once enough DNA is analysed around the world, science will have a panoramic view of human genetic variation across races, ethnicities and regions. We will start reconstructing a detailed family tree that links all living humans, discovering many surprises about mis-attributed paternity and covert mating between classes, castes, regions and ethnicities.
I enjoy being wrong too much to change my mind.
Three observations:
- It would be very amusing if science did find significant genetic differences across human societies and populations that affect behavior and intelligence.
- Epigenetic changes could account for much of the observed variations in traits and diseases. These are DNA methylation patterns and other factors that determine which tracts of DNA are turned "on" and "off". These differences will not show up in traditional sequencing, are partially inheritable, and result in significantly different phenotypes.
- The advent of safe and effective RNA interference therapy in the next 10 years will allow direct translation of sequenced genetic information into therapy. It will be possible to create synthetic nucleic acid based "molecular devices" which will be able to go into each cell in a type of human tissue and sense whether disease genes are being expressed. If disease genes are found, the devices will be able to respond with targeted therapy. Some of the first therapeutic applications will be removal of latent viral infections (HIV-1, Herpes, chicken pox). Later applications will see management of cancer in much more sophisticated and personalized ways. In other words, the golden age may very well be coming. It's just below the public radar at the moment.
The idea of maintaining a strict social order in perpetuity has fascinated many great men throughout history, from Nimrod to Hitler. The availability of genetic information would help facilitate such a goal by determining the genealogy of each person and so assigning him/her to a specific social class. It presents some rather discomforting possibilities.Human geneticists have reached a private crisis of conscience, and it will become public knowledge in 2010. The crisis has depressing health implications and alarming political ones. In a nutshell: the new genetics will reveal much less than hoped about how to cure disease, and much more than feared about human evolution and inequality, including genetic differences between classes, ethnicities and races.
**********************
If the shift from GWAS to sequencing studies finds evidence of such politically awkward and morally perplexing facts, we can expect the usual range of ideological reactions, including nationalistic retro-racism from conservatives and outraged denial from blank-slate liberals.
On the side, one upside of the Imjin War is that the Japanese invaders destroyed, among peasant villages and other things, the Joseon royal archives, which contained detailed genealogical information used by Joseon officials to determine the hereditary class of each subject. After the destruction of said archives, the Koreans had to draft both slaves and nobles into military service - as well as establish new registries.
Here is the separation between the boys and the menThe few who really understand the genetics will gain a more enlightened, live-and-let-live recognition of the biodiversity within our extraordinary species—including a clearer view of likely comparative advantages between the world’s different economies.
On the hand, it may be that many people will turn out to have been the product of cross fertilization complicating the task of assigning them to one or another social or racial class. I think is what the author is getting at.Originally Posted by Crocodylus
To be Truly ignorant, Man requires an Education - Plato
I think the author is getting at what University of Chicago geneticist Bruce Lahn wrote about a few months ago in Nature. The idea of biological egalitarianism which was created in response to WWII, isn't likely to remain. Lahn notes that society needs a good moral framework to approach this.The idea of maintaining a strict social order in perpetuity has fascinated many great men throughout history, from Nimrod to Hitler. The availability of genetic information would help facilitate such a goal by determining the genealogy of each person and so assigning him/her to a specific social class. It presents some rather discomforting possibilities.
On the hand, it may be that many people will turn out to have been the product of cross fertilization complicating the task of assigning them to one or another social or racial class. I think is what the author is getting at.
It is important to note that group differences are statistical in nature and do not imply anything about particular individuals. Rather than rely on the scientifically unsupported claim that we are all equal, it would be better to emphasize that we all have inalienable human rights regardless of our abilities or genetic makeup.
Box*2 : Let's celebrate human genetic diversity : NatureThe current moral position is a sort of ‘biological egalitarianism’. This dominant position emerged in recent decades largely to correct grave historical injustices, including genocide that were committed with the support of pseudo scientific understandings of group diversity. The racial-hygiene theory promoted by German geneticists Fritz Lenz, Eugene Fischer and others during the Nazi era is one notorious example of such pseudoscience. Biological egalitarianism is the view that no or almost no meaningful genetically based biological differences exist among human groups, with the exception of a few superficial traits such as skin colour. Proponents of this view seem to hope that, by promoting biological sameness, discrimination against groups or individuals will become groundless.
We believe that this position, although well intentioned, is illogical and even dangerous, as it implies that if significant group diversity were established, discrimination might thereby be justified. We reject this position. Equality of opportunity and respect for human dignity should be humankind’s common aspirations, notwithstanding human differences no matter how big or small. We also think that biological egalitarianism may not remain viable in light of the growing body of empirical data.
Many people may acknowledge the possibility of genetic diversity at the group level, but see it as a threat to social cohesion. Some scholars have even called for a halt to research into the topic or sensitive aspects of it, because of potential misuse of the information. Others will ask: if information on group diversity can be misused, why not just focus on individual differences and ignore any group variation? We strongly affirm that society must guard vigilantly against any misuse of genetic information, but we also believe that the best defence is to take a positive attitude towards diversity, including that at the group level. We argue for our position from two perspectives: first, that the understanding of group diversity can benefit research and medicine, and second, that human genetic diversity as a whole, including group diversity, greatly enriches our species...
RNAi is a remarkable phenomenon and a wonderful lab technique, but therapeutic uses are complete pie in the sky at the moment. Is there potential? Yes. Will it pay out? Maybe. I wouldn't bet on it. And certainly not within the next 10 years. I'm placing my bets on viral gene therapy- of course I'm biased since that's what I want to study. :P
Of course, as has already been mentioned, all of this is moot with a lot of diseases that have a genetic component that isn't easily localizable to a specific gene.
I enjoy being wrong too much to change my mind.
Armchair,
There's a general sentiment in the community at the moment that RNAi has not yet produced a therapeutic, but a lot of problems have actually been solved.
Santaris recently showed that LNA can be delivered to the liver without modification, bind to mir-122 and significantly affect Hep C without creating resistance..... in monkeys.
Calando is making good progress (iirc stage 1) on delivering siRNA to solid tumors via cyclodextrin nanoparticles. Previously, they successfully used similar particles to deliver a very toxic small molecule to similar tumors (I believe they are at stage 2 clinical trials on that).
Recent work on chemically modified siRNAs have shown that they are largely non-toxic when coupled with delivery vehicles such as nanoparticles, liposomes, and dendrimers, and delivery is efficient to certain types of tissues.
At the moment there are several drugs in the clinical pipeline by Merck, Alnylam, Calendo, Santaris and otherss and one of them will likely pan out within 3 to 5 years. My 10 year estimate is conservative. That's a more appropriate time horizon for the sensor controlled molecular devices.
Viral vectors are interesting technologies. However, people have been working on them for 30 years and it's still a struggle. Key issues are immune response, control of integration site (so the patient doesn't get cancer), and maintenance of long term expression. There are some problems where you might have to use viral transduction for gene replacement therapy, there are other cases where you might use vectors to transform cells ex vivo and then reinject them, but I think true in vivo application will continue to be very very difficult.I'm placing my bets on viral gene therapy- of course I'm biased since that's what I want to study. :P
Yes. However, there are plenty of diseases that do have specific genetic components. Viruses and cancers are obvious ones.Of course, as has already been mentioned, all of this is moot with a lot of diseases that have a genetic component that isn't easily localizable to a specific gene.
Last edited by citanon; 07 Dec 09, at 21:19.
That's fascinating. Good luck to them.
Yes, but there have been significant advances in recent years. There's some really interesting work with cystic fibrosis that has managed to (so far) avoid the problems with leukemia that earlier methods had. It's certainly hard to say how successful viral vectors will be. I think that gene therapy in general may turn out to be more limited than we would like. But who knows? It certainly has incredible potential.Viral vectors are interesting technologies. However, people have been working on them for 30 years and it's still a struggle. Key issues are immune response, control of integration site (so the patient doesn't get cancer), and maintenance of long term expression. There are some problems where you might have to use viral transduction for gene replacement therapy, there are other cases where you might use vectors to transform cells ex vivo and then reinject them, but I think true in vivo application will continue to be very very difficult.
I enjoy being wrong too much to change my mind.
AG:
Good on you. We need more like you.
To be Truly ignorant, Man requires an Education - Plato
Interesting. What are the CF people doing different?
I'll have to dig around some to find where I saw it. I've been looking at craploads of grad schools recently, and it was probably somewhere in there. Could take a while.
Last edited by ArmchairGeneral; 08 Dec 09, at 20:16.
I enjoy being wrong too much to change my mind.
Genes vs. environment and the role of genomic "dark matter"
Genes vs. environment and the role of genomic "dark matter"
Two studies highlight how there is some genomic "dark matter" lurking in human populations, but that environmental differences, such as the contrast between rural and urban settings, appear to be more potent drivers of changes in gene expression.
By John Timmer | Last updated December 8, 2009 1:21 PM
The argument over the relative weight of nature and nurture—genes vs. the environment—has a history that predates anything that even resembles formal biology. With the advent of molecular biology and the completion of the human genome, we've now got a much better idea of what, precisely, genes contribute to human differences. Two studies printed in different Nature journals have now used molecular tools to look into two questions related to the central debate: how much do the genomes of different human populations differ, and what sorts of changes do environmental differences trigger.
The genome's missing matter
First, the genome results, which were published in Nature Biotechnology. The study tackles what might be considered the human genome's equivalent of dark matter: large areas of the genome that may be common in some populations that we simply haven't studied yet.
When the human genome was completed, researchers created what's called a "reference genome," a sequence that was meant to represent the one that, on average, was possessed by every human on the planet. If you compare a typical human to this reference genome, they'll have, on average, one base that's different per every 1,000; additional differences are caused by areas that have copy number variations, where a segment of the genome is duplicated or deleted. Various techniques make it easy to identify how an individual differs from this reference sequence.
But this approach leaves another area of potential difference unexplored: individuals could be carrying DNA that doesn't match anything in the reference sequence, and none of these techniques would tell us anything about that. The new study aims to correct that, in part by using raw data from the sequencing of the genomes of individuals with African and Asian origins that is being pursued by the NIH (the researchers simply downloaded 250 gigabases of DNA sequence from the NIH—for comparison, the human genome is only about 3 gigabases). They then eliminated likely contaminants and anything that was already in the reference sequence, and assembled the remainder.
The end result was about 5 megabases of DNA that hadn't been previously described, about half of which was shared by the two individuals (about a megabase of it also appeared in the genomes of James Watson and Craig Venter).
The authors performed a population survey, and found that the distribution of these sequences are generally what you'd expect from a migrational perspective: some sequences were more rare, others more common in populations that are further from humanity's African origins. In a few cases, like Pacific island populations, there appear to be instances of a founder effect, where otherwise rare sequences are overrepresented.
But maybe it's not the genes
Based on the distribution of these new sequences, the authors conclude that the entire human population probably harbors about 20-40 megabases of sequence that don't appear in the reference genome, or roughly one percent of the total genome size. Overall, these regions appear to contain a few hundred genes, most of which have no known biological function. But a number of them are transcription factors, which control the expression of other genes. This raises the prospect that the differences they drive could have a major impact on human traits.
That's why the second study, from Nature Genetics, is rather significant. Its authors obtained blood samples from about 200 individuals on Morocco's Atlantic coast, some from small villages, others from urban environments. They then tested for gene expression levels, since DNA differences don't matter unless they are registered by the cell as a whole. Differences there were correlated with a complete scan of the genome—or, more accurately, the known genome—for base differences.
And there was a definite impact from the genes. For about 350 of the genes that had significant expression differences, there was a clear association with a difference in DNA sequences. Anywhere from 15 to 60 percent of the expression differences in these 350 genes can be accounted for by genetics.
All of that sounds pretty impressive until you consider the larger picture, though. Those 350 genes represent only about five percent of the total number genes that varied among the study population. For most of these genes, the environment, urban or rural, appeared to correlate more strongly than genetics. The effect was so pronounced that the authors were left wondering whether genetics mattered. "The robustness of the associations observed to the environmental effect," they wrote, "raises the issue of whether genotype-by-environment interactions influence the peripheral blood transcriptome at all."
The obvious caveat here is that the study relied on blood samples, which will be dominated by immune cells that are specifically primed to respond to the environment. If there's any place you might expect to see environmental influences dominating, this (or possibly the digestive tract) would seem to be the most likely candidate. But the genes that regulate immune function are also among the most rapidly evolving in the human genome; if there's any place that you might expect genetic differences, this is also it.
So where does this leave us? Given that most of the DNA described in the first study seems to be in small segments that are scattered throughout the genome, its influence should have been picked up by the second study. It obviously wasn't. But the second study would be strengthened by looking at the impact of genetics on other tissues and within more diverse populations.
Nature Biotechnology, 2009. DOI: 10.1038/nbt.1596
Nature Genetics, 2009. DOI: 10.1038/ng.495
Bah. I lied. It's not CF. Got some CF studies I was reading about mixed up with this:
Hematopoietic Stem Cell Gene Therapy with a Lentiviral Vector in X-Linked Adrenoleukodystrophy -- Cartier et al. 326 (5954): 818 -- Science
A good piece on it is here: Three viruses join forces to treat X-linked adrenoleukodystrophy : erv
Still flippin' sweet, but not cystic fibrosis.
And the chimpanzee genome differs from the reference genome by approximately one percent... A much more important one percent, I guess. Weird to think that two humans could theoretically differ in sequence as much as a human and a chimpanzee, though......roughly one percent of the total genome size.
I enjoy being wrong too much to change my mind.
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