Make a bee-line for truly important research!

You may think it's been too cold too long, but this was a really hard winter for honeybees.  Winters take their toll on bees even in a good year, with 5 - 10% mortality, but with the 'colony collapse disorder' (CCD) that has been affecting honeybees since it was first reported after the winter of 2006-7, mortality has risen to 20-30% and more.  If you like to eat, that's already pretty ominous news, since bees fertilize much of our food sources, but a story in The New York Times last week reports that this year 40 to 50% of all hives were wiped out (the accompanying video is worth a look), and no one is sure why.

“They looked so healthy last spring,” said Bill Dahle, 50, who owns Big Sky Honey in Fairview, Mont. “We were so proud of them. Then, about the first of September, they started to fall on their face, to die like crazy. We’ve been doing this 30 years, and we’ve never experienced this kind of loss before.”

This is of course devastating to beekeepers, but it's also going to be devastating to farmers who depend on bees to pollinate their crops -- almonds in California are a huge such crop.  A story at NBCNews.com reports that bee pollination is responsible for $15 billion in increased food value every year, perhaps a quarter of all foods.  And food losses will mean higher prices.  If this keeps getting worse, our own species itself could be in danger of starvation.  So of course we look hopefully to science to explain, and stop, the devastation of our buzzing friends.

According to the US Environmental Protection Agency, and this list of possible causes is fairly standard,

There have been many theories about the cause of CCD, but the researchers who are leading the effort to find out why are now focused on these factors: 

• increased losses due to the invasive varroa mite (a pest of honeybees);
• new or emerging diseases such as Israeli Acute Paralysis virus and the gut parasite Nosema;
• pesticide poisoning through exposure to pesticides applied to crops or for in-hive insect or mite control;
• bee management stress;
• foraging habitat modification
• inadequate forage/poor nutrition and
• potential immune-suppressing stress on bees caused by one or a combination of factors identified above.
• potential immune-suppressing stress on bees caused by one or a combination of factors identified above.

Additional factors may include poor nutrition, drought, and migratory stress brought about by the increased need to move bee colonies long distances to provide pollination services.

These possibilities have been proposed since the onset of CCD, and they are still live possibilities, but most have proven less explanatory than they'd seemed, and they don't explain why this winter was particularly hard.  Perhaps it was the drought in the midwest followed by a hard winter, though some beekeepers are reporting heavy losses despite good summer conditions.  The increase in pesticide resistant mites is another possibility, or viruses.  Or, perhaps it's a number of stressors in combination.

The explanation getting the most play these days is the increasing use of pesticides, fungicides and herbicides, although the EPA says there is no definitive evidence that pesticides are the cause ("To date, we’re aware of no data demonstrating that an EPA-registered pesticide used according to the label instructions has caused CCD."). And indeed, each of the chemicals now used on crops has been certified safe, but are our guardian officials being too lenient?  For example, any given combination may have unforeseen effects, and combinations haven't been tested.  Of particular concern is the only new class of pesticides developed in the last 50 years, neonicotinoids, derived from nicotine and developed in the 1980s and 90s.

A paper published online in Science March 29, 2012 (Whitehorn et al.) reported that neonicotinoids indeed do have a negative effect on bees.

Growing evidence for declines in bee populations has caused great concern because of the valuable ecosystem services they provide. Neonicotinoid insecticides have been implicated in these declines because they occur at trace levels in the nectar and pollen of crop plants. We exposed colonies of the bumble bee Bombus terrestris in the laboratory to field-realistic levels of the neonicotinoidimidacloprid, then allowed them to develop naturally under field conditions. Treated colonies had a significantly reduced growth rate and suffered an 85% reduction in production of new queens compared with control colonies. Given the scale of use of neonicotinoids, we suggest that they may be having a considerable negative impact on wild bumble bee populations across the developed world.

A second paper published in Science at the same time  (Henry et al.) tested the effects of a sublethal dose of a single one of these compounds on the homing behavior of honeybees, suspecting that it might affect the bee's ability to find its way home because of how it affects the insect nervous system.

They are highly potent and selective agonists of nicotinic acetylcholine receptors, which are important excitatory neurotransmitter receptors in insects.  Effects of sublethal neonicotinoid exposures in honey bees may include abnormal foraging activity, reduced olfactory memory and learning performance, and possibly impaired orientation skills.

They found that the neonicotinoid they tested affected forager survival, which may indeed have severe consequences for the survival of the hive.

Neonicotinoids are applied to the seed, and then travel through the sap to all parts of the plant as it grows.  They are said to be less toxic to mammals than other pesticides, and so have been used more liberally.  Because of the suspicion that they may be at least one of the agents responsible for colony collapse disorder, they've been banned in some European countries, and the ban may widen throughout Europe.  Indeed, Whitehorn et al. conclude their paper "...we suggest that there is an urgent need to develop alternatives to the widespread use of neonicotinoid pesticides on flowering crops wherever possible."

Several of these compounds are now under review by the EPA to determine whether they still meet requirements for certification.  If we were to bet, we'd bet they do.  Big agriculture relies heavily on chemicals to grow the food we eat.  Much less of this would be needed in more traditional, smaller-scale less corporately-tied agricultural practices, that many argue could still feed the earth.  Enough said.

Priorities when there's too much on our plate
We are currently pouring research resources into massive but mildly incremental topics like genomic disease and personalized genomic medicine (PGM).  Many, if not all, of these are the common diseases we get after living a long time in a sedate, well-fed (or over-fed) lifestyle.  These diseases are consequences of ease and privilege, and could clearly be  prevented, or greatly delayed, by basically painless changes in how we life.  They are not 'genetic' in any serious sense.  As a result, the payoff of these studies, in most cases, even if things were to work out as promised by PGM's advocates, would with some exceptions be exceedingly not-exceeding.  Indeed, it would be minor.  Minor relative to using the experience of relatives (heritability) rather than individualized genomes, minor relative to the baseline risk, minor relative to environmental exposures, and minor because genomic risk doesn't generally lead to gene-specific treatment.

Meanwhile, we really do have an important problem, one with orders of magnitude more potential for harm if not understood quickly and enormous potential for human good: colony collapse in bees.  A sane research policy would be aimed at solving societal problems in a rational priority order, rather than the vested-interest order that so predominates today.  These areas pale in importance compared to the problem of having adequate food.  That's even more important than climate change, though climate change may be a major threat to agriculture and our food sources as well.

Major problems often turn out to be complex and difficult to solve, and CCD may or may not turn out to be simple.  But it is an example, along with others like antibody resistance and overpopulation that are huge threats to our essential well-being.  Why aren't we pulling funds from what is sexy and media-exploitable research, but is entrenched and in many ways about problems of privilege, to areas that are much closer to the nitty-gritty of our very survival?

Be afraid of fear, not personal genomics.

It's just the way it is now. This headline. This story.
(click to read/hear)

As Genetic Sequencing Spreads, 

Excitement, Worries Grow

It follows the recipe. (1) Start with a headline that demonstrates controversy. (2) Present a story about science-related news (which does not require controversy to be news). (3) End it ever-so briefly and vaguely with dissent, doubt, outcry or warning. 

This recipe applied to personal genomics is particularly bad.

If you read or hear that story you might be primed before you start to wonder, okay what's the worry? Glad this article will tell me, finally, what we should be concerned about concerning this brave new world of personal genomics.

But you'll be sorry when you reach the end and this is all you get:

But the idea of widespread sequencing is setting off alarm bells. How accurate are the results? How good are doctors at interpreting the results, which are often complicated and fuzzy? How well can they explain the subtleties to patients? The fear is that a lot of people could end up getting totally freaked out for no reason. And there are concerns about privacy. Scientists recently even sequenced a fetus in the womb, raising the possibility of everyone getting sequenced before or at birth — a prospect with a whole new set of questions and concerns. "I think there are lots of populationwide and individual dangers," said Mark Rothstein, a bioethicist at the University of Louisville. "We're basically not ready for a society in which very exquisite, detailed genomic information about every individual, potentially, is out there."

Why? Tell us? And I don't mean the "us" who have access to the academic journals. Or the "us" who have the patience to bushwhack through the jargon. I mean, here is your chance to share with the public who you're concerned about: Since you brought it up, tell us why we should worry.

It's unclear who deserves the complaints and the criticism for producing pieces like this, since much of the "telling us" that I'm begging for might be lying on the cutting room floor.

I'm clenched about this because right now about 20 students in my Human Varition (Anthropology 350) course at the University of Rhode Island are voluntarily participating in genotyping through 23andMe. And I'm using this curriculum for the second semester now. After last spring, where over 100 students in both Human Variation and also the introductory level Human Origins (Anthropology 201) did 23andMe, not one student got "totally freaked out." This along with much of my experience with genotyping and undergraduates indicates that, with education and with understanding, personal genomics does not induce fear. Not coincidentally, participating in personal genomics aides in education.

And the same fear that I'm trying to mitigate through education is the same fear that some journalists and ethicists seem to be perpetuating if not creating.

In my experience, if you're informed, you're likely to appreciate biological complexity rather than cling to genetic determinism. If you're informed, you understand the positive and negative consequences and aspects of personal genomics. If you're informed, you don't get lured into personal genomics for all the wrong reasons. You don't order an expensive 23andMe spit kit as if it's snake oil. You don't send your vial of saliva to California, along with 300 of your precious bucks, because you think it will help you to live a longer, healthier life, or because you think it will show you your future.  Spit kits are not crystal balls, are not medicine, are not cures. Plus, the results will also most certainly change! Not your genotypes, but how they're interpreted. That genomes must even be "interpreted" should be a flag shouldn't it?

Informed citizens and consumers don't buy into personal genomics thinking it's their one and only answer-- their key to "me"-- because "me" will be increasingly different the more we learn about genetics and the links between genotypes and phenotypes. "Me" is, for most, too stubborn and conservative, while at once too big and too free, to be dictated by genotypes and probabilistic phenotypes.

All that is guaranteed with a 23andMe spit kit is that you will see parts of yourself that you haven't seen before. There's not a whole lot on the planet that's cooler than that. For most of us who will never go to Mars, at least we've got this, at least we've got innerspace.

Even if you don't get an ounce of joy from the experience, when you're informed you don't fall uncritically for claims that spit kits are dangerous or venomous.

Considering the engaging educational opportunites provided by personal genomics, considering its power to inform, spit kits may just be much-needed anti-venom.

In my experience education diminishes fear about genetic determinism because it diminishes genetic determinism. That leads me to see fear of personal genomics as a symptom of ignorance. And that's something worth being afraid of.

**

Note: Ken, Anne and I have differing views on direct-to-consumer (DTC) personal genomics like 23andMe so please remember that I speak only for myself when I write. Also, I am not paid  or sponsored by 23andMe to endorse their product. I use their product, at the educational rate, to teach anthropology at the University of Rhode Island.

Genomic medicine reality check

Dumping cold water on personalized genomic medicine
A news focus piece in last week's Science about cancer geneticist Bert Vogelstein is right up our alley. The piece begins, "Their lab helped reveal how faulty genes cause cancer, but Bert Vogelstein and [laboratory co-director] Kenneth Kinzler sometimes irk colleagues with their “reality check” comments on genomic medicine." Their point? Whole genome sequencing is not going to be useful for predicting who will and who won't get cancer. And they back this up with a study of disease risk in identical twins, described in an April Science Translational Medicine paper ("The predictive capacity of personal genome sequencing").

Vogelstein has long been interested in characterizing genes that are mutated in tumors, long ago identifying genes associated with the development of colorectal cancer. He and Kinzler when the latter was a student in Vogelstein's lab, showed how the slow accumulation of mutations in previously identified genes, including tumor repressor genes that no longer do their job when mutated, lead to tumor growth.

In the last decade, Vogelstein and Kinzler were the first lab to publish an extensive tumor exome sequence, all the coding regions of breast and colorectal cancers. They identified both known and novel genes involved in tumorigenesis. The work was done in the days before high-throughput sequencing was commonplace, however, and their work was criticized as not having been thorough enough or well-analyzed statistically. Though, their results were subsequently confirmed by others.

Whole genome tumor sequencing is much easier and more complete now, but Vogelstein and Kinzler don't see much more to be gained with it, and they've moved on. Their recent work has involved looking at identical twins to determine whether what they call the "genometype" would allow prediction of disease risk. That is, based on the assumption that monozygotic twins share essentially the same genotype, is it possible to predict risk of disease to a second twin if the first one has it? This of course depends on the extent to which the disease is genetically determined.

This basic observation, that monozygotic twins of a pair are not always afflicted by the same maladies, combined with extensive epidemiologic studies of twins and statistical modeling, allows us to estimate upper- and lower- bounds of the predictive value of whole-genome sequencing.

On the negative side, our results show that the majority of tested individuals would receive negative tests for most diseases. Moreover, the predictive value of these negative tests would generally be small, as the total risk for acquiring the disease in an individual testing negative would be similar to that of the general population.

The authors go on to point out that this is consistent with what has been found with GWAS -- many genes explain little risk. 

Thus, our results suggest that genetic testing, at its best, will not be the dominant determinant of patient care and will not be a substitute for preventative medicine strategies incorporating routine checkups and risk management based on the history, physical status and life style of the patient.

The story is different, they point out, for rare monogenic diseases, where whole genome sequencing has already been shown to be informative -- but then, so have association studies and the like.

Why the cold water is warranted

The first point one would make is that most genetic disease susceptibility seems to be due to what is known as the constitutive genome, that is, the DNA sequence you inherited when you were just a single cell, a fertilized egg. As they divide and divide during life, all your cells have a copy of the same genotype--almost. Each time they divide, some DNA copying errors are made, and the descendant 'daughter' cells are slightly different. Since you're made of billions upon billions of cells you have just as many different genotypes.

Most such somatic mutations are never seen clinically. Whether they help or harm, they're just in a single cell, and their effects are swamped by the sea of surrounding cells in the same tissue, that basically have your constitutive genotype at genes relevant to that tissue. If the constitutive genotype confers risk, then basically all cells in that tissue are at risk.

The difference with regard to cancer is that when a bad combination of mutations occurs in a single cell, it doesn't just die or stagger along doing no harm to you, but it proliferates, amplifying the signal of that mutation. It takes many different mutations to transform a cell from normal to cancerous. This is why cancer risk is poorly predictive from your constitutive genotype: most of the changes that lead to disease occur somatically in this or that cell until a bad combo arises in one of billions of cells.

So you'd think at least looking at the tumor cells would show what mutations were important. To some extent that's true, and though it isn't much use in predicting cancer (since the mtuations are found after you already have cancer!), this may provide ideas on how to target the cancer cells. The problem with even that is that a cancer in a single person is continually evolving, rapidly accumulating even more mutations, so that not all cells in the same tumor are cancerous for the same reasons.

You'd have to sample many different parts of the tumor to identify the different variants. And some recent studies have done just that, and shown that different secondary tumors--descendants of the primary tumor, within one patient's body--are genetically different. In part, at least, this is what enables cancer to metastasize, to colonize different parts of the body from the tissue they started in.

But if cancer is therefore not well predicted from your constitutive genome, one might expect that diabetes and heart disease would be predictable because they aren't the same kind of proliferating disorder. But despite what the genome-selling companies would like you to believe, that is turning out not to be true, either, and we have discussed this countless times before, in the context of GWAS and other studies.

Evolutionary implications

This is all consistent with evolution as well. The same genomic complexity that makes your traits, but makes finding single genes 'for' the trait difficult, is exactly what means that natural selection is not working very closely on one or a small number of specific genes. If GWAS can't find causal genes for a trait, even if you have the trait, natural selection can't do that either.

This means that traits can evolve adaptively via natural selection in the way Darwin explained, without this being very tractably understood at specific single genes, and indeed the indirect genomic effects of selection that is merely screening traits is what led causation to be so complex in the first place.

There are many parallels between what happens among cells in your body, and individuals in a species, and Ken wrote about that in 2005 in Trends In Genetics, where he discussed ways in which diseases other than cancer might be caused by somatic mutations whose effect could somehow be amplified so you would notice it at the organism level. Diseases like epilepsy were examples discussed there.

Causation may be genetic in the trait or evolutionary sense, but the specific genotypes that are responsible may be difficult or impossible to detect, or so variable among cases and individuals that by and large it's not worth taking that approach--something roughly consistent with what Vogelstein was saying in the story about him.

Ho hum, you're SO close to average!

So a new study confirms (we would claim) what we have been saying for many years,  repeatedly on MT, and in print before it was popular to say it:  Personalized genotyping is not going to be very useful in predicting disease.

The new story in Science shows from twin data--how close can you get!--that overall, individualized prediction of disease is not much different from saying 'you're average'.  Being just like everybody else is not a nice way to feel, but it is what is expected in this kind of situation.  Identical twins are far from identical in terms of their life expectancy of disease history.

Still, appropriate as this story is in refuting the blatantly self-interested claims of many parties in the discussion these days, a Times report of it is also very misleading.  They don't point out the issue.  Neither do the authors of the original paper.

The idea of the twin study is, like heritability studies, that if you look at the whole genome, integrating whatever information it contains, the overall predictive power is slight.  That's essentially because a multitude of minor-effect variants may contribute to risk but individually too little to identify statistically by themselves.  So you look at the aggregate.  But even there, the predictive power is slight.

This is not new!  It's been shown in twin studies before (without having genotype data) and in mouse studies with or without such data.  And it makes sense.

But this does not mean that personalized genotyping is useless.  There are known genes in  which specific mutations confer clearly higher-than-average risk of a given disease (and, should anyone look for them, there must be protective variants as well).

Most twins would receive negative personalized genome tests (that is, reports of risk alleles for what the twin got).  But this doesn't take away from the finding, also long known, that specific high-risk variants with mainly single-gene effects (e.g., cystic fibrosis, some breast cancer variants, etc.) are detectable by genome tests and are useful.

The bottom line:  unless you have such single-gene disorders in your family, generally speaking, skip the test--and the McFood. And if you're worried, go take a walk.

Ethical issues in personalized 'genomic' medicine

Ken was just at a very interesting conference on ethical issues that will pertain to the use of genomic data to 'personalize' medicine in the 21st century. Of course, all such conferences are presumptuous in the sense that nobody can really know what things will be like. The record of pundits and experts (scientific, economic, or political) is so poor it's a wonder there is employment for any of us. In biomedicine and genetics, we've made so many false promises that if we were Pinocchio we'd all be sprouting giant Sequoias for noses.

Nonetheless, using individual genotypes to try to predict or diagnose disease is going to be a fad for at least some years until it either proves to be a bonanza for health care, or a bust with little definitive power. So much effort is going to be invested in the effort, that if it doesn't pay off it will be for good reasons -- that is, we'll have learned a lot about biology in the process of not improving medicine very much.

Likewise, if individual genotypes do prove to be of high predictive or diagnostic value, that will mean we know the genes and hence will be able to figure out why they lead to disorders and then, presumably, we'll be able to engineer some prevention or therapy.

'Personalized medicine' is a lobbying phrase in that medicine has always been personalized, and adding the term 'genomic' is also a lobbying phrase for support to attempt to boil your and my health (and who knows what else?) to estimable, powerful genetically based effects. The fact that's it's a catch-phrase to sell personal direct to consumer genetic advice, or other clinical or commercial products, does not mean it's bad or won't work. But at this stage, we need to be aware of the vested-interest component. In principle (but not in America), we could keep quiet until we actually knew it would work before we started selling predictive genomic services.

In fact, there are many traits for which an aberrant gene is indisputably known. Many investigators are working on trying to understand them. They are the 'Mendelian' diseases that are almost always due to aberrant function in the same gene (like cystic fibrosis or sickle-cell anemia), and fractions of more complex diseases in which some cases are due to a single gene (like breast cancer associated with mutations in the BRCA1 and 2 genes) but most cases aren't. Personalized medicine, whether predictive, diagnostic, or clinical is quite important in these instances, and the main ethical issues are things like whether prenatal screening or abortion are justified, etc.

Ethical issues abound, however, in the case of most traits, where genotypes are only vaguely known or have weak predictive power. There the question is what the relationship between a known genotype and actual risk is, and at what level of risk something should be done about it. Or whether, if nothing can be done about it, it is useful to worry people.

Who gets to see the information in either case is important. Can or should it be used to force treatment or preventive measures on people as a condition of insurability? Or to adjust health insurance premiums? Or to screen relatives? Or decide about employability?

Weak predictive power often means such incomplete knowledge that the genotype may not, in fact, make reliable or replicable effect on risk. The problem here, which we are already beginning to see, is that genotyping leads people to confront their physicians with diagnoses that the physician may or may not agree with (or understand, since much of this area is quite complex), but may feel obliged to do something about.

In a country in which the health care system is already overburdened, and will become even more so as the population ages, personalized genotyping can lead to large-scale over-diagnosis, new and unnecessary testing, and lifelong costly maintenance such as multiple screening checkups, preventive medication, and so on. Much in the way of profit to the system, much in the way of distraction for lawyer-wary doctors, but not much in the way of additional health. Indeed, overdiagnosis leads to overtreatment and hence actual increase in risk.

These and other issues, like the value (or not) of 'racial profiling' in medicine, were discussed at this meeting. There aren't answers, exactly, but at least the issues are being raised. Whether the issues are being examined deeply enough -- for example, as to ask whether some of these activities should be legal, or how much research money should be invested (or wasted, depending on your viewpoint), get less discussion, because our system places vested interests across the spectrum of people from commercial to academic to clinical.

Certainly, as everyone agreed, the genomics perspective is here to stay at least for a while. Probably, much of the promise and hype will prove to be false and will simply fade away. What is discovered that is useful will become part of standard practice and a source of better diagnosis and treatment. It is usual that most of what people claim at this or any time proves to be rather worthless. That's likely to be the same in this instance. But, as is also usual, some gains are made and they set the stage for the next wave of ideas about how genes work and how health can be improved.