Whoops! (sorry folks)

For the last few hours a very drafty post has been up... whoops! Took it down. Official post on "Evolution's P.R. problem" coming in a few days...

Mermadness

Merdog. (source)

We're thrilled when people who are looking to learn something land on our blog.

We have good reason to assume that many of the most recent "mermaid" googlers that lead people here to the Mermaid's Tale are people who have seen the new mermaid shows on television and are looking to find out more about what they learned in those programs.

Part of that assumption has to do with the search terms that  have directed people here lately:

"dr stephen pearson mermaid"

"anthropology explanation of mermaids"

"mermaid research"

"bbc mermaids not real"

"hominin mermaid"

"aquatic ape"

"dog eat mermaid"

If you're one of these seekers, this post is for you.

The Animal Planet / Discovery Channel documentary on mermaids is actually, literally, truly fiction. Like a mockumentary.

Like Spinal Tap.

But not nearly as awesome.

The mermaid show is entirely* dramatized. Made up. Fake.

Like Waiting for Guffman.

But not nearly as awesome.

Those scientists in the mermaid show are not. They're actors.

If those were real scientists, then when you google their names plus their institutions you will land on their professional websites. You didn't find a single professional website for any of those scientists in the mermaid show because they're fake characters made up for a fake documentary.

Like A Mighty Wind.

But not nearly as awesome.

When it says "dramatization" and shows actors acting on behalf of the scientists, you might be fooled into thinking that those parts are the only fake parts, but the whole thing's fake.

Like Best in Show.

But not nearly as awesome.

If mermaids were real, we would know about it already...with absolutely no need for a cable channel documentary to reveal it for the first time to us.

Animal Planet and Discovery Channel are purveyors of entertainment, not beacons of education, knowledge or truth.

Sad mermaid. (source)

But it's okay! There are lots of awesome things to learn about in the natural world that actually do exist. Piles of amazing wonderful things.

Like nuts, for example.

A lot of people confuse skepticism with intelligence. A lot of people confuse beliefs in government cover-ups about weird creatures like mermaids and aliens with intelligence. Don't be one of those.  It's common to feel this way upon entering college, for example, when you start to realize that a lot of the dogma that we learn in K-12 is biased, is complicated, is less solid than it seemed, or has since been overturned.

Truth and knowledge often change, but truth and knowledge are also devised by humans. So, yes, question everything, but mostly question sources that want your money.

Here's what you find when you google "mermaid mockumentary." And here's a twitter-famous recent treatment, "Mermaids: The New Evidence is a Fake Documentary"

If today's post didn't help, then hopefully all those links above will.

Or this just did. (source)

*"Entirely" is only referring to the mermaids. e.g. They do talk about real evidence for human activity in oceans that's harming real sea creatures.

Human evolution, locally.

Our university's PIO (public information officer) knows I care about and get a kick out of outreach so he sets me up with folks who are looking to learn about evolution. It's great. Recently I've visited a sixth grade science class and helped to kick off their evolution unit with humans (!). Also recently, a retirement community invited me to bring my hominin casts and share what I know about the human fossil record. And I've got another retirement community visit lined up for next week.

But I wanted to highlight one particular occasion that occurred recently here:

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We set up a projector, passed around bones and casts, and with far too many slides I discussed human evolution with seven people from the area.

My title slide...

A slide of books that I recommended...

One patron took this list to heart and checked out Shubin's book before going home!

A journalist caught wind of the event (thanks to the advertisement the librarian had published in The Westerly Sun) and sat with laptop, typing as we went along. This is the article he wrote that made it into a few of the local newspapers in our area: http://www.ricentral.com/content/primates-humans-follow-evolutionary-path

Some of those quotes, out of context, sound a bit dumber than they deserve. (But only a bit.) To my knowledge, I never spoke of woolly mammoths. (I prefer to talk about woolly rhinos.) The photo's not what I'd shoot or how I'd caption it. (Didn't participate in that.)

But by far I'm thrilled that human evolution was the theme of the afternoon at the Ashaway Free Library, I was delighted to speak about (and learn from) the folks at the event including the journalist, and I'm thrilled that our little evolution love-in got such in-depth coverage in our local newspapers!

I'm sharing here for a number of reasons but most of all because it's something that our group "Reporting Across the Culture Wars" (see also) at NESCent came together to try to encourage... and it happened without really any effort on my end except making it roaringly obvious how much I care about outreach to my university's PIO and then accepting the invitation from this librarian when he passed it along to me.

If this is something you think you'd enjoy doing, both personally and professionally, go for it. It's like having a college honors seminar right in your neighborhood!

Now, here's a fun guessing game. Can you spot the cranium that's out of place in this photo from the article?

My dogs' evolutionary history. Part 2: Results

Yesterday we made the predictions of the breed signatures we'd find in our dogs' DNA.

If you didn't already, please consider going back to yesterday's post first before reading today's. Predictions are key! It's best if you confirm our guesses and/or add your own. (...what are the reasons for your predictions? Size? Color? Ears? Tails? Fur? Snout? Furnishings?)

Sadly (yes, sadly), predictions are not part of the official Wisdom Panel or 23andMe experiences. When I teach with 23andMe predicting the results is a major assignment early in the semester. Not only is making predictions the best practice for later scientific evaluation of the results, and it's the best way to force yourself to come to terms with how inheritance and gene expression work (and don't work), but guessing the outcome first makes reading the results orders of magnitude more fun ... not to mention how it makes things a lot less nerve-wracking when it's about your own DNA with 23andMe.

Briefly, before I reveal our dogs' results, let's consider a couple important things first...

Dog breed markers are mutations. 
Just like anything else alive right now, all dog breeds, no matter how "pure" or revered, are mutants. All of their dog traits just like all of our human traits, good and bad, started out as new mutations. Even the ones we all share that contain little variation now (like our genes involved in the development of five fingers and five toes), but also the ones that vary among our populations (like our genes that affect our pigmentation).

And mutations aren't just a population thing; each of us has a tiny fraction of our genome that's mutated compared to our parents. As far as we know, mutations occur in the making of all babies and puppies, etc. Most are neutral, some are bad, some are good.

We're all mutants because mutation, perpetual change generation upon generation within a lineage, is constant. Stasis is not.

This constant change in every puppy is fundamental to why we can have hundreds of dog breeds today.

Many dog breed traits are genetically simple.
Dogs seem to be particularly simple kinds of mutants.

The mutated genes that determine the traits that distinguish one dog breed from another are remarkably few and remarkably simple, but that simplicity makes a lot of sense.

Since humans coaxed these breeds out of ancestral dog stocks and also out of other breeds (as they still do today), it's easy to imagine that new simple traits, not new complex ones, had the best potential to be easily and quickly propagated into future generations and eventually into new breeds.

If a trait arose that was preferred, and it was caused by the kind of genetic mutation that could be simply and somewhat reliably expressed in offspring that inherited it, that mutation and the trait it produced could be increased in future generations by promoting breeding of those new attractive mutant dogs and their offspring.

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If dog breed traits were genetically complex (based on many genes, for example), they would be terribly difficult to produce through controlled breeding of parents with those traits... at all... let alone during one human breeder's lifetime! That's at least partly because there would be far too many puppies without the preferred trait and it would be far too difficult to preserve a trait at an appreciable frequency in a lineage. Of course, inbreeding with very close relatives that share the mutations helps a great deal with this.

Humans have taken advantage of the simple mutations that have popped up in dogs (as they pop up in all living things!), due to sheer feasibility of the breeding outcomes those simple mutations allowed. Like that new coat curl or those new furnishings? Some puppies will have the exact same look. And we're off and running with a new kind of dog...

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I don't know about the genes for Dalmatian spots (and honestly haven't even looked) but I do know about this paper by Cadieu and colleagues from 2009. Apparently you need only three genes (FGF5, RSPO2 and KRT71), each with two alleles (i.e. gene variants; denoted +/- in the figure below) to explain all this coat variation among dogs:

Cadieu et al., 2009

Dog genes are made of the same goop that ours are, and their genomes are very similar to ours because of our shared mammalian ancestry, but they're described as "simple." Evan Ratliff explains some more about why dog genes are simple in "How to Build a Dog:"

The vast mosaic of dog shapes, colors, and sizes is decided largely by changes in a mere handful of gene regions. The difference between the dachshund's diminutive body and the Rottweiler's massive one hangs on the sequence of a single gene. The disparity between the dachshund's stumpy legs—known officially as disproportionate dwarfism, or chondrodysplasia—and a greyhound's sleek ones is determined by another one. The same holds true across every breed and almost every physical trait. In a project called CanMap, a collaboration among Cornell University, UCLA, and the National Institutes of Health, researchers gathered DNA from more than 900 dogs representing 80 breeds, as well as from wild canids such as gray wolves and coyotes. They found that body size, hair length, fur type, nose shape, ear positioning, coat color, and the other traits that together define a breed's appearance are controlled by somewhere in the neighborhood of 50 genetic switches. The difference between floppy and erect ears is determined by a single gene region in canine chromosome 10, or CFA10. The wrinkled skin of a Chinese shar-pei traces to another region, called HAS2. The patch of ridged fur on Rhodesian ridgebacks? That's from a change in CFA18. Flip a few switches, and your dachshund becomes a Doberman, at least in appearance. Flip again, and your Doberman is a Dalmatian. "The story that is emerging," says Robert Wayne, a biologist at UCLA, "is that the diversity in domestic dogs derives from a small genetic tool kit."

So it's this simplicity that allows companies like Wisdom Panel to genetically distinguish breeds and then look for the signatures/markers of those breeds in our dogs' DNA. It's also the recency of most of these breeds (no more than a few to several hundred years at most) that allows us to assume (maybe not rightly but still...) that so much of what genetically identifies a breed today is similar to what the breed was working with all along.

And so... without further ado...

Here are the results of mailing off our dogs' cheek swabs and having 321 markers for 200 breeds analyzed.

For Elroy...
This is his "Breed Ancestry Certificate"

The report notes how Rottweiler and Chow Chow are the only ones with confidence. 

How do they make the pedigree chart? 

What I think they do is estimate what percent of the breed contributes to the dog's ancestry and if it's something like 50%, it's one parent. If it's like 25%, it's one grand-parent and if it's like 12.5%, it's one great-grandparent. Any % less than that is lumped into "mixed breed" ... the details of those are guessed at below.  So those placements on either side of his chart are just best fit in terms of percentage. 

What I'm not sure about is why we must assume that 100% of Elroy's ancestry comes from any breed. But, remember that 100% of the markers in the Wisdom Panel test distinguish breeds. That means, this Breed Ancestry Certificate is missing all the information about Elroy that's not analyzed by Wisdom Panel. 

Non-surprises.
We guessed the breeds that they were confident about! There must be something to this test. Especially since we had seen his litter mates and were told by the adoption agency that he was probably rott/sharpei (and later on we figured he was just as likely chow chow as sharpei). SCIENCE works.

Surprises.
German Shepherd and Collie aren't terribly surprising either. He came from Ohio. Those breeds are abundant enough in the region, are allowed to roam free and probably mated like that too for decades upon decades in those regions. And he's a big boy!

But Westie? Westie is a bit of a head-cocker.

Or is it? Westies had to have had big ancestors, first of all, since they descended from wolf ancestors like all other dogs. But something that distinguishes Westies from other breeds is in Elroy's DNA. That means a relatively recent Westie left a signature in his genome. So was it kamasutra lovemaking between tiny Elroy ancestor and big Elroy ancestor?  Or are we talking about love between mixed breeds and pure breeds and mixed breeds over time? Probably.

Here are their best guesses about what contributed to those "mixed breed" mysteries on his certificate.

Mostly big dogs, some ancient and awesome. The Dogo! (Ugh, don't google it... so many fighting and abuse videos.)

Nothing to really take home from this list because they're far off guesses without even a report of percentage there with the bar graph.

For Murphy...
This is her "breed ancestry certificate"

Akita, German Shepherd and Lab are the only confident ones (as noted in the report). 

And here are the most likely breeds contributing to those "mixed breed" mysteries on her certificate.

Non-surprises.

Shepherd! And Lab is another good one considering friends and relatives see lab in her.
Many of her mix guesses are herders!

Surprises.
Akita? That's phenotypically (and maybe genetically(?) will have to check) close to Husky which is another guess we often hear for her. So this is only a little bit surprising.

French Bulldog? Now that's a real head-cocker.

But again, like with the Westie, it's not noted as "confident" in the report, but on the other hand, why not French Bulldog in her ancestry? It just means this is a marker, like with the Westie, that's not tied to outward appearance/phenotype.*

Not enough information...
I wonder what these markers are then; if Westie and French Bulldog are showing up, why? As the website explains, “Physical features characteristic of certain breeds, such as the flattened face of the English Bulldog or the extremely curled tail of the Pug, seldom survive even the first crossbreeding.”

So these markers for unseen traits are fascinating but not explained in the report.  I'm spoiled rotten by 23andMe that tells you everything, down to the A,T,C, or G you have for your allele for whatever gene. I'm guessing that Wisdom Panel keeps all this under wraps because (a) most consumers don't care to know those details and (b) it's in their best competitive and economic interests to keep their methods to themselves.

What's interesting is how some of the hype about these dog tests is similar to 23andMe: They're "for your health!" But unlike with 23andMe, Wisdom Panel says that you're good just going to your vet and saying "she's got Akita in her blood" when you're dealing with health issues.  While 23andMe advocates that you know each and every SNP.  My health is more important than my dog's I suppose, but what's absolutely not clear is how these two very different approaches (ancestry and family history vs. SNP data) are resulting in different health outcomes.

As you might imagine, there's a lot more to say about the evolutionary and anthropological issues these dog tests raise, so please stay tuned.

Kevin and me and our Westie, Elroy, and our French Bulldog, Murphy.

*Or if it is, it's present in only one recessive copy and would require two copies for the visible trait in the Westie or French Bulldog  to be expressed (added June 14)

My dogs' evolutionary history. Part 1: Predictions

You might remember Murphy and Elroy from the time we used science to solve the book-eating mystery. Or the time they figured out evolution. (Still looking for puplisher! [sick]) Or maybe you already know Elroy because you follow him (@ElroyBeefstu) on Twitter.

Elroy (I fit in your phone!)

Murphy (awww)

These are the mutts that inhabit our lives, and we theirs.

It's because of our tremendous love for these dogs but mostly because of our tremendous fascination with evolution that we ordered Wisdom Panel kits for each, for my birthday.

What we do

With Wisdom Panel, the process on the consumer end isn't a whole lot different from 23andMe. You purchase the kits online, they arrive at your house, you activate the kits online, you swab your dogs' mouths, pop the kits back in the mail with the postage-prepaid packaging, and wait for an email with the results.

Wisdom panel needs far less of the contents of a dog's mouth than 23andMe requires. And that's not only because the analysis will be far less extensive, but because dogs' lips and face muscles aren't hooked up for spitting into a test tube.

The turnaround was speedy. We sent in the samples on May 28 and got the results June 6.

At this stage in the process, the only red flag is that they require you to submit your dog's weight during online registration. For the love of science, there should be no phenotypic hints required. I hope they don't use weight to discard or confirm dog breeds for their results report.

What they do
Here's what the FAQ says:

Testing your dog with Wisdom Panel® 2.0 begins when you use the cheek swabs to simply collect a small DNA sample from inside your dog’s cheek and send the swabs into the laboratory. Once your sample is received at our lab it is scanned into our database and assigned to a batch for testing. It then undergoes processing to extract the DNA from your dog’s cells which is examined for the 321 markers that are used in the test. The results for these markers are sent to a computer that evaluated them using a program designed to consider all of the pedigree trees that are possible in the last three generations. The trees considered include a simple pedigree with a single breed (a likely pure-bred dog), two different breeds at the parental level (a first-generation cross), all the way up to a complex tree with eight different great-grandparent breeds allowed. Our computer used information from our extensive breed database to fill these potential pedigrees. For each of the millions of combinations of ancestry trees built and considered, the computer gave each a score representing how well that selected combination of breeds matched to your dog’s data. The pedigree with the overall best score is the one which is selected and provided to you in your dog’s individualized report.

This doesn't really cut it for me. I want to know what the methods are and this is all they provide in answers to "Science Based Questions!" This isn't helping much:

Not only does the computer analyze a dog’s DNA for the breeds and their likely proportions in the dog’s ancestry, but it also models which side of a dog’s ancestry each breed is likely coming from.

I'll just have to assume for now that they use something like a chip (because sequencing is still not thrifty) to identify markers that they've already linked to breeds and then they're applying their probability-based analyses to those markers in our dogs in order to provide an estimate of our dogs' ancestry. And what are those markers?

Wisdom Panel only uses what are called autosomal DNA markers, chromosomes that contain most of the genetic instructions for every canine’s body make up (height, weight, size etc.). There are no markers from either the so-called sex chromosomes (the canine X or Y chromosomes). Mitochondrial DNA, or Y-chromosome DNA testing, is rather different as these parts of the genome are passed on intact from mother to child and father to son respectively, but are therefore only representative of either the female or the male lineage. Autosomal DNA is inherited both from the maternal and paternal lineages equally and constantly shuffled by a process called recombination at each successive generation, and therefore is able to give useful information on the breeds found on both sides of a dog’s lineage.
To find the genetic markers that performed best at distinguishing between breeds, Mars Veterinary™ tested over 4,600 SNPs (single nucleotide polymorphisms or genetic markers, where genetic variation has been found between different dogs), from positions across the whole canine autosomal genome from over 3,200 dogs. To further refine the search, Mars Veterinary determined the best 1,536 genetic variations and ran them against an additional 4,400 dogs from a wide range of breeds. This stage of testing resulted in the selection of the final panel of DNA markers that performed best at distinguishing between breeds, ultimately creating the Wisdom Panel genetic database which presently covers over 200 different breeds.

Predicting our results
Both Elroy and Murphy are mixed breed dogs. Here's the list of breeds they say they can detect.  And here's more from the website:

Wisdom Panel® 2.0 breaks down a dog’s lineage in the form of an ancestry tree.  This allows you to see which breeds are present at a parent, grandparent, or great-grandparent level.  Keep in mind that a parent contributes 50% of their DNA to the puppy while a grandparent contributes about 25% of their DNA on average to the puppy.  It follows that a great-grandparent would contribute approximately 12.5% of their DNA to the puppy on average.
Since each of these different levels can contribute different amount of DNA to the puppy, you can see a variety of influence in the puppy’s physical and behavioral traits.  With a parental breed, you are likely to see some physical and behavioral traits from this breed represented unless some of the genes are recessive (requires two copies of the gene variant to show it).  Examples of recessive traits include longhair in most breeds, a clear yellow or red hair coat, a brown or chocolate hair coat, and prick or upright ear set (e.g. like a German Shepherd Dog).  You may see traits from breeds at the grandparent level and it becomes less likely to see physical and behavioral traits from breeds at the great-grandparent level unless those traits are dominant (requires only one copy of the gene variant to show it).  Examples of dominant traits include shorthair in most breeds, black hair coat, black nose, a drop or down ear set (e.g. like a Beagle), and merle/dapple (e.g. like a Australian Shepherd or Great Dane).

For Elroy (85 lbs)
Our guesses = 50% sharpei or chow chow; 50% rottweiler

Kevin was told he was half sharpei and half rottweiler when he adopted him and all his litter mates were black and looked like rotts. He's got tiny ears and a huge square head and heavy neck relative to his body.

We started to wonder whether he was chow chow instead of sharpei when I checked my best dog reference for another breed with a black tongue.

If he's part chow chow then my envy of his fur is no longer so crazy, since the breed was long made for that... and for dinner too. It makes me chuckle every time I call Elroy's dinnertime, "chow time."

For Murphy (40 lbs)
My guess = 25 % German shepherd; 25 % Border collie; 25 % Hound of some kind; 25% unknown village dog. Kevin's guess = 25% German shepherd; 75% Border Collie

Before her greybeard took over.

Unlike for Elroy, Murphy's behavior came into play for these predictions. Her main occupation is to herd each car that comes down the lane along the edge of our lot. She also stalks squirrels and chases shorebirds. And compared to Elroy, she doesn't have as many breed-specific morphological traits.

Who knows? We could be way off. After all, I just took this Dog Bark Interactive Quiz and failed miserably despite knowing exactly what Elroy and Murphy's vocalizations mean.

Results and analysis, right here, tomorrow...

Bee colony collapse: A hyper-polygenic trait?

Honeybee: Wikimedia

Colony collapse disorder (CCD) is a sudden dying-out of a honeybee colony.  Among other things, the bees--of most or all types in the hive--leave the hive and just don't return.  The hive empties out.  It's not littered with corpses in whom autopsies could identify pathogens or toxins or the like.  We recently posted on the possible causal role of neonicotinoids in CCD, and the response of the European Union.

CCD became what appeared to be a dire threat to humans about 6 years ago, because it was so widespread and catastrophic and so much of our food requires bee pollination.  Industrial-scale agriculture requires industrial-scale beekeepers, because megafields of one crop, or mega-orchards and the like have a short blossoming period when zillions of bees are needed to pollinate the flowers, or there will be no almonds, cherries, cranberries, blueberries and the like.  But after the harvest, in general the fields produce nothing else for the rest of the year.  Local wild bees simply would not be numerous enough to do the amount of pollination industrial ag requires, so bees are trucked in from around the country.

But if you bring in megahives, you have to then truck them elsewhere to do their next job so the bees themselves have food enough to survive. The result has been big bee-businesses that maintain hives in the tens of thousands and, on a contract basis, truck them around from crop to crop.  Unfortunately, and probably contributing to CCD, each area and each crop involve different exposures to things like viruses, pesticides, herbicides and so on.  So it has been very difficult (i.e., hasn't worked) to find a local virus or pesticide that is responsible for the disorder worldwide.  Or even nationwide.

Controlled studies of different hives or different agricultural areas have identified different candidate risk factors.  Each, under controlled experiments, seems to cause problems for at least some strains of bees.  So each seems to be a legitimate factor.  Yet it doesn't by itself cause the widespread CCD occurring around the world.

One response to such facts is to say that CCD is multifactorial, but that doesn't seem to wash, because if that were the case, then why would CCD have reached such proportions so quickly, with 30-40% of hives being wiped out this past winter, e.g.?

One possible explanation is that the industrial trucking of bees from location to location has brought bees who winter in very different environments, or who spend time in different series of crops, together for some particular crop--like the massive California almond crop, where bees are pollinating on the order of 1000 of trees.  This is the largest single bee-related monocrop area in the world.  Bees from all over, thousands of miles distant, who have spent their past seasons working in other environments with other crops involving various pesticide, virus and parasite exposures etc., are brought together.  In, say, the almond groves, they can exchange pathogens they are carrying or perhaps mix in other ways, and then after the blossoming is over, be transported to the next crop, maybe half-way across the country where they encounter ore bees from other areas.

Local causation, or not?
One spokesperson on a BBC documentary program that led to this post* likened this to bringing people from all over the world to a single location, where they sniffle and sneeze and exchange their viruses, only to fly back to homes all around the world.  Whatever might be causing disease would not stay local, just as CCD has not stayed local.  Had it done so, local factors in a specific population of bees and hives, might have led to a clearer causal understanding.

More possible, however, is that there really is a mix of multiple contributing causes, and no local area would have had a serious, confined problem until the mixing of bees from so many areas, carrying a diversity of afflictions.

This is like a polygenic trait in humans or other species.  Many different genes contribute, but no one gene contributes enough to cause the trait on its own.  Only individuals who have disease-associated variants at many different genes will manifest the trait.  Here we are talking about individuals, and the distribution of trait values (e.g., blood pressure related to stroke) in the population reflects the distribution of genetic variants at the many contributing genes.

Except that here it is not individuals with different genotypes in a population, but hives of different exposure types brought together in a population of hives.  If this is the reason for CCD it is a kind of hyper-individual polygenic-like trait for which complexity really is the story and the manifestation is only on a population basis.

As with natural selection, over time the fraction of individuals with vulnerable genotypes can diminish if the causation is polygenic.  Likewise, perhaps the fraction of hives that have the bad combination of risk factors and hence don't survive, is reduced and the disorder changes prevalence--declining--over the years.  That may explain in general principle why CCD seemed to be declining, at least before the decimation that seems to have happened in much of the US this past winter.

In any case, this explanation would be one of a kind of hyper-polygenic (hyper-risk-factor) causation where it really is true that many minor factors have, by the demography of bee-keeping in modern times, comprised a kind of population in which the CCD trait has appeared.
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*If you want to learn more, painlessly and even entertainingly, listen to BBC Radio4 'Discovery' broadcasts (online or as podcasts). 

Personalized medicine and Fragile X: complexity, disease and economics

Fragile X is a genetic disorder that typically causes distinct facial features as well as moderate to severe mental impairment and social withdrawal, and as such it is considered to be the most common single-gene cause of autism.  The disorder was determined some time ago to be  "caused by the unstable expansion of a CGG repeat in the FMR1 gene and abnormal methylation, which results in suppression of FMR1 transcription and decreased protein levels in the brain" (Lutz et al., 1998, cited in OMIM).  That this repeat expansion is causal, for whatever reason, it well established by a strong association between the genetic variant and the trait. As with nearly all genetic disorders, even when 'the' cause has been identified as a variant or variants in a single gene, the manifestation of this disorder is a spectrum of severity.

There is currently no drug treatment for the "core symptoms" of fragile X, though several drugs that treat various behavioral symptoms are available.  A recent story in the New York Times describes the experiences of several families with a drug that was developed to reduce social withdrawal in children with fragile X or autism, manufactured by Seaside Therapeutics, but was still undergoing clinical trial.  Why autism should have any physiological connection with fragile X is not known, but there is an overlap of symptoms.  The drug, arbaclofen, or STX209, affects neurotransmitter signaling and hence, brain function and its behavioral implications.

A Phase 2 clinical trial was carried out over three years ago, and the results announced in 2011.  Seaside said

...clinically meaningful improvements on global and specific neurobehavioral outcomes were observed in the general study population. The improvements were statistically significant in pediatric patients with more severe impairments in sociability -- a core symptom of fragile X syndrome.

Following the trial, Seaside Therapeutics continued to supply the drug to some children for whom the drug was considered to be beneficial.  According to the NYT, the drug made an enormous difference in the lives of a number of children.  Some were able to speak for the first time, others halted aggressive behaviors, and so forth.  This seemed at least statistically, as well as subjectively, to be a cause-effect relationship.  There were parents, of children with autism as well as fragile X, who considered arbaclofen a miracle drug.

In 2012 Seaside initiated a Phase 3 trial, to further test the drug.  In announcing this trial, the president of Seaside said,

“In our Phase 2 study, we were very excited to observe clinically meaningful improvements in social impairment in patients receiving STX209—marking the first time a drug candidate has positively impacted a core symptom of fragile X syndrome. The Phase 3 study is the most comprehensive study ever undertaken in patients with fragile X syndrome and represents the first time that a drug candidate will be evaluated for a core symptom of fragile X syndrome as the primary endpoint.”

But, production is now being halted because the drug has not proven to be a successful enough treatment for social withdrawal in children with autism in the Phase 3 study.  This seems to be a bureaucratic and financial issue rather than a scientific one.  According to a Seaside vice president, quoted on the "Age of Autism" website,

The FDA requires companies to pick one, and only one, assessment as the “primary endpoint” of the study. In their eyes, the result on that one pre-selected endpoint makes or breaks the study. In our recent autism study, STX209 did not show an advantage over placebo (see above) on the primary endpoint of social withdrawal, so the FDA and some news reporters regard it as a negative study. In fact, STX209 did show advantages over placebo on a number of other assessments. Some of these secondary endpoints are just as meaningful as the social withdrawal assessment, or even more so, but in the FDA’s eyes, they don’t make the study a positive study, because they were not pre-selected as the “primary endpoint.”

The pharmaceutical giant, Roche, had been backing development of the drug, but they've recently pulled their support as they cut back on research and development in general, and it seems that Seaside cannot afford to continue manufacturing the drug alone.

Seaside released this statement:

"The study termination is due to resource limitations at seaside, and is not due to any safety issue associated with STX209. We know that this termination will be disruptive and disappointing for many. We are planning to complete phase 3 and the results of this study should be available late summer. If the results are positive, seaside will discuss with FDA the required next steps for approval of STX209. 

"This means the drug could potentially become available in the future but there is still nothing guaranteed."

Parents who saw tremendous improvement in their children on this medication are devastated.

Well, we started this post after reading the piece in the New York Times, thinking that we knew where we were going with it -- like most other genetic disorders, fragile X is a complex disorder, and only a subset of children in the studies would respond favorably to the drug because of the heterogeneity of the phenotype and variation in genetic background, and so of course it's understandable that it's difficult to ascertain the drug's efficacy.  By implication, genetic background determines whether a child responds poorly or well to STX209, and which children respond well and which respond poorly hasn't been determined.

While that may well be true, that's not the real story here.  Instead it's economics.  And that's heartbreaking.  So here is a case when 'personalized genomic medicine' might be a correct way to identify cause or predict effect, and here, where the association actually works (regardless of why), we have other issues interfering with effective care.  Life is complex, but our culture often advances things that don't do good, and impedes ones that actually do.