Friday, October 9, 2015

The Elephant (not) in the Cancer Ward

Recently, Tomasetti and Vogelstein (the latter a senior and highly regarded cancer geneticist) suggested that most cancer is due just to bad luck.  We discussed that study here.  When cells divide, DNA is copied, but that is a molecular process that isn't perfect (see discussion of Wednesday's Nobel Prize in Chemistry, e.g., for the discovery of DNA repair mechanisms and their association with cancer).  There are mutation detection mechanisms of various sorts (the BRCA1 gene whose mutations are associated with breast and some other cancers, is one with that sort of function).  The more at-risk cell divisions, the more mutations, and the higher the likelihood that one cell will experience a combination of mutations that (along with inherited variation) transforms the cell into the founder of a cancer.  T and V's assertion based on statistical analysis of numbers of cells at risk, their division rate for given tissues, and age of onset patterns, was that random mutation was a major contributor to cancer, rather than inherited genotype or environmental exposures, which they argue would account for this substantial fraction of cases.

Naturally, those whose grant fortunes depending on the idea that cancer is 'genetic' and/or 'environmental' roared in opposition to an idea that could threaten their perspective (and empires). Some of the T and V paper's statistical methods were questioned, and perhaps their paper was over-stated or less definitive than claimed.  Nobody can doubt that genetic variation and environmental exposures that could cause cells to be more likely to experience mutations, play a role in cancer.  But in any practical sense, it is hard to deny that luck plays a role (even with environmental exposures, because if they cause mutations, they basically strew them randomly across the genome, rather than causing them in any particular gene, etc.).

But we mentioned an important issue then that had been raised 40 years ago by epidemiologist Richard Peto.  Essentially it is that other mammals, like mice, experience a similar array of cancer types, with similarly increasing risk with age....but that increase is roughly calibrated with their life span. In fact, mice have far fewer stem cells in, say, their intestine or blood than humans, but their risk of cancer in these tissues increases far more rapidly (in years) than does human risk, though we have orders of magnitude more at risk cells and cell divisions.  This became known as Peto's Paradox.  It has not really been answered though there are some attempts to determine how it is that different species, of different sizes, calibrate their cancer risk in relation to their observed typical lifespan.

"Elephas maximus (Bandipur)" by Yathin S Krishnappa - Own work. Licensed under CC BY-SA 3.0 via Commons - 

For example a 2014 paper in Nature Reviews Genetics by Gorbunova et al. documents the very different typical lifespans of rodent species, and suggests some plausible genetic mechanisms that may protect the longer-lived species from cancer.  There must be some such mechanism, or else we misunderstand something very important in the carcinogenesis process.

Now a new commentary has been discussed in the NY Times of a JAMA paper, that makes similar genetic arguments for the very out-of-line cancer-free longevity of elephants.  Based on their numbers of at-risk cells, elephants should drop over with cancer at a very young age, but instead they typically live for a very long time.  How can this be?

The JAMA authors, Abegglen et al., found that a gene, called TP53, that is clearly related (when mutated) to cancer susceptibility in humans and in experimental assays, at least in part because it detects and effectively kills misbehaving mutated cells.  The study included humans with Li Fraumeni syndrome (LFS), a genetic disorder that greatly increases the risk of developing cancer, susceptibility to which has long been known to be associated with variants in TP53, and blood samples from Asian and African elephants.  

The study needs close scrutiny for methodological issues, but the authors make what they feel, reasonably, is a relevant finding.  There is only one copy of the TP53 gene in humans, but in elephants there are 20.  In blood cell assays this gene's activity was higher than in humans.  The inference is that elephants' longevity relative to cancer is due to this gene. If that is indeed the (or at least, an) explanation for the elephants' cancer-related longevity, it raises some other important questions, which should at least raise eyebrows and the need for ever-present skepticism.

Questions raised by the results

As in the rodent paper cited above, single-gene mechanisms for complex traits are appealing and publication-worthy, but in a sense such claims raise questions about themselves.  Elephants live long lives relative to other diseases that essentially have little if anything to do with cancer.  One can think of heart disease, dementia, stroke, kidney failure, liver disease, neuromuscular and joint disease, and waning immune systems.  Are these traits all due to having more TP53?  That seems unlikely.  

Alternatively, apparently whales are known not to have multiple TP53 duplicates, and I don't know about other very large animals like rhinos, giraffes, and so on.  A standard argument would be that in ecological circumstances when natural selection favors longer lives for some species, it uses whatever mechanism happens to be available--that is, selection has no foresight and can't just choose genes to duplicate.  Each species will have experienced the longevity advantage in its own local time, place, and ecosystem.  Just as the genes whose mutation yields resistance to malaria in humans vary from continent to continent, so will longevity-related genes favored by selection

So, Peto's Paradox remains curious.  If each species has its own protective mechanism (and perhaps several for its different organ and physiological systems), then we can account in a reasonable way for longevity patterns.  There is no need to find, or even to expect the same thing in all species' evolution: variation in response to selection can vary by organ system, species, and location even among species.  This is exactly the sort of thing that we should expect when we think of the complexity of genomic mechanisms--and what has consistently been found by genome mapping studies (GWAS) of late onset traits (and, for that matter, even early onset ones).

In turn, that means that each paper that claims subtly or overtly to have found 'the' or even a widespread important mechanism related to aging needs to be taken circumspectly.  Aging and lifespans are complex phenomena.  We will learn from each example we document, as with GWAS results, that a simple anti-aging strategy can't be inferred.  It's not likely to be a single magic bullet.

Tuesday, October 6, 2015

The Blind Men and the Elephant -- a post-modern parable

It's an ancient parable; a group of blind men are lead to an elephant and asked to describe what they feel.  One feels a tusk, another a foot, a third the tail, and so on, and of course they disagree entirely about what it is they are feeling. This tale is usually used as an illustration of the subjectivity of our view of reality, but I think it's more than that.

I heard a talk by Anthropologist Agustin Fuentes here at Penn State the other day, on blurring the boundaries between science and the humanities.  He used the parable to illustrate why science needs the humanities and vice versa; each restricted view of the world is enhanced by the other to become complete.

But, this assumes that the tales that science tells, and the tales that the humanities tell are separate but equally true -- scientists feel the tail, humanities feel the tusk and accurately report what they feel.  Once they listen to each other's tales, they can describe the whole elephant.

"Blind monks examining an elephant" by Hanabusa Itchō (Wikipedia)

But I don't think so.  I don't think that all that scientists are missing is a humanities perspective, and vice versa.  I think in a very real sense we're all blind all of the time, and there's no way to know what we're missing and when it matters.  You feel the tusk, and you might be able to describe it, but you have no clue what it's made of.  Or, you feel the tail but you have no idea what the elephant uses it for, if anything.

Here's my own personal version of the same parable -- some years ago we purchased a new landline with answering machine.  Oddly, we have a lot of power outages here, and it seemed that every time I set the time and day on the answering machine, we'd have another outage and the time and day would disappear, having to be set once again.  I decided that was a nuisance, and I stopped setting time and day.

The next time the machine said we had a message, I listened to it, but it was blank. There was no message!  Naturally enough (I thought), I concluded that the time and day had to be set for the machine to record a message.  Unhappy consumers, we contacted the maker, and they said no, the machine should record the message anyway.  Which of course it would have if the caller had left a message, as was proven the next time someone called on unknown day at unknown time and ... left a message.

My conclusion was reasonable enough for the data I had, right? It just happened not to be based on adequate data (aka reality).  But, we always think we've got enough data to draw a conclusion, no matter how much we're in fact missing.  This is true in epidemiology, genetics, medical testing, the humanities, interpersonal relationships; we think we know enough about our partner to commit to marrying him or her, but half of us turn out to be wrong.  Indeed, if all you've seen are white swans, you'll conclude that all swans are white -- until you see your first black one.

No, you say, we did power tests and we know we've got enough subjects to conclude that gene X causes disease Y.  But, it's possible that all your subjects are from western Europe, or even better, England, say, and what you've done is identify a gene everyone shares because they share a demographic history.  You won't know that until you look at people with the same disease from a different part of the world -- until you collect more data.  Until you see your first black swan.

But, you say, no one would make such an elementary mistake now -- you've drawn you controls from the same population, and they will share the same population-specific allele, so differences between cases and controls will be disease-specific.  But, western Europe is a big area, and even England is heterogeneous, and it's possible that everyone with your disease is more closely related than people without.  So, you really might have identified population structure rather than a disease allele but you can't know, until you collect more data -- you look at additional populations, or more people in the same population.

Even then, say you look at additional populations and you don't find the same supposedly causal allele.  You can't know why -- is it causal in one population and not another?  Is it not causal in any population, and your initial finding merely an artifact of ill-conceived study design?

Without belaboring this particular example any further, I hope the point is clear.  You feel the tail, but that doesn't tell you everything about the tail.  But you can't know what you're missing until you ask more questions, and gather more data.

Darwin explained inheritance with his idea of gemmules.  He was wrong, of course, but he had no way to know how or why, and it wasn't until Mendel's work was rediscovered in 1900 that people could move on.  Everything we know about genetics we've learned since then, but that doesn't mean we know everything about genetics.  But theories of inheritance (and much else) don't include acknowledgement of glaring holes: "My theory is obviously inadequate because, as always, there is a lot we don't yet understand but we don't know what that is so I'm leaving gaps, but I don't know how big or how many."  And, in a related issue that we write about frequently here, it's also true that instead of coming clean, we often claim more than we know (and often we know what we're doing in doing so).

Even very sophisticated theories just 15 or 20 years ago had no way to include, say, epigenetics, or the importance of transcribed but untranslated RNAs (that is, RNA not coding for genes but doing a variety of other things, some of them still unknown), or interfering RNAs, and so on, and we have no idea today what we'll learn tomorrow.  But, like the blind men, we act as though we can draw adequate conclusions from the data we've got.

Science is about pushing into the unknown.  But, because it's unknown, we have no idea how far we need to push.  I think in most cases, there's always further, we're never done, but we often labor under the illusion that we are.  Or, that we're close.

But, should ductal cancer in situ, a form of breast cancer, be treated?  And how will we know for sure?  Systems biology sounds like a great idea, but how will we ever know we've taken enough of a given system into account to explain what we're trying to explain?  Will physicists ever know whether the multiverse, or the symmetry theory is correct (whatever those elusive ideas actually mean!)?

Phlogiston was once real, as were miasma and phrenology, the four humors, and the health benefits of smoking.  It's not that we don't make progress -- we do now know that smoking is bad for our health (even if only 10% of smokers get lung cancer; ok, smoking is associated with a lot of other diseases as well, so better not to smoke) -- but we've always got the modern equivalent of phlogiston and phrenology.  We just don't know which they are.  We're still groping the elephant in the dark.

Monday, October 5, 2015

Life in 'trans'-it: Why genomic causation is often so elusive

We are in a time when genes are in the daily news, with reports of how this gene or that gene is related to disease, evolution, race, ancestry, and even social behavior.  But what are 'genes', and what do they do?  This is so often presented--in classes, even at higher levels of education--as a simple story presenting genes as bits of DNA that code for a protein, and proteins the molecules that do the functions of life.  We are still heavily influenced by the pioneering work of Gregor Mendel, who did his famous experiments with peas more than 150 years ago.  So, we still think of genes as elements with one or more variant states in a population, transmitted from parents to offspring, which cause some trait (he studied traits like size, shape, or color in his pea plants to try use this fact to breed better agricultural crops).

Mendel's intentionally focused, single-cause approach opened the way for an understanding of the mechanisms of inheritance and enabled one of the most powerful research strategies in all of science. But the idea of one gene and one function is a 19th century legacy that has put a conceptual cage around our thinking ever since.  Mendelian inheritance and its terms (like dominance and recessiveness, and even some of his notation) are still around, and indeed it all is rather ubiquitous even at the university level.  But we now know better, and can do better, and the many discoveries of the last century in biology and genetics present us with many 'mysterious' facts, basically unanticipated by the long, persistent shadow of Mendel's well-chosen simplifications.  It requires some thinking outside the Mendelian box to understand what they might mean.  

The cis image of the world
DNA is located in the nucleus of our cells, but where does genetic function take place?  The usual Mendelian way of thinking is that the action occurs in a particular place in our DNA where a 'gene' is. The gene codes for protein and (usually) has nearby DNA sequences that regulate the gene's usage---turning on its expression by transcribing the gene into messengerRNA.  That is, the gene itself determines how it's used.  It's in a given place in our DNA, and the presence of a complex of regulatory proteins that attach to nearby sequence cause the gene to be transcribed into messenger RNA, which exits the nucleus and is in turn translated into an amino acid chain specified by the sequence.  The amino acid chain is then folded up into a functional protein.

This local, focal view of gene action is what is called a cis perspective.  The Latin origin has a meaning like 'right here', or 'on this side'.  The specifics of this process differ depending on the gene, as no two genes work exactly alike, but the variation in the details is not central to the main point here,  the widespread perception of genes  as modular, chromosomally local self-standing functional units.

But this common idea of how genes work is inaccurate--it's a fundamentally inaccurate way to understand genes and genomic function.

The fundamental nature of life in trans-it
DNA is itself essentially an inert molecule.  It doesn't do anything by itself.  In turn that means that each nucleotide, and that means each new mutational change, cannot be said to have a function or effect, or effect size, on its own.  It only has an effect in terms of its interactions with other aspects of the genome in the same cell, other materials in that cell, that cell in its respective organ and that organ in the organism as a whole, and indeed all of this in relation to environmental factors. While some gene-regulatory regions are near a coding gene, and act in cis, most function involves things elsewhere, on the same chromosome or on others.  This is the trans causal world of life, and it means we cannot really understand what's 'here' without knowing what's elsewhere.

Indeed even Darwinian evolution is fundamentally an ecological phenomenon--it's about organisms' resources, threats, mates, and so on, at any given time.  As well as luck, there may be many levels and aspects of life that are about competition for resources and so on, that are important to survival and reproduction.  But cooperating, in the sense of appropriate interaction, is by far the most prevalent, immediate, and vital aspect of life (Richard Dawkins' ideological 'selfish gene' excessive assertions notwithstanding).

Trans means cooperation in life and evolution
Trans interactions are just that: interactions.  That means multiple components working together, which involves the 'right' combinations in the 'right' time and the 'right' cellular place.  By 'right' I mean functionally viable.  During development and subsequent live, organisms require suitable expression patterns of genes and the dispersion and processing pattern of gene products.  If this combinatorial action--this cooperation--doesn't occur to a suitable degree, the organism fails and its reproduction is reduced.  The extent of this failure depends on the nature of the combinatorial action.

In this sense, trans interactions may be reproductively better or worse and that can be a form of natural selection, whose result is the 'better' (more viably successful) patterns proliferate.  But this does not require Darwinian selection among organisms competing for limited resource.  Genomic variants whose cooperative interactions do not function can lead to embryonic lethality, for example, which need have nothing whatever to do with competition, and certainly not with other organisms seeking mates, food, or safety.  Ineffective cooperation is an evolutionary factor not identical to natural selection in its mechanism, but with similarly 'adaptive' effects.

In our view, cooperation based on trans interactions is more important, more prevalent, and more fundamental than Darwinian natural selection (as we write in our book The Mermaid's Tale).  Interactions that are successful become increasingly installed in the life history of organisms ('canalized' to use CH Waddington's venerable term for it), and this constrains the way and perhaps the rate at which evolution can occur.  This is neither heresy nor surprise.  For example, genes present today are the descendants of 4 billion years of evolutionary history, and most are used in multiple ways in the organism (at least in complex multicellular organisms; we don't know how true this is of simple or single-celled species).  They are less likely to suffer mutational change without serious effect, mainly negative. This is a very long-established idea, and is clearly supported by the high degree of sequence conservation of genes in genomes.

Genomewide mapping of most traits identifies many different genome regions that can statistically affect a trait's presence or measure.  But mapping rarely identifies coding regions.  Most 'hits' are in regulatory regions or regions with other (usually unknown) function.

This should surprise no one.  First, as noted above, 'genes' (protein coding regions) are largely of evolutionary long standing and embedded in interaction patterns usually in multiple contexts (they are 'pleiotropic'), so the coding parts are harder than regulatory parts to modify viably by mutation. It is empirically much more likely that their expression patterns can be varied.  Second, every gene is a complex of many different components (protein code, splice and polyadenylation signals--where the required AAAAA... tail of a mRNA molecule is attached--promoter sites, enhancer sites, and so on). Each of these is mutable in principle, and ample evidence shows that regulatory regions are especially so.  And each transcription factor or other gene product that is needed to activate a given gene (that is, the tens of proteins and their DNA binding sites that must assemble to cause a nearby gene  to be expressed) is itself a gene with all the same sort of complex modular structures.  RNA has to be processed, transported and translated by factors that, again, are potentially mutable.  And so on.  And then most final functions, physiological, developmental, metabolic, or physical are the result of complex processes over time, involving many genes and systems.

In fact, in recognition of biological complexity, many investigators suggest that the proper level of analysis should be of systems, that is, organized pathways of interaction that bring about some end result.  Gene regulation, physiology and metabolism, and so on, represent such entities.  The 'emergence' of the result cannot be predicted by listing the individual contributing elements, in the same sense that the effect of a new mutational change cannot be understood without considering its context.  However, systems themselves have overlap, redundancy, and elements that contributed in different systems at different times, and many systems may themselves interact in what one might call hyper-systems for a result--like you--to come about.  Analyzing emergent systems is at present an active but in many ways immature endeavor, because we still probably don't have adequate understanding, or perhaps not even adequate technology for the job.  But it's important that people are considering the trans world in this and other ways.

Causal complexity is predictable, and what we expect is what we see
Causation in life is fundamentally about cooperation which is about trans interactions.  Since cells are isolated from each other, so they can sense their own environments and respond to them, they actively signal to each other and a major way gene expression is regulated is through complex signal sending and receiving mechanisms.  'Signals' can mean gene-coded proteins secreted from cells, or the detection by cells of ions or other chemicals in their environment, and so on.  Signaling and responding to environmental conditions involves large numbers of genes and their regulation in time and space.  Most genes, in fact, have such cooperative, communicative function.

In turn, this implies that traits have many contributing genes, and their modular coding and regulatory sequences (and other forms of genome function, such as packaging and many different types of RNA), and each of these is potentially mutable and potentially variable within and between samples, populations, and species.  The result is the high level of causal complexity that is being so clearly documented.  A very large amount of viable contributing variation can be expected, if the individual variants have small effect.  The trait itself must be viable, but viability can coexist with large amounts of variation in the hundreds of contributing components.  This is what GWAS consistently finds, and is wholly consistent with how evolution works.

Life is complex in these ways in very understandable (and predictable) ways.  Enumeration of causes or even defining 'causes' are often  fool's errands because different variants in different genome regions in different samples and populations are to be expected.

It's a highly cooperative trans world out there!

Wednesday, September 30, 2015

Does Mark Watney dream of red potatoes?


Before we get down to business ...

As commander of this blog post, I order you to read The Martian by Andy Weir before you even watch the trailer for the upcoming movie. If you watch the trailer before you read the book you will ruin your life. Plain and simple. I can't even imagine what horrible things will happen to you if you see the whole movie without reading the book first.

Do not deprive yourself of this head trip. There is just no way this film will walk you through this astronaut's brain like the book does. Movies can be wonderful, but this is one of those reading experiences (of which there are infinitely finite) that cannot be matched on screen. 

You'll notice that I'm not linking the movie trailer here. I'm not even pasting a picture of Matt Damon in this post, knowing full well that it will get me more clicks and will beautify this screen, because I don't want anyone looking at any of that until they've read the book. If you're really hearing me, stop reading this blog post and don't come back until you've read the book. Do you read me? Over.

Layers at the base of Mount Sharp (source)
With the movie  The Martian opening this Friday, many people will soon be familiar with Mark Watney and his incredible ordeal. 

This is not a book review. I'm done with those for the time being. The last one I did turned out to be a bit of a disaster.  

I just have a few thoughts about Mark Watney's Martian diet that need to escape through my fingers and out onto your computer screens.

To survive on Mars and to think his way to salvation, he eats a lot of venison, kale, and blueberries.

Psych! He eats a lot of potatoes. You know, the "problem" food that causes disease. The food that so many trademarked diet plans avoid, like the Paleo Diet. 

There was some pre-made, pre-packaged NASA fare for Watney, but no way would it last as long as he needed if he was to try to get off Mars. So he actually grew potatoes. A shitload of them. With a shitload of astronaut shit as fertilizer. 

The whole spirit of the book is one that inspires us to think our way out of problems. To remember that possibility is a state of mind. To be skeptical of our inner skeptics who speak of impossibilities. And it's with that skepticism that I wonder about those potatoes.

Let's forget our questions about soil volume, nutrients, and moisture  (mostly because I don't know how to usefully critique the thorough explanations that Watney provides for his decisions about these things). 

And let's drop the question that drove me crazy until the very end of the book when Watney finally explained that he was microwaving the potatoes and thereby getting more calories from them than he would by eating them raw. Given all the calorie-calculations he ran through while sciencing, the chance that Watney might be eating raw potatoes was slowly killing me (and, potentially, him). 

Now I'm curious about something more fundamental: would potatoes grow the same on Mars as they do on Earth given the gravity's different? Could Watney's Earth botany translate as well as it did on Mars?

His training and thinking might not translate well on Mars if we're talking about making a different kind of tot. I'm fond of this paper hypothesizing how difficult it might be to extend the evolution of our own species, extra-terrestrially. Earth's gravity may matter a whole lot to human reproduction, especially those earliest stages of development. 

link to paper

We're not potatoes, sure, but potatoes aren't yeast. Given that there's less gravity on Mars, can we assume that sciencing all those Earth potatoes in Martian conditions is as straightforward as Watney makes it sound?

I don't think anyone knows the answer to this, however, tons of anyones (like Andy Weir) have more informed guesses than I do. Indeed, it is possible to grow spuds on the space station. So maybe my gravitational question lacks gravitas.  

(That groaner was for you, Mark.)

But one thing is for sure. In The Martian, as in life on Earth, a diet based primarily on potatoes fueled a human for quite some time. Maybe not all humans could handle this, and maybe not all humans could be as extraordinarily brilliant while eating mostly potatoes for so many cold and lonely days. But the potato industry has got to be thrilled. 

Not only is one of humanity's best (fictitious) members existing as one of humanity's best members thanks to potatoes, but the food's public image got a separate but related boost recently. Potatoes, and other similar carbohydrate sources, might have been crucial to our lineage's brain evolution. 

Anthropologists have known for a good while now that "underground storage organs" or USOs, like potatoes past and present and many other species, have probably been a big deal during the last several million years of human evolution. But a recent review paper in the Quarterly Review of Biology argues, based on up-to-the-minute cross-disciplinary findings, that cooked starches were crucial to the evolution of our big glucose-sucking, calorie-burning brains. Here's the paper's abstract:

source (and see Zimmer's write up)

So, Paleo dieters and potato-haters of the world, you have just been publicly flogged by both science fiction and science faction. What do you do now?

Well, if you haven't read The Martian, I'll plug it one last time. 

When you're on about page two you might be cursing me. By then I was cursing the book and everyone who liked it. I nearly gave up at the start for reasons to do with the style of writing (gasp! a blog! Ugh!) and my narrow-minded expectations of astronauts, but I'm so glad I dominated my inner bigot and turned the page. All the pages. To the last page. In solidarity with my new favorite Martian blogger, I'm moved to thank you for reading this gasp! a blog! Thank you. Now get to reading Watney's.

P.S. If you can't access the two articles I reference, email me and I'll send them to you: holly_dunsworth at

Friday, September 25, 2015

On Being Mortal

Ken and I have written a lot about disease causation, prediction and prevention but we haven't written much about the other side, when prediction, prevention and treatment aren't enough, when disease becomes fatal.  We have just read Dr Atul Gawande's book Being Mortal, a beautifully written heartfelt exploration of the end of life.  Dr Gawande is a surgeon at a major teaching hospital, and a professor of health policy, and his job is to save lives, and to teach medical students how to do the same.  He is presumably very good at this.  In the book, though, he writes about the process of learning how to be a doctor when there is no cure and he can't save a patient's life, something he didn't learn in school, and that has taken him decades to learn.  Presumably these are lessons he now teaches to his students, to the great benefit of us all.

Dr Gawande tells his story through many case histories, including that of his father, as he made decisions about how to live, and die, with an untreatable cancer.  He told some of these same stories in the BBC Reith Lectures last fall.  He writes about the tremendous regret he now has about instances in which he just was not able to have the kind of conversation with a dying patient that he now knows he should have had.

We are used to two common medical models, he says, the 'paternalistic' model of the 1960's, when a patient could be treated with a blue pill or a red pill, and the doctor made the choice. "Take the red pill.  It will do you good."  Then, the 'information' model took over -- the doctor supplied information, telling the patient that his/her disease could be treated with a blue pill or a red pill, explaining the pros and cons of each and then asking the patient to choose.  But, we don't face the end of our lives statistically, and weighing the pros and cons of different treatments is not what helps us make decisions about how to proceed, which is what Gawande finally realized after too many painful conversations with his very sick patients.

When terminally ill, a patient is overwhelmed with fears and concerns, and recognizing and acknowledging these is the truly important role a doctor can play when a patient is facing life-threatening illness. After much thought, hundreds of conversations with gerontologists, palliative care physicians, managers of the best assisted living facilities, and with patients, Gawande has come to see that there's another model, the 'interpretive' or 'shared decision making' model.

Gawande now asks his patients, What are your priorities if your time is limited?  What are your goals for treatment?  What are your fears?  And what trade-offs are you willing to accept as a result of your care?  And, he, the patient, and the patient's family choose the course of treatment with the patient's answers in mind.

One patient said that as long as he could watch football and eat chocolate ice-cream he wanted to keep living, so treatment continued for this man longer than it did for, for example, Gawande's father who said that he wanted not to suffer, did not want to be paralyzed, and if he couldn't enjoy seeing friends and family, he wanted no more treatment.  So, he refused further chemotherapy when the trade-offs were no longer acceptable to him.

In modern medicine, it's important to recognize that 'no cure' is not the same as 'no treatment'.  There is almost always something else that can be tried, some heroic measure, some experimental surgery or medicine that can be used to give a patient hope, or even a little more time, even when the illness can't be cured.  Doctors are very good at plugging ahead with all of this, without stopping to ask their patients the kinds of things that Gawande now asks.  The proper goal of the medical system, Gawande now believes, is not to stave off death as long as possible, or even to make a good death, but instead to assist in assuring "a good life to the very end."

According to Dr Gawande, modern medicine is very good at a lot of things, but preventing and treating aging and death are not among them.  Until the 1950's, people in the developed world most often died at home.  Then, increasingly, as it became more and more possible for medicine to intervene in the process, people began to die in hospital -- indeed, at ever increasing expense.  Now, however, people are beginning to choose to die at home again, and the hospice movement is largely responsible for making this work as well as it can.

The primary role of nursing homes (an industry which, according to Gawande, began to grow when the number of hospital beds for the elderly wasn't sufficient once aging and dying were medicalized) is to keep the elderly safe, but at the cost of lost privacy, dignity and control over one's own life. Nursing homes are run for the convenience of the system, not the residents. Fortunately, there are increasingly alternatives that allow people to 'age in place,' in their own homes, or if that's not possible, in an assisted living alternative, with as much or as little aid as they want or need.  

If Gawande's book is an indicator that we are wresting aging and dying back from a system that appropriated it, at great cost in money and suffering, it is reminiscent of the movement to demedicalize pregnancy and childbirth, with the increasing popularity of birthing centers and home births, or of menopause, which once meant hormone replacement therapy for all but no longer does.  There are many things modern medicine does very well, of course.  But there are things it can't and will never do well, including preventing aging and death.  

Still, many people do opt for heroic measures at the end of life.  This is in a sense because of the hope that they can be cured, and perhaps a deeper yearning for immortality.  Is this because medicine has over-promised?  Surely in part.  As Gawande says, patients are usually thinking in terms of 10 or 15 additional years when they hear that yet another treatment can be tried, not weeks or months, but it's more like weeks or months that these heroic measures have to offer.  

But this over-promising is nothing new.  Genetics has been doing it for decades, and the new commitment to precision medicine, genetics and so much more, is more of the same.  Some of this is because of snake oil salesmen, certainly, but not entirely.  Just as we have to blame Trump's popularity not just on Trump, but on the people buying his 'message' as well, it is the age of genetics because the people have bought the message being sold.  This isn't so different from the promise of miraculous cures by some religions (or mountebanks).

Surely there will come a time when we recognize that all that has been promised just can't be done, we won't be able to foretell our medical, academic, economic, or romantic futures from our genomes at birth,  and we'll understand that geneticizing our lives is as much over-promising as is the idea that one more experimental chemotherapy is going to finally cure our incurable disease.    

We put our faith in medicine when we are most vulnerable, hoping against hope that it will save us.  Perhaps it was the miracle drugs of the mid 19th century that encouraged this faith -- antibiotics really did save lives.  And then technology -- kidney dialysis and heart transplants, hip replacements and triple bypass surgeries.  We're very good at technology.  But, we still don't really understand cancer, or mental illnesses, or the cause of so many diseases.  And we won't be able to predict complex disease from our genes (which we've written about many times before on the MT), and we certainly can't prevent aging or death.  Despite the promises.  

Atul Gawande's message is sane and oddly reassuring, but as such it's a radical one as he aims to return control of a patient's present and future back to the patient.  This is a challenge to vested interests, yes, as well as a challenge to the usual way medicine is done in the industrialized world.  But it's a welcome and important one, because it's something we all will face.

Wednesday, September 16, 2015

Lourdes save me!: "Hankering after the lie"

Emile Zola's emotionally powerful book, Lourdes, published in 1894, is a poignantly detailed account of people suffering from severe disease, traveling to Lourdes, France, in the hopes of a miracle cure at the hands of a young maid, Bernadette Soubirous.  It was her visions, years earlier, that started the phenomenon by which the Virgin Mary was supposed to have endowed the local waters with miraculous healing properties.  Zola spent some time at Lourdes, to soak himself in the phenomenon and live up to his idea of 'naturalism', making the novel a kind of fictionalized documentary.

Bernadette Soubirous (source: Wikipedia)
Bernadette's story turned the Grotto at Lourdes into a major pilgrimage destination for those most in agony.  They crowded together in trainloads by the tens of thousands, rumbling across France to Lourdes in the hope of a cure centered around the intervention of God, prayer, priests, or angels. In his sympathetic empathy for people "hankering after the lie" of a miracle just down the track, Zola was understanding, but his explicit, highly angry skepticism was made, one might say, painfully clear.

Zola's tale is full of the wrenching tears, sadness and suffering of people with the most desperate of problems that medicine couldn't cure.  Indeed, this is as most of us will be when our time finally comes.  Most of humanity have died not knowing that their hoped-for miracles never happened. Today there are still desperate or credulous people who seek cures from God or from mountebanks, but at least those who are reasonably educated and have the access mainly trust to empirical medical science; that seems a huge conceptual jump beyond simple, desperate prayers.  Medical science is a huge conceptual jump beyond simple, desperate prayers, and has marvelously transformed our health experience, especially in the developed world. We have to be entirely thankful to the biomedical research and clinical systems for this.  Who would trade our medical (or dental) lives for those of the 19th century?  Still, I'll wonder below whether there's some potential irony in that.

Flooding to miracle waters by the trainload.  Source: Wikipedia
"The need of the Lie, that necessity for credulity, which is characteristic of human nature."
A young woman, Marie, a suffering heroine in Lourdes, had become paralyzed in an accident. She poignantly believes in St Bernadette,  and says glowingly after hours of intense prayers at Lourdes that "At four o'clock I shall be cured!"  And she was--but it was no miracle, as we'll see.

Zola noted in great and angry detail how the simple purity of Bernadette in her (apparent) apparitions and belief in the curative powers of the waters, were quickly shunted aside, and co-opted as a grotesque source of mammon by Church officials, turning Lourdes into a kind of health-tourist Disneyland: "An elaborate organisation had been gradually perfected, donations of considerable amounts were collected in all parts of the world, sufferers were enrolled in every parish...."  Do we not have our equivalent in much of the biomedical system today?  Research clearly is costly, but one must note the similar self-serving and open-ended nature of this enterprise side of things, engaged in by our particular version of the high priests, the academic 'church', and the magical waters it promises in our own time.  This is actually not new, even to medicine, and the various territory-guarding priesthoods of health go back to Hippocrates.

One could perhaps, write a similar novel today.  Patients wouldn't be in crowded trains but in crowded waiting rooms in hospitals, or in the skilled nursing sections of a modern retirement center. The struggle to get 'hospitalisation' care in Zola's time, or tickets on the trains to the curative waters of Lourdes, is today the struggle to get care covered by insurance, or to get a bed or scheduled treatment.  It might seem more orderly, and be administered by bureaucrats rather than nuns and priests, though as Zola clearly documents, the Church was a massive bureaucracy of its own, even when it comes to formal committees--including at Lourdes--to give the imprimatur to claims of miracle (not so unlike today's PR empires trumpeting each daily research miracle?).  The psychological and even material circumstances are quite similar, because the old pathos and wishful thinking are still here, along with the hopes, dreams and judgments, though perhaps they're often harder to see as people sit quietly waiting for the nurse to call their names.

Ironic cautionary notes?
Zola rants at length against a world driven by superstition and false hopes, exploited by religions.  He pleads for a new religion, one based on reason, as he calls it, that is about the realities of finite life and its imperfections, rather than imaginary wishful-thinking.  But there is an irony in his emotional plea, one we might listen to carefully: he notes that this superstition still existed after what, even then, had been a century of science with its touted powers and promises.  The failure of science to cure their diseases was leading people to return to superstition, rejecting science--rejecting reason.

Zola bemoaned that the "thirst for the Divine, which nothing had quenched....seemed to have returned with increased violence at the close of our century of seemed that science alone cold not suffice, and one would be obliged to leave a door open on the Mysterious....what divine falsehood...could be made to germinate in the contemporary world, ravaged as it had been upon all sides, broken up by a century of science?  Ah! unhappy mankind, poor ailing humanity, hungering for illusion, and in the weariness of this waning century distracted and sore from having too greedily acquired science, it fancies itself abandoned by the physicians of both the mind and the body, and, in great danger of succumbing to incurable disease, retraces its steps and asks the miracle of its cure of the mystical Lourdes of a past forever dead!"

We've now had an additional century of science since Zola's book was published.  That we still have unconquered disease is understandable.  Diseases are diverse, and those we still cannot cure or prevent present massive challenges.  Of course, the target is an ever-moving one, with solved problems giving way to the unsolved ones that remain.  For the latter, even highly touted new treatments often only help some patients and it is not at all unusual to see that highly hyped new treatments in reality add but a few months of life, or a partial remission, for but a fraction of those who received them--and it is not necessarily true that those extra months are all that tolerable.  We are aided and abetted in the strong claims by the media, university or commercial spinners, and the interlocked careerist, funding-based mutually reinforcing systems.  So far, in our century, the public is buying it, as ever.

No fault lies in our not having divined (forgive the metaphor!) a cure, and the exaggerated promises of transformative advances are understandable in human terms--but not so different than what was coming from other pulpits in times past.  Is there any danger that the public will again see science, with its opulent cathedrals and assertive promises that often mammonize hope, as an enterprise of false illusions?  The suffering remain, after all, in the realm of fear, not reason.  To what alternative solution--or lie--might their hopes turn?

Of course, our inherent inevitable mortality means even our modern system will ultimately fail every one of us. As sentient organisms we don't want pain, and as knowing organisms we don't want death, and it is all too easy to 'Tsk, tsk' the system when it is others than ourselves suffering from awful diseases, and it's not yet our turn.  Ultimate failure is an open secret that neither the system nor its patients like to acknowledge.  The currently growing hospice movement is facing these realities, unless it too becomes co-opted as a 'system' with its own self-interested self-promotion.  Precedent suggests that may happen, but it's a very good thing at present, as we've noted here before.


Zola visiting Lourdes.  Wikipedia, from the magazine Gil Blas, 1894
Maybe some day we'll have the promised cures, sipping genetics or whatever other magic waters come along.  If so, then the medical priests will have earned their respect in every way.  But of course that, too, is a dream.  If all known diseases were cured by one miracle or another, we would still degenerate or even if that could be prevented, we'd be so numerous as to be stacked many-high on top of each other, struggling for food or water and so on--a geriatric nightmare of its own sort.

An ironical year
A century on from Zola's time we may still be at risk of people again turning away from the exaggerated promises of science, and given much of the world today it would be ironic but not so strange if there were a turn to some form of religion or mysticism, some emotional rejection of 'objective' science.  

But there is another sort of irony in the story of Lourdes.  In 1858, eerily reflecting the impending conceptual clash that Zola writes of, while the real Bernadette Soubirous was having the visions that would lead to the pilgrimages to the waters of Lourdes, Charles Darwin and Alfred Wallace publicly announced their discovery of evolution, that directly threatened religious explanations and led steadily to the altars of science instead as a competing explanation for human affairs. 

Zola's touching kind of docudrama makes one aware of the nature of hope, as well as false hope, and our willingness to believe what our particular day's preachers promise.  Zola himself bitterly debunks the claims at Lourdes.  Many of the pilgrims died, some reported improvement (almost always temporary), and only a few were 'cured'.  The trains left somewhat emptier than they were a few days earlier, populated by the returning survivors, still with their ailments, each inspired that the cure will surely happen to them at Lourdes next year!

As described in the link given below, a biography of Zola suggests that he saw a cured case of tuberculosis but changed that to a fatality in his book, to make his main point against superstition. But he was very clear that, as we often see reports today of, for example, placebo effects, it was nervous afflictions (that we refer to by terms like 'psychosomatic') that seemed most likely to be 'cured'.  Real physical problems were not.  The hero in Zola's book, a doubting priest who even had carnal feelings for Marie, understood that that was the nature of her 'cure', but in deference to her faith in Bernadette he made the altruistic decision to let Marie live with her illusions, thus permanently distancing her from his non-belief.

Such a book, though sometimes a bit ponderous in realistic details, is a good reminder of the human rather than just the sociopolitical, economic or even coldly scientific sides of the story.  But this should not take our eye off the importance of keeping science's eye on the proper ball: not that of self-serving empire building and inertia, but of truly addressing human agonies in the best way possible, fallible though we be.

Overall, perhaps we never learn--or, maybe, in being mortal it is not possible that we can learn, and completely accept the grim-reaper's realities that we know, in our hearts, are there.  At least, each of us will have to learn this in his or her own way, at the end.  No miracle can prevent that.

An afternote for fiction lovers
Here is a very nice blog post discussing Lourdes.  The blog is a fine one, about great literature that has survived fads and fashions and stands on its own legs.

Tuesday, September 15, 2015

And there will be humans no more? A review-ish of Greg Graffin's "Population Wars"

Perhaps best known as the leader of Bad Religion, Greg Graffin is also an evolution scholar. His latest book, Population Wars, is out today. 

I was hooked by the description that this is a "paradigm-shifting" book about human behavior, particularly for readers of Dawkins, Diamond, and Wilson. I was surprised at how heavily autobiographical it is throughout. But memoirs do make a lot of sense, given the many fans who are bound to read it, and given how the argument takes shape by the end. 

Graffin is appealing to our inner humans, but without appealing to our inner saps. If I had to sum up the book in one phrase, I'd say it's the least sentimental argument for saving humankind from extinction that you'll ever read. 

That's meant to be entirely neutral, but I don't think I can convey this next thing neutrally: 

I wouldn't have finished reading my advance copy of Population Wars if the publisher hadn't offered me a Q&A with the rockstar.

It wasn't because of his voice. I was thrilled when the first few pages beat just like Bad Religion when the volume's right. 

It was because of the content. I'm not one to throw many punches, let alone at members of my own tribe of evolutionary scientists-slash-authors. But I share this awkward fact (that the only thing that kept me reading this book was my eventual interview with a rockstar) for two reasons: 

Graffin can handle it. And, my experience taught me an important lesson. Because I stuck it out and read through the many pages of cyanobacteria, and the many, many pages of Iroquois history, I was reminded of the importance of learning what we're not necessarily very interested in learning--ever, or at a given moment, or from a particular human's perspective, or whatever. 

Population Wars didn't just teach me new things about natural history,history, and environmentalism, it incidentally taught me something bigger that I think I lost my grip on. It reminded me why we read books.
Books. Neatly stacked and bound piles of paper. This is where so many humans pour our hearts and souls. Whatever one thinks of Graffin's book, it's his blood and guts expertly smeared into teeny tiny perfectly discernible shapes. And you can feel how he honestly believes that humans can figure out a way to prevent our future extinction. That's utterly beautiful even if you don't see things that way. It's there for readers if they stick it out, turn each of those pages, and make it to the end where they can meditate over this human's heart and soul at once. 

When we're finished reading even the best books, the books that light us up from head to toe, we merely shut them and shelve them. CDs of music too. 

We've been married for over seven years and just last week I hear Kevin's "Rockers Galore" for the very first time. It's like a dream mix-tape of The Clash with interviews and it's my new favorite album. It's got Joe Strummer explaining what he was trying to say in Rock the Casbah: "There's no tenderness or humanity in fanaticism.

That fleck of gold was just crammed into a cabinet this whole fucking time? That one sentence that elevates an already great song into the outer dimensions of the rock'n'roll-sphere was hiding in plain sight inside my own fucking house? 

CDs. Books. Even when they're not earth-moving, they contain more human creative and emotional energy than we deserve. But the ones who write them believe that we deserve it, which makes them even more magical. When we leave CDs and books sitting there, unexplored, we're failing humanity.

Population Wars charges us to find the humanity within ourselves to collaborate, globally, as a species to clean up and preserve our planet. Graffin describes how someone can see all of history through an evolutionary lens. His aim is to spread this worldview because it's this perspective, over common ancestry and deep time, that literally unites us as a species, even if we are divided culturally. Unfortunately, saving the planet is too big a job for anything less than all of us. Graffin's book is one voice toward our unification in the face of all the fanaticism.  
This is the first but won’t be the last time I write about the dinner I had with an astronaut. One of the small group of us, one of us who hadn’t walked on the moon, seemed desperate to get an inspired nugget of Truth out of the one man who had. He certainly was a remarkable human, but he clearly wasn’t supernatural. His body language and his seamless diversions showed he was as skilled at avoiding sentimentality as he was oxygen depletion.

In the presence of astronauts and other rockstars people want to have their hearts melted or their minds blown. They want to transcend. To quote Twitter: they want all the feels. When they’re not preoccupied with selfies, they’re begging rockstars for God and they expect to get it. Even in someone’s kitchen, over a casserole and some beers.  Even when they’re hardly fans of Bad Religion and they read its leader’s evolution book? I hope not. I think no one who picks up Population Wars, especially Bad Religion fans, is going to expect kumbaya. Yet, tree-hugging is something for Grateful Dead shows, not punk ones.

Graffin's argument isn't to save the planet for our babies or the polar bears', it's to save the planet because we can. Let's make it our moonshot. Let's boldly go, together, globally, here on Earth. 

That thing that we don't have that could unite us while give us purpose as individuals? That thing that Eggers' protagonist desperately wants? That thing Jon Stewart always talked about? That thing that binds us together with a goal? That thing is saving the species by saving the planet.

And if you're going to save the planet, you've got to learn about things that might not rock you to your core, things that might require more stubbornness than anything to hold your attention. I didn't want to read about Graffin's cyanobacteria. I even got angry about it, but if we're to make a dent in saving the planet, we should be reading about such tedious things. 

Point blank: We humans should be reading as much as we can, whatever we can get our hands on, and without a carrot dangling at the end of the book, without the promise of an interview with a rockstar. 

Because sharing our unique human experiences with one another unites us as humans. 

And also because rockstars go on tour. When you're all done reading and you write to the publicist to say, This is an important book, thank you for sending it to me. I want to write about it. Please set up a Q&A and please send the music that accompanies the book... She is likely to respond with an apology (and without the music too).  

So lessons learned! I read Population Wars and all I got was one brilliant human's heart and soul, one human's bold and hopeful vision for our species.  
Questions for Dr. Graffin

  1. Is Population Wars punk rock?
  2. Both perpetual mutation as well as genetic drift are fundamental to how I have come to understand natural selection as being much weaker than many still believe it to be. However, you have come to this seemingly same conclusion about natural selection without genetic drift and without much consideration of perpetual mutation. Can you help us understand how you did this? And can you explain why you left genetic drift out of your book?
  3. I am drawn to discussions of free will, but it's hard for me to reconcile your argument that it does not exist with the goal of your book urging humankind to save the planet and ourselves. If there is no free will, how will your book's will be done?
  4. What do you want readers to do after reading your book? I'm thinking specifically of the readers who cannot afford to emulate you by building an eco-friendly home and turning down big financial offers from natural gas companies. The book demonstrates your evolutionary worldview, but does not contain many directives. What can we do toward your goal of saving the planet and the species?
  5. How do we join together as a species to accomplish anything together when there's such massive inequality?