Wednesday, December 26, 2012

Doing violence to genetics

We were going to take it slow this week, but, well, some stories we just can't ignore.  So, a piece in this week's New York Times says that geneticists at the University of Connecticut are planning to genotype Adam Lanza in an effort to figure out what caused him to kill 20 children and 7 adults in Newtown, Connecticut.  Indeed, in an effort to explain the biology of extreme violence. As the story tells it,
They could look at all of Mr. Lanza’s genes, searching for something unusual like gene duplications or deletions or unexpected mutations, or they might determine the sequence of his entire genome, the genes and the vast regions of DNA that are not genes, in an extended search for aberrations that could determine which genes are active and how active they are.
Some -- many -- people believe that behavior such as Lanza's is so extreme that there must be a genetic explanation.  But, if it is that extreme, and there is a genetic explanation -- and we'd say this is very unlikely, but let's just say for the sake of argument that there is -- it will mean nothing about the rest of us.  Every behavioral distribution has extremes, and when genetic associations have been found, they often pertain only to the extremes, and are generally rare, and so do essentially nothing to explain the rest of the distribution.  But, that's assuming Lanza's behavior was extreme in the distribution of violent behavior, and that it was biologically determined.  Was it in fact any more violent than any other premeditated murder, most of which don't make the news? 

Further, Mr. Lanza, like all of us, is more than likely to have numerous "aberrations" or uncommon mutations or regions in his genome.  The scientific question is how to determine what they mean. The suggestion in the NYT story is that any uncommon stretch of DNA might be causal, but we know that's not true, since we all have something uncommon, and most of us are not prone to extreme behaviors. Most people with 'Asperger's' syndrome, if that even is what Lanza was affected by, if that is even properly called a 'disease', do not commit any crimes whatever, and don't go over the edge like he did, either.

Perhaps the geneticists will be looking for mutations that have previously been suggested to be associated with violence, or "risk taking" or whatever else might strike them as explanatory.  But, any such mutations will be common in most populations, will be found in many people who aren't violent or risk takers, and will, as with all genes associated with complex traits, explain a very small fraction of the behavior.  They have very little, if any, predictive power, and certainly can't predict one-off running-amok as Lanza did.

Or, perhaps they'll be looking for genes for 'mental illness' -- again, very few if any genes have been identified that explain very much of the variation in mental illnesses, whose definition is often hopelessly vague anyway, including those such as schizophrenia that seem to run in families.  The vast majority of such traits are polygenic and seem to have an environmental component as well. And, of course very few people with mental illness of any type are mass murderers, so this seems another fruitless avenue.

Of course, there are those geneticists who claim we can't afford not to do this study.  That is, to us, thoroughly wrong.  If anything, we should not waste the money for this, because there are vastly more important issues we could and should address than trying to geneticize a unique event.   And, by the way, that is not so unique in the US, and one might be tempted, therefore, to say that many people here have the genotype 'for' such murderous mayhem.  But then does that suggest in any serious way that people in other countries that have hardly any of this kind of behavior don't have the genotypes?  That would be a real stretch.

So it's hard to believe that the people doing this work aren't doing much more than blatantly and shallowly exploiting a tragedy based on very little evidence that they'll find what they are looking for. They are apparently motivated by the assumption that behavior is genetically determined, or they wouldn't be doing it.  But where does that road take us?  Let's say they find something -- again, that's unlikely -- but what would society do with the answer?  Would it really be predictive?  Would we genotype everyone at birth and quarantine -- or worse -- anyone with what looks like a genetic predisposition to violence?  Or, would we just send them off to military school at a very young age? Did we learn absolutely nothing in the long 20th century, about the morality and ethics of such eugenic measures?

Clearly, violent behavior doesn't have a simple explanation; like most traits, some people blame society, some people genes, and where you come down on this is likely to be based on your prior beliefs about nature vs nurture rather than any ironclad scientific evidence.  Like most complex behaviors, it's likely that violence is a product of genes and environment, and every Adam Lanza will have gotten to their tragic end in their own way. That's unfortunate for the idea that we could avoid such things by anticipating them, but perhaps is a clear signal that we need other approaches -- like gun removal, early counseling for people with disturbed personalities, and so on.  There is far less 'science' in that, but perhaps far more cure.

Tuesday, December 25, 2012

The Elfin genome project (EGP)

We annually hear about Santa Claus and his world travels.  It may be thrilling or enthralling to kids, but why he goes in an open sleigh with some dowdy reindeer pulling him around in the age of Business Class travel is a mystery for us adults to ponder.  With his agenda, Santa would quickly earn enough frequent flyer points to qualify for early Red Carpet boarding and more leg (and belly) room than we ordinary folks can more than dream of.  Instead, Mr Claus stubbornly sticks to his antediluvian transport.  Why is that, we wonder?

An obvious answer is that he would have to check in so much baggage that the usual panoply of  plastic fall-apart toys would cost more to check, at $25 each, than they were worth in the first place.  Reindeer would seem a rather malodorous and awkward kind of 'engine' to maintain, especially for 364 days a year, getting only one night's use from them.  Aircraft have to be used more often than that, to keep their parts oiled, but at least they get around faster and with more comfort.  In the latter regard, as an old man like Santa should note, that also means more 'comfort' facilities (i.e., rest rooms).  Think what it must be to be Santa, and in house after house after house: each one provides a drink and cookies, but he must start having bladder retention issues after the first few hundred homes.

We could go on, but you probably get the point.  Instead, there is a serious scientific issue that the Good St N raises.  For centuries we've been told that these little toys and other gifts are manufactured in the polar cold by a bunch of 'elves'.

Norman Rockwell, Sat Evening Post, 1922; Wikimedia

The Elfin genome Project (EGP)
 Elves are portrayed as very miniature, pointy-eared people.  They have shoes with pointy toes and wear clothes that seem to be in a rather Alpine style.  Yet they are never seen by we who are the recipients of their good work.  They are normal-looking rather than microcephalic or of any anomalous stunted growth.  They are smaller than the African Ituri ('pygmies') or San ('bushmen'), Mexican Mayans or Amazonian Yanomami, but they appear roughly 'European' in physiognomy.  They are often portrayed as congenially middle-aged, and as far as we know are all males.  We are not told if they have children, or parents, or if there is anyone around to serve as feminine company.  Many questions are thus raised.

Surely it would be important to find out what their genomes may reveal about their traits and their ancestry!  It would be, one might dare suggest, vastly more important than the results of the latest GWAS or whole genome sequencing study of ordinary humans, when we know just what kind of 'revolutionary' data (as the major journals like the NY Times daily report) such studies provide us.

An Elfin Genome Project (EGP) would, by contrast, be truly transformative of our understanding of 'human' (if they are human) evolution and variation.  Clearly elfin stature and traits are not just normal but quite positively to their benefit, so the selective history that is responsible--and where that adaptive evolution to diminutiveness occurred--would be of major value to human geneticists who are currently flailing around trying to make major careers out of incremental enumeration of polygenes for traits that aren't really genetic in the first place.
(image from http://www.minibite.com/christmas/allyouneediselves.htm)

These days, it would not cost very much for the EGP to do an entire elfin genome sequence, which could be done in any self-respecting human genetics lab sporting 'Next-Generation' sequencing equipment.  The EGP would provide not just the raw genome sequence of 'the elf', but would be immediately aligned to 'the' human genome sequence and those of other primates, to see just where these little guys fit, in the branching tree of descent.  Would they appear to be recently diverged from, say, Scandinavians?  Swiss?  Or more distantly related to the very short-statured Pacific Homo floresiensis (the 'Hobbits') fossils found on a southeast Asian island?

Translational medicine for the elfin population
We would of course entrust to NIH-funded researchers the job of identifying disease genes that would quickly be discovered in the EGP sequence.  Whether or how one could get treatment delivered to any such person is not so clear.  However, NIH is absolutely determined to have another named Project they can promote to justify their funding, and the EGP data could fit right into their Translational Medicine 'offensive'--no pun intended, though it implies that previous NIH work was never actually  about helping with health and disease.  The claim is that NIH will actually now (finally!) try to 'translate' research findings into clinical practice and benefit.  But since human genetics has in fact always been largely about  improved medical care since Archibald Garrod founded the profession around 1900--by studying alkaptonuria and other metabolic genetic diseases--NIH"s highly publicized "translation" project might be viewed (by a cynic) as yet another image-enhancing hype designed to persuade Congress to increase their budget, rather than much that is actually new.  We would never subscribe to such cynicism, however.

On the other hand we can suggest a legitimate Translation project, for the elves, based on the EGP.  For example, we could leave pills or an appropriately filled syringe, along with the cookies and milk, for Santa to take back and administer to the affected elf.  However, this would assume that 'the' elf genome we would get from one sample represents all of them.  That would be tantamount to saying that, for example, being very short and jolly was a genetic disorder requiring 'treatment'.  Of course, these days people seem determined to characterize just about everything as genetic, so that wouldn't be so surprising.  Or, such universal treatment would suggest that if you've seen one elf you've seen 'em all.  No, no; much better to have many sequences from different elves, to find out which of them suffered from, or we could predict will suffer from, any number of terrifying diseases, other than runtiness, for some of which we might have translational treatment such as suggested above, but for others at least we could warn them that they were a ticking time bomb, and just hope they wouldn't worry about it too much and start sabotaging the toys they make.

There is a problem here, of course.  Since we don't actually know where Santa and the elves live, we would not know where to send a hit-and-run medical team to collect blood and get signed informed consent from the elves, that (as is the current practice) ceded to the investigators any profits from developing the 'translation' research the subjects' taxes are paying for--or even what language to write such a legalistic document in.

Santa's not there!
Unfortunately, rumors that Santa & Co. live at the North Pole are greatly exaggerated. Recent expeditions to the pole have discovered, exposed by the melting snow due to climate change, huge piles of unopened letters to Santa from children, requesting toys that never actually showed up under the tree (how the parents rationalize this to their disappointed children is a separate question).  Santa could not be so cruel as to give a North Pole mail drop but never to visit the site, without a good reason. Maybe he figured most of the mail would be--as it is for the rest of us--tasteless and often misleading advertising solicitations and bills, and he just would rather be able to say "Gee, I never saw that bill for sleigh repair or reindeer-feed and jingle bells".

But wherever he and his impish crew actually live, science knows how to be intrusive and can outsmart him, yes, even Santa.  In his genial approach, he accepts the bag of gifts wrapped by the elves rather than he or the Missus doing the packing themselves.  Now we know that when the elves made or wrapped these products, all sorts of their DNA would have settled onto the materials (e.g., in flakes of dandruff from their bearded chins).  Any forensic team worthy of a CSI designation could easily wipe these toys, paper, and ribbons and obtain spitloads of DNA, for analysis in their labs.

So, the EGP is possible!  Any of you whose lab personnel have little to do this holiday season (meaning that your Dec 1 grant application's in and the Jan 1 ones are more or less written), and may be idle enough to be reading this post, should hasten to start the EGP, and get the jump on your competition--then you'll get a huge grant as your Christmas present (and from Francis Collins, not some puny elf or pudgy, aging, silly sleigh-riding multi-centenarian).  So, get started!

A sad, parting thought, however
Finally, on another note, we must wonder whether the ice caps and snow-melt will cause problems for Santa's deer, elves, sleigh, or even his home?  Could his good Ms Claus be pestering him to relocate to a more salubrious clime?  Could a retirement home be in her thinking?  With Obamacare in the offing, they would not have to worry about their medical welfare, even though they, not being elves, wouldn't benefit from the EGP.

We'll leave you to ponder that, over what we hope will be a Merry Christmas and a delicious dinner with friends or family!

Monday, December 24, 2012

The Zen of Christmas

A Buddhist friend once told us, after reading our book The Mermaid's Tale, after which we named this blog, that it reminded him of the Genjo koan. Not being Buddhists ourselves, he tried to explain that, to him, our book had a sense of wonder and selflessness that was familiar from his practice.
To study the way is to study the self,
to study the self is to forget the self,
to forget the self is to be enlightened by the ten-thousand things.
As well as continually changing perspective.  We have been thinking about this lately, as we prepare to celebrate Christmas with family and friends. We aren't Buddhists, or any formal religion in fact, so why do we celebrate? What are we celebrating?

In The Mermaid's Tale, we tried to convey a non-jargon sense of 'oneness' that can come from attempting to synthesize much of what is known about life into a few simple principles.  The principles can be generalized to life on all its time scales: as it has developed and will develop in every organism that has ever existed, or will ever exist, within a single lifetime; as it has evolved over 4 billion years; and within ecosystems as beings interact, depend on each other, and, yes, exploit each other for their existence.  (We have blogged about these principles, including recently here.)  

The Western view of life as relentlessly competitive, red in tooth and claw, easily fades if you recognize instead how essential cooperation is to to maintaining the dense, interacting whole, at all levels.  'Cooperation' here doesn't refer sappily to harmonious society kinds of things, though they are included, but to the requirement, on which life is based, that countless factors must interact successfully.  This is true from the use of DNA, to cells, organs, organ systems, whole organisms, species, and ecosystems.  There's nothing mystical about these facts, even if they don't serve the blood-lust of competition that is so central to our society at present.  No, the reality is that we are each at once a whole of tiny parts and and a tiny part of a whole, dependent on the rest to nurture and maintain us from conception to death.  In a more philosophical but again not necessarily mystical sense, indeed, after death we become part of the sustenance of the life that follows ours, ad infinitum.

In a reductionist world that insists on seeing existence as centrally a competition of selfish entities does not account very adequately for the highly integrated kinds of cooperation that pervade life .  Certainly what proliferates more becomes more common, in the usual evolutionary sense, and sometimes that may, as Darwin made clear, be due to a better fit to circumstances (called natural selection).  But even this isn't basically about individual genes or vitamins or any other type of molecule, but about integrated organisms.

Darwin clearly had his own sense of oneness.  He formalized that feeling into an explicitly cosmic idea that all of life shared a common ancestor, and grew as a global panoply of diversity, which his thousands of observations, and those of his many naturalist informants, consistently confirmed time after time after time, and which has never been challenged by biology since.

Darwin was not mystical, and did not feel the need to invoke the hand of a supernatural being in his understanding of the world, so his sense of the whole was an intellectual view of the world, yes.  He saw it as ruthlessly competitive, though he was personally generous and kind, and indeed his view of the world may have led to a sense of selflessness similar to that toward which Buddhists strive, but if he said anything explicit about that is not known, at least to us, but perhaps.  He did write of the grandeur of life in the famous last paragraph of The Origin of Species, and it's not hard to imagine that he wrote this with the feeling of humility that one gets in the face of the sheer awesomeness of nature.   Though, he explicitly rued having turned his mind only to science, which he describes late in his autobiography:
My mind seems to have become a kind of machine for grinding general laws out of large collections of facts. . . . and if I had to live life over again, I would have made a rule to read some poetry and listen to some music at least once every week; for perhaps the parts of my brain now atrophied would thus have been kept active through use. The loss of these tastes is a loss of happiness, and may possibly be injurious to the intellect, and more probably to the moral character, by enfeebling the emotional part of our nature.
Some scientists who press relentlessly for a reductionist enumerative ('omic') solution to problems that actually have their importance at a higher level of interaction, would do well to learn this lesson, perhaps.  To do that in a way that acknowledges wonderment, but is not mystical and is grounded in the world is a real challenge for science today, we would argue.

In any case, there are Christians who arrive at the sense of oneness through their own path -- God made the Earth and everything in it, and we must be good stewards of this Earth.  But, people who take hallucinogens often report the same sense.  So, there are many paths to the same shall we say understanding of the wholeness of life.  We can get there spiritually or intellectually, it doesn't seem to matter.

Stars, Hubble telescope (Wikimedia)
But it is this sense that we personally celebrate at Christmas.  The idea that we are one with all in the flow of life, but more: this is at once a humbling and perplexing realization that is most likely, in an ironic twist, unique to humans.  So, let Christmas be a reminder that we are smaller than atoms in the universe, but that at the same time we have the capability to love, many of us to choose our path through life, to create our own sense of meaning and to make sense of our lives in the face of the instantaneous nature of our existence.  

Happy Holidays to you all. 

Thursday, December 20, 2012

'Twas the night before Christmas, revised 2012



'Twas the  night before Christmas
(revised by Ken, 2012, After Clement C Moore, 1823)

'Twas the night before Christmas, when all through the house
Not a lab-tech was stirring, nor even a mouse;
The grant had been written with meticulous care,
In hopes that the funding soon would be there;




The mice all in cages were snug in their beds,
While visions of pellet food danced in their heads;
The post-docs and students, with notes in their laps,
Had just nodded off for unauthorized naps,

When out in the hall there arose such a clatter,
I sprang from my bench to see what was the matter.
Away to the window I flew like a flash,
Tossed on my lab coat and tightened the sash.


The moon on the breast of the new-fallen snow
Gave the lustre of mid-day to objects below,
When, what to my wondering eyes should appear,
But the boss of the lab, a professor not dear,

With inquisitive glances, so lively and quick,
I knew in a moment it was a lab-check.
More rapid than eagles his paces they came,
And he whistled, and shouted, and called us by name;

"Now, DASCHLE! now, DANZIG! now, PONTZER and NIXON!
On, COMER! on COOPER! on, CONNOR and HIXSON!
Snap out of your doze, don’t continue to stall!
Now work away! work away! work away all!"

He knew not that our gels had defied PCR,
And failed to yield meaningful sequence so far,
So back to our toiling (with cursing) we flew,
With our Eppendorf tubes, and our pipetters, too.


And then, in a twinkling, I dreamed up my ‘proof’,
Carefully covering each little goof,
In results that he needed, and was turning around,
As into the lab the Prof came with a bound.

He was sweating in fury, from his head to his foot,
A smoker, his clothes were tarnished with ashes and soot;
A sackful of reprints he had flung on his back,
And he looked like a peddler just opening his pack.

His eyes -- how they squinted! his wrinkles a-worry!
His cheeks were all pasty, his nose like a cherry!
A drool from his mouth dripped down in a flow,

With a visage of terror as white as the snow;

The deadline approaching, he tight-gritted his teeth,
And horror belikened his head to a wraith;
He had a proud face and a little round belly,
That were he not Funded would quiver like jelly.

When he's fattened with grants, a right jolly old elf,
(And I laughed when I saw him, in spite of myself).
A glaze in his eye and a twist of his head,
Soon gave me to know he was living in dread;

He spoke not a word, but he'd dreamt that his work,
Had filled all his wishes--til he'd waked with a jerk,
And realizing what happened and snorting his nose,
As somberly nodding, from this reverie he rose:

    That he'd sprung to his mailbox, where erupted a tear,
    The envelope opened—and we'd all heard him swear, 
    “The grant will be funded!  The budget’s all right!
    HAPPY CHRISTMAS TO ALL, AND TO ALL A GOOD-NIGHT!”




Wednesday, December 19, 2012

Is it 'progress' to identify 100s of genes for a trait? If not...what is it?

What is known
Crohn's disease (CD), an inflammatory bowel disease, has a large genetic component, but specific genes, as for most such complex diseases, have been elusive.  A paper in this month's American Journal of Human Genetics, "Refinement in Localization and Identification of Gene Regions Associated with Crohn Disease," Elding et al, reports that they believe they are zeroing in on the answer.

The gene most closely associated with Crohn's disease is one that plays a role in the immune response, NOD2 which codes for a protein that recognizes peptidoglycans, or bacterial molecules, and stimulates the immune system to respond.  It makes sense that genes involved in immunity would be involved, as the disease is inflammatory in nature, perhaps due to an impaired innate immune system which leads to chronic inflammatory response by the adaptive immune system to microbes in the gut.

A number of genomewide association studies (GWAS) of Crohn's disease have been done, but none has identified genes with large explanatory power.  A recent meta-analysis of six studies (reported here) identified 32 new loci associated with Crohn's, which, added to the 31 that had been identified in 2010, brought the total to 71.  This doesn't mean 71 single genes but instead stretches of chromosomes that generally contain multiple genes -- sometimes hundreds -- and 'gene' may mean other kinds of function than protein coding, such as regulatory, directly functional RNA, and so on.  The 2010 report explained 20% of the variation in the disease, and the additional 32 brought that total to 23.2%, which indicated that most of these loci represented genes with very small effect, and that many more loci were left to be found. And what about the 77% that is still unexplained?

The Elding et al. paper reports use of a "mapping approach that localizes causal variants based on genetic maps in linkage disequilibrium units (LDU maps)." That means chromosome locations, but not specific to any nucleotide or functional element.  The authors confirm 66 of the previously reported 71 loci, and narrow in on "more precise location estimates" in those intervals (that is, they come closer to identifying candidate genes rather than just chromosomal intervals). They identified 78 additional regions that were statistically significant, and which provide "strong evidence for 144 genes." They also found 56 "nominally significant signals, but with more stringent and precise colocalization." So, this paper reports 200 gene regions in total associated with Crohn's disease, most of which, the authors say, unambiguously implicate single genes. The reason for that inference isn't clear, since clusters of DNA units can function together.  Again, many of these loci contain genes involved in the immune system. The authors suggest that "The precise locations and the evidence that some genes reflect phenotypic subgroups will help identify functional variants and will lead to greater insight of CD etiology."

The immune system is complex and involves many components so that mapping that 'hits' in a region that has some immune system elements might happen by chance if you have 200 hits.  Also, the immune system is involved in response to external threats (like viruses and bacteria) as well as to internal problems (recognizing and repairing damaged tissues), so the reason for 'immune' involvement is unclear -- and a challenge to determining what is responding to what.

The authors have previously demonstrated genetic heterogeneity within the NOD2 gene region -- that is, that different genes explain risk in different people. They also found independent involvement of a nearby gene, CYLD. They further demonstrated the importance of precise definition of the phenotype to identify loci that might explain risk in multiple cases.  In this new paper they use a high-resolution linkage disequilibrium map, basically meaning that their test markers are closely spaced so that implicated regions are fairly short, which helps to identify genes in the implicated region of the chromosome, and fine-tune phenotype definition as well.  They were able to replicate 66 of the previous 71 gene locations, and identified an additional 134 signals, many of which contain genes.  One might always quibble with this or the other statistical issue, but the overall conclusion is unlikely to change.  In the authors words:
This is a major step forward in identifying the relevant genes and functional variants and thus elucidating the genetics of CD etiology. The very large numbers of genes [we identify] confirm that CD is truly polygenic and complex in nature. Many genes show functions that are compatible with involvement in immune and/or inflammatory processes as well as integrity of the intestinal epithelium and differentiation.  
But
In fact, do we know anything more than we did before this study?  It has long been clear that CD is polygenic and complex, with immune and/or inflammatory gene involvement.  Whether 71 genes are involved or 200, it means that this disease is another instance of many pathways leading to a complex trait.

Much money and effort by the highest quality investigators has been expended on this disease.  This means that by now we probably can't claim the complexity is an artifact of imprecise methods.  The complexity seems to be real.  Each CD individual is affected by a different combination of variants at their two copies of these 200 genes -- and, if this is 'simple' complexity, another 600 unidentified genes to top up the current 23% explained causation.

This also doesn't include any serious identification of environmental contributions.  That is, environments like, say, diet at some point in  life, may have different effects on different genotypes, so that a given genotype may have no harmful consequences in one lifestyle and be harmful in another.  And if there are complex interactions among the different contributing genomic regions, then enumerating the variants at 200 (much less 800) genome regions will not make prediction or perhaps not even treatment very genome-dependent.

It is likely that after all of this, some genetic variants will have predictive power or medical treatment relevance, and that of course will be genuine progress.  But it leaves the question that so many traits leave: how do we actually deal usefully with this sort of routine-level complexity?

Tuesday, December 18, 2012

Plant miRNAs regulate human gene expression: believe it or not?

Plant miRNAs R us?
Just as we're starting to get used to the idea that our genomes include our microorganismal friends, who outnumber our own genes in our own bodies by a factor of 100, a paper that's not new but that has recently come to our attention, and may be new to you, too, suggests that we now have to make room for plants in this equation.  We blogged about a paper in BioEssays in the spring reporting micro RNA from plants regulating animal genes, but this second paper makes the story more interesting, in several ways.

The paper (Zhang et al.), published online in Cell Research a year ago, reports finding about 30 different plant miRNAs in human sera and tissues. They were surprised by this, and went on to explore a possible association between eating rice and the regulation of specific genes by micro RNA from that rice.  MicroRNAs (miRNAs) are 19-24 nucleotide pieces of non-coding RNA that mediate the regulation of about 30% of mammalian genes by silencing them, meaning that the proteins they code for are not made.

When this process was first discovered it was thought to be intrinsic to an organism's own gene regulation, and exclusively so, but foreign miRNAs have subsequently been found in human blood and tissues and have been seen to be potentially useful biomarkers for disease. From Zhang et al.:
miRNAs have been widely shown to modulate various critical biological processes, including differentiation, apoptosis, proliferation, the immune response, and the maintenance of cell and tissue identity. Dysregulation of miRNAs has been linked to cancer and other diseases. Recently, we and others found that mammalian miRNAs exist stably in the sera and plasma of humans and animals. Specific serum miRNA expression profiles show a great potential to serve as a novel class of biomarkers for the diagnosis of cancer and other diseases. Numerous reports have subsequently shown that unique expression patterns of circulating miRNAs reflect various physiological and pathological conditions.
The paper suggests that these extrinsically acquired miRNAs may play a role in disease as well.

Zhang et al. report that miRNAs can "pass through the GI tract of the mouse and enter the sera and organs." They suspected that the predominant miRNAs in human tissues were derived from rice, and thus must have been acquired through the diet. This is surprising, since RNA is generally quite unstable and easily degraded, and the GI tract is very acidic. The authors suggest that these miRNAs are protected from degradation by a form of chemical modification called methylation.

The researchers identified 50 human gene sequences that were perfect matches to one of the rice miRNAs they'd found in human sera. The most highly conserved such sequence is in the low-density lipoprotein receptor adapter protein 1 (LDLRAP1), a gene highly expressed in the liver and critical to the removal of ldl from the circulatory system. They determined with an in vitro assay determined that the miRNA was intact in liver cells, and that the level of LDLRAP1 protein was significantly decreased, while the LDLRAP1 mRNA was not affected, indicating that the miRNA was in fact silencing translation of the gene. This had the effect of keeping ldl levels high.

This is very interesting, and apparently the first demonstration of the possible effect of exogenous miRNAs on human health. It could be a demonstration of epigenetic effects on health, and gene by environment interaction, both of which seem to be significant players in human health, but only beginning to be understood. And it demonstrates surprising characteristics of RNA. If it is true it's a significant finding.

But then, if it's true, why didn't it appear in a major journal? Cell Research is a publication of the Nature Publishing Group in association with the Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), and calls itself the "leading research journal in China and the Asia-Pacific region." So, is it fair to suggest this significant of a finding should be published someplace else? The study got some play in the journal itself, discussed as a "Research Highlight, " e.g., and it has been cited 50 times to date, but primarily in lesser journals as well.  

Who believes what stories...and why?
This is an interesting example of the sociology of science.  The journal is not a mainstream Western journal, even if it is in collaboration with a major Western publisher, the authors are unknown to us, and the results are surprising, even though the researchers report what appear to be very careful and considered confirmation each step of the way (though they did need to publish a correction to an error in their figures in the next issue of the journal, which we actually find rather confusing, but that's another story).  This, at least for us, makes this work a bit difficult to interpret and accept.  That may seem unfair, but in fact this is how science should work -- replication of results, particularly if they are unlikely, may not constitute proof but it does make them more likely.

Another side of this is the social side of the politics of science in society.   The paper was the subject of some commentary when it appeared because of worry about genetically modified crops and their potential to interfere with gene regulation in the same way.  GM giant Monsanto saw fit to comment on the paper, saying essentially that very few plant miRNAs are found in human sera and tissues, and that the amount consumed would have to be much more than it is to have any effect. 

There are other reasons to oppose genetically modified crops (as there are reasons to think they are a great idea for a crowded planet).  The point here is that a study is seized upon by those whose point of view it supports, and there may be a tendency to accept it uncritically.  But people didn't seem skeptical about the results, which we find interesting.

On the other side of the coin, of course, is the possibility that the study didn't receive top billing because many research and commercial interests would be threatened by it.  So biased use of work goes both ways.

All we, who only know what we've seen in the story itself, can say is that if it's accurate, it really does deserve to be taken seriously.  It would challenge many notions of whose genome is whose, could give us another pathway for understanding health and disease, and it would surely present potentially important risks and issues about safety in us and/or in other agricultural or other human-associated species.

Monday, December 17, 2012

Principles of life exemplified (again): cell membrane domains

Principles of life
As regular readers know, one of the core ideas we present in our book, The Mermaid's Tale, is that there is a basic set of principles that explain life in the short term (development), the long and extremely long term (evolution) and the simultaneous (ecosystems).  These principles are being used implicitly or explicitly in biology labs around the world as researchers design and interpret their experiments because they derive from everything we know about life.  That they work everywhere and at all time scales isn't our invention, we just happened to have drawn up the list.  (We've blogged about this before, e.g citing examples of the principles in action.)

We think the list is important because we feel that it is far too widely assumed, even if just tacitly or subliminally, that the only theory about variation in life is the Darwinian theory of competitively based evolution.   This is not to assert that natural selection is unimportant, but we do think that it is far less important or pervasive than the kinds of relationships and properties we have tried to enumerate--indeed, without these coming first, there wouldn't be anything for selection to select for.  One hundred and fifty years of discoveries since Darwin have given us much broader insight into how life works, which we think our list exemplifies.

The principles as we formulate them (annotated here, and of course in our book):
1. Inheritance with memory
2. Modularity
3. Sequestration
4. Coding and interaction
5. Contingency
6. Chance
7. Adaptability
8. Cooperation
This comes up again today because of a paper in the December 7 issue of Cell which illustrates exactly our point about these principles -- they are all around us, and can be used to predict and interpret the kinds of findings in biology that are made all the time.  The paper, "General Protein Diffusion Barriers Create Compartments within Bacterial Cells," Schlimpert et al., describes modularity in the cell membrane of prokaryotes, single-celled organisms without a nucleus, which is similar to that already known in eukaryotes.



In eukaryotes, things that stick off the cellular membrane, like cilia or neuronal axons, 'know' what and where to be because of proteins that are partitioned non-uniformly into specific domains on the plasma membrane through specialized barriers that pick and choose what can pass through.  Schlimpert et al. describe the "protein-mediated membrane diffusion barrier" in the stalked bacterium, Caulobacter crescentus, which, ultimately is "critical for cellular fitness because [such barrier structures] minimize the effective cell volume, allowing faster adaptation to environmental changes that require de novo synthesis of envelope proteins."

Caulobacter have two forms of daughter cell.  'Swarmer' cell with flagellum for moving; 'Stalked' cell, with adhesive organelle, for adhering to surfaces. Swarmer cells soon differentiate into stalked cells (Wikipedia).
Like eukaryotes, prokaryotes also segregate proteins in the cytoplasm, the interior of the cell, into specialized "micrcompartments."  This is important, because different kinds of functions and reactions need their own local environmental conditions (e.g., pH, particular proteins or other molecules), without interference from other stuff in the cell.  So they do share this local organizing principle, but that prokaryotes also had protein-mediated diffusion barriers that determined the organization of the membrane was not previously known. Schlimbert et al. demonstrate this by showing that the stalk-cell body boundary behaves differently from the rest of the cell membrane, as molecules that are allowed to diffuse through the rest of the membrane cannot pass through this boundary.  The work is described in much detail in the paper, but for our purposes here, these are the important points:
Unlike in eukaryotic cells, these diffusion barriers not only laterally compartmentalize cellular membranes but also limit the free diffusion of soluble proteins, thereby providing a significant fitness advantage. Diffusion barrier formation in Caulobacter therefore represents a thus far unrecognized mechanism to optimize the growth of a prokaryote by restricting protein mobility within the cell.
Principles in action
This one very specific example of a microorganism in action illustrates very nicely some of the basic principles we've proposed. In particular, modularity, sequestration and adaptability.  If one were to have hypothesized ahead of time how prokaryotic membranes were organized, the idea that they were composed of specialized domains -- modules -- would have been an obvious first guess, and not just because that's how eukaryotic cell membranes are organized but because that's how all of life is organized.  And, modularity goes hand-in-hand with sequestration, but sequestration that isn't complete because some communication between the inside and the outside of the cell is essential.

Schlimpert et al. write that the presence of the cell membrane domains allows "faster adaptation to environmental changes that require de novo synthesis of envelope proteins."  Again, no surprise that adaptability is enhanced by membrane modularity, as adaptability is one of the most important traits that organisms have evolved, and probably one of the earliest because it's so ubiquitous.

As for the rest of our list of principles, they are simply inherent in the mechanics of life, and so of course in Caulobacter. Inheritance with memory is so basic that it's a given in terms of how organisms reproduce; memory being embodied in DNA.  Coding and interaction are fundamental to how all genes are expressed, and how receptors receive signal and so on, and because life is a 4 dimensional process, contingency is equally inherent; every step of development and of maintaining homeostasis or reproducing depends on what has come before.  Life also is inherently random and dependent upon cooperation; among genes, cellular organelles, micro compartments and so on.

So, again, a simple set of principles predicts and explains a tiny piece of life, because all of life shares a common ancestor; descent with modification for the last 3.5 billion years has given us the incredible diversity of life we see around us, but it hasn't changed the fundamentals.

Friday, December 14, 2012

Cat(fish) among the pigeons! Now how would an 'evolutionary biologist' explain it??

Here's a story -- catfish have been observed actually sneakily stalking, seizing, and eating pigeons!  Yes, real feathery pigeons hanging out on the riverbank, not some sort of pigeon-fish.  Here is the story that appeared in the journal PLoS One,  that has understandably been all over the news this week.



Now this is very interesting, not least because it's not clear how the fish do it.  Their vision is not generally thought to be good enough to be up to the task of spotting, then grabbing pigeons.  Instead, the 'whiskers' on the front of their face, technically called 'barbels' and from which the fish get their feline name, are sensory structures.  One explanation for their ability to hunt as predatory carnivores, and indeed prey on land-based, flying-capable, much more biologically advanced(?) birds, is that the barbels can pick up some aspect of the motion of the pigeons, perhaps the vibration that the birds make when they are drinking.

This may be so, but the video doesn't suggest that the pigeons, who appear to be searching for food at the river-bank's edge, are moving around or doing anything that might be detectable in that way.  Be that as it may, the fish are definitely succeeding as predators.

An evolutionary explanation?
Now, what would your normal Darwinian, selection-obsessed biologist (including reporters for leading science journals like the BBC and NYTimes) make of this?   Well, of course, they'd have to adopt some story about how the barbels evolved motion-sensing capability in times when water-based prey or other foods were unavailable, or for some other reason that led those with more sensible barbels lived longer, grew faster, had more spawn, and so on.  Over eons of time, the sensitive barbels evolved, and their duller compatriots went the way of all fish.

Such cock-sure explanations are the stock and trade of 'evolutionary biologists', a self-assigned title that seems to entitle a person to spin off any Just-So story that s/he can dream up. Darwinian adaptation via natural selection does seem to be real, and important, even if its actual day-to-day mechanism is much more elusive than is routinely assumed, and even if we can't really be sure of the 'why' of  adaptation even if we can be sure of the 'what' as it appears today.  That is, we can see what a structure can do, or does do, today, and nothing stops us from also 'assuming' that that same function is what the structure was evolved by natural selection for.  Indeed, we are making a leap of faith to assume that the function is what the structure is for today.

That would be like assuming my thumb is 'for' hitting the space bar, and evolved for that purpose back in Neandertal days.  Clearly my thumb is useful for such tool-related things, but just as surely it didn't evolve specifically for this type of use--or, perhaps, any type of tool use (though tool-use is certainly a plausible explanation).

Well, maybe not Just-So after all!
Unfortunately for our evolutionary biologist (or journalist echoing his/her story), these fish were observed pigeon-hunting in France, but are known historically to have been introduced from eastern Europe only just over a century ago.  They are, as far as we can tell from the paper, or another paper on the introduction of these fish into places like France (reference 11 in the PLoS One paper we link to above), not known to prey on pigeons or shore-wandering birds in the Old Country.

No surprise, the authors delve right away into showing, with a certain amount of technical flash, that the fish seem to be dividing up their ecology so only some prefer roast pigeon, others dine on more traditional fare.  And, right off the bat, they offer speculation about fitness and natural selection and adaptive strategies (with no direct evidence--as the authors acknowledge).  Even in something so quick to arise and so clearly behavioral, there seems to be a need to show that it simply must have 'evolutionary' importance.  It can't just be choice and intelligence and adaptability.

It may turn out that there are similar scenarios of birds on the river banks in the fish's homelands, and that the French fish's relatives do hunt them.  This could tend to confirm the story, and indeed it might add to its plausibility.  But the birds might be recent shore-dwellers there, thanks to human occupation or alteration of the local ecologies, too recent for selective stories to have much credence.  Or, the fish there could just be trolling without any genetic basis involved.

The absolutely vital research agenda
Now, premised on the belief that everything just has to be due to this kind of a Darwinian process, what can we expect from these new behavioral findings?

It is likely that we'll see proposals saying that studies are 'needed' to identify the genetic nature of this adaptation.  Some large number of poor unlucky catfish will suffer gruesome 'experimental' alterations or removal of  their barbels to show what it is about them that 'causes' this specific behavior.  These procedures will be dressed in language ('barbelotomies, sensory barbelneurectomies, barbelhemisections, translateral barbel reimplantations,....) so research review boards can approve them as not inhumane and worth doing for human good on various rationales.  Tissue will need to be imaged by CT scans and the fish wired for fMRIs as they hunt.  Costly  high-speed videography will need to be done to document the behavior down to the microsecond.  Then thousands of fish will have to be sequenced to find genotypes in those that hunt along the shore versus at the bottom in the usual catfishy way.  Big GWAS will find candidate genes, and then thousands more catfish will be studied with genetic variants introduced that makes them no longer able to tell a pigeon from a rock.  The news media and journals will hype periodic Big Stories about this, of course.

This will not be done by small fishery research labs, but by the major medical schools, who will snap up money in big gulps from NIH, faster than, say, a catfish grabbing pigeons.  Society will be the pigeons in this case, and the reach into our pockets will be justified by the argument (excuse?) that this will tell us about sensory behavior and eventually lead to cure all sorts of human behavioral diseases.  The promise will be that at birth people will then be 'diagnosed' if they have variants in the evolutionary same gene, so we can apply preventive measures.

Are these just our own kind of fish stories, or is this how it might actually go?

A cat among the pigeons?
In any case, the automatic assumption of a plausibility story as the true story is unjustified no matter how routinely such things are offered up.  There is an aspect of evolution, called genetic assimilation, that could be involved if there is any fitness (reproductive) advantage, even if there is no genetic basis for the behavior today.  In genetic assimilation, when or if genetic mutations arise that tend to push a fish to do this successful pigeon-shoot, and hence to have higher reproductive success, then Darwinian natural selection could favor those individuals and over a long time period the behavior really would become 'genetic'.  The species of catfish would become mandatory birdivores.  But this is many steps beyond the current data and there is no reason to think that such selection would occur.

Indeed, it might be--we'd say might far more likely be--that being smart enough to find different types of food is what's good for fitness, and getting hard-wired for skeet could make you vulnerable.  After all, if there's a cat among the pigeons, the pigeons that don't go to the shore for their vacations will live to fly another day and either for genetic reasons, or just because they're smart enough to stay away from danger, there would come a day, perhaps sooner than the catfish could evolve their birding behavior, when there just weren't any birds to hunt!  Then, their 'adaptive' species would simply starve to death--unless they were smart enough, and could override their genetic birding mandate,  to figure out what their distant ancestors did, and go scruffing around the river bottom for the less glamorous sources of food. 

A genetically-based Darwinian explanation is simply not required. Animals figure things out without having to be genetically programmed to do the specific thing they're figuring out. The most plausible Darwinian explanation is that fish evolved flexibility and sufficient brainpower to do what best presents itself to them.  Work by Victoria Braithwaite and a friend of ours named Paula Droege, here at Penn State, are in fact showing remarkably complex behavioral abilities in fish.

We are by no means the first to argue that reflex selectionism is a mistake, not science.  Even Darwin occasionally tempered his rhetoric about adaptation.  But his intellectual descendants (us) rarely have his level of IQ points, and are all too susceptible to giving standard sermons (that may be the right word for them) about how Nature is.  Sometimes they may be true.  Sometimes they may be true but not demonstrable by sufficient evidence--and in the absence of videos from thousands or millions of years ago, that makes them suppositions that are no more than  plausible from the point of view of science.

One should be more cautious if one wants to claim to be doing 'science'.

Thursday, December 13, 2012

Your genome is showing.

Thanks to my university's support of my new anthropology teaching initiative--using 23andMe as part of the curriculum--and thanks to its visibility here at The Mermaid's Tale, I was asked to speak about the experience at the California Academy of Sciences last month.

Because it was all arranged and sponsored by the Leakey Foundation, I tailored it for an audience interested in human origins and human evolution, which felt natural considering that's me.

Because I was slotted to speak while "NightLife" was also going on, I thought an album cover art-themed slideshow, something I've long wanted to do (thank you King Crimson), would be appropriate.
"Aaah! You mean 23andMe can tell all that from just my spit?"
The film of the talk is up at fora.tv, here at this link.

While I was in San Francisco I had two wonderful opportunities to visit schools, one high school and one middle school. At the high school I got to sit down for an hour and talk genetics with an evolution and genetics course! And at both schools I gave a presentation called "Your evolutionary history is showing," part of which included a little about how science is part of everyday life, like when you want to figure out which dog ate Kevin's book.

For the Cal Academy talk, I considered posting my transcript here, but I think I'll just post my gratitude.

THANK YOU
The California Academy of Sciences
The Leakey Foundation
Students in my APG 350 and APG 201 courses
The University of Rhode Island Provost’s Office
All the artists who created these album covers.
Timetree.org
Anne Buchanan - Penn State University
Ken Weiss - Penn State University
Jennifer Wagner -  University of Pennsylvania
Ellen Quillen -  Texas Biomedical Institute
Misha Angrist -  Duke University
Niall Howlett -  University of Rhode Island
Abigail Bigham -  University of Michigan
Chanika Phornphutkul -  Brown University
Lorraine Santy - Penn State University
Juliet Dunsworth – Oviedo, FL
Kevin Stacey - Peace Dale, RI
Marisa Nelson & Mark Ackerly - 23andMe*

*I am not paid by 23andMe.  I use 23andMe at the educational rate to teach anthropology.

Careful what you ask that gene.

One last thing. Please check out my students' reflections on their experience with 23andMe and with learning biological anthropology this semester at URI at their blog "human variation style" ...http://humanvariationstyle.blogspot.com/

Wednesday, December 12, 2012

Positive genetics

Ken and I spend a lot of time here on MT writing about what's wrong with human genetics.   We feel that too much money is being spent on approaches that don't and won't work, for reasons that should be obvious to all.  But, vested interests rule, not us, so there's no stopping the train.

But nothing in life or in science is black and white, and even when correctives might be due (or overdue), it would be wrong to suggest that there are no successes or that the claims are always exaggerated.  So, it's good to see a rare good genetics story, on the front page of the New York Times (and our local newspaper).  A girl from Phillipsburg, PA, just down the road from us here in State College, has been one of the first people to benefit from a new genetically driven approach to treating leukemia.

Emma Whitehead developed leukemia several years ago, at age 5, and was treated with chemotherapy in the traditional way, a treatment that is beneficial 85% of the time, but she was one of the 15% for whom it wasn't.  So, her parents sought and found an experimental treatment at the University of Pennsylvania that had been tried on a handful of people, including adults with a different form of blood cancer.

The treatment has had mixed results, for different reasons, some known and some not, but because it has worked so well for some patients the method is seen has having great potential.  So much so that, to the surprise of the researchers, Novartis, the drug company involved has committed to building a research center at Penn to advance the work.  Presumably they envision widespread application, and profit, even though the therapy must be individually produced for each patient.

The idea, described in the New England Journal of Medicine in August 2011 (no paywall) is to enlist the patient's immune system to specifically target his or her cancer cells by training his or her own T-cells to do the job.  Researchers remove T-cells from the patient, introduce cancer cell-specific antigen receptors into them with a lentivirus vector which inserts the receptor, and itself, into the cell's DNA (in this case, it's an inactivated HIV) and then reintroduce these treated T-cells into the patient.

When all goes well it seems to eliminate all cancerous cells, at least for some time -- in Emma Whitehead's case, 7 months so far, and in another case, also described in the NYT, over a year.  It's too early to declare patients cured, their doctors say, but some have gotten their lives back.

The case of the crossing-guard
Ken clearly remembers serving as a 'safety patrol' with a crossing-guard when he was in elementary school.  The guard regularly reported on a child living in her neighborhood who had been diagnosed with leukemia.  She reported seeing the child (of Ken's age) marching daily up and down the street happily engaged in day-dreams ....until one day the child did not appear.  He had died.

So, some anonymous little person simply disappears from the earth.  It was a poignant moment etched forever in Ken's memory, but that tiny, passing event was an unimaginable tragedy for the person and his family.  Every instance of such a thing that can be avoided should be avoided.  If striving towards such an end doesn't give a biomedical scientist's life meaning, it's hard to know what would.  Indeed, the piece in our local paper, a story by reporter Heather Hottle, ends with this quote from Emma's doctor:
“I’ve shown (Emily’s) picture when I’ve given talks internally at Penn and a couple times when I’ve given talks outside ... and every time I show that slide, I have a hard time getting through without choking up,” he said.
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Decades later, it had become clear that some chemotherapeutic approaches to leukemia worked better in children than in adults, and in fact had achieved substantial success.  We remember sitting next to a pediatric geneticist from Penn State's medical school, at some rubber-chicken dinner a few years ago, and he explained that this better result in children was due at least in part to their ability to withstand much more intensive dose levels than adults could tolerate.  So the cures were coming at a price, and in addition, they were based on the sledgehammer nature of much of cancer chemotherapy: if you kill all dividing cells, you'll kill all the cancer cells, and if the patient is still alive you can stop the therapy and the healthy cells will start dividing again.

More refined, specifically targeted approaches have problems (such as immune resistance to the therapy, and indeed in this case, the elimination of B-cells and thus the need for regular gamma globulin injections to prevent infection) but clearly are better both conceptually and in practice.  So this therapeutic approach serves as a heartening example of exactly the kind of application of genetics that Ken and I advocate all the time -- a problem like this for which a genetic approach can actually make a difference.  The treatment described here isn't genetic in the usual sense of inherited disease, but it does take advantage of knowledge about genes to produce a result.  While caution is still due this fledgling approach, it seems to have promise.  Yes, spend the money. 

Tuesday, December 11, 2012

One cause of aging does not fit all.....or does it?

Why do we age?  How can we stop it?  How best to study it?  These questions and more on aging are the focus of the Dec 6 Nature "Outlook" Supplement (open access).  The same questions that have been asked for decades -- if not millennia.  The Supplement abstract asserts that "Research into the mechanisms of ageing is yielding insights, many of them diet-related, into how we might not only live longer but also stay healthier as we do," and the introductory piece promises that:
Scientific efforts to extend lifespan are progressing on several fronts. A short-lived species can evolve into a long-lived one, and researchers are keen to find out how (S10). Studies in other species have already shown that a severely restricted diet can add years of healthy living (S18). Diet affects ageing in humans too — how our food influences our gut microbes, and how they in turn affect our health and longevity, is under investigation (S14). Another line of enquiry focuses on harnessing the regenerative powers of stem cells (S12).
Progress! So, having a long-standing interest in this subject, we thought we'd better check this out.  We read the papers, and, alas, it turns out that the Fountain of Youth has not yet been found.  Even with the latest technology -- stem cells, fMRI, genomics, etc -- basic questions about aging remain unanswered.

For example, what happens to the brain as it ages?  In the piece, "Cognition: The brain's decline," Alison Abbott writes that it's surprising how little is known about healthy aging of the brain.
Researchers still don't understand the mechanisms underlying the decline or the order of events. They can't explain why some people manage to stay cogent and alert well into their 80s, whereas others become slow-witted and forgetful in their 60s. They don't even know whether Alzheimer's disease is an abnormal pathological condition or simply an acceleration of normal ageing. And no one knows of any drugs that can help those who lose cognitive function as they age, or whether brain training programmes really help.
What is healthy aging anyway?  Aging researcher Eva Kahana says that her study on aging in a Florida retirement community shows that healthy aging happens when people move away from their families and into retirement homes in Florida.  Against all expectations.  Hmm....could there be a reason that reflects the kinds of study design issues we write often about?  Well of course, unhealthy people are a lot less likely to move away from their families into retirement homes in Florida.

Stem cells would seem to hold the key to un-aging, but stem cells in older people don't behave the way they do in younger people because, well, they're older, and figuring out how to enlist them in the quest to rejuvenate tissues and organs is a challenge.  And, might have unintended consequences, writes Peter Wehrwein.

Technology can be harnessed, however, and is being used increasingly to help elderly people with limited mobility or memory issues to retain some or full independence.  Sensors, beepers and so forth can call for help as needed, or remind people to take medication and so forth.  But then, we're very good at making technological advances, and figuring out how to use them, so this isn't a surprise.  And it is good news.

"Scientists are searching for a genetic blueprint that will enable humans to stay healthy and vital well into their old age," writes Michael Eisenstein.  The idea is that extremely old people are genetically protected from diseases of aging, such as cancer or cardiovascular disease, until well into old age.  So, researchers are looking for genes for "compression of morbidity" in "longevity genotypes."  This means genomewide association studies in centenarians, by and large.

It's hard to imagine how genes 'for' old age evolved, since natural selection doesn't have any way to act on traits that are post-reproductive, but researchers suggest that perhaps they arose and then hung around in long-lived families as "family heirlooms," without the "evolutionary momentum" to spread.  If so, they would presumably be fairly recent, since living past 100 is largely a recent invention.  A more likely suggestion is that, if there are in fact genes that contribute to long life, they have some other function as well. 

Sarah Deweerdt suggests ("Comparative Biology: Looking for a master switch") that by using short-lived animals like C. elegans and mice as model study subjects researchers are studying exactly the wrong species.  Instead it might be more fruitful to look at long-lived animals, to try to figure out why they live so long.  If there is in fact a single answer, or 'master switch.'

Single gene mutations apparently can have an effect on mouse longevity, extending life spans significantly as described in the piece by Katherine Bourzac ("Interventions: Live long and prosper").  But, this doesn't necessarily mean that single genes are responsible for the long lives of elephants or Galapagos turtles, or human centenarians.  Traits on the extremes of normal distributions are often found to have different genetic bases than the traits in the middle.  Intelligence and stature are examples of traits that work this way.  Single genes associated with longevity may explain it in the extremes, but may not explain the bulk of the population of, say, healthy octogenarians.    

And then there's the idea that calorie deprivation leads to longer lives, an idea for which the data seem to be equivocal.  Rhesus monkeys living on starvation diets for 25 years did not live longer than those on more calories (which we blogged about here).  They may have more resistance to disease, however.

Finally, researchers are studying the microbiome of elderly people and finding it to be different from that of younger subjects ("Microbiome: Cultural differences").  And the gut of sick people is populated by different bacteria than that of healthy people.  Whether the different microbiome is a cause or an effect of aging, or illness, is an unanswered question.

One size fits all, again?  Not!
There have been many decades now of aging research, and Ken has done his share of it (years ago).  The fervor for a simple explanation fits very well with our current era's belief in and hope for point-causation, something we can make a pill for, or engineer out of our genomes, etc.  Point causation is something conceptually derived from classical physics in a way.  And we have in biomedical history, decades when everything, so to speak, was caused by infection.  This all reinforced the materialist or 'physicalist' assumption that simple laws must account for everything, and in life that 'physical' must mean genes.

Whetting this feeling, besides all the careerist and other such motives, was a generally simple relationship among mammals between body size and length of life.  There were tons of misapplied evolutionary arguments and billions in grant funds wasted chasing down what some of us said clearly at the time were naive beliefs based on this, and the more serious underlying questions were rather neglected.

Still, the idea of a body-size determinant of how long an animal lives is appealing to one searching for one cause.  That's why telomeres and energy turnover per pound of body weight (with associated damage) and other magic answers had such appeal.  One cause, if we can only find it, must explain when we die.

That's strange, and again some of us were pointing this out long ago, because why we die shows no such thing.  We die of a diversity of causes that basically share no simple physiological or genetic relationship.  Cancer involves many mutations accumulating among cells during life; heart attacks from arteries clogging slowly up, diabetes from too much body weight or gradual resistance to insulin; stroke from arteries gradually hardening or weakening until one bursts.  There is no single physiological process that seems able to account for this.  Yet, the same disorders strike humans, dogs, horses, and mice at similar ages relative to their typical lifespan.  There is this total apparent difference in process, but a species, and perhaps brain or body size calibration (other branches of life have their own 'calibrations' and they don't follow the same pattern as mammals, though trees and frogs and sea urchins have their own general aging--see our recent 'immortal' jellyfish post for an interesting take on all of this).

But maybe there is 'a' way, after all...
One way (in principle) may account for it.  This is based on the observation that cells accumulate all sorts of damage.  Some of it includes mutation, but not all.  Some of it can be repaired but not all.  As cells divide and then cook along and then divide during life, there can be an increasingly damaged overall state for an increasing fraction of cells in a particular organ and, because each organ is physiologically different, among organs.  A paper in the current issue of the journal BioEssays presents some ideas of this kind in a newer, integrated way than was possible in the past.

When enough damage--whatever the specifics be--strikes enough cells, or strikes one cell badly enough (to start a cancer), then the organism, and not just its cell, is in trouble.  Call the preacher and schedule the service!

The interesting thing about this, which is again something Ken wrote about as long ago as the 1980s when much less was known about the cellular details, is that very different processes can accumulate damage in a way that increases similarly with age.  The rate of death from different causes may be hugely different in absolute terms (say, one in a thousand per year to one in ten thousand, etc., for different causes of death).  But they increase in a curve (called the 'hazard function') that has the same accelerating 'shape' when you graph it.

You are at risk from all of these causes every year, and every year the chance that you escape all of them to live another year diminishes.  As a result, we need not have a single cause that turns us off at some typical age. 

In a general way, this can explain how we can have a characteristic curve in our risk of death with age, even if each person goes by his or her own cause.  There need not be one underlying bullet with our name on it.  But this leaves open an interesting question, and in a way returns us to the reason that thoughtful people, at least, thought that aging might have a unitary cause:  Why do these accelerating processes accelerate at different rates in different species, in a way that leads to the correlation of length of life with body or brain size?

For example, a problem noted in a general way in the early 80s or before, by Richard Peto the British epidemiologist, but that we can put more precisely today is this:  Mice have similar cell types and similar genes and similar diseases and these even have similar rates of risk acceleration with age.  But if the same kind of accumulating damage is causing the same kind of result, why would a particular type of cancer hit a mouse more than 100 times earlier than it does a human?  If this reflects some underlying common cause, how can that affect so many different cell types so differently.

One can suggest an answer, but it's premature and this is not the place to air it....

---------
(Hefty contribution to this post from Ken.)

Monday, December 10, 2012

Adding the human context to disease ecology


Sometimes there exist subregions where, for a variety of reasons, diseases just tend to lurk and persist regardless of what is occurring in the surrounding regions.  An excellent example can be seen in Southeast Asia, where there exists malarious pockets surrounded by malaria free regions.  In Southeast Asia, these places tend to be hilly, forested regions and international borders.  For example, both Thailand and China have been relatively successful at eradicating malaria from much of their nations while continuing to have a malaria problem along their borders with Myanmar (also known as Burma).

So what is it about these places that make malaria eradication so difficult, at least on the China or Thai sides of the border?  Well, the simple answer is that it’s complicated.

This last summer I made a trip to the border between China and Myanmar to visit one of the field sites we are using in our malaria research.  My trip to Nabang, China began in Kunming (the capital of Yunnan Province), where I caught a plane to Tengchong and then caught a five hour ride through steep mountains to the relatively small border town called Nabang.

Directly across the China-Myanmar border from Nabang is a town called Laiza which at one point was a tourist attraction for wealthy Chinese, offering a legal gambling outlet.  Today the fancy new gambling halls are still up and running in Laiza and there are several relatively nice hotels in Nabang, both mostly empty and waiting for the tourists to come.  Lining the streets of much of Nabang are brand new, fancy looking street lights, none of which have ever been turned on.  Nabang has the feel of a Wild West gold mining town after the gold is all gone.

So what happened to this place?  Basically, war happened.

Downtown Nabang, with Laiza in the distance.
Laiza, which is in Kachin state, is named after the indigenous group (the Kachin) that has historically lived in this region of Northern Myanmar.  The Kachin are known for their fighting skill, they were our allies in this region during WWII, and they have historically been at odds with the ruling national government.  In 2011, after a 17 year truce, civil war broke out between the Kachin and the government military.  Unless you’re familiar with this region though, you’ve probably never heard of this war.  This isn’t the type of shock and awe war that we all saw when the U.S. went to war with Iraq or even the high-level shelling currently occurring in Syria.  Villages get burned in the middle of the night, women and children are kidnapped, raped and forced into labor, and military camps are occasionally ambushed.  It is a low grade, slow-and-steady war that claws at the psyche of the people living in this area.   

The KIA (Kachin Independence Army) is currently located in the Laiza Hotel, right in the middle of what was once a tourist retreat.  

What does this mean for the human ecology of the place?  
For one, it means that many people are clustering up near the border in make-shift camps for ‘internally displaced persons’ (what you’re called when you’re a refugee in your own nation).  When I was there, the people living in camps were working together in preparation for many more people to arrive.  

Villagers preparing for new people to arrive.
It also means that the population has a very unique composition, made up mostly of women, children, and the elderly.  Working aged men were mostly absent, except for the occasional young adults that would zip by on their motor bikes, donning camouflage and carrying AK47s.  Instead of helping out with household chores and working in the near-by agricultural fields, the men are moving covertly through the mountainous and forested landscape, engaged in warfare with the Burmese military.    

A KIA soldier riding through town.
And what does this mean for the disease ecology of the place?
By disrupting the everyday lives of populations, conditions are primed for disease.  Close-quarters mean that easily transmittable diseases will almost certainly move through the population rather than be confined to individual households.  Diarrheal diseases that are common in children may become a problem for everyone.  The same is true for airborne diseases such as influenza and tuberculosis.  For already stressed and sometimes malnourished people, this is an added threat.

Furthermore, vector borne diseases are an increased threat.  Newly cleared fields easily form water puddles when it rains, making excellent breeding grounds for mosquitoes.  Dengue fever could easily thrive in these camps.  And for a variety of reasons, malaria is already a growing problem.  

Some preliminary research in this area has indicated that working-aged males appear to disproportionately acquire falciparum malaria infections.  Given that most of these working aged males are living in the conditions of war, moving through the jungles at night, sleeping out-doors, and almost constantly being exposed to a range of mosquito vectors, perhaps this is no surprise.  

And what happens when they are too sick to fight?  One could imagine that they then come home, with a thriving population of parasites swimming in their blood.  A potential real danger, and one that my research is particularly aimed at, is that these individuals could then pass the disease on to their families and neighbors. 

Also, given that artemisinins have been available in Myanmar and China for decades, and since there clearly is no regulation of their use in Myanmar (especially in this part of the nation), conditions are also primed for drug-resistant parasites.  We are already seeing this on the Thai-Myanmar border, it isn’t a stretch to expect to find it in this region next.  

And if these pretty terrible conditions weren’t bad enough, there is another disease that has predominated in this area for some time.  It is a hotspot for HIV/AIDS –because there are thriving sex and opium trades.  (Note: The sex and opium trade bring in problems of their own, even outside of infectious disease.)  Much of the world has been privy to the knowledge about where HIV/AIDS comes from, how it is spread, and how to keep from becoming infected.  However, Myanmar has been largely closed to the world until the last several years, meaning that such educational campaigns are unlikely to have reached many outside of the wealthy, urban, or elite of this nation.   

What does this all of this mean for public health efforts?  
Clearly this isn’t an easy place to work.  It isn’t even an easy place to get to.  Our collaborators at Kunming Medical University have sent several teams of graduate students to the field sites here in order to collect demographic and epidemiological data.  Many of them don’t stay for long.  It is a depressing environment, there are frequent earthquakes, the heat is almost unbearable and AC units don’t work when the electricity is out.  Oh… and it’s a war zone.   This makes getting data difficult, and given the fluctuating population size and composition, it makes epidemiological modeling difficult.  This means it is really hard to fully understand the disease situation.  

The hospital in Nabang, China has been badly damaged by earthquakes.  Here it is being repaired and expanded.  This hospital sees a lot of malaria cases as well as wounded soldiers from the fighting.
Not all malaria endemic places in Southeast Asia are the same but there certainly are some commonalities.  Another malaria endemic border zone, along the Thai-Myanmar border, was until very recently also a site of ethnic tensions and occasional war.  The Thai-Cambodian border zone was a strong-hold for the Khmer Rouge up until the 1990s.  It was also a site of heavy, informal mining efforts, which led to living conditions that appeared very similar to the refugee camps I’ve seen in Northern Myanmar on the Chinese border.  Perhaps a common theme across these regions is the disruption of ‘normal’ human ecology.  These are places where people haven’t had the chance to settle in, to develop their homes and villages, and to fix problems associated with sanitation and hygiene.  

Perhaps it is too much to think that some of these regions will ever be malaria free.  But I can’t help but think that conditions would be much more controllable, perhaps even with a low, maximally acceptable, background level of malaria, if only the socio-economic and political conditions weren’t as they are.  And while it’s easy for me to say that if we could just stop warfare and fix poverty that we’d have a lot more success at controlling disease, clearly doing these things isn’t anywhere near easy.  However, these challenges can’t even begin to be approached until there is a widespread realization that these are in fact the underlying, downstream conditions that lead to bad human health outcomes.  

Main road through one of the study villages near Laiza, Myanmar.