Thursday, December 31, 2009

Cancer as an 'environmental' disease -- a revolution?

Cancer and the environment
There is a very good story in the New York Times by Gina Kolata, one of their long-standing best science writers, about the nature of cancer as an 'environmental' disease. She lauds a paper by a Dr Mina Bissell some 20 years ago that, she writes, has proved prophetic.

Prophetic, but one might say that cancer has always been viewed as environmental in that it can be thought of as a set of diseases that arise because of exposure to mutagens, like cigarettes smoke, dangerous chemicals, radiation, and so on--as well, of course, as our old nemesis, chance (because mutations can always arise by chance).

The usual idea is that carcinogens cause mutations that lead cells to go out of control, locally forming a primary tumor, then sloughing off into the circulation to spread elsewhere in the body (that's a process called metastsis). These somatic, or body-cell, mutations are not inherited because they're not in the germ line (sperm or egg cells), but they are inherited by descendants of the mutant cell in the body. In this sense, at the level of a cell, cancer is a disorder of mutant cells going off on their own, an invasion of genetic aliens. The cell does this because its genes have been modified to make it not respond as a normal part of you as it should, but as a kind of genetic alien.

The cellular environment
But this story seems to be different. It's about the cellular environment. Kolata lauds work of several decades' standing that shows that cancer is about cells whose behavior is abnormal relative to the context of their local tissue environment. That is, the cells are not just bad actors per se, but bad in that they don't listen to instructions from their neighbors about how and when to divide.

This is just the kind of thing that our book The Mermaid's Tale is about--the way life works at the cell level, in which genetic messages regulate interactions and their dynamics in time and space. Cancer is a good illustration of these principles, of partially sequestered units whose actions depend on their sensing of their immediate environment. Cancer cells resemble the 'cytospecies' we discuss, referring to separately differentiated cells that, despite the same genome, behave differently to form our various tissues. That's how development works, and how it can go awry even in adults ('awry' for normal cells, but of course the mutant cells are having a proliferative blast at your expense!).

However, Ms Kolata refers to cancers that arise apparently as the result of other causes, such as injuries, in which cells become confused and misbehave not just because of mutation but because the event leads them to misperceive their cellular context. She quotes the much-overused phrase 'paradigm shift' in the lauding of Dr Bissell's ideas by an award committee. By itself, that's a mistake. There is nothing conceptually new or unusual about viewing cancer as a disease of context-misbehavior of cells. That is the prevailing view of cancer.

Dizzied into incoherence
Now, if anything is novel here, it would be that after injury the misbehaving cells are not mutant, but are just part of the person's genetically normal cells that, dizzied by injury into incoherence, start to express aberrant receptors or respond to signals from nearby cells in a way that is erroneous for that particular tissue type. But once confused in this way, the cell doesn't come to its senses and regain its bearings.

If that is the case, then cancer would be a disease of aberrant signaling not necessarily due to bad genes (mutated by environmental agents, chance, or inheritance), but to bad genetic behavior whatever the cause. If cellular life is complex, you can get screwed up in lots of ways, some by permanent genetic change, others by misunderstanding. Either way then, of course, you're screwed.

Some evidence that could be interpreted this way has to do with regressed tumors that never become lethal (we've referred to such evidence in commenting about the risks of over-treatment due to excessive 'diagnosis' by over-screening such as by mammography). Of course, there are other ways tumors, even caused by somatic mutation, could eventually be detected by surveillance mechanisms of various kinds. So, regressed tumors don't really give unqualified support to Bissell's ideas.

Another possibility is that the injury-induced tumors did, in fact, result because of mutant cells that by chance hadn't yet produced a tumor. It has long been the standard theory that other factors (often called 'promoters') work with somatic mutation to cause tumors: examples are irritants that lead to cell proliferation that could make cells vulnerable to mutation. That's one idea of why colon polyps may predispose to colon cancer.

Since every cell division leads to mutations in genome, every organism is loaded with cells that have slightly different genotypes from what the individual inherited. Recent papers have confirmed this idea and suggested that large numbers, even thousands, of somatic mutational changes may be involved in cancer 'transformation'. So an injury may simply give an advantage to cells that are mutated to be hyper-responsive to the blow and then spin out of control.

Paradigm shift?
This won't be a real paradigm shift in the proper sense of a truly transforming change in ideas, like Darwin vs creationism was. If trauma is just a trigger that gives environmental advantage to mutant cells, it won't even be a change in current thinking. But if the injury is inducing genetically normal cells to misperceive their environment, this would be a change in our understanding of the proximate nature of cancer (which has been that it takes abnormal genotypes leading cells to misbehave). Even then, it would not change our understanding of cancer as errors in cellular signaling and response, and hence in local cellular 'environment.'

So this is an interesting article and stimulates thought about the nature of an important class of diseases, and the continuity of life-processes from the cell-to-cell, to the organism-to-organism and on up, as they evolve in response to each other. Avoiding mutagens may not be enough to avoid cancer. 'Promotors' may be enough. But it is a lesson not in paradigm shifts but in understanding the ultimate cause of cancer, rather than its proximal or immediate mechanisms.

Wednesday, December 30, 2009

The (lawless) laws of (human) nature

This week on The Forum, a BBC radio program, Bridget Kendall presented a show on translation -- specifically, the translation of Chinese poetry into English, the translation of science for the public, and the translation of the fall of the Berlin Wall -- what is gained and what is lost in translation. One of her guests was British Astronomer Royal, Lord Martin Rees, who has written a number of popular books about cosmology and astronomy.

Kendall asked Rees how scientists benefit from interpreting their science for popular consumption. He said that scientists often have a difficult time thinking beyond the details and remembering the larger picture, so that having to explain the big ideas is good for them. Kendall said that it must be particularly difficult for a cosmologist because people tend to feel that everyday phenomena should be easy to understand, but grander things like the cosmos are much harder. Rees says that's not true, that everyday things that people really care about, like diet or child rearing, are in fact much harder to understand than the stars; even experts don't understand them. If they did, ideas about what's healthy to eat or how to bring up a child wouldn't be changing all the time.

Now, we can't say whether or not cosmologists really have deciphered the stars. But, in some senses it doesn't really matter how much they've got wrong, because what we do with what we know about stars isn't nearly as relevant to everyday life as what we make of advice about what to eat and the like. Rees's point is reminiscent of things we write about all the time.

Why don't we know these things? We aren't stupid (well, 'we' here refers to science generally!). What is it about complex phenomena that's so hard to deconstruct? How on earth can a measly human be more problematic than zillions of stars, galaxies, and even voracious Black Holes!?

Why can't science even tell us what to eat? Here's our explanation -- we think it's because organisms have evolved to survive in a wide range of environments, and environmental changes can have from no to little to crippling to fatal effects, and their effects can vary along that continuum, even within a given species. This makes prediction nearly impossible, and the effects of change nearly undecipherable, due to the confounding effects of other, unnoticed, unmeasured changes, or to the fact that most changes don't happen in isolation.

Just as genes don't function in isolation, but in networks of genes, all of which are taking the measure of their environment all the time, via signaling, and responding by emitting signals of their own, to which other genes respond. And even when the information is false, in our current society, as soon as the latest Now-Eat-This story appears in the media, we modify what we eat, what kind of exercise we do, and so on, which then can change gene function and interaction, and down the road, disease risk. Stars, so far as we know, don't change their orbits just because some astronomer announces a different equation!

Which all, in a convoluted way, brings us back to Freud. Freud's explanation for behaviors was that they were the result of early childhood. One's upbringing. As opposed to the genetic determinism that's so prevalent today (though, in either case, mothers still get the blame). Well, we wouldn't go all the way with Uncle Sigmund, but there is clear evidence that even things happening in utero affect later life -- behavior, language, and even the late-onset disease risks. And add to this the way we meander according to our cultural fads and self-help advice, much less our exposures to chemicals, diets, lifestyles, and so on.

What's built in is our ability to assess our environment and act as we think is best, and that starts right at the beginning. What we're wired 'for' is not to be too wired, but to be responsive. That's a claim Betelgeuse can't match, and why the stars are condemned to circle obediently while our fault is in ourselves, not in our stars.

Saturday, December 26, 2009

Blown out of proportion, or culture rules!

So, to 'celebrate' the holiday of peace, some guy tried to blow up a passenger plane on Christmas. That's religion for you!

Martyrdom is self-willed unfitness from an evolutionary point of view, unless misguided Islamic martyrdom-seekers think that screwing the promised 72 virgins will increase their fitness (if that's what they think, too bad for their misguided souls, because the text apparently promises raisins, not virgins....but that's another tale). So how does hard martyrdom, and its softer versions such as the self-imposed chastity of priests (sorry to be disappointing, but little boys don't count towards evolutionary fitness) come about?

After 4 billion years of evolution, how can these various forms of self-willed non-fitness be possible? How can the genomes of any species, much less the most 'advanced' one on earth, still allow it? This has been a driving question in sociobiology, and many answers have been given. Religion is an illusion due to a 'God' gene, that evolved because it leads to group cohesion. Altruistic self-sacrifice perpetuates your relatives' genes. And other post hoc excuses.

Before the field went off the deep end, anthropologists did their duty to point out that culture, the characteristic human way of life, is a phenomenon of its own that  basically does not depend on specific genotypes. What's in the human genome in some senses that we don't yet understand is the ability to have culture, not the details of any given culture.

Individual humans can behave in all sorts of ways, and clearly some of them are affected by specific genotypes (like the famous inability to digest milk in adults, or various psychiatric disorders that clearly have a genetic component). But overall, any humans can have any culture. Culture is a phenomenon that evolves in its own way, basically independent of the specific genomes of its bearers.

One can be the most promiscuous or the most martyrial in the same culture. Harems and jihad, prostitutes and priests. The possible states range across the entire spectrum, within any given culture. Clearly too much self-sacrifice would doom a group, but even that has occurred (as in the Spartans defending Thermopylae). But on the scale of human evolution, and given the pre-human billions of years, these things are not specifically tied to specific individuals' genotypes (the two Spartans who passed on Thermopylae later committed suicide, one at home and the other in his next battle).

That we are affected by our genotypes in both our physical traits and our behavior certainly seems true. But that we are pre-determined by them is not an accurate way to view human life. What we are pre-determined 'for' is the ability not to be predetermined for specifics, but to be able to absorb our societal environment (our culture), to assess our specific circumstances in that context, and to act upon it. But the range of action, and the accuracy of our assessment are wide and not, by and large, due to our specific genotype. Or, if they are, as we noted in a recent post on randomness, there is so much individuality that we are largely unpredictable in terms of individual genotypes.

It is the determinism of our nondeterminism that we think should be the object of neuroscience research. How material forces can follow natural law yet, in aggregate, evolve to be unpredictable is as philosophically and scientifically profound a question as any that humans have to think about.

Friday, December 25, 2009

Murder and mayhem illustrated, thanks to Gary Larson

Ken was very pleased to receive The Complete Far Side for Christmas.  He loved Walt Kelly's Pogo when he was growing up, and the only other cartoonist who ever came close was Gary Larson.  So, the collection is a real treat.

Not to mention a cartoon for every occasion, including our recent post on murder and mayhem in the kitchen.

Thursday, December 24, 2009

More than just 'holidays'

Many if not most human cultures have some kind of celebration at around the beginning of winter -- our holiday season.  Not just a time for food, drink, and gifts, we are supposed to reflect on life -- peace on earth, goodwill and all that.

But peace? Goodwill? Is't possible? Can humans really manage that, or are we programmed for selfishness and conflict, as is so often asserted?

If our genes make us what we are, then the prospects are bleak. The philosophical idea of 'free will' is a phantom.

But, to us, that's too simple -- even without becoming misty eyed, much less mystic, one can assert that, mere collections of molecules though we may be, we are not automotons.

There are at least two substantial ways in which this is so. First, there may be truly probabilistic aspects of nature and thus, if each atom is essentially probabilistic -- moving around and bumping into other molecules at random, then the law of large numbers may mean that in some ways our states are constrained -- it's exceedingly unlikely, even if possible, that all your molecules and a wall's molecules would line up such that you can walk through the wall. However, the countless molecules and cells of which we're made work, and developed as we were embryos and as we live, in so many probabilistic ways that there is much greater latitude in our behavior than is often stated by people searching for what makes us human. Even if each molecule's movement follows some probabilistic behavior, development and subsequent life are contingent: the state today, no matter how probabilistically derived, sets the stage for tomorrow with its own probabilistic elements.

This would be true even if there is nothing truly probabilistic in Nature. If even the positions of electrons, that seem to be probabilistic, are actually following some law that we just haven't figured out yet, still there is so much unpredictability in ourselves, and in our social and physical environments, that we are largely unpredictable, when it comes to complex things like behaviors, which are often, if not typically, hard even to define.

That means that, generally speaking, the amount of predetermination in our behavior is small, perhaps even negligible. And thus, there is at least a substantial degree of what is for every practical purpose free will, so that we can in principle will freedom from genetic determination in many ways. If as a species we can't manage to do that in practice and persistently repeat tragic actions, it is in ourselves, and not in our stars, that we are underlings.

Perhaps in this season of reflection we might put more attention on how our molecular nature allows us to be unpredictable and hence able to make decisions, than the amount of attention that is currently spent on trying to find out how we are predetermined in almost any trait you can name.

So we don't celebrate holidays because our genes (or the devil, or the advertisers) make us do it -- it's a choice we make. But can we do more than that? Can we be better at living up to what we say we believe in? At least, it is a hope we would express at this time of year.

Tuesday, December 22, 2009

Murder and mayhem in the kitchen!

Now, those of you who worry about the turkeys that have been slaughtered for Christmas, or the pig whose ham many people will be dining on, give a thought to what those turkeys are being stuff with or those hams being eaten with: the poor, unsung vegetables.

If you think that the yam you pop in the oven to roast or the potatoes you boil only to mash, or the carrots and onions you dice up to cram into the turkey, love to be roasted, boiled, mashed, diced and crammed, then think again.

As a story in the New York Times today describes in nice detail, plants want to live life to the full just as much as you do! A tomato is filled with seeds, live little babies, and they don't want you crushing them with your teeth any more than you want your neighbor's dog to crush your leg with his! Natalie Angier points out in her story that plants have many defense mechanisms to prevent being eaten, and they often work well against caterpillars and insects -- but most plants have developed no defense against humans.

Well, from an evolutionary point of view, that's totally untrue, you might say! Nothing has been so good for cowdom or tomatodom than humans. We've given them huge selective advantages over their scrubby wild competitors. Corn and soya rejoice! Of course, unlike the holiday spirit, evolution works by differential survival, not by euphoria. So the price the agricultural species pay for their incredible success is that they live short lives, ending in capital punishment--often of cruel and inhuman (and hence thoroughly unconstitutional) means. A lot of people against the aborting of human fetuses, don't give a lick of a thought about aborting the lives of thousands of tomato fetuses in every bite of their lasagne. Except the lick of their chops. So unfair and inconsistent are we!

Our food decisions are thus already a bit of a negative capability dilemma for many of us, as we decide to eat fish but not mammals, or anything without a face, or free-range chicken but not factory raised. But, extending our sympathy to vegetables makes it a bigger dilemma yet, as we have to eat something. It forces us all to recognize that, no matter how we manage the ethics of our food decisions, we all kill to eat.

We have no answer for this dilemma, but as we said above, at least include the innocent victims in the thanks you give to Whomever you give them to for the blessings of your holiday meal.

Monday, December 21, 2009

"There is a triple sight in blindness keen"

Well, it's the quiet season, one for peace and reflection on the nature of life and friendship. So while everyone is (over)indulging in good times, we felt we would not just slow down our post-speed but also change pace a bit. Here is something to think about:

I had not a dispute but a disquisition, with Dilke on various subjects; several things dove-tailed in my mind, and at once it struck me what quality went to form a Man of Achievement, especially in Literature, and which Shakespeare possessed so enormously - I mean Negative Capability, that is, when a man is capable of being in uncertainties, mysteries, doubts, without any irritable reaching after fact and reason-

So wrote the poet, John Keats, in a letter to his brothers in 1817. And, in a related vein, he wrote in his sonnet, To Homer, in 1818:

...Aye on the shores of darkness there is light,
And precipices show untrodden green,
There is a budding morrow in midnight,
There is a triple sight in blindness keen...

Negative Capability has been read by some to mean, as in the example Keats uses in his letter, the Shakespearean ability to suspend judgment and have complete empathy for a character, or by others to mean suspension of disbelief, so that a mystery needn't be considered a mystery. Still others have applied the term to people like Barack Obama and his ability to find no contradiction in making peace through war. Indeed, Keats himself in his sonnet seems to be making non-contradiction of contradiction, reinventing Yin and Yang.

Negative capability can also be related to the understanding of what we don't understand in what our old friend, Stanford historian Robert Proctor, coined as the field of 'agnotology', the study of culturally induced ignorance. It occurs when things are intentionally misrepresented by scientists or those who have something to gain by doing so.

Negative capability seems to be a Rohrschach test, interpreted in many ways, and applied as people see fit. So, we here apply it as we see fit, to genetics.

We've written often before on this blog (e.g., here and here) about genomewide association studies, and why they don't, and can't be expected to explain more than a fraction of complex disease risk. And we've published papers on why we shouldn't expect complex diseases to be reducible to single genes (e.g., here). So let's here define negative capability as the ability to accept complexity on its own terms. The beauty of Keats' idea, to us, is that rather than knocking our heads against the wall of reductionism, we should accept that complex diseases are complex, accept that our methods aren't capable of explaining each case of disease genetically when everyone has his or her own unique genome, because science relies on replication for explanation and prediction.  But more importantly, we should accept that we really do understand complexity. The mystery is that people continue to see it otherwise.

It is ironic because in this, the season of trying to understand life and its meaning, we think that science shows us what we don't know as much as what we know. Really knowing what we don't know, or even that which with current methods and concepts we can't know, is a valuable kind of knowledge. Most scientists seem to fear this and indulge in agnotology by promulgating ideas that what we don't know we soon will know (if we have enough more grant money).

Instead, much of life's mysteries are not as mysterious as they seem. When things are really complex, it may be that our methods in science cannot untangle them into usefully understood individual components or interactions, if only for statistical reasons of the sample sizes needed to do it meaningfully.  No need for irritable reaching after meaning that can't be found.

Meanwhile, we do know that many things could be done with respect to preventing complex disease, if that were really the goal. For example, nutritional reduction would remove vastly more diseases related to obesity than genetic measures, and at a fraction of the cost. How much climate change is due to humans may be unknown, but we do know that climate is changing and we know what that's doing. We do know that cutting back on our level of consumption will have many material benefits, and history shows that people can be just as 'happy' as they are today when consuming less.  And so on.

So, in this time of reflection we might reflect on how to use what we do know to further societal objectives, and understand what we don't know, rather than just hoping Santa will come down the chimney with all the answers. 

Enjoy being in mysteries, uncertainties and doubts...

Happy Holidays
  Anne and Ken

Friday, December 18, 2009

Goat massage

One of the great things about having goats, and there are many great things, is the massages they give, if you ask my sister, Jennifer.  When she has a free minute, she'll often go out into the barn, lie on the hay, and treat herself to a well-earned massage.   I've done it, too.  It's the perfect way to go from, say, putting in hay much of an afternoon to mucking out a barn.

The other day, a reporter came up to do a story on the farm.  One of the first things she asked was if she could have a goat massage, because the same picture here is up on the Polymeadows Farm website, and she liked what she saw.  Jennifer said, yep, as soon as they'd finished talking, the woman was welcome to a massage.  The goats would be delighted to oblige.

So, at the end of their tour, Jennifer lay down some fresh hay in the barn, the one where the youngest kids hang out, lent the reporter an old barn coat because she'd showed up in not-really-farm clothes (a nice pair of black leggings and a jacket) and showed her what to do.  The reporter lay down and got her massage.  She loved it.  When she was finished, she stood up, brushed the hay off her knees, and swapped the barn coat for her own.  She was ready to take off for her next stint.

"Where you going after this?" Jennifer asked.

"A wine-tasting," the woman replied.

Jennifer smiled.  "Those hoof prints on the backs of your legs are going to be a nice conversation starter!"

Thursday, December 17, 2009

Copy cat!

Yesterday's post on the cancers likely to be induced by CT (sometimes called "CAT') scans in medicine raised the feline image, and we'll pursue it a bit further, but in a totally different way: about the biology of copy cats.

One of the recent flurries in genetics, which is using up a lot of ink, paper, publicity, and grant funding, has to do with what is called copy number variation (CNV). People are finding that genomes are loaded with additions or deletions of segments of DNA such that in some human genomes there will be one copy of a segment with whatever genes or other functional units it contains, and other human genomes will have that segment duplicated (or even sometimes multiplied more than that) or deleted.

The fact that we vary either between the two copies of the genome that we each carry (one inherited from each parent), or between the genomes of different people, explains the 'V' in CNV--for 'variation'. The realization that there's all this variation is very different from the standard, stereotypical view of 'the' human genome, which doesn't actually exist: each of us has two sets of chromosomes, no two of which are alike. 'The' human genome is an arbitrarily accepted reference sequence, not even of any one particular individual, that we use for comparative and other purposes. Sequences that differ from this reference sequence are then called variants.

CNVs are potentially important discoveries and of course, for various reasons, have become the focus of searches for genetic causes of diseases that refuse to be mapped the old fashioned way (by variation in specific gene sequences). Some evidence for this has been found, and it may prove useful, at least in relation to some disorders.

But the ballyhoo over CNVs reveals a few things that are telling about the way science works, and in a sense, about the not-so-profound level of understanding that is widespread even in much of the biomedical community. It's the idea that we have a particular genome structure that varies by single nucleotide changes (the standard idea of 'mutation'), or else by unusual one-off chromosomal anomalies (such as in the triplicated chromosome 21 found in Down Syndrome).

That simple idea of inheritance was the classical one, largely due to Mendel's work in peas that showed that variation is due to altered states of specific entities we now call 'genes'. It seemed valid, more or less, until a bit past the middle of the last century, and it is still widely assumed and taught today.

Thus, when CNVs are discovered, much ado is raised as if this is some sort of paradigm-shifting change in our thinking. But that's not true. Even by around 1970 it had become clear that most new genes arise as duplications of various sorts of existing genes. The highly structured nature of genes (with coding and non-coding parts and so on) would be very unlikely to arise by accumulations of single nucleotide mutations. What happens is genes change by mutation, but arise by duplication (we discuss this and some of its nuances in our book, because regulatory regions seem often to arise by the latter, classical form).

In fact, it appears that in many living lineages including our own vertebrate ancestry, there have been duplications of the entire genome.

We've known for decades about the gene 'families' that result from duplication and, essentially, that all genes are members of gene families with this kind of history. For the reason of that universality, there's no point in citing an 'example'.

So what's the big deal? Nobody can be surprised that gene copy numbers vary, since we've known for 50 years that that is how genomes evolve. This obviously means that copy numbers must be variable in their population until the ones that eventually become fixed and hence part of their species' stereotype genome sequence do become fixed.

Unless you don't believe in evolution, or believe that it stopped in ancient times, which would almost have to be explained by some kind of made-up theological view, you'd have no reason not to expect that the same must still be going on today. CNVs would have to have some kind of frequency and population distribution that, like those of any single-nucleotide mutations, reflected their effect, population size, and other things that control the change of frequency of genetic variation.

And how can it be a surprise that CNVs have effects on traits? After all, the members of gene families that we have long known of, like the hemoglobin genes and countless others, have different functions: the more ancient their duplication origin sometimes the more different those functions are.

Nor can it be a surprise that a sudden copy number change might alter various cellular balances that were established over long time periods, and hence could be related to disease.

CNVs might not have been specifically predicted in their current biomedical obsession, but they have long been entirely predictable. We knew gene duplication occurred, and their subsequent dynamics necessarily means they are variable in their respective populations.

CNVs may or may not turn out to be highly important in a public health sense, but they seem surely to be so in some specific instances. Technology has enabled their discovery to accelerate and provides ways to look for CNVs. But they are in no way surprising or conceptually new. The conceptual issue is how, in our thirst for simplicity, anyone could be surprised. Indeed, if genetics and evolution are taught properly, CNVs are simply part of the way that evolution works.

The copy cats have been those books and instructors (yes, including yours truly) and classes that somehow ignored these things. We taught that once genes were duplicated they could accrue different functional variation, but we simply ignored or didn't think about the fact that each one that appears to be different between species had to have a long sojourn of polymorphism on the way to becoming fixed. And the new copy cats are copying the fad and treating CNVs as if they were some sort of astounding new finding in our understanding of life. That's mainly grantsmanship.

Wednesday, December 16, 2009

Scat CAT! Get the picture?

A story on the Dec 15th NPR site (Radiation From CT Scans May Raise Cancer Risk) provides a discussion of the risks of cancer induced by the proliferating use of CT scans in medicine. The estimate is that as many as 29,000 future cancers may be caused by the 72 million CT scans done in 2007 alone, and as many new cases induced each coming year if practices don't change. The story also presents a graph of these possible cases (and about 15,000 of them estimated to be fatal).

It's sometimes said, reassuringly, that the amount of radiation a patient receives from one chest scan is equivalent to the natural radiation exposure from one transcontinental flight, but the amount of radiation can vary so much per scan that some are equivalent to 500 transcontinental flights. Or even the dose received by survivors of the atomic bombs dropped on Hiroshima or Nagasaki. And those caused, and are still causing, increases in cancer rates in those survivors (more or less so, depending on distance from the epicenter). This is no joke, if you get the picture.

We've said many things before about competing risks, and this is an excellent example. It is directly comparable to the recent controversies about mammography, though (as we've discussed in previous posts) the recent controversy has been about over-detection of tumors that would regress on their own, rather than about the risk of x-ray induced cancer, but that was a major reason why the recommendation has been not to start until menopausal or post-menopausal years.

A major part of our book is devoted to describing how life is characterized by partially sequestered environments -- in this case, cells -- that respond to each other and behave as a result of signaling and related processes. Radiation damages DNA and can cause a gene to be mutated and or misexpressed, altering the cell's function. Our cells have DNA-repair mechanisms that can detect changes under some conditions (e.g., when the two strands no longer match and fit closely together because one of the corresponding nucleotides has been altered).

But if the cell doesn't detect and repair the change, the cell permanently is on a misbehavior track. This can be especially dangerous when the mutation is in the genes responsible for DNA repair itself.

Since a tumor cell, unlike a bacterial cell, is part of you, your immune system may not be able to tell that it's not doing its proper job. It or other tissue-order-retaining mechanisms may thus fail to maintain the proper order. The tumor cell divides, and divides, and divides: it is an internal engine of life that is no longer receptive to external signals, and the external police can't detect it.

But the whole picture is more than a CT inset. If CT is useful, it's presumably because it detects serious disorders. We know now that a fraction of those would not actually need to be treated, as in the case of mammography and other diagnostic tests. That means needless cost and morbidity. On the other hand, if the CT scans do lead to effective treatment of serious disease, then people will live longer. This means that some of them will get cancer (unrelated to the CT radiation exposure) or other diseases of aging, as well as the iatrogenic (doctor-induced) cancers. So there's no simple winning or losing here.

Tuesday, December 15, 2009

The non-humanness of human language

The aspects of human language that make it uniquely human remain an open question, but the short answer is that there isn't as much that's unique as had once been thought. That is, it seems that much of the foundation for our language perception and speech abilities was laid down long before the evolution of hominids, and is shared by even distantly-related species. And, a surprising lot about language that seems uniquely human seems to be learned rather than innate.

We've blogged here before about birds and cows, among many other non-human purveyors of sound and meaning, having regional dialects, about non-human primates, and dogs, learning and responding to basic human language, and human newborns seeming to cry in a way that reflects their native language. Language acquisition and its evolution are very active areas of research. The results of two studies published last week are further evidence of language abilities that aren't ours alone.

A paper published in the Proceedings of the Royal Society B (Zebra finches exhibit speaker-independent phonetic perception of human speech, Ohms et al., paper published online Dec 2, 2009) reports that finches are able to discriminate between two vowels in single-syllable words, independent of the speaker.
There is an ongoing debate about whether the ability to form phonetic categories that underlie such distinctions indicates the presence of uniquely evolved, speech-linked perceptual abilities, or is based on more general ones shared with other species. We demonstrate that zebra finches (Taeniopygia guttata) can discriminate and categorize monosyllabic words that differ in their vowel and transfer this categorization to the same words spoken by novel speakers independent of the sex of the voices. Our analysis indicates that the birds, like humans, use intrinsic and extrinsic speaker normalization to make the categorization. This finding shows that there is no need to invoke special mechanisms, evolved together with language, to explain this feature of speech perception.
And, a report of a long-term study of vocalization among Campbell's monkeys in the Ivory Coast, suggests that these animals are able to combine sounds to make new meaning in response to external events, such as the sighting of predators (Campbell’s monkeys concatenate vocalizations into context-specific call sequences, Ouattaraa et al., PNAS, published online Dec 9, 2009). "These call combinations were not random, but the product of a number of principles, which governed how semantic content was obtained."

The trend seems to be toward a chipping away at specifics that have previously been thought to make human language a singular attribute of our species, or at least as singular as many would fancy it to be. It seems likely that there's no one aspect of our language and perception capabilities that can explain how we alone have the ability to give abstract meaning to sound or to convey completely new ideas between ourselves in the open-ended ways that we do.

Language is another complex trait that can't be explained by reducing it to its many parts -- the use of prefixes, suffixes, the effect of a single gene, our sound discrimination abilities, and so on. Instead, it's an emergent property that flows from what our brain allows us to make of the world, combined with our biological ability to make and detect sound (although, that's clearly secondary and not essential, as the complexity of sign language used around the world demonstrates), and built on a foundation that has been evolving for millions of years. Hundreds or thousands of genes are required for this, as the plethora of mutations in genes that affect cognitive abilities including language clearly show.

This makes sense. Every trait evolves from precursors. Every step of the way we humans are shown not to be unique but to be more a part of the Nature that produced us -- even if, albeit, every species is, almost by definition, unique. It is hubris to think otherwise, be it with respect to language or even consciousness. That doesn't take away in any sense from the interesting question of what humans are and how we got that way -- and why we are as much different from other species as we are.

And, of course, if anything, it is more evidence against those who cling hopefully to the idea that we were specially created outside of Nature rather than evolved within it. Each discovery of the role of environments in molding our basic abilities, or of characteristics we share with other species, even very distant ones, confirms our place in Nature. And it stimulates further interesting research. But it won't lead to easy categorical conclusions.

Monday, December 14, 2009

Personalized Genomics--for the investigator!

GWAS, or genomewide association studies, that claim that major common diseases are due in major part to identifiable genetic variation, have largely been discredited relative to the heavily over-hyped promises that led to its massive global funding levels. Many variants associated with studied diseases have been found, but they typically account for only a small amount of risk, even though many large studies have been done. The promise of near immortality that was made by those who would benefit from the grant largesse for GWAS has not exactly been met.

Of course, being discredited is only in the sense of its being used by the same perps as justification for even bigger and more of the same, only under a different name (e.g., biobanks and personalized genomic medicine). Those in the know know, and knew, that this kind of research was hyped from the beginning. We've discussed why in many earlier posts so won't do that now.

A recent commentary in The Economist points out these disappointing results as a dirty little secret that, the author says, will be revealed in 2010 when analysis of all the GWAS in the pipeline is completed, and it turns out they don't explain much. What then for disease genetics? The commentary doesn't really say, but it does end with a sales pitch for a different point: we'll be getting whole genome sequences on large numbers of individuals, and this will lead us to understand group (read 'race') differences. He acknowledges that this might have some negative consequences, but is basically sanguine about it.

That approval might seem curious, until you see that the author is an evolutionary psychologist. That's a field built on an insistent belief in genetic determinism, and the commentary ends with absolutely standard determinism and essentially the justification for continuing more and more DNA-based approaches to everything and anything, in this case racial differences.

The Economist is a business publication so the logic and layout of the commentary is just what you might expect: raise a specter of investment risk, but then explain why it's OK to do it in a way that the author approves of and could benefit from.

The author is correct to raise the potential for a new era of Darwinian racist determinism, a revisit to the bad days of eugenics based on new claims of group traits dressed in modern genetic technological rhetoric. But it is totally self-serving to discredit excessive genetic determinism in relation to current GWAS approaches for disease, and then credit the very same kinds of approaches to every other kind of trait.

The problem is that nobody wants to take a serious look at the issues. There can be no denying that genes affect every kind of trait, normal and otherwise. There can be no doubt that different groups of people, no matter how you define them, will have at least some differences in almost any trait: how could two groups be exactly identical in anything, after all? There will always be some traits for which any two groups you might choose will differ so substantially that not only is the average different but there is relatively little overlap (for example, skin color between Swedes and Somalis). We can't be in denial about that.

On the other hand, to suggest that whole genome sequences will have widespread use in identifying variants with important deterministic effects is simply to ignore all the GWAS evidence that we currently have, and there's a ton of it, that even though most traits have a substantial genetic contribution to their variation, most of the individual contributing variants are too weak to identify or enumerate.

One problem with evolutionary psychology is that the traits that are chosen for study are those of clear cultural interest. The problem with that is that such traits are exactly the ones on which societal discrimination has been based. To say that we'll have to learn to deal with uncomfortable truths is to say that, whether meant that way by the author or not, some races will have to face the reality that they are rather deficient in certain areas (as a group!).

That is because difference is quickly equated with importance. There is little hesitation, even though defining behavioral traits is notoriously difficult and obviously culture-loaded. Why else would race and IQ (high class behavior of certain groups that just by chance include the investigators) or sexual behavior and innate sports ability (i.e., an animalistic kind of 'talent' of some others) be the objects of study? Why not shape of lung lobes or tarsal bones, or more abstract but less socially loaded traits?

These are not new points, but humans have a history and it's a mistake to ignore it. It would be nice if we could address the real issues more seriously without political correctness or the hyped vested-interest and funding-driven predominance, or glee of the elite who dream of and would be able to afford to design their Einstein children. And it would be good also if we could face the potential for human harm if we continue to accept the idea that you are not what you eat but what you inherit. We've seen how that can loose the forces that eat at people about other people they may not like or may have to compete with, and we know where that leads.

The actual scientific issues are subtle, but are buried beneath all sorts of biases, vested interests, and self-fulfilling preconceptions.

Thursday, December 10, 2009

One climate getting warmer, the other cooler

I read in our Penn State student newspaper that our internal investigation of the 'Climategate' emails is under way, and properly being kept totally confidential so hearsay and rumor don't sully anyone's reputation (one of our meteorology faculty is a major correspondent in the emails).

The good news out of Copenhagen, if there will actually be any, is that those who defend the idea of global warming are warming to the task of defending the cold shower that the hijacked emails were used to put on the idea that we're mucking about with our childrens' climatic future.

The scientists at the meeting are not circling their wagons and just defending the questionable-sounding emails or the Fox 'News' style reactionary assault. They're on the proactive side, presenting in clear and strong terms the wealth of evidence, none of it dependent on the emails' content, for global change.

Hopefully, they'll replace the disappearing glaciers with a glacial chill put on the muckrakers, regardless of whether those particular guys acted questionably or not.

Wednesday, December 9, 2009

Ardi Comes to Town!

Well, actually it was Tim White who came, to talk about Ardi. It was a pleasure to see his impressive pictures of the Awash Valley of Ethiopia, where the fossilized bones of Ardi and so many other species were found, as well as to hear his description of the truly painstaking work it was over 15 years to piece together the parts of the skeleton they have, and to catalog all the other fossils they found over many field seasons.

And it was fascinating to get a glimpse into the passion that drives White's life's work. As he pointed out, in The Descent of Man, in an often cited passage, Charles Darwin is frequently read as predicting that human progenitors originated in Africa.
In each great region of the world the living mammals are closely related to the extinct species of the same region. It is therefore probably that Africa was formerly inhabited by extinct apes closely allied to the gorilla and chimpanzee; and as these two species are now man’s nearest allies, it is somewhat more probable that our early progenitors lived on the African continent than elsewhere.
Though some scholars quibble with how prescient Darwin really was about human origins here, given the lack of fossil evidence at the time, White clearly seems to feel that he is a direct intellectual descendant of Darwin's, rising to the challenge Darwin laid down so long ago. The man of vision is there by his side as Tim scours the earth for our early ancestors in the Awash Valley.

White has a deep appreciation for his finds as important pieces of world heritage, as well as for their value as direct confirmation of Darwin's prediction. Of course, as he also said, we don't need the fossils to know that our closest ancestors lived in Africa and to know something about the time it has taken to make us from them; DNA sequence data have long ago settled that to within a reasonable approximation.

In his talk, Tim finished up by listing a number of ideas of Darwin's about human origins that have turned out to be true, supported by the fossil evidence (which he also discusses in an essay on the National Science Foundation website honoring the 150th anniversary of the publication of the Origin).

But Darwin's predictions about inheritance are much less au courant in molecular biology because he was so wrong about so much, and the field has come so far in 150 years (and in fact, Ken also has written an essay that appears on the NSF site, where he chips away a bit at the often rather uncritical Darwinian ancestor-worship). This is in no way to detract from Darwin, who set the research stage for the biologists who followed him, even where he was wrong, or making wild guesses (which he did quite a lot of).

Darwin recognized the importance of inheritance (as had some of his predecessors as well as Wallace), but his ideas were very wrong and much more conventional than the usual image of Darwin-the-pathfinder. We know a lot better today, and it's possible to recognize Darwin's fundamental insights -- common origin, life as history, and natural selection as a force (given the right conditions), and nothing yet discovered by biology contradicts these facts of life -- while also recognizing where he was wrong. It's important to do that, because otherwise the Origin of Species can morph into an equivalent of the Bible, and that would not be good for science.

Darwin is still treated by many molecular biologists as having the same kind of driving presence as Tim White the paleontologist seems to feel he has, however. But that is a rather careless view that rests on assumptions about natural selection as an all-powerful force, and the inference, without really reading him carefully or looking at data critically, that Darwin's was The Word.

That reservation aside, it was still nice to hear that as Tim trudges over the blistering sands of Ethopia, he feels Darwin watching over his shoulder.

Tuesday, December 8, 2009

Today's Big Surprise: How you live affects how long you live!

Caloric intake, lifespan and fecundity revisited
A number of studies have found an inverse correlation between lifespan and fertility as a result of caloric restriction. This is true in fruit flies, worms, rodents, and mammals, including primates -- we blogged about the recently reported primate study here. The results of a recently reported experiment on flies that takes the question one step further, teasing out the specific dietary components responsible, was reported in Nature last week (Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila, Grandison et al., published online 2 Dec 2009).

Although Grandison et al. carefully don't stress a selective aspect to their finding, they do mention an idea that others have proposed, which is that in times of scarcity, organisms can expend their limited supplies of energy on survival or on reproduction, but not on both, and one view can be that it makes sense to delay reproduction until food becomes more abundant. The literature on this subject suggests that this is an evolved response. In their study, Grandison et al. tested the prediction that it's not possible to optimize both lifespan and fecundity with the same dietary conditions.

In laboratories, fruit flies are fed yeast and sugar. Grandison et al. diluted their flies' usual diet, and indeed found that this resulted in longer lifespan and fertility reduction (which they measured as number of eggs laid). After finding the expected effect, they sought to maximize lifespan and fecundity by adding back specific components of the diet and determining whether a nutrient had an effect on both.

Among other things, the investigators found that replacing vitamins, lipids (fats) or carbohydrates had no effect, which suggests that caloric intake in and of itself is not what reduces lifespan in these flies, and that these aren't the components of the diet that affect fecundity. They did find an effect of reintroducing essential amino acids, however. Adding back essential amino acids increased fecundity to the level found at full feeding, specifically methionine, although they also saw increased fecundity with the addition of tryptophan.

And, adding back methionine didn't reduce lifespan, leading the investigators to conclude that "the fact that high fecundity and high lifespan can co-occur is inconsistent with the idea that any aspect of reproduction directly inflicts damage on the soma to shorten lifespan", which has been suggested by some. In addition, they conclude that "the responses of lifespan and fecundity to full feeding are independently mediated by different amino acids."

Finally, they suggest that there is "thus an imbalance in the ratio of amino acids in yeast relative to the ratio the fly requires for the high fecundity from full feeding, and some consequence of this imbalance decreases lifespan."
The mechanisms that influence lifespan are conserved over the large evolutionary distances between invertebrates and mammals, and our results hence imply that in mammals also the benefits of dietary restriction for health and lifespan may be obtained without impaired fecundity and without dietary restriction itself, by a suitable balance of nutrients in the diet.

But is it adaptive?
This is all very interesting, but natural selection need have had nothing to do with it in species in which lifespan extends past the reproductive span, so that natural selection essentially can't 'see' it (there are some technical ways in which there can be a fitness effect, but these are very indirect and often seem quite forced, a way of ensuring that every trait has to have a selective explanation). 

The fact that there's so much play in the caloric intake that can sustain life suggests that this is yet one more example of the imprecision of life. But, if one must force an adaptive explanation, it could be something that happened very early in evolution because all organisms have it, and that's the ability to adapt to change, both minute-to-minute, by modulating heart rate or body temperature or increasing bile production after a fatty meal, or over the annual cycle, by dropping leaves when temperatures fall and daylight decreases or going into hibernation, and so forth.

Cells use receptors to detect and capture nutrients that are passing by, in the circulation for example. They can respond to low nutrient levels by increasing the number or density of receptor molecules they put on their surface, or by storing the energy they are able to extract from their environment. This is very generic. Since there are so many more somatic than germ-line cells, one consequence could easily be that in hard times the germ line receives a proportionately lower fraction of what's available. There need be no particular selective competition between these types of cells, though of course it's easy to dream up all kinds of scenarios about this if one feels compelled to do that.

In the face of constantly changing environments, organisms have to be able to respond and keep up. That is why life is organized the way it is, a major feature of our book, in terms of protected, sequestered environments that monitor and respond to what's outside. That is the basic nature of life, or even the reason for life, as a cellular phenomenon.

Responsiveness has its bounds, of course, and some organisms have much wider tolerance for change than others, but the ways in which organisms can adapt is astounding. In addition, almost any physiologic system you look at shows a continuum of 'normal' levels; vitamin D, potassium, calcium, sodium, cholesterol, body mass index, the environmental temperature at which the organism can survive, etc., can all vary, all compatible with life.

And let's expand that continuum beyond 'normal' to survivable -- body mass index, or amount of body fat, is just one measure that can vary greatly and still allow survival, and successful reproduction. So, it's not surprising that the idea of an 'optimal' caloric intake might have little biological importance.

It's common to think in terms of 'survival of the fittest', as though the odds of surviving to reproduce only favor the extremes, but that would suggest that there's one optimal cholesterol or potassium level, or number of eggs to lay and so on. But, life didn't seem to evolve that way, as perhaps there would have been too few survivors for populations to be viable, and perhaps it's just built into the nature of many-component biochemical processes.

We think it's more accurate to think in terms of 'failure of the frail'; for example, an organism whose cholesterol level varies significantly above or below normal may not survive, but otherwise, a wide range of cholesterol levels is compatible with survival and even reproduction. And this is true of most traits. Selection is a lot more tolerant than its reputation in popular culture and even within most of biology.

Sunday, December 6, 2009

Going mano a mano with vaccines against non-infectious disease

Many chronic conditions now thought to be due to passive (genetic) rather than active environmental exposures may turn out to be due to infection, or to somatic changes of various kinds that build up with age.  Many of the chronic disease candidate genes identified by genomewide association studies (GWAS) and other approaches seem to relate to immune function or 'inflammation', whatever that may include (e.g., recent schizophrenia results)  Autoimmune diseases also may involve exogenous pathogens. 

Progress in vaccine production research may bring a host of infectious diseases under preventive control (see our "getting the bugs out" post)--and this would be preventive with respect to infection-related chronic diseases, as well. Here it's molecule against molecule--antigen against antibody in a molecular mano a mano combat.

But the same ideas may actually apply even more broadly. As we discuss at length in our book, life is about molecular recognition. In the case of infectious disease, it's molecules on bacteria and viruses that the immune system recognizes. But even most non-infectious diseases involve undesirable molecular recognition problems (too much or too little signal molecule or response to it, for example). Networks of interacting gene products (protein and RNA-based) are being identified.

Malfunctioning networks become dangerous if they affect too many cells, such as cells early in development that are the ancestors of major segments of the celllular/embryological descent tree that makes major organs. Thus, one mutant liver-precursor cell could have devastating effects, while the same mutation occurring in a cell in a mature liver will have no discernible effect (because the rest of the liver cells will be normal).

In complex non-infectious diseases, signaling malfunctions can amplify if a cell or set of cells produces too much or too little signal, it can induce other nearby cells to start doing the same or at least start hyper- or hypo-responding. Some traits, like epilepsies, may amplify from a single or small number of cells in this way. Many other diseases may be similar in this regard, such as diabetes or hormone-dependent diseases in which signal or receptor concentrations may be off-level.

To date, we're much better at treating infection than we are genetic diseases, but targeting a genetic network in some molecular-recognition way may be an eventual treatment approach to such complex diseases. If, as must usually be the case, the disease involves some sort of molecular misbehavior, some kind of nanochip, say, to test relative levels of various molecular components may be able to detect something going wrong. If the effect circulates so that the nano-detector 'sees' it, then perhaps some antibody-like 'vaccine' can target the protein that is produced in excess, bringing its level back to within safe limits.

So here could, at least in principle, be a way in which we can meld infectious disease strategies and network or systems biology concepts, to provide detection and treatment of complex diseases. To do that, individual genotyping would not be needed; all we would need would be a micro-implant that could detect component (or even sets of components) levels that were out of health range.

This may be dreamworld thinking at present, but it is not a stretch to think that infectious disease approaches rather than 'genetic' approaches (in the sense of inherited variation) will lead the way to major health advances (assuming we can afford them!).

Friday, December 4, 2009

Jon Stewart on ClimateGate

Jon Stewart says it so well.

Science and the ACLU -- Let ClimateGate Run its Course

The American Civil Liberties Union (ACLU) is our famous guardian of civil rights. They protect our right to say almost anything we want on the blogosphere, and much more besides. Most of the time they are a mainstay that obstructs governmental abuse of power (you know, that's what happens when the party you don't happen to like is in office!).

But some of the time, they take very unpopular stances for the exact same reason. They defend gross murderers when the latter haven't had a fair enough trial. They defend pornography or ugly speech like that of the Klu Klux Klan and other unpleasantness. Whether you think that's disgusting or not.

Most of us believe the ACLU is important, or even a vital element of a free society, because unrestrained government is repressive government.

A gut check and teachable moment
The Climategate problem (reviewed in this week's Science here, if you have a subscription, but of course many other places as well) is a challenge to us in a similar way. No matter how convinced we may be that global warming is happening and is human-made, we must allow complete investigation of the controversial emails. And we must condemn cover-ups and data massaging if that is what actually happened.

The result may be food for the Hummer crowd. It may set back the cause of definitive preventive constraints on energy use for years. It may give a great opportunity for those who can't spell 'science' much less understand it, to gloat in triumph (til their houses flood).

But this is a gut check and we must not flinch, even if we can't stand to see their smirks. We have to defend the integrity of science, no matter where it is compromised. And however it turns out, it's a teachable moment for everyone, professionals and students alike.

Competing causes everywhere

We've written about recent studies in which one has to do risk-benefit analysis in order to statistically determine the least (or most) beneficial treatment outcome, as in the currently hot debate about mammography. Risk-benefit concepts are a manifestation of causal complexity, in which many factors are at play.

The problem arises when a cause doesn't act alone to produce an outcome of interest, or when a factor is causally associated with more than one outcome, in which other such causes are also involved. Thus, lowering exposure to the cause may reduce the likelihood of outcome A, but increase the likelihood of outcome B.Genetic pleiotropy, in which a gene has more than one biological effect, is widespread if not nearly universal. Indeed, it is difficult even to determine all of a gene's 'functions' since even the definition of what a gene is is expanding rapidly as we learn more and realize how much more we have to learn about genomes.Biological traits are universally the result of many genetic factors interacting (signals and their receptors, genes and the transcription factors that activate or repress them, the mechanism that translates them into active protein, etc.).

Evolution works on the net result and while one manifestation of a gene's action may be favorable to survival or reproductive success, some other action of the gene may be unfavorable. Evolution takes some viable middle ground.This is one major reason why genetic causation is often so difficult to work out. It is likely why many drugs work well for their intended purpose, but have negative side effects in some people. It's why some drugs turn out not to work as well as expected on their intended target, while having a surprising Viagra effect that one might say makes hope 'rise' in other aspects of life.

In biomedical research, investigators study one disease, like diabetes, aiming to prevent or cure it. But inevitably, if they succeed, the rates of some other diseases will increase. If you've effectively dodged the diabetes bullet you’ll live longer, or be more active, or eat more, or drive more aggressively at night (because your vision’s not impaired), and so on. Each of those things increases risks of other negative outcomes.A commentary on page 1731 of the Nov 21 issue of the Lancet is by a Dr Nutt, a British doctor sacked from his position on the governments Advisory Council on the Misuse of Drugs, illustrates some of these issues. Dr Nutt stated what is rather obviously true, that "alcohol was more dangerous than many illegal drugs, including cannabis, ecstasy, and LSD." This apparently outrageous if true statement -- a threat, if implemented in regulatory policy, to every pub owner in the Kingdom! -- was simply too much.

But it's timely for us, because the fact of societal and other consequences of alcohol abuse is, along with a number of diseases for which alcohol abuse seems a clear risk factor, goes against the findings that risk of other diseases, like heart disease, seems to be reduced by alcohol consumption. And this does not include the moral side of alcohol use, which to many can even be a religious issue of abusing the body--the temple of the soul, or damage that the cost and results of drinking does to innocent family members.

Once again, we have competing causes to deal with. Were there a single standard, alcohol might be regulated like tobacco or even currently illegal drugs, given the societal harm it causes. Yet at the same time it might be prescribed as a preventive medicine. Neither science nor society has a good way of deciding how to respond to this mix of factors. This is an unavoidable dilemma, a philosophical or even existential conundrum.

Even if biomedical research were to reach its oft-hinted goal of near-immortality (yes, leading geneticists have seriously and publicly promised even centuries of healthy life as the payoff from our NIH dollars), the consequences might not be so rosy. The earth would be deeper in humans than Darwin’s estimated elephant-jammed world (in the Origin of Species). Food supplies would inevitably be threatened. There would be fights over other resources, adding violence to the causes of death and misery. New York apartments would become even smaller than the closets they are now. Psychological existence might be much worse.

Unless, of course, we colonize outer space? Though probably not, because if science is right about the universe, the same laws of complexity will operate on Mars as they do here at home. So when science has social or policy implications, it's always a balancing act.

Thursday, December 3, 2009

We are gathered together to . . . .

There's an interesting paper (or, actually, it's not a paper, it's a description of an ongoing study; Lee et al., Cohort Profile: The biopsychosocial religion and health study (BRHS)) in the December International Journal of Epidemiology, (2009 38(6):1470-1478) but it probably interests us for all the wrong reasons. It's a teaser of a piece, a profile of a sample that's been chosen for a study of the effects of religion on mortality, and a call for collaborators.

The piece describes the aims of the study, and the characteristics of the cohort being studied, thousands of Seventh Day Adventists living in Loma Linda, CA, both black and white. The idea is that Seventh Day Adventists live longer than non-Adventists, even when their healthy lifestyle is controlled for (the relevant lifestyle factors mentioned in the piece are vegetarian diet, not smoking, social support and eating nuts -- the Adventists' position statement on diet doesn't emphasize nuts, we notice, but maybe in Loma Linda, CA, nuts are a big part of the diet?). The investigators are collecting piles of data on religious observance, social and economic variables, as well as health indicators, to try to figure out what it is about religion that contributes to longer life.

This is curious, really, and not a little tantalizing. Because the Loma Linda study is still underway, there are no results yet to report, so we turned to the literature to see what's already been written on the correlation of religion and mortality. It turns out there's quite a lot, including, for example, this meta-analysis of 42 different studies of this question, which concludes that "[r]eligious involvement was significantly associated with lower mortality (odds ratio = 1.29; 95% confidence interval: 1.20-1.39), indicating that people high in religious involvement were more likely to be alive at follow-up than people lower in religious involvement." Indeed, the IJE paper notes that "In fact, Hall concluded religious attendance was more cost-effective in increasing longevity than statin-type medications." Powerful stuff.

Obviously, the question is Why? What is it about religion that protects people from death? (This is a little paradoxical, since religion is ultimately supposed to protect people after death, or maybe even increase their desire to hasten death so as to get to Heaven quicker -- but, ok, we'll stick with the premise.) Do religious people live healthier lives?  Is it healthier people who answer 20 page questionnaires on their religious views?  Could it be simply the fact of belonging to a group (which, admittedly isn't really so 'simple', since what is it about group membership that would be protective, and how would you figure it out?)? In which case, do people in book groups or Elks Clubs or stamp collecting clubs live longer, too? That is, is religion a proxy variable for group cohesion? If so, why all these studies considering religion as though there were something specific and unique about its practice that explains longer lifespans?

Which there is. It's prayer. But the possibility that the power of prayer is the explanation doesn't seem to get mentioned in this field, where instead it's all talk of social and psychological variables. (The way to test the power of prayer, of course, is to look at whether Unitarians live longer, too. ) We're not suggesting that it is prayer, just pointing out that it's odd that epidemiologists are looking at the association of religion with health when religion has everything in common with any other group behavior, except this one thing, which isn't being considered. Why privilege religion, then?  It just throws confounding variables into the mix, already a potential problem in even the best of studies.

Though, at least one recent study did look at the power of prayer to heal the sick. What the investigators found was that if you knew people were praying for you, it improved your recovery. But if you didn't know that, you didn't recover more quickly. So this suggests that it's the power of knowledge of prayer rather than divine intervention because of prayer. That's consistent with the psychological effects of believing you have something going for you -- the placebo effect, if you will.

And, anyway, if the vast majority of the American people consider themselves to be religious, as shown in poll after poll, who are all these religious people living longer than? Why is our life expectancy embarrassingly lower than that of much more secular societies such as in Japan or Europe? Would it be enough for us to move to Europe, take advantage of their civilized national health care systems (where society really is trying to make you better), and forget Mass?

Wednesday, December 2, 2009

Einstein meets Newton, or Diabetes and the Theory of Relativity

Isaac Newton was one of the founders of modern science. He helped promulgate the idea of formal Laws of Nature, that Nature was law-like in that everywhere and every time the same fixed principles were at work, like the totally deterministic Law of Universal Gravitation. Because the Law worked everywhere and was deterministic, it worked at the smallest possible level, such as in time or space. That's why Newton could formulate natural law in terms of the calculus or, rather, that's why Newton developed what we call calculus. And this worked in part because space and time were absolutes. In that sense, causation was absolute as well.

Charles Darwin was clearly a product of the Newtonian age. He repeatedly wrote about natural selection as if it were at Law of Nature -- one Nature, indivisible, with Liberty and Justice for all. Justice here, would be the realization of your inherent fitness.

But life is not necessarily like that. Einstein spoiled Newton's party by showing, so to speak, that things were not absolute but only had meaning in terms relative to each other.

In evolution, we usually frame natural selection in relative terms -- this variant at a gene does better than that one does in this particular population and time. We could also view evolution in more absolute terms: this species or population, as a whole, does better today than it did yesterday. Usually this would refer to population expansion which would come at the expense of some other species, so would be relative in that sense.

In genetics, we tend to want to be Newtonian/Darwinians. We want genes to cause things in a rigorously predictable, law-like way. Thus we think of genetic variants as having inherent fitness value. And the important area of biomedical genetics is GWASh in such deterministic thinking.

But life's not like that! There is, for starters, a substantial number of 'known' disastrous disease-associated variants in humans that are normal in other vertebrates (one estimate is that 10% of our 'disease' mutations are like that). In fact, it's true even within our own species: in every individual whose whole genome sequence has been published to date, there are many 'disease' alleles, though the person is unaffected as of his current age.

And then there's the environment, which geneticists pray to Newton will go away! Genes have their effect in context, a point so obvious that it's easy to ignore if it's bad for business.

An area of Finland had the world's highest recorded risk of heart disease. But over a 20 year period, change of diet was the major factor in reducing heart disease mortality in Finland by something like 65% (that's no typo!).

And a new paper in The Lancet on diabetes, comparing outcomes in progression to diabetes in at-risk adults reports that "intensive lifestyle intervention" was significantly more effective in preventing diabetes than medication or placebo.

We've talked of Newton and Einstein, and how causation is relative. But even Einstein hungered for Newtonian lawlike deterministic Nature. And along came quantum mechanics.....

Tuesday, December 1, 2009

The Feminine Mystique?

Ok, here's a story that was the second most emailed article at the New York Times website for most of Monday.  Oddly, a story about hiking the Grand Canyon had even more appeal than this one, and this morning, a story about kindergartners in forests is number one.  But, in keeping with Holly's racy tendencies, we could hardly pass up this also-ran (its place in the queue suggesting that New Yorkers crave nature more than they crave sex?).  Called "Women Who Want to Want", the story is about curing an affliction that is apparently common among women, to judge by interest in this article -- lack of sexual desire.  It's also about whether that's a disease or not -- pharmaceutical companies seem to be training us to think it is in case they come up with a female form of Viagra, so we'll all get in line to buy it when they do, but that's not news (in fact, the Times also ran a story saying that there's already a product that will do the trick, but that's beyond our scope today, and anyway, no brand names here).

All that is interesting enough, sociologically and so on, but here's what really interests us about the article, given all our posts on how to determine cause-and-effect, and evidence-based medicine etc.  Bear with us as we quote at length, just so you get the full effect.
Various pharmaceutical companies, at various times, have pursued testosterone as a remedy for women’s lack of desire, and some doctors prescribe it for the condition — Laura Berman, Oprah's anointed sex expert, avidly promotes this method — though the Food and Drug Administration hasn’t approved this use. Brotto and Basson [sexologists] are about to publish research demonstrating that low levels of testosterone in women do not correspond with low libido. Yet there is a paradox. Brotto explained that giving extra testosterone to women with desire problems can, it appears, spike sexual interest. For reasons unknown, the administered hormone has a unique effect. But there’s a further complication. In studies, women given a placebo report a similar result, not quite as marked but definitely not insignificant either. To add to the intrigue, the women using a placebo often report testosterone’s unwanted side effects: facial hair; acne. Speaking about all this, Brotto smiled in bewilderment — and in something close to awe at the inscrutability of the human mind, the organ that is the locus of desire.
Did you get that??! Giving women a placebo instead of testosterone can cause the same unwanted side effects, facial hair and acne, as giving them the hormone itself! That is so beautiful, and says more in one sentence than anything we've come up with yet about the difficulty of determining causation.